Rutter's Child and Adolescent Psychiatry Book 2

well as more antisocial, aggressive and destructive behavior. There are many anecdotal accounts of preschool children showing repetitive drawing and play involving themes about the trauma they experienced. Although parents and teachers initially report that young children do not easily talk about the trauma, recent experience has been that many young children easily give very graphic accounts of their experiences and were also able to report how distressing the re-experiencing in thoughts and images was (Misch, Phillips, Evans, & Berelowitz, 1993; Sullivan, Saylor, & Foster, 1991). All clinicians and researchers need to have a good understanding of children’s development to be able to assist them express their inner distress. Manifestations of Stress Reactions in Children and Adolescents Immediately following a very frightening experience, children are likely to be very distressed, tearful, frightened and in shock. They need protection and safety. They need to be reunited with their families wherever possible. Clinical experience, surveys and clinical descriptive studies quoted below show that the main manifestations of stress reactions are as follows. Starting almost immediately, most children are troubled by repetitive, intrusive thoughts about the accident. Such thoughts can occur at any time, but particularly when the children are otherwise quiet, as when they are trying to drop off to sleep. At other times, the thoughts and vivid recollections are triggered off by reminders in their environment. Vivid, dissociative flashbacks are uncommon. In a flashback, the child reports that he or she is re-experiencing the event, as if it were happening all over again. It is almost a dissociated experience. Sleep disturbances are very common, particularly in the first few weeks. Fears of the dark and bad dreams, nightmares, and waking through the night are widespread (and often manifest outside the developmental age range in which they normally occur). Separation difficulties are frequent, even among teenagers. For the first few days, children may not want to let their parents out of their sight, even reverting to sleeping in the parental bed. Many children become much more irritable and angry than previously, both with parents and peers. Although child survivors experience a pressure to talk about their experiences, paradoxically they also find it very difficult to talk with their parents and peers. Often they do not want to upset the adults, and so parents may not be aware of the full extent of their children’s suffering. Peers may hold back from asking what happened in case they upset the child further; the survivor often feels this as a rejection. Children report a number of cognitive changes. Many experience difficulties in concentration, especially in school work. Others report memory problems, both in mastering new material and in remembering old skills such as reading music. They become very alert to danger in their environment, being adversely affected by reports of other disasters. Survivors have learned that life is very fragile. This can lead to a loss of faith in the future or a sense of foreshortened future, or a premature awareness of their own mortality. Their priorities change. Some feel they should live each day to the full and not plan far ahead. Others realize they have been overconcerned with materialistic or petty matters and resolve to rethink their values. Their “assumptive world” has been challenged (Janoff-Bulman, 1985). Not surprisingly, many develop fears associated with specific aspects of their experiences. They avoid situations they associate with the disaster. Many experience “survivor guilt” – about surviving when others died; about thinking they should have done more to help others; about what they themselves did to survive. Adolescent survivors report significantly high rates of depression, some becoming clinically depressed, having suicidal thoughts and taking overdoses in the year after a disaster. A significant number become very anxious after accidents, although the appearance of panic attacks is sometimes considerably delayed. Some children may have been bereaved and may develop traumatic grief reactions. In summary, children and adolescents surviving a traumatic event may show a wide range of symptoms which tend to cluster around signs of re-experiencing the traumatic event, trying to avoid dealing with the emotions that this gives rise to, and a range of signs of increased physiological arousal. In a substantial minority, this cluster of symptoms will amount to a diagnosable PTSD. Just as in adults, a broad range of adverse outcomes is common (Bolton, O’Ryan, Udwun, Boyle, & Yule, 2000; Pine & Cohen, 2002): there may be considerable overlap of symptoms with depression, generalized anxiety or pathological grief reactions, although whether this indicates the presence of mixed disorders or comorbidity of separate disorders remains to be clarified. However, this has implications for assessment. It is not sufficient to enquire solely about symptoms of PTSD. Symptoms of anxiety, depression and grief need also to be formally investigated. Nor are self-completed questionnaires measuring these aspects sufficient to make a diagnosis. They have an important role, but sensitive clinical interviews with the child and separately with the parents remain the cornerstone of good assessment. Developmental Aspects Considerable debate remains as to whether the very young child’s limited cognitive development is protective against developing a chronic post-traumatic stress reaction. Certainly, the diagnostic criteria in both of the major classification schemes are not appropriate for preschool children. In a series of studies, Scheeringa, Zeanah, Drell et al. (1995); Scheeringa, Peebles, Cook et al. (2001); Scheeringa, Zeanah, Myers et al. (2003); Scheeringa, Wright, Hunt et al. (2006) examined the phenomenology reported in published cases of trauma in infants and young children and evolved an alternative POST-TRAUMATIC STRESS DISORDER 687 9781405145497_4_042.qxd 29/03/2008 02:53 PM Page 687

set of criteria for diagnosing PTSD in very young children. Re-experiencing was seen as being manifested in post-traumatic play; re-enactment of the trauma; recurrent recollection of the traumatic event; nightmares; flashbacks or distress at exposure to reminders of the event. Only one positive item was needed. Numbing was present if one of the following was manifested: constriction of play; socially more withdrawn; restricted range of affect; or loss of previously acquired developmental skill. Increased arousal was noted if one of the following was present: night terrors; difficulty getting off to sleep; night waking; decreased concentration; hypervigilance; or exaggerated startle response. A new subset of new fears and aggression was suggested and is said to be present if one of the following is recorded: new aggression; new separation anxiety; fear of toileting alone; fear of the dark or any other unrelated new fear. Prospective 2-year follow-up studies have demonstrated good concurrent and predictive validity for this alternative method of diagnosing PTSD in young children. Almqvist & Brandell-Forsberg (1997) provided evidence on how a standard set of play materials can be used to obtain objective data on traumatic stress reactions from preschool children. Thus, one can anticipate further refining of criteria and methods of assessment of PTSD in preschool children in the next few years. Incidence and Prevalence Estimates of the incidence of PTSD in trauma-exposed children vary enormously, partly as a result of differing methodologies, and partly as a result of different types of traumatic event. Studies of the mental health of child refugees from war-torn countries find the incidence to be close to 67%. Sexual abuse results in high rates of PTSD (Salmon & Bryant, 2002), as does witnessing violence (Margolin & Gordis, 2000). In various studies of the effects of traffic accidents (that did not result in an overnight stay in hospital), rates of 25–30% are reported (Stallard, Salter, & Velleman, 2004). A study of 200 adolescent survivors of the sinking of the cruise ship Jupiter (Yule, Bolton, Udwin et al., 2000) reported an incidence of PTSD of 51%. Most cases manifested within the first few weeks with delayed onset being rare. Following a nightclub fire in Gothenburg, 25% of the 275 adolescent survivors met DSM-IV criteria for PTSD 18 months after the fire (Broberg, Dyregrov, & Lilled, 2005). Overall, it has been estimated that 36% of children will meet criteria for PTSD following a range of traumas (Fletcher, 1996). This appears fairly constant across developmental levels. In other words, significantly increased demands will be made at all levels of primary and secondary child and adolescent mental health services following traumatic events. Most epidemiological studies have been of older adolescents and adults. Giaconia, Reinherz, Silverman et al. (1995) reported a lifetime prevalence of 6% in a community sample of older adolescents. Kessler, Sonnega, Bromet et al. (1995) reported a lifetime prevalence of 10% using data collected from older adolescents and adults in the (USA) National Comorbidity Survey. A national sample of eighth grade Danish students estimated a 9% lifetime prevalence (Elklit, 2002). By contrast, the British National Survey of Mental health of over 10,000 children and adolescents (Meltzer, Gatward, Goodman, 2003) reported that only 0.4% of 11- to 15-year-olds were diagnosed with PTSD, with girls showing twice the rate of boys. Below age 10, it was scarcely registered. This lower rate is a point prevalence estimate and is bound to be lower than a lifetime prevalence estimate. Moreover, the screening instrument was not specifically developed to screen for PTSD. The implication is that while the numbers of children and adolescents experiencing PTSD at any one point in time may be as low as 1%, this is still a significant level of morbidity in any community. Prospective Longitudinal Studies Data from numerous adult studies show that there is substantial natural recovery from PTSD in the initial months after the trauma. Many individuals recover from PTSD without treatment, and the steepest decline in rates of PTSD is usually seen in the first year. Of course, this still leaves a substantial minority – roughly one-third – who are likely to develop a chronic disorder which may persist for years if left untreated (NICE, 2005). A similar picture is emerging from recent prospective follow-up studies of children. For example, Meiser-Stedman, Yule, Smith et al. (2005) found that among young survivors of assaults and traffic accidents, nearly one in five met criteria for Acute Stress Disorder 2–4 weeks after the event. When reinterviewed at 6 months post-trauma, the rate of PTSD was 12%. The question remains: what factors distinguish those children who will recover spontaneously from those who will go on to develop a chronic reaction requiring treatment (see p. 690)? There have been very few long-term follow-up studies of children who developed PTSD. The 5–7 year follow-up study of adolescents who survived the sinking of the cruise ship Jupiter found that 15% still met criteria for PTSD that long after the event (Yule, Bolton, Udwin et al., 2000). More recently, a 33 year follow-up of the children who survived the Aberfan landslide disaster found that 29% of those traced and interviewed still met criteria for PTSD (Morgan, Scourfield, Williams et al., 2003). Thus, the long-term effects of life-threatening traumatic events in childhood can be severe and long-lasting. Risk, Protective and Maintaining Factors Not all children exposed to trauma will develop PTSD, and of those who do, many will recover without treatment. From this it follows that factors other than exposure to trauma must CHAPTER 42 688 9781405145497_4_042.qxd 29/03/2008 02:53 PM Page 688

POST-TRAUMATIC STRESS DISORDER 689 influence the onset and maintenance of the disorder. Recent research efforts have attempted to characterize these factors in order to better understand chronic stress reactions, and inform treatment approaches. Exposure–Response Relationship One of the key concepts in PTSD is that anyone can develop the disorder, irrespective of prior vulnerabilities, provided the stressor is sufficiently great. There is therefore considerable interest in whether there is any evidence for an exposure–response relationship between stressor and pathology. A number of studies bear on this point in relation to children. In an early study of a sniper attack on a Californian school, Pynoos and colleagues (Pynoos & Eth, 1986; Pynoos & Nader, 1988; Pynoos, Frederick, Nader et al., 1987) reported that approximately 1 month after the event, nearly 40% of the children had moderate to severe PTSD on their Post Traumatic Stress Reaction Index. There was a very strong relationship between exposure and later effects in that those children who were trapped in the playground scored much higher than those who had left the vicinity of the school before the attack or were not in school that day. Evidence for an exposure–response relationship has also emerged in studies of young people exposed to disasters and war. For example, among children affected by the Armenian earthquake of 1988, there was a clear exposure–response relationship, with the most exposed children at the epicenter reporting highest scores (Goenjian, Pynoos, Steinberg et al., 1995). In a large sample of Rwandese children, Gupta, Dyregrov, Gjestad, & Mukanoheli (1996) found a significant relationship between the number of traumatic events children had been exposed to during the genocide and later stress reactions. In a systematic study of nearly 3000 9- to 14-year-old children following the Bosnian war in Mostar, a very strong relationship between exposure to war trauma and self-reported psychopathology was found (Smith, Perrin, Yule, Hacam, & Stuvland, 2002). Whereas studies of adults have shown that some types of traumatic event are consistently associated with higher rates of PTSD, data are lacking in this regard with respect to children. Findings from the child studies above strongly suggest that given the same type of exposure, there is a relationship between level of exposure to the stressor and subsequent adjustment. Nevertheless, in most studies, the “objective” level of trauma exposure accounts for a surprisingly small proportion of variance in later adjustment. Family Influences Various aspects of children’s family environment have been found to be associated with children’s reports of post-traumatic symptoms. These include maternal post-traumatic stress symptoms in cases where mother and child have been exposed to the same trauma (Smith, Perrin, Yule, & Rabe-Hesketh, 2001). Maternal depression (Smith, Perrin, Yule et al., 2002; Wolmer, Laor, Gershon, Mayes, & Cohen, 2000) and general family functioning or emotional atmosphere (Green, Korol, Grace et al., 1991; McFarlane, 1987) have also been implicated. In a recent prospective study of child and adolescent attendees at Accident and Emergency Departments, MeiserStedman, Yule, Dalgleish, Smith, & Glucksman (2006) found that parental depression was related to child post-traumatic symptoms at both 2–4 weeks post-accident and again at 6 months after the trauma. Parental worry mediated the relationship between parental depression and child symptoms of stress, but general family functioning appeared less important. The mechanisms underlying these familial associations remain unclear. In part, they may derive from a complex interaction between parents and children, who can become locked into cycles of not talking about the event for fear of upsetting each other. That is, parents and children may negatively reinforce each other for avoiding processing their traumatic memories, and this is likely to maintain the symptoms of both. Cognitive Aspects and Cognitive Models Early work recognized that objective measures of exposure were insufficient to explain the variability in children’s posttraumatic stress reactions; subjective appraisal also has a key role. For example, among children exposed to war (Nader, Pynoos, Fairbanks, Al-Ajeel, & al-Asfoir, 1993; Smith, Perrin, Yule et al., 2002) or genocide (Gupta, Dyregrov, Gjestad et al., 1996), perceived direct life threat is strongly related to later PTSD. Similarly, among adolescents involved in a shipping accident, those who made guilt or shame-inducing attributions showed higher levels of PTSD symptoms (Joseph, Brewin, Yule, & Williams, 1993). More recent work has investigated the applicability to children of adult cognitive models of the disorder (Brewin, 2001; Ehlers & Clark, 2000; Meiser-Stedman, 2002; Salmon & Bryant, 2002). For example, under Ehlers and Clark’s (2000) model, PTSD is maintained by: the disjointed nature of the memory; misappraisals of the trauma and its sequelae; and maladaptive (i.e., avoidant) coping strategies. Retrospective analyses (Stallard, 2003) and well-designed prospective studies (Ehlers, Mayou, & Bryant, 2003; Meiser-Stedman, Yule, Smith et al., 2005) provide evidence that such models do indeed apply to children, at least from the age of about 8 years old. That is, characteristic cognitive distortions and misappraisals appear to have a central role in maintaining PTSD in older children and adolescents, and this has clear implications for treatment (see p. 692). However, dissociation, which was initially thought to be a key cognitive aspect of the trauma response, appears to be unrelated to the maintenance of PTSD symptoms. Acute stress disorder (ASD) is explicitly conceived as a dissociative response to trauma, requiring three of a possible five dissociation symptoms (APA, 2000). Two recent studies with children show that although acute stress disorder in the first 4 weeks post-trauma is a good predictor of later PTSD, dissociation symptoms do not have a significant role (Kassam-Adams & Winston, 2004; Meiser-Stedman, Yule, Smith et al., 2005). These findings require replication, but are in line with recent adult work which showed that the dissociation criteria do not 9781405145497_4_042.qxd 29/03/2008 02:53 PM Page 689

CHAPTER 42 690 enhance the ability of ASD to predict later PTSD (Brewin, Andrews, & Rose, 2003). Finally, there is a small but growing literature on cognitive biases in memory and attention in children with PTSD (for an overview see Dalgleish, Meiser-Stedman, & Smith, 2005). This approach seeks to examine how basic cognitive processes are affected by trauma exposure, and how such changes may in turn function to maintain post-traumatic stress reactions. An intriguing set of findings has emerged from a handful of experimental studies using the emotional Stroop task, the dotprobe paradigm, and recall tasks. Some studies report evidence for an “avoidant” bias with respect to traumarelated material (Pine, Mogg, Bradley et al., 2005), whereas other studies find a bias in favor of trauma or threat-related material (Moradi, Taghavi, Neshat-Doost, Yule, & Dalgleish, 2000), consistent with the adult literature. In terms of memory, there is evidence for a memory bias for negative material in children with PTSD compared with non-traumatized controls (Moradi, Taghavi, Neshat-Doost et al., 2000). Given the small number of studies, and the mixed set of findings, further research is called for. Protective Factors There have been few studies that have set out to identify protective factors properly and so inferences have had to be drawn from the general literature on psychopathology and some cross-sectional studies. The main factors commented on have been age, gender, ability and attainment, family factors and coping strategies. In brief, developmental level acts in two opposing ways: younger children may not fully appreciate the extent of the danger facing them, but also immature cognitions may produce more distorted memories. There is generally good agreement from a number of studies that developing PTSD following a traumatic experience is more common in females than in males. Prior poor adjustment and difficult family relationships, including domestic violence, are all associated with a higher risk of developing PTSD and so the opposite, positive attributes are seen as protective. Perceived and actual social support, especially from the family, are noted as being protective, as is possessing a range of effective coping strategies. Where there has been material loss – of home or other possessions – following a natural disaster, then higher income in the family is a protective factor (for reviews see Udwin, Boyle, Yule, Bolton, & O’Ryan, 2000; Yule, Perrin, & Smith, 1999). Summary In addition to objective exposure severity, subjective appraisals, maladaptive coping strategies and family influences, a number of other factors are implicated in risk for onset and maintenance of PTSD in children. Findings on the role of individual child characteristics such as age, sex and ethnicity have been inconsistent (Vernberg, La Greca, Silverman, & Prinstein, 1996), although there is an emerging consensus that, as with other emotional disorders, girls are more at risk than boys. Udwin, Boyle, Yule et al. (2000) reported that a history of previous exposure to violence and a psychiatric history prior to the trauma increased risk of developing PTSD. In line with adult work (Brewin, Andrews, & Valentine, 2000), the availability of social support in the aftermath of a trauma appears to be import-ant in the subsequent duration and severity of the disorder (Udwin, Boyle, Yule et al., 2000; Vernberg, La Greca, Silverman et al., 1996). Further work is needed to clarify these sets of risk factors. The implications for intervention remain to be worked out in detail. The successful trials of Narrative Exposure Therapy and of Trauma Focused cognitive–behavioral therapy (CBT) indicate that active CBT therapies must pay close attention both to the trauma narrative and to correcting cognitive distortions in memory. Simple exposure is not enough. The findings from the protective function of social support again indicate that therapists must pay attention to sources of support for the child both within the family and at school. Physiological Reactions Children’s exposure to trauma can result in biological as well as psychological changes. Recent investigations of a variety of physiological changes in traumatized children have been driven by contemporary neuroscience accounts of fear and stress. These accounts draw on animal models, and have been tested most thoroughly in trauma-exposed adults. In broad summary, traumatic stress activates the locus ceruleus and the sympathetic nervous system (SNS), leading to increased catecholamine turnover, and resulting in increased heart rate, blood pressure, metabolic rate, alertness and circulating catecholamines (adrenaline, noradrenaline and dopamine) – a classic “flight or flight” reaction. During stress, the locus ceruleus also stimulates the hypothalamic–pituitary–adrenal (HPA) axis. The resulting release of corticotropin-releasing factor (CRF) from the hypothalamus stimulates the pituitary to secrete adrenocorticotropin, which in turn promotes cortisol release from the adrenal gland, further stimulating the SNS, and causing intense arousal. Cortisol then suppresses the HPA axis, acting via negative feedback inhibition on the hypothalamus, pituitary and hippocampus, leading to homeostasis. In animals, these neurophysiological processes lead to behaviors consistent with anxiety, hyperarousal and hypervigilance – core symptoms of PTSD. In adults and children, investigation of these two major stress systems – the catecholamine system and the HPA axis – and associated brain structures has therefore been the focus of recent research (for reviews see Cohen, Perel, DeBellis, Friedman, & Putnam, 2002; De Bellis, 2001; Pine, 2003). There is evidence that the catecholamine system is disrupted in traumatized children with and without full-blown PTSD. De Bellis, Chrousos, Dorn et al. (1994); De Bellis, Baum, Birmaher et al. (1999a); De Bellis, Keshavan, Clark et al. (1999b) reported significantly increased dopamine in the urine of sexually abused girls, and of maltreated boys and girls with PTSD, which was correlated with the severity of PTSD symptoms. It is hypothesized that excessive dopamine results in under-functioning of the prefrontal cortex, which normally acts 9781405145497_4_042.qxd 29/03/2008 02:53 PM Page 690

to extinguish conditioned fear responses. These same studies (De Bellis, Chrousos, Dorn et al., 1994; De Bellis, Baum, Birmaher et al., 1999a; De Bellis, Keshavan, Clark et al., 1999b) also found that children with abuse-related PTSD showed increased 24-h urinary adrenaline and noradrenaline and/or their metabolites. Consistent with a malfunctioning adrenergic response, Perry (1994) found that abused children with PTSD had greater increases in heart rate when exposed to a physiological challenge, compared with non-PTSD control children. In line with this work, Scheeringa, Zeanah, Myers et al. (2004) have more recently shown that even very young (preschool) children with PTSD resulting from exposure to violence or highly invasive medical procedures show increased heart rate in response to trauma reminders, compared to nontraumatized controls. Importantly, it appears that early changes in peripheral physiology may predict later symptoms of PTSD in children. Kassam-Adams, Garcia-España, Fein et al. (2005) reported that among children involved in a road traffic accident, acute heart rate (measured in hospital within hours of the accident) was significantly associated with severity of PTSD symptoms some 6 months later. In contrast to this relatively straightforward sensitization of the catecholamine system, investigations of HPA axis functioning in traumatized children show that this system works in a rather complex manner. Different patterns of dysregulation may arise, related to time since trauma exposure, and to whether the child has subsequently been exposed to further stress or trauma. In acutely traumatized children, there is evidence for hypersecretion of cortisol (Carrion, Weems, Ray et al., 2002). In contrast, investigations of young samples with chronic PTSD reveal lower resting baseline levels of cortisol (Goenjian, Yehuda, Pynoos et al., 1996) and a blunted corticotropin response (De Bellis, Chrousos, Dorn et al., 1994). The suggestion is that compensatory downregulation of the HPA axis occurs in children with chronic PTSD, leading to an increasingly maladaptive response over time. Furthermore, children with a history of severe maltreatment plus concurrent exposure to new stressors showed an increased corticotropin response and high levels CRF in one study (Kaufman, Birmaher, Perel et al., 1997). De Bellis (2001) suggests that individuals with a history of chronic PTSD may demonstrate a hyperresponding of the HPA axis when encountering new stressors. Evidence for disruption to the HPA axis has led to the administration of low-dose cortisol to treat symptoms of PTSD in adults (Aerni, Traber, Hock et al., 2004), but similar treatments have not been tested in children. In addition to the study of neurotransmitter systems and neuroendocrine axes, a small number of studies have examined related brain morphology. Of particular interest is the hippocampus, which has a central role in memory processing. High levels of cortisol are toxic to the hippocampus, and studies of adults with chronic PTSD have found the predicted decreased hippocampal volume (Bremner, Randall, Scott et al., 1995; Bremner, Randall, Vermetten et al., 1997). However, studies with young children have not found this expected damage to the hippocampus (De Bellis, Keshavan, Clark et al., 1999b). It is possible that the adult findings were confounded by alcohol misuse among those with chronic PTSD (because alcohol is also toxic to the hippocampus). Alternatively, the absence of decreased volume in young samples may be because hippocampal damage depends on chronicity of PTSD, occurs at a later developmental stage, or is masked by the normal increase in volume seen during adolescence. Although the expected specific changes to the hippocampus have not been found, it appears that children with PTSD show global adverse brain development: De Bellis, Keshavan, Clark et al. (1999b) found children with PTSD to have smaller intracranial volume and a smaller corpus callosum than controls. Finally, a number of other psychobiological systems are activated during acute stress. In adults, evidence exists for disruption to the endogenous opiate system, the serotonin system, and to the amygdala and prefrontal cortex, but studies of children are lacking. In summary, there is growing evidence that children with symptoms of PTSD may show alterations to a number of interrelated neurophysiological systems. Further work will help to develop a better understanding of the complex interplay between physiological and psychological responses to traumatic events. Nevertheless, the need for early identification and treatment of PTSD is already highlighted by studies that have shown that an abnormal neurophysiological response in trauma-exposed children may persist for many years (Goenjian, Yehuda, Pynoos et al., 1996; Ornitz & Pynoos, 1989). Evidence-based Intervention There are very few randomized controlled trials of any therapy with children, let alone therapies specifically for PTSD. One has therefore to be cautious in drawing conclusions solely by downward extension of results from work with adults. There have been a number of recent reviews that summarize the published evidence, and they agree to a substantial extent on which studies are included in their reviews (Feeny, Foa, Treadwell et al., 2004; NICE, 2005; Stallard, 2006). Early Interventions Whereas prevention is seen as better than cure, in respect of PTSD this has to be seen as preventing the occurrence of traumatic events or children’s exposure to them. Early intervention would be attractive if it could be shown that it prevented later development of PTSD or other disorders, but, as with adult studies, there have been few properly controlled trials of any early intervention. The only one known is that of Stallard Velleman, Salter et al. (2006), in which a trauma-focused discussion on an individual basis was compared with a generally supportive talk. At follow-up, both groups of road traffic accident (RTA) survivors had made good progress and both reported how helpful it had been to talk about the accident (presumably when establishing what happened and inadvertently validating reactions by asking about them systematically). POST-TRAUMATIC STRESS DISORDER 691 9781405145497_4_042.qxd 29/03/2008 02:53 PM Page 691

At 3 months post treatment, the treated group had significantly lower scores on the Child PTSD Symptom Scale (Foa, Johnson, Feeney et al., 2000). Significant differences were also found on measures of depression and psychosocial dysfunction. Teacher-rated behavioral difficulties did not reflect improvement. The delayed treatment group then made significant PTSD improvement following treatment. In both of these studies, children were recruited from school-based screening rather than from clinic-referred children. Not all participants had diagnoses of PTSD. The first RCT to report the effects of an individual Trauma Focused Cognitive Behavioural Therapy (TF-CBT) intervention for children following a single event trauma avoided many of the design problems noted above and used a flexible manualized approach to treating 12 children who developed clinicianvalidated PTSD following assault or RTA (Smith, Yule, Perrin et al., 2007). Treatment was based on Ehlers and Clark’s (2000) model of PTSD, and included a variety of components aimed at reducing known maintaining factors (see p. 689). Post treatment, 11 of the 12 young people who received CBT no longer met criteria for PTSD compared to 5 of the 12 on the waitlist. Treated children also showed significant reductions in symptoms of depression and anxiety. The effect size was 2.20 on the self-report measure and 1.59 on the CAPS-CA (the clinician rated severity on standardized interview). The differences remained at 6 month follow-up. As predicted, therapeutic gains in the CBT group were mediated via changes in maladaptive cognitions. PTSD and Child Sexual Abuse In recent years, many of the reactions children develop to sexual abuse have been formulated as part of a spectrum of post-traumatic stress reactions. This has resulted in a number of therapeutic trials of CBT to treat these reactions, including full PTSD. Ramchandani and Jones (2003) report a systematic review of RCTs treating a range of psychological symptoms in sexually abused children. They identified 12 RCTs: three investigating group CBT; six investigating individual CBT; one of adding group therapy to a family therapy intervention; and two comparing individual (non-CBT) therapy with group therapy. However, the dependent (outcome) measures were very varied, and only four studies looked at recognized specific measures of PTSD. Celano, Hazzard, Webb et al. (1996) compared 15 girls in an abuse-specific program with 17 given a parallel set of 8 non-directive supportive sessions. There were no differences on child scores including on the Child Impact of Traumatic Events Scale Revised (CITES-R). Deblinger, Stauffer, Steer (2001) enrolled 67 children aged 2–8 years. Although only 44 completed all 11 sessions of treatment, 21 completed group CBT and 23 completed a support group. There was significantly better outcome for CBT, but that group had had higher scores to start with. King, Tonge, Mullen et al. (2000) studied 36 sexually abused children aged 5–17 years who met criteria for PTSD. There were 12 children in each of three conditions: CHAPTER 42 692 A later development of this study was to examine a group of survivors of RTAs only at the equivalent time the follow-up interviews were undertaken (i.e., without the baseline interview). This group was also doing well. The study had been designed when single, brief interventions were considered as possible ways of providing early intervention. It is now widely agreed that such one-off, brief, individually administered interventions do not help reduce later PTSD, but this follow-on study demonstrated that children were not upset by talking about their traumatic accident, and this alone should help adults when uncertain about whether to talk to affected children or not. Cognitive–Behavioral Therapies PTSD and Single Event Traumas Few studies have examined the efficacy of psychological treatments for children who have developed PTSD following single event traumas. Goenjian, Karayan, Pynoos et al. (1997) reported that a 7-session schools-based CBT intervention for young people with PTSD some 1.5 years after an earthquake resulted in symptom reduction, whereas an untreated control group showed no such improvement. March, AmayaJackson, Murray et al., (1998) used a single-case design to evaluate an 18-session group CBT intervention for 17 young people who had developed PTSD following a variety of trauma (RTAs, accidental injury, gunshot injury and fires). After treatment, there were significant reductions in PTSD symptoms and associated psychopathology (anxiety, depression and anger). This methodologically strong study (using reliable and valid self-report instruments, and a semi-structured interview to evaluate the effect of a manualized treatment protocol) laid the groundwork for subsequent randomized controlled trials (RCTs). To date, three RCTs of psychological interventions with children who developed PTSD symptoms as a result of single event traumas have been reported (Chemtob, Nakashima, & Hamada, 2002; Smith, Yule, Perrin et al., 2007; Stein, Jaycox, Kataoka et al., 2003). After Hurricane Iniki hit Hawaii, all elementary school children were screened for serious stress reactions and the highrisk group of 248 children were randomly assigned to one of three treatments (Chemtob, Nakashima, & Hamada, 2002). This comprised four sessions delivered either individually or in groups. The specially developed, manualized treatment had many elements in common with other CBT approaches. Both individual and group treatment had equally good results compared with controls and achieved an effect size of 0.50 on the Kauai Recovery Index (Hamada, Kameoka, & Yanagida, 1996). On the better known Child PTSD Reaction Index (Pynoos, Frederick, Nader et al., 1987) completed on a sample of children by clinicians, the effect size was 0.76. More children dropped out of individual than group treatment. Stein, Jaycox, Kataoka et al. (2003) report an RCT in which 61 children who had been exposed to violence were given 10 sessions of group CBT and compared with 65 children who were allocated to a delayed intervention condition. 9781405145497_4_042.qxd 29/03/2008 02:53 PM Page 692

CBT with child and family; CBT with child alone; and waitlist control. Both treatment conditions consisted of 20 sessions. Using Anxiety Disorders Interview Schedule for Children and Adolescents (ADIS-C) to assess PTSD, there was a significant improvement on PTSD, as well as on self-reported anxiety scales. Both ways of delivering CBT were equally effective. Cohen, Deblinger, Mannarino et al.’s (2004) more recent multisite RCT provides further convincing evidence in favor of CBT. The immediate and long-term psychological effects of childhood sexual abuse are many, varied and serious (see chapter 29). The studies reviewed by Ramchandani and Jones strongly indicate that CBT is currently the treatment of choice, although there is clearly a great need for better RCTs. As Feeny, Foa, Treadwell et al. (2004) noted, child survivors of sexual abuse may present a different symptom picture to that of children exposed to single incident traumas and so generalization of findings to those may be problematic (see also American Academy of Child and Adolescent Psychiatry, 1998). Eye Movement Desensitization and Reprocessing Eye Movement Desensitization and Reprocessing (EMDR) was discovered by chance by Shapiro (2001) and has been applied with good results in adults (NICE, 2005). Again, there are a number of case reports claiming effectiveness of EMDR in treating PTSD in children, but a dearth of published RCTs or even other group studies. EMDR is an empirical treatment with little theoretical underpinning. The detailed protocols for treatment include a careful history and ensuring that the patient can have a break if the intrusions during treatment prove too frightening. Essentially, the child is asked to focus on a bad memory while simultaneously following the moving fingers of the therapist. This “dual attention” task is thought to help the child confront the frightening memory and so “process” the emotional reaction to that memory. There is some controversy about the active components of treatment in EMDR. For example, dismantling studies (Pitman, Orr, Altman et al., 1996) have not provided evidence for a cardinal role for saccadic eye movements. The overlap between treatment components of CBT and EMDR (e.g., therapeutic exposure) have led some to suggest that the mechanisms of change may be broadly similar in both approaches. Chemtob, Nakashima, & Hamada (2002) identified 32 children who still met criteria for PTSD after other attempts at treatment. They achieved significant drops in children’s PTSD symptoms following three sessions of EMDR, with significant but lower drops on depression and anxiety. DeRoos, Greenwald, de Jongh et al. (2004) reported an RCT involving 52 children following the 2000 Enschede (Netherlands) fireworks disaster. Both EMDR and CBT produced significant lowering of stress symptoms, with EMDR doing slightly better in fewer sessions. Whereas the NICE report (2005) found good evidence from RCTs with adults that allowed a firm recommendation that it be available to patients in the UK NHS, the evidence base with children is far less robust. Even despite the lack of POST-TRAUMATIC STRESS DISORDER 693 a theoretical basis for EMDR, it appears that it can work very quickly and so should be considered as a possible treatment with children. Narrative Exposure Therapy Arising in part from South American methods of helping victims of torture and in part from a thoroughgoing analysis of the neurobiology of autobiographical memory and ways of completing fragmented memories, Schauer, Neuner, & Elbert (2004) have developed Narrative Exposure Therapy (NET) and used it in RCTs with adult refugees in the Sudan (Neuner, Schauer, Klascik, Karynakara, & Elbert, 2004) and war-affected children in Sri Lanka (Schauer, Neuner, Elbert et al., 2004). Pennebaker (1995) has long demonstrated that writing about emotional events in structured ways can have very positive effects, and so one can anticipate that structured writing therapies and NET will develop more in the near future. Medication Despite the paucity of proper trials on children by pharmaceutical companies in developing psychotropic drugs, many children are indeed prescribed such medication following traumas (often by general practitioners rather than child specialists). Given the recent disclosures that trials of selective serotonin reuptake inhibitors (SSRIs) increased suicidal ideation in depressed adolescents, one’s confidence in the use of medication with children is not great. Indeed, the NICE Guideline Development Group (2005) found no study that met its stringent criteria. Medication is not recommended as a treatment for PTSD in children. Contingency Planning When trauma affects a large number of children at once, as in an accident at school, then a public health approach to dealing with the emergency is required (Pynoos, Goenjian, & Steinberg, 1995). Schools need to plan ahead, not only to deal with large-scale disasters, but also to respond to the needs of children after threatening incidents that affect only a few of them. There are now a number of texts written especially for schools to help them develop contingency plans to deal with the effects of a disaster (Johnson, 1993; Klingman, 1993; Yule & Gold, 1993). Most developed countries have well-established plans to deal with major civil emergencies. Increasingly, these include a psychosocial or mental health component and it is advisable for child and adolescent mental health services to be involved in the planning (Canterbury & Yule, 1999). UN agencies are increasingly prepared to meet the mental health needs of children after war and major disasters (Machel, 2001) and again mental health services need to collaborate with other agencies to meet such needs. In considering the need to plan for “Mental Health in Complex Emergencies,” Mollica, Lopes Cardoza et al. (2004) argued that all countries should develop plans to meet mental health sequelae of disasters. Because most disasters occur in developing countries, it is vital that appropriate assessment 9781405145497_4_042.qxd 29/03/2008 02:53 PM Page 693

and intervention tools are developed that are culturally appropriate. It is also essential that such interventions are properly evaluated. Research is essential, not a luxury; that message needs to be accepted by non-governmental officers responding to disasters. Given that disasters happen with great frequency, then by planning ahead, proper consideration can be given to the ethical aspects of intervening soon after a crisis. Unless early interventions are evaluated responsibly, significant resources are wasted and survivors suffer unnecessarily. Conclusions and Recommendations Since its formulation in 1980, the diagnosis of PTSD has become widely used in child mental health practice. Using standard criteria and measures, significant minorities of children and adolescents have been diagnosed with PTSD following a variety of major stressors, from transport accidents, natural disasters such as hurricanes or earthquakes, and war. These reactions have now been shown to be long-lasting and disabling in many cases. Most research to date has concerned children of school age, and further work is needed in more closely delineating the stress reactions of very young children. While it is comforting to children who develop PTSD to be told that their frightening symptoms are “normal,” not all children do react this way, and so greater emphasis is needed on attempts to discover why some children are more vulnerable than others. The recent research focus on identifying risk and maintaining factors in carefully designed prospective studies has been fruitful, and has led to effective interventions which aim to reverse those maintaining factors. Further work in identifying modifiable maintaining factors is still required, especially with regard to parent–child interactions in traumaaffected families. There is considerable overlap in disorders that present after a major traumatic event (Bolton, O’Ryan, Udwin et al., 2000). However, there seems to be more than heuristic value in regarding PTSD to be separate from both other anxiety disorders and from depression. For example, available evidence suggests that PTSD and depression in children are associated with different risks post trauma (Smith, Perrin, Yule et al., 2001), and show a different course and treatment response (Goenjian, Yehuda, Pynoos et al., 1996). Further attention to multiple outcomes following trauma would enhance our understanding of the broad range of reactions that children may show, and may lead to more effective treatments for them. The treatment outcome literature is small but growing. It remains the case that the most solid evidence relates to children traumatized by sexual abuse: here, the evidence is strong for TF-CBT as an effective treatment (NICE, 2005). In contrast, there is a paucity of well-controlled treatment studies for children with PTSD following relatively common single incident stressors such as RTAs and assaults. Published studies support TF-CBT as the treatment of choice for these young people too, but further RCTs are clearly needed. A range of treatments is now available, including EMDR and NET in addition to CBT, and it is expected that RCTs involving more than one active treatment will shed further light on what works for whom. Studying PTSD has proved a remarkably rich, fertile ground for studying child psychopathology. It is a diagnostic category that helps focus mental health professionals on the needs of children – always providing that they ask the children themselves about their inner experiences and reactions. References Aerni, A., Traber, R., Hock, C., Roozendaal, B., Schelling, G., Papassotiropoulos, A., et al. (2004). Low-dose cortisol for symptoms of posttraumatic stress disorder. American Journal of Psychiatry, 161, 1488–1490. Almqvist, K., & Brandell-Forsberg, M. (1997). Refugee children in Sweden: Post-traumatic stress disorder in Iranian preschool children exposed to organized violence. Child Abuse and Neglect, 21, 351– 366. American Academy of Child and Adolescent Psychiatry. (1998). Practice parameters for the assessment and treatment of children and adolescents with post traumatic stress disorder. Journal of the American Academy of Child and Adolescent Psychiatry, 37, 4–26. American Psychiatric Association (APA). (2000). Diagnostic and Statistical Manual of Mental Disorders (4th edn.). Text Revision. Washington, DC: American Psychiatric Association. Bolton, D., O’Ryan, D., Udwin, O., Boyle, S., & Yule, W. (2000). The long-term psychological effects of a disaster experienced in adolescence. II. General psychopathology. Journal of Child Psychology and Psychiatry, 41, 513–523. Bremner, J. D., Randall, P., Scott, T. M., Bronen, R. A., Seibyl, J. P., Southwick, S. M., et al. (1995). MRI-based measurement of hippocampal volume in patients with combat-related posttraumatic stress disorder. American Journal of Psychiatry, 152, 973–981. Bremner, J. D., Randall, P., Vermetten, E., Staib, L., Bronen, R. A., Capelli, S., et al. (1997). MRI-based measurement of hippocampal volume in posttraumatic stress disorder related to childhood physical and sexual abuse: A preliminary report. Biological Psychiatry, 41, 23–32. Brewin, C., Andrews, B., & Valentine, J. (2000). Meta-analysis of risk factors for posttraumatic stress disorder in trauma-exposed adults. Journal of Consulting and Clinical Psychology, 68, 748– 766. Brewin, C. R. (2001). A cognitive neuroscience account of posttraumatic stress disorder and its treatment. Behaviour Research and Therapy, 39, 373–393. Brewin, C. R., Andrews, B., & Rose, S. (2003). Overlap between acute stress disorder and PTSD in victims of violent crime. American Journal of Psychiatry, 160, 783–785. Broberg, A., Dyregrov, A., & Lilled, L. (2005). The Goteborg discotheque fire: Posttraumatic stress, and school adjustment as reported by the primary victims 18 months later. Journal of Child Psychology and Psychiatry, 46, 1279–1286. Canterbury, R., & Yule, W. (1999). Debriefing and crisis intervention. In W. Yule (Ed.), Post Traumatic Stress Disorder (pp. 221– 238). Chichester: Wiley. Carrion, V. G., Weems, C. F., Ray, R. D., Glaser, B. H., Hessl, D., & Reiss, A. L. (2002). Diurnal salivary cortisol in pediatric posttraumatic stress disorder. Biological Psychiatry, 51, 575–582. Celano, M., Hazzard, A., Webb, C., & McCall, C. (1996). Treatment of traumagenic beliefs among sexually abused girls and their mothers: An evaluation study. Journal of Abnormal Child Psychology, 24, 1–17. Chemtob, C. M., Nakashima, J. P., & Hamada, R. S. (2002). Psychosocial intervention for postdisaster trauma symptoms in CHAPTER 42 694 9781405145497_4_042.qxd 29/03/2008 02:53 PM Page 694

elementary school children: A controlled community field study. Archives of Pediatrics and Adolescent Medicine, 156, 211–216. Cohen, J. A., Deblinger, E., Mannarino, A. P., & Steer, R. A. (2004). A multisite, randomized controlled trial for children with sexual abuse-related PTSD symptoms. Journal of the American Academy of Child and Adolescent Psychiatry, 43, 393–402. Cohen, J. A., Perel, J. M., DeBellis, M., Friedman, M., & Putnam, F. W. (2002). Treating traumatized children: Clinical implications of the psychobiology of posttraumatic stress disorder. Trauma, Violence, & Abuse, 3, 91–108. Dalgleish, T., Meiser-Stedman, R., & Smith, P. (2005). Cognitive aspects of posttraumatic stress reactions and their treatment in children and adolescents: an empirical review and some recommendations. Behavioural and Cognitive Psychotherapy, 33, 459–486. De Bellis, M. D. (2001). Developmental traumatology: The psychobiological development of maltreated children and its implications for research, treatment, and policy. Development and Psychopathology, 13, 539–564. De Bellis, M. D., Chrousos, G. P., Dorn L. D., Burke, L., Helmers, K., Kling, M. A., et al. (1994). Hypothalamic–pituitary–adrenal axis dysregulation in sexually abused girls. Journal of Clinical Endocrinology and Metabolism, 78, 249–255. De Bellis, M. D., Baum, A. S., Birmaher, B., Keshavan, M. S., Eccard, C. H., Boring, A. M., et al. (1999a). A. E. Bennett Research Award Developmental traumatology. 1. Biological stress systems. Biological Psychiatry, 45, 1259–1270. De Bellis, M. D., Keshavan, M. S., Clark, D. B., Casey, B. J., Giedd, J. N., Boring, A. M., et al. (1999b). A. E. Bennett Research Award Developmental traumatology. 2. Brain development. Biological Psychiatry, 45, 1271–1284. Deblinger, E., Stauffer, L. B., & Steer, R. A. (2001). Comparative efficacies of supportive and cognitive behavioral group therapies for young children who have been sexually abused and their nonoffending mothers. Child Maltreatment: Journal of the American Professional Society on the Abuse of Children, 6, 332–343. de Roos, C., Greenwald, R., de Jongh, A., & Noorthoorn, E. E. (2004). EMDR versus CBT for disaster-exposed children: A controlled study. Poster presented at ISTSS 20th Annual Meeting, New Orleans, November. Ehlers, A., & Clark, D. M. (2000). A cognitive model of posttraumatic stress disorder. Behaviour Research and Therapy, 38, 319–345. Ehlers, A., Mayou, R. A., & Bryant, B. (2003). Cognitive predictors of posttraumatic stress disorder in children: Results of a prospective longitudinal study. Behaviour Research and Therapy, 41, 1–10. Elkit, A. (2002). Victimization and PTSD in a Danish national youth probability sample. Journal of the American Academy of Child and Adolescent Psychiatry, 41, 174–181. Feeny, N. C., Foa, E. B., Treadwell, K. R., & March, J. (2004). Posttraumatic stress disorder in youth: A critical review of the cognitive and behavioral treatment outcome literature. Professional Psychology: Research and Practice, 35, 466–476. Fletcher, K. E. (1996). Childhood posttraumatic stress disorder. In E. J. Mash, & R. A. Barkley (Eds.), Child psychopathology (pp. 242–276). New York: Guilford. Foa, E. B., Johnson, K., Feeney, N. C., & Treadwell, K. (2000). The child PTSD symptom scale: A preliminary examination of its psychometric properties. Journal of Clinical Child Psychology, 30, 376–384. Foa, E. B., Steketee, G., & Olasov-Rothbaum, B. (1989). Behavioral/ cognitive conceptualizations of post-traumatic stress disorder. Behavior Therapy, 20, 155–176. Frederick, C. J. (1985). Children traumatized by catastrophic situations. In S. Eth, & R. Pynoos (Eds.), Post-traumatic stress disorder in children (pp. 73–99). Washington: American Psychiatric Press. Giaconia, R. M., Reinherz, H. Z., Silverman, A. B., Pakiz, B., Frost, A. K., & Cohen, E. (1995). Traumas and posttraumatic stress disorder in a community population of older adolescents. Journal of the American Academy of Child and Adolescent Psychiatry, 34, 1369–1380. Goenjian, A. K., Karayan, I., Pynoos, R. S., Minassian, D., Najarian, L. M., Steinberg, A. M., et al. (1997). Outcome of psychotherapy among early adolescents after trauma. American Journal of Psychiatry, 154, 536–542. Goenjian, A. K., Pynoos, R. S., Steinberg, A. M., Najarian, L. M., Asarnow, J. R., Karayan, I., et al. (1995). Psychiatric comorbidity in children after the 1988 earthquake in Armenia. Journal of the American Academy of Child and Adolescent Psychiatry, 34, 1174– 1184. Goenjian, A. K., Yehuda, R., Pynoos, R. S., Steinberg, A. M., Tashjian, M., Yang, R. K., et al. (1996). Basal cortisol, dexamethasone suppression of cortisol, and MHPG in adolescents after the 1988 earthquake in Armenia. American Journal of Psychiatry, 153, 929–934. Green, B., Korol, M., Grace, M., Vary, M., Leonard, A. C., Gleser, G. C., et al. (1991). Children and disaster: Age, gender, and parental effects on PTSD symptoms. Journal of the American Academy of Child and Adolescent Psychiatry, 30, 945–951. Gupta, L., Dyregrov, A., Gjestad, R., & Mukanoheli, X. (1996). Trauma, exposure, and psychological reactions to genocide among Rwandan refugees. Paper presented at the 12th Annual Convention of the International Society for Traumatic Stress Studies (November), San Francisco, CA. Hamada, R. S., Kameoka, V., & Yanagida, E. (1996). The Kauai recovery inventory; screening for posttraumatic stress symptoms in children. Paper presented at the 12th Annual meeting of the International Society for Traumatic Stress Studies (November), San Francisco, CA. Janoff-Bulman, R. (1985). The aftermath of victimization: Rebuilding shattered assumptions. In C. R. Figley (Ed.), Trauma and its wake. New York: Brunner/Mazel. Johnson, K. (1993). School crisis management: A team training guide. Alameda, CA: Hunter House. Jones, J. C., & Barlow, D. H. (1992). A new model of posttraumatic stress disorder. In P. A. Saigh (Ed.), Posttraumatic stress disorder: A behavioral approach to assessment and treatment (pp. 147–165). New York: Macmillan. Joseph, S., Brewin C. R., Yule, W., & Williams, R. (1993). Causal attributions and post-traumatic stress in adolescents. Journal of Child Psychology and Psychiatry, 34, 247–253. Kassam-Adams, N., & Winston, F. K. (2004). Predicting child PTSD: The relationship between acute stress disorder and PTSD in injured children. Journal of the American Academy of Child and Adolescent Psychiatry, 43, 403–411. Kassam-Adams, N., Garcia-España, F., Fein, J. A., & Winston, S. K. (2005). Heart rate and posttraumatic stress in injured children. Archives of General Psychiatry, 62, 335–340. Kaufman, J., Birmaher, B., Perel, J., Dahl, R. E., Moreci, P., Nelson, B., Wells, W., & Ryan, N. D. (1997). The corticotropin-releasing hormone challenge in depressed abused, depressed non-abused, and normal control children. Biological Psychiatry, 42, 669–679. Kessler, R. C., Sonnega, A., Bromet, E., Hughes, M., & Nelson, C. B. (1995). Post-traumatic stress disorder in the National Comorbidity Survey. Archives of General Psychiatry, 52, 1048–1060. King, N. J., Tonge, B. J., Mullen, P., Myerson, N., Heyne, D., Rollings, S., et al. (2000). Treating sexually abused children with posttraumatic stress symptoms: A randomized clinical trial. Journal of the American Academy of Child and Adolescent Psychiatry, 39, 1347–1355. Klingman, A. (1993). School-based intervention following a disaster. In C. F. Saylor (Ed.), Children and disasters (pp. 187–210). New York: Plenum. McFarlane, A. C. (1987). Family functioning and overprotection following a natural disaster: The longitudinal effects of post-traumatic morbidity. Australia and New Zealand Journal of Psychiatry, 21, 210–218. POST-TRAUMATIC STRESS DISORDER 695 9781405145497_4_042.qxd 29/03/2008 02:53 PM Page 695

McFarlane, A. (2005). Psychiatric morbidity following disasters: Epidemiology, risk and protective factors. In J. Lopez-Ibor, G. Christodoulou, M. Maj, N. Sartorius, & A. Okasha (Eds.), Disasters and mental health (pp. 37–63). New York, NY: John Wiley & Sons. Machel, G. (2001). The impact of war on children: A review of progress since the 1996 United Nations report on the impact of armed conflict on children. London, UK: Hurst & Co. March, J. S., Amaya-Jackson, L., Murray, M. C., & Schulte, A. (1998). Cognitive–behavioral psychotherapy for children and adolescents with post-traumatic stress disorder after a single incident stressor. Journal of the American Academy of Child and Adolescent Psychiatry, 37, 585–593. Margolin, G., & Gordis, E. B. (2000). The effects of family and community violence on children. Annual Review of Psychology, 51, 445–479. Meiser-Stedman, R. (2002). Towards a cognitive–behavioral model of PTSD in children and adolescents. Clinical Child and Family Psychology Review, 5, 217–232. Meiser-Stedman, R., Yule, W., Dalgleish, T., Smith P., & Glucksman E. (2006). The role of the family in child and adolescent posttraumatic stress following attendance at an emergency department. Journal of Pediatric Psychology, 31, 397–402. Meiser-Stedman, R., Yule, W., Smith, P., Glucksman, E., & Dalgleish, T. (2005). Acute stress disorder and posttraumatic stress disorder in children and adolescents involved in assaults or motor vehicle accidents. American Journal of Psychiatry, 162, 1381–1383. Meltzer, H., Gatward, R., Goodman, R., & Ford, T. (2003). Mental health of children and adolescents in Great Britain. International Review of Psychiatry, 15, 185–187. Misch, P., Phillips, M., Evans, P., & Berelowitz, M. (1993). Trauma in pre-school children: A clinical account. In G. Forrest (Ed.), Trauma and crisis management. ACPP Occasional Paper. Mollica, R. F., Lopes Cardoza, B., Osofsky, H. J., Raphael, B., Ager, A., & Salama, P. (2004). Mental health in complex emergencies. Lancet, 364, 2058–2067. Morgan, L., Scourfield, J., Williams, D., Jasper, A., & Lewis, G. (2003). The Aberfan disaster: 33-year follow-up of survivors. British Journal of Psychiatry, 182, 532–536. Moradi, A., Taghavi, M. R., Neshat-Doost, H., Yule, W., & Dalgleish, T. (2000). Memory bias for emotional information in children and adolescents with posttraumatic stress disorder. Journal of Anxiety Disorders, 14, 521–534. Nader, K., Pynoos, R., Fairbanks, L., Al-Ajeel, M., & al-Asfour, A. (1993). A preliminary study of PTSD and grief among the children of Kuwait following the Gulf crisis. British Journal of Clinical Psychology, 32, 407–416. Neuner, F., Schauer, M., Klaschik, C., Karunakara, U., & Elbert, T. (2004). A comparison of narrative exposure therapy, supportive counseling, and psychoeducation for treating posttraumatic stress disorder in an African refugee settlement. Journal of Consulting and Clinical Psychology, 72, 579–587. National Institute for Clinical Excellence (NICE). (2005). Post traumatic stress disorder: The management of PTSD in adults and children in primary and secondary care (Clinical Guideline 26). London: Gaskell and the British Psychological Society. O’Donohue, W., & Eliot, A. (1992). The current status of posttraumatic stress disorder as a diagnostic category: Problems and proposals. Journal of Traumatic Stress, 5, 421–439. Ornitz, E. M., & Pynoos, R. S. (1989). Startle modulation in children with post-traumatic stress disorder. American Journal of Psychiatry, 146, 866–870. Pennebaker, J. W. (Ed.). (1995). Emotion, disclosure, and health. Washington, DC: American Psychological Association. Perry, B. D. (1994). Neurobiological sequelae of childhood trauma: Post-traumatic stress disorder in children. In M. M. Murburg (Ed.), Catecholamine function in posttraumatic stress disorder: Emerging concepts (pp. 233–255). Washington, DC: American Psychiatric Press. Pine, D. S. (2003). Developmental psychobiology and response to threats: Relevance to trauma in children and adolescents. Biological Psychiatry, 53, 796–808. Pine, D. S., & Cohen, J. (2002). Trauma in children and adolescents: risk and treatment of psychiatric sequelae. Biological Psychiatry, 51, 519–531. Pine, D. S., Mogg, K., Bradley, B. P., Montgomery, L., Monk, C. S., McClure, E., et al. (2005). Attention bias to threat in maltreated children: Implications for vulnerability to stress-related psychopathology. American Journal of Psychiatry, 162, 291–296. Pitman, R. K., Orr, S. P., Altman, B., Longpre, R. E., Poiré, R. E., & Macklin, M. L. (1996). Emotional processing during eye movement desensitization and reprocessing therapy of Vietnam veterans with chronic posttraumatic stress disorder. Comprehensive Psychiatry, 37, 419–429. Pynoos, R. S., & Eth, S. (1986). Witness to violence: The child interview. Journal of the American Academy of Child Psychiatry, 25, 306–319. Pynoos, R. S., Frederick, C., Nader, K., Arroyo, W., Steinberg, A., Eth, S., et al. (1987). Life threat and posttraumatic stress in schoolage children. Archives of General Psychiatry, 44, 1057–1063. Pynoos, R. S., Goenjian, A., & Steinberg, A. M. (1995). Strategies of disaster interventions for children and adolesacents. In S. E. Hobfoll, & M. deVries (Eds.), Extreme stress and communities: Impact and intervention. Dordrecht, Netherlands: Kluwer. Pynoos, R. S., & Nader, K. (1988). Psychological first aid and treatment approach for children exposed to community violence: research implications. Journal of Traumatic Stress, 1, 243–267. Ramchandani, P., & Jones, D. P. H. (2003). Treating psychological symptoms in sexually abused children: From research findings to service provision. British Journal of Psychiatry, 183, 484–490. Salmon, K., & Bryant, R. (2002). Posttraumatic stress disorder in children: The influence of developmental factors. Clinical Psychology Review, 22, 163–188. Schauer, M., Neuner, F., & Elbert, T. (2005). Narrative exposure therapy: A short-term intervention for traumatic stress disorders after war, terror, or torture. OH, USA: Hogrefe & Huber Publishers. Schauer, E., Neuner, F., Elbert, T., Ertl, V., Onyut, L. P., Odenwald, M., et al. (2004). Narrative exposure therapy in children: A case study. Intervention: International Journal of Mental Health, Psychosocial Work and Counselling in Areas of Armed Conflict, 2, 18–32. Scheeringa, M., Peebles, C. D., Cook, C., & Zeanah C. H. (2001). Toward establishing procedural, criterion, and discriminant validity for PTSD in early childhood. Journal of the American Academy of Child and Adolescent Psychiatry, 40, 52–60. Scheeringa, M., Wright, M., Hunt, J. P., & Zeanah, C. H. (2006). Factors affecting the diagnosis and prediction of PTSD symptomatology in children and adolescents. American Journal of Psychiatry, 163, 644–651. Scheeringa, M. S., Zeanah, C. H., Drell, M. J., & Larrieu, J. A. (1995). Two approaches to the diagnosis of posttraumatic stress disorder in infancy and early childhood. Journal of the American Academy of Child and Adolescent Psychiatry, 34, 191–200. Scheeringa, M., Zeanah, C. H., Myers, L., & Putnam, F. (2003). New findings on alternative criteria for PTSD in preschool children. Journal of the American Academy of Child and Adolescent Psychiatry, 42, 561–570. Scheeringa, M. S., Zeanah, C. H., Myers, L., & Putnam, F. (2004). Heart period and variability findings in preschool children with posttraumatic stress symptoms. Biological Psychiatry, 55, 685–691. Shapiro, F. (2001). Eye movment desensitization and reprocessing: Basic principles, protocols and procedures (2nd edn.). New York: Guilford Press. Smith, P., Perrin, S., Yule, W., & Rabe-Hesketh, S. (2001). War exposure and maternal reactions in the psychological adjustment of children from Bosnia-Hercegovina. Journal of Child Psychology and Psychiatry, 42, 395–404. CHAPTER 42 696 9781405145497_4_042.qxd 29/03/2008 02:53 PM Page 696

Terr, L. C. (1991). Childhood traumas: An outline and overview. American Journal of Psychiatry, 148, 10–20. Udwin, O., Boyle, S., Yule, W., Bolton, D., & O’Ryan, D. (2000). Risk factors for long-term psychological effects of a disaster experienced in adolescence: Predictors of post traumatic stress disorder. Journal of Child Psychology and Psychiatry, 41, 969–979. Vernberg, E. M., La Greca, A., Silverman, W. K., & Prinstein, M. J. (1996). Prediction of posttraumatic stress symptoms in children after hurricane Andrew. Journal of Abnormal Psychology, 105, 237–248. Wolmer, L., Laor, N., Gershon, A., Mayes, L. C., & Cohen, D. J. (2000). The mother–child dyad facing trauma: A developmental outlook. Journal of Nervous and Mental Disease, 188, 409– 415. World Health Organization (WHO). (1996). Multiaxial classification of child and adolescent psychiatric disorders: The ICD-10 classification of mental and behavioural disorders in children and adolescents. Cambridge, UK: Cambridge University Press. Yehuda, R., & McFarlane, A.C. (1995). Conflict between current knowledge about posttraumatic stress disorder and its original conceptual basis. American Journal of Psychiatry, 152, 1705– 1713. Yule, W., Bolton, D., Udwin, O., Boyle, S., O’Ryan, D., & Nurrish, J. (2000). The long-term psychological effects of a disaster experienced in adolescence. I. The incidence and course of post traumatic stress disorder. Journal of Child Psychology and Psychiatry, 41, 503–511. Yule, W., & Gold, A. (1993). Wise before the event: Coping with crises in schools. London: Calouste Gulbenkian Foundation. Yule, W., Perrin, S., & Smith, P. (1999). Post-traumatic stress disorders in children and adolescents. In W. Yule (Ed.), Post traumatic stress disorder (pp. 25–50). Chichester: Wiley. POST-TRAUMATIC STRESS DISORDER 697 Smith, P., Perrin, S. G., Yule, W., Hacam, B., & Stuvland, R. (2002). War exposure among children from Bosnia-Hercegovina: Psychological adjustment in a community sample. Journal of Traumatic Stress, 15, 147–156. Smith, P., Yule, W., Perrin, S., Tranah, T., Dalgleish, T., & Clark, D. M. (2007). A randomized controlled trial of cognitive behavior therapy for PTSD in children and adolescents. Journal of the American Academy of Child and Adolescent Psychiatry, 46, 1051– 1061. Stallard, P. (2003). A retrospective analysis to explore the applicability of the Ehlers and Clark (2000) cognitive model to explain PTSD in children. Behavioural and Cognitive Psychotherapy, 31, 337–345. Stallard, P. (2006). Psychological interventions for post-traumatic stress reactions in children and young people: A review of randomised controlled trials. Clinical Psychology Review, 26, 895–911. Stallard, P., Salter, E., & Velleman, R. (2004). Posttraumatic stress disorder following road traffic accidents: A second prospective study. European Child and Adolescent Psychiatry, 13, 172–178. Stallard, P., Velleman, R., Salter, E., Howse, I., Yule, W., & Taylor, G. (2006). A randomised controlled trial to determine the effectiveness of an early psychological intervention with children involved in road traffic accidents. Journal of Child Psychology and Psychiatry, 47, 127–134. Stein, B. D., Jaycox, L. H., Kataoka, S. H., Wong, M., Tu, W., Elliott, M. N., et al. (2003). A mental health intervention for schoolchildren exposed to violence: A randomized controlled trial. Journal of the American Medical Association, 290, 603–611. Sullivan, M. A., Saylor, C. F., & Foster, K. Y. (1991). Post-hurricane adjustment of preschoolers and their families. Advances in Behaviour Research and Therapy, 13, 163–171. 9781405145497_4_042.qxd 29/03/2008 02:53 PM Page 697

698 Definition: the Concept and Current Issues Obsessive-compulsive disorder was once considered rare in childhood, but recent advances in diagnosis and treatment have led to recognition that the disorder is a common cause of distress for children and adolescents. It is characterized by the presence of obsessions (unwanted, repetitive or intrusive thoughts) and compulsions (unnecessary repetitive behaviors or mental activities). Because the obsessive-compulsive thoughts and rituals are usually recognized by the child as nonsensical, they are often kept hidden for as long as possible – from both parents and practitioners. This secrecy may have contributed to the fact that until the 1980s OCD was unfamiliar to most child psychiatrists, even though classic descriptions of the disorder featured cases with childhood presentation (Janet, 1903). The recognition that OCD was more common in adults than previously believed, and retrospective reports that one-half to one-third of adult subjects had their onset in childhood or adolescence, focused the attention of the child psychiatric community on this chronic and often disabling disorder (Karno & Golding, 1991; Karno, Golding, Sorenson et al., 1988). Until the mid-nineteenth century, obsessive-compulsive phenomena were considered to be a variant of insanity. However, as the disorder was better defined, it came into focus as one of the neuroses. The descriptions of repetitive unwanted thoughts or rituals, often characterized by magical thinking and usually kept private by the sufferer, were relatively constant observations in those early reports. Debate about core deficits and the relative importance of volitional, intellectual and emotional impairments (all of which are in some way abnormal in OCD) have flourished for over 100 years (Berrios, 1989). Freud (1906; 1958) speculated about the similarity between obsessive-compulsive phenomena, children’s games and religious rites. Although psychoanalytic theory is empirically unproved and has not been shown to be effective in the treatment of OCD, the broad questions raised by Freud about continuity and discontinuity within individual development and OCD, as well as with regard to secular and religious rituals, remain fascinating issues. In addition, the association between certain neurological disorders, such as Tourette’s disorder (see chapter 44), and OCD, supported by current imaging research, has led to possible localization of brain circuits mediating obsessive-compulsive behaviors as well as mechanisms for behavioral encoding. Over the past decade, interest in these general questions, as well as the possibility of unique pediatric subgroups of OCD, has generated a wealth of clinical and translational research (Apter, Fallon, Jr., King et al., 1996; Fitzgerald, MacMaster, Paulson et al., 1999; Graybiel & Rauch, 2000; Rapoport & Inoff-Germain, 2007). Key issues which appear throughout this chapter are the degree to which at least some cases with childhood onset represent a distinct subtype (e.g., patients with Tourette’s/tics and/or patients with a possible infectious trigger or Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infections – PANDAS) and the extent to which there is continuity with normal development. Another important topic is how to optimize treatment for this often chronic condition. Epidemiology The Epidemiological Catchment Area (ECA) study of over 18,500 individuals in five different sites in the USA included OCD as a separate category and provided the first large-scale information on the prevalence of this disorder in adults (Karno & Golding, 1991; Karno, Golding, Sorenson et al., 1988) (see page 699). Using the Diagnostic Interview Schedule, a structured interview designed for lay interviewers, lifetime prevalence rates without DSM-III exclusions ranged from 1.9 to 3.3% across sites. Even with DSM-III exclusions, the rates were 1.2–2.4%. These rates were 25–60 times greater than had been estimated on the basis of clinical populations. The mean age of onset across the sites ranged from 20 to 25 years with 50% developing symptoms in childhood or adolescence (Karno & Golding, 1991), providing further support for the retrospective accounts of the frequent pediatric onset of this disorder (Black, 1974). More recent cross-cultural studies with adults have been supportive of similar rates of between 1.9 and 2.5 percent prevalence across widely differing cultures (Horwath & Weissman, 2000). Higher rates are found using DSM-IV than with ICD-10, with only 64% agreement between the two systems (Andrews, Slade, & Peters, 1999). As about a half of adult patients report onset after adolescence or childhood, the similar rates for adult and child populations suggest that Obsessive-Compulsive Disorder 43 Judith L. Rapoport and Philip Shaw 9781405145497_4_043.qxd 29/03/2008 02:53 PM Page 698 Rutter’s Child and Adolescent Psychiatry, 5th Edition, Edited by M. Rutter, D. V. M. Bishop D. S. Pine, S. Scott, J. Stevenson, E. Taylor and A. Thapar © 2008 Blackwell Publishing Limited. ISBN: 978-1-405-14549-7

OBSESSIVE-COMPULSIVE DISORDER 699 some pediatric patients must remit. This apparent discrepancy from the chronic nature of most pediatric OCD studied clinically has not been resolved (see discussion below), but may reflect in part that adult cases are typically identified using only one informant, whereas childhood cases are frequently diagnosed on the basis of two informants (the child and parent). A number of early epidemiological studies of OCD focused on children and adolescents [see review by Zohar (1999)]. One recent additional study examined the results of a large foursite community survey in the USA (the National Institute of Mental Health [NIMH] Methods for the Epidemiology of Child and Adolescent Mental Disorders [MECA] Study) (Rapoport, Inoff-Germain, Weissman et al., 2000). The lifetime prevalence across eight studies (from these two articles combined) indicates relative consistency with a lifetime prevalence from 0.7 to 2.9%. (Also see Table 43.1). Males have an earlier onset than females, contributing to a striking preponderance of males in most pediatric samples (Geller, Biederman, Jones et al., 1998). The variance in prevalence rates is likely to reflect differences in study design, particularly whether clinicians or non-clinicians conducted interviews. Additionally, prevalence estimates may also be sensitive to the diagnostic tools employed. Structured interviews in particular may yield false positives when given to children, who are apt to misinterpret the questions (Breslau, 1987). There is increasing reliance on standardized interviews and rating scales for both the study and clinical management of OCD. Structured interviews are covered in detail in chapter 19. The most commonly used tools, the Diagnostic Interview for Children and Adolescents (Herjanic & Campbell, 1977; Herjanic & Reich, 1982) and the Schedule for Affective Disorder and Schizophrenia for School-Age Children (Kaufman, Birmaher, Brent et al., 1997), have sections on OCD. In addition, there are several rating scales in general use, including the child version of the Leyton Obsessional Inventory (Berg, Rapoport, Whitaker et al., 1989) and the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) (Goodman, Price, Rasmussen, Mazure, Delgado et al., 1989; Goodman, Price, Rasmussen, Mazure, Fleischmann et al., 1989). Diagnostic Issues Continuity with Normal Development The boundaries of diagnosis are complex in any disorder, and this is clearly the case with OCD. Individual “habits” that Table 43.1 Community studies of OCD prevalence in children & adolescents. Study Flament et al. (1988) Zohar et al. (1992) Reinherz et al. (1993) Lewinsohn et al. (1993) Valleni-Basile et al. (1994) Douglas et al. (1995) Apter et al. (1996) Wittchen et al. (1998) Rapoport et al. (2000) Prevalence (%) 1.0 & 1.9 (current & lifetime, respectively) 3.6 (point) 1.3, 1.3, 2.1 (1-mo, 6-mo, & lifetime, respectively) 0.06, 0.53 (current & lifetime, respectively) 2.95 (wt. current) 4.0 (1-yr) 2.3 (lifetime) 0.6 & 0.7 (1-yr & lifetime, respectively) 0.3, 2.5, 2.7 (parentreport, child-report, & total, respectively) Ascertainment & evaluation Initial screening with Leyton, epidemiological version; 356 subject meeting screening criteria for OCD were then evaluated using semi-structured interview by clinicians Short semi-structured interview by a child psychiatrist Structured interview by trained interviewers with research or clinical experience Semi-structured interview mostly by trained, clinically experienced interviewers 3,283 screened; 488 mother–child pairs then given semi-structured interview by psychiatric nurses Structured interview by trained mental health interviewers Initial screening by an OCD self-report questionnaire followed by a structured interview by a child psychiatrist Semi-structured interview by clinical interviewers & trained professional health research interviewers Structured interview by trained interviewers Sample, age of 5596 students grades 9–12 (USA) 562 consecutive army recruits, ages 16–17 yrs (Israel) 384 mostly 18 yr olds (USA) 1,710 14–18 yr olds (USA) 3,283 (mostly) 12–15 yr olds (USA) 930 18 yr olds from a birth cohort followed since birth (New Zealand) 861 consecutive army recruits, years 16–17 (Israel) 3,021 14–24 yrs (Germany) NIMH MECA four-site sample of caretaker-child dyads of 1,285 9–17 yr olds (USA) 9781405145497_4_043.qxd 29/03/2008 02:53 PM Page 699

are typical of OCD are extremely common across populations. For example, in one Israeli study, only 18% of the sample endorsed no obsessive-compulsive symptoms at all. Moreover, many ritualistic and “magical” behaviors are part of normal development (Leonard, 1989). As is the case with many disorders, family genetic studies seem to indicate that familiarity of obsessive-compulsive symptoms may extend across the entire range of severity, and similarly twin studies support the model of OCD as the extreme of a continuously distributed trait with biological continuity between normal and abnormal behaviors (Jonnal, Gardner, Prescott, & Kendler, 2000). However, there is evidence from a pediatric sample that symptom levels below the level needed for a categorical diagnosis of OCD do not predict the disorder at follow-up, although interestingly there was some prediction of depression (Berg, Rapoport, Whitaker et al., 1989). The Importance of Informant History Secrecy appears to be a hallmark of childhood onset OCD. The children recognize that their symptoms are nonsensical and are embarrassed by them, so they go to great lengths to hide them. Hand-washing might be disguised as more frequent voiding and rituals are carried out in private, so that children are often symptomatic for months before their parents are aware of a problem. Teachers and peers typically are aware only for cases with greater severity. As with Tourette’s disorder, children may expend effort controlling their behaviors in public and “let go” when at home. This partial voluntary control of symptoms often baffles and angers parents. Because of the variable degree and timing of the control of symptoms, the nature of the informant has a particularly important influence on recognition and diagnosis of OCD. As shown for the MECA data (Rapoport, Inoff-Germain, Weissman et al., 2000), only 0.3% were identified by parents while 2.5% were identified through self-report from the child, with only one overlapping case. Issues with DSM-IV Diagnosis OCD is defined in both ICD-10 and DSM-IV as repetitive intrusive thoughts and/or rituals that are unwanted and which interfere significantly with function or cause marked distress. The severity criteria avoid confusion of OCD with many childhood habits that are part of normal development. Both the content and relative insight into the unreasonableness of the thoughts/behaviors differentiate OCD from other disorders. Whereas clinical experience suggests that the adult criteria can be applied to childhood cases, there are several important caveats. Both DSM-IV and ICD-10 state that compulsions are designed to neutralize or prevent some dreaded event. This may not always be the case, at least for childhood OCD. While some children may not be willing or able to verbalize their obsessive thoughts, long-term contact has demonstrated that about 40% of children with OCD do not have obsessive thoughts; they steadfastly report the presence of only compulsive rituals accompanied by a vague sense of discomfort if the rituals are not carried out (Swedo, Rapoport, Leonard, Lenane, & Cheslow, 1989). At least a third of pediatric patients report that certain stimuli trigger their rituals and that avoidance of the trigger “protects” them from the obsessive-compulsive symptoms (Karno, Golding, Sorenson, & Burnam, 1988). The degree of insight needed for the diagnosis is also in dispute as some patients, at least some of the time, “believe” their obsessive thoughts. It is probable that for both children and adolescents and particularly in severe cases, diagnostic criteria should allow some partial “belief” in the necessity for these thoughts/ behaviors. Changes in diagnostic systems have an obvious impact on estimates of the prevalence of a disorder. In the case of OCD, the most recent version of DSM includes impairment and distress as criteria, as opposed to the earlier version, which included these features only as modifiers. Thus, because of exclusion of either false positives or milder cases, rates of OCD tend to be lower with DSM-IV, with a 12-month prevalence rate of 0.6% being reported in a recent study (Crino, Slade, & Andrews, 2005). Estimates of lifetime prevalence appear to be less affected by the change in diagnostic criteria (Angst, Gamma, Endrass et al., 2004; Swedo, Leonard, & Rapoport, 2004). There are several important differences between the ICD-10 and DSM-IV criteria, such as whether exclusions are made based on comorbid psychotic disorders, such as schizophrenia. DSM-IV (and DSM III-R) allow patients to receive a diagnosis of OCD even in the presence of schizophrenia (APA, 2000) in light of convincing evidence of coexistence with schizophrenia (Byerly, Goodman, Acholonu, Bugno, & Rush, 2005; Poyurovsky & Koran, 2005). Continuity with Obsessive-Compulsive Spectrum Disorders Another diagnostic issue involves potential “obsessive-compulsive spectrum disorders.” These proposed “spectrum” disorders represent a range of candidates, such as body dysmorphic disorder, hypochondriasis and trichotillomania (involving tension-related, recurrent pulling out of one’s hair). The phenomenological similarities are often striking. For example, similarly to OCD, body dysmorphic disorder and hypochondriasis are characterized by anxiety-arousing concerns and anxiety-reducing rituals, and several impulse control disorders have very prominent compulsive aspects, particularly the repetitive and typically anxiety-relieving motor behavior of trichotillomania. A neurobiological overlap with OCD is suggested by the increased rate of subclinical OCD features in relatives of those with spectrum disorder (Bienvenu, Samuels, Riddle et al., 2000). There are also many studies that have suggested some efficacy for serotonin reuptake inhibiting drugs in the treatment of these disorders, although there are also several notable negative treatment trials (Christenson, Mackenzie, Mitchell, & Callies, 1991; Hollander, 1996; Hollander, King, Delaney, Smith, & Silverman, 2003; Hollander & Wong, 1995; Karno, Golding, Sorenson, & Burnam, 1988). We will consider later the overlap between the neural substrates of OCD and the spectrum disorders. Children with disorders that are less obviously related to OCD, such as pervasive developmental disorder, frequently CHAPTER 43 700 9781405145497_4_043.qxd 29/03/2008 02:53 PM Page 700

OBSESSIVE-COMPULSIVE DISORDER 701 exhibit a compulsive need for sameness but lack other features such as ego-dystonicity (the individual’s sense that the contents of his symptoms are alien and unlike his normal self). Several other disorders exhibit a high comorbidity with OCD but share few of the cardinal symptoms of OCD itself. Thus, disorders such as pyromania, pathological gambling disorder and anorexia nervosa overlap with OCD principally in that their symptoms involve over-focused ideation. There continues to be debate about classification of OCD as an anxiety disorder. Whereas both involve intense internal preoccupation, depression rather than anxiety is the major comorbidity with OCD, and there is evidence from family studies that OCD does not segregate with other anxiety disorders and may have a different pattern of genetic transmission (for a review of this issue, see Bartz & Hollander, 2006). Unique Childhood Onset Subtypes This leads to a related question as to whether OCD with very early onset represents an important subtype of the disorder or possibly a different disorder altogether. There is growing evidence that at the very least, early age of onset represents a more familial form of the disorder, particularly for pediatric cases with ordering compulsions (Pauls, Alsobrook, Goodman, Rasmussen, & Leckman, 1995). In one study, no patient with adult onset of OCD had a first-degree relative with OCD (Nestadt, Samuels, Riddle et al., 2000). Additionally, very early onset OCD appears to be more frequently associated with tics and/or Tourette’s disorder (Chabane, Delorme, Millet et al., 2004; Grados, Riddle, Samuels et al., 2001). Moreover, family studies have found that tic disorders are more likely to occur in patients who have relatives with OCD than in patients who lack a familial loading for OCD (Pauls, Alsobrook, Goodman, Rasmussen, & Leckman, 1995). The postulation of a post-infectious subgroup of pediatric OCD came about as a result of early reports of the association of OCD with Sydenham’s chorea (Freeman et al., 1965; Osler, 1894). This supported converging evidence of basal ganglia involvement in the etiology and/or maintenance of OCD (Wise & Rapoport, 1989). One example of a possible post-infectious subgroup has been identified by research at the NIMH which identified a group of pediatric patients in whom symptom onset or exacerbations are triggered by streptococcal infections; the subgroup is identified by the acronym PANDAS (Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infections) (Swedo, Leonard, & Rapoport, 2004). This group of patients appears to have a relatively sudden onset of symptoms, typically has an abnormal neurological examination during exacerbations (particularly tic or choreiform movements – see chapter 44) and tends to have a better outcome. The disorder is thought to arise through a process of molecular mimicry, with the group A ß-hemolytic streptococcus (Streptococcus pyogenes) (GABHS) evoking antibodies that are capable of cross-reacting with specific areas of the human brain (e.g., the basal ganglia) to produce neuropsychiatric and behavioral symptoms. However, there remains considerable controversy around the diagnosis, particularly in view of some studies failing to detect elevated levels of autoantibodies in those otherwise meeting criteria for PANDAS (Singer, Hong, Yoon, & Williams, 2005). Clinical Presentation Childhood onset OCD has been documented as early as age 2 but more typically begins later in childhood or early adolescence (APA, 1994). In general, the symptoms of OCD in children mirror those in adult patients. Thus, obsessions on the themes of contamination, danger to self or others (such as fears that parents will be harmed), symmetry or moral issues are common; and typical compulsions include washing, checking and repeating – particularly until the child experiences a feeling of “getting it just right” (Despert, 1955; Masi, Millepiedi, Mucci et al., 2005; Thomsen, 1991). Most children have a combination of obsessions and rituals, and pure obsessives are rare compared with the more frequent pure ritualizers. Children with an early age at onset (below age 6) usually begin their rituals or obsessions in an easily recognizable fashion, such as excessive hand-washing or ritualized checking and repeating. In some cases, however, the clinical presentation is altered by the child’s developmental immaturity. For example, one 6-year-old boy, who was compelled to draw zeros repetitively, had started at age 3 to circle manhole covers on city streets. His tantrums when the circling was interrupted, his subjective distress during the behavior and his lack of other psychosocial abnormalities or disorders (such as autism or pervasive developmental disorder) led to the diagnosis of OCD. Another child, who presented at age 7 with clinically significant checking compulsions, had been evaluated previously at 3 years of age when he developed a “compulsion” to walk only on the edges of the floor tiles. Cleaning rituals in children too young to reach the water faucet can present as excessive hand-wiping or licking. A large community-based study of young adolescents found females more frequently reported compulsions and males more commonly reported obsessions (Valleni-Basile, Garrison, Jackson et al., 1994). The most common compulsions were arranging (56%), counting (41%), washing (17%) and checking (12%). The presenting symptoms of 70 children and adolescents consecutively evaluated at the NIMH are summarized in Table 43.2 (Swedo, Rapoport, Leonard, Lenane, & Cheslow, 1989), which gives greater detail on the content of obsessions. While there is considerable overlap in the symptom profile between the community and clinic samples’ symptom profile, washing compulsions were the most common symptom in the NIMH sample, occurring at some time during the course of the illness in over half of the patients. Hand washing and showering were the most common, and the use of chemicals such as alcohol or detergents provoked eczematoid dermatitis in several cases. A cluster analysis of symptoms in 213 children with OCD produced five clusters: mental rituals/touching/ordering; cleaning/ contamination; superstitions; obsessions/checking/confessing; 9781405145497_4_043.qxd 29/03/2008 02:53 PM Page 701

CHAPTER 43 702 and somatic concerns (Ivarsson & Valderhaug, 2006). A similar factor structure of OCD symptoms in children and adolescents was found in an independent analysis (McKay, Piacentini, Greisberg et al., 2006). This shows some overlap with factor analytic studies of symptoms in adult OCD, which have consistently indicated four main symptom clusters in OCD: symmetry/ordering, contamination/cleaning, hoarding and obsessions/checking (Mataix-Cols, Rosario-Campos, & Leckman, 2005). The symptom profiles differ, however, in the absence of a hoarding subgroup in children as well as the prominence of a “superstition” symptom cluster in children with magical thinking and acts as central features. The usefulness of these factors in treatment prediction and genetic studies is being explored (see below). Approximately one third of pediatric patients report that certain stimuli trigger their rituals and that avoidance of the trigger “protects” them from the obsessive-compulsive symptoms (Swedo, Rapoport, Leonard, Lenane, & Cheslow, 1989). For example, a 16-year-old girl with elaborate front door touching and stepping rituals would “sneak” into her house by a side door, avoiding the sight of the front door and successfully averting the compulsion. Several children avoided looking at certain parts of a room (e.g., “corners of the ceiling”) which set off various gaze rituals. These phenomena have been viewed from an ethological perspective, with the compulsions conceptualized as “fixed action patterns” released by key environmental stimuli (Modell, Mountz, Curtis, & Greden, 1989; Wise & Rapoport, 1989). These triggers are of particular interest for treatment as they often determine the key approach during behavioral desensitization, namely, exposure with response prevention (see below). Course and Natural History Epidemiological studies indicate that over 50% of adults with OCD report that their symptoms started during childhood or adolescence, with males generally having earlier onset than females (Rasmussen & Tsuang, 1984). A single epidemiological study of OCD in a group of 18-year-olds suggested that past depression and substance abuse were predictive of onset of OCD (Douglass, Moffitt, Dar, McGee, & Silva, 1995). There may also be a prodromal phase: parents of nearly half of the NIMH sample revealed that their children had displayed “micro episodes of OCD” years before developing full-blown symptoms. During these episodes, excessive rigidity and repetitive rituals (e.g., wearing the same clothes for a month, refusal to take a different path through the house) were a source of concern, albeit briefly. A prospective epidemiological survey of 976 children, initially assessed between the ages of 1 and 10 years and then 8, 10, and 15 years later, delineated predictors of OCD symptoms Reported symptoms at initial interview N % Obsessions Concerns with dirt, germs, environmental toxins 28 40 Something terrible happening (e.g., death of loved one) 17 24 Symmetry, order or exactness 12 17 Scrupulosity (religious obsessions) 9 13 Concern or disgust with bodily waste or secretions 6 8 Lucky or unlucky numbers 6 8 Forbidden, aggressive or perverse sexual thoughts, images or impulses 3 4 Fear of harming others or self 3 4 Concern with household items 2 3 Intrusive nonsense sounds, words or music 1 1 Compulsions Excessive or ritualized hand-washing, showering, bathing or grooming 60 86 Repeating rituals (e.g., going in and out of the door) 36 51 Checking (e.g., doors, locks, stoves) 32 46 Miscellaneous rituals (e.g., writing, moving, speaking) 18 26 Rituals to remove contact with contaminants 16 23 Touching 14 20 Measures to prevent harm to self or others 11 16 Ordering or arranging 12 17 Counting 13 18 Hoarding/collecting rituals 8 11 Rituals of cleaning household or inanimate objects 4 6 Note: As multiple obsessions and compulsions are possible, the total thus exceeds 70. Based on Swedo et al. (1989). Table 43.2 Presenting symptoms in 70 consecutive children and adolescents with primary obsessive-compulsive disorder. 9781405145497_4_043.qxd 29/03/2008 02:53 PM Page 702

(Peterson, Pine, Cohen, & Brook, 2001). In prospective analyses, tics in childhood and early adolescence predicted an increase in OCD symptoms in late adolescence and early adulthood, whereas ADHD symptoms in adolescence predicted more OCD symptoms in early adulthood. The clinical course of the disorder indicates some developmental influence on symptoms over time. In a clinic sample, this sensitivity to developmental stage was found firstly in symptom profile, with the presenting obsessions and compulsions changing over time in 90% of the NIMH pediatric patients (Rettew, Swedo, Leonard, Lenane, & Rapoport, 1992). Most children began with a single obsession or compulsion and continued with this for months to years, and then gradually acquired different obsessions or rituals. Although the primary symptom would change (e.g., from counting to washing and then checking), some earlier symptoms often remained problematic, although to a lesser degree. The nature of the compulsive rituals also changed over time. A study of adolescents demonstrated that counting and symmetry were most prominent during grade school years, but were replaced by washing rituals during early and mid adolescence (Maina, Albert, Bogetto, & Ravizza, 1999). The outcome of OCD may also have a similar relationship to developmental stage. In their longitudinal epidemiological study of tics, OCD, and ADHD described above, Peterson and colleagues found in prospective analyses that both younger and older adolescents with OCD were more likely to develop depressive and ADHD symptoms. Early adolescents with OCD, however, were especially likely to develop more anxiety and simple phobias in later adolescence. Epidemiological studies of adults suggest that spontaneous remissions occur in as many as one-third of patients (Karno & Golding, 1990). A recent prospective study of 591 adult subjects assessed patients at six time points between ages 20 and 40 (Angst, Gamma, Endrass et al., 2004). While OCD was chronic in 60% of the cases, there was considerable improvement over time, even in those who continued to meet diagnostic criteria. It is often argued that pediatric cases will have a more chronic course, and a recent meta-analysis of studies based on sixteen independent samples (521 OCD participants) followed for a mean of 11.2 years indicated earlier age of onset to be a poor prognosis factor, along with comorbid psychiatric illness and poor initial treatment response (Stewart, Geller, Jenike et al., 2004). Overall, there was a 41% persistence for full and 60% for full or sub-threshold OCD. However, the pathways determining clinical outcome are complex, and any one single developmental variable, such as age of onset, is likely to account for only a modest amount of the overall variance in final outcome. OCD patients with comorbid tics or Tourette’s have a waxing and waning course (Bloch, Peterson, Scahill et al., 2006). In patients with comorbid Tourette’s and OCD, tics generally start to improve around age 10, while the obsessivecompulsive symptoms typically continue for several more years. PANDAS are also characterized as relapsing/remitting in relation to streptococcal infection (Leonard, Swedo, Garvey et al., 1999). OBSESSIVE-COMPULSIVE DISORDER 703 Associated Disorders Both epidemiological (Karno & Golding, 1991) and clinical (LaSalle, Cromer, Nelson et al., 2004) studies indicate broad and complex comorbidity for OCD similar to that seen for other major Axis I disorders. The patterns of comorbidity among childhood onset cases are generally comparable with those of adult samples, but with tic disorders and specific developmental disorders appearing more frequently in the pediatric population. In the NIMH sample, only 25% of the pediatric subjects had OCD as a single diagnosis (Swedo, Rapoport, Leonard, Lenane, & Cheslow, 1989). Tic disorders (30%), major depression (26%) and specific developmental disabilities (17%) were the most common comorbidities, and there were also high rates of simple phobias (17%), over-anxious disorder (16%), adjustment disorder (11%), attention deficit disorder (10%), conduct disorder (7%), separation anxiety disorder (7%), and enuresis/encopresis (4%). While our own experience with comorbid bipolar disorder is limited, other groups find increased bipolar comorbidity in severely affected pediatric OCD cases (Masi, Perugi, Toni et al., 2004). This broad comorbidity remains to be explained (for this and other disorders) and is not accounted for by any of the etiological models discussed below. An interesting exception to the broad comorbidity is the lack of association between obsessivecompulsive or anankastic personality disorder and OCD in adults, although the rates (or even the definition, in childhood) of this personality disorder are not known in children and adolescents (Albert, Maina, Forner, & Bogetto, 2004; Masi, Perugi, Toni et al., 2004). Case Illustrations Case 1 A 14-year-old boy, whose symptoms had begun gradually, recalls at a very early age having to wash his hands repetitively. He was unable to associate an obsessive thought with this ritual, but he felt compelled to perform it. By age 6, he had developed an obsessive fear of tornadoes. He would repeatedly check the sky for clouds, listen to all weather reports and query his mother about approaching storms. The tornado obsession faded over time and was replaced by a generalized fear of harm coming to himself or his family. He responded with extensive rituals to protect himself and his family. Particularly at times of separating, such as bedtime or leaving for school, the patient would be compelled to repeat actions perfectly or to check repetitively. When asked how many times he would have to repeat an action, he replied, “It depends. The number isn’t always the same, I just have to do it right.” When asked how he knew when it was right, he said, “I don’t know, it just feels right.” As the patient entered puberty, he became obsessed with acquired immunodeficiency syndrome (AIDS) and was convinced he would acquire it through his mouth. He began spitting in an effort to cleanse his mouth and would spit every 15–20 seconds. In addition, he began extensive washing rituals. Despite these cleansing and washing compulsions, his personal appearance 9781405145497_4_043.qxd 29/03/2008 02:53 PM Page 703

was slovenly and dirty. He never tied his shoelaces because they had touched the ground and were “contaminated”; if he tied them, his hands would be “dirty” and he would have to wash until they were “clean” again. Remarkably, although his family was aware that “something had been wrong for a long time,” most of the content of his obsessions was kept secret. This case illustrates the contamination concerns common to adolescents as well as the variety and evolution of obsessivecompulsive symptoms during development. Case 2 A 16-year-old girl had symptoms that began abruptly, shortly after the onset of menses. She called herself “a prisoner of my own mind.” Her obsessions centered around a fear of harm to her parents. She was plagued by recurrent thoughts of her mother dying in a car accident, her father being killed by an intruder, or both her parents dying of burns received in a house fire. Always a light sleeper, she began to get up during the night to check. She spent hours checking that the doors were locked, that the coffee pot was unplugged, and that the family dog was safely ensconced in the garage. Despite her obsessions about fire, however, she did not check the smoke detector, an excellent example of the irrationality of this superficially rational disorder. This patient involved her family in her rituals. Her mother made a checklist that the daughter carried to school, and both parents had to check the twentyfour items on the list, signing that they had done so. At night she would wake her father to help her check. The family involvement was so profound that behavioral treatment could only take place after a period of family counseling in which the parents were helped to separate from their daughter’s illness. The Differential Diagnosis: Distinguishing OCD from Other Disorders The broad comorbidity of OCD and an array of associated features make the diagnosis in theory seem difficult; in practice, however, it is usually more straightforward. The diagnosis of OCD must be made only if the “obsessive worries” are true obsessions, rather than symptoms of another disorder such as depressive ruminations or phobic avoidance. For example, when OCD is comorbid with bulimia or anorexia, the content of the obsessions or compulsions must be typical for OCD, e.g., washing, arranging, counting and repeating, and not be solely over-focused ideas about food or diet. Depressive ruminations and psychotic preoccupations are also distinguished by the negative content (e.g., everyone dislikes me, I fail at everything). Phobic disorders are distinguished not only by the content of the preoccupation (more often heights, spiders, the dark, etc.), but also by the absence of discomfort when the patient is not confronted with the phobic object. It may be more difficult to separate the obsessional concerns of OCD from the fears and worries of generalized anxiety disorder (Brown, Moras, Zinbarg, & Barlow, 1993). Comorbidity of OCD and anxiety disorders is common, so assigning specific symptoms to a specific disorder may be less important than identifying the presence of OCD in a child presenting with generalized anxiety or separation anxiety disorder. Asperger syndrome can be differentiated from OCD by its lack of ego-dystonicity and, in addition, by the content of the preoccupations. For example, in Asperger’s disorder, concerns about danger or contamination occur only rarely, while these are common among children with OCD. Autistic patients also may exhibit obsessive-compulsive symptoms, but these occur within the context of cognitive and psychosocial abnormalities and should not be confused with symptoms of OCD. The differential diagnosis from Tourette’s disorder is problematic, and the relationship between the two disorders remains obscure. Distinguishing between a compulsion and a tic may be difficult, given the presence of premonitory urges before tics and the complexity of some motor tics (Miguel, do RosárioCampos, Prado et al., 2000). Some 20–80% of patients with clear Tourette’s disorder have been reported to have obsessivecompulsive symptoms or OCD, while 24–67% of children with primary OCD have been observed to have comorbid tics (Leonard, Lenane, Swedo et al., 1992; Zohar, Ratzoni, Pauls et al., 1992). Tics are seen often in younger patients, those with acute illness and in males. Preliminary impressions are that compulsions associated with Tourette’s disorder may be more likely to involve symmetry, rubbing, touching, or staring and blinking rituals than washing and cleaning (Baer, 1994; Leckman, Grice, Barr et al., 1994). Additionally, aggressive and/or sexual thoughts or rituals have been reported as more frequent in patients with tics and OCD than in those with OCD alone (Despert, 1955; Masi, Millepiedi, Mucci et al., 2005; Thomsen, 1991). However, although some features distinguish the two disorders, the overlapping clinical profiles and family studies provide partial support for the speculation that some cases of OCD and Tourette’s may be alternative forms of the same disorder. Any Tourette/OCD formulation, however, is likely to be oversimplified, as both tic disorders and OCD may be symptoms of basal ganglia-frontal circuitry dysfunction for which genetic, toxic, traumatic and infectious agents can be etiological. In particular, the working model of PANDAS involves the origin of both the tics and OCD through an autoimmune response to group A beta-hemolytic streptococcus. Theories of Etiology Over the past thirty years, it has become increasingly clear that OCD is not caused solely by psychological factors as had been posited by Kanner when he cited “an ‘overdose’ of parental perfectionism” as the source of obsessional neuroses (Kanner, 1962). Instead, accumulated evidence suggests that OCD is caused by a combination of biological and psychological factors, with both genetic and environmental influence. Biological Factors OCD is remarkable in the consistency of support for a conceptual model which links a disorder characterized by endless, repetitive thoughts and actions with uncontrolled activity of CHAPTER 43 704 9781405145497_4_043.qxd 29/03/2008 02:53 PM Page 704

OBSESSIVE-COMPULSIVE DISORDER 705 parallel, discrete loops within the brain. These loops connect the basal ganglia, prefrontal cortex – particularly the orbitofrontal and anterior cingulate regions – and thalamus, the socalled cortico-striato-thalamocortical (CSTC) loops (Alexander, DeLong, & Strick, 1986; Kopell, Greenberg, & Rezai, 2004; Modell, Mountz, Curtis, & Greden, 1989; Rapoport & Wise, 1988; Saxena, Bota, & Brody, 2001). Several CSTCs have been assumed to be of particular importance in OCD, based on clinical, imaging and lesion studies. The first “direct” pathway is in essence a positive feedback loop that results in the initiation and continuation of thought and action. It is counterbalanced by an “indirect” pathway that acts as a check on the activation of the direct pathway (Fig. 43.1). The direct pathway starts with a glutamatergic signal to the striatum, which in turn sends an inhibitory GABA-ergic signal to the globus pallidus. This results in a disinhibition of the thalamus which is fed forward to the prefrontal cortex, particularly orbitofrontal regions. The indirect pathway differs in that the striatum projects an inhibitory signal to the globus pallidus, which increases inhibition on the thalamus and thus decreases prefrontal cortical activation. While there are multiple neurotransmitters involved in this circuit, including substance P and GABA, there are also serotonergic projections to this component from the dorsal raphe to the ventral striatum. These projections are speculated to be inhibitory. OCD symptoms could arise when an aberrant positive feedback loop develops in the first circuit, which is inadequately modulated by the output from the second circuit. Finally, some have recently argued for the need to incorporate limbic structures to account for the strong anxiety component of OCD. Neuroanatomical Anomalies The implication of abnormal activity in CSTCs is supported by consistent findings of structural and functional anomalies within these circuits in children with OCD. For example, a host of neurological disorders that affect the basal ganglia, including Huntington’s chorea, post-encephalitic Parkinsonism and acquired lesions of the caudate and putamen, have been linked with the development of OCD in adulthood (Chacko, Corbin, & Harper, 2000). The autoimmune sequelae of streptococcal infection, which may target the caudate, have long been recognized in the pathogenesis of Sydenham’s chorea, and may be of particular importance in the etiology of obsessions in a subgroup of children (PANDAS) (Swedo, Leonard, & Rapoport, 2004). All the components of the basal ganglia (caudate, putamen and globus pallidus) have been reported as abnormal in children with OCD – see Table 43.3. Volumetric studies of the caudate are typical for the field in the inconsistency of findings, with reports of increase, decrease and no change in caudate volume in children with OCD (Giedd, Rapoport, Garvey, Perlmutter, & Swedo, 2000; Luxenberg, Swedo, Flament et al., 1988; Rosenberg, Averbach, O’Hearn et al., 1997; Szeszko, MacMillan, McMeniman et al., 2004). The marked variability in findings may reflect not only technical aspects relating to heterogeneity of definitions of regions of interest, but also comorbidities such as tic disorder and Fig. 43.1 The direct and indirect circuitry thought to underlie the pathogenesis of OCD. OFC=orbitofrontal cortex; GPi=globus pallidus pars interna, GPe=globus pallidus pars externa; SNr=substantia nigra pars reticulata. Excitatory links are shown in thick black lines and inhibitory connections in dashed black lines. In the DIRECT pathway the frontal cortex projects to the striatum and then to the GPi/SN complex which provides the main output of the basal ganglia. This in turn projects to the thalamus and finally back to the frontal cortex. The pathway has two excitatory and two inhibitory projections and thus is a net positive feedback loop. This circuit is balanced by the INDIRECT pathway which has a net inhibitory effect. This differs in the projection from the striatum to the GPe and subthalamic nuclei (which also receive direct frontal input) before relaying onto the output station of the basal ganglia. Interactions with the limbic system have been increasingly recognized in view of deficits in emotional processing and the anxiety prominent in OCD. FRONTAL CORTEX Cingulate OFC THALAMUS Medial Dorsal Anterior LIMBIC CIRCUITRY STRIATUM Ventromedial Caudate + + + + + + + + + + − − − + − + GPi + SNR GPe + Subthalamic Nuclei 9781405145497_4_043.qxd 29/03/2008 02:53 PM Page 705

CHAPTER 43 706 the possible contribution of post-infectious inflammatory processes contributing to volume enlargement, as is proposed in PANDAS (Swedo & Grant, 2005). Importantly, some structural changes normalize as symptoms resolve, suggesting that they may be epiphenomenal and do reflect underlying neurobiological vulnerability. Prompted partly by the inconsistent volumetric findings in the basal ganglia, Bartha and colleagues (1998) examined ultrastructural features of the caudate nucleus using magnetic resonance spectroscopy (MRS) in adults with OCD. They reported no gross structural changes in the volume of the caudate but found a reduced amount of N-acteylaspartate (NAA) in the left caudate. The exact physiological function of NAA is unclear, but appears to relate to the regulation of metabolic processes within neurons and may thus reflect subtle neuronal dysfunction within the caudate, not usually detectable by gross anatomic techniques. Turning to the frontal lobes, acquired lesions of the ventromedial and polar frontal cortex have also been linked with the de novo onset of OCD and some of its cardinal symptoms, such as hoarding (Anderson, Damasio, & Damasio, Table 43.3 Anatomic brain MRI studies of OCD in children and adolescents. Basal ganglia Szeszko et al. (2004) Giedd et al. (2000) Luxenberg et al. (1988) Rosenberg et al. (1997) Thalamus Gilbert et al. (2000) Frontal lobes Szeszko et al. (2004) Szeszko et al. (1999) Rosenberg et al. (1998) Rosenberg et al. (1997) Comments Medication naïve. Conflicts with earlier reports from this center of decreased volume in putamen (Rosenberg, Keshavan et al., 1997). Attributed to sample differences Increased volume similar to that reported in Sydenham’s chorea. Included 16 children with tics – also showed similar enlargement Patients were heavily comorbid with tic disorder, which may have contributed independently to the volume reduction Successful treatment with paroxetine in 10 of the subjects was associated with a partial normalization of the volume of the thalamus No reduction noted in the gray matter of the superior frontal gyrus, in line with predictions No reduction in total anterior cingulate cortex as this study did not separately measure gray and white matter Positive correlation between volume of anterior cingulate and obsessive symptoms scores Findings Decreased volume of L globus pallidus: caudate and putamen did not differ Increased volume of caudate, putamen and globus pallidus Decreased volume of caudate bilaterally Decreased volume of caudate and putamen Increased volume of thalamus in OCD Increase in gray matter in left anterior cingulate cortex Reduction in total volume of orbitofrontal cortex Increase of volume in anterior cingulate only (not posterior cingulate/ dorsolateral prefrontal cortex) No difference in volume of gray or white matter in prefrontal lobes Technique Manual tracing of regions of interest Manual tracing of regions of interest Manual tracing of region of interest on CT scans Manual tracing of region of interest Manual tracing of region of interest Separately measured gray and white matter in frontal regions Manual tracing of region of interest Manual tracing of region of interest Measured entire frontal lobes Subjects Childhood study: 23 patients with OCD and 27 controls 18 children with OCD arising in context of streptococcal infection Childhood onset OCD; 10 males with OCD and 10 healthy controls Childhood study: 19 children with OCD and 19 healthy controls Childhood study: 21 children with OCD and 21 matched healthy controls See above Childhood study: 26 children with OCD and 26 matched controls Childhood study: 21 treatment naïve See above 9781405145497_4_043.qxd 29/03/2008 02:53 PM Page 706

2005). In children with OCD, specific reduction in the volume of the orbitofrontal cortex has been reported, a finding congruent with our preliminary reports of a highly localized thinning of the cortex in right orbitofrontal and polar frontal regions in early onset OCD (Shaw & Rapoport, unpublished data; Szeszko, Robinson, Alvir et al., 1999). Expansion of gray matter in the left anterior cingulate cortex in an unmedicated pediatric OCD population, which was not found in other prefrontal regions, was found to be positively correlated with obsessive symptoms scores and has been consistently reported by several groups (Rosenberg & Keshavan, 1998; Szeszko, MacMillan, McMeniman et al., 2004). Positive correlations between expansion of the anterior cingulate and the putamen were also reported, compatible with the postulation of abnormal cingulate-striatal circuitry. Reports of anomalies in the dorsolateral prefrontal cortex are less common, although magnetic resonance spectroscopy has demonstrated anomalies in the level of the putative neuronal marker NAA in the dorsolateral prefrontal cortex of unmediated children with OCD (Russell, Cortese, Lorch et al., 2003). Thalamic hyperactivation, which is fed forward to the frontal cortex, is the final component of the pathophysiological circuit in OCD, and might be predicted to have trophic effects. Indeed, thalamic enlargement which resolves following successful treatment with paroxetine has been reported in pediatric OCD (Gilbert, Moore, Keshavan et al., 2000). This is complemented by reports of abnormal thalamic NAA and choline levels in pediatric OCD (Fitzgerald, Moore, Paulson, Stewart, & Rosenberg, 2000). One interpretation is that the NAA levels reflect neuronal perturbations and the abnormal choline levels reflect anomalous myelination in childhood; both factors could contribute to volume change in the thalamus. Turning to white matter, Rosenberg and colleagues have demonstrated a positive correlation between increased surface area of the corpus callosum and symptoms scores in children with OCD. They also found abnormal signal intensity (which might reflect anomalous myelination) in the portion of the corpus callosum that connects the ventral prefrontal cortex with the striatum (MacMaster, Keshavan, Dick, & Rosenberg, 1999; Rosenberg, Averbach, O’Hearn et al., 1997; Rosenberg, Keshavan, O’Hearn et al., 1997). More recent developments in white matter imaging such as the use of diffusion tensors to assess the integrity and coherence of white matter tracts have been reported in adults only and similarly show anomalies in the region of the anterior cingulate (Russell, Cortese, Lorch et al., 2003). The white matter changes may represent a possible neuroanatomical substrate for aberrant connectivity between these regions. Functional neuroimaging studies also support the frontostriatal model. Both functional MRI (fMRI, measuring change in blood flow) and positron emission tomography (PET, measuring glucose utilization as an index of brain activity) studies have demonstrated symptom-provoked hyperactivation (fMRI) and resting hypermetabolism (PET) in the orbitofrontal cortex, cingulate gyrus and the caudate in patients with OCD (Szeszko, Ardekani, Ashtari et al., 2005). The specificity of these regional anomalies is demonstrated by the partial normalization following effective treatment (Saxena, Brody, Maidment et al., 1999). Functional imaging studies using the OCD symptomprovocation paradigm report additional hyperactivation of many of the same regions, with some recent work suggesting that different components of the fronto-striato-thalamic circuit may mediate the anxiety associated with different symptom clusters (Mataix-Cols, Cullen, Lange et al., 2003; MataixCols, Wooderson, Lawrence et al., 2004; Perani, Colombo, Bressi et al., 1995). Neurochemistry Monoaminergic neurotransmitters which extensively project from the brain stem to regions within the fronto-striatothalamic circuitry may contribute to the pathogenesis of OCD. OCD symptoms are frequently exacerbated by serotonin agonists (such as meta-chlorophenylpiperazine), and the serotonin reuptake inhibitors are the most effective therapeutic agents (Gross-Isseroff, Cohen, Sasson, Voet, & Zohar, 2004). Abnormalities of serotonergic transmission in OCD are suggested by imaging studies of central serotonin receptors using specific ligands, which have demonstrated a reduction in 5-HT synthesis in the ventral prefrontal cortex and caudate in eleven treatment-naïve pediatric subjects, which partially normalized following successful treatment (Simpson, Lombardo, Slifstein et al., 2003). Inconsistent findings on the levels of central serotonin transporter availability may be partly attributable to developmental effects, as an increase in central serotonin transporter availability (indexed by the binding profiles of a ligand thought to bind to the transporter) was reported only for those with child- but not adult-onset OCD (Pogarell, Hamann, Popperl et al., 2003; Simpson, Lombardo, Slifstein et al., 2003; Stengler-Wenzke, Muller, Angermeyer, Sabri, & Hesse, 2004). There are less consistent findings for the dopaminergic system, with mixed results concerning changes in peripheral dopaminergic markers and the provocation of obsessive symptoms by dopamine agonists (Denys, Zohar, & Westenberg, 2004). PET neuroimaging studies, however, have demonstrated higher caudate dopamine transporter densities in tandem with lower concentrations of the dopamine D2 receptor, consistent with receptor down-regulation resulting from higher synaptic concentrations of striatal dopamine in adults with OCD (Denys, van der Wee, Janssen, De Geus, & Westenberg, 2004; van der Wee, Stevens, Hardeman et al., 2004). Glutamate is the major excitatory neurotransmitter in the fronto-striatal circuitry, and magnetic resonance spectroscopy has demonstrated elevation in levels of glutamate and glutamine in the thalamus of treatment-naïve children with OCD, with a reduction in symptoms occurring in tandem with normalization of the glutamatergic marker (Rosenberg, MacMaster, Keshavan et al., 2000). A decrease in glutamate levels in the anterior cingulate has also been found, although this may not be specific to OCD as it was also seen in children with major depression (Rosenberg, Mirza, Russell et al., 2004). There is, thus, some direct support for anomalous serotonergic neurotransmission and more indirect and somewhat OBSESSIVE-COMPULSIVE DISORDER 707 9781405145497_4_043.qxd 29/03/2008 02:53 PM Page 707

inconsistent evidence of abnormal dopaminergic and glutamatergic signaling. Neuroendocrinology Several lines of evidence suggest that endocrine perturbations may play an etiological role in OCD. Obsessive symptoms frequently worsen around the time of menses and during the post-partum period, and there are case reports of improvement with anti-androgen therapy (Brandes, Soares, & Cohen, 2004; Casas, Alvarez, Duro et al., 1986; Rasmussen & Eisen, 1992). The finding of short stature in children with OCD (Hamburger, Swedo, Whitaker, Davies, & Rapoport, 1989) implicates the growth hormone (GH) axis and is supported by evidence of a lower bone age in OCD (Katz, Gothelf, Hermesh et al., 1998). However, assaying the growth hormone axis using a clonidine challenge (which acts at the alpha 2 adrenergic receptor to cause GH release) found an enhanced GH response in children with OCD and comorbid anxiety, suggesting an intact growth axis (Sallee, Richman, Sethuraman et al., 1998). Additionally, the only direct study of growth hormone in OCD found no difference from healthy controls in baseline levels, but did find reduced sensitivity for the OCD group following stimulation of growth hormone with growth hormone releasing hormone (Brambilla, Bellodi, Perna, Arancio, & Bertani, 1998). Neuropsychological Models Failure to resist obsessions and compulsions has been conceptualized as a failure of cognitive control in childhood OCD (Chamberlain, Blackwell, Fineberg, Robbins, & Sahakian, 2005). Deficits in suppressing prepotent motor responses in children with OCD have been reported, which in turn have been linked to reduced amplitude of evoked potentials in the orbitofrontal cortex (Malloy, 1987). Similarly, children with OCD have deficits in suppressing oculomotor reflexive responses to external cues, suggesting compromise in prefrontal cortical circuitry (Rosenberg, Dick, O’Hearn, & Sweeney, 1997). Using a probe designed to assess cognitive control (requiring the monitoring of repeated or conflicting information), anomalous activation in the anterior cingulate was found in a group of young adult OCD subjects, with much more extensive anomalous activation of posterior brain regions in those subjects who reported little resistance to their obsessions (Viard, Flament, Artiges et al., 2005). Similarly, deficits in the inhibition of irrelevant information have been demonstrated using variants of the Stroop task (Nakao, Nakagawa, Yoshiura et al., 2005). A related model of OCD views the disorder as the result of over-activation of a system designed to monitor performance completion, leading to a constant feeling that an action is “not just right”, which thus creates a need to correct perceived mistakes. A range of tasks assessing aspects of performance monitoring, error detection and response to conflicts have converged to show hyperactivity in the anterior cingulate in patients with OCD (Fitzgerald, Welsh, Gehring et al., 2005; Maltby, Tolin, Worhunsky, O’Keefe, & Kiehl, 2005; Ursu, Stenger, Shear, Jones, & Carter, 2003; van Veen & Carter, 2002). Other fMRI studies have delineated aberrant processing of affectively charged material in OCD, by both the amygdala (for frightening stimuli) and the insula (for disgust) in OCD (Cannistraro, Wright, Wedig et al., 2004; Shapira, Liu, He et al., 2003; van den Heuvel, Veltman, Groenewegen et al., 2004). These data provide the basis for the incorporation of the rich structural and functional interactions between these components of the limbic system with the fronto-striato-thalamic loops in current models of OCD (for such a model see Figure 43.1). A wide range of deficits on standard neuropsychological tasks has been reported, particularly in visuospatial ability and non-verbal memory (reviewed in Kuelz, Hohagen, & Voderholzer, 2004). Some of these deficits can be related to dysfunction in frontostriatal circuitry. For example, implicit learning (knowledge acquired through repetition or exposure and expressed without conscious reference to the learning experience) is thought to rely on the striatum, in contrast to explicit learning (learning with conscious coding and retrieval), which relies on fronto-temporal cortical integrity. Subjects with OCD show normal implicit learning, but unlike healthy controls do not recruit the striatum during this learning, but rather show possible compensatory activation of the medial temporal lobes (Rauch, Whalen, Curran et al., 2001). Planning abilities have been inconsistently reported as impaired in OCD (Chamberlain, Blackwell, Fineberg, Robbins, & Sahakian, 2005; Veale, Sahakian, Owen, & Marks, 1996) and, in one functional imaging study, such dysfunction was accompanied by abnormal activation of the dorsal prefrontal cortex and caudate in patients with OCD (van den Heuvel, Veltman, Groenewegen et al., 2005). However, many of these neuropsychological deficits are not specific to OCD, their causal relationship with the symptoms of OCD is unclear, and the deficits are more consistently reported in adults rather than children with OCD (Douglass, Moffitt, Dar, McGee, & Silva, 1995; Thomsen & Jensen, 1991). Behavioral formulations of compulsions have formed the mainstay of psychological treatments and view compulsive behaviors as a form of avoidance that maintains obsessive fears through reducing anxiety (negative reinforcement) and by blocking opportunities for habituation to feared situations. Cognitive psychologists emphasize elements such as the interaction of intrusive thoughts with dysfunctional underlying assumptions (e.g., having an over-inflated sense of personal responsibility) in maintaining symptoms (for a review, see Salkovskis, Shafran, Rachman, & Freeston, 1999). How specific is this neural substrate to OCD? Similar anomalous interaction between the striatum and prefrontal cortex is also held to be important in ADHD (see Castellanos & Tannock, 2002; see also chapter 33). Additionally, the neural circuitry underpinning several anxiety disorders, particularly social phobia and post-traumatic stress disorder, includes the limbic regions implicated in more recent refinements of models of OCD (Shin, Wright, Cannistraro et al., 2005; Stein, 2002). Some degree of overlap is perhaps inevitable, CHAPTER 43 708 9781405145497_4_043.qxd 29/03/2008 02:53 PM Page 708

OBSESSIVE-COMPULSIVE DISORDER 709 but there are several unique features in the OCD model outlined above, most importantly, the emphasis on an imbalance of the direct and indirect pathways in OCD and the prominence given to glutaminergic neurotransmission. The overlap between the neural substrates for OCD and the spectrum disorders is harder to disentangle, as only a few studies have attempted a direct comparison of the neural circuitry. For example, specific attentional biases to specific OCDrelated stimuli, underpinned by anomalous fronto-striatal activation, were found in an fMRI study of adults with OCD, which was distinct from a more pervasive attentional bias to all affectively arousing material found in patients with panic disorder and hypochondriasis (van den Heuvel, Veltman, Groenewegen, Witter et al., 2005). Genetics There is now little doubt that OCD is a highly heritable neuropsychiatric disorder. Twin studies show a much higher concordance rate in monozygotic (~80 –90%) over dizygotic twins (~50%), and family studies report an increased prevalence of 7–15% in first-degree relatives of children with OCD (reviewed in Grados, Walkup, & Walford, 2003). In a study of over 4,000 child twin pairs, Hudziak and colleagues used structural equation modeling (see chapter 9) to estimate that genetic (~50%) and unique environmental (~50%) factors both equally influence parental ratings of obsessive and compulsive symptoms in children (Hudziak, Van Beijsterveldt, Althoff et al., 2004). Most studies have focused on the heritability of the DSM-IV diagnosis of the disorder. Others, however, have looked at other aspects of the OCD endophenotype which may be more meaningful for genetic studies, such as symptom dimensions, or have tried to fractionate the disorder into subcategories (e.g., by age of onset or by association with common comorbidities). Candidate gene studies have examined the monoaminergic and glutamatergic neurotransmitters in OCD, and more recently there has been interest in the trophic factors which regulate brain development. One of the most promising genes lies on the small arm of chromosome 9 (9p24), a region which has been linked with OCD in two independent genomewide scans on different families with multiply-affected individuals (Hanna, Veenstra-VanderWeele, Cox et al., 2002; Willour, Yao Shugart, Samuels et al., 2004). This region contains the gene SLC1A1 which codes for the neural glutamate transporter excitatory amino acid carrier 1. While one initial study failed to show biased transmission in a family-based associated analysis of two single nucleotide polymorphisms (VeenstraVanderWeele, Kim, Gonen et al., 2001), two more recent comprehensive and independent analyses, including more polymorphisms within the gene, found a positive association between the gene and OCD in males (Arnold, Sicard, Burroughs, Richter, & Kennedy, 2006; Dickel, Veenstra-VanderWeele, Cox et al., 2006). The functional significance of these findings is unclear, but SLC1A1 is a strong candidate for OCD given the evidence for altered glutamate neurotransmission in the disorder. Most of the remaining genetic findings are more typical for the field, with few being replicated and even fewer polymorphisms having been shown to have clear functional effects that can be linked plausibly to the pathogenesis of the disorder. Association studies of functional variants of a promter region variant in the serotonergic transporter (l and s variants of the SLC6A4 gene on chromosome 17) (Bengel, Greenberg, CoraLocatelli et al., 1999; Billett, Richter, King et al., 1997) and one receptor gene (5-HT1Dß) have given inconsistent evidence for linkage with OCD (Di Bella, Cavallini, & Bellodi, 2002; Mundo, Richter, Zai et al., 2002). Polymorphisms of genes encoding the monoaminergic system enzymes, monoamine oxidase A, and catechol-O-methyl-transferase (COMT) have also been linked to OCD, particularly in males (Karayiorgou, Sobin, Blundell et al., 1999). Moves to examine associations between risk genes and specific symptom dimensions have proved promising, with reports of links between the serotonin transporter polymorphisms and clusters of religious and somatic concerns (Camarena, Aguilar, Loyzaga, & Nicolini, 2004; Kim, Lee, & Kim, 2005) and between polymorphisms of COMT and compulsive hoarding (Lochner, Kinnear, Hemmings et al., 2005). Association with the dopaminergic DRD4 receptor gene emerges, particularly when probands who have comorbid tic disorder are studied, demonstrating the promise of phenotypic definitions which may cut across traditional diagnostic boundaries (Cruz, Camarena, King et al., 1997; Millet, Chabane, Delorme et al., 2003). Within the glutamatergic neurotransmitter system, positive associations have been reported for N-methyl d-aspartate (NMDA) receptors (GRIN2B) and for GRIK2 (a kainate receptor) recently also associated with autism (Arnold, Rosenberg, Mundo et al., 2004; Delorme, Krebs, Chabane et al., 2004). As some cases of pediatric OCD may represent an impaired immune response to streptococcal infection, the association between alleles of the myelin oligodendrocyte glycoprotein (MOG) gene, which plays an important role in mediating the complement cascade in the immune response, and OCD is of interest (Zai, Bezchlibnyk, Richter et al., 2004). Neurodevelopmental models of OCD emphasize anomalies of the neurotrophic factors which regulate cell survival, differentiation and death, particularly in early development. Animal models show that deficiencies of brain-derived neurotrophic factor (BDNF) in early development lead to a loss of serotonergic transmission in adulthood. Interestingly, different sequence variants of this gene in humans are associated with not only the risk for OCD, but also its age of onset (Hall, Dhilla, Charalambous, Gogos, & Karayiorgou, 2003). Treatment Approaches Psychological Treatment The cornerstone of psychological therapies for children is exposure and response prevention (ERP), and its efficacy has been demonstrated in multiple open studies and two randomized controlled trials (Barrett, Healy-Farrell, & March, 2004; POTS, 2004). A hierarchy of increasingly intense anxiety-provoking 9781405145497_4_043.qxd 29/03/2008 02:53 PM Page 709

situations that trigger obsessional thinking is constructed, and subjects are exposed gradually to these situations and encouraged to refrain from engaging in compulsive behaviors (March & Mulle, 1998). Gradually, the patient progresses through the hierarchy so that situations can be tolerated with minimal anxiety, thus attaining an ever-decreasing urge to engage in compulsions. In clinical practice, and in all controlled studies, ERP is usually combined with other behavioral techniques, such as anxiety management training and extinction (e.g., instructing parents not to give reassurance when a child compulsively seeks it). This makes it difficult to disentangle the relative therapeutic importance of each element. Frequently, cognitive components are added, such as normalizing intrusive thoughts and reappraising notions of personal responsibility. Again, the necessity of these cognitive components is unclear in children as there are no controlled trials comparing these approaches. Tailoring therapy to the symptom profile of the child may be helpful. For example, ERP may be ideal for younger children as it has been shown to be effective in those under 11 and may be particularly helpful for symptoms such as contamination fears and symmetry rituals (Barrett, Healy, & March, 2003). By contrast, cognitive approaches may be more suited to the child with obsessional moral guilt or pathological doubt. The involvement of the family in treatment is essential. Psycho-education can help the family to avoid both punitive responses and the alternative “enabling” that can occur if the family becomes enmeshed in rituals. A randomized controlled study demonstrated that such family-based cognitive behavioral therapy may be equally efficacious when conducted either with individual families or in a group setting (Barrett, HealyFarrell, & March, 2004). While the efficacy of behavior therapy (BT) with ERP as a core component is accepted, the most efficient and efficacious method of providing this treatment is less clear. At one extreme lies computer-based delivery systems with minimal therapist contact time (Kenwright, Marks, Graham, Franses, & MataixCols, 2005); at the other extreme are highly intensive day or in-patient treatment programs. Only one trial has directly compared once weekly with daily therapy; no significant differences in outcome were found, although this study was not randomized and thus limited conclusions can be drawn (Franklin, Kozak, Cashman et al., 1998). A meta-analysis suggested that while more therapist-intensive approaches were more efficacious, even those involving relatively little therapist contact time (less than 10 hours) were also effective (NICE, 2005). In practice, the severity of the symptom profile, the complexity of comorbidity, and resources available within the family and local health care services are likely to determine the treatment intensity. Many countries also have self-help groups which provide a valuable source of support and information, as well as act as advocates for those living with the disorder. Pharmacotherapy There is a relative abundance of randomized controlled trials demonstrating the efficacy of clomipramine and of selective serotonin re-uptake inhibitors – SSRIs (sertraline, fluoxetine, paroxetine and fluvoxamine) in the acute phase treatment of childhood OCD, reviewed in Table 43.4. A meta-analysis of 12 studies of SSRIs and clomipramine (an SRI) found all medications to be superior to placebo and found that clomipramine showed superiority over all the SSRIs, which did not differ from one another (Geller, Biederman, Stewart et al., 2003). However, clomipramine is associated with several adverse side effects, including potential arrhythmogenic effects. Although generally well tolerated, SSRIs are associated with a range of side effects, with nausea, headache and agitation being common to all in this class. Of greatest concern are reports of increased suicidal ideation and behavior, which have led to recommendations that treatment should be closely monitored with regular follow-up, perhaps ideally in conjunction with BT. As a result of these concerns, the pharmacological options have become limited in several countries. Depression is highly comorbid with OCD, and the treatment of this combination is often challenging. Two studies have found that adding imipramine (Foa, Kozak, Steketee, & McCarthy, 1992) or SSRIs (Abramowitz, Franklin, Street, Kozak, & Foa, 2000) either before or during ERP may be effective for alleviating depressive symptoms but did not potentiate ERP. There are case reports supporting the use of cognitive therapeutic techniques to increase motivation and compliance in the depressed patient to help them engage with difficult exposure assignments (Abramowitz, 2004). In children, low initial doses with slow upward titration is the rule. Patients should be made aware of the common side effects and the need for a 12-week treatment trial. Partial or complete failure to respond to the first SSRI should prompt treatment with BT and consideration of another SSRI. The use of augmenting agents for youths with treatment-resistant OCD is discussed below. Combination Treatment How do pharmacological and psychological treatments compare? The best current evidence comes from the Pediatric OCD Treatment (POTS) multi-center study, which randomized 112 children to either sertraline, cognitive behavioral therapy (CBT), the treatments combined or pill placebo for 12 weeks (POTS, 2004). All active treatments were superior to pill placebo. Combined treatment also proved superior to CBT alone and to sertraline alone, which did not differ from each other. Site differences emerged for CBT and sertraline but not for combined treatment, suggesting that combined treatment is less susceptible to setting-specific variations, and, given this generalizability, combined treatment may be the option of choice. Notably, there was no evidence of treatment-emergent suicidality. Much smaller studies similarly found that a combination of behavior therapy (based on ERP) and fluvoxamine was superior to medication alone, both in short-term response and at a follow-up period of one year (Neziroglu, Yaryura-Tobias, Walz, & McKay, 2000). A direct comparison of behavior therapy with clomipramine in 22 children found a non-significant superiority for psychotherapy (de Haan, CHAPTER 43 710 9781405145497_4_043.qxd 29/03/2008 02:53 PM Page 710

OBSESSIVE-COMPULSIVE DISORDER 711 Hoogduin, Buitelaar, & Keijsers, 1998). Overall, it is clear that while medication alone is effective and generally safe and well tolerated, CBT may have the edge in terms of a firstline treatment, particularly when combined with an SSRI or clomipramine. Augmenting Strategies for Partial Responders Up to 50% of children will show only a partial response to initial SSRI treatment (Geller, Biederman, Jones et al., 1998). For adults showing such sub-optimal response to an SSRI, several trials have shown a significant reduction of obsessive Table 43.4 Controlled studies of medication in the treatment of pediatric OCD. Study Clomipramine DeVeaugh-Geiss et al. (1992) Greist et al. (1990) Flament et al. (1985) Leonard et al. (1989) SSRIs POTS (2004) March et al. (1998) Geller et al. (2001) Liebowitz et al. (2002) Riddle et al. (1992) Geller et al. (2004) Riddle et al. (2001) Design RCT, 8 weeks RCT, 8 weeks Cross-over, 5 weeks in each treatment Cross-over, 5 weeks in each treatment (double bind) and 2 weeks on placebo (single bind) RCT, DB 12 weeks RCT, DB 10 weeks RCT, DB 13 weeks RCT, DB 12 weeks Cross-over DB 16 weeks RCT, BD 10 weeks RCT, DB 10 weeks followed by 1 year open label extension Participants N=60, mean age=14 N=32, mean age=15 N=27, mean age=14 N=49, mean age=14 N=112, mean age =12 N=189, mean age=13 N=103, mean age=11.4 N=43, mean age=13 N=14, mean age=12 N=207, mean age=11 N=120, mean age=13 Interventions Clomipramine vs placebo Clomipramine vs placebo Clomipramine vs placebo Clomipramine vs desipramine vs placebo CBT vs CBT+sertraline vs sertraline Sertraline vs placebo Fluoxetine vs placebo Fluoxetine vs placebo Fluoxetine vs placebo Paroxetine vs placebo Fluvoxamine vs placebo Outcomes Mean reduction in Children’s Yale-Brown Obsessive Compulsive Scale (CY-Bocs) score of 37% compared to 8% in the placebo group. Sustained at 1 year Of 15 patients who received at least 3wks of CMI, 11 (73%) improved, 5 (33%) improved by more than 50%, and none worsened. Only 2 (12.5%) of the 16 placebo-treated patients improved, 1 (6%) by more than 50%; two (12.5%) worsened Clomipramine significantly more effective than placebo in reduction on all symptom scores Clomipramine significantly more effective than desipramine in symptom reduction. Higher rate of relapse when desipramine was substituted for clomipramine Combined treatment proved superior to CBT alone and to sertraline alone, which did not differ from each other. CBT alone was associated with (non-significantly) higher rates of remission than sertraline Sertraline produced significantly greater improvement in CY-BOCS. Based on CGI-I ratings at end point, 42% of patients receiving sertraline and 26% of patients receiving placebo were very much or much improved. Neither age nor sex predicted response to treatment Fluoxetine produced significantly greater improvement in CY-BOCS (fall of 9.5 points compared to 5.2 for placebo) No significant difference at 8 weeks; but by 16 weeks, fluoxetine was associated with greater reduction in CY-BOCS (9.74 points) than was placebo (4.14 points) CY-BOCS total score decreased 44% (N = 7, p = 0.003) after the initial 8 weeks of fluoxetine treatment, compared with a 27% decrease (N = 6, p = 0.13) after placebo Paroxetine produced significantly greater improvement in CY-BOCS (fall of 8.78 points compared to 5.34 points in placebo group) The CY-BOCS total score decreased 44% after the initial 8 weeks of fluoxetine treatment, compared with a 27% decrease after placebo 9781405145497_4_043.qxd 29/03/2008 02:53 PM Page 711

symptoms in patients with either adjunctive haloperidol or risperidone (Li, May, Tolbert et al., 2005; McDougle, Epperson, Pelton, Wasylink, & Price, 2000). Other treatment strategies in adults include augmentation with clonazepam or oral morphine or combining two SSRIs (for a review see Walsh & McDougle, 2004). There are some case reports demonstrating the potential for the use of each of these strategies in children, although there are no controlled studies to guide the clinician in this complex field (Figueroa, Rosenberg, Birmaher, & Keshavan, 1998; Leonard, Topol, Bukstein et al., 1994; Lombroso, Scahill, King et al., 1995). Clearly, the side effects of each augmenting agent need to be considered, particularly the risk of tardive dyskinesia with haloperidol, metabolic side effects of risperidone, and risk of tolerance and dependence with clonazepam. In spite of the major advances in drug treatment, at least 10% of the OCD population remains severely affected. In adults, for extreme cases there is an option for neurosurgical procedures, which are aimed at disrupting the CSTC loops either through creating a permanent lesion through excision or through repetitive deep brain stimulation (Greenberg, Price, Rauch et al., 2003). Such physical therapies are not appropriate for children, and less invasive alternatives such as transcranial magnetic stimulation, while giving insight into the abnormal responsivity of the motor cortex in OCD (Gilbert, Bansal, Sethuraman et al., 2004; Greenberg, Murphy, & Swedo, 1998) have not proved effective in the treatment of adults and remain untested in children (Martin, Barbanoj, Perez, & Sacristan, 2003). Maintenance treatment OCD is frequently a chronic disorder and long-term maintenance therapy should be anticipated, with the current recommendation being a minimum treatment period of six months following full remission. The need for such maintenance was illustrated by an 8-month study of 26 children and adolescents with severe OCD who had received clomipramine for a mean of 17 months; a 2-month double-blind desipramine-substitution phase resulted in 89% of the substituted (versus 18% of the non-substituted) subjects relapsing during the substitution phase (Leonard, Swedo, Lenane et al., 1991). Immunomodulatory treatments Based on the observation that some childhood-onset OCD patients had onset apparently related to infection with group A beta-hemolytic streptococcus (GABHS), a subgroup of children were proposed who were hypothesized to have an autoimmune based form of the disorder – PANDAS (Swedo, Leonard, & Rapoport, 2004). As a partial test of this model, two treatments were examined. A controlled treatment trial of intravenous immunoglobulin was carried out, together with an open trial of plasmaphoresis (Perlmutter, Leitman, Garvey et al., 1999). Both treatments were effective in lessening of symptom severity for children with infection-triggered OCD and tic disorders. Penicillin or arithromycin prophylaxis of sufficient intensity to decrease streptococcal infections was also found to decrease neuropsychiatric symptom exacerbations among children in the PANDAS subgroup (Snider, Lougee, Slattery, Grant, & Swedo, 2005). This study is limited by the absence of a placebo control, particularly as a previous placebo-controlled trial using penicillin prophylaxis was negative (Garvey, Perlmutter, Allen et al., 1999). These fascinating findings have yet to be replicated but raise the possibility of the prevention of OCD in at least a subset of children with the disorder. Conclusions Public awareness of OCD has increased greatly over recent years, allowing this once “secret” disorder to be more readily recognized by both families and mental health professionals. Functional neuroimaging studies increasingly inform and refine models of the pathogenesis of the disorder, and are being matched by neuroanatomical imaging studies which allow a delineation of structural change at an ever-increasing level of resolution. Whereas candidate gene studies have provided some validation of the implication of monoaminergic anomalies in the disorder, the application of new technologies to scan the entire genome is likely to provide novel insights into the genetics of OCD. Of most practical importance, though, are the strengthening of the evidence base for treatment through recent large-scale double-blind trials and the renewed interest in the management of those with treatment-resistant symptoms. The strides in understanding the neurobiology of the disorder are thus matched by definitive demonstrations of treatment efficacy in children, and make it all the more important that children, parents and health care professionals remain aware of the disorder and the availability of effective help. References Abramowitz, J. S. (2004). Treatment of obsessive-compulsive disorder in patients who have comorbid major depression. Journal of Clinical Psychology, 60, 1133–1141. Abramowitz, J. S., Franklin, M. E., Street, G. P., Kozak, M. J., & Foa, E. B. (2000). Effects of comorbid depression on response to treatment for obsessive-compulsive disorder. Behavior Therapy, 31, 517–528. Albert, U., Maina, G., Forner, F., & Bogetto, F. (2004). DSM-IV obsessive-compulsive personality disorder: prevalence in patients with anxiety disorders and in healthy comparison subjects. Comprehensive Psychiatry, 45, 325–332. Alexander, G., DeLong, M., & Strick, P. (1986). Parallel organization of functionally segregated circuits linking basal ganglia and cortex. Annual Review of Neuroscience, 9, 357–381. Anderson, S. W., Damasio, H., & Damasio, A. R. (2005). A neural basis for collecting behaviour in humans. Brain, 128, 201–212. Andrews, G., Slade, T., & Peters, J. L. (1999). Classification in psychiatry: ICD-10 versus DSM-IV. British Journal of Psychiatry, 174, 3–5. Angst, J., Gamma, A., Endrass, J., Goodwin, R., Ajdacic, V., Eich, D., et al. (2004). Obsessive-compulsive severity spectrum in the community: prevalence, comorbidity, and course. European Archives of Psychiatry & Clinical Neuroscience, 254, 156–164. American Psychiatric Association. (2000). Diagnostic and Statistical Manual of Mental Disorders (4th ed.). Text Revision. Washington DC: American Psychiatric Press. CHAPTER 43 712 9781405145497_4_043.qxd 29/03/2008 02:53 PM Page 712

Apter, A., Fallon, T. J., Jr., King, R. A., Ratzoni, G., Zohar, A. H., Binder, M., et al. (1996). Obsessive-compulsive characteristics: from symptoms to syndrome. Journal of the American Academy of Child & Adolescent Psychiatry, 35, 907–912. Arnold, P. D., Rosenberg, D. R., Mundo, E., Tharmalingam, S., Kennedy, J. L., & Richter, M. A. (2004). Association of a glutamate (NMDA) subunit receptor gene (GRIN2B) with obsessive-compulsive disorder: a preliminary study. Psychopharmacology, 174, 530–538. Arnold, P. D., Sicard, T., Burroughs, E., Richter, M. A., & Kennedy, J. L. (2006). Glutamate transporter gene SLC1A1 associated with obsessive-compulsive disorder. Archives of General Psychiatry, 63, 769–776. Baer, L. (1994). Factor analysis of symptom subtypes of obsessive compulsive disorder and their relation to personality and tic disorders. Journal of Clinical Psychiatry, 55, 18–23. Barrett, P., Healy-Farrell, L., & March, J. S. (2004). Cognitivebehavioral family treatment of childhood obsessive-compulsive disorder: a controlled trial. Journal of the American Academy of Child & Adolescent Psychiatry, 43, 46–62. Barrett, P., Healy, L., & March, J. S. (2003). Behavioral avoidance test for childhood obsessive-compulsive disorder: a home-based observation. American Journal of Psychotherapy, 57, 80–100. Bartha, R., Stein, M. B., Williamson, P. C., Drost, D. J., Neufeld, R. W. J., Carr, T. J., et al. (1998). A short echo 1H spectroscopy and volumetric MRI study of the corpus striatum in patients with obsessive-compulsive disorder and comparison subjects. American Journal of Psychiatry, 155, 1584–1591. Bartz, J. A., & Hollander, E. (2006). Is obsessive-compulsive disorder an anxiety disorder? Progress in Neuro-Psychopharmacology & Biological Psychiatry, 30, 338–352. Bengel, D., Greenberg, B. D., Cora-Locatelli, G., Altemus, M., Heils, A., Li, Q., et al. (1999). Association of the serotonin transporter promoter regulatory region polymorphism and obsessive-compulsive disorder. Molecular Psychiatry, 4, 463–466. Berg, C. Z., Rapoport, J. L., Whitaker, A., Davies, M., Leonard, H., Swedo, S. E., et al. (1989). Childhood obsessive compulsive disorder: a two-year prospective follow-up of a community sample. Journal of the American Academy of Child & Adolescent Psychiatry, 28, 528–533. Berrios, G. E. (1989). Obsessive-compulsive disorder: its conceptual history in France during the 19th century. Comprehensive Psychiatry, 30, 283–295. Bienvenu, O. J., Samuels, J. F., Riddle, M. A., Hoehn-Saric, R., Liang, K. Y., Cullen, B. A., et al. (2000). The relationship of obsessive-compulsive disorder to possible spectrum disorders: results from a family study. Biological Psychiatry, 48, 287–293. Billett, E. A., Richter, M. A., King, N., Heils, A., Lesch, K. P., & Kennedy, J. L. (1997). Obsessive compulsive disorder, response to serotonin reuptake inhibitors and the serotonin transporter gene. Molecular Psychiatry, 2, 403–406. Black, A. (1974). The natural history of obsessional neurosis. In H. Beech (Ed.), Obsessional States (pp. 19–54). London: Methuen. Bloch, M., Peterson, B. S., Scahill, L., Otka, J., Katsovich, L., Zhang, H., et al. (2006). Adult outcome of tic and obsessive-compulsive severity in children with Tourette syndrome. Archives of Pedatric and Adolescent Medicine, 160, 65–69. Brambilla, F., Bellodi, L., Perna, G., Arancio, C., & Bertani, A. (1998). Growth hormone response to growth hormone-releasing hormone stimulation in obsessive-compulsive disorder. Psychiatry Research, 81, 293–299. Brandes, M., Soares, C. N., & Cohen, L. S. (2004). Postpartum onset obsessive-compulsive disorder: diagnosis and management. Archives of Women’s Mental Health, 7, 99–110. Breslau, N. (1987). Inquiring about the bizarre: false positives in Diagnostic Interview Schedule for Children (DISC) ascertainment of obsessions, compulsions, and psychotic symptoms. Journal of the American Academy of Child & Adolescent Psychiatry, 26, 639–644. Brown, T. A., Moras, K., Zinbarg, R., & Barlow, D. (1993). Diagnostic and symptom distinguishability of genralized anxiety disorder and obsessive-compulsive disorder. Behavior Therapy, 24, 227–240. Byerly, M., Goodman, W., Acholonu, W., Bugno, R., & Rush, A. J. (2005). Obsessive compulsive symptoms in schizophrenia: frequency and clinical features. Schizophrenia Research, 76, 309–316. Camarena, B., Aguilar, A., Loyzaga, C., & Nicolini, H. (2004). A family-based association study of the 5-HT–1D beta receptor gene in obsessive-compulsive disorder. International Journal of Neuropsychopharmacology, 7, 49–53. Cannistraro, P. A., Wright, C. I., Wedig, M. M., Martis, B., Shin, L. M., Wilhelm, S., et al. (2004). Amygdala responses to human faces in obsessive-compulsive disorder. Biological Psychiatry, 56, 916–920. Casas, M., Alvarez, E., Duro, P., Garcia-Ribera, C., Udina, C., Velat, A., et al. (1986). Antiandrogenic treatment of obsessive-compulsive neurosis. Acta Psychiatrica Scandinavica, 73, 221–222. Castellanos, F. X., & Tannock, R. (2002). Neuroscience of attentiondeficit/hyperactivity disorder: the search for endophenotypes. Nature Reviews. Neuroscience, 3, 617–628. Chabane, N., Delorme, R., Millet, B., Moureau, M., Leboyer, M., & Pauls, D. (2004). Early-onset obsessive-compulsive disorder: a subgroup with a specific clinical and familial pattern? Journal of Child Psychology and Psychiatry, 46, 881–887. Chacko, R. C., Corbin, M. A., & Harper, R. G. (2000). Acquired obsessive-compulsive disorder associated with basal ganglia lesions. Journal of Neuropsychiatry & Clinical Neurosciences, 12, 269–272. Chamberlain, S. R., Blackwell, A. D., Fineberg, N. A., Robbins, T. W., & Sahakian, B. J. (2005). The neuropsychology of obsessive compulsive disorder: the importance of failures in cognitive and behavioural inhibition as candidate endophenotypic markers. Neuroscience & Biobehavioral Reviews, 29, 399–419. Christenson, G. A., Mackenzie, T. B., Mitchell, J. E., & Callies, A. L. (1991). A placebo-controlled, double-blind crossover study of fluoxetine in trichotillomania. American Journal of Psychiatry, 148, 1566–1571. Crespo-Facorro, B., Cabranes, J. A., Lopez-Ibor Alcocer, M. I., Paya, B., Fernandez Perez, C., Encinas, M., et al. (1999). Regional cerebral blood flow in obsessive-compulsive patients with and without a chronic tic disorder. A SPECT study. European Archives of Psychiatry & Clinical Neuroscience, 249, 156–161. Crino, R., Slade, T., & Andrews, G. (2005). The changing prevalence and severity of obsessive-compulsive disorder criteria from DSM-III to DSM-IV. American Journal of Psychiatry, 162, 876–882. Cruz, C., Camarena, B., King, N., Paez, F., Sidenberg, D., de la Fuente, J. R., et al. (1997). Increased prevalence of the seven-repeat variant of the dopamine D4 receptor gene in patients with obsessivecompulsive disorder with tics. Neuroscience Letters, 231, 1–4. de Haan, E., Hoogduin, K. A., Buitelaar, J. K., & Keijsers, G. P. (1998). Behavior therapy versus clomipramine for the treatment of obsessivecompulsive disorder in children and adolescents. Journal of the American Academy of Child & Adolescent Psychiatry, 37, 1022– 1029. Delorme, R., Krebs, M. O., Chabane, N., Roy, I., Millet, B., MourenSimeoni, M. C., et al. (2004). Frequency and transmission of glutamate receptors GRIK2 and GRIK3 polymorphisms in patients with obsessive compulsive disorder. Neuroreport, 15, 699–702. Denys, D., van der Wee, N., Janssen, J., De Geus, F., & Westenberg, H. G. (2004). Low level of dopaminergic D2 receptor binding in obsessive-compulsive disorder. Biological Psychiatry, 55, 1041–1045. Denys, D., Zohar, J., & Westenberg, H. G. (2004). The role of dopamine in obsessive-compulsive disorder: preclinical and clinical evidence. Journal of Clinical Psychiatry, 65, 11–17. Despert, J. L. (1955). Differential diagnosis between obsessivecompulsive neurosis and schizophrenia in children. In P. H. Hoch & J. Zubin (Eds.), Psychopathology of Childhood (pp. 240–253). New York: Grune and Stratton. OBSESSIVE-COMPULSIVE DISORDER 713 9781405145497_4_043.qxd 29/03/2008 02:53 PM Page 713

DeVeaugh-Geiss, J., Moroz, G., Biederman, J., Cantwell, D., Fontaine, R., Greist, J. H., et al. (1992). Clomipramine hydrochloride in childhood and adolescent obsessive-compulsive disorder – a multicenter trial. Journal of the American Academy of Child & Adolescent Psychiatry, 31, 45–49. Di Bella, D., Cavallini, M. C., & Bellodi, L. (2002). No association between obsessive-compulsive disorder and the 5-HT(1Dbeta) receptor gene. American Journal of Psychiatry, 159, 1783–1785. Dickel, D. E., Veenstra-VanderWeele, J., Cox, N. J., Wu, X., Fischer, D. J., Van Etten-Lee, M., et al. (2006). Association testing of the positional and functional candidate gene SLC1A1/EAAC1 in early-onset obsessive-compulsive disorder. Archives of General Psychiatry, 63, 778–785. Douglass, H. M., Moffitt, T. E., Dar, R., McGee, R., & Silva, P. (1995). Obsessive-compulsive disorder in a birth cohort of 18-year-olds: prevalence and predictors. Journal of the American Academy of Child & Adolescent Psychiatry, 34, 1424–1431. Figueroa, Y., Rosenberg, D. R., Birmaher, B., & Keshavan, M. S. (1998). Combination treatment with clomipramine and selective serotonin reuptake inhibitors for obsessive-compulsive disorder in children and adolescents. Journal of Child & Adolescent Psychopharmacology, 8, 61–67. Fitzgerald, K. D., MacMaster, F. P., Paulson, L. D., & Rosenberg, D. R. (1999). Neurobiology of childhood obsessive-compulsive disorder. Child and Adolescent Psychiatric Clinics of North America, 8, 533–575, ix. Fitzgerald, K. D., Moore, G. J., Paulson, L. A., Stewart, C. M., & Rosenberg, D. R. (2000). Proton spectroscopic imaging of the thalamus in treatment-naive pediatric obsessive-compulsive disorder.[see comment]. Biological Psychiatry, 47, 174–182. Fitzgerald, K. D., Welsh, R. C., Gehring, W. J., Abelson, J. L., Himle, J. A., Liberzon, I., et al. (2005). Error-related hyperactivity of the anterior cingulate cortex in obsessive-compulsive disorder. Biological Psychiatry, 57, 287–294. Flament, M. F., Rapoport, J. L., Berg, C. J., Sceery, W., Kilts, C., Mellstrom, B., et al. (1985). Clomipramine treatment of childhood obsessive-compulsive disorder. A double-blind controlled study. Archives of General Psychiatry, 42, 977–983. Flament, M. F., Whitaker, A., Rapoport, J. L., Davies, M., et al. (1988). Obsessive compulsive disorder in adolescence: An epidemiological study. Journal of the American Academy of Child & Adolescent Psychiatry, 27, 764–771. Foa, E. B., Kozak, M. J., Steketee, G. S., & McCarthy, P. R. (1992). Treatment of depressive and obsessive-compulsive symptoms in OCD by imipramine and behaviour therapy. British Journal of Clinical Psychology, 31, 279–292. Franklin, M. E., Kozak, M. J., Cashman, L. A., Coles, M. E., Rheingold, A. A., & Foa, E. B. (1998). Cognitive-behavioral treatment of pediatric obsessive-compulsive disorder: an open clinical trial. Journal of the American Academy of Child & Adolescent Psychiatry, 37, 412–419. Freud, S. (1906). Obsessive actions and religious practices. In J. A. Strachey (Ed.), The Standard Edition of the Complete Psychological Works of Sigmund Freud (Vol. 9, pp. 117–127). London: Hogarth Press. Freud, S. (1958). The disposition to obsessional neurosis (1913). In J. A. Strachey (Ed.), The Standard Edition of the Complete Psychological Works of Sigmund Freud (Vol. 12, pp. 311–326). London: Hogarth Press. Garvey, M. A., Perlmutter, S. J., Allen, A. J., Hamburger, S., Lougee, L., Leonard, H. L., et al. (1999). A pilot study of penicillin prophylaxis for neuropsychiatric exacerbations triggered by streptococcal infections. Biological Psychiatry, 45, 1564–1571. Geller, D. A., Biederman, J., Jones, J., Shapiro, S., Schwartz, S., & Park, K. S. (1998). Obsessive-compulsive disorder in children and adolescents: a review. Harvard Review of Psychiatry, 5, 260–273. Geller, D. A., Biederman, J., Stewart, S. E., Mullin, B., Martin, A., Spencer, T., et al. (2003). Which SSRI? A meta-analysis of pharmacotherapy trials in pediatric obsessive-compulsive disorder [see comment]. American Journal of Psychiatry, 160, 1919–1928. Geller, D. A., Hoog, S. L., Heiligenstein, J. H., Ricardi, R. K., Tamura, R., Kluszynski, S., et al. (2001). Fluoxetine treatment for obsessive-compulsive disorder in children and adolescents: a placebo-controlled clinical trial [see comment]. Journal of the American Academy of Child & Adolescent Psychiatry, 40, 773–779. Geller, D. A., Wagner, K. D., Emslie, G., Murphy, T., Carpenter, D. J., Wetherhold, E., et al. (2004). Paroxetine treatment in children and adolescents with obsessive-compulsive disorder: a randomized, multicenter, double-blind, placebo-controlled trial. Journal of the American Academy of Child & Adolescent Psychiatry, 43, 1387– 1396. Giedd, J. N., Rapoport, J. L., Garvey, M. A., Perlmutter, S., & Swedo, S. E. (2000). MRI assessment of children with obsessive-compulsive disorder or tics associated with streptococcal infection. American Journal of Psychiatry, 157, 281–283. Gilbert, A. R., Moore, G. J., Keshavan, M. S., Paulson, L. A., Narula, V., Mac Master, F. P., et al. (2000). Decrease in thalamic volumes of pediatric patients with obsessive-compulsive disorder who are taking paroxetine. Archives of General Psychiatry, 57, 449– 456. Gilbert, D. L., Bansal, A. S., Sethuraman, G., Sallee, F. R., Zhang, J., Lipps, T., et al. (2004). Association of cortical disinhibition with tic, ADHD, and OCD severity in Tourette syndrome. Movement Disorders, 19, 416–425. Goodman, W. K., Price, L. H., Rasmussen, S. A., Mazure, C., Delgado, P., Heninger, G. R., et al. (1989). The Yale-Brown Obsessive Compulsive Scale. II. Validity. Archives of General Psychiatry, 46, 1012–1016. Goodman, W. K., Price, L. H., Rasmussen, S. A., Mazure, C., Fleischmann, R. L., Hill, C. L., et al. (1989). The Yale-Brown Obsessive Compulsive Scale. I. Development, use, and reliability. Archives of General Psychiatry, 46, 1006–1011. Grados, M. A., Riddle, M. A., Samuels, J. F., Liang, K. Y., HoehnSaric, R., Bienvenu, O. J., et al. (2001). The familial phenotype of obsessive-compulsive disorder in relation to tic disorders: the Hopkins OCD family study. Biological Psychiatry, 50, 559–565. Grados, M. A., Walkup, J., & Walford, S. (2003). Genetics of obsessive-compulsive disorders: new findings and challenges. Brain & Development, 25 (Suppl), S55–S61. Graybiel, A. M., & Rauch, S. L. (2000). Toward a neurobiology of obsessive-compulsive disorder. Neuron, 28, 343–347. Greenberg, B. D., Murphy, D. L., & Swedo, S. E. (1998). Symptom exacerbation of vocal tics and other symptoms associated with streptococcal pharyngitis in a patient with obsessive-compulsive disorder and tics. American Journal of Psychiatry, 155, 1459– 1460. Greenberg, B. D., Price, L. H., Rauch, S. L., Friehs, G., Noren, G., Malone, D., et al. (2003). Neurosurgery for intractable obsessivecompulsive disorder and depression: critical issues. Neurosurgery Clinics of North America, 14, 199–212. Greist, J. H., Jefferson, J. W., Rosenfeld, R., Gutzmann, L. D., March, J. S., & Barklage, N. E. (1990). Clomipramine and obsessive compulsive disorder: a placebo-controlled double-blind study of 32 patients.[see comment]. Journal of Clinical Psychiatry, 51, 292–297. Gross-Isseroff, R., Cohen, R., Sasson, Y., Voet, H., & Zohar, J. (2004). Serotonergic dissection of obsessive compulsive symptoms: a challenge study with m-chlorophenylpiperazine and sumatriptan. Neuropsychobiology, 50, 200–205. Hall, D., Dhilla, A., Charalambous, A., Gogos, J. A., & Karayiorgou, M. (2003). Sequence variants of the brain-derived neurotrophic factor (BDNF) gene are strongly associated with obsessive-compulsive disorder. American Journal of Human Genetics, 73, 370–376. CHAPTER 43 714 9781405145497_4_043.qxd 29/03/2008 02:53 PM Page 714

Hamburger, S. D., Swedo, S., Whitaker, A., Davies, M., & Rapoport, J. L. (1989). Growth rate in adolescents with obsessive-compulsive disorder. American Journal of Psychiatry, 146, 652–655. Hanna, G. L., Veenstra-VanderWeele, J., Cox, N. J., Boehnke, M., Himle, J. A., Curtis, G. C., et al. (2002). Genome-wide linkage analysis of families with obsessive-compulsive disorder ascertained through pediatric probands. American Journal of Medical Genetics, 114, 541–552. Herjanic, B., & Campbell, W. (1977). Differentiating psychiatrically disturbed children on the basis of a structured interview. Journal of Abnormal Child Psychology, 5, 127–134. Herjanic, B., & Reich, W. (1982). Development of a structured psychiatric interview for children: agreement between child and parent on various symptoms. Journal of Abnormal Child Psychology, 10, 307–324. Hollander, E. (1996). Obsessive-compulsive disorder-related disorders: the role of selective serotonergic reuptake inhibitors. International Clinical Psychopharmacology, 11, 75–87. Hollander, E., King, A., Delaney, K., Smith, C. J., & Silverman, J. M. (2003). Obsessive-compulsive behaviors in parents of multiplex autism families. Psychiatry Research, 117, 11–16. Hollander, E., & Wong, C. M. (1995). Body dysmorphic disorder, pathological gambling, and sexual compulsions. Journal of Clinical Psychiatry, 56, 7–12; discussion 13. Horwath, E., & Weissman, M. M. (2000). The epidemiology and crossnational presentation of obsessive-compulsive disorder. Psychiatric Clinics of North America, 23, 493–507. Hudziak, J. J., Van Beijsterveldt, C. E., Althoff, R. R., Stanger, C., Rettew, D. C., Nelson, E. C., et al. (2004). Genetic and environmental contributions to the Child Behavior Checklist ObsessiveCompulsive Scale: a cross-cultural twin study. Archives of General Psychiatry, 61, 608–616. Ivarsson, T., & Valderhaug, R. (2006). Symptom patterns in children and adolescents with obsessive-compulsive disorder (OCD). Behaviour Research and Therapy, 44, 1105–1116. Janet, P. (1903). Les Obsessions et la Psychiatrie. Vol. 1. Paris: Felix Alan. Jonnal, A. H., Gardner, C. O., Prescott, C. A., & Kendler, K. S. (2000). Obsessive and compulsive symptoms in a general population sample of female twins. American Journal of Medical Genetics, 96, 791–796. Kanner, L. (1962). Chld Psychiatry (3rd ed.). Springfield, IL: Charles C. Thomas. Karayiorgou, M., Sobin, C., Blundell, M. L., Galke, B. L., Malinova, L., Goldberg, P., et al. (1999). Family-based association studies support a sexually dimorphic effect of COMT and MAOA on genetic susceptibility to obsessive-compulsive disorder. Biological Psychiatry, 45, 1178–1189. Karno, M., & Golding, J. (1990). Obsessive-compulsive disorder. In L. Robins & D. A. Regier (Eds.), Psychiatric Disorders in America: the Epidemiological Catchment Area Study (pp. 207–229). New York: Free Press. Karno, M., & Golding, J. M. (1991). Obsessive compulsive disorder. In L. N. Robins & D. A. Regier (Eds.), Psychiatry Disorders in America (pp. 204–219). New York: The Free Press. Karno, M., Golding, J. M., Sorenson, S. B., & Burnam, M. A. (1988). The epidemiology of obsessive-compulsive disorder in five US communities. Archives of General Psychiatry, 45, 1094– 1099. Katz, N., Gothelf, D., Hermesh, H., Weizman, A., Apter, A., & Horev, G. (1998). Bone age in adolescents with schizophrenia and obsessivecompulsive disorder. Schizophrenia Research, 33, 119–122. Kaufman, J., Birmaher, B., Brent, D., Rao, U., Flynn, C., Moreci, P., et al. (1997). Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version (K-SADS-PL): initial reliability and validity data. Journal of the American Academy of Child & Adolescent Psychiatry, 36, 980–988. Kenwright, M., Marks, I., Graham, C., Franses, A., & Mataix-Cols, D. (2005). Brief scheduled phone support from a clinician to enhance computer-aided self-help for obsessive-compulsive disorder: randomized controlled trial. Journal of Clinical Psychology, 61, 1499–1508. Kim, S. J., Lee, H. S., & Kim, C. H. (2005). Obsessive-compulsive disorder, factor-analyzed symptom dimensions and serotonin transporter polymorphism. Neuropsychobiology, 52, 176–182. Kopell, B. H., Greenberg, B., & Rezai, A. R. (2004). Deep brain stimulation for psychiatric disorders. Journal of Clinical Neurophysiology, 21, 51–67. Kuelz, A. K., Hohagen, F., & Voderholzer, U. (2004). Neuropsychological performance in obsessive-compulsive disorder: a critical review. Biological Psychology, 65, 185–236. LaSalle, V. H., Cromer, K. R., Nelson, K. N., Kazuba, D., Justement, L., & Murphy, D. L. (2004). Diagnostic interview assessed neuropsychiatric disorder comorbidity in 334 individuals with obsessivecompulsive disorder. Depression and Anxiety, 19, 163–173. Leckman, J. F., Grice, D. E., Barr, L. C., de Vries, A. L., Martin, C., Cohen, D. J., et al. (1994). Tic-related vs. non-tic-related obsessive compulsive disorder. Anxiety, 1, 208–215. Leonard, H. L. (1989). Childhood rituals and superstitions: developmental and cultural perspective. In J. L. Rapoport (Ed.), ObsessiveCompulsive Disorder in Children & Adolescents (pp. 289–309). Washington DC: American Psychiatric Press. Leonard, H. L., Swedo, S. E., Garvey, M., Beer, D., Perlmutter, S., Lougee, L., et al. (1999). Postinfectious and other forms of obsessivecompulsive disorder. Child & Adolescent Psychiatric Clinics of North America, 8, 497–511. Leonard, H. L., Lenane, M. C., Swedo, S. E., Rettew, D. C., Gershon, E. S., & Rapoport, J. L. (1992). Tics and Tourette’s disorder: a 2- to 7-year follow-up of 54 obsessive-compulsive children. American Journal of Psychiatry, 149, 1244–1251. Leonard, H. L., Swedo, S. E., Lenane, M. C., Rettew, D. C., Cheslow, D. L., Hamburger, S. D., et al. (1991). A double-blind desipramine substitution during long-term clomipramine treatment in children and adolescents with obsessive-compulsive disorder. Archives of General Psychiatry, 48, 922–927. Leonard, H. L., Swedo, S. E., Rapoport, J. L., Koby, E. V., Lenane, M. C., Cheslow, D. L., et al. (1989). Treatment of obsessivecompulsive disorder with clomipramine and desipramine in children and adolescents. A double-blind crossover comparison. Archives of General Psychiatry, 46, 1088–1092. Leonard, H. L., Topol, D., Bukstein, O., Hindmarsh, D., Allen, A. J., & Swedo, S. E. (1994). Clonazepam as an augmenting agent in the treatment of childhood-onset obsessive-compulsive disorder. Journal of the American Academy of Child & Adolescent Psychiatry, 33, 792–794. Lewinsohn, P. M., Hops, H., Roberts, R. E., Seeley, J. R., & Andrews, J. A. (1993). Adolescent psychopathology: I. Prevalence and incidence of depression and other DSM-III-R disorders in high school students. Journal of Abnormal Psychology, 102, 133– 144. Li, X., May, R. S., Tolbert, L. C., Jackson, W. T., Flournoy, J. M., & Baxter, L. R. (2005). Risperidone and haloperidol augmentation of serotonin reuptake inhibitors in refractory obsessive-compulsive disorder: a crossover study. Journal of Clinical Psychiatry, 66, 736–743. Liebowitz, M. R., Turner, S. M., Piacentini, J., Beidel, D. C., Clarvit, S. R., Davies, S. O., et al. (2002). Fluoxetine in children and adolescents with OCD: a placebo-controlled trial. Journal of the American Academy of Child & Adolescent Psychiatry, 41, 1431– 1438. Lochner, C., Kinnear, C. J., Hemmings, S. M., Seller, C., Niehaus, D. J., Knowles, J. A., et al. (2005). Hoarding in obsessive-compulsive disorder: clinical and genetic correlates. Journal of Clinical Psychiatry, 66, 1155–1160. OBSESSIVE-COMPULSIVE DISORDER 715 9781405145497_4_043.qxd 29/03/2008 02:53 PM Page 715

Lombroso, P. J., Scahill, L., King, R. A., Lynch, K. A., Chappell, P. B., Peterson, B. S., et al. (1995). Risperidone treatment of children and adolescents with chronic tic disorders: a preliminary report. Journal of the American Academy of Child & Adolescent Psychiatry, 34, 1147–1152. Luxenberg, J. S., Swedo, S. E., Flament, M. F., Friedland, R. P., Rapoport, J., & Rapoport, S. I. (1988). Neuroanatomical abnormalities in obsessive-compulsive disorder detected with quantitative X-ray computed tomography. American Journal of Psychiatry, 145, 1089–1093. MacMaster, F. P., Keshavan, M. S., Dick, E. L., & Rosenberg, D. R. (1999). Corpus callosal signal intensity in treatment-naive pediatric obsessive compulsive disorders. Progress in NeuroPsychopharmacology & Biological Psychiatry, 23, 601–612. Maina, G., Albert, U., Bogetto, F., & Ravizza, L. (1999). Obsessivecompulsive syndromes in older adolescents. Acta Psychiatrica Scandinavica, 100, 447–450. Malloy, P. (1987). Frontal lobe dysfunction in OCD. In E. Perecman (Ed.), The Frontal Lobes Revisited (pp. 207). New York: IRBN Press. Maltby, N., Tolin, D. F., Worhunsky, P., O’Keefe, T. M., & Kiehl, K. A. (2005). Dysfunctional action monitoring hyperactivates frontal-striatal circuits in obsessive-compulsive disorder: an eventrelated fMRI study. Neuroimage, 24, 495–503. March, J. S., Biederman, J., Wolkow, R., Safferman, A., Mardekian, J., Cook, E. H., et al. (1998). Sertraline in children and adolescents with obsessive-compulsive disorder: a multicenter randomized controlled trial.[see comment][erratum appears in Journal of the American Medical Association 2000 Mar 8;283(10):1293]. JAMA, 280, 1752–1756. March, J. S., & Mulle, K. (1998). OCD in children and adolescents: A cognitive-behavioral treatment manual (No. 1-57230-242-9 (hardcover)). Martin, J. L., Barbanoj, M. J., Perez, V., & Sacristan, M. (2003). Transcranial magnetic stimulation for the treatment of obsessivecompulsive disorder. Cochrane Database of Systematic Reviews (3), CD003387. Masi, G., Millepiedi, S., Mucci, M., Bertini, N., Milantoni, L., & Arcangeli, F. (2005). A naturalistic study of referred children and adolescents with obsessive-compulsive disorder. Journal of the American Academy of Child & Adolescent Psychiatry, 44, 673– 681. Masi, G., Perugi, G., Toni, C., Millepiedi, S., Mucci, M., Bertini, N., et al. (2004). Obsessive-compulsive bipolar comorbidity: focus on children and adolescents. Journal of Affective Disorders, 78, 175– 183. Mataix-Cols, D., Cullen, S., Lange, K., Zelaya, F., Andrew, C., Amaro, E., et al. (2003). Neural correlates of anxiety associated with obsessive-compulsive symptom dimensions in normal volunteers. Biological Psychiatry, 53, 482–493. Mataix-Cols, D., Rosario-Campos, M. C., & Leckman, J. F. (2005). A multidimensional model of obsessive-compulsive disorder. American Journal of Psychiatry, 162, 228–238. Mataix-Cols, D., Wooderson, S., Lawrence, N., Brammer, M. J., Speckens, A., & Phillips, M. L. (2004). Distinct neural correlates of washing, checking, and hoarding symptom dimensions in obsessive-compulsive disorder. Archives of General Psychiatry, 61, 564–576. McDougle, C. J., Epperson, C. N., Pelton, G. H., Wasylink, S., & Price, L. H. (2000). A double-blind, placebo-controlled study of risperidone addition in serotonin reuptake inhibitor-refractory obsessive-compulsive disorder [see comment]. Archives of General Psychiatry, 57, 794–801. McKay, D., Piacentini, J., Greisberg, S., Graae, F., Jaffer, M., & Miller, J. (2006). The structure of childhood obsessions and compulsions: dimensions in an outpatient sample. Behaviour Research and Therapy, 44, 137–146. Miguel, E. C., do Rosário-Campos, M. C., Prado, H. S., do Valle, R., Rauch, S. L., Coffey, B. J., et al. (2000). Sensory phenomena in obsessive-compulsive disorder and Tourette’s disorder. Journal of Clinical Psychiatry, 61, 150–156; quiz 157. Millet, B., Chabane, N., Delorme, R., Leboyer, M., Leroy, S., Poirier, M. F., et al. (2003). Association between the dopamine receptor D4 (DRD4) gene and obsessive-compulsive disorder. American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics: the Official Publication of the International Society of Psychiatric Genetics, 116, 55–59. Modell, J. G., Mountz, J. M., Curtis, G. C., & Greden, J. F. (1989). Neurophysiologic dysfunction in basal ganglia/limbic striatal and thalamocortical circuits as a pathogenetic mechanism of obsessivecompulsive disorder [see comments]. Journal of Neuropsychiatry & Clinical Neurosciences, 1, 27–36. Mundo, E., Richter, M. A., Zai, G., Sam, F., McBride, J., Macciardi, F., et al. (2002). 5HT1Dbeta receptor gene implicated in the pathogenesis of obsessive-compulsive disorder: further evidence from a family-based association study. Molecular Psychiatry, 7, 805–809. National Institute for Health and Clinical Excellence: Core interventions in the treatment of OCD and BDD: National clinical Practice Guideline Number 31. Published by the British Psychological Society and The Royal College of Psychiatrists (2006). Office of Public Sector Information, London. Nakao, T., Nakagawa, A., Yoshiura, T., Nakatani, E., Nabeyama, M., Yoshizato, C., et al. (2005). A functional MRI comparison of patients with obsessive-compulsive disorder and normal controls during a Chinese character Stroop task. Psychiatry Research, 139, 101–114. Nestadt, G., Samuels, J., Riddle, M., Bienvenu, O. J., 3rd, Liang, K. Y., LaBuda, M., et al. (2000). A family study of obsessive-compulsive disorder. Archives of General Psychiatry, 57, 358–363. Neziroglu, F., Yaryura-Tobias, J. A., Walz, J., & McKay, D. (2000). The effect of fluvoxamine and behavior therapy on children and adolescents with obsessive-compulsive disorder. Journal of Child & Adolescent Psychopharmacology, 10, 295–306. Osler, W. (1894). On Chorea and Choreiform Affections. Philadelphia: Blakiston & Sons. Pauls, D. L., Alsobrook, J. P., 2nd, Goodman, W., Rasmussen, S., & Leckman, J. F. (1995). A family study of obsessive-compulsive disorder. American Journal of Psychiatry, 152, 76–84. Perani, D., Colombo, C., Bressi, S., Bonfanti, A., Grassi, F., Scarone, S., et al. (1995). [18F]FDG PET study in obsessive-compulsive disorder. A clinical/metabolic correlation study after treatment. British Journal of Psychiatry, 166, 244–250. Perlmutter, S. J., Leitman, S. F., Garvey, M. A., Hamburger, S., Feldman, E., Leonard, H. L., et al. (1999). Therapeutic plasma exchange and intravenous immunoglobulin for obsessive-compulsive disorder and tic disorders in childhood. Lancet, 354, 1153–1158. Peterson, B. S., Pine, D. S., Cohen, P., & Brook, J. S. (2001). Prospective, longitudinal study of tic, obsessive-compulsive, and attention-deficit/hyperactivity disorders in an epidemiological sample. Journal of the American Academy of Child & Adolescent Psychiatry, 40, 685–695. Pogarell, O., Hamann, C., Popperl, G., Juckel, G., Chouker, M., Zaudig, M., et al. (2003). Elevated brain serotonin transporter availability in patients with obsessive-compulsive disorder. Biological Psychiatry, 54, 1406–1413. POTS Team. (2004). Cognitive-behavior therapy, sertraline, and their combination for children and adolescents with obsessive-compulsive disorder: the Pediatric OCD Treatment Study (POTS) randomized controlled trial. JAMA, 292, 1969–1976. Poyurovsky, M., & Koran, L. M. (2005). Obsessive-compulsive disorder (OCD) with schizotypy vs. schizophrenia with OCD: diagnostic dilemmas and therapeutic implications. Journal of Psychiatric Research, 39, 399–408. CHAPTER 43 716 9781405145497_4_043.qxd 29/03/2008 02:53 PM Page 716

Rapoport, & Wise. (1988). Obsessive-compulsive disorder: evidence for basal ganglia dysfunction. Psychopharmacology Bulletin, 24, 380–384. Rapoport, J. L., & Inoff-Germain, G. (2007). Neurobiology and pharmacotherapy of obsessive-compulsive disorder. In D. Sibley (Ed.), Handbook of Contemporary Neuropharmacology. Hoboken, NJ: Wiley and Sons. pp. 215–247. Rapoport, J. L., Inoff-Germain, G., Weissman, M. M., Greenwald, S., Narrow, W. E., Jensen, P. S., et al. (2000). Childhood obsessivecompulsive disorder in the NIMH MECA study: parent versus child identification of cases. Methods for the Epidemiology of Child and Adolescent Mental Disorders. Journal of Anxiety Disorders, 14, 535–548. Rasmussen, S. A., & Eisen, J. L. (1992). The epidemiology and differential diagnosis of obsessive compulsive disorder. Journal of Clinical Psychiatry, 53 Suppl, 4–10. Rasmussen, S. A., & Tsuang, M. T. (1984). The epidemiology of obsessive compulsive disorder. Journal of Clinical Psychiatry, 45, 450–457. Rauch, S. L., Whalen, P. J., Curran, T., Shin, L. M., Coffey, B. J., Savage, C. R., et al. (2001). Probing striato-thalamic function in obsessive-compulsive disorder and Tourette syndrome using neuroimaging methods. Advances in Neurology, 85, 207–224. Reinherz, H. H. Z., Giaconia, R. R. M., Lefkowitz, E. E. S., Pakiz, B. B., & Frost, A. A. K. (1993). Prevalence of psychiatric disorders in a community population of older adolescents. Journal of the American Academy of Child & Adolescent Psychiatry, 32, 369– 377. Rettew, D. C., Swedo, S. E., Leonard, H. L., Lenane, M. C., & Rapoport, J. L. (1992). Obsessions and compulsions across time in 79 children and adolescents with obsessive-compulsive disorder. Journal of the American Academy of Child & Adolescent Psychiatry, 31, 1050–1056. Riddle, M. A., Reeve, E. A., Yaryura-Tobias, J. A., Yang, H. M., Claghorn, J. L., Gaffney, G., et al. (2001). Fluvoxamine for children and adolescents with obsessive-compulsive disorder: a randomized, controlled, multicenter trial. Journal of the American Academy of Child & Adolescent Psychiatry, 40, 222–229. Riddle, M. A., Scahill, L., King, R. A., Hardin, M. T., Anderson, G. M., Ort, S. I., et al. (1992). Double-blind, crossover trial of fluoxetine and placebo in children and adolescents with obsessivecompulsive disorder. Journal of the American Academy of Child & Adolescent Psychiatry, 31, 1062–1069. Rosenberg, D. R., Averbach, D. H., O’Hearn, K. M., Seymour, A. B., Birmaher, B., & Sweeney, J. A. (1997). Oculomotor response inhibition abnormalities in pediatric obsessive-compulsive disorder. Archives of General Psychiatry, 54, 831–838. Rosenberg, D. R., Dick, E. L., O’Hearn, K. M., & Sweeney, J. A. (1997). Response-inhibition deficits in obsessive-compulsive disorder: an indicator of dysfunction in frontostriatal circuits. Journal of Psychiatry & Neuroscience, 22, 29–38. Rosenberg, D. R., & Keshavan, M. S. (1998). A. E. Bennett Research Award. Toward a neurodevelopmental model of obsessive-compulsive disorder. Biological Psychiatry, 43, 623–640. Rosenberg, D. R., Keshavan, M. S., O’Hearn, K. M., Dick, E. L., Bagwell, W. W., Seymour, A. B., et al. (1997). Frontostriatal measurement in treatment-naive children with obsessive-compulsive disorder [see comment]. Archives of General Psychiatry, 54, 824– 830. Rosenberg, D. R., MacMaster, F. P., Keshavan, M. S., Fitzgerald, K. D., Stewart, C. M., & Moore, G. J. (2000). Decrease in caudate glutamatergic concentrations in pediatric obsessive-compulsive disorder patients taking paroxetine. Journal of the American Academy of Child & Adolescent Psychiatry, 39, 1096–1103. Rosenberg, D. R., Mirza, Y., Russell, A., Tang, J., Smith, J. M., Banerjee, S. P., et al. (2004). Reduced anterior cingulate glutamatergic concentrations in childhood OCD and major depression versus healthy controls. Journal of the American Academy of Child & Adolescent Psychiatry, 43, 1146–1153. Russell, A., Cortese, B., Lorch, E., Ivey, J., Banerjee, S. P., Moore, G. J., et al. (2003). Localized functional neurochemical marker abnormalities in dorsolateral prefrontal cortex in pediatric obsessive-compulsive disorder. Journal of Child & Adolescent Psychopharmacology, 13 (Suppl), S31–S38. Salkovskis, P., Shafran, R., Rachman, S., & Freeston, M. H. (1999). Multiple pathways to inflated responsibility beliefs in obsessional problems: possible origins and implications for therapy and research. Behaviour Research & Therapy, 37, 1055–1072. Sallee, F. R., Richman, H., Sethuraman, G., Dougherty, D., Sine, L., & Altman-Hamamdzic, S. (1998). Clonidine challenge in childhood anxiety disorder. Journal of the American Academy of Child & Adolescent Psychiatry, 37, 655–662. Saxena, S., Bota, R. G., & Brody, A. L. (2001). Brain-behavior relationships in obsessive-compulsive disorder. Seminars in Clinical Neuropsychiatry, 6, 82–101. Saxena, S., Brody, A. L., Maidment, K. M., Dunkin, J. J., Colgan, M., Alborzian, S., et al. (1999). Localized orbitofrontal and subcortical metabolic changes and predictors of response to paroxetine treatment in obsessive-compulsive disorder. Neuropsychopharmacology, 21, 683–693. Shapira, N. A., Liu, Y., He, A. G., Bradley, M. M., Lessig, M. C., James, G. A., et al. (2003). Brain activation by disgust-inducing pictures in obsessive-compulsive disorder. Biological Psychiatry, 54, 751–756. Shin, L. M., Wright, C. I., Cannistraro, P. A., Wedig, M. M., McMullin, K., Martis, B., et al. (2005). A functional magnetic resonance imaging study of amygdala and medial prefrontal cortex responses to overtly presented fearful faces in posttraumatic stress disorder. Archives of General Psychiatry, 62, 273–281. Simpson, H. B., Lombardo, I., Slifstein, M., Huang, H. Y., Hwang, D. R., Abi-Dargham, A., et al. (2003). Serotonin transporters in obsessive-compulsive disorder: a positron emission tomography study with [(11)C]McN 5652. Biological Psychiatry, 54, 1414– 1421. Singer, H. S., Hong, J. J., Yoon, D. Y., & Williams, P. N. (2005). Serum autoantibodies do not differentiate PANDAS and Tourette syndrome from controls [see comment]. Neurology, 65, 1701– 1707. Snider, L. A., Lougee, L., Slattery, M., Grant, P., & Swedo, S. E. (2005). Antibiotic prophylaxis with arithromycin or penicillin for childhoodonset neuropsychiatric disorders. Biological Psychiatry, 57, 788– 792. Stein, D. J. (2002). Obsessive-compulsive disorder. Lancet, 360(9330), 397–405. Stengler-Wenzke, K., Muller, U., Angermeyer, M. C., Sabri, O., & Hesse, S. (2004). Reduced serotonin transporter availability in obsessive-compulsive disorder (OCD). European Archives of Psychiatry & Clinical Neuroscience, 254, 252–255. Stewart, S. E., Geller, D. A., Jenike, M., Pauls, D., Shaw, D., Mullin, B., et al. (2004). Long-term outcome of pediatric obsessivecompulsive disorder: a meta-analysis and qualitative review of the literature [see comment]. Acta Psychiatrica Scandinavica, 110, 4– 13. Swedo, S. E., & Grant, P. J. (2005). Annotation: PANDAS: a model for human autoimmune disease. Journal of Child Psychology & Psychiatry & Allied Disciplines, 46, 227–234. Swedo, S., Leonard, H., & Rapoport, J. (2004). The pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection (PANDAS) subgroup: Separating fact from fiction. Pediatrics, 113, 907–911. Swedo, S., Rapoport, J., Leonard, H., Lenane, M., & Cheslow, D. (1989). Obsessive-compulsive disorder in children and adolescents. Clinical phenomenology of 70 consecutive cases. Archives of General Psychiatry, 46, 335–341. OBSESSIVE-COMPULSIVE DISORDER 717 9781405145497_4_043.qxd 29/03/2008 02:53 PM Page 717

Szeszko, P. R., Ardekani, B. A., Ashtari, M., Malhotra, A. K., Robinson, D., Bilder, R. M., et al. (2005). White matter abnormalities in OCD. Archives of General Psychiatry, 62, 782–790. Szeszko, P. R., MacMillan, S., McMeniman, M., Chen, S., Baribault, K., Lim, K. O., et al. (2004). Brain structural abnormalities in psychotropic drug-naive pediatric patients with obsessive-compulsive disorder. American Journal of Psychiatry, 161, 1049–1056. Szeszko, P. R., Robinson, D., Alvir, J. M., Bilder, R. M., Lencz, T., Ashtari, M., et al. (1999). Orbital frontal and amygdala volume reductions in obsessive-compulsive disorder. Archives of General Psychiatry, 56, 913–919. Thomsen, P. H. (1991). Obsessive-compulsive symptoms in children and adolescents. A phenomenological analysis of 61 Danish cases. Psychopathology, 24, 12–18. Thomsen, P. H., & Jensen, J. (1991). Latent class analysis of organic aspects of obsessive-compulsive disorder in children and adolescents. Acta Psychiatrica Scandinavica, 84, 391–395. Ursu, S., Stenger, V. A., Shear, M. K., Jones, M. R., & Carter, C. S. (2003). Overactive action monitoring in obsessive-compulsive disorder: evidence from functional magnetic resonance imaging. Psychological Science, 14, 347–353. Valleni-Basile, L. A., Garrison, C. Z., Jackson, K. L., Waller, J. L., McKeown, R. E., Addy, C. L., et al. (1994). Frequency of obsessivecompulsive disorder in a community sample of young adolescents. Journal of the American Academy of Child & Adolescent Psychiatry, 33, 782–791. van den Heuvel, O. A., Veltman, D. J., Groenewegen, H. J., Cath, D. C., van Balkom, A. J., van Hartskamp, J., et al. (2005). Frontalstriatal dysfunction during planning in obsessive-compulsive disorder. Archives of General Psychiatry, 62, 301–309. van den Heuvel, O. A., Veltman, D. J., Groenewegen, H. J., Dolan, R. J., Cath, D. C., Boellaard, R., et al. (2004). Amygdala activity in obsessive-compulsive disorder with contamination fear: a study with oxygen-15 water positron emission tomography. Psychiatry Research, 132, 225–237. van den Heuvel, O. A., Veltman, D. J., Groenewegen, H. J., Witter, M. P., Merkelbach, J., Cath, D. C., et al. (2005). Disorder-specific neuroanatomical correlates of attentional bias in obsessive-compulsive disorder, panic disorder, and hypochondriasis. Archives of General Psychiatry, 62, 922–933. van der Wee, N. J., Stevens, H., Hardeman, J. A., Mandl, R. C., Denys, D. A., van Megen, H. J., et al. (2004). Enhanced dopamine transporter density in psychotropic-naive patients with obsessivecompulsive disorder shown by [123I]beta-CIT SPECT. American Journal of Psychiatry, 161, 2201–2206. van Veen, V., & Carter, C. S. (2002). The anterior cingulate as a conflict monitor: fMRI and ERP studies. Physiology & Behavior, 77, 477– 482. Veale, D. M., Sahakian, B. J., Owen, A. M., & Marks, I. M. (1996). Specific cognitive deficits in tests sensitive to frontal lobe dysfunction in obsessive-compulsive disorder. Psychological Medicine, 26, 1261–1269. Veenstra-VanderWeele, J., Kim, S. J., Gonen, D., Hanna, G. L., Leventhal, B. L., & Cook, E. H., Jr. (2001). Genomic organization of the SLC1A1/EAAC1 gene and mutation screening in early-onset obsessive-compulsive disorder. Molecular Psychiatry, 6,160–167. Viard, A., Flament, M. F., Artiges, E., Dehaene, S., Naccache, L., Cohen, D., et al. (2005). Cognitive control in childhood-onset obsessivecompulsive disorder: a functional MRI study. Psychological Medicine, 35, 1007–1017. Walsh, K. H., & McDougle, C. J. (2004). Pharmacological augmentation strategies for treatment-resistant obsessive-compulsive disorder. Expert Opinion on Pharmacotherapy, 5, 2059–2067. Willour, V. L., Yao Shugart, Y., Samuels, J., Grados, M., Cullen, B., Bienvenu, O. J., 3rd, et al. (2004). Replication study supports evidence for linkage to 9p24 in obsessive-compulsive disorder. American Journal of Human Genetics, 75, 508–513. Wise, S. P., & Rapoport, J. L. (1989). Obsessive compulsive disorder: is it a basal ganglia dysfunction? In J. L. Rapoport (Ed.), Obsessivecompulsive disorder in Children and Adolescents (pp. 327–344). New York, USA: American Psychiatric Press. Wittchen, H. U., Nelson, C. B., & Lachner, G. (1998). Prevalence of mental disorders and psychosocial impairments in adolescents and young adults. Psychological Medicine, 28, 109–126. Zai, G., Bezchlibnyk, Y. B., Richter, M. A., Arnold, P., Burroughs, E., Barr, C. L., et al. (2004). Myelin oligodendrocyte glycoprotein (MOG) gene is associated with obsessive-compulsive disorder. American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics: the Official Publication of the International Society of Psychiatric Genetics, 129, 64–68. Zohar, A. H. (1999). The epidemiology of obsessive-compulsive disorder in children and adolescents. Child & Adolescent Psychiatric Clinics of North America, 8, 445–460. Zohar, A. H., Ratzoni, G., Pauls, D. L., Apter, A., Bleich, A., Kron, S., et al. (1992). An epidemiological study of obsessive-compulsive disorder and related disorders in Israeli adolescents. Journal of the American Academy of Child & Adolescent Psychiatry, 31, 1057– 1061. CHAPTER 43 718 9781405145497_4_043.qxd 29/03/2008 02:53 PM Page 718

719 Tic disorders are transient or chronic conditions associated with difficulties in self-esteem, family life, social acceptance or school or job performance that are directly related to the presence of motor and/or phonic tics. Although tic symptoms have been reported since antiquity, systematic study of individuals with tic disorders dates only from the 19th century with the reports of Itard (1825) and Gilles de la Tourette (1885). Gilles de la Tourette described nine cases characterized by motor “incoordinations” or tics, “inarticulate shouts accompanied by articulated words with echolalia and coprolalia.” In addition to identifying the cardinal features of severe tic disorders, his report noted an association between tic disorders and obsessive-compulsive symptoms as well as the hereditary nature of the syndrome in some families. In addition to tics, individuals with tic disorders may present with a broad array of behavioral difficulties including disinhibited speech or conduct, impulsivity, distractibility, motoric hyperactivity, and obsessive-compulsive symptoms (Leckman & Cohen, 1998). Scientific opinion has been divided on how broadly to conceive the spectrum of maladaptive behaviors associated with Tourette syndrome (TS) (Comings, 1988; Shapiro, Shapiro, Young, & Freinberg, 1988). This controversy is fueled in part by the frustration that parents and educators encounter when they attempt to divide an individual child’s repertoire of problem behaviors into those that are “Tourette-related” and those that are not. Populationbased epidemiological studies and family-genetic studies have begun to clarify these issues, but much work remains to be done. In this chapter, a presentation of the phenomenology and classification of tic disorders precedes a review of the etiology, neurobiological substrates, assessment and management of these conditions. The general perspective presented is that TS and related disorders are model neurobiological disorders in which to study multiple genetic and environmental (epigenetic) mechanisms that interact over the course of development to produce a distinctive range of complex syndromes of varying severity. Definitions and Classifications Phenomenology of Tics A tic is a sudden repetitive movement, gesture or utterance that typically mimics some aspect or fragment of normal behavior. Individual tics rarely last more than a second. Many tics occur in bouts with brief inter-tic intervals (Peterson & Leckman, 1998). Individual tics can occur singly or together in an orchestrated pattern. They vary in their intensity or forcefulness. Motor tics vary from simple abrupt movements such as eye blinking, head jerks or shoulder shrugs to more complex, apparently purposive behaviors such as facial expressions or gestures of the arms or head. In extreme cases, these movements can be obscene (copropraxia) or self-injurious (e.g., hitting or biting). Phonic or vocal tics can range from simple throat clearing sounds to more complex vocalizations and speech. In severe cases, coprolalia (obscene or socially unacceptable speech) is present. By the age of 10 years, most individuals with tics are aware of premonitory urges that may be experienced either as a focal perception in a particular body region where the tic is about to occur (like an itch or a tickling sensation) or as a mental awareness (Leckman, Walker, & Cohen, 1993). Most patients also report a fleeting sense of relief after a bout of tics has occurred. These premonitory and consummatory phenomena contribute to an individual’s sense that tics are a habitual yet partially intentional response to unpleasant stimuli. Indeed, most adolescent and adult subjects describe their tics as either “voluntary” or as having both voluntary and involuntary aspects. In contrast, many young children are oblivious to their tics and experience them as wholly involuntary movements or sounds. Most tics can also be suppressed for brief periods of time. The warning given by premonitory urges may contribute to this phenomenon. Clinicians characterize tics by their anatomical location, number, frequency and duration. The intensity or “forcefulness” of the tic can also be an important characteristic. Finally, tics vary in terms of their “complexity.” Complexity usually refers to how simple or involved a movement or sound is, ranging from brief meaningless abrupt fragments (simple tics) to ones that are longer, more involved and seemingly more goal-directed in character (complex tics). Each of these elements has been incorporated into clinician rating scales, which have proven to be useful in monitoring tic severity (Leckman, Riddle, Hardin et al., 1989). Tic Disorders 44 James F. Leckman and Michael H. Bloch 9781405145497_4_044.qxd 29/03/2008 02:53 PM Page 719 Rutter’s Child and Adolescent Psychiatry, 5th Edition, Edited by M. Rutter, D. V. M. Bishop D. S. Pine, S. Scott, J. Stevenson, E. Taylor and A. Thapar © 2008 Blackwell Publishing Limited. ISBN: 978-1-405-14549-7

orders have been performed so that most of the information provided below is based on clinical experience and anecdotal reports. Transient Tic Disorder Almost invariably a disorder of childhood, transient tic disorder is usually characterized by one or more simple motor tics that wax and wane in severity over weeks to months. The anatomical distribution of these tics is usually confined to the eyes, face, neck or upper extremities. Transient phonic tics, in the absence of motor tics, can also occur, although more rarely. The age of onset is typically 3–10 years. Boys are at greater risk. The initial presentation may be unnoticed. Family practitioners, pediatricians, allergists and ophthalmologists are typically the first to see the child. Missed diagnoses are common, particularly as the symptoms may have completely disappeared by the time of the consultation. To meet diagnostic criteria for transient tic disorder, there must be fewer than 12 consecutive months of active symptomatology. This is therefore often a retrospective diagnosis as the clinician is unable to know with certainty which children will show progression of their symptoms and which children will display a self-limiting course. Chronic Motor or Vocal Tic Disorder This chronic condition can be observed among children and adults. As with other tic disorders, chronic motor tic disorder (CMTD) is characterized by a waxing and waning course and a broad range of symptom severity. Chronic simple and complex motor tics are the most common manifestations. A majority of tics involve the eyes, face, head, neck and upper extremities. Although some children may display other developmental difficulties such as attention deficit/hyperactivity disorder (ADHD), the disorder is not incompatible with an otherwise normal course of childhood. This condition can also appear as a residual state, where a predictable repertoire of tic symptoms may be seen only during periods of heightened stress or fatigue. Tourette Syndrome (Combined Vocal and Multiple Motor Tic Disorder) The most severe tic disorder is best known by the eponym Gilles de la Tourette’s syndrome. Typically, the disorder begins in early childhood with transient bouts of simple motor tics such as eye blinking or head jerks. These tics may initially come and go, but eventually they become persistent and begin to have adverse effects on the child and the family. The repertoire of motor tics can be vast, incorporating virtually any voluntary movement by any portion of the body. Although some patients have a “rostral–caudal” progression of motor tics (head, neck, shoulders, arms, torso), this course is not predictable. As the syndrome develops, complex motor tics may appear. Typically, they accompany simple motor tics. Often they have a “camouflaged” or purposive appearance (e.g., brushing hair away from the face with an arm), and can only be distinguished as tics by their repetitive character. CHAPTER 44 720 Diagnostic Categories Diagnostic categories provide a common basis for discussion and are an essential tool in epidemiological and clinical research. Several widely used diagnostic classifications currently include sections on tic disorders. These include both the DSM-IV classification system published by the American Psychiatric Association (1994), and the ICD-10 criteria by the World Health Organization (1996). Although differences exist, these classification schemes are broadly congruent, with each containing three major categories: TS or its equivalent; chronic motor or vocal tic disorder (CMT or CVT) or its equivalent; and transient tic disorder or its equivalent. To minimize error in case ascertainment and produce an instrument measuring lifetime likelihood of having had TS, clinical members of the American Tourette Syndrome Association International Genetic Collaboration have developed the Diagnostic Confidence Index (DCI) (Robertson, Banerjee, Kurlan et al., 1999). The DCI produces a score from 0 to 100 that is a measure of the likelihood of having or ever having had TS. However, the DCI along with the ICD-10 and DSM-IV diagnostic groupings suffer from uncertainties on how best to categorize conditions that potentially encompass a broad range of symptoms that wax and wane in severity. Because the current nosological boundaries are set by convention and clinical practice, they may not reflect true etiological differences. Prevalence Children are 5–12 times more likely to be identified as having a tic disorder than adults (Burd, Kerbeshian, Wikenheiser, & Fisher, 1986a,b). Although boys are more commonly affected with tic behaviors than girls, the male : female ratio in most community surveys is less than 2:1. For example, in the Isle of Wight study of 10- to 11-year-olds, approximately 6% of boys and 3% of girls were reported by their parents to have “twitches, mannerisms, tics of face or body” (Rutter, Tizard, & Whitmore, 1970). Once thought to be rare, current estimates of the prevalence of TS vary 100-fold, from 2.9 per 10,000 (Caine, McBride, Chiverton et al., 1988) to 299 per 10,000 (Mason, Banerjee, Eapen, Zeitlin, & Robertson, 1998). In the largest study to date, Apter, Pauls, Bleich et al. (1993) have reported a prevalence rate of 4.5 per 10,000 for full-blown TS among 16- to 17- year-olds in Israel. More recently, Khalifa and von Knorring (2003, 2005) studied a total population of 4479 Swedish children aged 7–15 years. Twenty-five were identified as having TS, yielding a prevalence estimate of 5.6 per 1000 pupils. Clinical Descriptions and Natural History With the exception of TS (Bloch, Landeros-Weisenberger, Kelmendi et al., 2006b; Leckman, Zhang, Vitale et al., 1998b), relatively few cross-sectional or longitudinal studies of tic dis9781405145497_4_044.qxd 29/03/2008 02:53 PM Page 720

TIC DISORDERS 721 They can involve dystonic movements. In a small fraction of cases (<5%), complex motor tics have the potential to be selfinjurious. These self-injurious symptoms may be relatively mild (e.g., slapping or tapping) or quite dangerous (e.g., punching one side of the face, biting a wrist or gouging eyes to the point of blindness). On average, phonic tics begin 1–2 years after the onset of motor symptoms and are usually simple in character (e.g., throat clearing, grunting and squeaks). More complex vocal symptoms such as echolalia (repeating another’s speech), palilalia (repeating one’s own speech) and coprolalia occur in a minority of cases. Other complex phonic symptoms include dramatic and abrupt changes in rhythm, rate and volume of speech. Motor and phonic tics tend to occur in bouts. Their frequency ranges from non-stop bursts that are virtually uncountable (>100 tics per minute) to rare events that occur only a few times a week. Single tics may occur in isolation or there may be orchestrated combinations of motor and phonic tics that involve multiple muscle groups. The forcefulness of motor tics and the volume of phonic tics can also vary from behaviors that are not noticeable (a slight shrug or a hushed guttural noise) to strenuous displays (arm thrusts or loud barking) that are frightening and exhausting. During periods of waxing tic symptoms, clinicians may find themselves under extreme pressure to intervene medically. While such interventions may be warranted, it is often the case that the tic symptoms will wane substantially within a few weeks. By the age of 10 years, most children and adolescents have some awareness of the premonitory urges that frequently precede both motor and vocal tics. These urges add to the subjective discomfort associated with having a tic disorder. They may also contribute to an individual’s ability to suppress their tics for longer periods of time. The factors that determine the degree of disability and handicap versus resiliency are largely unknown. They are likely to include the presence of additional developmental, mental and behavioral disorders; the level of support and understanding from parents, peers and educators; and the presence of special abilities (as in sports) or personal attributes (intelligence, social abilities and personality traits). The behavioral and emotional problems that frequently complicate TS range from impulsive, “disinhibited” and immature behavior to compulsive touching or sniffing. At present, there are no clear dividing lines between these disruptive behaviors and complex tics on the one hand and comorbid conditions of ADHD and obsessivecompulsive disorder (OCD) on the other. Some investigators believe that the “spectrum” of TS includes attentional deficits, impulsivity, hyperactivity, disruptive behavior, learning disabilities, pervasive developmental disorders and affective and anxiety disorders, as well as tics and OCD (Comings, 1988). Although children with TS can be loving and affectionate, maintaining age-appropriate social skills is a particularly difficult area for many of them (Bawden, Stokes, Camfield, Camfield, & Salisbury, 1998; Dykens, Leckman, Riddle et al., 1990; Stokes, Bawden, Camfield, Backman, & Dooley, 1991). Whether this is because of the stigmatizing effects of the tics, the patient’s own uneasiness or some more fundamental difficulty linked to the neurobiology of this disorder is unknown. Tic disorders tend to improve in late adolescence and early adulthood. In many instances, the phonic symptoms become increasingly rare or may disappear altogether, and the motor tics may be reduced in number and frequency. Complete remission of both motor and phonic symptoms has also been reported (Shapiro, Shapiro, Young et al., 1988). In contrast, adulthood is also the period when the most severe and debilitating forms of tic disorder can be seen. The factors that influence the continuity of tic disorders from childhood to adolescence to adulthood are not well understood but likely involve the interaction of normal maturational processes occurring in the CNS with the neurobiological mechanisms responsible for TS, the exposure to cocaine, other CNS stimulants, androgenic steroids and the amount of intramorbid emotional trauma and distress experienced by affected individuals during childhood and adolescence. In addition, tic disorders may be etiologically separable so that some of these factors, such as activation of the immune system or exposure to heat stress, may influence the pathogenesis and intramorbid course for some tic disorders but not others. Other factors, such as psychological stress, may have a more uniform impact. Coexisting Conditions The past decade has seen a renewed emphasis on the range of neurological and psychiatric symptoms seen in patients with TS (Leckman & Cohen, 1998). In both clinical and epidemiological samples, TS alone is the exception rather than the rule (Khalifa & von Knorring, 2005, 2006). Symptoms associated with ADHD and OCD have received the most attention. It is also becoming clear that the more severe the tic disorder, the greater the likelihood of detecting coexisting conditions, even in representative population-based samples (Khalifa & von Knorring, 2005). Coexisting Attention Deficit Hyperactivity Disorder Both clinical and epidemiological studies vary according to setting and established referral patterns, but it is not uncommon to see reports of 30–50% of children with TS diagnosed with comorbid ADHD (Khalifa & von Knorring, 2006). TS has the highest rate of ADHD relative to the other lesser variants of tic disorders. Although the etiological relationship between TS and ADHD is in dispute, it is clear that those individuals with both TS and ADHD are at a much greater risk for a variety of untoward outcomes (Carter, O’Donnell, Schultz et al., 2000; Peterson, Pine, Cohen, & Brook, 2001a; Sukhodolsky, Scahill, Zhang et al., 2003, Sukhodolsky, do Rosario-Campos, Scahill et al., 2005). They are often regarded as less likeable, more aggressive and more withdrawn than their classmates (Stokes, Bawden, Camfield et al., 1991). These social difficulties are amplified in a child with TS who also has ADHD (Bawden, Stokes, Camfield et al., 1998; Dykens, Leckman, Riddle et al., 1990; Sukhodolsky, Scahill, Zhang 9781405145497_4_044.qxd 29/03/2008 02:53 PM Page 721

CHAPTER 44 722 et al., 2003, Sukhodolsky, do Rosario-Campos, Scahill et al., 2005). Surprisingly, levels of tic severity are less predictive of peer acceptance than is the presence of ADHD (Bawden, Stokes, Camfield et al., 1998). Obsessive-Compulsive Symptoms More than 40% of individuals with TS experience recurrent obsessive-compulsive (OC) symptoms (Hounie, do RosarioCampos, Diniz et al., 2006; Khalifa & von Knorring, 2005; Leckman, Walker, Goodman et al., 1994, Leckman, Grice, Boardman et al., 1997). Genetic, neurobiological and treatment response studies suggest that there may be qualitative differences between tic-related forms of OCD and cases of OCD in which there is no personal or family history of tics. Specifically, tic-related OCD has a male preponderance, an earlier age of onset, a poorer level of response to standard antiobsessional medications and a greater likelihood of first-degree family members with a tic disorder (Hounie, do RosarioCampos, Diniz et al., 2006). Symptomatically, the most common OC symptoms encountered in TS patients are obsessions concerning a need for symmetry or exactness, repeating rituals, counting compulsions and ordering/arranging compulsions (Leckman, Grice, Boardman et al., 1997). Also, OC symptoms, when present in children with TS, appear more likely to persist into adulthood than the tics themselves (Bloch, LanderosWeisenberger, Kelmendi et al., 2006b). Coexisting Depression and Anxiety Disorders The co-occurrence of depression and anxiety symptoms with TS is commonplace and may reflect the cumulative psychosocial burden of having tics or shared biological diatheses or both (Robertson & Orth, 2006; Robertson, Williamson, & Eapen, 2006). Antecedent depressive symptoms do predict modest increases in tic severity (Lin, Katsovich, Ghebremichael et al., 2007). However, this study also documented that future depression severity is more closely associated with antecedent worsening of psychosocial stress and OC symptoms than it is with future measures of tic severity. Other Developmental and Neurological Disorders Children with a range of developmental disorders are at increased risk for tic disorders. Kurlan, Whitmore, Irvine, McDermott, and Como (1994) reported a four-fold increase in the prevalence of tic disorders among children in special educational settings in a single school district in upstate New York. These children were not intellectually impaired but did have significant learning disabilities or other speech or physical impairments. Children with autism and other pervasive developmental disorders are also at higher risk for developing TS (BaronCohen, Mortimore, Moriarty, Izaguirre, & Robertson, 1999). Neurophysiological Findings Although motor and phonic tics constitute the core elements of the diagnostic criteria for TS, perceptual and cognitive difficulties are also common. These neuropsychological symptoms are potentially informative about the pathobiology of the disorder. Moreover, these associated difficulties can be more problematic for school and social adjustment than the primary motor symptoms. Review of the literature suggests that the most consistently observed deficits occur on tasks requiring the accurate copying of geometric designs (i.e., “visual–motor integration” or “visual–graphic” ability; Schultz, Carter, Gladstone et al., 1998). Even after controlling statistically for visual–perceptual skill, intelligence and fine motor control, children with TS performed worse than controls on the visual–motor tasks, suggesting that the integration of visual inputs and organized motor output is a specific area of weakness. Poorer performance with the dominant hand on the Purdue Pegboard test during childhood is associated with worse adulthood tic severity (Bloch, Sukhodolsky, Leckman et al., 2006c). In studies of procedural memory (habit learning), children with severe tic symptoms had a higher level of impairment than those with less severe symptoms. In contrast, no deficits were seen in declarative memory functioning (Keri, Szlobodnyik, Benedek, Jenka, & Gadoros, 2002; Marsh, Alexander, Packard et al., 2004, Marsh, Alexander, Packard et al., 2005). Etiology and Pathogenesis Genetic Factors Twin and family studies provide evidence that genetic factors are involved in the vulnerability to TS and related disorders (Pauls & Leckman, 1986). The concordance rate for TS among monozygotic twin pairs is greater than 50% while the concordance of dizygotic twin pairs is about 10% (Price, Kidd, Cohen, Pauls, & Leckman, 1985). If cotwins with chronic motor tic disorder are included, these concordance figures increase to 77% for monozygotic and 30% for dizygotic twin pairs. These differences in the concordance of monozygotic and dizygotic twin pairs indicate that genetic factors have an important role in the etiology, but the fact that concordance for monozygotic twins is less than 100% also indicates that non-genetic factors are critical in determining the nature and severity of the clinical syndrome. Other studies indicate that first-degree family members of probands with TS are at substantially higher risk for developing TS, chronic motor tic disorder and OCD than unrelated individuals (Pauls, Raymond, Stevenson, & Leckman, 1991). The rates are substantially higher than might be expected by chance in the general population, and greatly exceed the rates for these disorders among the relatives of individuals with other psychiatric disorders except OCD. The pattern of vertical transmission among family members has led several groups of investigators to test specific genetic hypotheses. While not definitive, segregation analyses could not rule out autosomal transmission (Pauls & Leckman, 1986). However, subsequent efforts to identify susceptibility genes within large multigenerational families or using affected 9781405145497_4_044.qxd 29/03/2008 02:53 PM Page 722

sibling pair designs have met with limited success (Tourette Syndrome Association International Consortium for Genetics, 1999, 2007). In addition, a number of cytogenetic abnormalities have been reported in TS families (Cuker, State, King, Davis, & Ward, 2004; State, Greally, Cuker et al., 2003). Among the more recent findings, Verkerk, Mathews, Joosse et al. (2003) reported the disruption of the contactin-associated protein 2 gene on chromosome 7. This gene encodes a membrane protein located at nodes of Ranvier of axons that may be important for the distribution of the K+ channels, which would affect signal conduction along myelinated neurons. In addition, using a candidate gene approach identified by chromosomal anomalies, Abelson, Kwan, O’Roak et al. (2005) identified and mapped a de novo chromosome 13 inversion in a patient with TS. The gene SLITRK1 was identified as a brain-expressed candidate gene mapping approximately 350 kb from the 13q31 breakpoint. Mutation screening of 174 patients was undertaken with the resulting identification of a truncating frameshift mutation in a second family affected with TS. In addition, two examples of a rare variant were identified in a highly conserved region of the 3′ untranslated region of the gene corresponding to a brain-expressed micro-RNA binding domain. None of these anomalies was demonstrated in 3600 controls. In vitro studies showed that both the frameshift and the micro-RNA binding site variant had functional potential and were consistent with a loss-of-function mechanism. Studies of both SLITRK1 and the micro-RNA predicted to bind in the variant-containing 3′ region showed expression in multiple neuroanatomical areas implicated in TS neuropathology, including the cortical plate, striatum, globus pallidus, thalamus and subthalamic nucleus. Neural Circuits Neuroanatomy Investigators interested in procedural learning, habit formation and internally and externally guided motor control have focused their attention on multisynaptic cortico-striato-thalamocortical (CSTC) circuits or loops that link the cerebral cortex with several subcortical regions (Graybiel & Canales, 2001; Middleton & Strick, 2000). As a result the most widely accepted neuroanatomical model of TS proposes a regional imbalance of the direct vs. the indirect pathway within one of more of these CSTCs (Albin & Mink, 2006). In the direct pathway, an excitatory glutamatergic signal projects to the striatum, sending an inhibitory gamma-aminobutyric acid (GABA)-ergic signal to the internal part of the globus pallidus. This signal results in a decreased inhibition (disinhibition) of the thalamus and thus an increased excitatory effect on the prefrontal cortex. In the indirect pathway, the striatum projects an inhibitory signal to the external part of the globus pallidus and the subthalamic nucleus, sending an excitatory signal to the internal part of the globus pallidus. The net effect is an increased inhibition of the thalamus and decreased excitation of the prefrontal cortex. It is hypothesized that the direct pathway functions as a self-reinforcing positive feedback loop and contributes to the initiation and continuation of behaviors, whereas the indirect pathway provides a mechanism of negative feedback which is important for the inhibition of behaviors and in switching between behaviors. Based on postmortem studies, as well as structural and functional neuroimaging studies, it appears that an imbalance between these frontal–striatal circuits might mediate tic symptomatology as well as that of related disorders. Neuropathological Data Although neuropathological studies of postmortem TS brains are few in number, a recent stereological study indicates that there is a marked alteration in the number and density of GABA-ergic parvalbumin-positive cells in basal ganglia structures (Kalanithi, Zheng, Kataoka et al., 2005). In the caudate there was a greater than 50% reduction in the GABA-ergic fast spiking interneurons and a 30–40% reduction of these same cells in the putamen. This same study found a reduction of the GABA-ergic parvalbumin-positive projection neurons in the external segment globus pallidus (GPe) as well as a dramatic increase (>120%) in the number and proportion of GABA-ergic projection neurons of the internal segment of the globus pallidus. These alterations are consistent with a developmental defect in tangential migration of some GABA-ergic neurons. Further studies are needed to confirm and extend these findings, such as toward a more complete understanding of how the different striatal interneurons are affected, and to determine how alterations in GABA-ergic interneurons and globus pallidus projection neurons could lead to a form of thalamocortical dysrhythmia (Leckman, Vaccarino, Kalanithi, & Rothenberger, 2006; Llinas, Urbano, Leznik, Ramirez, & van Marle, 2005). Structural Brain Imaging Volumetric magnetic resonance imaging (MRI) studies of basal ganglia in individuals with TS are largely consistent with these postmortem results – with the finding of a slight reduction in caudate volume (Hyde, Stacey, Coppola et al., 1995; Peterson, Thomas, Kane et al., 2003). For example, in a study of 154 subjects with TS and 130 healthy controls, Peterson, Thomas, Kane et al. (2003) found a significant decrease in the volume of the caudate nucleus in both children and adults. Although there was no correlation between symptom severity and caudate volumes in this cross-sectional study, Bloch, Leckman, Zhu, and Peterson (2005) found an inverse correlation between caudate volumes measured in childhood and tic severity rated in early adulthood. The same group of individuals with TS had larger volumes in dorsal prefrontal regions, larger volumes in parieto-occipital regions, and smaller inferior occipital volumes (Peterson, Staib, Scahill et al., 2001b). Regional cerebral volumes were significantly associated with the severity of tic symptoms in orbitofrontal, midtemporal and parieto-occipital regions. This may reflect the natural history of the disorder, or brain compensations, or may yet be explained by other subtle confounding variables, such as the manner in which brain volumes are determined in different studies. In addition, Lee, Yoo, Cho TIC DISORDERS 723 9781405145497_4_044.qxd 29/03/2008 02:53 PM Page 723

et al. (2006) used volumetric MRI methods to compare thalamic volume in 18 treatment-naïve boys with 16 healthy control subjects, finding larger left thalamic volume in the TS cases. More volumetric studies using comparable methods across all implicated brain regions are needed to clarify the brain morphology of TS. Functional Brain Imaging Thus far, there have only been a few published studies of TS using functional magnetic resonance imaging (fMRI), which takes advantage of state-dependent blood oxygenation as a measure of brain activity. In adults with TS, Peterson, Skudlarski, Anderson et al. (1998a) compared brain activity during blocks of time during which tics were voluntarily suppressed or not suppressed. During tic suppression, prefrontal cortical, thalamic and basal ganglia areas were activated. These activations were inversely correlated with tic severity (i.e., lower activation was associated with higher tic severity). This suggests that a greater ability of basal ganglia to suppress cortical activity might be linked with decreased tic severity, and is in agreement with single photon emission computed tomography (SPECT) and positron emission tomography (PET) studies that suggest involvement of the basal ganglia in TS (Braun, Randolph, Stoetter et al., 1995). More recently, Bohlhalter, Goldfine, Matteson et al. (2006) studied the neural correlates of tics and associated urges using an event-related fMRI protocol. On the basis of synchronized video/audio recordings, fMRI activities were analyzed 2 s before and at tic onset. A brain network of paralimbic areas including the anterior cingulate and insular cortex, supplementary motor area and parietal operculum was found to be activated before tic onset. In contrast, at the beginning of tic action, significant fMRI activities were found in sensorimotor areas including superior parietal lobule bilaterally and cerebellum. The results of this study indicate that paralimbic and sensory association areas are critically implicated in tic generation. Changes in the coupling of the putamen and ventral striatum with a number of other brain regions also differentiate patients with TS from controls. For example in PET studies, Jeffries, Schooler, Schoenbach et al. (2002) noted a reversal in the pattern of CSTC circuit interactions in motor and lateral orbitofrontal cortices. Similarly, Stern, Silbersweig, Chee et al. (2000) found that increased activity in a set of neocortical, paralimbic and subcortical regions (including supplementary motor, premotor, anterior cingulate, dorsolateral–rostral prefrontal and primary motor cortices, Broca’s area, insula, claustrum, putamen and caudate) were highly correlated with tic behavior. Perhaps not surprisingly, in the one patient with prominent coprolalia the vocal tics were associated with increased activity in prerolandic and postrolandic language regions, insula, caudate, thalamus and cerebellum. Neurophysiology Non-invasive in vivo neurophysiological research in TS has led to several areas of significant progress. The first concerns the use of a startle paradigm to measure inhibitory deficits by monitoring the reduction in startle reflex magnitude. Swerdlow, Karban, Ploum et al. (2001) have confirmed and extended earlier findings indicating that patients with TS have deficits in sensory gating across a number of sensory modalities. Prepulse inhibition abnormalities have been observed across a variety of neuropsychiatric populations including schizophrenia, OCD, Huntington’s disease, nocturnal enuresis, ADHD, Asperger syndrome and TS, suggesting that some final common pathways mediate abnormal prepulse inhibition in all of these conditions. With respect to TS, these deficits are consistent with the idea that there is diminished ability to appropriately manage or “gate” sensory inputs to motor programs, which are released as tics (Swerdlow & Sutherland, 2006). A second advance has been the investigation of motor system excitability by means of single and paired pulse transcranial magnetic stimulation. Studies of groups of patients with TS have indicated that the cortical silent period (a period of decreased excitability following stimulation) is shortened. This intracortical excitability is frequently seen in children with ADHD comorbid with a tic disorder (Moll, Wischer, Heinrich et al., 1999; Ziemann, Paulus, & Rothenberger, 1997). This heightened level of cortical excitability may be related to a reduction in the number of GABA-ergic interneurons in the cortex. Serrien, Orth, Evans, Lees, & Brown (2005) recently identified similar sensorimotor–frontal connections involved in the acute suppression of involuntary tics as evidenced by increased EEG coherence in the alpha frequency band (8–12 Hz) during suppression of voluntary movements in individuals with TS and healthy subjects during a Go–NoGo task. This finding, taken with the functional findings from Peterson, Skudlarski, Anderson et al. (1998a), suggests that the frontal lobes may have a key role in tic suppression, and coherence in the alpha band may be part of this process. The preliminary findings that ablation (or high-frequency stimulation using deep brain electrodes) in regions of the globus pallidus and/or the midline thalamic nuclei can ameliorate tics in severe persistent cases of TS (Hassler & Dieckmann, 1973; Vandewalle, Van der Linden, Groenwegen, & Caemaert, 1999) powerfully support the view that electrophysiological studies and interventions hold promise just as they do for disorders such as Parkinson’s disease. Prospective longitudinal studies with higher resolution will be needed to examine fully the developmental processes, sexual dimorphisms and possible effects of medication on critical cell compartments. It will also be important to confirm if any of these volumetric and functional findings in childhood are predictive of later clinical outcomes. The combination of imaging techniques with real-time neurophysiological techniques, such as electroencephalography or magnetoencephalography, may help to determine whether any abnormalities seen on brain imaging contribute to the production of tics or whether they constitute a compensatory response (Leckman, Vaccarino, Kalanithi et al., 2006; Llinas, Urbano, Leznik et al., 2005). CHAPTER 44 724 9781405145497_4_044.qxd 29/03/2008 02:53 PM Page 724

and an increased number of GABA-ergic projection neurons in the globus pallidus are confirmed, this may provide a basis for understanding the anatomical and neurophysiological origins of some cases of severe TS (Kalanithi, Zheng, Kataoka et al., 2005; Leckman, Vaccarino, Kalanithi et al., 2006). Cholinergic Systems Cholinergic projections from the basal forebrain are found throughout the cortex and within key structures of the basal ganglia and mesencephalon, including the internal segment of the globus pallidos (GP), the pars reticulata of the substantia nigra, and the locus ceruleus. Evidence of cholinergic involvement in the pathobiology of TS comes from the reported potentiation of D2 dopamine receptor blocking agents through the use of transdermal nicotine or nicotine gum (Sanberg, Silver, Shytle et al., 1997). Noradrenergic Systems Noradrenergic projections from the locus ceruleus project innervate the prefrontal and other cortical regions. Noradrenergic pathways are also likely to indirectly influence central dopaminergic pathways via projections to areas near the ventral tegmental area (Grenhoff & Svensson, 1989). Speculation that noradrenergic mechanisms might be relevant to the pathobiology of TS was based initially on the beneficial effects of α2-adrenergic agonists including clonidine and guanfacine. The involvement of the noradrenergic pathways may be one mechanism by which stressors influence tic severity. For example, a series of adults with TS had elevated levels of cerebrospinal fluid (CSF) norepinephrine (Leckman, Goodman, Anderson et al., 1995) and excreted high levels of urinary norepinephrine in response to the stress of the lumbar puncture (Chappell, Riddle, Anderson et al., 1994). These elevated levels of CSF norepinephrine may also contribute to the elevation in levels of CSF corticotopin-releasing factor seen in some patients with TS (Chappell, Leckman, Goodman et al., 1996). Serotonergic Systems Ascending serotonergic projections from the dorsal raphe have been invoked as playing a part in the pathophysiology of both TS and OCD. The most compelling evidence relates to OCD and is based largely on the well-established efficacy of potent serotonin reuptake inhibitors such as clomipramine and fluvoxamine in the treatment of OCD. However, some investigators have reported that the serotonin reuptake inhibitors are less effective in treating tic-related OCD than other forms of OCD (McDougle, Goodman, Leckman et al., 1993). Gender-Specific Endocrine Factors Males are more frequently affected with TS than females (Shapiro, Shapiro, Young et al., 1988), but male–male transmission within families rules out the presence of an X-linked vulnerability gene. This observation has led us to hypothesize that androgenic steroids act at key developmental periods to influence the natural history of TS and related disorders TIC DISORDERS 725 Neurochemical and Neuropharmacological Data Extensive immunohistochemical studies of the basal ganglia have demonstrated the presence of a wide spectrum of classic neurotransmitters, neuromodulators and neuropeptides. The most compelling data have implicated central dopaminergic systems in the pathobiology of TS (Albin & Mink, 2006). Dopaminergic Systems Explicit “dopamine” hypotheses for TS posit either an excess of dopamine release or an increased sensitivity of D2 dopamine receptors. These hypotheses are consistent with multiple lines of empirical evidence as well as emerging data from animal models of habit formation. Data implicating central dopaminergic mechanisms include the results of doubleblind clinical trials in which haloperidol, pimozide, tiapride and other neuroleptics that preferentially block dopaminergic D2 receptors have been found to be effective in the temporary suppression of tics for a majority of patients (Scahill, Erenberg, Berlin et al., 2006). Tic suppression has also been reported following administration of agents such as tetrabenazine that reduce dopamine synthesis (Kenney & Jankovic, 2006). Increased tics have been reported following withdrawal of neuroleptics or following exposure to agents that increase central dopaminergic activity such as l-dopa and CNS stimulants, including cocaine. Using these imaging techniques, a number of investigators have also found increased levels of dopaminergic innervation of the striatum in TS subjects compared with controls (Albin, Koeppe, Bohne et al., 2003; Cheon, Ryu, Namkoong et al., 2004; Malison, McDougle, van Dyck et al., 1995; Singer, Szymanski, Giuliano et al., 2002; Wolf, Jones, Knable et al., 1996). Although not all studies agree, the strongest evidence suggests an increased density of dopaminergic terminals in the ventral striatum (Albin, Koeppe, Bohne et al., 2003). Postmortem brain studies have reported alterations in the number or affinity of presynaptic dopamine carrier sites in the striatum (Singer, Hahn, & Moran, 1991). In summary, while the evidence that dopaminergic pathways are intimately involved in the pathobiology of TS is compelling, the exact nature of the abnormality remains to be elucidated but likely involves the potentiation of limbic inputs to the striatum. Amino Acid Systems The excitatory neurotransmitter glutamate is released upon depolarization by the corticostratial, corticosubthalamic, subthalamic and thalamocortical projection neurons. These excitatory neurons are key players in the functional anatomy of the basal ganglia and the CSTC loops and likely have a crucial role in the emergence of tics as well as related normal behaviors. Neurons containing inhibitory amino acid neurotransmitters, particularly GABA, also form major portions of CSTC loops and are also present in key sets of interneurons in the cortex, striatum and thalamus. If the initial reports of a reduced number of GABA-ergic fast-spiking interneurons in the caudate 9781405145497_4_044.qxd 29/03/2008 02:53 PM Page 725

(Peterson, Leckman, Scahill et al., 1992). These developmental periods include the prenatal period when the brain is being formed, adrenarche when adrenal androgens first appear at age 5–7 years, and puberty. Androgenic steroids may be responsible for these effects or they may act indirectly through estrogens formed in key brain regions by the aromatization of testosterone. The importance of gender differences in expression of associated phenotypes is also clear given the observation that women are more likely than men to develop OC symptoms without concomitant tics (Pauls, Raymond, Stevenson et al., 1991) and that boys with TS are much more likely than girls to display ADHD disruptive behaviors. Surges in testosterone and other androgenic steroids during critical periods in fetal development are involved in the production of long-term functional augmentation of subsequent hormonal challenges (as in adrenarche and during puberty) and in the formation of structural CNS dimorphisms (Sikich & Todd, 1988). Sexually dimorphic brain regions include portions of the amygdala (and related limbic areas) and the hypothalamus (including the medial preoptic area, which mediates the body’s response to thermal stress; Boulant, 1981). These regions contain high levels of androgen and estrogen receptors and influence activity in the basal ganglia both directly and indirectly. Indeed, a proportion of patients with TS appear to be uniquely sensitive to thermal stress such that when their core body temperature increases and they begin to sweat their tics increase (Lombroso, Mack, Scahill, King, & Leckman, 1991). It is also of note that some of the neurochemical and neuropeptidergic systems implicated in TS and related disorders, such as dopamine, serotonin and the opioids, are involved with these regions and appear to be regulated by sex-specific factors. Further support for a role for androgens comes from anecdotal reports of tic exacerbation following androgen use (Leckman & Scahill, 1990) and from trials of antiandrogens in patients with severe TS and/or OCD (Peterson, Zhang, Anderson, & Leckman, 1998b). In the most rigorous study to date, Peterson, Zhang, Anderson et al. (1998b) found that the therapeutic effects of the antiandrogen flutamide were modest in magnitude and these effects were short-lived, possibly because of physiological compensation for androgen receptor blockade. The view that sex steroids of gonadal origin organize the neural circuits of the developing brain has recently been challenged by the finding that, independent of the masculinizing effects of gonadal secretions, XY and XX brain cells have different patterns of gene expression that influence their differentiation and function. Remarkably, one of the male-specific genes, Sry, is specifically expressed in the dopamine-containing cells of the substantia nigra (Dewing, Chiang, Sinchak et al., 2006). It appears that Sry directly affects the function of these dopaminergic neurons and the specific motor behaviors they control. Because these results demonstrate a direct malespecific effect on the brain by a gene encoded only in the male genome, without any mediation by gonadal hormones, it is possible that allelic variation or epigenetic effects at this locus may be important in the pathophysiology of TS. Perinatal Risk Factors The search for non-genetic factors that mediate the expression of a genetic vulnerability to TS and related disorders has also focused on the role of adverse perinatal events. This interest dates from the report of Pasamanick and Kawi (1956) who found that mothers of children with tics were 1.5 times more likely to have experienced a complication during pregnancy than the mothers of children without tics. Further, among monozygotic twins discordant for TS, the index twins with TS had lower birth weights than their unaffected cotwins (Hyde, Stacey, Coppola et al., 1995; Leckman, Price, Walkup et al., 1987). Low Apgar scores, severity of maternal life stress during pregnancy, maternal smoking, and severe nausea and/ or vomiting during the first trimester have also emerged as potential risk factors in the development of tic disorders (Burd, Severud, Klug, & Kerbeshian, 1999; Leckman, Dolnansky, Hardin et al., 1990; Mathews, Bimson, Lowe et al., 2006). Finally, there is limited evidence that smoking and alcohol use, as well as forceps delivery, can predispose individuals with a vulnerability to TS to develop comorbid OCD (Santangelo, Pauls, Goldstein et al., 1994). The only nested case–control study to date, which examined TS cases arising in a Swedish community sample, found that the mothers of children with TS were two times more likely to have had complications during pregnancy (Khalifa & von Knorring, 2005). Post-Infectious Autoimmune Mechanisms It is well established that group A β hemolytic streptococci (GABHS) can trigger immune-mediated disease in genetically predisposed individuals (Bisno, 1991). Speculation concerning a post-infectious (or at least a post-rheumatic fever) etiology for tic disorder symptoms dates from the late 1800s (Kushner, 1999). Acute rheumatic fever is a delayed sequela of GABHS, occurring approximately 3 weeks following an inadequately treated upper respiratory tract infection. Rheumatic fever is characterized by inflammatory lesions involving the heart (rheumatic carditis), joints (polymigratory arthritis) and/or central nervous system (Sydenham’s chorea). The immune response in the CNS of patients with Sydenham’s chorea appears to involve molecular mimicry between streptococcal antigens and self-antigens (Kirvan, Swedo, Heuser, & Cunningham, 2003). Sydenham’s chorea and TS, OCD and ADHD share common anatomical targets – the basal ganglia of the brain and the related cortical and thalamic sites (Husby, van de Rijn, Zabriskie, Abdin, & Williams, 1976). Furthermore, people with Sydenham’s chorea frequently display motor and vocal tics, OC and ADHD symptoms, suggesting the possibility that at least in some instances these disorders share a common etiology (Swedo, Rapoport, Cheslow et al., 1989). It has been proposed that pediatric autoimmune neuropsychiatric disorder associated with streptococcal infection (PANDAS) represents a distinct clinical entity, and includes Sydenham’s chorea and some cases of TS and OCD (see CHAPTER 44 726 9781405145497_4_044.qxd 29/03/2008 02:53 PM Page 726

and ADHD. However, these data are not compelling with regard to specific immunological mechanisms, nor do they establish where in the sequence of causal events these immune changes occur. These potentially important findings require replication in independent samples and warrant more intensive investigation using prospective longitudinal designs. Psychological Factors Tic disorders have long been identified as “stress-sensitive” conditions. Typically, symptom exacerbations follow in the wake of stressful life events. As noted by Shapiro, Shapiro, Young et al. (1988), these events need not be adverse in character. Clinical experience suggests that in some instances a vicious cycle is initiated in which attempts to suppress the symptoms by punishment and humiliation lead to a further exacerbation of symptoms and further increase in stress in the child’s interpersonal environment. Unchecked, this vicious cycle can lead to the most severe manifestations of TS. Prospective longitudinal studies have shown that patients with TS experience more stress than matched healthy controls (Findley, Leckman, Katsovich et al., 2003) and that antecedent stress may have a role in subsequent tic exacerbation (Lin, Katsovich, Ghebremichael et al., 2007). Increases in depressive symptoms have also emerged as a significant predictor of future tic severity (Lin, Katsovich, Ghebremichael et al., 2007). In addition to the intramorbid effects of stress, anxiety and depression, premorbid stress may also act as a sensitizing agent in the pathogenesis of TS among vulnerable individuals (Leckman, Cohen, Price et al., 1984). It is likely that the immediate family environment (e.g., parental discord) and the coping abilities of family members have some role (Leckman, Dolnansky, Hardin et al., 1990), and this may lead to a sensitization of stress responsive biological systems such as the hypothalamic–pituitary–adrenal axis (Chappell, Riddle, Anderson et al., 1994, Chappell, Leckman, Goodman et al., 1996; Leckman, Goodman, Anderson et al., 1995). Differential Diagnosis The differential diagnosis of simple motor tics includes a variety of hyperkinetic movements: myoclonus, tremors, chorea, athetosis, dystonias, akathitic movements, paroxysmal dyskinesias, ballistic movements and hyperekplexia (Jankovic & Mejia, 2006). These movements may be associated with genetic conditions such as Huntington’s chorea or Wilson’s disease; structural lesions, as in hemiballismus (associated with lesions to the contralateral subthalamic nucleus); infectious processes as in Sydenham’s chorea; idiopathic functional instability of neuronal circuits, as in myoclonic epilepsy; and pharmacological treatments such as acute akathisia and dystonias associated with the use of neuroleptic agents. Differentiation between these conditions and tic disorders is usually based on the presentation of the disorder and its natural history. Although aspects of tics such as their abruptness, their paroxysmal timing or their suppressible nature may be similar TIC DISORDERS 727 chapter 43; Swedo, Leonard, Garvey et al., 1998). The most compelling evidence of an etiological link between these disorders and GABHS infection comes from a study that found an increased proportion of GABHS infections (odds ratio 13.6) within the preceding 12 months in children newly diagnosed with TS compared with well-matched controls (Mell, Davis, & Owens, 2005). The PANDAS hypothesis is indirectly supported by the presence of high levels of antistreptococcal antibodies in some patients with TS (Cardona & Orefici, 2001; Church, Dale, Lees, Giovannoni, & Robertson, 2003). Thus far, however, prospective longitudinal studies have provided little support for the idea that GABHS infections induce future tic exacerbations (Luo, Leckman, Katsovich et al., 2004; Perrin, Murphy, Casey et al., 2004). A number of studies have been designed to detect and characterize the putative cross-reactive epitopes. Patients with TS may have higher levels of circulating antineural antibodies (Church, Dale, Lees et al., 2003; Morshed, Parveen, Leckman et al., 2001; Singer, Giuliano, Hansen et al., 1998), but no specific epitopes have been unequivocally identified (Dale, Candler, Church, & Pocock, 2004; Kirvan, Swedo, Heuser, & Cunningham, 2006; Singer, Hong, Yoon, & Williams, 2005a). Animal models that involve the injection of patient sera high in levels of antineural antibodies into tic-related basal ganglia areas have also led to equivocal results (Singer, Mink, Loiselle et al., 2005b). However, there is evidence that tic and OC symptoms may improve following plasma exchange in selected patients with the PANDAS phenotype (Perlmutter, Leitman, Garvey et al., 1999). Additional evidence that acute exacerbations of TS and OCD could also be triggered by GABHS comes from four independent reports demonstrating that the majority of patients with childhood-onset TS or OCD have elevated expression of a stable B-cell marker (Hoekstra, Bijzet, Limburg et al., 2001; Luo, Leckman, Katsovich et al., 2004; Swedo, Leonard, Mittleman et al., 1997). The D8/17 marker identifies close to 100% of rheumatic fever patients (with or without Sydenham’s chorea) but is present at low levels of expression in healthy control populations. The bias for studies addressing the role of B-cell immunity in TS pathogenesis has been driven by the common view that GABHS is an extracellular bacterium and that its clearance is mediated primarily by antibodies. However, GABHS can be internalized in human cells with the same frequency as the classic intracellular pathogens Listeria and Salmonella species and activates human T lymphocytes (Degnan, Kehoe, & Goodacre, 1997). This topic is just beginning to be addressed with the finding that there may be a reduced number of regulatory T cells in selected patients with TS (Kawikova, Leckman, Kronig et al., 2007). There is also a single report that suggests that individuals with TS may have elevated levels of proinflammatory cytokines under baseline conditions and a further increase during periods of tic exacerbations (Leckman, Katsovich, Kawikova et al., 2005). In summary, a substantial body of circumstantial evidence links post-infectious autoimmune phenomena with TS, OCD 9781405145497_4_044.qxd 29/03/2008 02:53 PM Page 727

to symptoms seen in other conditions, it is rare for all of these features to be combined in the absence of a bona fide tic disorder. Occasionally, diagnostic tests are needed to exclude alternative diagnoses. Complex motor tics can be confused with other complex repetitive behaviors such as stereotypies or compulsive rituals. Differentiation among these behaviors may be difficult, particularly among retarded individuals with limited verbal skills. In other settings where these symptoms are closely intertwined, as in individuals with both TS and OCD, efforts to distinguish between complex motor tics and compulsive behaviors may be futile. In cases of a tic disorder, it is unusual to see complex motor tics in the absence of simple tics. Involuntary vocal utterances are uncommon neurological signs in the absence of a tic disorder. Examples include sniffing and uttering brief sounds in Huntington’s disease and involuntary moaning in Parkinson’s disease, particularly as a result of l-dopa toxicity. Complex phonic tics characterized by articulate speech typically can be distinguished from other conditions including voluntary coprolalia. Because of their rarity in other syndromes, phonic tics can have an important role in differential diagnosis. Anamnesis, family history, observation and neurological examination are usually sufficient to establish the diagnosis of a tic disorder. There are no confirmatory diagnostic tests. Neuroimaging studies, electroencephalography (EEG) based studies and laboratory tests are usually non-contributory except in atypical cases. Assessment Once the diagnosis has been established, care should be taken to focus on the overall course of an individual’s development, not simply on his or her tic symptoms. This may be a particular problem in the case of TS, where the symptoms can be dramatic and there is the temptation to organize all of an individual’s behavioral and emotional difficulties under a single all-encompassing rubric. The principal goal of an initial assessment is to determine the individual’s overall level of adaptive functioning and to identify areas of impairment and distress (Leckman, King, Scahill et al., 1998a). Close attention to the strengths and weaknesses of the individual and his or her family is crucial. Relevant dimensions include the presence of comorbid mental, behavioral, developmental or physical disorders; family history of psychiatric and/or neurological disease; relationships with family and peers; school and/or occupational performance; and the history of important life events. Medication history is important, particularly if the disorder is long-standing or if medications have been prescribed for physical disorders. It may be necessary to evaluate the adequacy of the prior trials with pharmacological agents used to treat tic disorders. Inventories such as the Yale Child Study Center: Tourette’s Syndrome Obsessive-Compulsive Disorder Symptom Questionnaire (Leckman & Cohen, 1998, Appendix 1) completed by the family prior to their initial consultation can help gain a long-term perspective of the child’s developmental course and the natural history. In addition, several valid and reliable clinical rating instruments have been developed to quantify recent tic symptoms including the Yale Global Tic Severity Scale (YGTSS; Leckman, Riddle, Hardin et al., 1989), the Shapiro Tourette Syndrome Severity Scale (Shapiro, Shapiro, Young et al., 1988) and the Hopkins Motor and Vocal Tic Scale (Walkup, Rosenberg, Brown, & Singer, 1992). The YGTSS is a state-of-the-art, clinician-rated, semistructured scale that begins with a systematic inventory of tic symptoms that the clinician rates as present or absent over the past week. Current motor and phonic tics are then rated separately according to number, frequency, intensity, complexity and interference on a 6-point ordinal scale (0 = absent; 1–5 for severity) yielding three scores. Direct observational methods include videotaping ticcounting procedures or in vivo evaluation of tic symptoms (Chappell, Riddle, Anderson et al., 1994; Goetz, Pappert, Louis, Raman, & Leurgans, 1999). These direct observational methods are objective, but the frequency of tics varies according to setting and activity. In addition, many individuals with TS can suppress their symptoms for brief periods of time. In practice, videotaped tic counting appears to be most useful for acute research procedures that take place over several hours. Clinically, videotaping can be valuable when the diagnosis is in doubt or when tics are not observed in the consultation room. Treatment Tic disorders are frequently chronic, if not lifelong, conditions. Continuity of care is desirable and should be considered before embarking on a course of treatment. Usual clinical practice focuses initially on the educational and supportive interventions. Pharmacological treatments are typically held in reserve. Given the waxing and waning course of the disorders, it is likely that whatever is done (or not done) will lead in the short term to some improvement in tic severity. The decision to employ psychoactive medications is usually made after the educational and supportive interventions have been in place for a period of months and it is clear that the tic symptoms are persistently severe and are themselves a source of impairment in terms of self-esteem, relationships with the family or peers, or school performance. Educational and Supportive Interventions Educational activities are among the most important interventions available to the clinician. They should be undertaken first, not only with children with TS but also with those with milder presentations. Although the efficacy of these educational and supportive interventions has not been rigorously assessed, they appear to have positive effects by reshaping familial expectations and relationships (Cohen, Ort, Leckman, Riddle, & Hardin, 1988). This is particularly true when the family and others have misconstrued the tic symptoms as being CHAPTER 44 728 9781405145497_4_044.qxd 29/03/2008 02:53 PM Page 728

intentionally provocative. Families also find descriptions of the natural history comforting in that the disorders tend not to be relentlessly progressive and usually improve during adulthood. This information often contradicts the impressions gained from the available lay literature on TS, which typically focuses on the most extreme cases. Armed with this knowledge, patients and family members and others can begin to understand why waiting before beginning medical treatment makes sense. If a child is in the midst of a bad period of tics it is likely that, whether or not a new medication is prescribed, the tics will improve in the near future. This insight will also help children and their families realize why at times in the past their medications have suddenly stopped working. These dialogs can be relieving and can interrupt a vicious cycle of recrimination that leads to further tic exacerbation, and it can help parents shift the focus from blame to problem-solving. For children, contact with their teachers can be enormously valuable. By educating the educators, clinicians can make significant progress towards securing for the child a positive and supportive environment in the classroom. If possible, teachers need to respond to outbursts of tics with grace and understanding. Repeatedly scolding a child for his or her tics can be counterproductive. The child may develop a negative attitude to authority figures and may be reluctant to attend school, and classmates may feel freer to tease the child. If tics interfere with a student’s ability to receive information in the classroom, it is imperative to find alternative ways to present the material. By helping the student find a way to function even during periods of severe tics, teachers model problemsolving skills that will foster future self-esteem. It is also important for teachers to know that in unstructured settings such as the cafeteria, gym, playground and school bus, peers who tease or taunt tend to take advantage of the lack of adult supervision. The assignment of a paraprofessional aide to accompany the student can be remarkably beneficial – particularly in situations where there is a history of teasing. Other useful strategies that teachers may consider include providing short breaks out of the classroom to let the tics out in private, allowing students with severe tics to take tests in private so that a child does not have the pressure to suppress tics during the test period, and being flexible with regard to scheduling so that the child is not expected to make an oral presentation at a point when the tics are severe (Bronheim, 1991). A compendium of educational accommodations is available at http://www.tourettesyndrome.net/. Educated peers are equally important. Many clinicians actively encourage children, families and teachers to help educate peers and classmates about TS. It is remarkable what can be tolerated in the classroom and playground when teachers and peers simply know what the problem is and learn to disregard it. Finally, it is important for clinicians to determine the family’s awareness of and potential interest in advocacy organizations such as the Tourette Syndrome Association (www.tsa-usa.org/), Obsessive Compulsive Foundation (http://www.ocfoundation. org/) and the Children and Adults with Attention Deficit Disorder (http://www.chadd.org/). In the USA, these organizations have made a positive contribution to the lives of many patients and their families by providing support and information. They can also be a valuable outlet for families – to advance research and raise the general level of awareness among health care professionals, educators and the public at large. Behavioral, Cognitive and Other Psychotherapeutic Treatments The presence of premonitory urges and the characteristic suppressibility of tic symptoms may have broad implications for behavioral interventions and treatment. Prior to seeking professional consultation, many families will have experimented with a variety of ad hoc behavioral approaches on their own. It is useful to elicit information concerning these efforts and their sequelae. A variety of cognitive and behavioral approaches have been used with TS (King, Scahill, Findley, & Cohen, 1998). Although success with various techniques such as assertiveness training, biofeedback, massed practice, time-out, hypnosis and differential reinforcement has been reported, most of these studies have involved small numbers of poorly characterized participants with no replication (Piacentini & Chang, 2006). To date, only habit reversal training has been shown to be efficacious in two randomized clinical trials with moderately to severely affected adults with TS (Deckersbach, Raunch, Buhlmann, & Wilhelm, 2005; Wilhelm, Deckersbach, Coffey et al., 2003). This intervention includes a number of techniques: awareness training, self-monitoring, contingency management, inconvenience review, relaxation and competing responses. For example, awareness training includes: 1 Response description (i.e., the patient is trained to describe tic occurrences in detail and to re-enact tic movements while looking in a mirror); 2 Response detection, where the therapist helps the patient’s ability to detect tics; 3 An early warning procedure, in which the patient is taught to become aware of the earliest signs of tic occurrence (such as the premonitory urge); and 4 Situation awareness training, in which situations that make tics more likely are identified. When the patient is able to detect the tic and related urges, he or she is instructed to invoke a Competing Response at each occurrence of the tic or the urge and to hold it until the urge passes. Azrin and Nunn (1973) proposed that the Competing Response should be opposite to the tic movement, be able to be maintained for several minutes, produce heightened awareness of the tic movements by contraction of involved muscles, be socially inconspicuous and compatible with normal activities. Patients using habit reversal training are taught to design their own Competing Response to ensure that the responses are acceptable to them and to prepare them for potential changes in tic repertoire. Although not indicated for the treatment of tics, individual and family counseling may alleviate secondary symptoms such as low self-esteem, defiant and disruptive behavior as well as TIC DISORDERS 729 9781405145497_4_044.qxd 29/03/2008 02:53 PM Page 729

family conflict. These interventions may also serve to reduce a significant source of psychological stress. Pharmacological Treatments The decision whether or not to use medication is based on the level of symptoms and the clinical presentation of the individual case. Given the waxing and waning of tic symptoms, it is best to withhold psychotropic medications until the tics, even at their best, are a significant source of impairment. Many cases of TS can be successfully managed without medication. When patients present with coexisting ADHD, OCD, depression or bipolar illness it is often better to treat these comorbid conditions first, as successful treatment of these disorders often will diminish tic severity. Pharmacotherapy of Tics A variety of therapeutic agents are now available to treat tics (Scahill, Erenberg, Berlin et al., 2006). Each medication should be selected on the basis of expected efficacy and potential side effects. Clonidine and guanfacine are potent α2-receptor agonists that are thought to reduce central noradrenergic activity. Initial randomized trials of clonidine had mixed results (Goetz, Tanner, Wilson et al., 1987; Leckman, Hardin, Riddle et al., 1991). However, a subsequent trial involving 136 subjects with chronic tics or TS confirmed the efficiacy of clonidine in the treatment of tics (Tourette’s Syndrome Study Group, 2002). Clinical trials indicate that subjects can expect on average a 25–35% reduction in their symptoms over an 8–12-week period. Motor tics may show greater improvement than phonic symptoms. The usual starting dose is 0.05 mg on arising. Further 0.05-mg increments at 3–4-h intervals are added weekly until a dosage of 5 μg·kg−1 is reached or the total daily dose exceeds 0.25 mg. Although clonidine is clearly less effective than haloperidol and pimozide for immediate tic suppression, it is considerably safer. The principal side effect associated with its use is sedation, which occurs in 10–20% of subjects and usually abates with continued use. Other side effects include dry mouth, transient hypotension and rare episodes of worsening behavior. Clonidine should be tapered and not withdrawn abruptly, to reduce the likelihood of symptom or blood pressure rebound (Leckman, Ort, Caruso et al., 1986). Guanfacine is another α2-receptor agonist that has been demonstrated in double-blind studies to be effective in the treatment of TS and TS with comorbid ADHD (Scahill, Chappell, Kim et al., 2001). Guanfacine is generally preferred to clonidine because it is less sedating and not associated with rebound hypertension following withdrawal. Guanfacine is generally started at a dose of 0.5 mg at night and then gradually increased by approximately 0.5 mg weekly to three times daily dosing with a maximum dose of 4 mg·day−1 (Scahill, Chappell, Kim et al., 2001). Dopamine D2 receptor antagonists remain the most predictably effective tic-suppressing agents in the short term. Documentation of the effectiveness of haloperidol in the early 1960s was a landmark in the history of TS as it called into question the prevailing view that tics were psychogenic in nature. The most widely used typical D2 receptor antagonists are haloperidol, pimozide, fluphenazine and tiapride (not currently available in the USA). Favorable data from doubleblind clinical trials are available for haloperidol, pimozide and tiapride (Eggers, Rothenberger, & Berghaus, 1988; Sallee, Nesbitt, Jackson, Sine, & Sethuraman, 1997; Shapiro, Shapiro, Fulop et al., 1989; Tourette’s Syndrome Study Group, 1999). The US Food and Drug Administration has approved TS as an indication for haloperidol and pimozide use. Long-term experience has been less favorable, and the “reflexive” use of these agents should be avoided. Typically, treatment is initiated with a low dose (0.25 mg haloperidol or 1 mg pimozide) given before sleep. Further increments (0.5 mg haloperidol or 1 mg pimozide) may be added at 7–14-day intervals if the tic behaviors remain severe. In most instances, 0.5–6.0 mg·day−1 haloperidol or 1.0–10.0 mg·day−1 pimozide administered over a period of 4–8 weeks is sufficient to achieve adequate control of tic symptoms. Common potential side effects include tardive dyskinesia, acute dystonic reactions, sedation, depression, school and social phobias and/or weight gain. In many instances, by starting at low doses and adjusting the dosage upwards slowly, clinicians can avoid these side effects. The goal should be to use as little of these medications as possible to render the tics “tolerable.” Efforts to stop the tics completely risk overmedication. To avoid the extrapyramidal side effects associated with typical neuroleptics, atypical neuroleptics (e.g., risperidone, olanzapine and ziprasidone) have been used to treat tic symptoms. These agents have potent 5-HT2 blocking effects as well as more modest blocking effects on dopamine D2. Four randomized controlled trials have shown that risperidone was superior to placebo (Bruggeman, van der Linden, Buitelaar et al., 2001; Dion, Annable, Sandor, & Choinard, 2002; Gaffney, Perry, Lund et al., 2002; Scahill, Leckman, Schultz, Katsovich, & Peterson, 2003). Dosage in the range 1.5–3.5 mg·day−1 was effective and neurological side effects were rare. The most common adverse effects were weight gain, lipid metabolism abnormalities, sedation and sleep disturbance; social phobia and erectile dysfunction occurred in a few patients. Pergolide is a mixed dopamine agonist used in Parkinson’s disease which, in lower doses, is thought to have a greater effect on presynaptic autoreceptors, and lead to decreased dopamine release. Pergolide has been evaluated in two placebo-controlled trials (Gilbert, Sethuraman, Sine, Peters, & Sallee, 2000), which suggest that it has a positive, but moderate effect on tics. Adverse effects include nausea, syncope, sedation and dizziness. This agent may be especially useful if a child presents with comorbid restless legs syndrome. Only small open-label pilot studies are available for medications such as tetrabenazine and benzodiazepines. Tetrabenazine is a non-antipsychotic dopamine antagonist, approved as an investigational drug; it may be useful but more study is needed (Scahill, Erenberg, Berlin et al., 2006). The benzodiazepines (e.g., clonazepam) are used as anxiolytics and occasionally as an adjunctive treatment for tics, although it has not been well studied (Scahill, Erenberg, Berlin et al., 2006). Common CHAPTER 44 730 9781405145497_4_044.qxd 29/03/2008 02:53 PM Page 730

side effects with benzodiazepine use include sedation, ataxia, short-term memory problems, disinhibition, depression and addiction. Given these drawbacks, clonazepam is not used widely in TS. The use of botulinum toxin injections to weaken temporarily muscles associated with severe motor or vocal tics also appears effective (Jankovic, 1994; Kwak, Hanna, & Jankovic, 2000), and also appears to significantly reduce the premonitory urges associated with both motor and vocal tics in the regions injected. Pharmacotherapy of Coexisting ADHD The stimulants methylphenidate, d-amphetamine, and mixtures of d- and l-amphetamine are first-line agents for the medical management of ADHD (Brown, Amler, Freeman et al., 2005). However, the use of stimulants in ADHD associated with a tic disorder is controversial. While many patients with both ADHD and a pre-existing tic disorder will do well on stimulants, data from clinical case reports and controlled studies indicate that some children with ADHD will exhibit tics de novo when exposed to a stimulant. In other cases, tics may increase to a level that warrants discontinuation of the stimulant. To address this question, a multicenter randomized double-blind clinical trial was conducted with 136 children with ADHD and a chronic tic disorder (Tourette’s Syndrome Study Group, 2002). Subjects were randomly administered clonidine alone, methylphenidate alone, or the combination in a 2 × 2 factorial design. Significant improvements in ADHD symptoms occurred for subjects assigned to clonidine alone and those assigned to methylphenidate alone. Compared with placebo, the greatest benefit occurred with combination regimens. Clonidine appeared to be most helpful for impulsivity and hyperactivity, while methylphenidate appeared to be most helpful for inattention. The proportion of individuals reporting a worsening of tics was no higher in those treated with methylphenidate (20%) than those being administered clonidine alone (26%) or placebo (22%). Sedation was common with clonidine treatment (28% reported moderate or severe sedation), but otherwise the drugs were tolerated well, with no evidence of cardiac toxicity. This trial did not support prior recommendations to avoid methylphenidate in these children because of concerns of worsening tics. Commonly used nonstimulants for the treatment of ADHD include the tricyclic antidepressants desipramine and nortriptyline, atypical antidepressants such as bupropion, and α2-agonists clonidine and guanfacine (Brown, Amler, Freeman et al., 2005). The latter has been demonstrated to be effective in subjects with both ADHD and coexisting tics (Scahill, Chappell, Kim et al., 2001). Pharmacotherapy of Coexisting OCD Unfortunately, many patients with OCD and a coexisting tic disorder do not respond well to cognitive–behavioral therapies, which are the standard interventions for OCD (McDougle, Goodman, Leckman et al., 1993). Controlled clinical trials have shown that addition of small doses of the neuroleptic haloperidol, or the atypical neuroleptic risperidone increases the response to serotonin reuptake inhibitors (Bloch, Peterson, Scahill et al., 2006a; McDougle, Goodman, Leckman et al., 1994). Special Populations – PANDAS Although initial results from immunomodulatory treatments, including plasma exchange, are promising, caution is warranted (Perlmutter, Leitman, Garvey et al., 1999). It is also premature to recommend prophylactic antibiotic treatment (King, 2006). Neurosurgical Interventions Neurosurgical interventions for TS have been appropriately reserved for adults with intractable tics that severely affect social functioning. Many neurosurgical sites have been targeted for tics in previous lesioning studies: frontal cortex, limbic cortex, thalamus, infrathalamic area and cerebellum (Rauch, Baer, Cosgrove, & Jenike, 1995). Deep brain stimulation (DBS) is a relatively reversible, stereotactic technique, which has been looked to as the preferred method of neurosurgical treatment for medically intractable tics. The original electrode placement for DBS surgery was in the medial part of the thalamus, based on the results of previous lesioning studies (Hassler & Dieckmann, 1973). All four patients who received bilateral medial thalamic DBS surgery experienced a substantial improvement in tic severity (Ackermans, Temel, Cath et al., 2006; Visser-Vandewalle, Temel, Boon et al., 2003). Subsequent case reports demonstrated comparable efficacy in bilateral palladial stimulation compared with bilateral medial thalamic stimulation (Mink, Walkup, Frey et al., 2006). However, currently in DBS for tics, the site of electrode placement and the electrode stimulation parameters have not been examined in carefully controlled clinical studies and differ markedly in the few sites willing to engage in this procedure. Therefore DBS is currently not advisable for all but the most severe and treatment-refractory adults with TS (Mink, Walkup, Frey et al., 2006). Future Directions Along with a deepening appreciation of the clinical phenomenology of TS and related disorders, recent progress in genetics, neuroanatomy, systems neuroscience and functional in vivo neuroimaging has set the stage for a major advance in our understanding of TS and related disorders. Success in this area will lead to the targeting of specific brain circuits for more intensive study. Diagnostic and prognostic advances can also be anticipated (e.g., which circuits are involved and to what degree?). How does that degree of involvement affect the patient’s symptomatic course and outcome? Given this potential, TS can be considered a model disorder to study the dynamic interplay of neurobiological systems during development. It is likely that the research paradigms utilized in these studies and many of the empirical findings resulting from them will be relevant to other disorders of childhood onset and will enhance our understanding of normal development. TIC DISORDERS 731 9781405145497_4_044.qxd 29/03/2008 02:53 PM Page 731

drome: An FDG-PET Study. II. Relationships between regional cerebral metabolism and associated behavioral and cognitive features of the illness. Neuropsychopharmacology, 13, 151–168. Bronheim, S. (1991). An educator’s guide to Tourette syndrome. Journal of Learning Disabilities, 24, 17–22. Brown, R. T., Amler, R. W., Freeman, W. S., Perrin, J. M., Stein, M. T., Feldman, H. M., et al. (2005). Treatment of attentiondeficit/hyperactivity disorder: Overview of the evidence. Pediatrics, 115, e749–757. Bruggeman, R., van der Linden, C., Buitelaar, J. K., Gericke, G. S., Hawkridge, S. M., & Temlett, J. A. (2001). Risperidone versus pimozide in Tourette’s disorder: A comparative double-blind parallelgroup study. Journal of Clinical Psychiatry, 62, 50–56. Burd, L., Kerbeshian, J., Wikenheiser, M., & Fisher, W. (1986a). Prevalence of Gilles de la Tourette’s syndrome in North Dakota adults. American Journal of Psychiatry, 143, 787–788. Burd, L., Kerbeshian, J., Wikenheiser, M., & Fisher, W. (1986b). A prevalence study of Gilles de la Tourette syndrome in North Dakota school-age children. Journal of the American Academy of Child Psychiatry, 25, 552–553. Burd, L., Severud, R., Klug, M. G., & Kerbeshian, J. (1999). Prenatal and perinatal risk factors for Tourette disorder. Journal of Perinatal Medicine, 27, 295–302. Caine, E. D., McBride, M. C., Chiverton, P., Bamford, K. A., Rediess, S., & Shiao, J. (1988). Tourette’s syndrome in Monroe County school children. Neurology, 38, 472–475. Cardona, F., & Orefici, G. (2001). Group A streptococcal infections and tic disorders in an Italian pediatric population. Journal of Pediatrics, 138, 71–75. Carter, A. S., O’Donnell, D. A., Schultz, R. T., Scahill, L., Leckman, J. F., & Pauls, D. L. (2000). Social and emotional adjustment in children affected with Gilles de la Tourette’s syndrome: Associations with ADHD and family functioning. Attention Deficit Hyperactivity Disorder. Journal of Child Psychology and Psychiatry, 41, 215– 223. Chappell, P., Leckman, J., Goodman, W., Bissette, G., Pauls, D., Anderson, G., et al. (1996). Elevated cerebrospinal fluid corticotropinreleasing factor in Tourette’s syndrome: Comparison to obsessive compulsive disorder and normal controls. Biological Psychiatry, 39, 776–783. Chappell, P. B., Riddle, M., Anderson, G., Scahill, L., Hardin, M., Walker, D., et al. (1994). Enhanced stress responsivity of Tourette syndrome patients undergoing lumbar puncture. Biological Psychiatry, 36, 35–43. Cheon, K. A., Ryu, Y. H., Namkoong, K., Kim, C. H., Kim, J. J., & Lee, J. D. (2004). Dopamine transporter density of the basal ganglia assessed with [123I] IPT SPECT in drug-naive children with Tourette’s disorder. Psychiatry Reseach, 130, 85–95. Church, A. J., Dale, R. C., Lees, A. J., Giovannoni, G., & Robertson, M. M. (2003). Tourette’s syndrome: A cross sectional study to examine the PANDAS hypothesis. Journal of Neurology, Neurosurgery and Psychiatry, 74, 602–607. Cohen, D. J., Ort, S. I., Leckman, J. F., Riddle, M. A., & Hardin, M. T. (1988). Family functioning and Tourette’s syndrome. In D. J. Cohen, R. D. Bruun, & J. F. Leckman (Eds.), Tourette’s syndrome and tic disorders (p. 179). New York: John Wiley and Sons. Comings, D. E. (1988). Tourette syndrome and human behavior. Daurte, CA: Hope Press. Cuker, A., State, M. W., King, R. A., Davis, N., & Ward, D. C. (2004). Candidate locus for Gilles de la Tourette syndrome/obsessive compulsive disorder/chronic tic disorder at 18q22. American Journal of Medical Genetics A, 130, 37–39. Dale, R. C., Candler, P., Church, A. R., & Pocock, J. G. (2004). Glycolytic enzymes on neuronal membranes are candidate autoantigens in post-streptococcal neuropsychiatric disorders. Movement Disorders, 9, 19. CHAPTER 44 732 Acknowledgments We are indebted to the Yale Tourette’s Syndrome and Obsessive-Compulsive Disorder Research Group. Portions of the research described in this review were supported by grants from the National Institutes of Health: MH18268, MH49351, MH30929, HD03008, NS16648 and RR00125, as well as by the Tourette Syndrome Association. References Abelson, J. F., Kwan, K. Y., O’Roak, B. J., Baek, D. Y., Stillman, A. A., Morgan, T. M., et al. (2005). Sequence variants in SLITRK1 are associated with Tourette’s syndrome. Science, 310, 317–320. Ackermans, L., Temel, Y., Cath, D. C., van der Linden, C., Bruggeman, R., Kleijer, M., et al. (2006). Deep brain stimulation in Tourette’s syndrome: Two targets? Movement Disorders, 21, 709–713. Albin, R. L., Koeppe, R. A., Bohne, A., Nichols, T. E., Meyer, P., Wernette, K., et al. (2003). Increased ventral striatal monoaminergic innervation in Tourette syndrome. Neurology, 61, 310–315. Albin, R. L., & Mink, J. W. (2006). Recent advances in Tourette syndrome research. Trends in Neurosciences, 29, 175–182. American Psychiatric Association (APA). (2000). Diagnostic and Statistical Manual of Mental Disorders (4th edn.). Text Revision. Washington, DC: American Psychiatric Association. Apter, A., Pauls, D. L., Bleich, A., Zohar, A. H., Kron, S., Ratzoni, G., et al. (1993). An epidemiologic study of Gilles de la Tourette’s syndrome in Israel. Archives of General Psychiatry, 50, 734– 738. Azrin, N. H., & Nunn, R. G. (1973). Habit-reversal: A method of eliminating nervous habits and tics. Behavior Research and Therapy, 11, 619–628. Baron-Cohen, S., Mortimore, C., Moriarty, J., Izaguirre, J., & Robertson, M. (1999). The prevalence of Gilles de la Tourette’s syndrome in children and adolescents with autism. Journal of Child Psychology and Psychiatry, 40, 213–218. Bawden, H. N., Stokes, A., Camfield, C. S., Camfield, P. R., & Salisbury, S. (1998). Peer relationship problems in children with Tourette’s disorder or diabetes mellitus. Journal of Child Psychology and Psychiatry, 39, 663–668. Bisno, A. L. (1991). Group A streptococcal infections and acute rheumatic fever. New England Journal of Medicine, 325, 783– 793. Bloch, M. H., Landeros-Weisenberger, A., Kelmendi, B., Coric, V., Bracken, M. B., & Leckman, J. F. (2006b). A systematic review: antipsychotic augmentation with treatment refractory obsessivecompulsive disorder. Molecular Psychiatry, 11, 622–632. Bloch, M. H., Leckman, J. F., Zhu, H., & Peterson, B. S. (2005). Caudate volumes in childhood predict symptom severity in adults with Tourette syndrome. Neurology, 65, 1253–1258. Bloch, M. H., Peterson, B. S., Scahill, L., Otka, J., Katsovich, L., Zhang, H., et al. (2006a). Adulthood outcome of tic and obsessivecompulsive symptom severity in children with Tourette syndrome. Archives of Pediatric and Adolescent Medicine, 160, 65–69. Bloch, M. H., Sukhodolsky, D. G., Leckman, J. F., Schultz, R. T. (2006c). Fine-motor skill deficits in childhood predict adulthood tic severity and global psychosocial functioning in Tourette’s syndrome. Journal of Child Psychology and Psychiatry, 47, 551–559. Bohlhalter, S., Goldfine, A., Matteson, S., Garraux, G., Hanakawa, T., Kansaku, K., et al. (2006). Neural correlates of tic generation in Tourette syndrome: An event-related functional MRI study. Brain, 129, 2029–2037. Boulant, J. A. (1981). Hypothalamic mechanisms in thermoregulation. Federation Proceedings, 40, 2843–2850. Braun, A. R., Randolph, C., Stoetter, B., Mohr, E., Cox, C., Vladar, K., et al. (1995). The functional neuroanatomy of Tourette’s syn9781405145497_4_044.qxd 29/03/2008 02:53 PM Page 732

Deckersbach, T., Rauch, S., Buhlmann, U., & Wilhelm, S. (2005). Habit reversal versus supportive psychotherapy in Tourette’s disorder: A randomized controlled trial and predictors of treatment response. Behavior Research and Therapy, 44, 1079–1090. Degnan, B. A., Kehoe, M. A., & Goodacre, J. A. (1997). Analysis of human T cell responses to group A streptococci using fractionated Streptococcus pyogenes proteins. FEMS Immunology and Medical Microbiology, 17, 161–170. Dewing, P., Chiang, C. W., Sinchak, K., Sim, H., Fernagut, P. O., Kelly, S., et al. (2006). Direct regulation of adult brain function by the male-specific factor SRY. Current Biology, 16, 415–420. Dion, Y., Annable, L., Sandor, P., & Chouinard, G. (2002). Risperidone in the treatment of Tourette syndrome: A double-blind, placebo-controlled trial. Journal of Clinical Psychopharmacology, 22, 31–39. Dykens, E., Leckman, J., Riddle, M., Hardin, M., Schwartz, S., & Cohen, D. (1990). Intellectual, academic, and adaptive functioning of Tourette syndrome children with and without attention deficit disorder. Journal of Abnormal Child Psychology, 18, 607–615. Eggers, C., Rothenberger, A., & Berghaus, U. (1988). Clinical and neurobiological findings in children suffering from tic disease following treatment with tiapride. European Archives of Psychiatry and Neurological Sciences, 237, 223–229. Findley, D. B., Leckman, J. F., Katsovich, L., Lin, H., Zhang, H., Grantz, H., et al. (2003). Development of the Yale Children’s Global Stress Index (YCGSI) and its application in children and adolescents with Tourette’s syndrome and obsessive-compulsive disorder. Journal of the American Academy of Child and Adolescent Psychiatry, 42, 450–457. Gaffney, G. R., Perry, P. J., Lund, B. C., Bever-Stille, K. A., Arndt, S., & Kuperman, S. (2002). Risperidone versus clonidine in the treatment of children and adolescents with Tourette’s syndrome. Journal of the American Academy of Child and Adolescent Psychiatry, 41, 330–336. Gilbert, D. L., Sethuraman, G., Sine, L., Peters, S., & Sallee, F. R. (2000). Tourette’s syndrome improvement with pergolide in a randomized, double-blind, crossover trial. Neurology, 54, 1310– 1315. Gilles de la Tourette, G. (1885). Étude sur une affection nerveuse caractérisée par l’incoordination motrice, accompagnée d’écholalie et de coprolalie. Archive Neurologie, 9, 19–42, 158–200. Goetz, C. G., Pappert, E. J., Louis, E. D., Raman, R., & Leurgans, S. (1999). Advantages of a modified scoring method for the Rush Video-Based Tic Rating Scale. Movement Disorders, 14, 502–506. Goetz, C. G., Tanner, C. M., Wilson, R. S., Carroll, V. S., Como, P. G., & Shannon, K. M. (1987). Clonidine and Gilles de la Tourette’s syndrome: Double-blind study using objective rating methods. Annals of Neurology, 21, 307–310. Graybiel, A. M., & Canales, J. J. (2001). The neurobiology of repetitive behaviors: Clues to the neurobiology of Tourette syndrome. Advances in Neurology, 85, 123–131. Grenhoff, J., & Svensson, T. H. (1989). Clonidine modulates dopamine cell firing in rat ventral tegmental area. European Journal of Pharmacology, 165, 11–18. Hassler, R., & Dieckmann, G. (1973). Relief of obsessive-compulsive disorders, phobias and tics by stereotactic coagulations of the rostral intralaminar and medial-thalamic nuclei. In L. Laitinen, & K. Livingston (Eds.), Surgical approaches in psychiatry: Proceedings of the Third International Congress of Psychosurgery (pp. 206–212). Cambridge: Garden City Press. Hoekstra, P. J., Bijzet, J., Limburg, P. C., Steenhuis, M. P., Troost, P. W., Oosterhoff, M. D., et al. (2001). Elevated D8/17 expression on B lymphocytes, a marker of rheumatic fever, measured with flow cytometry in tic disorder patients. American Journal of Psychiatry, 158, 605–610. Hounie, A. G., do Rosario-Campos, M. C., Diniz, J. B., Shavitt, R. G., Ferrao, Y. A., Lopes, A. C., et al. (2006). Obsessivecompulsive disorder in Tourette syndrome. Advances in Neurology, 99, 22–38. Husby, G., van de Rijn, I., Zabriskie, J. B., Abdin, Z. H., & Williams, R. C. Jr. (1976). Antibodies reacting with cytoplasm of subthalamic and caudate nuclei neurons in chorea and acute rheumatic fever. Journal of Experimental Medicine, 144, 1094–1110. Hyde, T. M., Stacey, M. E., Coppola, R., Handel, S. F., Rickler, K. C., & Weinberger, D. R. (1995). Cerebral morphometric abnormalities in Tourette’s syndrome: A quantitative MRI study of monozygotic twins. Neurology, 45, 1176–1182. Itard, J. M. G. (1825). Memoire sur quelques fonctions involontaries ses appareils de la locomotion de la prehension et de la voix. Archives Générales de Médecine, 8, 385–407. Jankovic, J. (1994). Botulinum toxin in the treatment of dystonic tics. Movement Disorders, 9, 347–349. Jankovic, J., & Mejia, N. I. (2006). Tics associated with other disorders. Advances in Neurology, 99, 61–68. Jeffries, K. J., Schooler, C., Schoenbach, C., Herscovitch, P., Chase, T. N., & Braun, A. R. (2002). The functional neuroanatomy of Tourette’s syndrome: an FDG PET study. III. Functional coupling of regional cerebral metabolic rates. Neuropsychopharmacology, 27, 92–104. Kalanithi, P. S., Zheng, W., Kataoka, Y., DiFiglia, M., Grantz, H., Saper, C. B., et al. (2005). Altered parvalbumin-positive neuron distribution in basal ganglia of individuals with Tourette syndrome. Proceedings of the National Academy of Sciences of the USA, 102, 13307–13312. Kawikova, I., Leckman, J. F., Kronig, H., Katsovich, L., Bessen, D. E., Ghebremichael, M., et al. (2007). Decreased number of regulatory T cells suggests impaired immune tolerance in children with Tourette’s syndrome. Biological Psychiatry, 61, 273–278. Kenney, C., & Jankovic, J. (2006). Tetrabenazine in the treatment of hyperkinetic movement disorders. Expert Review of Neurotherapeutics, 6, 7–17. Kéri, S., Szlobodnyik, C., Benedek, G., Janka, Z., & Gádoros, J. (2002). Probabilistic classification learning in Tourette syndrome. Neuropsychologia, 40, 1356–1362. Khalifa, N., & von Knorring, A. L. (2003). Prevalence of tic disorders and Tourette syndrome in a Swedish school population. Developmental Medicine and Child Neurology, 45, 315–319. Khalifa, N., & von Knorring, A. L. (2005). Tourette syndrome and other tic disorders in a total population of children: Clinical assessment and background. Acta Paediatrica, 94, 1608–1614. Khalifa, N., & von Knorring, A. L. (2006). Psychopathology in a Swedish population of school children with tic disorders. Journal of the American Academy of Child and Adolescent Psychiatry, 45, 1346–1353. King, R. A. (2006). PANDAS: to treat or not to treat? Advances in Neurology, 99, 179–183. King, R. A., Scahill, L., Findley, D., & Cohen, D. J. (1998). Psychosocial and behavioral treatments. In J. F. Leckman, & D. J. Cohen (Eds.), Tourette’s syndrome tics, obsessions, compulsions: Developmental psychopathology and clinical care (pp. 338–359). New York: John Wiley and Sons. Kirvan, C. A., Swedo, S. E., Heuser, J. S., & Cunningham, M. W. (2003). Mimicry and autoantibody-mediated neuronal cell signaling in Sydenham chorea. Nature Medicine, 9, 914–920. Kirvan, C. A., Swedo, S. E., Kurahara, D., & Cunningham, M. W. (2006). Streptococcal mimicry and antibody-mediated cell signaling in the pathogenesis of Sydenham’s chorea. Autoimmunity, 39, 21–29. Kurlan, R., Whitmore, D., Irvine, C., McDermott, M. P., & Como, P. G. (1994). Tourette’s syndrome in a special education population: A pilot study involving a single school district. Neurology, 44, 699– 702. Kushner, H. I. (1999). A cursing brain? The histories of Tourette syndrome. Cambridge, MA: Harvard University Press. TIC DISORDERS 733 9781405145497_4_044.qxd 29/03/2008 02:53 PM Page 733

Kwak, C. H., Hanna, P. A., & Jankovic, J. (2000). Botulinum toxin in the treatment of tics. Archives of Neurology, 57, 1190–1193. Leckman, J. F., & Cohen, D. J. (1998). Tourette’s syndrome tics, obsessions, compulsions: Developmental psychopathology and clinical care. New York, NY: John Wiley and Sons. Leckman, J. F., Cohen, D. J., Price, R. A., Minderaa, R. B., Anderson, G. M., & Pauls, D. L. (1984). The pathogenesis of Gilles de la Tourette’s syndrome: A review of data and hypothesis. In A. B. Shah, N. S. Shah, & A. G. Donald (Eds.), Movement disorders. New York: Plenum. Leckman, J. F., Dolnansky, E. S., Hardin, M. T., Clubb, M., Walkup, J. T., Stevenson, J., et al. (1990). Perinatal factors in the expression of Tourette’s syndrome: An exploratory study. Journal of the American Academy of Child and Adolescent Psychiatry, 29, 220–226. Leckman, J. F., Goodman, W. K., Anderson, G. M., Riddle, M. A., Chappell, P. B., McSwiggan-Hardin, M. T., et al. (1995). Cerebrospinal fluid biogenic amines in obsessive compulsive disorder, Tourette’s syndrome, and healthy controls. Neuropsychopharmacology, 12, 73–86. Leckman, J. F., Grice, D. E., Boardman, J., Zhang, H., Vitale, A., Bondi, C., et al. (1997). Symptoms of obsessive-compulsive disorder. American Journal of Psychiatry, 154, 911–917. Leckman, J. F., Hardin, M. T., Riddle, M. A., Stevenson, J. Ort, S. I., Cohen, D. J. (1991). Clonidine treatment of Gilles de la Tourette’s syndrome. Archives of General Psychiatry, 48, 324–328. Leckman, J. F., Katsovich, L., Kawikova, I., Lin, H., Zhang, H., Kronig, H., et al. (2005). Increased serum levels of interleukin-12 and tumor necrosis factor-alpha in Tourette’s syndrome. Biological Psychiatry, 57, 667–673. Leckman, J. F., King, R. A., Scahill, L., Findley, D., Ort, S., & Cohen, D. J. (1998a). Yale approach to assessment and treatment. In J. F. Leckman, & D. J. Cohen (Eds.), Tourette’s syndrome tics, obsessions, compulsions: Developmental psychopathology and clinical care (pp. 285–309). New York: John Wiley and Sons. Leckman, J. F., Ort, S., Caruso, K. A., Anderson, G. M., Riddle, M. A., Cohen, D. J. (1986). Rebound phenomena in Tourette’s syndrome after abrupt withdrawal of clonidine. Behavioral, cardiovascular, and neurochemical effects. Archives of General Psychiatry, 43, 1168–1176. Leckman, J. F., Price, R. A., Walkup, J. T., Ort, S., Pauls, D. L., & Cohen, D. J. (1987). Nongenetic factors in Gilles de la Tourette’s syndrome. Archives of General Psychiatry, 44, 100. Leckman, J. F., Riddle, M. A., Hardin, M. T., Ort, S. I., Swartz, K. L., Stevenson, J., et al. (1989). The Yale Global Tic Severity Scale: Initial testing of a clinician-rated scale of tic severity. Journal of the American Academy of Child and Adolescent Psychiatry, 28, 566–573. Leckman, J. F., & Scahill, L. (1990). Possible exacerbation of tics by androgenic steroids. New England Journal of Medicine, 322, 1674. Leckman, J. F., Vaccarino, F. M., Kalanithi, P. S., & Rothenberger, A. (2006). Tourette syndrome: A relentless drumbeat. Journal of Child Psychology and Psychiatry, 47, 537–550. Leckman, J. F., Walker, D. E., & Cohen, D. J. (1993). Premonitory urges in Tourette’s syndrome. American Journal of Psychiatry, 150, 98–102. Leckman, J. F., Walker, D. E., Goodman, W. K., Pauls, D. L., & Cohen, D. J. (1994). “Just right” perceptions associated with compulsive behavior in Tourette’s syndrome. American Journal of Psychiatry, 151, 675–680. Leckman, J. F., Zhang, H., Vitale, A., Lahnin, F., Lynch, K., Bondi, C., et al. (1998b). Course of tic severity in Tourette syndrome: The first two decades. Pediatrics, 102, 14–19. Lee, J. S., Yoo, S. S., Cho, S. Y., Ock, S. M., Lim, M. K., & Panych, L. P. (2006). Abnormal thalamic volume in treatment-naive boys with Tourette syndrome. Acta Psychiatrica Scandinavica, 113, 64–67. Lin, H., Katsovich, L., Ghebremichael, M., Findley, D., Grantz, H., Lombroso, P. J., et al. (2007). Psychosocial stress predicts future symptom severities in children and adolescents with Tourette syndrome and/or obsessive-compulsive disorder. Journal of Child Psychology and Psychiatry, 48, 157–166. Llinas, R., Urbano, F. J., Leznik, E., Ramirez, R. R., & van Marle, H. J. (2005). Rhythmic and dysrhythmic thalamocortical dynamics: GABA systems and the edge effect. Trends in Neurosciences, 28, 325–333. Lombroso, P. J., Mack, G., Scahill, L., King, R. A., & Leckman, J. F. (1991). Exacerbation of Gilles de la Tourette’s syndrome associated with thermal stress: A family study. Neurology, 41, 1984– 1987. Luo, F., Leckman, J. F., Katsovich, L., Findley, D., Grantz, H., Tucker, D. M., et al. (2004). Prospective longitudinal study of children with tic disorders and/or obsessive-compulsive disorder: Relationship of symptom exacerbations to newly acquired streptococcal infections. Pediatrics, 113, e578–585. Malison, R. T., McDougle, C. J., van Dyck, C. H., Scahill, L., Baldwin, R. M., Seibyl, J. P., et al. (1995). [123I] β-CIT SPECT imaging of striatal dopamine transporter binding in Tourette’s disorder. American Journal of Psychiatry, 152, 1359–1361. Marsh, R., Alexander, G. M., Packard, M. G., Zhu, H., & Peterson, B. S. (2005). Perceptual-motor skill learning in Gilles de la Tourette syndrome: Evidence for multiple procedural learning and memory systems. Neuropsychologia, 43, 1456–1465. Marsh, R., Alexander, G. M., Packard, M. G., Zhu, H., Wingard, J. C., Quackenbush, G., et al. (2004). Habit learning in Tourette syndrome: A translational neuroscience approach to a developmental psychopathology. Archives of General Psychiatry, 61, 1259– 1268. Mason, A., Banerjee, S., Eapen, V., Zeitlin, H., & Robertson, M. M. (1998). The prevalence of Tourette syndrome in a mainstream school population. Developmental Medicine and Child Neurology, 40, 292–296. Mathews, C. A., Bimson, B., Lowe, T. L., Herrera, L. D., Budman, C. L., Erenberg, G., et al. (2006). Association between maternal smoking and increased symptom severity in Tourette’s syndrome. American Journal of Psychiatry, 163, 1066–1073. McDougle, C. J., Goodman, W. K., Leckman, J. F., Barr, L. C., Heninger, G. R., & Price, L. H. (1993). The efficacy of fluvoxamine in obsessive-compulsive disorder: Effects of comorbid chronic tic disorder. Journal of Clinical Psychopharmacology, 13, 354–358. McDougle, C. J., Goodman, W. K., Leckman, J. F., Lee, N. C., Heninger, G. R., & Price, L. H. (1994). Haloperidol addition in fluvoxamine-refractory obsessive-compulsive disorder: A double-blind, placebo-controlled study in patients with and without tics. Archives of General Psychiatry, 51, 302–308. Mell, L. K., Davis, R. L., & Owens, D. (2005). Association between streptococcal infection and obsessive-compulsive disorder, Tourette’s syndrome, and tic disorder. Pediatrics, 116, 56–60. Middleton, F. A., & Strick, P. L. (2000). Basal ganglia and cerebellar loops: Motor and cognitive circuits. Brain Research. Brain Research Reviews, 31, 236–250. Mink, J. W., Walkup, J., Frey, K. A., Como, P., Cath, D., Delong, M. R., Erenberg, G., Jankovic, J., Juncos, J., Leckman, J. F., Swerdlow, N., Visser-Vandewalle, V., Vitek, J. L; Tourette Syndrome Association, Inc. (2006). Patient selection and assessment recommendations for deep brain stimulation in Tourette syndrome. Movement Disorders, 21, 1831–1838. Moll, G. H., Wischer, S., Heinrich, H., Tergau, F., Paulus, W., & Rothenberger, A. (1999). Deficient motor control in children with tic disorder: Evidence from transcranial magnetic stimulation. Neuroscience Letters, 272, 37–40. Morshed, S. A., Parveen, S., Leckman, J. F., Mercadante, M. T., Bittencourt Kiss, M. H., Miguel, E. C., et al. (2001). Antibodies against neural, nuclear, cytoskeletal, and streptococcal epitopes in CHAPTER 44 734 9781405145497_4_044.qxd 29/03/2008 02:53 PM Page 734

children and adults with Tourette’s syndrome, Sydenham’s chorea, and autoimmune disorders. Biological Psychiatry, 50, 566–577. Pasamanick, B., & Kawi, A. (1956). A study of the association of prenatal and paranatal factors with the development of tics in children: A preliminary investigation. Journal of Pediatrics, 48, 596–601. Pauls, D. L., & Leckman, J. F. (1986). The inheritance of Gilles de la Tourette’s syndrome and associated behaviors: Evidence for autosomal dominant transmission. New England Journal of Medicine, 315, 993–997. Pauls, D. L., Raymond, C. L., Stevenson, J. M., & Leckman, J. F. (1991). A family study of Gilles de la Tourette syndrome. American Journal of Human Genetics, 48, 154–163. Perlmutter, S. J., Leitman, S. F., Garvey, M. A., Hamburger, S., Feldman, E., Leonard, H. L., et al. (1999). Therapeutic plasma exchange and intravenous immunoglobulin for obsessive-compulsive disorder and tic disorders in childhood. Lancet, 354, 1153–1158. Perrin, E. M., Murphy, M. L., Casey, J. R., Pichichero, M. E., Runyan, D. K., Miller, W. C., et al. (2004). Does group A betahemolytic streptococcal infection increase risk for behavioral and neuropsychiatric symptoms in children? Archives of Pediatric and Adolescent Medicine, 158, 848–856. Peterson, B. S., & Leckman, J. F. (1998). The temporal dynamics of tics in Gilles de la Tourette syndrome. Biological Psychiatry, 44, 1337–1348. Peterson, B. S., Leckman, J. F., Scahill, L., Naftolin, F., Keefe, D., Charest, N. J., et al. (1992). Steroid hormones and CNS sexual dimorphisms modulate symptom expression in Tourette’s syndrome. Psychoneuroendocrinology, 17, 553–563. Peterson, B. S., Pine, D. S., Cohen, P., & Brook, J. S. (2001a). Prospective, longitudinal study of tic, obsessive-compulsive, and attention-deficit/hyperactivity disorders in an epidemiological sample. Journal of the American Academy of Child and Adolescent Psychiatry, 40, 685–695. Peterson, B. S., Skudlarski, P., Anderson, A. W., Zhang, H., Gatenby, J. C., Lacadie, C. M., et al. (1998a). A functional magnetic resonance imaging study of tic suppression in Tourette syndrome. Archives of General Psychiatry, 55, 326–333. Peterson, B. S., Staib, L., Scahill, L., Zhang, H., Anderson, C., Leckman, J. F., et al. (2001b). Regional brain and ventricular volumes in Tourette syndrome. Archives of General Psychiatry, 58, 427–440. Peterson, B. S., Thomas, P., Kane, M. J., Scahill, L., Zhang, H., Bronen, R., et al. (2003). Basal ganglia volumes in patients with Gilles de la Tourette syndrome. Archives of General Psychiatry, 60, 415–424. Peterson, B. S., Zhang, H., Anderson, G. M., & Leckman, J. F. (1998b). A double-blind, placebo-controlled, crossover trial of an antiandrogen in the treatment of Tourette’s syndrome. Journal of Clinical Psychopharmacology, 18, 324–331. Piacentini, J. C., & Chang, S. W. (2006). Behavioral treatments for tic suppression: Habit reversal training. Advances in Neurology, 99, 227–233. Price, R. A., Kidd, K. K., Cohen, D. J., Pauls, D. L., & Leckman, J. F. (1985). A twin study of Tourette syndrome. Archives of General Psychiatry, 42, 815–820. Rauch, S. L., Baer, L., Cosgrove, G. R., & Jenike, M. A. (1995). Neurosurgical treatment of Tourette’s syndrome: A critical review. Comprehensive Psychiatry, 36, 141–156. Robertson, M. M., Banerjee, S., Kurlan, R., Cohen, D. J., Leckman, J. F., McMahon, W., et al. (1999). The Tourette syndrome diagnostic confidence index: Development and clinical associations. Neurology, 53, 2108–2112. Robertson, M. M., & Orth, M. (2006). Behavioral and affective disorders in Tourette syndrome. Advances in Neurology, 99, 39–60. Robertson, M. M., Williamson, F., & Eapen, V. (2006). Depressive symptomatology in young people with Gilles de la Tourette Syndrome: A comparison of self-report scales. Journal of Affective Disorders, 91, 265–268. Rutter, M., Tizard, J., & Whitmore, K. (1970). Education, health, and behaviour. Longman, London. Sallee, F. R., Nesbitt, L., Jackson, C., Sine, L., & Sethuraman, G. (1997). Relative efficacy of haloperidol and pimozide in children and adolescents with Tourette’s disorder. American Journal of Psychiatry, 154, 1057–1062. Sanberg, P. R., Silver, A. A., Shytle, R. D., Philipp, M. K., Cahill, D. W., Fogelson, H. M., et al. (1997). Nicotine for the treatment of Tourette’s syndrome. Pharmacology and Therapeutics, 74, 21–25. Santangelo, S. L., Pauls, D. L., Goldstein, J. M., Faraone, S. V., Tsuang, M. T., & Leckman, J. F. (1994). Tourette’s syndrome: What are the influences of gender and comorbid obsessive-compulsive disorder? Journal of the American Academy of Child and Adolescent Psychiatry, 33, 795–804. Scahill, L., Chappell, P. B., Kim, Y. S., Schultz, R. T., Katsovich, L., Shepherd, E., et al. (2001). A placebo-controlled study of guanfacine in the treatment of children with tic disorders and attention deficit hyperactivity disorder. American Journal of Psychiatry, 158, 1067–1074. Scahill, L., Erenberg, G., Berlin, C. M. Jr., Budman, C., Coffey, B. J., Jankovic, J., et al. (2006). Contemporary assessment and pharmacotherapy of Tourette syndrome. NeuroRx, 3, 192–206. Scahill, L., Leckman, J. F., Schultz, R. T., Katsovich, L., & Peterson, B. S. (2003). A placebo-controlled trial of risperidone in Tourette syndrome. Neurology, 60, 1130–1135. Schultz, R. T., Carter, A. S., Gladstone, M., Scahill, L., Leckman, J. F., Peterson, B. S., et al. (1998). Visual-motor integration functioning in children with Tourette syndrome. Neuropsychology, 12, 134– 145. Serrien, D. J., Orth, M., Evans, A. H., Lees, A. J., & Brown, P. (2005). Motor inhibition in patients with Gilles de la Tourette syndrome: Functional activation patterns as revealed by EEG coherence. Brain, 128, 116–125. Shapiro, A. K., Shapiro, E. S., Young, J. G., & Freinberg, T. E. (1988). Gilles de la Tourette syndrome (2nd edn.). New York: Raven Press. Shapiro, E., Shapiro, A. K., Fulop, G., Hubbard, M., Mandeli, J., Nordlie, J., et al. (1989). Controlled study of haloperidol, pimozide and placebo for the treatment of Gilles de la Tourette’s syndrome. Archives of General Psychiatry, 46, 722–730. Sikich, L., & Todd, R. D. (1988). Are the neurodevelopmental effects of gonadal hormones related to sex differences in psychiatric illnesses? Psychiatric Developments, 6, 277–309. Singer, H. S., Giuliano, J. D., Hansen, B. H., Hallett, J. J., Laurino, J. P., Benson, M., et al. (1998). Antibodies against human putamen in children with Tourette syndrome. Neurology, 50, 1618–1624. Singer, H. S., Hahn, I. H., & Moran, T. H. (1991). Abnormal dopamine uptake sites in postmortem striatum from patients with Tourette’s syndrome. Annals of Neurology, 30, 558–562. Singer, H. S., Hong, J. J., Yoon, D. Y., & Williams, P. N. (2005a). Serum autoantibodies do not differentiate PANDAS and Tourette syndrome from controls. Neurology, 65, 1701–1707. Singer, H. S., Mink, J. W., Loiselle, C. R., Burke, K. A., Ruchkina, I., Morshed, S., et al. (2005b). Microinfusion of antineuronal antibodies into rodent striatum: Failure to differentiate between elevated and low titers. Journal of Neuroimmunology, 163, 8–14. Singer, H. S., Szymanski, S., Giuliano, J., Yokoi, F., Dogan, A. S., Brasic, J. R., et al. (2002). Elevated intrasynaptic dopamine release in Tourette’s syndrome measured by PET. American Journal of Psychiatry, 159, 1329–1336. State, M. W., Greally, J. M., Cuker, A., Bowers, P. N., Henegariu, O., Morgan, T. M., et al. (2003). Epigenetic abnormalities associated with a chromosome 18(q21–q22) inversion and a Gilles de la Tourette syndrome phenotype. Proceedings of the National Academy of Sciences of the USA, 100, 4684–4689. Stern, E., Silbersweig, D. A., Chee, K. Y., Holmes, A., Robertson, M. M., Trimble, M., et al. (2000). A functional neuroanatomy TIC DISORDERS 735 9781405145497_4_044.qxd 29/03/2008 02:53 PM Page 735

de la Tourette syndrome. The Tourette Syndrome Association International Consortium for Genetics. American Journal of Human Genetics, 65, 1428–1436. Tourette’s Syndrome Study Group. (1999). Short-term versus longerterm pimozide therapy in Tourette’s syndrome: A preliminary study. Neurology, 52, 874–877. Tourette’s Syndrome Study Group. (2002). Treatment of ADHD in children with tics: A randomized controlled trial. Neurology, 58, 527–536. Vandewalle, V., Van der Linden, C., Groenewegen, H. J., & Caemaert, J. (1999). Stereotactic treatment of Gilles de la Tourette syndrome by high frequency stimulation of thalamus. Lancet, 353, 724. Verkerk, A. J., Mathews, C. A., Joosse, M., Eussen, B. H., Heutink, P., & Oostra, B. A. (2003). CNTNAP2 is disrupted in a family with Gilles de la Tourette syndrome and obsessive compulsive disorder. Genomics, 82, 1–9. Visser-Vandewalle, V., Temel, Y., Boon, P., Vreeling, F., Colle, H., Hoogland, G., et al. (2003). Chronic bilateral thalamic stimulation: A new therapeutic approach in intractable Tourette syndrome. Report of three cases. Journal of Neurosurgery, 99, 1094–1100. Walkup, J. T., Rosenberg, L. A., Brown, J., & Singer, H. S. (1992). The validity of instruments measuring tic severity in Tourette’s syndrome. Journal of the American Academy of Child and Adolescent Psychiatry, 31, 472–477. Wilhelm, S., Deckersbach, T., Coffey, B. J., Bohne, A., Peterson, A. L., & Baer, L. (2003). Habit reversal versus supportive psychotherapy for Tourette’s disorder: A randomized controlled trial. American Journal of Psychiatry, 160, 1175–1177. Wolf, S. S., Jones, D. W., Knable, M. B., Gorey, J. G., Lee, K. S., Hyde, T. M., et al. (1996). Tourette syndrome: Prediction of phenotypic variation in monozygotic twins by caudate nucleus D2 receptor binding. Science, 273, 1225–1227. World Health Organization (WHO). (1996). Multiaxial classification of child and adolescent disorders: The ICD-10 classification of mental and behavioural disorders in children and adolescents (pp. 43–45). Cambridge: World Health Organization, Cambridge University Press. Ziemann, U., Paulus, W., & Rothenberger, A. (1997). Decreased motor inhibition in Tourette’s disorder: Evidence from transcranial magnetic stimulation. American Journal of Psychiatry, 154, 1277– 1284. CHAPTER 44 736 of tics in Tourette syndrome. Archives of General Psychiatry, 57, 741–748. Stokes, A., Bawden, H. N., Camfield, P. R., Backman, J. E., & Dooley, J. M. (1991). Peer problems in Tourette’s disorder. Pediatrics, 87, 936–942. Sukhodolsky, D. G., do Rosario-Campos, M. C., Scahill, L., Katsovich, L., Pauls, D. L., Peterson, B. S., et al. (2005). Adaptive, emotional, and family functioning of children with obsessivecompulsive disorder and comorbid attention deficit hyperactivity disorder. American Journal of Psychiatry, 162, 1125–1132. Sukhodolsky, D. G., Scahill, L., Zhang, H., Peterson, B. S., King, R. A., Lombroso, P. J., et al. (2003). Disruptive behavior in children with Tourette’s syndrome: Association with ADHD comorbidity, tic severity, and functional impairment. Journal of the American Academy of Child and Adolescent Psychiatry, 42, 98–105. Swedo, S. E., Leonard, H. L., Garvey, M., Mittleman, B., Allen, A. J., Perlmutter, S., et al. (1998). Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections: Clinical description of the first 50 cases. American Journal of Psychiatry, 155, 264–271. Swedo, S. E., Leonard, H. L., Mittleman, B. B., Allen, A. J., Rapoport, J. L., Dow, S. P., et al. (1997). Identification of children with pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections by a marker associated with rheumatic fever. American Journal of Psychiatry, 154, 110–112. Swedo, S. E., Rapoport, J. L., Cheslow, D. L., Leonard, H. L., Ayoub, E. M., Hosier, D. M., et al. (1989). High prevalence of obsessive-compulsive symptoms in patients with Sydenham’s chorea. American Journal of Psychiatry, 146, 246–249. Swerdlow, N. R., Karban, B., Ploum, Y., Sharp, R., Geyer, M. A., & Eastvold, A. (2001). Tactile prepuff inhibition of startle in children with Tourette’s syndrome: In search of an “fMRI-friendly” startle paradigm. Biological Psychiatry, 50, 578–585. Swerdlow, N. R., & Sutherland, A. N. (2006). Preclinical models relevant to Tourette syndrome. Advances in Neurology, 99, 69–88. Tourette Syndrome Association International Consortium for Genetics, Centre National de Génotypage. (2007). Genome scan for Tourette’s disorder in affected sib-pair and multigenerational families. American Journal of Human Genetics, 80, 265–272. Tourette Syndrome Association International Consortium for Genetics. (1999). A complete genome screen in sib pairs affected by Gilles 9781405145497_4_044.qxd 29/03/2008 02:53 PM Page 736