Rutter's Child and Adolescent Psychiatry Book 2

In this chapter we describe the clinical picture of unipolar depressive disorders, diagnostic subcategories, differential diagnosis and common comorbidities. The descriptive epidemiology, onset, course, sequelae and predictors are discussed. Evidence-based psychopharmacological and psychosocial acute and continuation treatments of depression are presented, along with current controversies. More general issues of clinical management such as determination of intensity of care and the role of hospitalization are also reviewed. Clinical Picture Clinical Presentation and Classification Depressive disorders in childhood and adolescence are characterized by persistent and pervasive sadness, anhedonia, boredom or irritability that is functionally impairing, and relatively unresponsive to pleasurable activities, interactions and attention from other people. In one of the first studies of the clinical picture of depression in preschoolers, anhedonia was found to be characteristic of depression in these children (Luby, Heffelfinger, Mrakotsky, et al., 2003). Functional impairment is most salient in distinguishing depression from the “normal ups and downs” of childhood and adolescence. Depressive disorders exist on a continuum, and are classified on the basis of severity, pervasiveness and presence or absence of mania. At the mildest end of the spectrum are adjustment disorders with depressed mood, which are mild, self-limited and occur in response to a clear stressor. Depression not otherwise specified (NOS), also referred to as “minor” or subsyndromal depression, is diagnosed in the presence of depressed mood, anhedonia or irritability, and up to three symptoms of major depression. This term “minor” depression is misleading in so far as depression NOS is associated with functional impairment and increased risk of major depression (Fergusson, Horwood, Ridder et al., 2005). Dysthymic disorder also has fewer symptoms than major depression, but its most notable characteristic is its chronicity, lasting a minimum of a year. In explaining this condition to parents and children, it may be helpful to describe major depression as a “cloudy sky,” and dysthymia as “partly cloudy” (Birmaher, Ryan, Williamson et al., 1996b). The co-occurrence of dysthymic disorder and major depression, termed “double depression,” is associated with a chronic course. Major depression is the “full-blown” condition, with either sad or irritable mood, or anhedonia, along with at least five other symptoms, such as social withdrawal, worthlessness, guilt, suicidal thoughts or behavior, increased or decreased sleep, decreased motivation and/or concentration, and increased or decreased appetite (American Psychiatric Association, 2000). Rarely, depressed patients also have psychotic symptoms such as auditory hallucinations or delusions, usually with some self-derogatory, paranoid or depressive content. Differential Diagnosis The most important differential diagnosis is between unipolar and bipolar depression (see chapter 38), the latter being characterized by past or current mania or hypomania (e.g., expansive mood, hypersexuality, grandiosity, decreased need for sleep). Often, young bipolar patients present with either rapid cycling or a mixed state (an admixture of depressive and manic symptoms), so that detection of bipolarity requires care, persistence and longitudinal follow-up (Birmaher, Axelson, Strober et al., 2006). Anxiety disorders are often associated with significant dysphoria that is relieved if the anxiogenic situation, such as that of separation or social situations, is eliminated. The social withdrawal of depression should be differentiated from the avoidance of social situations because of anxiety. Altered concentration is not only a symptom of depression, but is also a key feature of attention deficit/hyperactivity disorder (ADHD; see chapter 34). Concentration difficulties in ADHD are not associated with changes in mood-related symptoms. Moreover, ADHD usually has a much earlier onset. Children with ADHD often become demoralized because of peer rejection and difficulties at school. This demoralization can be ascribed to ADHD in absence of other depressive symptoms. Irritability is a prominent symptom of conduct and oppositional disorders (see chapter 35), and, in the absence of other mood symptoms, this symptom is more likely to be caused by the behavioral disorder than depression. Substance abuse (see chapter 36) can mimic mood disorder by disrupting sleep, concentration, motivation and appetite; moreover, these conditions frequently co-occur with mood disorders in clinical practice. A careful history and, when warranted, a drug toxicology screen 587 Depressive Disorders in Childhood and Adolescence David Brent and V. Robin Weersing 37 9781405145497_4_037.qxd 29/03/2008 02:52 PM Page 587 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

is often the only way to detect this important and serious condition. Patients with eating disorders (see chapter 41) often show lassitude and dysphoria, which can in part be attributed to poor nutritional status. A diagnosis of current depression in an eating disordered patient should not be made until adequate nutritional status has been restored. Comorbidity Differential diagnosis notwithstanding, comorbidity is the rule rather than the exception in depressed children and adolescents, especially in clinical samples (Angold, Costello, & Erkanli, 1999; see also chapter 2). Comorbidity may result from shared etiology, or as a cause or consequence of depression. Comorbid conditions affect both the course and outcome of depression. Anxiety is frequently a precursor of mood disorder. Anxiety and depression may be comorbid because of a shared genetic diathesis (Middeldorp, Cath, van Dyck et al., 2005). ADHD and depression are also often comorbid. Comorbidity between depression and behavioral disorders and substance abuse may be attributable to shared family risk factors, such as abuse, exposure to family violence and discord, and parental substance abuse (Fergusson & Woodward, 2002). Alcohol, drug and tobacco abuse are associated with depression, and longitudinal studies suggest a bidirectional causality, with substance abuse both leading to, and occurring as a consequence of depression. Depression increases the likelihood of initiation and development of substance abuse problems, but substance abuse problems lead to life events that increase the likelihood of depression (Kuo, Gardner, Kendler et al., 2006; Libby, Orton, Stover et al., 2005). Conduct disorder is frequently comorbid with depression, particularly in prepubertal samples (Harrington, 2000). Assessment The psychiatric interview is the “gold standard” for assessment of depressive diagnoses (Myers & Winters, 2002). The main advantages of psychiatric interview over self- or parentreport are that interviews can determine the temporal sequence, course and functional significance of different symptoms, determine to what extent these symptoms should be attributed to a depressive disorder or to another condition, and facilitate the integration and resolve discrepancies between parent and child sources of information. The main disadvantages of direct interviews are cost and time, and for semistructured interviews a high level of training and ongoing quality monitoring. Interviews are conducted with both the parent and the child. Parents are usually better informants about past history treatment and symptoms that are tied to external behavior, such as social withdrawal, decline in school performance and agitation. Children are better reporters about internal experiences and thoughts, such as suicidal ideation, anhedonia, guilt, psychosis and lack of motivation. Epidemiological studies have found fairly consistent results using both fully structured (Diagnostic Interview Schedule for Children [DISC] and Composite International Diagnostic Interview [CIDI], the latter just in adolescents; Shaffer, Fisher, & Lucas, 2004) and semistructured interviews (Schedule for Affective Disorders and Schizophrenia–Epidemiological version [K-SADS-E], Schedule for Affective Disorders and Schizophrenia for School-Age Children–Present and Lifetime version [K-SADS-PL], Child and Adolescent Psychiatric Assessment [CAPA]; Angold, Prendergast, Cox et al., 1995; Kaufman, Birmaher, Brent et al., 1997a). The Preschool Age Psychiatric Assessment (PAPA), a downward extension of the CAPA, shows good reliability and internal consistency with regard to assessment of preschool psychopathology, including depression (Egger, Erkanli, Keeler et al., 2006). The advantages, disadvantages and psychometric properties of each of these instruments are reviewed in more detail in chapter 19. The most commonly used continuous interview-based measure of depressive symptomatology is the Children’s Depression Rating Scale–Revised (CDRS-R), a 17-item assessment that is analogous to the Hamilton Depression Rating Scale (Poznanski, Freeman, & Mokros, 1985). The measure ranges from 17 to 113, with 40 or above associated with clinically significant depression, and less than 29 with symptomatic remission. Discriminant and convergent validity, as well as sensitivity to treatment effects, have been demonstrated (Emslie, Rush, Weinberg et al., 1997). Among its limitations are that the CDRS-R emphasizes neurovegetative rather than cognitive symptoms and has less than straightforward anchor points for the suicide ideation item. The Mood and Feelings Questionnaire (MFQ) is the only self-report scale validated for both children and adolescents and comes in a 37-item and 13-item form; the latter is useful for screening for depressive disorders (Thapar & McGuffin, 1998). This measure also has a parent report version. Internal consistency, convergent and discriminant validity have been reported, with the ability to discriminate depression from anxiety and from conduct disorder. The Children’s Depression Inventory (CDI) was developed as a downward extension of the Beck Depression Inventory (BDI), and has a self, parent and teacher report form, although usually the former is used in the literature (Kovacs, 1985). The CDI is highly correlated with other measures of depression, but does not discriminate well from anxiety disorders and so is better used as a measure of emotional disturbance rather than depression per se. The Center for Epidemiological Studies–Depression Scale (CES-D) has been used in several epidemiological and treatment studies of adolescents of diverse ethnic origin, works well as a screen for depression, has good discriminant validity and is sensitive to treatment effects (Dierker, Albano, Clarke et al., 2001; Lewinsohn, Rohde, & Seeley, 1998). One weakness is that it does not have a suicide ideation item. The Beck Depression Inventory (BDI) is very widely used in studies of adolescents, is a good screen for depressive disorders, is sensitive to treatment effects and may be a more effective screen for major depression than the CES-D (Dierker, Albano, Clarke et al., 2001; Roberts, Lewinsohn, & Seeley, 1991). It has strong psychometric properties of the adolescent instruments but emphasizes the cognitive component of depressive disorders. CHAPTER 37 588 9781405145497_4_037.qxd 29/03/2008 02:52 PM Page 588

The Reynolds Adolescent Depression Scale (RADS) is another scale with very good psychometric properties that is sensitive to treatment effects (March, Silva, Petrycki et al., 2004; Reynolds & Mazza, 1998). The Preschool Feelings Checklist is a 16-item parent report measure that, in a preliminary report, appears to have high sensitivity and specificity for preschool depressive disorders (Luby, Heffelfinger, Koenig-McNaught et al., 2004). Studies of adults in primary care have shown that a two-item screen (about low mood and anhedonia) is as efficient as longer self-report inventories, but no studies in children or adolescents have yet been published (Whooley, Avins, Miranda et al., 1997). Descriptive Epidemiology The point prevalence of depressive disorders is 1–2% in prepubertal children and 3–8% in adolescents, with a lifetime prevalence by the end of adolescence of around 20% (Costello, Mustillo, Erkanli et al., 2003; Fergusson, Horwood, Ridder et al., 2005; Lewinsohn, Rohde, & Seeley, 1998). The point prevalence of clinically significant depressive symptomatology in multinational studies is even higher (10–13% in boys and 12–18% for girls; Ruchkin, Sukhodolsky, Vermeiren et al., 2006). The prevalence of depression in preschoolers is unknown. The rate of depressive disorders may be increasing in subsequent birth cohorts, with the age of onset becoming earlier (Kovacs & Gatsonis, 1994; Ryan, Williamson, Iyengar et al., 1992b). Whereas some or even most of this apparent effect might be attributable to recall bias, a cohort effect is consistent with a concomitant rise in the youth suicide rate from the 1950s to the early 1990s (Costello, Erkanli, & Angold, 2006). Age and Gender There is an upsurge in the rate of depression that accompanies the onset of puberty, at which point the dramatic female predominance in mood disorders first emerges (Angold, Costello, & Worthman, 1998), perhaps mediated by increases in estradiol and testosterone. The higher female than male rate of depression may also be a result of higher rates of anxiety disorder in females, greater tendency to engage in ruminative thinking, greater total cortisol excretion after the corticotropinreleasing hormone challenge and increased interpersonal sensitivity, all of which may increase vulnerability for depression (Breslau, Schultz, & Peterson, 1995; Nolen-Hoeksema, Larson, & Grayson, 1999; Stroud, Papandonatos, Williamson et al., 2004). Prepubertal depression appears to be of two types. The first, more common presentation of pre-pubertal depression is with comorbid behavioral problems, parental criminality, parental substance abuse and family discord. The course of these children resembles those with conduct disorder much more than those with mood disorders, without an increased risk for recurrence of depression into adult life (Harrington, Rutter, Weissman et al., 1997; Weissman, Wolk, Wickramaratne et al., 1999a). The second, less common, form is highly familial, with multigenerational loading for depression, with high rates of anxiety and bipolar disorder, and recurrences of depression in adolescence and adulthood. Adolescent onset depressive disorder has a high risk of recurrent mood disorder into adulthood (Harrington, 2000; Harrington, Rutter, Weissman et al., 1997; Weissman, Wolk, Goldstein et al., 1999b). Twin studies suggest a greater genetic component in adolescent versus pre-pubertal onset depression, supportive of the view that child and adolescent onset depression may differ in etiology (Scourfield, Rice, Thapar et al., 2003). In clinical samples, depressed adolescents, compared to depressed children, showed more hopelessness, decreased energy, and fatigue, hypersomnia, suicidality and substance abuse, whereas depressed children showed more comorbid separation anxiety and ADHD (Yorbik, Birmaher, Axelson et al., 2004). Developmental Factors Girls with earlier onset of puberty may be at increased risk for depression and other disorders (Graber, Seeley, BrooksGunn et al., 2004). The relationship between early onset of puberty and depressive symptoms is complex, because early onset of puberty is related to factors that are also related to risk for depression onset, including maternal depression, mother–child discord and child–step-parent discord (Ellis & Garber, 2000). As girls undergo the transition to adolescence, there is also an increase in child-generated parent–child and peer–peer interpersonal conflict, which may increase the likelihood of depressive disorder (Rudolph & Hammen, 1999). A greater physiological need for sleep, along with a tendency to actually obtain less sleep may also increase vulnerability to depression (Dahl, 2004). Course and Outcome Episode Length and Recovery Depression is a chronic and recurrent condition. The duration for depressive episodes is 3–6 months for community samples and 5–8 months for referred samples (Birmaher, Arbelaez, & Brent, 2002). Greater episode length is associated with comorbid dysthymic disorder, comorbidity with anxiety disorder or substance abuse, greater initial severity of the depressive condition, current or past suicidal ideation or behavior, chronicity and number of episodes of parental depression and other disorders and family discord (Birmaher, Brent, Kolko et al., 2000a; Kovacs, Feinberg, Crouse-Novak et al., 1984a; Warner, Weissman, Fendrich et al., 1992). In both clinical and community samples, around 20% of adolescents with a lifetime history of depression have a persistent depression of 2 years or greater (Birmaher, Arbelaez, & Brent, 2002; Lewinsohn, Rohde, & Seeley, 1998). Risk for Recurrence In one meticulously conducted study that examined the course of depressive disorder in 8- to 13-year-olds, the risk DEPRESSIVE DISORDERS 589 9781405145497_4_037.qxd 29/03/2008 02:52 PM Page 589

of recurrence was 40% in 2 years, and 72% in 5 years (Kovacs, 1996; Kovacs, Feinberg, Crouse-Novak et al., 1984b). Other longitudinal studies have shown that the risk for recurrent depression in adolescent depression followed forward is extremely high, with the rate of relapse or recurrence ranging 30–70% in 1–2 years of follow-up in clinical samples, and 16–33% in 2–4 year follow-up in community samples (Birmaher, Arbelaez, & Brent, 2002; Lewinsohn, Rohde, & Seeley, 1998). Prepubertal depressed children with a family history of depression have a similar risk of recurrence (Birmaher, Williamson, Dahl et al., 2004; Harrington, Rutter, Weissman et al., 1997). Risk factors for recurrence include early onset of mood disorder in a parent, lack of complete recovery (defined as either subsyndromal depression or return to a dysthymic baseline), pre-existing social dysfunction, history of sexual abuse and family discord (Birmaher, Arbelaez, & Brent, 2002; Lewinsohn, Rohde, & Seeley, 1998). Other Sequelae Both depressed children and adolescents are at increased risk for conduct disorder, personality disorders, alcohol, tobacco and drug abuse, and suicidal behavior (Fergusson & Woodward, 2002; Lewinsohn, Rohde, Seeley et al., 2003). They also are at increased risk for obesity, risky sexual behavior, unfulfilling and problematic social relationships, and educational and occupational underachievement (Fergusson & Woodward, 2002; Pine, Goldstein, Wolk et al., 2001). Whereas some studies conclude that most negative sequelae are the residue of incomplete depressive symptom resolution (Lewinsohn, Rohde, Seeley et al., 2003), others find that these “sequelae” may result from common factors that contribute to risk for depression, and for other problems, namely, parental criminality, parental substance abuse, physical or sexual abuse and family discord (Fergusson & Woodward, 2002). Alcohol and Substance Abuse Whereas alcohol and substance abuse are more likely to occur in depressed adolescents, many predictors of alcohol and substance abuse are also risk factors for depression, including comorbid behavior disorder, neuroticism, parental history of substance abuse, parental criminality, history of sexual abuse, low parental education, family discord and association with a deviant peer group (Fergusson & Woodward, 2002; Rao, Ryan, Dahl et al., 1999). Alcohol and substance use appears to be a consequence of depression, but can also lead to negative life events that precipitate depression (Libby, Orton, Stover et al., 2005; Kuo, Gardner, Kendler et al., 2006). Suicidal Behavior Depression is a strong predictor of suicide attempts and completion (Brent, Baugher, Bridge, et al., 1999; Gould, King, Greenwald, et al., 1998; Shaffer, Gould, Fisher, et al., 1996). Among depressed children and adolescents, greater severity and chronicity of depression, current ideation with a plan or a history of a suicide attempt, comorbid conduct disorder, substance abuse, or impulsive-aggressive personality traits, greater hopelessness, a family history of suicidal behavior, a history of abuse, family conflict and lack of support, distinguish depressed suicide attempters and non-attempters both crosssectionally and prospectively (Bridge, Goldstein, & Brent, 2006; and see chapter 40). Risk for Bipolar Disorder The risk of bipolar disorder in early onset depression is estimated to be around 10–20% (Geller, Zimerman, Williams et al., 2001), with elevated risk in patients who present with hypomania in response to treatment, psychotic features, hypersomnia (in some studies) and a family history of bipolar disorder (Geller, Zimerman, Williams et al., 2001; Strober & Carlson, 1982). Children and younger adolescents exposed to antidepressants, according to one pharmaco-epidemiological study, are at particularly high risk for manic switch (Martin, Young, Leckman et al., 2004). Risk Factors Genetic Twin studies demonstrate that depressive symptoms have a greater concordance among monozygotic than among dizygotic twins, with a heritability of around 40% (Glowinski, Madden, Bucholz et al., 2003; Todd & Botteron, 2002). If cases are defined by longitudinal, rather than just cross-sectional data, the heritability of depression is higher, around 65% (O’Connor, Neiderhiser, Reiss et al., 1998; Todd & Botteron, 2002). Thus, 35–60% of variance is explained by non-genetic factors, such as family adversity and protective factors described below. Adolescent onset depression symptomatology has a greater heritable component than does child onset depressive symptomatology (Scourfield, Rice, Thapar et al., 2003). However, this finding of developmentally mediated differential heritability of depression may be because of the relatively low number of younger children in these twin samples, or due to an increase in the number of behavior-dependent life events that emerge in adolescence (Rice, Harold, & Thapar, 2003; Todd & Botteron, 2002). There is evidence that liability to depression is co-transmitted along with anxiety symptoms, with heritability of co-transmission estimated to be 61–65% (Hudziak, Rudiger, Neale et al., 2000; Thapar & McGuffin, 1997). The genetic relationship between anxiety and depression, according to one series of twin studies, is as follows: 1 Genes that affect liability to anxiety also lead to an increased sensitivity to life events; and 2 Genes that increase risk for anxiety also increase the likelihood of exposure to depressogenic life events (Eaves, Silberg, & Erkanli, 2003). This formulation is consistent with several longitudinal studies that show an association between child characteristics, child-generated life events and eventual depression (Daley, Hammen, Davila et al., 1998). The first-degree relatives of depressed children or adolescents have a two- to four-fold increased risk of depression (Kovacs CHAPTER 37 590 9781405145497_4_037.qxd 29/03/2008 02:52 PM Page 590

& Devlin, 1998). Family studies of prepubertal depressives find increased parental rates of criminality, abuse, antisocial disorder and mania (Harrington, Rutter, Weissman et al., 1997; Wickramaratne, Warner, & Weissman, 2000b). In contrast, family studies of adolescent depression have more consistently found an increased rate of mood disorders in firstdegree relatives (Harrington, Rutter, Weissman et al., 1997; Wickramaratne, Warner & Weissman, 2000). “Top-down” studies have also shown an increased risk of depressive disorder in the offspring of depressed parents (Klein, Lewinsohn, Rohde et al., 2005). Greater family loading, such as depression in two generations and increased rates of parental anxiety disorders, was associated with an increased risk and earlier onset of depression, and an increased rate of anxiety disorders, further supporting the view that the liability to depression and that to anxiety are co-transmitted (Weissman, Pilowsky, Wickramaratne et al., 2006; Williamson, Birmaher, Axelson et al., 2004). There are ongoing genetic studies of recurrent depression that suggest linkage, but none has focused particularly on childhood and adolescent depression (McGuffin, Knight, Breen et al., 2005). The risk of depression, in the presence of stressful life events, is higher in those who had a shorter allele variant of the serotonin transporter (SLC6A4), which results in less vigorous transcription of this gene (Caspi, Sugden, Moffitt et al., 2003). A polymorphism of the gene encoding brainderived neurotrophic factor (BDNF) has been reported to be associated with early-onset depression, both alone and in interaction with early childhood adversity (Kaufman, Yang, Douglas-Palumberi et al., 2006; Strauss et al., 2005). Cognitive Bias and Emotional Regulation Depressed individuals have been shown to have a cognitive bias towards a negative view of self, future and the world. Prospective studies have found that in non-depressed individuals, especially those at risk for depression, these biases predispose to depressive symptomatology when confronted with stressful life events (Garber, Keiley, & Martin, 2002; Hammen, 1988; Lewinsohn, Joiner, & Rohde, 2001). Moreover, the relationship between negative mood and self-critical cognitions appears to be bidirectional (Kelvin, Goodyer, Teasdale et al., 1999; Park, Goodyer, & Teasdale, 2005; Rudolph, Hammen, & Burge, 1997; Stewart, Kennard, Lee et al., 2004). Depressive symptoms are correlated positively with experimental increases in rumination and negatively with distraction (Lyubomirsky, Caldwell, & Nolen-Hoeksema, 1998). Neurocognitive studies of depressed adolescents and youth at risk for depression are consistent with the cognitive theory of depression. Both currently and previously depressed youth show greater attention to negative affect, sad words and other negative emotional distractors, whereas youth at low risk for depression show greater attention to positive distractors (Kyte, Goodyer, & Sahakian, 2006; Ladouceur, Dahl, Williamson et al., 2005). Other probes of emotional regulation in children and adolescents at risk for depression, compared to those at low risk, show greater difficulty in inhibition of negative affect, less use of active distraction and less ability to generate positive affect in the face of distraction (Forbes, Fox, Cohn et al., 2006a; Goodyer, 2002; Silk, Shaw, Skuban et al., 2006). It is unclear if these deficits in inhibition are affectively specific, or reflect more global executive function difficulties, consistent with deficits in categorical autobiographic memory and poorer decision-making on gambling tasks associated with adolescent depression (Kyte, Goodyer, & Sahakian, 2006; Park, Goodyer, & Teasdale, 2002). For example, children with a past depression showed deficits in memory for fearful faces (Pine, 2004). Comorbid Diagnoses The trait of fearfulness, as well as anxiety disorder per se, and especially social phobia, are associated with increased risk of depression (Goodwin, Fergusson, & Horwood, 2004b; Pine, Cohen, & Brook, 2001; Pine, Cohen, Gurley et al., 1998). The rates of depression are increased both in patients with ADHD and their parents (Faraone & Biederman, 1997). Early symptoms of impulsivity and hyperactivity have been reported as precursors of depression (Jaffee, Moffitt, Caspi et al., 2002). The rates of depression are elevated in children with conduct disorder, perhaps because of shared risk factors (Fergusson & Woodward, 2002). Furthermore, conduct-disordered individuals tend to associate with like-minded peers, which leads to further conduct difficulties, resultant stressful life events (e.g., getting arrested) and more depressive episodes (Fergusson, Wanner, Vitaro et al., 2003). Family Environmental Factors Twin studies show a greater role for shared environment in explaining concordance of depressive symptoms in prepubertal children by comparison with adolescents, for whom non-shared environment has a much larger role than shared environment (Scourfield, Rice, Thapar et al., 2003). Family discord and expressed emotion directed towards the child predicted onset or recurrence in at-risk subjects (Asarnow, Goldstein, Tompson et al., 1993; Frye & Garber, 2005). Greater chronicity and severity of maternal depression have been related to greater liability for parent–child conflict, and for cognitive distortions, both of which increase liability for and persistence of child depressive symptoms (Garber & Flynn, 2001). Longitudinal studies show reciprocal interrelationships between maternal and child interpersonal and emotional difficulties, child cognitive distortions and child depressive outcome (Frye & Garber, 2005; Garber & Robinson, 1997; Garber, Keiley, & Martin, 2002; Hammen, Burge, & Stansbury, 1990). Physical and sexual abuse are among the most potent family–environmental risk factors for the onset and recurrence of depression, and also increase risk for comorbid post-traumatic stress disorder, substance abuse, conduct disorder and suicidal behavior (Barbe, Bridge, Birmaher et al., 2004; Fergusson, Horwood, & Lynskey, 1996; and see chapters 28 and 29). These effects are strongest for more severe and chronic abuse, such as sexual abuse resulting in intercourse (Fergusson, Horwood, & Lynskey, 1996). However, it is difficult to DEPRESSIVE DISORDERS 591 9781405145497_4_037.qxd 29/03/2008 02:52 PM Page 591

isolate the effects of abuse from the other adverse aspects of parental functioning and home environment that are associated with it: parental mood disorder, substance abuse, criminality, lower parental education and income, and marital discord. The relationship between depression and abuse is much stronger in the presence of other family–genetic risk factors such as a family history of depression and a specific genotype of an SLC6A4 polymorphism (Caspi, Sugden, Moffitt et al., 2003; Kaufman, Birmaher, Brent et al., 1998a). Bullying and Same Sex Attraction Both bulliers and the bullied have higher rates of depression than controls (Ivarsson, Broberg, Arvidsson et al., 2005; Kaltiala-Heino, Rimpela, Rantanen et al., 2000). Same sex attraction, activity, and bisexual or homosexual identification have been related to increased rates of depression, as well as substance abuse and suicidal behavior (Fergusson, Horwood, & Beautrais, 1999). The relationship between sexual attraction/activity/orientation and depression may be mediated by gender atypical behavior, peer rejection, bullying and parental rejection (D’Augelli, Grossman, Salter et al., 2005). Bereavement and Other Stressful Life Events Most generally, there is a relationship between stressful life events and depressive disorder in children and adolescents, observed both prospectively and concurrently (Brent, Perper, Moritz et al., 1993; Lewinsohn, Rohde, & Seeley, 1998; Williamson, Birmaher, Ryan et al., 2003), and experience of stress is more likely to result in depression in those with a diathesis as determined by family history or presence of certain genotypes (Brent, Perper, Moritz et al., 1993; Caspi, Sugden, Moffitt et al., 2003; Kaufman, Birmaher, Brent et al., 1998a, 2006). Studies of bereaved children and adolescents find rates of diagnosable depression around 30% within a year of the death, but these occur almost exclusively among those who are at risk because of other factors such as a previous personal or family history of depression (Brent, Perper, Moritz et al., 1993). The impact of parent loss may be mediated by a cascade of other factors, such as a drop in living standard, geographic dislocation and mental health of the surviving parent (Tremblay & Israel, 1998). Protective Factors A positive connection to parents and to school may protect against depression and associated health risk behaviors such as suicidal behavior, substance use, binge eating and binge drinking, tobacco use and lack of exercise (Resnick, Bearman, Blum et al., 1997). More specifically, these protective factors include a positive connection between parent and child, active parental supervision and clear behavioral and academic expectations on the part of the parent for the child, parents and children spending leisure and meal time together, academic success, a positive connection between child and school, and a pro-social peer group (Conrad & Hammen, 1993; Fergusson & Lynskey, 1996; King, Schwab-Stone, Flisher et al., 2001). Surprisingly few of these findings have found their way into the intervention literature, with some notable exceptions (Thompson, Eggert, Randell et al., 2001). Comorbid Medical Illness A relationship between less than ideal physical health and depression has been reported in community studies of adolescents (Lewinsohn, Rohde, & Seeley, 1998). Lewinsohn, Rohde, & Seeley (1998) posit that illness interferes with activities that are likely to be enjoyable or enhance a sense of mastery, which in turn predisposes to depression. There may also be systemic effects of some chronic illnesses or their treatments in diseases such as epilepsy ( Jones, Hermann, Barry et al., 2003; Plioplys, 2003), juvenile onset diabetes (Kovacs, Goldston, Obrosky et al., 1997), inflammatory bowel disease (Addolorato, Capristo, Stefanini et al., 1997) and asthma (Goodwin, Fergusson, & Horwood, 2004a). Twin studies suggest co-transmission of liability to eczema and mood disorder (Wamboldt, Hewitt, Schmitz et al., 2000). There is also an increased risk of medical problems in depressed offspring of depressed parents, suggesting that factors associated with risk for depression may also increase risk for ill health, an observation also made in a genetic linkage study of early-onset recurrent depression (Kramer, Warner, Olfson et al., 1998; Zubenko, Zubenko, Spiker et al., 2001). Neuroendocrine Direct measures of cortisol secretion have not distinguished between early-onset depressives and controls (Feder, Coplan, Goetz et al., 2004; Puig-Antich, Dahl, Ryan et al., 1989). There were no differences between depressed children and controls with regard to adrenocorticotropin hormone (ACTH) release, after stimulation with corticotropin releasing hormone (CRH), although a small subgroup of melancholic children showed a blunted response (Birmaher, Dahl, Perel et al., 1996a), and ACTH release was increased in depressed children who had a history of abuse (Kaufman, Birmaher, Perel et al., 1997b). Increased cortisol secretion around sleep onset is associated with adolescent depression and predicts depressive recurrence and substance abuse in young adults who were studied during adolescence (Dahl, Ryan, Puig-Antich et al., 1991; Rao, Ryan, Dahl et al., 1999). Goodyer et al. found that in adolescents at high risk for depression, increased morning dehydroepiandrosterone (DHEA) was associated with onset of depression, and high morning cortisol : DHEA ratio at intake was related to persistence of depressive symptoms (Goodyer, Herbert, & Tamplin, 2003; Goodyer, Herbert, Tamplin et al., 2000). A decrease in growth hormone (GH) release in response to a provocative challenge of growth hormone releasing hormone (GHRH), which may be related to central norepinephrine neurotransmission, has been reported in depressed children versus controls during both episode and recovery, and in never-depressed children of depressed parents (Birmaher, Dahl, Williamson et al., 2000b; Dahl, Birmaher, Williamson et al., 2000). In a longitudinal study of depressed children grown up, increased amount of GH release in the first 4 hours of sleep was related to recurrence of CHAPTER 37 592 9781405145497_4_037.qxd 29/03/2008 02:52 PM Page 592

depression and suicide attempt (Pine, Coplan, Wasserman et al., 1997). A blunted cortisol and exaggerated prolactin response (the latter in girls only) to L-5 hydroxytryptophan (L-5HT) has been found in both depressed children and neverdepressed children at risk for depression due to parental depression, compared to controls (Birmaher, Kaufman, Brent et al., 1997; Ryan, Birmaher, Perel et al., 1992a), consistent with central dysregulation of serotonin neurotransmission. Increased gastrointestinal distress in response to this challenge predicted an increased risk of anxiety or depression over time (Campo, Dahl, Williamson et al., 2003). However, similar neuroendocrine responses to provocative challenge may be found in those with adverse home environments, and with high levels of aggression (Kaufman, Birmaher, Perel et al., 1998b; Pine, Coplan, Wasserman et al., 1997). Sleep Subjective sleep complaints are a very prominent component of early-onset depression, although subjective complaints and objective observations of sleep in a sleep laboratory are not closely correlated (Bertocci, Dahl, Williamson et al., 2005). Decreased rapid eye movement (REM) latency and increased latency of sleep-onset are not frequently observed in prepubertal depression, although the presence of these markers was associated with greater depressive severity (Dahl, Ryan, PuigAntich et al., 1991). Decreased REM latency and increased latency of sleep-onset is observed in depressed adolescents, but only after a strict sleep–wake schedule was imposed. Decreased REM latency, increased REM density and decreased sleep efficiency have been reported to be associated with depressive onset, recurrence and persistence more consistently in older adolescents (Dahl & Lewin, 2002). Studies of Hemispheric Lateralization Studies of infants and children at high risk for depression have found evidence of decreased left hemisphere electroencephalogram (EEG) activity (Dawson, Frey, Panagiotides et al., 1997; Tomarken, Dichter, Garber et al., 2004). Low left frontal EEG activity was also related to greater negative affect and less positive affiliative behavior in babies of depressed mothers (Bruder, Tenke, Warner et al., 2005; Forbes, Shaw, Fox et al., 2006b). In adolescent and adult offspring of depressed and non-depressed parents, those at risk for depression had less activity over right central and parietal regions, whereas those offspring with a history of depression had less left frontal activity (Bruder, Tenke, Warner et al., 2005; Kentgen, Tenke, Pine et al., 2000; Shankman, Tenke, Bruder et al., 2005). Neuroimaging Studies Structural imaging studies of adult subjects with early-onset familial depression as well as in adolescents with depression have found reduced volume of the left subgenual prefrontal cortex, with others finding more global differences between familial and non-familial pediatric depression (Botteron, Raichle, Drevets et al., 2002; Drevets, Price, Simpson et al., 1997; Lyoo, Kyu Lee, Hyun Jung et al., 2002; Nolan, Moore, Madden et al., 2002). Preliminary studies of female adolescent depressed twins suggest that this structural difference is genetically transmitted and may mediate the heritability of depression (Todd & Botteron, 2002). Decreased amygdala size has been reported in depressed children and adolescents (Rosso, Cintron, Steingard et al., 2005). Steingard, Renshaw, Hennen et al. (2002) reported decreased prefrontal cortex and increased third and fourth ventricular volume in depressed adolescents, although these findings have now been reported in a variety of neuropsychiatric disorders and may be a marker for the effects of chronicity. Other findings, such as altered hippocampal size, may be attributable to early trauma (Kaufman & Charney, 2001; Vythilingam, Heim, Newport et al., 2002). In studies using magnetic resonance imaging (MRI) spectroscopy, lower glutamate concentrations have been reported in the anterior cingulate cortex in depressed children and adolescents versus non-depressed controls (Mirza, Tang, Russell et al., 2004). The degree of functional impairment was inversely correlated with glutamate concentration. However, this finding is not specific to major depression, as lower anterior cingulate glutamate is also found in children with obsessive-compulsive disorder (Rosenberg, Mirza, Russell et al., 2004). Increased choline concentrations in the left dorso-lateral and in orbitofrontal prefrontal cortex of depressed children and adolescents have also been reported (Farchione, Moore, & Rosenberg, 2002; Steingard, Yurgelun-Todd, Hennen et al., 2000). Thomas, Drevets, Dahl et al. (2001) evaluated responses of depressed and anxious children and control children to fearful faces, and found increased amygdala activation in anxious children and decreased amygdala activation in depressed children. In contrast, increased amygdala activation has been found in depressed adolescents during recall of fearful faces. Increased amygdala activation was also found in depressed adolescents, relative to controls, during participation in reward-related decision-making and response to outcome (Forbes, May, Siegle et al., 2006c; Roberson-Nay, McClure, Monk et al., 2006). Clinical Management Risk Assessment and Treatment Planning The first determination in the assessment of a depressed child or adolescent is whether the child can safely be treated as an out-patient. A patient with suicide ideation with a plan and intent, or who has made a recent suicide attempt with continued intent, should initially be hospitalized or treated in a more acute setting than out-patient unless the patient, clinician and family can develop a safety plan for coping with future suicidal urges upon which all can mutually agree (Birmaher & Brent, 2007; National Institute for Health and Clinical Excellence [NICE], 2005; Shaffer & Pfeffer, 2001; see also chapter 40). In addition, patients who are acutely psychotic, in a bipolar mixed state or are substance dependent may not be able to be treated as out-patients. Patients who are being abused at home should be removed from the home DEPRESSIVE DISORDERS 593 9781405145497_4_037.qxd 29/03/2008 02:52 PM Page 593

temporarily, although not necessarily to hospital. Whereas most US standards of care recommend psychiatric hospitalization for greater acuity and safety concerns, there has been almost no empirical assessment of the value of psychiatric hospitalization versus other types of treatment. Therefore, if a patient and family refuse hospital admission, unless there appears to be an obvious clinical counterindication (e.g., patient psychotic and refusing to eat), it may be preferable to preserve an alliance with the patient and family and schedule out-patient visits several times per week in the initial stabilization phase. As a general framework, clinicians need to consider the following hierarchy of priorities: 1 Life-threatening issues (e.g., suicidality, homicidality, exposure to domestic violence, intravenous drug use); 2 Therapy-threatening issues (hopelessness about treatment, chronically depressed parent who is unable to bring the child for treatment); and 3 Symptom and functionally oriented treatment. Patient and Family Education Because depression is often a chronic and recurrent illness, it is vital to establish a long-term partnership with the patient and family with regard to its management. This can be achieved by providing the patient and family with all the requisite information about depression and its treatment, and then making treatment decisions collaboratively (Brent, Poling, McKain et al., 1993). As described in Table 37.1, education focuses on depression as an illness, recognition and monitoring of depressive symptomatology, knowing risks and benefits of different treatments, and, if symptom relief is achieved, development of a plan to prevent relapse and recurrence. Family, Social and Individual Context The treatment plan for depressed children and adolescents should consider four levels of contextual factors: parents, peers, school and individual. Depressed children and adolescents who are clinically referred often have parents who have active psychiatric difficulties, most commonly depression, anxiety and substance abuse (Hammen, Rudolph, Weisz et al., 1999). These difficulties may make it very difficult for the family to comply with treatment recommendations, and may also create stressors that make it less likely for the patient to respond to treatment. For example, three different research groups have reported that current parental depressive symptoms make it less likely that a child will respond to cognitive–behavioral therapy (CBT) for depression or anxiety (Brent, Kolko, Birmaher et al., 1998; Lewinsohn, Rohde, & Seeley, 1998; Southam-Gerow, Kendall, & Weersing, 2001). Treatment of maternal depression is associated with amelioration of child symptomatology (Weissman, Pilowsky, Wickramaratne et al., 2006). Therefore, facilitation of a treatment referral for the depressed parent should be part of the child’s treatment plan. Abuse, exposure to family violence or high levels of criticism or discord must be addressed because of safety issues for the child as well as the negative impact of these factors on duration and recurrence of depressive episodes. When parents are unable to provide the necessary support for treatment, they sometimes are willing to allow involvement of adult surrogates, such as older siblings, other relatives or close friends who may temporarily step in and help with transportation and even monitoring of treatment response. Depressed adolescents, particularly those with comorbid behavioral traits and substance use, often are involved in friendships with similarly depressed, substance abusing and disaffected youth, which tend to reinforce depressive attitudes and also encourage antisocial acts that in turn lead to depressogenic life events (Fergusson, Wanner, Vitaro et al., 2003). Therefore, the possibility of developing more prosocial relationships should be on the treatment agenda. As a result of decreased energy and concentration and motivational difficulties, depressed children and adolescents often fall behind in school, which in turn leads to a sense of failure, increased anxiety and a tendency to give up and disconnect from school. There also may be specific school-related stressors that contribute to depressive symptomatology, such as being the target of bullying, or teasing by students or teachers. Conversely, cross-sectional data and one intervention study suggest that a positive connection between school and student, as well as high parental academic expectations appropriate to the child, are protective against depression (Resnick, Bearman, Blum et al., 1997; Thompson, Eggert, Randell et al., 2001). Therefore, the clinician should assess the depressed child’s current school function, identify any school-related stressors, and, if the patient has fallen behind academically, develop a plan, in conjunction with the school, for a reduced workload and a plan for catching up that is mutually acceptable to school, family and student. With regard to individual context, it is important to identify comorbid health risk behaviors or psychiatric disorders that are likely to be life-threatening or disruptive to therapy, in which case, they should be attended to first. Life-threatening behavior, like intravenous drug use, aggressive criminal behavior or non-compliance with a serious chronic illness, should be addressed prior to treatment of depression, even recognizing that depression may be contributing to this problem. Higher priority to targeting comorbid conditions should be given if these symptoms are causing the greatest functional impairment and if the treatment of depression is likely not to CHAPTER 37 594 Table 37.1 Psychoeducation: key elements for parents and patients. Depression is an illness and not the fault of the patient or family How to recognize and monitor depressive symptoms, detect early relapse and recurrence Modal course, in order to have reasonable expectations for pace and extent of recovery Risks and benefits of different treatment options, in order to make an informed decision How to collaborate in development of a plan for relapse prevention, continuation and maintenance treatment 9781405145497_4_037.qxd 29/03/2008 02:52 PM Page 594

be successful unless the other condition is addressed first. For example, the treatment of a patient with both depression and ADHD whose main difficulties are decrease in motivation, suicidal ideation and hopelessness should probably initially focus on the depression, whereas a patient with similar comorbidity whose depression emerges secondary to school and peer failure due to impulsivity and inattention should probably have the ADHD addressed first. Treatment There are currently three treatments for adolescent depression with some empirical support: antidepressant treatment, CBT and interpersonal therapy. Meta-analyses show support for the efficacy of fluoxetine in prepubertal depression but, because of small numbers and a smaller effect size, not for other agents (Bridge, Iyengar, Salary et al., 2007). There has been considerably less research on treatment of prepubertal children with depression, although there is some support for the efficacy of antidepressants. Each of these three approaches will be discussed, followed by a recommendation for “best practice” which is based on both empirical support and expert consensus (Brent, 2004; Brent & Birmaher, 2002; Birmaher & Brent, 2007; NICE, 2005). Because of the controversies surrounding the efficacy of antidepressants and of psychotherapy for pediatric depression, we provide a synopsis of the effect sizes of the extant clinical trials in Tables 37.2–37.4. Antidepressant Medication Evidence of Efficacy Both the single largest placebo-controlled comparison study of tricyclic antidepressants (TCAs) and placebo, and a subsequent meta-analysis showed no difference between drug and placebo (Hazell, O’Connell, Heathcote et al., 1995; Keller, Ryan, Strober et al., 2001), whereas several studies have demonstrated efficacy with selective serotonin reuptake inhibitor (SSRI) antidepressants, especially using fluoxetine (Bridge, Iyengar, Salary et al., 2007). This may be reflective of an overall developmental difference in so far as adolescents and younger adults may respond better to serotonergic agents, whereas older adults respond equally as well to serotonergic and to noradrenergic agents (Mulder, Watkins, Joyce et al., 2003). Fluoxetine is the best-studied antidepressant with the strongest efficacy data, and consequently is the only antidepressant to receive US Food and Drug Administration (FDA) and Medicine and Healthcare Products Regulatory Agency (MHRA) approval for the treatment of depression in children and adolescents (Emslie, Rush, Weinberg et al., 1997, 2002; March, Silva, Petrycki et al., 2004). In the three published studies of fluoxetine, a higher proportion of those treated with fluoxetine were “much or very much improved” compared to those treated with placebo (52–61% versus 33–37%), with a number needed to treat (NNT) = 5. In the Treatment of DEPRESSIVE DISORDERS 595 Table 37.2 Differences in efficacy outcomes for antidepressant-treated and placebo-treated groups. (Table provided by Jeffrey Bridge, PhD.) Response rate %* Primary scalar Medication Placebo Risk difference measure of efficacy Drug Study n Group Group (95% CI) NNT (95% CI) Hedges’s g (95% CI) Fluoxetine Simeon et al. (1990) – – – – – 0.21 Fluoxetine Emslie et al. (1997) 96 56 33 23 0.60 Fluoxetine Emslie et al. (2002) 210 65 54 12 9 0.50 Fluoxetine TADS Study Team 2004 221 61 35 26 4 0.040 Fluoxetine Pooled estimates 527 62 42 20 (11 to 29) 6 (4 to 10) 0.46 (0.29 to 0.62) Paroxetine Keller et al. (2001) 177 67 55 12 9 0.22 Paroxetine Berard et al. (2006) 268 61 58 2 46 0.07 Paroxetine Emslie et al. (2006) 201 49 46 3 40 −0.06 Paroxetine Pooled estimates 646 59 53 5 (−3 to 13) 20 (8 to ∞ to NNH 38) 0.07 (−0.09 to 0.23) Sertraline Wagner et al. (2004) 364 69 59 10 10 – Citalopram Wagner et al. (2004) 174 36 24 12 9 0.32 Escitalopram Wagner et al. (2006) 261 63 52 11 10 0.13 Venlafaxine Study 382 141 50 41 9 12 0.16 Venlafaxine Study 394 193 68 61 7 14 0.13 Venlafaxine Pooled estimates 334 61 52 8 (−2 to 18) 13 (6 to ∞ to NNH 42) 0.14 (−0.07 to 0.35) Nefazadone CN104-141 195 62 42 20 6 (3 to 17) 0.28 Mirtazapine 003-045 249 57 49 7 14 (5 to ∞ to NNH 18) 0.20 Overall 2750 60 48 11 9 (7 to 14) 0.23 CI, confidence interval; NNH, number needed to treat to harm; NNT, number needed to treat to benefit. * Clinical Global Impression-Improvement Score (CGI-I) <2. 9781405145497_4_037.qxd 29/03/2008 02:52 PM Page 595

Adolescent Depression Study (TADS), fluoxetine was more efficacious than both cognitive–behavior therapy and placebo (proportion “significantly improved,” 61% versus 43% versus 35%; March et al., 2004). However, combined treatment (fluoxetine plus CBT) resulted with the highest rate of symptomatic remission (37% versus 20% on fluoxetine alone; Kennard, Silva, Vitiello et al., 2006). A meta-analysis of all available clinical trials, both published and unpublished, shows that SSRIs are superior to placebo, with the average response rate for drug versus placebo for antidepressants 60% versus 49%, with NNT = 9, with a comparable effect size on scalar measures (Hedges’s G = 0.23; Bridge, Iyengar, Salary et al., 2007; see Table 37.2). The relatively low effect size in SSRIs versus placebo in child and adolescent depression is caused in part by the high placebo response rate. The drug–placebo difference was inversely proportional to the number of study sites involved in the trial, suggesting that some studies with large numbers of sites may have been less selective in recruitment (Bridge, Iyengar, Salary et al., 2007). Duration was also inversely proportional to response. Other explanations for the relative modest effects of antidepressants include use of inadequate dosage, duration of treatment too short to achieve the full effect, and aggregation of results of children and adolescents when, in some studies, there were significant effects for adolescents but not for children. Besides fluoxetine, other drugs with published efficacy data include citalopram, paroxetine and sertraline (Keller, Ryan, Strober et al., 2001; Wagner, Ambrosini, Rynn et al., 2003, 2004), although the effect sizes were relatively small and there are other negative studies for these agents (Emslie, Kratochvil, Vitiello et al., 2006; von Knorring, Olsson, Thomsen et al., 2006). A review of the published and unpublished studies indicates that, for paroxetine and for venlafaxine, the response to medication was superior to placebo for adolescents, but not for children (Emslie, Yeung, Kunz et al., 2007). In some studies, such as those for venlafaxine, the doses appeared to be substantially below those recommended for clinical practice (Emslie, Kratochvil, Vitiello et al., 2006). Amfebutamone, a monocyclic aminoketone that inhibits the reuptake of dopamine and norepinephrine, has been found in open trials to improve depressive symptoms and ADHD symptoms in patients comorbid for both conditions (Daviss, Bentivoglio, Racusin et al., 2001), but this agent has not been studied in randomized trials in depressed children or adolescents. Antidepressant efficacy is correlated with concentration of amfebutamone and metabolites, most significantly, hydroxyamfebutamone (Daviss, Perel, Brent et al., 2006). Adverse Events in Antidepressant Treatment The US FDA conducted a meta-analysis that found a higher rate of spontaneously reported suicide-related adverse events on drug than on placebo (4% versus 2%; Hammad, Laughren, & Racoosin, 2006). There were relatively few suicide attempts, no completions and most suicidal events occurred early in treatment. The increased risk for suicidality was found in subjects treated for depression, obsessive compulsive disorder (OCD) and anxiety. Another meta-analysis that included additional studies not reported on in the FDA meta-analysis and using random rather than fixed effects models reported rates of suicidal adverse events for drug and placebo of 2.5% versus 1.7%, respectively, for a risk difference of 0.8%, and a number needed to harm (NNH) of 125. Thus, the number of those who benefit from SSRIs (NNT = 10) compared to those who become suicidal (NNH = 125) is around 14 : 1. (Bridge, Iyengar, Salary et al., 2007). Baseline predictors of spontaneously reported events in all pooled studies using paroxetine identified suicidal ideation at intake, agitation at baseline and female gender as risk factors (Apter, Lipschitz, Fong et al., 2006). No mechanism has been established that explains the relationship between SSRI use and suicidality, although some speculate that it could be a result of rapid metabolism, non-compliance and/or withdrawal symptoms, induction of a mixed state (combination of manic and depressed symptoms), akathisia or SSRI-induced disinhibition (Brent, 2004). The clinical significance of these spontaneously reported suicide-related adverse events is unclear. Almost all are increased suicidal ideation or suicidal threats, with very few attempts and no completions in over 4300 subjects (Hammad, Laughren, & Racoosin, 2006). Moreover, no difference between drug and placebo has been detected in the subset of studies that also assessed for suicidality using standard measures, although there was an effect of medication on suicidality on the Suicide Ideation Questionnaire in the TADS study (Emslie, Kratochvil, Vitiello et al., 2006). If SSRIs significantly increased suicidal risk, one would expect to see a recent increase in the rate of adolescent suicide, given the dramatic increase in the use of SSRIs in adolescents. However, the adolescent suicide rate has declined over the past decade, and some pharmaco-epidemiological studies find a relationship between increased prescription and sales of SSRIs and a decline in completed suicide, which is particularly notable among the young (Brent, 2004; Gibbons, Hur, Bhaumik et al., 2006; Olfson, Shaffer, Marcus et al., 2003). In one record linkage study, the rate of attempted suicide in both adults and adolescents started on SSRIs was highest in the month before initiation of medication (Simon, Savarino, Operskalski et al., 2006). Nonetheless, caution and close monitoring for increased suicidality are warranted in mood-disordered patients treated with SSRIs. In addition to the concern over suicide and self-injurious behavior, antidepressants are associated with increased incidence of sleep disruption, vivid dreams, nausea and gastrointestinal distress, increase in agitation, akathisia, anxiety, headache, serotonin syndrome (particularly in combination with other serotonergic agents) and bruising (caused by a prolongation of clotting time; Goldstein & Goodnick, 1998). The last side-effect is usually not clinically significant, but can become so in patients with intrinsic coagulation disorders or who are undergoing surgery. One pharmaco-epidemiological study found that the risk of SSRI-treatment-associated mania CHAPTER 37 596 9781405145497_4_037.qxd 29/03/2008 02:52 PM Page 596

was greatest in patients under the age of 14 (Martin, Young, Leckman et al., 2004). Predictors of Antidepressant Response One naturalistic study found that comorbid attentional problems predicted poorer response to an SSRI in depressed adolescents (Hamilton & Bridge, 1999). A naturalistic follow-up after a clinical trial found that poorer outcome was predicted by family discord, comorbidity and greater severity at intake (Emslie, Rush, Weinberg et al., 1998). In the TADS study, predictors of poor outcome, regardless of treatment assignment, were severity (depressive symptoms and functional impairment), complexity (comorbidity) and chronicity (Curry, Rohde, Simons et al., 2006). A higher dose may lead to better outcome in those patients who fail to respond to a lower dose of SSRI (Heiligenstein, Hoog, Wagner et al., 2006). There is evidence that adolescents metabolize sertraline, citalopram and paroxetine (but not fluvoxamine) faster than do adults, so that higher doses than typically recommended for adults may be needed (Axelson, Perel, Birmaher et al., 2002; Findling, McNamara, Stansbrey et al., 2006; Labellarte et al., 2004). Biological Predictors of Response Two small studies found a correlation between percent reuptake of serotonin in platelet receptors and clinical response (Axelson et al., 2005; Sallee, Hilal, Dougherty et al., 1998). One study found an association between up-regulation of glucocorticoid type II receptors and response to sertraline (Sallee, Nesbitt, Dougherty et al., 1995). Several studies found that the short allelic variant of the serotonin transporter gene (SLC6A4) is associated with a poorer response to SSRIs in adults (Lerer & Macciardi, 2002), and preliminary data in depressed children and adolescents are consistent with these findings. Depressed adults who responded to CBT showed high amygdala and low subgenual cingulate cortex response to sustained emotional processing. Depressed adults who responded to fluoxetine showed greater left versus right hemisphere activation to dichotic listening, whereas the reverse predicted poor outcome (Bruder, Stewart, Tenke et al., 2001; Siegle, Carter, & Thase, 2006). Role in Continuation In patients who have been successfully treated with fluoxetine for the acute phase, a 32-week double-blind comparison of continuation treatment with fluoxetine versus placebo showed a relapse rate of 30% on continuation versus 60% on placebo, with a median time to relapse of 6 versus 2.3 months (Emslie, Heiligenstein, Hoog et al., 2004). Cognitive–Behavior Therapy Theory and Techniques CBT is based on the theory of depression that holds that depressed individuals show “distortions” in their thinking and information processing, tending to emphasize the negative aspects of a situation and to underemphasize the positive, as has been demonstrated in self-report and neurocognitive evaluations (see p. 604; Beck, Rush, Shaw et al., 1979). This tendency to focus differentially on the negative appears to have a role in the genesis and maintenance of depressive episodes and negative mood states during times of stress (Garber & Robinson, 1997; Garber, Keiley, & Martin, 2002; Lewinsohn, Joiner, & Rohde, 2001). CBT treatments for depression focus on interrupting this cycle of negative thinking, depressed mood and maladaptive behavior, through a variety of cognitive techniques and behavioral skill-building exercises. Central to CBT is cognitive restructuring, that is, making the patient aware of negative “distortions” and teaching the individual how to counteract them, with subsequent relief of depression. Another key component of CBT is behavioral activation; for example, encouraging patients to normalize their routine and engage in rewarding activities, even if they do not feel like it at the time. This component of CBT is derived from the observation that depressed mood has been shown to fluctuate proportionally to the degree of involvement in potentially reinforcing activities (Lewinsohn, Rohde, & Seeley, 1998). However, the content of CBT treatment manuals, tested in clinical trials, varies greatly in the emphasis on each of these techniques (behavior activation, cognitive restructuring) and the inclusion of other adjunctive skill-building elements (e.g., problem-solving, emotion regulation, relaxation, social skills training). In addition, CBT approaches vary with regard to the length, structure and emphasis format (e.g., group or individual), which makes differences in outcome across studies difficult to interpret. Efficacy of CBT Many pioneering studies of CBT for child depression involved symptomatic volunteers (Weisz, McCarty, & Valeri, 2006). However, in order to allow comparability to the above-noted medication trials, we focus our review on studies enrolling samples that meet formal diagnostic criteria for a depressive disorder (Table 37.3). All of these investigations are in depressed adolescents; as yet there are no published CBT efficacy trials in diagnosed samples composed primarily of prepubertal youth, although an open trial of a psychosocial treatment with a focus on emotional regulation with some cognitive elements, described below, has been reported (Kovacs, Sherril, George et al., 2006). A comprehensive meta-analysis of child psychotherapy studies found an overall effect size for CBT treatment of depression of 0.34, although in the absence of the large, and essentially negative contrast between CBT and placebo in the TADS study, the overall effect size was 0.48 (Weisz, McCarty, & Valeri, 2006). The most commonly studied intervention for depressed adolescents is the CBT-based course Coping with Depression for Adolescents (CWD-A), a group-administered structured program that includes psychoeducation, pleasant activity scheduling, social skills training, problem-solving and cognitive DEPRESSIVE DISORDERS 597 9781405145497_4_037.qxd 29/03/2008 02:52 PM Page 597

restructuring. Two studies compared CWD-A, with or without a multisession parent curriculum, and a waitlist control group (Clarke, Lewinsohn, Rohde et al., 1999; Lewinsohn, Clarke, Hops et al., 1990). In both of these investigations, CWD-A was superior to waitlist at the end of treatment, with regard to diagnosed depression and dimensional measures of depression. However, the addition of the parent group had no additive effect to the group CBT alone. In the second study, one to two booster sessions were provided, which did not reduce the rate of depressive recurrence, but did seem to be helpful to those who had not yet recovered from their depressive episode (Clarke, Lewinsohn, Rohde et al., 1999). Subsequently, the program has been employed with depressed conduct-disordered youth, and has been adapted for depressed incarcerated youth (Rohde, Clarke, Mace et al., 2004a; Rohde, Jorgensen, Seeley et al., 2004b). The success rate was more modest for these more clinically complex youth, but the effect sizes for reduction in rates and severity of depression between the experimental treatment and waitlist controls were comparable to the initial studies. To date, there have been four studies to test the efficacy of CBT in clinically referred depressed adolescents. Vostanis, Feehan, Grattan et al. (1996) compared CBT to supportive treatment and found no difference between treatment groups (86% versus 75% no longer depressed). Treatment was very brief (around six sessions) and was offered over an extended time frame (1–5 months). In contrast, Wood, Harrington, and Moore (1996), who used a similar but more concentrated treatment model (5–8 sessions of CBT over 12 weeks), found that brief CBT was superior to relaxation therapy in depressed adolescents; improvements were also noted in functional impairment, anxiety and dimensional measures of depression. Upon follow-up, there was a tendency for those treated with CBT to relapse so that differences were no longer statistically significant. Brent, Holder, Kolko et al. (1997) compared 12–16 sessions of CBT that was an adaptation of Beck’s approach (Beck et CHAPTER 37 598 Table 37.3 Cognitive–behavioral therapy (CBT) for adolescents with clinically diagnosed depression. (After Weersing et al., 2006.) Study Brent et al. (1997) Clarke et al. (1999) Clarke et al. (2002) Lewinsohn et al. (1990) Rosello & Bernal (1999) Treatment of Adolescent Depression Study (TADS) (2004) Vostanis et al. (1996) Wood et al. (1996) BDI, Beck Depression Inventory; CBT, Cognitive–behavioral therapy; CBTP, CBT – parent design; CDI, Children’s Depression Inventory; CDRS-R, Children’s Depression Rating Scale – Revised; CES-D, Center for Epidemiological Studies, Depression; CGI-I, Clinical Global Impression-Improvement; IPT-A, Interpersonal psychotherapy for depressed adolescents; MFQ-P, Mood and Feelings Questionnaire, Parent; NNT, Number needed to treat; School TAU, school counseling services. n 107 123 88 69 71 223 63 53 Treatment and control conditions CBT Family Supportive CBT CBTP Waitlist CBT+TAU TAU CBT CBTP Waitlist CBT IPT-A Waitlist Placebo CBT Supportive CBT Relaxation Mean sessions 12.1 10.7 11.2 16 16 + 9 – 16 CBT 8 week 14 14 + 7 – 12 12 – 11 6 6 6.4 6.2 Source of sample Clinic, diagnosed depression Community, screened for diagnosis Community, offspring of depressed parents, screened for diagnosis Community, screened for diagnosis Community, screened for diagnosis Clinic, diagnosed depression Clinic, diagnosed depression Clinic, diagnosed depression Definition of clinical response No mood diagnosed and normal BDI No mood diagnosed No mood diagnosed No mood diagnosed Normal CDI CGI-I ≤ 2 No mood diagnosed “Clinical remission” Responding at posttreatment (%) 60 38 39 65 69 48 58 53 43 47 5 59 82 – 43 35 86 75 54 21 NNT 5 5–6 20 3 – 12 9 4 Primary symptom measure BDI BDI CES-D BDI CDI CDRS-R MFQ-P MFQ-P CBT effect size CBT: 0.40 CBT: 0.58 CBTP: 0.24 0.20 CBT: 0.92 CBTP: 1.45 0.34 –0.03 0.51 0.40 9781405145497_4_037.qxd 29/03/2008 02:52 PM Page 598

al., 1979) with family therapy and with supportive treatment, all delivered by therapists who were trained in and adherents of their treatment model. At post-treatment, CBT produced outcomes superior to the alternative intervention, with regard to decline in depressive symptoms, achievement of remission and speed of response. Upon 2-year follow-up, there were no statistically significant differences among the three randomized groups (Birmaher, Brent, Kolko et al., 2000a). The final CBT efficacy trial in a diagnosed sample is the Treatment of Adolescents with Depression Study (TADS; March, Silva, Petrycki et al., 2004). TADS is the only published study to compare CBT, fluoxetine, their combination and placebo. In this large well-powered investigation, CBT (43% significantly improved) was not superior to placebo (35%), whereas both combination of CBT and fluoxetine (71%) and fluoxetine alone (61%) were markedly superior to both CBT and to placebo. Given the generally positive effects of CBT in other investigations, why did CBT fail to outperform placebo in TADS? The authors posit that CBT was less efficacious because of severity, comorbidity and economic disadvantage of the sample. However, other studies found stronger effects for CBT in poorer samples that had comparable severity and comorbidity, with comorbid anxiety actually being a positive prognosticator (Brent, Holder, Kolko et al., 1997, 1998; Rohde, Clarke, Lewinsohn et al., 2001). TADS subjects did have greater duration of depression than was reported in other studies, which, in turn, was associated with poorer response to treatment in the TADS study and one meta-analysis of all antidepressant trials for depression (Bridge, Iyengar, Salary et al., 2007; Curry, Rohde, Simons et al., 2006). Another possible explanation for the relatively weak performance of CBT in this study could be the type of treatment delivered. The TADS treatment package attempted to deliver, in a relatively brief treatment, a large number of accepted approaches: problemsolving, behavior activation, cognitive restructuring, emotion regulation, relaxation training and parent–child sessions, whereas some of the more successful interventions have mainly focused on cognitive restructuring or on behavior activation and problem-solving. It is possible that in the TADS manual’s attempt to be inclusive of a variety of successful techniques, subjects never received an adequate “dose” of any one of these specific CBT techniques (Hollon, Garber, & Shelton, 2005). Combined CBT and Medication In TADS the combination of CBT and fluoxetine was superior to drug alone in the overall sample, and also for the subgroup with mild to moderate depression, with regard to speed and completeness of response (Curry, Rohde, Simons et al., 2006; Kennard, Silva, Vitiello et al., 2006; Vitiello, Rohde, Silva et al., 2006). Overall combination treatment resulted in the best functional outcomes and highest rates of remission (37% versus 20% for placebo). However, the combination treatment was not superior to medication alone for more severely depressed subjects, although the trends favored combination (effect size [ES] 0.84 for combination versus 0.69 for fluoxetine alone; Curry, Rohde, Simons et al., 2006). In addition to the TADS study, there have been two other investigations of the impact of combined CBT and antidepressant management compared with antidepressant alone, which, in aggregate, do not make a strong case for the use of combined treatment, counterintuitive as this seems. Clarke, Debar, Lynch et al. (2005) studied the addition of the CWD-A treatment to antidepressant management in primary care. This combined treatment resulted in some modest improvement in quality of life, but improvement in depressive symptoms never reached statistical significance; moreover, patients in the combined treatment were more likely to stop their antidepressants. A study conducted in the UK compared combination treatment, using the CBT model that had been used successfully by Wood, Harrington, & Moore (1996), with fluoxetine alone, for moderate to severely ill depressed adolescents. CBT did not add to medication alone with regard to global functioning, quality of life or depressive symptomatology (Goodyer, 2006). Effectiveness Three published investigations have produced findings relevant to the effectiveness of CBT in practice. As noted above, Clarke, Debar, Lynch et al. (2005) found in their primary care investigation that adding CBT to high-quality medication management provided only modest benefits on measures of symptoms and functioning. However, these very small improvements occurred as youths significantly reduced their use of psychotropic medication in the CBT plus SSRI arm. In another study based in primary care, depressed adolescents were randomized to either clinical monitoring and usual care or clinical monitoring plus on-site specialty mental health care, with the latter consisting of the patient’s choice of CBT, medication, or both (Asarnow, Jaycox, Duan et al., 2005). The quality improvement (QI) arm, which most often consisted of CBT, was superior to treatment as usual in increasing teens’ access to depression care (i.e., number of sessions) and on improving depression symptoms and quality of life, similar to parallel studies in adults (Wells, Sherbourne, Schoenbaum et al., 2000). One benchmarking study compared CBT to an unselected, clinically complicated sample of depressed adolescents with the results of CBT delivered in a research study at the same site (Weersing, Iyengar, Kolko et al., 2006). Results of clinic-based CBT were quite similar to the published effects of CBT, once symptom trajectories in the research subjects were adjusted for the difference in the proportion of subjects who came by advertisement, as the latter tended to respond more favorably to treatment (Brent, Kolko, Birmaher et al., 1998; Weersing, Iyengar, Kolko et al., 2006). Predictors of Outcome Greater intake severity, older age of onset, low involvement in pleasurable activities, greater hopelessness and other cognitive distortions, history of sexual abuse and parental depression were found to be predictive of less positive response in CBT clinical trials (Barbe et al., 2004; Brent, Kolko, Birmaher et al., 1998; Clarke, Hops, Lewinsohn et al., 1992; DEPRESSIVE DISORDERS 599 9781405145497_4_037.qxd 29/03/2008 02:52 PM Page 599

Clarke, Hornbrook, Lynch et al., 2001; Lewinsohn, Rohde, & Seeley, 1998; Rohde, Clarke, Lewinsohn et al., 2001). Parental depressive symptoms moderated treatment response to CBT in so far as in the absence of maternal depression CBT was superior to alternative treatments whereas in its presence, CBT was no better than the alternatives (Brent, Kolko, Birmaher et al., 1998; Lewinsohn, Rohde, & Seeley, 1998). Family discord and comorbid substance abuse predicted a slower response to treatment overall (Birmaher, Brent, Kolko et al., 2000a; Rohde, Clarke, Lewinsohn et al., 2001). In contrast, referral by advertisement as compared to clinical referral predicted a good response in all conditions, and comorbid anxiety disorder predicted a particularly positive response to CBT (Brent, Kolko, Birmaher et al., 1998; Rohde, Clarke, Lewinsohn et al., 2001). In some studies, changes in cognitive distortions or improvements in involvement in pleasurable activities are associated with improvement (Ackerson, Scogin, McKendree-Smith et al., 1998; Kaufman, Rohde, Seeley et al., 2005; Kolko, Brent, Baugher et al., 2000). Findings from the TADS study were mostly but not completely consistent with the above-noted results. In contradistinction, greater cognitive distortion predicted better response, at least in the combination cell, and source of referral was unrelated to outcome. Higher family income (≥$75,000/year) also predicted better response to CBT, both alone and in combination with medication (Curry, Rohde, Simons et al., 2006). Prevention of Onset, Relapse or Recurrence An adaptation of the CWD-A program reduced the risk of onset of major depression in two groups of at-risk adolescents, those with subsyndromal depression (15% in CBT versus 26% control; Clarke, Hawkins, Murphy et al., 1995) and in at-risk adolescent offspring with either subsyndromal depression or a past history of depression or depressed parents (9% CBT versus 28% control; Clarke, Hornbrook, Lynch et al., 2001). A meta-analysis of CBT prevention packages has found that selected or indicated interventions that focus on youth with subsyndromal symptoms show more positive effects than universal programs both at the end of the intervention (ES 0.30 versus 0.12) and upon follow-up (ES 0.31–0.34 versus 0.02), in part because at-risk youth continue to become more symptomatic over time (Horowitz & Garber, 2006). With regard to the prevention of relapse, CBT does not appear to produce significantly greater benefit than other interventions at intermediate or long-term follow-up after brief acute treatment of depression (Birmaher, Brent, Kolko et al., 2000a; Wood, Harrington, & Moore, 1996). While the addition of up to six individual CBT monthly booster sessions reduced the rate of relapse from 50% to 20%, the addition of 1–2 group or individual booster sessions did not, suggesting a dose effect (Birmaher, Brent, Kolko et al., 2000a; Clarke, Lewinsohn, Rohde et al., 1999; Kroll, Harrington, Jayson et al., 1996). Although several studies highlight the role of family conflict in onset, duration of episode and risk of recurrence, family interventions have not yet been studied with regard to these outcomes. Interpersonal Therapy (Table 37.4) Theory and Techniques Interpersonal psychotherapy for adolescents (IPT-A) is an adaptation of interpersonal therapy (IPT), a well-established efficacious treatment for adult unipolar depression (Mufson, Weissman, Moreau et al., 1999). IPT-A conceptualizes depression as occurring within an interpersonal matrix, and targets resolution of interpersonal stress that seems to be associated with the adolescent’s depression. IPT-A begins by taking an interpersonal inventory of important relationships in order to determine appropriate treatment targets. The types of problems typically targeted by IPT-A are loss, role disputes, role transitions, interpersonal skills deficits or adjustment to a single-parent family. The goal of treatment is to replace conflictual, unfulfilling relationships with meaningful lower-conflict relationships. Evidence of IPT Efficacy Mufson, Weissman, Moreau et al. (1999) conducted the first efficacy trial of IPT-A in a patient population of depressed adolescents. Forty-eight adolescents were randomized to either IPT-A or monthly clinical management. A much higher proportion of adolescents met recovery criteria (Hamilton Depression Scale-Depression ≤6) in the IPT-A group (75% versus 46%). There was a much higher attrition rate in the clinical monitoring group. Analyses of dimensional measures of depressive symptomatology, functional status and social adaptation also favored IPT-A. In an independent investigation, Rossello and Bernal (1999) compared the efficacy of IPT, “culturally adapted” CBT, with a waitlist control condition in a sample of depressed Puerto Rican adolescents. There was a high rate of attrition, as only 68% and 52% of IPT and CBT-treated subjects completed the 12-session intervention. Using a clinical cut-off on the CDI in completer analyses, 59% of those in the CBT condition and 82% of those treated with IPT achieved a clinically significant improvement by post-treatment. Thus, on some measures of depression and functional status, IPT was superior to CBT. Effectiveness Mufson, Dorta, Wickramaratne et al. (2004) tested IPT-A versus usual care in school-based mental health clinics with school social workers delivering both interventions. Those in the IPT-A arm had a brief training in IPT-A and weekly supervision. IPT-A was superior to usual care on dimensional measures of depression, global function, social adjustment and global clinical status (50% versus 33% symptomatically improved). This strongly supports the transportability of IPT-A into community sites. Predictors of Response and Adverse Events Mufson, Weissman, Moreau et al. (1999) found that IPT-A was differentiated from clinical monitoring only in those subCHAPTER 37 600 9781405145497_4_037.qxd 29/03/2008 02:52 PM Page 600

jects who had moderate or severe depression. Improvements in depression were also associated with improvements in social functioning and problem-solving in IPT-A treatment (Mufson, Weissman, Moreau et al., 1999, 2004). In a followup analysis of the school-based effectiveness study, comorbid anxiety was found to result in a poorer overall outcome with regard to depression. In the subgroup with comorbid anxiety, the effect size for IPT-A did appear to be larger than the effect size for usual care, although this escaped statistical significance (Young, Mufson, & Davies, 2006), similar to CBT trial results (Brent, Kolko, Birmaher et al., 1998; Rohde, Clarke, Lewinsohn et al., 2001). In one trial, the rate of suicidal events was similar in IPT-A and clinical management (Mufson, Weissman, Moreau et al., 1999). Prevention of Onset, Relapse or Recurrence Thus far, there have been no prevention or continuation studies conducted, but one open study showed a high rate of sustained recovery 1 year after receipt of IPT-A (Mufson & Fairbanks, 1996). Other Available Interventions The involvement of family factors in the pathogenesis and recurrence of early-onset depression suggests that targeted family interventions aimed at reducing criticism, facilitating treatment of parental depression and increasing protective factors such as support and time spent together may prove to be efficacious. One study did not demonstrate superior efficacy of a systemic behavioral family therapy over supportive therapy (Brent, Holder, Kolko et al., 1997). One small randomized treatment study found that a family intervention that focused on interpersonal attachment, when compared with a minimal contact waitlist control, resulted in a reduction in both depression and anxiety, with sustained improvement on 6-month follow-up (Diamond, Reis, Diamond et al., 2002). One study piloted the additive benefit of “family psychoeducation” to treatment as usual for depressed adolescents (Sanford, Boyle, McCleary et al., 2006). The treatment consisted of 12 90-minute sessions, and provided education about depression and its treatment, enhanced communication skills, family problem-solving, DEPRESSIVE DISORDERS 601 Table 37.4 Interpersonal, family treatments for adolescents with depression. (After Weersing et al., 2006.) Study Brent et al. (1997) Diamond et al. (2002) Mufson et al. (1999) Mufson et al. (2004) Rosello & Bernal (1999) Young et al. (2006) BDI, Beck Depression Inventory; CBT, Cognitive–behavior therapy; CDI, Children’s Depression Inventory; Ham-D, Hamilton Rating Scale for Depression; IPT-A, Interpersonal psychotherapy for depressed adolescents; MDD, major depressive disorder; NNT, Number needed to treat; RADS, Reynolds Adolescent Depression Scale; SSAI, Structured Social Adjustment Interview (A, Adolescent, P, Parent); School TAU, school counseling services. * At 6 and 9 months after intake. n 107 32 48 63 71 31 Treatment and control conditions Family Supportive CBT Family Waitlist Family Waitlist IPT-A School TAU IPT-A CBT Waitlist Family psychoeducation + TAU TAU Mean sessions 10.7 11.2 12.1 12 6 week 9.8 2.8 10.5 7.9 12 12 9.9 – Source of sample Clinic diagnosed depression Unclear, screened for diagnosis Clinic diagnosed depression Community screened for diagnosis Community screened for diagnosis Clinic diagnosed depression Definition of clinical response No mood diagnosed and normal BDI No mood diagnosed Normal HAM-D Normal HAM-D Normal CDI No MDD Responding at posttreatment (%) 38 39 60 81 47 75 46 50 34 82 59 79 50 NNT 99 3 6 – 4 Primary symptom measure BDI BDI BDI BDI CDI RADS SSAI-A SSAI-P Target treatment effect size (symptoms) 0.07 0.75 0.57 0.40 0.74 0.52–0.64* 0.93–1.14 0.96–1.17 9781405145497_4_037.qxd 29/03/2008 02:52 PM Page 601

increasing support and decreased unproductive interactions. The family treatment resulted in improved social functioning in the adolescent, improved quality of parent–child relationship and a trend towards greater improvement in adolescent depressive symptoms. An open trial of a new psychosocial treatment, Contextual Emotion-Regulation Therapy (CERT) was reported in 20 chronically depressed prepubertal children (Kovacs, Sherril, George et al., 2006). CERT focuses on improving the depressed child’s emotion regulation and coping skills, helping the child to identify triggers for mood dysregulation, and development of adaptive coping and problem-solving strategies to improve mood and overall functioning. Parents are involved as an “assistant coach,” which also serves to strengthen the parent– child relationship. In open treatment, which consisted of 30 sessions delivered over 10 months, a very high proportion of children achieved remission of their depression (80%) and dysthymia (92%). Beardslee, Gladstone, Wright et al. (2003) compared clinicianfacilitated 6–11-session family psychoeducation with a didactic intervention for families with a depressed parent and nondepressed children aged 8–15. Both interventions aimed at demystifying depression, decreasing guilt and blame, and building resilience, with the clinician-facilitated intervention individualizing the intervention to the particular circumstances of each family. The children in both groups had a decrease in emotional disturbance, although there were no between-group differences (Beardslee et al., 2003). With regard to non-medication somatic treatments, light therapy has been shown to be beneficial for pediatric seasonal affective disorder (Swedo, Allen, Glod et al., 1997). One small randomized trial of depressed children aged 6–12 found that treatment with omega-3 fatty acids (eicosapentanoic acid and docosahexanenoic acid) resulted in significant improvement in depressive symptoms, with effects comparable to those for SSRIs (Nemets, Nemets, Apter et al., 2006). Although electroconvulsive therapy (ECT) has not been rigorously studied in adolescent depression, there is general clinical consensus that it has a role in the management of early-onset depression that is refractory to pharmacological and psychosocial management, particularly for adolescents without significant personality disorder traits (Walter & Rey, 2003). Recommendations for Current Best Practice Treatment Because there is a relatively high response rate to placebo or brief supportive treatment and education in many of the published treatment studies, the first approach for mild depression should be family education, supportive counseling, case management and problem-solving (Birmaher & Brent, 2007; Bridge, Iyengar, Salary et al., 2007; Goodyer, 2006; NICE, 2005; Renaud, Brent, Baugher et al., 1998). For more persistent or severe depression, one of the three empirically validated treatments, SSRI medication, CBT or IPT, is indicated. Current US guidelines recommend initial treatment with any of the three treatments for moderate depression, with the choice informed primarily by patient preference and the availability of local expertise. The British guidelines vary slightly in so far as they recommend use of an indicated psychotherapy for moderate to severe depression for 3 months prior to initiation of an antidepressant medication. They also emphasize that medication should not be given without concomitant psychotherapy. Both sets of guidelines recommend continuing a given treatment for at least 6–8 weeks, assessing response to treatment and, if the patient is not responding, consider combination of psychotherapy and medication, a dose adjustment or switch in medication, or a medication augmentation strategy (Birmaher & Brent, 2007; NICE, 2005). The extant evidence suggests that more generic psychotherapies practiced in the community may not be helpful in the treatment of youth depression (Brent, Holder, Kolko et al., 1997; Weersing & Weisz, 2002; Weisz, McCarty, & Valeri, 2006; Wood, Harrington, & Moore, 1996). In the absence of available specialized psychotherapy, or in the face of a patient’s disinclination to engage in psychotherapy, use of an antidepressant as a first-line intervention is indicated. Some evidence suggests that for more severely depressed adolescents, particularly those with difficulties with motivation, concentration, sleep and appetite, medication should be a first-line treatment (Curry, Rohde, Simons et al., 2006; Goodyer, 2006). In adults, combination of psychotherapy and medication is superior to either monotherapy in chronic and severe depression, although the support for the use of combined treatment in younger populations is more modest (Clarke, Debar, Lynch et al., 2005; Goodyer, 2006; Keller, McCullough, Klein et al., 2000; March, Silva, Petrycki et al., 2004; Thase, Greenhouse, Frank et al., 1997). Relative contraindications for use of antidepressant medication are a history of mania or hypomania, when mood stabilization should be undertaken prior to the use of antidepressants, and for those with a strong family history of bipolar disorder, for whom it may be safer to begin with psychotherapy for the same reasons. Given that the most evidence for efficacy exists for fluoxetine, this should be a first-line medication. For those who have failed to respond to fluoxetine, cannot tolerate it or for some reason do not wish to take it, use of one of the other SSRIs for which there is some evidence of efficacy is warranted. Current clinical recommendations are to begin with half the usual initial target dose (e.g., 10 mg fluoxetine) for 1 week, to determine if the patient can tolerate the medication, and then increase to 20 mg for the next 3 weeks. If the patient is still depressed, then one can continue to increase the dosage around every 4 weeks because it takes around that amount of time to tell if an increase is going to be helpful (Nierenberg, McLean, Alpert et al., 1995). Most patients who respond to fluoxetine achieve symptomatic relief at 20–80 mg fluoxetine. Once symptomatic relief has been achieved, treatment should continue for a minimum of 6–12 months in order to prevent relapse. If a patient fails to respond to a fluoxetine at an adequate dose and duration (i.e., around 40–80 mg), then it is reasonable CHAPTER 37 602 9781405145497_4_037.qxd 29/03/2008 02:52 PM Page 602

to switch to another SSRI. However, it is important to rule out reasons for continued depression such as rapid drug metabolism, non-compliance, severe family conflict, parental depression, covert substance abuse or the influence of other comorbid conditions, such as OCD, ADHD or anxiety, an undiagnosed mixed state, psychosis, or medical illness, such as hypothyroidism. There are no empirical studies in adolescents to guide clinicians for patients who have failed to respond to an SSRI, although clinical guidelines based upon expert consensus exist (Birmaher & Brent, 2007; Hughes, Emslie, Crismon et al., 1999). However, based on clinical consensus and some studies in adults, if one has obtained a partial response, it is reasonable to augment with lithium, another antidepressant such as amfebutamone, or one of the empirically supported psychotherapies. If one has obtained no response, a reasonable second step is to switch to a second SSRI, or to add psychotherapy. If after treatment with a second SSRI there is still complete non-response, most clinicians recommend using a different class of medication, such as venlafaxine, amfebutamone or lamotrigine (Birmaher & Brent, 2007). Future Clinical and Research Challenges Depression in childhood and adolescence is a complex and debilitating disease that frequently has a lifelong chronic recurrent course. In this concluding section, we focus on the unknowns of youth depression and suggest several key areas for future investigation. Genetic and Environmental Determinants of Unipolar Depression Adolescent depressive symptomatology is highly familial, with genetic and non-shared environmental factors each contributing half of the variance for familial occurrence. Future work should focus on identification of clinical endophenotypes (chronic depression, anxiety plus depression, “neuroticism”) and those determined by laboratory measures (e.g., neurocognitive measures of emotional information processing and brain correlates thereof) that may help to more precisely map genes onto behavior. Moreover, it is critical that future research recognizes the importance of gene × environmental interactions, including seemingly environmental factors (e.g., life events) that in fact are genetically influenced. With a greater understanding of genetics, we can identify youth at risk, and use our knowledge of environment and gene × environment interaction to attenuate familial transmission. Neurobiology of Depression Functional neuroimaging shows promise of being able to delineate brain regions and circuitry most closely implicated in depressive onset and recovery, thereby helping to clarify both the clinical phenotype and potential targets for prevention and treatment. Neuroimaging studies of youth at high risk for depression may help to better identify the biological and genetic factors involved in the onset of depressive illness. Genetic neuroimaging, in which functional MRI (fMRI) tests the effects of genotype in moderating response to a specific probe, may be a particularly promising approach (Hariri, Mattay, Tessitore et al., 2002). Moreover, neurobiological effects may not only be genetic, but be caused by early adversity or continued stress, including continued depression. Matching Patients to Treatments The approach to the treatment of pediatric depression is currently determined more by the comfort and expertise of the clinician than the patient profile, in part because of the lack of knowledge about how patient characteristics should inform treatment approach. Future studies should attempt to take what is known about treatment response to see if addressing those issues (e.g., comorbidity, parental depression) can actually improve treatment outcome. Remarkably, no studies have examined the relationship of drug level and metabolites to treatment outcome in any pharmacological clinical trial, which means that non-response and non-compliance cannot be distinguished. One possible promising measure for SSRI action is a measurement of platelet receptor serotonin reuptake inhibition. Moreover, future investigations should harness advances in genetics and neuroscience to predict individual differences in treatment response. More specifically, future studies should examine the relationship between candidate gene polymorphisms and treatment response, controlling for pharmacokinetic factors. Both pharmacological and psychotherapy studies should examine the impact of treatment on neurocognitive and neuroimaging measures, which may help elucidate mechanisms of action and also provide some clues as to how to further boost outcome. Incomplete Symptomatic and Functional Recovery In the TADS study, as is true in other pharmacological and psychotherapy trials, a very high rate of continued depressive symptoms and functional impairment was reported at the end of 12 weeks of treatment across treatments (Brent, Holder, Kolko et al., 1997; Emslie, Rush, Weinberg et al., 1997; Kennard, Silva, Vitiello et al., 2006; Vitiello, Rohde, Silva et al., 2006). While patients may continue to improve with time, the rate of incomplete recovery is high, which in turn increases the risk for another depressive episode, as well as interpersonal difficulties, educational underachievement, substance abuse, suicidal behavior and other health risk behaviors. There appear to be some common family and social factors that protect against most of these outcomes. Can a parsimonious treatment package such as “Well-Being Therapy” used by Fava in adults, be developed to improve overall functional outcome for depressed youth that increases these protective factors (Fava, Ruini, Rafanelli et al., 2005)? Management and Prevention of Suicidal Behavior The most serious correlates of depressive disorder are suicidal ideation and behavior, which in depressed patients are associated with greater severity, chronicity and comorbidity (Lewinsohn, Rohde, & Seeley, 1996, 1998). It is an open question as to DEPRESSIVE DISORDERS 603 9781405145497_4_037.qxd 29/03/2008 02:52 PM Page 603

whether treatment of depression is sufficient to prevent suicidality or whether additional types of interventions are required, because reductions in depression and in suicidality do not always occur together (Harrington, Kerfoot, Dyer et al., 1998b; Wood, Trainor, Rothwell, Moore et al., 2001). However, patients with serious suicidality are often excluded from clinical trials, and suicidal outcomes are not often reported. Interventions, including those that involve the treatment of depression, can only be evaluated with regard to their impact on suicidal risk if patients at high suicidal risk are admitted to such studies. The design of studies that meet human subject standards is an important step to addressing this pressing issue. Our ability to predict and influence suicidality is particularly salient, given current concerns about suicidal adverse events in SSRI treatment. It is important to better understand the clinical, pharmacokinetic, pharmacogenetic and neurocognitive predictors of suicidal adverse events in youth treated with SSRIs. Treatment of Prepubertal Depression Currently, there are no established psychological approaches to prepubertal depression. Moreover, because in some studies the response to medication in pre-adolescent children was less vigorous than in adolescents, the role of antidepressants and psychological treatments needs focused evaluation in younger children. Treatment of Bipolar Depression, and Youth At Risk for Bipolar Disorder The pharmacological management of depression in youth at risk for bipolar disorder carries with it a risk for inducing a mixed or manic state, yet, at the same time, depressive symptoms are a considerable source of the morbidity of this condition. Research should address pharmacological and psychosocial approaches to the management of depression in those at risk for bipolar disorder, including identification of clinical, genetic and neurocognitive predictors of manic switch. Early Intervention and Public Health Interventions Convergent evidence supports the view that the more chronic the depression, the more difficult it becomes to treat. Yet tertiary care mental health is not equipped to facilitate early identification and intervention, because of inadequate capacity and other barriers to access such as stigma. Consequently, capacity for treatment of children at earlier stages of risk and disorder needs to be developed in other sectors, such as primary care and school-based mental health services. The costeffectiveness of interventions delivered in alternative settings should be studied. Another key factor in reducing the public health burden of depression likely will be the efficient dissemination of our best practice models to the youth health and education systems. As discussed on p. 593, there are still very few data on the effectiveness of SSRIs, CBT and IPT when delivered in actual practice settings. The data that are available on CBT and IPT are promising, suggesting that bringing these research-based psychosocial interventions to the community may substantially improve on current models of depression care. Similar data are not available for the SSRIs, despite the fact that SSRI prescriptions are dramatically more prevalent and are more available in community settings than either of the empirically based psychosocial interventions. In the adult literature, there is a growing evidence base on the efficacy and costeffectiveness of relatively brief psychosocial, antidepressant and combined treatments for mild to moderate depression, delivered in settings such as primary care, that may serve as models for future investigations in younger populations (Katon, Unutzer, & Simon, 2004). Decreasing the Public Burden of Depression Two extreme views with regard to decreasing the public health burden of early-onset depression are well articulated by Harrington and Clarke (1998): on the one hand, focus the bulk of resources on the relatively small number with moderate to severe disease, or, alternatively, provide preventive intervention to those who are at risk or mildly depressed. From a public health point of view, the impairment burden on the population is mostly from “subsyndromal depression,” so that a small reduction in depressive symptoms in a large number of people may indeed benefit more people. Horowitz and Garber (2006), in their meta-analysis, found much greater effect sizes for indicated and selective interventions, but acknowledged that the appropriate metric is really the cost per effect, which may be comparable with a cheaper, less selective intervention that does not involve the costs of screening. Harrington and Clarke (1998) argued that a universal approach that enhances protective factors such as problem-solving, interpersonal skills, family connection and school connection may be more acceptable and have broader impact. Research on the relative utility of these different approaches to prevention on the overall public mental health of youth is warranted. References Ackerson, J., Scogin, F., McKendree-Smith, N., & Lyman, R. D. (1998). Cognitive bibliotherapy for mild and moderate adolescent depressive symptomatology. Journal of Consulting and Clinical Psychology, 66, 685–690. Addolorato, G., Capristo, E., Stefanini, G., & Gasbarrini, G. (1997). Inflammatory bowel disease: A study of the association between anxiety and depression, physical morbidity, and nutritional status. Scandinavian Journal of Gastroenterology, 31, 1013–1021. American Psychiatric Association. (2000). Diagnostic and Statistical Manual of Mental Disorders: DSM-IV-TR. (4th edn.). Text revision. Washington, DC: American Psychiatric Association. Angold, A., Costello, E. J., & Erkanli, A. (1999). Comorbidity. Journal of Child Psychology and Psychiatry, 40, 57–87. Angold, A., Costello, E. J., & Worthman, C. M. (1998). Puberty and depression: The roles of age, pubertal status and pubertal timing. Psychological Medicine, 28, 51–61. Angold, A., Prendergast, M., Cox, A., Rutter, M., & Harrington, R. (1995). The Child and Adolescent Psychiatric Assessment (CAPA). Psychological Medicine, 25, 739–753. Apter, A., Lipschitz, A., Fong, R., Carpenter, D. J., Krulewicz, S., Davies, J. T., et al. (2006). Evaluation of suicidal thoughts and behaviors in children and adolescents taking paroxetine. Journal of Child and Adolescent Psychopharmacology, 16, 77–90. CHAPTER 37 604 9781405145497_4_037.qxd 29/03/2008 02:52 PM Page 604

Asarnow, J. R., Goldstein, M. J., Tompson, M., & Guthrie, D. (1993). One-year outcomes of depressive disorders in child psychiatric in-patients: Evaluation of the prognostic power of a brief measure of expressed emotion. Journal of Child Psychology and Psychiatry, 34, 129–137. Asarnow, J. R., Jaycox, L. H., Duan, N., LaBorde, A. P., Rea, M. M., Murray, P., et al. (2005). Effectiveness of a quality improvement intervention for adolescent depression in primary care clinics: a randomized controlled trial. Journal of the American Medical Association, 293, 311–319. Axelson, D., Perel, J., Birmaher, B., Rudolph, G., Nuss, S., & Brent, D. (2002). Sertraline pharmacokinetics and dynamics in adolescents. Journal of the American Academy of Child and Adolescent Psychiatry, 41, 1037–1044. Axelson, D. A., Perel, J. M., Birmaher, B., Rudolph, G., Nuss, S., Yurasits, L., et al. (2005). Platelet serotonin reuptake inhibition and response to SSRIs in depressed adolescents. American Journal of Psychiatry, 162, 802–804. Barbe, R. P., Bridge, J., Birmaher, B., Kolko, D. J., & Brent, D. A. (2004). Lifetime history of sexual abuse, clinical presentation, and outcome in a clinical trial for adolescent depression. Journal of Clinical Psychiatry, 65, 77–83. Beardslee, W., Gladstone, T. R. G., Wright, E. J., & Cooper, A. B. (2003). A family-based approached to the prevention of depressive symptoms in children at risk: Evidence of parental and child change. Pediatrics, 112, e119–e131. Beck, A. T., Rush, A. J., Shaw, B. F., & Emery, G. (1979). Cognitive therapy of depression. New York: Guilford Press. Berard, R., Fong, R., Carpenter, D. J., Thomason, C., & Wilkinson, C. (2006). An international, multicenter, placebo-controlled trial of paroxetine in adolescents with Major Depressive Disorder. Journal of Child and Adolescent Psychopharmacology, 16, 59–75. Bertocci, M. A., Dah, R. E., Williamson, D. E., Isof, A. M., Birmaher, B., Axelson, D. A., et al. (2005). Subjective sleep complaints in pediatric depression: A controlled study and comparison with EEG measures of sleep and waking. Journal of the American Academy of Child and Adolescent Psychiatry, 44, 1158–1166. Birmaher, B., Arbelaez, C., & Brent, D. (2002). Course and outcome of child and adolescent major depressive disorder. Child and Adolescent Psychiatric Clinics of North America, 11, 619–637. Birmaher, B., Axelson, D., Strober, M., Gill, M. K., Valeri, S., Chiappetta, L., et al. (2006). Clinical course of children and adolescents with bipolar spectrum disorders. Archives of General Psychiatry, 63, 175–183. Birmaher, B., & Brent, D. (2007). Practice parameters for the assessment and treatment of children and adolescents with depressive disorders. Journal of the American Academy of Child and Adolescent Psychiatry, 46, 1503–1526. Birmaher, B., Brent, D. A., Kolko, D., Baugher, M., Bridge, J., Iyengar, S., et al. (2000a). Clinical outcome after short-term psychotherapy for adolescents with major depressive disorder. Archives of General Psychiatry, 57, 29–36. Birmaher, B., Dahl, R. E., Perel, J., Williamson, D. E., Nelson, B., Stull, S., et al. (1996a). Corticotropin-releasing hormone challenge in prepubertal major depression. Biological Psychiatry, 39, 267– 277. Birmaher, B., Dahl, R. E., Williamson, D. E., Perel, J. M., Brent, D. A., Axelson, D. A., et al. (2000b). Growth hormone secretion in children and adolescents at high risk for major depressive disorder. Archives of General Psychiatry, 57, 867–872. Birmaher, B., Kaufman, J., Brent, D. A., Dahl, R. E., Perel, J. M., Al-Shabbout, M., et al. (1997). Neuroendocrine response to L-5- hydroxytryptophan in prepubertal children at high risk for major depressive disorder. Archives of General Psychiatry, 54, 1113–1119. Birmaher, B., Ryan, N. D., Williamson, D. E., Brent, D. A., Kaufman, J., Dahl, R. E., et al. (1996b). Child and adolescent depression: A review of the past 10 years. Part 1. Journal of the American Academy of Child and Adolescent Psychiatry, 35, 1427– 1439. Birmaher, B., Williamson, D. E., Dahl, R. E., Axelson, D. A., Kaufman, J., Dorn, L., et al. (2004). Clinical presentation and course of depression in youth: Does onset in childhood differ from onset in adolescence? Journal of the American Academy of Child and Adolescent Psychiatry, 43, 63–70. Botteron, K. N., Raichle, M. E., Drevets, W. C., Heath, A. C., & Todd, R. D. (2002). Volumetric reduction in left subgenual prefrontal cortex in early onset depression. Biological Psychiatry, 51, 342– 344. Brent, D. A. (2004). Antidepressants and pediatric depression: The risk of doing nothing. New England Journal of Medicine, 351, 1598–1601. Brent, D. A., Baugher, M., Bridge, J., Chen, J., & Beery, L. (1999). Age and sex-related risk factors for adolescent suicide. Journal of the American Academy of Child and Adolescent Psychiatry, 38, 1497–1505. Brent, D. A., & Birmaher, B. (2002). Adolescent depression. New England Journal of Medicine, 347, 667–671. Brent, D. A., Holder, D., Kolko, D., Birmaher, B., Baugher, M., Roth, C., et al. (1997). A clinical psychotherapy trial for adolescent depression comparing cognitive, family, and supportive treatments. Archives of General Psychiatry, 54, 877–885. Brent, D. A., Kolko, D., Birmaher, B., Baugher, M., Bridge, J., Roth, C., et al. (1998). Predictors of treatment efficacy in a clinical trial of three psychosocial treatments for adolescent depression. Journal of the American Academy of Child and Adolescent Psychiatry, 37, 906–914. Brent, D. A., Perper, J. A., Moritz, G., Allman, C., Schweers, J., Roth, C., et al. (1993). Psychiatric sequelae to the loss of an adolescent to suicide. Journal of the American Academy of Child and Adolescent Psychiatry, 32, 509–517. Brent, D. A., Poling, K., McKain, B., & Baugher, M. (1993). A psychoeducational program for families of affectively ill children and adolescents. Journal of the American Academy of Child and Adolescent Psychiatry, 32, 770–774. Breslau, N., Schultz, L., & Peterson, E. (1995). Sex differences in depression: A role for preexisting anxiety. Psychiatry Research, 58, 1–12. Bridge, J., Iyengar, S., Salary, C. B., Barbe, R. P., Birmaher, B., Pincus, H., et al. (2007). Clinical response and risk of reported suicidal ideation and suicide attempts in pediatric antidepressant treatment: A meta-analysis of randomized controlled trials. Journal of the American Medical Association, 297, 1683–1696. Bridge, J. A., Goldstein, T. R., & Brent, D. A. (2006). Adolescent suicide and suicidal behavior. Journal of Child Psychology and Psychiatry, 47, 372–394. Bruder, G. E., Stewart, J. W., Tenke, C. E., McGrath, P. J., Leite, P., Bhattacharya, N., et al. (2001). Electroencephalographic and perceptual asymmetry differences between responders and nonresponders to an SSRI antidepressant. Biological Psychiatry, 49, 416–425. Bruder, G. E., Tenke, C. E., Warner, V., Nomura, Y., Grillon, C., Hille, J., et al. (2005). Electroencephalographic measures of regional hemispheric activity in offspring at risk for depressive disorders. Biological Psychiatry, 57, 328–335. Campo, J. V., Dahl, R. E., Williamson, D. E., Birmaher, B., Perel, J. M., & Ryan, N. D. (2003). Gastrointestinal distress to serotonergic challenge: A risk marker for emotional disorder? Journal of the American Academy of Child and Adolescent Psychiatry, 42, 1221–1226. Caspi, A., Sugden, K., Moffitt, T. E., Taylor, A., Craig, I. W., Harrington, H., et al. (2003). Influence of life stress on depression: Moderation by a polymorphism in the 5-HT gene. Science, 301, 386–389. Clarke, G., Hops, H., Lewinsohn, P. M., Andrew, J., & Williams, J. (1992). Cognitive–behavioral group treatment of adolescent depression: Prediction of outcome. Behavioral Therapy, 23, 341–354. DEPRESSIVE DISORDERS 605 9781405145497_4_037.qxd 29/03/2008 02:52 PM Page 605

Clarke, G. C., Debar, L., Lynch, F., Powell, J., Gale, J., O’Connor, E., et al. (2005). A randomized effectiveness trial of brief cognitivebehavior therapy for depressed adolescents receiving antidepressant medication. Journal of the American Academy of Child and Adolescent Psychiatry, 44, 888–898. Clarke, G. N., Hawkins, W., Murphy, M., Sheeber, L. B., Lewinsohn, P. M., & Seeley, J. R. (1995). Targeted prevention of unipolar depressive disorder in an at-risk sample of high school adolescents: A randomized trial of group cognitive intervention. Journal of the American Academy of Child and Adolescent Psychiatry, 34, 312– 321. Clarke, G. N., Hornbrook, M., Lynch, F., Polen, M., Gale, J., Beardslee, W., et al. (2001). A randomized trial of a group cognitive intervention for preventing depression in adolescent offspring of depressed parents. Archives of General Psychiatry, 58, 1127–1134. Clarke, G. N., Lewinsohn, P. M., Rohde, P., Hops, H., & Seeley, J. R. (1999). Cognitive–behavioral group treatment of adolescent depression: Efficacy of acute group treatment and booster sessions. Journal of the American Academy of Child and Adolescent Psychiatry, 38, 272–279. Conrad, M., & Hammen, C. (1993). Protective and resource factors in high- and low-risk children: A comparison of children with unipolar, bipolar, medically ill and normal mothers. Development and Psychopathology, 5, 593–607. Costello, E. J., Mustillo, S., Erkanli, A., Keeler, G., & Angold, A. (2003). Prevalence and development of psychiatric disorders in childhood and adolescence. Archives of General Psychiatry, 60, 837– 844. Costello, E. J., Erkanli, A., & Angold, A. (2006). Is there an epidemic of child or adolescent depression? Journal of Child Psychology and Psychiatry, 47, 1263–1271. Curry, J., Rohde, P., Simons, S., Silva, S., Vitiello, B., Kratochvil, C., et al. (2006). Predictors and moderators of acute outcome in the Treatment for Adolescents with Depression Study (TADS). Journal of the American Academy of Child and Adolescent Psychiatry, 45, 1427–1439. Dahl, R. E. (2004). Regulation of sleep and arousal: Comments on Part VII. In R. E. Dahl, & L. P. Spear (Eds.), Adolescent brain development: Vulerabilities and opportunities (pp. 292–293). New York: New York Academy of Sciences. Dahl, R. E., Birmaher, B., Williamson, D. E., Dorn, L., Perel, J., Kaufman, J., et al. (2000). Low growth hormone response to growth hormone-releasing hormone in child depression. Biological Psychiatry, 48, 981–988. Dahl, R. E., & Lewin, D. S. (2002). Pathways to adolescent health: Sleep regulation and behavior. Journal of Adolescent Health, 31, 175–184. Dahl, R. E., Ryan, N. D., Puig-Antich, J., Nguyen, N. A., AlShabbout, M., Meyer, V. A., et al. (1991). 24-hour cortisol measures in adolescents with major depression: A controlled study. Biological Psychiatry, 30, 25–36. Daley, S. E., Hammen, C., Davila, J., & Burge, D. (1998). Axis II symptomatology, depression, and life stress during the transition from adolescence to adulthood. Journal of Consulting and Clinical Psychology, 66, 595–603. D’Augelli, A. R., Grossman, A. H., Salter, N. P., Vasey, J. J., Starks, M. T., & Sinclair, K. O. (2005). Predicting the suicide attempts of lesbian, gay, and bisexual youth. Suicide and Life-threatening Behavior, 35, 646–660. Daviss, W. B., Bentivoglio, P., Racusin, R., Brown, K. M., Bostic, J. Q., & Wiley, L. (2001). Bupropion sustained release in adolescents with comorbid attention deficit hyperactivity disorder and depression. Journal of the American Academy of Child and Adolescent Psychiatry, 40, 307–314. Daviss, W. B., Perel, J. M., Brent, D. A., Axelson, D. A., Rudolph, G. R., Gilchrist, R., et al. (2006). Acute antidepressant response and plasma levels of bupropion and metabolites in a pediatric-aged sample: An exploratory study. Therapeutic Drug Monitoring, 28, 190–198. Dawson, G., Frey, K., Panagiotides, H., Osterling, J., & Hessl, D. (1997). Infants of depressed mothers exhibit atypical frontal brain activity: A replication and extension of previous findings. Journal of Child Psychology and Psychiatry, 38, 179–186. Diamond, G. S., Reis, B. F., Diamond, G. M., Siqueland, L., & Isaacs, L. (2002). Attachment based family therapy for depressed adolescents: A treatment development study. Journal of the American Academy of Child and Adolescent Psychiatry, 41, 1190–1196. Dierker, L., Albano, A. M., Clarke, G. N., Heimberg, R. G., Kendall, P. C., Merikangas, K. R., et al. (2001). Screening for anxiety and depression in early adolescence. Journal of the American Academy of Child and Adolescent Psychiatry, 40, 929–936. Drevets, W. C., Price, J. L., Simpson Jr, J. R., Todd, R. D., Reich, T., Vannier, M., et al. (1997). Subgenual prefrontal cortex abnormalities in mood disorders. Nature, 386, 824–827. Eaves, L., Silberg, J., & Erkanli, A. (2003). Resolving multiple epigenetic pathways to adolescent depression. Journal of Child Psychology and Psychiatry, 44, 1006–1014. Egger, H. L., Erkanli, A., Keeler, G., Potts, E., Walter, B. K., & Angold, A. (2006). Test–retest reliability of the Preschool Age Psychiatric Assessment (PAPA). Journal of the American Academy of Child and Adolescent Psychiatry, 45, 538–549. Ellis, B. J., & Garber, J. (2000). Psychosocial antecedents of variation in girls’ pubertal timing: Maternal depression, stepfather presence, and marital and family stress. Child Development, 71, 485–501. Emslie, G., Heiligenstein, J. H., Wagner, K. D., Hoog, S. L., Ernest, D. E., Brown, E., et al. (2002). Fluoxetine for acute treatment of depression in children and adolescents: A placebo-controlled, randomized clinical trial. Journal of the American Academy of Child and Adolescent Psychiatry, 41, 1205–1215. Emslie, G., Kratochvil, C., Vitiello, B., Silva, S., Mayes, T., McNulty, S., et al. (2006). Treatment for Adolescents with Depression Study (TADS): Safety results. Journal of the American Academy of Child and Adolescent Psychiatry, 45, 1440–1455. Emslie, G., Rush, J. A., Weinberg, W. A., Kowatch, R. A., Hughes, C. W., Carmody, T., et al. (1997). A double-blind, randomized placebo-controlled trial of fluoxetine in children and adolescents with depression. Archives of General Psychiatry, 54, 1031–1037. Emslie, G. J., Heiligenstein, J. H., Hoog, S. L., Wagner, K. D., Findling, R. L., McCracken, J. T., et al. (2004). Fluoxetine treatment for prevention of relapse of depression in children and adolescents: A double-blind, placebo-controlled study. Journal of the American Academy of Child and Adolescent Psychiatry, 43, 1397–1405. Emslie, G. J., Rush, A. J., Weinberg, W. A., Kowatch, R. A., Carmody, T., & Mayes, T. L. (1998). Fluoxetine in child and adolescent depression: Acute and maintenance treatment. Depression and Anxiety, 7, 32–39. Emslie, G. J., Wagner, K. D., Kutcher, S., Krulewicz, S., Fong, R., Carpenter, D. J., et al. (2006). Paroxetine treatment in children and adolescents with major depressive disorder: A randomized, multicenter, double-blind, placebo-controlled trial. Journal of the American Academy of Child and Adolescent Psychiatry, 45, 709– 719. Emslie, G. J., Yeung, P. P., Kunz, N. R., & Li, Y. (2007). Venlafaxine ER for the treatment of pediatric subjects with de-pression: Results of two placebo-controlled trials. Journal of the American Academy of Child and Adolescent Psychiatry, 46, 479–488. Faraone, S. V., & Biederman, J. (1997). Do attention deficit hyperactivity disorder and major depression share familial risk factors? Journal of Nervous and Mental Disease, 185, 533–541. Farchione, T. R., Moore, G. T., & Rosenberg, D. R. (2002). Proton magnetic resonance spectroscopic imaging in pediatric major depression. Biological Psychiatry, 52, 86–92. CHAPTER 37 606 9781405145497_4_037.qxd 29/03/2008 02:52 PM Page 606

Fava, G. A., Ruini, C., Rafanelli, C., Finos, L., Salmaso, L., Mangelli, L., et al. (2005). Well-being therapy of generalized anxiety disorder. Psychotherapy and Psychosomatics, 74, 26–30. Feder, A., Coplan, J. D., Goetz, R. R., Mathew, S. J., Pine, D. S., Dahl, R. E., et al. (2004). Twenty-four-hour cortisol secretion patterns in prepubertal children with anxiety or depressive disorders. Biological Psychiatry, 56, 198–204. Fergusson, D. M., Horwood, J., & Beautrais, A. L. (1999). Is sexual orientation related to mental health problems and suicidality in young people? Archives of General Psychiatry, 56, 876–880. Fergusson, D. M., Horwood, L., & Lynskey, M. T. (1996). Childhood sexual abuse and psychiatric disorder in young adulthood. II. Psychiatric outcomes of childhood sexual abuse. Journal of the American Academy of Child and Adolescent Psychiatry, 35, 1365–1374. Fergusson, D. M., Horwood, L. J., Ridder, E. M., & Beautrais, A. L. (2005). Subthreshold depression in adolescence and mental health outcomes in adulthood. Archives of General Psychiatry, 62, 66–72. Fergusson, D. M., & Lynskey, M. T. (1996). Adolescent resiliency to family adversity. Journal of Child Psychology and Psychiatry, 37, 281–292. Fergusson, D. M., Wanner, B., Vitaro, F., Horwood, L. J., & SwainCampbell, N. (2003). Deviant peer affiliations and depression: confounding or causation? Journal of Abnormal Child Psychology, 31, 605–618. Fergusson, D. M., & Woodward, L. J. (2002). Mental health, educational, and social role outcomes of adolescents with depression. Archives of General Psychiatry, 59, 225–231. Findling, R. L., McNamara, N. K., Stansbrey, R. J., Feeny, N. C., Young, C. M., Peric, F. V., et al. (2006). The relevance of pharmacokinetic studies in designing efficacy trials in juvenile major depression. Journal of Child and Adolescent Psychopharmacology, 16, 131–145. Forbes, E. E., Fox, N. A., Cohn, J., Galles, S., & Kovacs, M. (2006a). Children’s affect regulation during a disappointment: Psychophysiological responses and relation to parent history of depression. Biological Psychiatry, 71, 264–277. Forbes, E. E., Shaw, D. S., Fox, N. A., Cohn, J. F., Silk, J. S., & Kovacs, M. (2006b). Maternal depression, child frontal asymmetry, and child affective behavior as factors in child behavior problems. Journal of Child Psychology and Psychiatry, 47, 79–87. Forbes, E. E., May, C., Siegle, G. J., Ladouceur, C. D., Ryan, N. D., Carter, C. S., et al. (2006c). Reward-related decision-making in pediatric major depressive disorder: An fMRI study. Journal of Child Psychology and Psychiatry, 47, 1031–1040. Frye, A. A., & Garber, J. (2005). The relations among maternal depression, maternal criticism, and adolescents’ externalizing and internalizing symptoms. Journal of Abnormal Child Psychology, 33, 1–11. Garber, J., & Flynn, C. (2001). Predictors of depressive cognitions in young adolescents. Cognitive Therapy and Research, 25, 353–376. Garber, J., Keiley, M. K., & Martin, N. C. (2002). Developmental trajectories of adolescents’ depressive symptoms: Predictors of change. Journal of Consulting and Clinical Psychology, 70, 79–95. Garber, J., & Robinson, N. S. (1997). Cognitive vulnerability in children at risk for depression. Cognition and Emotion, 11, 619–635. Geller, B., Zimerman, B., Williams, M., Bolhofner, K., & Craney, J. L. (2001). Bipolar disorder at prospective follow-up of adults who had prepubertal major depression disorder. American Journal of Psychiatry, 158, 125–127. Gibbons, R. D., Hur, K., Bhaumik, D. K., & Mann, J. J. (2006). The relationship between antidepressant medication use and rate of early adolescent suicide. American Journal of Psychiatry, 163, 1898– 1904. Glowinski, A. L., Madden, P. A. F., Bucholz, K. K., Lynskey, M. T., & Heath, A. C. (2003). Genetic epidemiology of self-reported lifetime DSM-IV major depressive disorder in a population-based twin sample of female adolescents. Journal of Child Psychology and Psychiatry and Allied Disciplines, 44, 988–996. Goldstein, B. J., & Goodnick, P. J. (1998). Selective serotonin reuptake inhibitors in the treatment of affectives disorders. III. Tolerability, safety and pharmacoeconomics. Journal of Psychopharmacology, 12, S55–S87. Goodwin, R. D., Fergusson, D. M., & Horwood, L. J. (2004a). Asthma and depressive and anxiety disorders among young persons in the community. Psychological Medicine, 34, 1465–1474. Goodwin, R. D., Fergusson, D. M., & Horwood, L. J. (2004b). Early anxious/withdrawn behaviours predict later internalising disorders. Journal of Child Psychology and Psychiatry, 45, 874–883. Goodyer, I. M. (2002). Social adversity and mental functions in adolescents at high risk of psychopathology. British Journal of Psychiatry, 181, 383–386. Goodyer, I. M. (2006). A randomised controlled trial of SSRIs with and without cognitive behaviour therapy in adolescents with major depression. Cambridge, UK: NHS Research and Development Coordinating Centre for Health Technology Assessment (HTA). Goodyer, I. M., Herbert, J., & Tamplin, A. (2003). Psychoendocrine antecedents of persistent first-episode major depression in adolescents: A community-based longitudinal enquiry. Psychological Medicine, 33, 601–610. Goodyer, I. M., Herbert, J., Tamplin, A., & Altham, P. M. (2000). First-episode major depression in adolescents. Affective, cognitive and endocrine characteristics of risk status and predictors of onset. British Journal of Psychiatry, 176, 142–149. Gould, M. S., King, R., Greenwald, S., Fisher, P., Schwab-Stone, M., Kramer, R., et al. (1998). Psychopathology associated with suicidal ideation and attempts among children and adolescents. Journal of the American Academy of Child and Adolescent Psychiatry, 37, 915–923. Graber, J. A., Seeley, J. R., Brooks-Gunn, J., & Lewinsohn, P. M. (2004). Is pubertal timing associated with psychopathology in young adulthood? Journal of the American Academy of Child and Adolescent Psychiatry, 43, 718–726. Hamilton, J. A., & Bridge, J. (1999). Outcome at 6 months for 50 adolescents with major depression treated in a health maintenance organization. Journal of the American Academy of Child and Adolescent Psychiatry, 38, 1340–1346. Hammad, T. A., Laughren, T., & Racoosin, J. (2006). Suicidality in pediatric patients treated with antidepressant drugs. Archives of General Psychiatry, 63, 332–339. Hammen, C. (1988). Self-cognitions, stressful events, and the prediction of depression in children of depressed mothers. Journal of Abnormal Child Psychology, 16 (3), 347–360. Hammen, C., Burge, D., & Stansbury, K. (1990). Relationship of mother and child variables to child outcomes in a high-risk sample: A causal modeling analysis. Developmental Psychology, 26, 24– 30. Hammen, C., Rudolph, K., Weisz, J., Rao, U., & Burge, D. (1999). The context of depression in clinic-referred youth: Neglected areas in treatment. Journal of the American Academy of Child and Adolescent Psychiatry, 38, 64–71. Hariri, A. R., Mattay, V. S., Tessitore, A., Kolachana, B., Fera, F., Goldman, D., et al. (2002). Serotonin transporter genetic variation and the response of the human amygdala. Science, 297, 400–403. Harrington, R. (2000). Childhood depression: Is is the same disorder? In J. Rapoport (Ed.), Childhood onset of “adult” psychopathology: Clinical and research advances (pp. 223–243). Washington: American Psychiatric Publishing. Harrington, R., & Clark, A. (1998). Prevention and early intervention for depression in adolescence and early adult life. European Archives of Psychiatry and Clinical Neuroscience, 248, 32–45. Harrington, R., Kerfoot, M., Dyer, E., McNiven, F., Gill, J., Harrington, V., et al. (1998). Randomized trial of a home-based DEPRESSIVE DISORDERS 607 9781405145497_4_037.qxd 29/03/2008 02:52 PM Page 607

family intervention for children who have deliberately poisoned themselves. Journal of the American Academy of Child and Adolescent Psychiatry, 37, 512–518. Harrington, R., Rutter, M., Weissman, M., Fudge, H., Groothues, C., Bredenkamp, D., et al. (1997). Psychiatric disorders in the relatives of depressed probands. I. Comparison of prepubertal, adolescent and early adult onset cases. Journal of Affective Disorders, 42, 9–22. Hazell, P., O’Connell, D., Heathcote, D., Robertson, J., & Henry, D. (1995). Efficacy of tricyclic drugs in treating child and adolescent depression: A meta-analysis. British Medical Journal, 310, 897– 901. Heiligenstein, J., Hoog, S. L., Wagner, K. D., Findling, R. L., Galil, N., Kaplan, S., et al. (2006). Fluoxetine 40–60 mg versus fluoxetine 20 mg in the treatment of children and adolescents with a less-than-complete response to nine-week treatment with fluoxeting 10–20 mg: A pilot study. Journal of Child and Adolescent Psychopharmacology, 16, 207–217. Hollon, S. D., Garber, J., & Shelton, R. C. (2005). Treatment of depression in adolescents with cognitive behavior therapy and medications: A commentary on the TADS project. Cognitive and Behavioral Practice, 12, 149–155. Horowitz, J. L., & Garber, J. (2006). The prevention of depressive symptoms in children and adolescents: A meta-analytic review. Journal of Consulting and Clinical Psychology, 74, 401–415. Hudziak, J. J., Rudiger, L. P., Neale, M. C., Heath, A. C., & Todd, R. D. (2000). A twin study of inattentive, aggressive, and anxious/ depressed behaviors. Journal of the American Academy of Child and Adolescent Psychiatry, 39, 469–476. Hughes, C. W., Emslie, G. J., Crismon, L., Wagner, K. D., Birmaher, B., Geller, B., et al. (1999). The Texas children’s medication algorithm project: Report of the Texas consensus conference panel on medication treatment of childhood major depressive disorder. Journal of the American Academy of Child and Adolescent Psychiatry, 38, 1442–1454. Ivarsson, T., Broberg, A. G., Arvidsson, T., & Gillberg, C. (2005). Bullying in adolescence: Psychiatric problems in victims and bullies as measured by the youth self report (YSR) and the depression selfrating scale (DSRS). Nordic Journal of Psychiatry, 59, 365–373. Jaffee, S. R., Moffitt, T. E., Caspi, A., Fombonne, E., Poulton, R., & Martin, J. (2002). Differences in early childhood risk factors for juvenile-onset and adult-onset depression. Archives of General Psychiatry, 59, 215–222. Jones, J. E., Hermann, B. P., Barry, J. J., Gilliam, F. G., Kanner, A. M., & Meador, K. J. (2003). Rates and risk factors for suicide, suicidal ideation, and suicide attempts in chronic epilepsy. Epilepsy and Behavior, 4 (Supplement 3), S31–S38. Kaltiala-Heino, R., Rimpela, M., Rantanen, P., & Rimpela, A. (2000). Bullying at school: An indicator of adolescents at risk for mental disorders. Journal of Adolescence, 23, 661–674. Katon, W. J., Unutzer, J., & Simon, G. (2004). Treatment of depression in primary care: Where we are, where we can go. Medical Care, 42, 1153–1157. Kaufman, J., Birmaher, B., Brent, D., Dahl, R., Bridge, J., & Ryan, N. D. (1998a). Psychopathology in the relatives of depressedabused children. Child Abuse and Neglect, 22, 171–181. Kaufman, J., Birmaher, B., Brent, D., Rao, U., Flynn, C., Moreci, P., et al. (1997a). 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 and Adolescent Psychiatry, 36, 980–988. Kaufman, J., Birmaher, B., Perel, J., Dahl, R., Stull, S., Brent, D., et al. (1998b). Serotonergic functioning in depressed abused children: Clinical and familial correlates. Biological Psychiatry, 44, 973–981. Kaufman, J., Birmaher, B., Perel, J., Dahl, R. E., Moreci, P., Nelson, B., et al. (1997b). The corticotropin-releasing hormone challenge in depressed abused, depressed nonabused, and normal control children. Biological Psychiatry, 42, 669–679. Kaufman, J., & Charney, D. (2001). Effects of early stress on brain structure and function: Implications for understanding the relationship between child maltreatment and depression. Development and Psychopathology, 13, 451–471. Kaufman, J., Yang, B. Z., Douglas-Palumberi, H., Grasso, D., Lipschitz, D., Houshyar, S., et al. (2006). Brain-derived neurotrophic factor-5-HHTLPR gene interactions and environmental modifiers of depression in children. Biological Psychiatry, 59, 673–680. Kaufman, N. K., Rohde, P., Seeley, J. R., Clarke, G. N., & Stice, E. (2005). Potential mediators of cognitive–behavioral therapy for adolescents with comorbid major depression and conduct disorder. Journal of Consulting and Clinical Psychology, 73, 38–46. Keller, M., Ryan, N. D., Strober, M., Klein, R. G., Kutcher, S. P., Birmaher, B., et al. (2001). Efficacy of paroxetine in the treatment of adolescent major depression: A randomized, controlled study. Journal of the American Academy of Child and Adolescent Psychiatry, 40, 762–772. Keller, M. B., McCullough, J. P., Klein, D. N., Arnow, B., Dunner, D. L., Gelenberg, A. J., et al. (2000). A comparison of nefazodone, the cognitive behavioral-analysis system of psychotherapy, and their combination for the treatment of chronic depression. New England Journal of Medicine, 342, 1462–1470. Kelvin, R. G., Goodyer, I. M., Teasdale, J. D., & Brechin, D. (1999). Latent negative self-schema and high emotionality in well adolescents at risk for psychopathology. Journal of Child Psychology and Psychiatry, 40, 959–968. Kennard, B., Silva, S., Vitiello, B., Curry, J., Kratochvil, C., Simons, A., et al. (2006). Remission and residual symptoms after acute treatment of adolescents with major depressive disorder. Journal of the American Academy of Child and Adolescent Psychiatry, 45, 1404–1411. Kentgen, L. M., Tenke, C. E., Pine, D. S., Fong, R., Klein, R. G., & Bruder, G. E. (2000). Electroencephalographic asymmetries in adolescents with major depression: Influence of comorbidity with anxiety disorders. Journal of Abnormal Psychology, 109, 797–802. King, R. A., Schwab-Stone, M., Flisher, A. J., Greenwald, S., Kramer, R. A., Goodman, S. H., et al. (2001). Psychosocial and risk behavior correlates of youth suicide attempts and suicidal ideation. Journal of the American Academy of Child and Adolescent Psychiatry, 40, 837–846. Klein, D. N., Lewinsohn, P. M., Rohde, P., Seeley, J. R., & Olino, T. M. (2005). Psychopathology in the adolescent and young adult offspring of a community sample of mothers and fathers with major depression. Psychological Medicine, 35, 353–365. Kolko, D. J., Brent, D. A., Baugher, M., Bridge, J., & Birmaher, B. (2000). Cognitive and family therapies for adolescent depression: Treatment specificity, mediation, and moderation. Journal of Consulting and Clinical Psychology, 68, 603–614. Kovacs, M. (1985). The children’s depression inventory (CDI). Psychopharmacology Bulletin, 21, 995–998. Kovacs, M. (1996). Presentation and course of major depressive disorder during childhood and later years of the life span. Journal of the American Academy of Child and Adolescent Psychiatry, 35, 705–715. Kovacs, M., & Devlin, B. (1998). Internalizing disorders in childhood. Journal of Child Psychology and Psychiatry, 39, 47–63. Kovacs, M., Feinberg, T., Crouse-Novak, M., Paulauskas, S., Pollock, M., & Finkelstein, R. (1984a). Depressive disorders in childhood. I. A longitudinal study of characteristics and recovery. Archives of General Psychiatry, 41, 229–237. Kovacs, M., Feinberg, T., Crouse-Novak, M., Paulauskas, S., Pollock, M., & Finkelstein, R. (1984b). Depressive disorders in childhood. II. A longitudinal study of the risk for a subsequent major depression. Archives of General Psychiatry, 41, 643–649. Kovacs, M., & Gatsonis, C. (1994). Secular trends in age at onset of major depressive disorder in a clinical sample of children. Journal of Psychiatric Research, 28, 319–329. CHAPTER 37 608 9781405145497_4_037.qxd 29/03/2008 02:52 PM Page 608

Kovacs, M., Goldston, D., Obrosky, D. S., & Bonar, L. K. (1997). Psychiatric disorders in youths with IDDM: Rates and risk factors. Diabetes Care, 20, 36–44. Kovacs, M., Sherril, J., George, C. J., Pollock, M., Tumuluru, R. V., & Ho, V. (2006). Contextual emotion-regulation therapy for childhood depression: Description and pilot testing of a new intervention. Journal of the American Academy of Child and Adolescent Psychiatry, 45, 892–903. Kramer, R. A., Warner, V., Olfson, M., Ebanks, C. M., Chaput, F., & Weissman, M. M. (1998). General medical problems among the offspring of depressed parents: A 10-year follow-up. Journal of the American Academy of Child and Adolescent Psychiatry, 37, 602–611. Kroll, L., Harrington, R., Jayson, D., & Fraser, J. (1996). Pilot study of continuation cognitive-behavioral therapy for major depression in adolescent psychiatric patients. Journal of the American Academy of Child and Adolescent Psychiatry, 35, 1156–1161. Kuo, P. H., Gardner, C. O., Kendler, K. S., & Prescott, C. A. (2006). The temporal relationship of the onsets of alcohol dependence and major depression: Using a genetically informative study design. Psychological Medicine, 36, 1153–1162. Kyte, Z. A., Goodyer, I. M., & Sahakian, B. J. (2006). Selected executive skills in adolescents with recent first episode major depression. Journal of Child Psychology and Psychiatry, 46, 995–1005. Labellarte, M. J., Biederman, J., Emslie, G., Ferguson, J., Khan, A., Ruckle, J., et al. (2004). Multiple-dose pharmacokinetics of fluvoxamine in children and adolescents. Journal of the American Academy of Child and Adolescent Psychiatry, 43, 1497–1505. Ladouceur, C. D., Dahl, R. E., Williamson, D. E., Birmaher, B., Ryan, N. D., & Casey, B. J. (2005). Altered emotional processing in pediatric anxiety, depression and comorbid anxiety-depression. Journal of Abnormal Child Psychology, 33, 165–177. Lerer, B., & Macciardi, F. (2002). Pharmacogenetics of antidepressant and mood-stabilizing drugs: A review of candidate-gene studies and future research. International Journal of Neuropsychopharmacology, 5, 255–275. Lewinsohn, P. M., Clarke, G. N., Hops, H., & Andrews, J. (1990). Cognitive–behavioral treatment for depressed adolescents. Behavior Therapy, 21, 385–401. Lewinsohn, P. M., Joiner, T. E., & Rohde, P. (2001). Evaluation of cognitive diathesis–stress models in predicting major depressive disorder in adolescents. Journal of Abnormal Psychology, 110, 203– 215. Lewinsohn, P. M., Rohde, P., & Seeley, J. R. (1996). Adolescent suicidal ideation and attempts: Prevalence, risk factors, and clinical implications. Clinical Psychology: Science and Practice, 3, 25–46. Lewinsohn, P. M., Rohde, P., & Seeley, J. R. (1998). Major depressive disorder in older adolescents: Prevalence, risk factors, and clinical implications. Clinical Psychology Review, 18, 765–794. Lewinsohn, P. M., Rohde, P., Seeley, J. R., Klein, D. N., & Gotlib, I. H. (2003). Psychosocial functioning of young adults who have experienced and recovered from major depressive disorder during adolescence. Journal of Abnormal Psychology, 112, 353–363. Libby, A. M., Orton, H. D., Stover, S. K., & Riggs, P. D. (2005). What came first, major depression or substance use disorder? Clinical characteristics and substance use comparing teens in a treatment cohort. Addictive Behaviors, 30, 1649–1662. Luby, J. L., Heffelfinger, A. K., Mrakotsky, C., Brown, K. M., Hessler, M. J., Wallis, J. M., et al. (2003). The clinical picture of depression in preschool children. Journal of the American Academy of Child and Adolescent Psychiatry, 42, 340–348. Luby, J. L., Heffelfinger, A., Koenig-McNaught, A. L., Brown, K., & Spitznagel, E. (2004). The Preschool Feelings Checklist: A brief and sensitive screening measure for depression in young children. Journal of the American Academy of Child and Adolescent Psychiatry, 43, 708–717. Lyoo, I. K., Kyu Lee, H., Hyun Jung, J., Noam, G. G., & Renshaw, P. F. (2002). White matter hyperintensities on magnetic resonance imaging of the brain in children with psychiatric disorders. Comprehensive Psychiatry, 43, 361–368. Lyubomirsky, S., Caldwell, N. D., & Nolen-Hoeksema, S. (1998). Effects of ruminative and distracting responses to depressed mood on retrieval of autobiographical memories. Journal of Personality and Social Psychology, 75, 166–177. March, J. S., Silva, S., Petrycki, S., Curry, J., Wells, K., Fairbank, J., et al. (2004). Fluoxetine, cognitive–behavioral therapy, and their combination for adolescents with depression. Treatment for Adolescent Depression Study (TADS) randomized controlled trial. Journal of the American Medical Association, 292, 807–820. Martin, A., Young, C., Leckman, J. F., Mukonoweshuro, C., Rosenheck, R., & Leslie, D. (2004). Age effects on antidepressantinduced manic conversion. Archives of Pediatrics and Adolescent Medicine, 158, 773–780. McGuffin, P., Knight, J., Breen, G., Brewster, S., Boyd, P. R., Craddock, N., et al. (2005). Whole genome linkage scan of recurrent depressive disorder from the depression network. Human Molecular Genetics, 14, 3337–3345. Middeldorp, C. M., Cath, D. C., van Dyck, R., & Boomsma, D. I. (2005). The co-morbidity of anxiety and depression in the perspective of genetic epidemiology: A review of twin and family studies. Psychological Medicine, 35, 611–624. Mirza, Y., Tang, J., Russell, A., Banerjee, P., Bhandari, R., Ivey, J., et al. (2004). Reduced anterior cingulate cortex glutamatergic concentrations in childhood major depression. Journal of the American Academy of Child and Adolescent Psychiatry, 43, 341–348. Mufson, L., Dorta, K. P., Wickramaratne, P., Nomura, Y., Olfson, M., & Weissman, M. M. (2004). A randomized effectiveness trial of interpersonal psychotherapy for depressed adolescents. Archives of General Psychiatry, 61, 577–584. Mufson, L., & Fairbanks, J. (1996). Interpersonal psychotherapy for depressed adolescents: A one-year naturalistic follow-study. Journal of the American Academy of Child and Adolescent Psychiatry, 35, 1145–1155. Mufson, L., Weissman, M. M., Moreau, D., & Garfinkel, R. (1999). Efficacy of interpersonal psychotherapy for depressed adolescents. Archives of General Psychiatry, 56, 573–579. Mulder, R. T., Watkins, W. G. A., Joyce, P. R., & Luty, S. E. (2003). Age may affect response to antidepressants with serotonergic and noradrenergic actions. Journal of Affective Disorders, 76, 143– 149. Myers, K., & Winters, N. C. (2002). Ten-year review of rating scales. II. Scales for internalizing disorders. Journal of the American Academy of Child and Adolescent Psychiatry, 41, 634–659. National Institute for Health and Clinical Excellence (NICE). (2005). Depression in children and young people. Identification and management in primary, community, and secondary care. Developed by the National Collaborating Centre for Mental Health. Nemets, H., Nemets, B., Apter, A., Bracha, Z., & Belmaker, R. H. (2006). Omega-3 treatment of childhood depression: A controlled, double-blind pilot study. American Journal of Psychiatry, 163, 1098–1100. Nierenberg, A. A., McLean, N. E., Alpert, J. E., Worthington, J. J., Rosenbaum, J. F., & Fava, M. (1995). Early nonresponse to fluoxetine as a predictor of poor 8-week outcome. American Journal of Psychiatry, 152, 1500–1503. Nolan, C. L., Moore, G. J., Madden, R., Farchione, T., Bartoi, M., Lorch, E., et al. (2002). Prefrontal cortical volume in childhood-onset major depression. Archives of General Psychiatry, 59, 173–179. Nolen-Hoeksema, S., Larson, J., & Grayson, C. (1999). Explaining the gender difference in depressive symptoms. Journal of Personality and Social Psychology, 77, 1061–1072. O’Connor, T. G., Neiderhiser, J. M., Reiss, D., Hetherington, E. M., & Plomin, R. (1998). Genetic contributions to continuity, change, and co-occurrence of antisocial and depressive symptoms in adolescence. Journal of Child Psychology and Psychiatry, 39, 323–336. DEPRESSIVE DISORDERS 609 9781405145497_4_037.qxd 29/03/2008 02:52 PM Page 609

Olfson, M., Shaffer, D., Marcus, S. C., & Greenberg, T. (2003). Relationship between antidepressant medication treatment and suicide in adolescents. Archives of General Psychiatry, 60, 978–982. Park, R. J., Goodyer, I. M., & Teasdale, J. D. (2005). Self-devaluative dysphoric experience and the prediction of persistent first-episode major depressive disorder in adolescents. Psychological Medicine, 35, 539–548. Park, R. J., Goodyer, I. M., & Teasdale, J. D. (2002). Categoric overgeneral autobiographical memory in adolescents with major depressive disorder. Psychological Medicine, 32, 267–276. Pine, D., Coplan, J., Wasserman, G. A., Miller, L. S., Fried, J. E., Davies, M., et al. (1997). Neuroendocrine response to fenfluramine challenge in boys: Associations with aggressive behavior and adverse rearing. Archives of General Psychiatry, 54, 839–846. Pine, D. S. (2004). Face-memory and emotion: Associations with major depression in children and adolescents. Journal of Child Psychology and Psychiatry, 45, 1199–1208. Pine, D. S., Cohen, P., & Brook, J. (2001). Adolescent fears as predictors of depression. Biological Psychiatry, 50, 721–724. Pine, D. S., Cohen, P., Gurley, D., Brook, J., & May, Y. (1998). The risk for early-adulthood anxiety and depressive disorders in adolescents with anxiety and depressive disorders. Archives of General Psychiatry, 55, 56–64. Pine, D. S., Goldstein, R. B., Wolk, S., & Weissman, M. M. (2001). The association between childhood depression and adulthood body mass index. Pediatrics, 107, 1049–1056. Plioplys, S. (2003). Depression in children and adolescents with epilepsy. Epilepsy and Behavior, 4, S39–S45. Poznanski, E. O., Freeman, L. N., & Mokros, H. B. (1985). Children’s Depression Rating Scale – Revised. Psychopharmacology Bulletin, 21, 979–989. Puig-Antich, J., Dahl, R., Ryan, N., Novacenko, H., Goetz, D., Goetz, R., et al. (1989). Cortisol secretion in prepubertal children with major depressive disorder. Episode and recovery. Archives of General Psychiatry, 46, 801–809. Rao, U., Ryan, N. D., Dahl, R. E., Birmaher, B., Rao, R., Williamson, D. E., et al. (1999). Factors associated with the development of substance use disorder in depressed adolescents. Journal of the American Academy of Child and Adolescent Psychiatry, 38, 1109–1117. Renaud, J., Brent, D. A., Baugher, M., Birmaher, B., Kolko, D. J., & Bridge, J. (1998). Rapid response to psychosocial treatment for adolescent depression: A two-year follow-up. Journal of the American Academy of Child and Adolescent Psychiatry, 37, 1184–1190. Resnick, M. D., Bearman, P. S., Blum, R. W., Bauman, K. E., Harris, K. M., Jones, J., et al. (1997). Protecting adolescents from harm: Findings from the National Longitudinal Study on Adolescent Health. Journal of the American Medical Association, 278, 823–832. Reynolds, W. M., & Mazza, J. J. (1998). Reliability and validity of the Reynolds Adolescent Depression Scale with young adolescents. Journal of School Psychology, 36, 295–312. Rice, F., Harold, G. T., & Thapar, A. (2003). Negative life events as an account of age-related differences in the genetic aetiology of depression in childhood and adolescence. Journal of Child Psychology and Psychiatry, 44, 977–987. Roberts, R. E., Lewinsohn, P. M., & Seeley, J. R. (1991). Screening for adolescent depression: a comparison of depression scales. Journal of the American Academy of Child & Adolescent Psychiatry, 30, 58–66. Roberson-Nay, R., McClure, E. B., Monk, C. S., Nelson, E. E., Guyer, A. E., Fromm, S. J., et al. (2006). Increased amygdala activity during successful memory encoding in adolescent major depressive disorder: An fMRI Study. Biological Psychiatry, 60, 966–973. Rohde, P., Clarke, G. N., Lewinsohn, P. M., Seeley, J. R., & Kaufman, N. K. (2001). Impact of comorbidity on a cognitive–behavioral group treatment for adolescent depression. Journal of the American Academy of Child and Adolescent Psychiatry, 40, 795–802. Rohde, P., Clarke, G. N., Mace, D. E., Jorgensen, J. S., & Seeley, J. R. (2004a). An efficacy/effectiveness study of cognitive–behavioral treatment for adolescents with comorbid major depression and conduct disorder. Journal of the American Academy of Child and Adolescent Psychiatry, 43, 660–668. Rohde, P., Jorgensen, J. S., Seeley, J. R., & Mace, D. E. (2004b). Pilot evaluation of the Coping Course: A cognitive–behavioral intervention to enhance coping skills in incarcerated youth. Journal of the American Academy of Child and Adolescent Psychiatry, 43, 669– 676. 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 and Adolescent Psychiatry, 43, 1146–1153. Rossello, J., & Bernal, G. (1999). The efficacy of cognitive-behavioral and interpersonal treatments for depression in Puerto Rican adolescents. Journal of Consulting and Clinical Psychology, 67, 734–745. Rosso, I. M., Cintron, C. M., Steingard, R. J., Renshaw, P. F., Young, A. D., & Yurgelun-Todd, D. (2005). Amygdala and hippocampus volumes in pediatric major depression. Biological Psychiatry, 57, 21–26. Ruchkin, V., Sukhodolsky, D. G., Vermeiren, R., Koposov, R. A., & Schwab-Stone, M. (2006). Depressive symptoms and associated psychopathology in urban adolescents: A cross-cultural study of three countries. Journal of Nervous and Mental Disease, 194, 106–113. Rudolph, K. D., & Hammen, C. (1999). Age and gender as determinants of stress exposure, generation, and reactions in youngsters: A transactional perspective. Child Development, 70, 660–677. Rudolph, K. D., Hammen, C., & Burge, D. (1997). A cognitiveinterpersonal approach to depressive symptoms in preadolescent children. Journal of Abnormal Child Psychology, 25, 33–45. Ryan, N. D., Birmaher, B., Perel, J. M., Dahl, R. E., Meyer, V., AlShabbout, M., et al. (1992a). Neuroendocrine response to L5-hydroxytryptophan challenge in prepubertal major depression. Archives of General Psychiatry, 49, 843–851. Ryan, N. D., Williamson, D. E., Iyengar, S., Orvaschel, H., Reich, T., Dahl, R. E., et al. (1992b). A secular increase in child and adolescent onset affective disorder. Journal of the American Academy of Child and Adolescent Psychiatry, 31, 600–605. Sallee, F. R., Hilal, R., Dougherty, D., Beach, K., & Nesbitt, L. (1998). Platelet serotonin transporter in depressed children and adolescents: 3H-paroxetine platelet binding before and after sertraline. Journal of the American Academy of Child and Adolescent Psychiatry, 37, 777–784. Sallee, F. R., Nesbitt, L., Dougherty, D., Hilal, R., Nandagopal, V. S., & Sethuraman, G. (1995). Lymphocyte glucocorticoid receptor: Predictor of sertraline response in adolescent major depressive disorder. Psychopharmacology Bulletin, 31, 339–345. Sanford, M., Boyle, M., McCleary, L., Miller, J., Steele, M., Duku, E., et al. (2006). A pilot study of adjunctive family psychoeducation in adolecent major depression: Feasibility and treatment effect. Journal of the American Academy of Child and Adolescent Psychiatry, 45, 386–395. Scourfield, J., Rice, F., Thapar, A., Harold, G. T., Martin, N., & McGuffin, P. (2003). Depressive symptoms in children and adolescents: Changing aetiological influences with development. Journal of Child Psychology and Psychiatry, 44, 968–976. Shaffer, D., Fisher, P., & Lucas, C. (2004). The Diagnostic Interview Schedule for Children (DISC). In M. J. Hilsenroth, & D. L. Segal (Eds.), Comprehensive handbook of psychological assessment, Volume 2: Personality assessment (pp. 256–270). Hoboken, NJ: John Wiley & Sons. Shaffer, D., Gould, M. S., Fisher, P., Trautman, P., Moreau, D., Kleinman, M., et al. (1996). Psychiatric diagnosis in child and adolescent suicide. Archives of General Psychiatry, 53, 339–348. CHAPTER 37 610 9781405145497_4_037.qxd 29/03/2008 02:52 PM Page 610

Shaffer, D., & Pfeffer, C. (2001). Summary of the practice parameters for the assessment and treatment of children and adolescents with suicidal behavior. Journal of the American Academy of Child and Adolescent Psychiatry, 40, 24S–51S. Shankman, S. A., Tenke, C. E., Bruder, G. E., Durbin, C. E., Hayden, E. P., & Klein, D. N. (2005). Low positive emotionality in young children: Association with EEG asymmetry. Development and Psychopathology, 17, 85–98. Siegle, G. J., Carter, C. S., & Thase, M. E. (2006). Use of fMRI predicts recovery from unipolar depression with cognitive behavior therapy. American Journal of Psychiatry, 163, 735–738. Silk, J. S., Shaw, D. S., Skuban, E. M., Oland, A. A., & Kovacs, M. (2006). Emotion regulation strategies in offspring of childhood-onset depressed mothers. Journal of Child Psychology and Psychiatry, 47, 69–78. Simeon, J. G., Dinicola, V. F., Ferguson, B., & Copping, W. (1990). Adolescent depression: A placebo-controlled fluoxetine treatment study and follow-up. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 14, 791–795. Simon, G. E., Savarino, J., Operskalski, B., & Wang, P. S. (2006). Suicide risk during antidepressant treatment. American Journal of Psychiatry, 163, 41–47. Southam-Gerow, M. A., Kendall, P. C., & Weersing, V. R. (2001). Examining outcome variability: Correlates of treatment response in a child and adolescent anxiety clinic. Journal of Clinical Child Psychology, 30, 422–436. Steingard, R., Renshaw, P. F., Hennen, J., Lenox, M., Bonella Cintron, C., Young, A. D., et al. (2002). Smaller frontal lobe white matter volumes in depressed adolescents. Biological Psychiatry, 52, 413–417. Steingard, R. J., Yurgelun-Todd, D., Hennen, J., Moore, J. C., Moore, C. M., Vakili, K., et al. (2000). Increased orbitofrontal cortex levels of choline in depressed adolescents as detected by in vivo proton magnetic resonance spectroscopy. Biological Psychiatry, 48, 1053–1061. Stewart, S., Kennard, B. D., Lee, P. W. H., Hughes, C. W., Mayes, T. L., Emslie, G. J., et al. (2004). A cross-cultural investigation of cognitions and depressive symptoms in adolescents. Journal of Abnormal Psychology, 113, 248–257. Strauss, J., Barr, C. L., George, C. J., Devlin, B., Vetro, A., Kiss, E., et al. (2005). Brain-derived neurotrophic factor variants are associated with childhood-onset mood disorder: Confirmation in a Hungarian sample. Molecular Psychiatry, 10, 861–867. Strober, M., & Carlson, G. (1982). Bipolar illness in adolescents with major depression: Clinical, genetic, and psychopharmacologic predictors in a three- to four-year prospective follow-up investigation. Archives of General Psychiatry, 39, 549–555. Stroud, L. R., Papandonatos, G. D., Williamson, D. E., & Dahl, R. E. (2004). Sex differences in the effects of pubertal development on responses to a corticotropin-releasing hormone challenge: The Pittsburgh psychobiologic studies. Annals of the New York Academy of Sciences, 1021, 348–351. Swedo, S. E., Allen, A. J., Glod, C. A., Clark, C. H., Teicher, M. H., Richter, D., et al. (1997). A controlled trial of light therapy for the treatment of pediatric seasonal affective disorder. Journal of the American Academy of Child and Adolescent Psychiatry, 36, 816–821. Thapar, A., & McGuffin, P. (1997). Anxiety and depressive symptoms in childhood: A genetic study of comorbidity. Journal of Child Psychology and Psychiatry, 38, 651–656. Thapar, A., & McGuffin, P. (1998). Validity of the shortened Mood and Feelings Questionnaire in a community sample of children and adolescents: A preliminary research note. Psychiatry Research, 81, 259–268. Thase, M. E., Greenhouse, J. B., Frank, E., Reynolds, C. F. III, Pilkonis, P. A., Hurley, K., et al. (1997). Treatment of major depression with psychotherapy or psychotherapy–pharmacotherapy combinations. Archives of General Psychiatry, 54, 1009–1015. Thomas, K. M., Drevets, W. C., Dahl, R. E., Ryan, N. D., Birmaher, B., Eccard, C. H., et al. (2001). Amydgala response to fearful faces in anxious and depressed children. Archives of General Psychiatry, 58, 1057–1063. Thompson, E. A., Eggert, L. L., Randell, B. P., & Pike, K. C. (2001). Evaluation of indicated suicide risk prevention approaches for potential high school dropouts. American Journal of Public Health, 91, 742–752. Todd, R. D., & Botteron, K. N. (2002). Etiology and genetics of earlyonset mood disorders. Child and Adolescent Psychiatric Clinics of North America, 11, 499–518. Tomarken, A. J., Dichter, G. S., Garber, J., & Simien, C. (2004). Resting frontal brain activity: Linkages to maternal depression and socioeconomic status among adolescents. Biological Psychiatry, 67, 77– 102. Tremblay, G. C., & Israel, A. C. (1998). Children’s adjustment to parental death. Clinical Psychology: Science and Practice, 5, 424– 438. Vitiello, B., Rohde, P., Silva, S., Wells, K., Casat, C., Waslick, B., et al. (2006). Effects of treatment on level of functioning, global health, and quality of life in depressed adolescents. Journal of the American Academy of Child and Adolescent Psychiatry, 45, 1427– 1429. von Knorring A. L., Olsson, G. I., Thomsen, P. H., Lemming, O. M., & Hulten, A. (2006). A randomized, double-blind, placebo-controlled study of citalopram in adolescents with major depressive disorder. Journal of Clinical Pharmacology, 26, 311–315. Vostanis, P., Feehan, C., Grattan, E., & Bickerton, W. (1996). A randomised controlled out-patient trial of cognitive-behavioural treatment for children and adolescents with depression: 9-month follow-up. Journal of Affective Disorders, 40, 105–116. Vythilingam, M., Heim, C., Newport, J., Miller, A. H., Anderson, E., Bronen, R., et al. (2002). Childhood trauma associated with smaller hippocampal volume in women with major depression. American Journal of Psychiatry, 159, 2072–2080. Wagner, K. D., Ambrosini, P., Rynn, M., Wohlberg, C., Yang, R., Greenbaum, M. S., et al. (2003). Efficacy of sertraline in the treatment of children and adolescents with major depressive disorder: two randomized controlled trials. Journal of the American Medical Association, 290, 1033–1041. Wagner, K. D., Jonas, J., Findling, R. L., Ventura, D., & Saikali, K. (2006). A double-blind, randomized, placebo-controlled trial of escitalopram in the treatment of piedatric depression. Journal of the American Academy of Child and Adolescent Psychiatry, 45, 280–288. Wagner, K. D., Robb, A. S., Findling, R. L., Jin, J., Gutierrez, M. M., & Heydorn, W. E. (2004). A randomized, placebo-controlled trial of citalopram for the treatment of major depression in children and adolescents. American Journal of Psychiatry, 161, 1079–1083. Walter, G., & Rey, J. M. (2003). Has the practice and outcome of ECT in adolescents changed? Findings from a whole-population study. Journal of ECT, 19, 84–87. Wamboldt, M. Z., Hewitt, J. K., Schmitz, S., Wamboldt, F. S., Rasanen, M., Koskenvuo, M., et al. (2000). Familial association between allergic disorders and depression in adult Finnish twins. American Journal of Medical Genetics, 96, 146–153. Warner, V., Weissman, M. M., Fendrich, M., Wickramaratne, P., & Moreau, D. (1992). The course of major depression in the offspring of depressed parents: Incidence, recurrence and recovery. Archives of General Psychiatry, 49, 795–801. Weersing, V. R., Iyengar, S., Kolko, D., Birmaher, B., & Brent, D. A. (2006). Effectiveness of cognitive–behavioral therapy for adolescent depression: A benchmarking investigation. Behavior Therapy, 37, 36–48. Weersing, V. R., & Weisz, J. R. (2002). Community clinic treatment of depressed youth: Benchmarking usual care against CBT clinical trials. Journal of Consulting and Clinical Psychology, 70, 299–310. DEPRESSIVE DISORDERS 611 9781405145497_4_037.qxd 29/03/2008 02:52 PM Page 611

Weissman, M. M., Wolk, S., Wickramaratne, P., Goldstein, R. B., Adams, P., Greenwald, S., et al. (1999a). Children with prepubertalonset major depressive disorder and anxiety grown up. Archives of General Psychiatry, 56, 794–801. Weissman, M. M., Pilowsky, D. J., Wickramaratne, P. J., Talati, A., Wisniewski, S. R., Fava, M., et al. (2006). Remissions in maternal depression and child psychopathology: A STAR*D child report. Journal of American Medical Association, 295, 1389–1398. Weissman, M. M., Wolk, S., Goldstein, R. B., Moreau, D., Adams, P., Greenwald, S., et al. (1999b). Depressed adolescents grown up. Journal of American Medical Association, 281, 1707–1713. Weisz, J. R., McCarty, C. A., & Valeri, S. M. (2006). Effects of psychotherapy for depresssion in children and adolescents: A metaanalysis. Psychological Bulletin, 132, 132–149. Wells, K. B., Sherbourne, C. D., Schoenbaum, M., Duan, N., Meredith, L., Unutzer, J., et al. (2000). Impact of disseminating quality improvement programs for depression in managed primary care: A randomized controlled trial. Journal of the American Medical Association, 283, 212–220. Whooley, M. A., Avins, A. L., Miranda, J., & Browner, W. S. (1997). Case-finding instruments for depression: Two questions are as good as many. Journal of General Internal Medicine, 12, 439– 445. Wickramaratne, P., Warner, V., & Weissman, M. M. (2000). Selecting early-onset MDD probands for genetic studies: Results from a longitudinal high-risk study. American Journal of Medical Genetics, 96, 93–101. Williamson, D. E., Birmaher, B., Axelson, D. A., Ryan, N. D., & Dahl, R. E. (2004). First episode of depression in children at low and high familial risk for depression. Journal of the American Academy of Child and Adolescent Psychiatry, 43, 291–297. Williamson, D. E., Birmaher, B., Ryan, N. D., Shiffrin, T. P., Lusky, J. A., Protopapa, J., et al. (2003). The Stressful Life Events Schedule for children and adolescents: Development and validation. Psychiatry Research, 119, 225–241. Wood, A., Harrington, R., & Moore, A. (1996). Controlled trial of a brief cognitive–behavioural intervention in adolescent patients with depressive disorders. Journal of Child Psychology and Psychiatry, 37, 737–746. Wood, A., Trainor, G., Rothwell, J., Moore, A., & Harrington, R. (2001). Randomized trial of a group therapy for repeated deliberate self-harm in adolescents. Journal of the American Academy of Child and Adolescent Psychiatry, 40, 1246–1253. Yorbik, O., Birmaher, B., Axelson, D., Williamson, D., & Ryan, N. D. (2004). Clinical characteristics of depressive symptoms in children and adolescents with major depressive disorder. Journal of Clinical Psychiatry, 65, 1654–1659. Young, J. F., Mufson, L., & Davies, M. (2006). Impact of cormorbid anxiety in an effectiveness study of interpersonal psychotherapy for depressed adolescents. Journal of the American Academy of Child and Adolescent Psychiatry, 45, 904–912. Zubenko, G. S., Zubenko, W. N., Spiker, D. G., Giles, D. E., & Kaplan, B. B. (2001). Malignancy of recurrent, early-onset major depression: A family study. American Journal of Medical Genetics, 105, 690–699. CHAPTER 37 612 9781405145497_4_037.qxd 29/03/2008 02:52 PM Page 612

613 There has been a recent marked upsurge in interest in pediatric bipolar disorder (PBD), with almost twice as many articles published on the subject in the past 5 years as in the entire previous decade. Several factors may be contributing to this trend. First, while it is clear that relatively few children have a classic adult-like presentation of bipolar disorder (BD), the number of US children being considered for the diagnosis has expanded as prominent researchers have suggested that BD presents differently in children than adults. Specifically, in a view that remains controversial, US researchers have suggested that children with severe irritability, hyperactivity and distractibility are exhibiting a “broad phenotype” of PBD (Leibenluft, Charney, Towbin et al., 2003; NIMH, 2001). Second, studies of children with either classic BD symptoms or the “broad phenotype” suggest that PBD is both markedly impairing and treatment-resistant, increasing the demand for relevant information and research (Biederman, Faraone, Wozniak et al., 2005a; Geller, Tillman, Craney et al., 2004b; Kowatch, Youngstrom, Danielyan et al., 2005b). Finally, because of increased interest in developmental psychopathology research generally, and the advent of safe and noninvasive techniques for studying brain function in children, PBD is one of several illnesses that have become the focus of pathophysiological research (Rich, Vinton, Roberson-Nay et al., 2006). We begin by reviewing the available data concerning the clinical presentation of PBD, including its phenomenology and course, and by providing guidelines for the assessment of children who may have PBD. We then describe research on associated illnesses, prodromes and age of onset. Next, we describe pathophysiological studies, including those using behavioral testing, neuroimaging and genetic/familial techniques. Finally, we conclude with a review of the pharmacological and psychotherapeutic treatment of PBD. Clinical Presentation Diagnosis, Phenomenology and Course Most investigators outside the USA, and some inside, use unmodified DSM-IV-TR diagnostic criteria and assessment techniques to assess bipolar disorder in children. These techniques ascertain whether distinct well-defined episodes of mania or hypomania are present. Using such techniques, researchers in Britain find that pre-adolescent mania is exceptionally rare (Harrington & Myatt, 2003). In the USA, researchers have recruited sizable samples of children meeting strict DSMIV-TR criteria. For example, the Course of Bipolar Youth (COBY) study in the USA recruited 263 children with clearly episodic bipolar illness (Axelson, Birmaher, Strober et al., 2006; Birmaher, Axelson, Strober et al., 2006). Of the children in the COBY study, 92% had euphoria and 84% had irritability, indicating that most youth with PBD have both symptoms. Over 2-year follow-up, patients (n = 152) had mixed mania or rapid cycling 29% of weeks, significantly more than BD adults (Birmaher, Axelson, Strober et al., 2006). In another sample of 90 children with clearly episodic BD, 86% had elevated mood, while 92% had irritability; also, 50% had a rapid cycling course, and periods of euthymia were identifiable but brief (Findling, Gracious, McNamara et al., 2001). However, in the USA, some recent PBD research has been shaped by case descriptions suggesting that BD presents differently in children than in adults. For example, in response to reports that children with PBD may have very rapid and complex mood cycles, Geller et al. developed a new semistructured interview for PBD (WASH-U-KSADS; Geller, Warner, Williams et al., 1998b; Geller, Williams, Zimerman et al., 1998c), and new conventions for describing cycling patterns. The WASH-U KSADS defines an episode as the entire duration of illness (rather than, as in DSM-IV-TR, a distinct symptomatic period) and defines cycles as mood changes lasting a minimum of 4 hours (Geller, Tillman, Craney et al., 2004b; Tillman & Geller, 2003). Also, given the overlap between symptoms of mania and attention deficit/hyperactivity disorder (ADHD), Geller et al. require that children with mania exhibit either elevated mood or grandiosity (Geller, Warner, Williams et al., 1998b,c). Using these techniques, Geller et al. described a BD sample (n = 86) in which most had mixed mania (88%), irritability (98%), elated mood (90%) and grandiosity (86%) as well as daily cycling (78%) and a mean of 3.5 ± 2.0 cycles/day. Similarly, Biederman and collaborators were influenced by case series suggesting that children with BD have irritability rather than euphoria, and that the severity of the irritability in PBD differentiates it from other illnesses. Thus, when assessing irritability, these investigators inquire about extremely Bipolar Disorder in Children and Adolescents Ellen Leibenluft and Daniel P. Dickstein 38 9781405145497_4_038.qxd 29/03/2008 02:52 PM Page 613 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

impairing and severe irritability (“super angry, grouchy, or cranky”). If such irritability is endorsed, then they consider the DSM-IV-TR episodicity criterion to be met, even if the irritability does not represent a distinct change from the patient’s usual level of function (Mick, Spencer, Wozniak et al., 2005). Using these techniques, Biederman et al. found that only 33% of children (n = 129) had euphoria while manic (considerably fewer than in the COBY study or Findling, Gracious, McNamara et al., 2001), while 92% had irritability (Biederman, Faraone, Wozniak et al., 2005a). Overall, four conclusions can be drawn from the literature on the phenomenology and course of PBD. First, descriptions of the “typical” bipolar child vary markedly across studies (Kowatch, Youngstrom, Danielyan et al., 2005b), probably because of different assessment techniques. The adoption of standard diagnostic procedures would facilitate future research, allowing comparisons among pediatric studies and, if adult procedures are used, with the rich clinical literature on adult BD. Second, data from the COBY study and Findling, Gracious, McNamara et al. (2001), obtained using diagnostic techniques comparable to those used in adults, contradict frequent statements in the literature that children with BD do not have euphoria, because almost all patients in these studies experienced euphoria, in addition to irritability (Axelson, Birmaher, Strober et al., 2006; Findling, Gracious, McNamara et al., 2001). On the other hand, several studies indicate that mixed states may be more common in youth versus adults with BD (Birmaher, Axelson, Strober et al., 2006; McElroy, Strakowski, West et al., 1997; Patel, DelBello, Keck et al., 2006). This developmental difference may reflect reporting bias (i.e., when assessing children, parents are also interviewed; irritability is more salient to others than to the patient themself), or the fact that children are unable to use coping strategies that hypomanic or manic adults often employ to avoid having their manic goals thwarted (e.g., skipping work/school, not going to bed). Third, studies support the contention that early-onset BD is associated with high episode frequency (Birmaher, Axelson, Strober et al., 2006; Findling, Gracious, McNamara et al., 2001; Lin, McInnis, Potash et al., 2006; Perlis, Miyahara, Marangell et al., 2004). However, the data do not indicate that children with BD have a non-episodic illness, because several investigators have recruited sizable samples of children with clearly defined episodes meeting DSM-IV duration criteria (Birmaher, Axelson, Strober et al., 2006; Dickstein, Nelson, McClure et al., 2007; Findling, Gracious, McNamara et al., 2001). Finally, consistent with the observation that children tend to cycle more frequently than adults with BD, all studies agree that PBD is a very impairing illness, leaving affected children symptomatic most of the time. Assessment and Differential Diagnosis Whereas investigators use a variety of techniques to diagnose PBD, there are advantages to using those that parallel the adult literature, albeit with developmentally appropriate thresholds. Thus, the interviewer should ask child and parent to identify episodes, lasting at least several days, during which the child had a distinct change in mood and became either euphoric, markedly irritable or depressed. Importantly, even an adult with classic euphoric mania is not euphoric 24 hours a day; therefore, symptoms present most of the day should be considered to be at threshold. Once episodes are identified, the interviewer should inquire whether the DSM-IV-TR “B” symptoms of mania or depression (e.g., sleep and activity changes, increased distractibility) occurred concurrent with mood changes. If the family cannot identify distinct episodes, then the appropriateness of the diagnosis of BD is called into question. Euphoria should exceed that which a typically developing child would experience in a very exciting situation, such as going to Disneyland, and true grandiosity should be distinguished from developmentally appropriate fantasy or oppositional behavior. Grandiosity or euphoria should represent a distinct change from the child’s usual level of function, and should occur at the same time as other symptoms of mania (e.g., decreased need for sleep, increased goal-directed activity). Decreased need for sleep should be differentiated from more typical insomnia, in which youth would prefer to sleep and may nap during the day. When manic symptoms are occurring, it is best for caretakers to bring the child to the clinic, to allow clinicians to observe behaviors first-hand. While the DSM-IV-TR diagnosis of Bipolar Disorder Not Otherwise Specified (BP-NOS) has been used in a number of clinical situations, it is best reserved for children who have distinct episodes that fail to meet the criteria for a manic episode because they are shorter than 4 days (see p. 615; Birmaher, Axelson, Strober et al., 2006). When assessing associated illnesses, clinicians should diagnose such illnesses only if symptoms are present when the patient is not in an acute mood episode (Axelson, Birmaher, Strober et al., 2006; Dickstein, Rich, Binstock et al., 2005b). For example, a child with BD should be diagnosed with ADHD only if ADHD symptoms are present when he or she is euthymic or subsyndromally ill. Conversely, for a symptom such as distractibility to count toward the diagnosis of mania in a child with ADHD, the distractibility must worsen significantly during the putative manic episode. Attempting to differentiate unipolar from bipolar depression is extremely important, because the treatment for the two conditions in adults differs. Careful interviewing to ascertain possible past hypomanic or manic symptoms is therefore essential. While a family history of BD is contributory, children should be treated on the basis of their own clinical presentation, not solely on the basis of family history. ADHD can be distinguished from mania in that children with ADHD alone do not have distinct episodes of mood change accompanied by DSM-IV-TR “B” criteria of mania. Similarly, BD youth with associated ADHD and oppositional defiant disorder (ODD) may have severe irritability, but irritability resulting from ADHD or ODD is distinct from manic irritability in that only the latter occurs, or worsens, during distinct time periods that last days or weeks and during which “B” mania criteria also occur. Therefore, using these techniques, the CHAPTER 38 614 9781405145497_4_038.qxd 29/03/2008 02:52 PM Page 614

BIPOLAR DISORDER 615 differentiation of ADHD, or ADHD and ODD, from BD is relatively straightforward. Whereas children with mania may have psychosis, it occurs concurrently with mood symptoms; psychosis in the absence of such symptoms suggests schizophrenia or schizoaffective disorder. Finally, adolescents should be assessed for substance abuse, because cocaine, amphetamine and a number of other illicit substances can cause symptoms resembling those of mania. Bipolar Spectrum Disorders Several investigators have suggested classification systems separating children who clearly meet DSM-IV criteria for BD from those whose nosological status is murky. For example, in addition to recruiting youth with DSM-IV-TR-defined BP-I (i.e., a disorder involving one or more definite manic or mixed episodes) and BP-II (i.e., recurrent major depressive episodes with hypomania episodes), the COBY study also recruited patients meeting criteria for BP-NOS, defined as having shorter episodes or fewer symptoms than required for BP-I or II (Birmaher, Axelson, Strober et al., 2006). Over 2- year follow-up, 25% of BP-NOS (n = 92) subjects, most of whom had episodes shorter than 4 days, converted to BP-I or II, and the BP-NOS subjects were ill (syndromally or subsyndromally) 65% of weeks. At the National Institute of Mental Health (NIMH) we have defined a phenotypic categorization system to facilitate research on the boundaries of PBD (Leibenluft, Charney, Towbin et al., 2003). The broad phenotype, or severe mood and behavioral dysregulation (SMD), operationalizes criteria for the children whose diagnosis is most controversial. Specifically, children with SMD have severe impairing irritability, characterized by baseline abnormal mood, noticeable to others, and developmentally inappropriate reactivity to negative emotional stimuli at least three times weekly. The irritability is persistent, rather than occurring in clearly defined episodes. Finally, children with SMD have ADHD-like symptoms (e.g., hyperactivity, distractibility, intrusiveness; Leibenluft, Charney, Towbin et al., 2003). Preliminary data indicate that SMD or severe chronic irritability in childhood is associated with major depressive disorder (MDD) in early adulthood (Leibenluft, Cohen, Gorrindo et al., 2006) and that the pathophysiology of narrow and broad phenotypes of PBD may differ (Rich, Schmajuk, Perez-Edgar et al., 2005, 2007). Associated Illnesses In all studies of PBD, associated illnesses are common, especially ADHD, anxiety disorders and ODD. Distractibility, hyperactivity and restlessness are symptoms of both ADHD and mania, and investigators consistently report that more than 70% of children with PBD also have ADHD (Axelson, Birmaher, Strober et al., 2006; Dickstein, Rich, Binstock et al., 2005b; Findling, Gracious, McNamara et al., 2001; Geller, Tillman, Craney et al., 2004b; Wozniak, Biederman, Kiely et al., 1995). It has been suggested that there is a familial association between ADHD and early-onset BD (Faraone, Biederman, Mennin et al., 1997). Rates of other associated illnesses in PBD vary widely. Those of ODD range from 46% (Axelson, Birmaher, Strober et al., 2006) to over 80% (Biederman, Faraone, Wozniak et al., 2005a), while those of conduct disorder (CD) range from 12% (Axelson, Birmaher, Strober et al., 2006) to 41% (Biederman, Faraone, Chu et al., 1999); higher rates are reported by investigators who view irritability as particularly characteristic of PBD. Rates of anxiety disorders range from 14% (Findling, Gracious, McNamara et al., 2001) to 76% (Harpold, Wozniak, Kwon et al., 2005). Substance abuse disorders have received little attention, although one study found that 32% of adolescents with BD (n = 57) also had a substance use disorder (Wilens, Biederman, Kwon et al., 2004). Age of Onset Two large epidemiological studies of BD adults report a median onset age of 18 (Christie, Burke, Regier et al., 1988) or 25 years (Kessler, Chiu, Demler et al., 2005). However, studies indicate that BD age of onset is not distributed normally, with two recent studies (Bellivier, Golmard, Rietschel et al., 2003; Lin, McInnis, Potash et al., 2006) each reporting three peaks of onset age. Early onset may be familial (Leboyer, Bellivier, McKeon et al., 1998; Lin, McInnis, Potash et al., 2006) and/or associated with a strong family history of BD (Bellivier, Golmard, Henry et al., 2001; Chengappa, Kupter, Frank et al., 2003; Johnson, Cohen, & Brook, 2000; Kennedy, Everitt, Boydell et al., 2005). Clinical Prodromes/Risk Factors Several longitudinal community-based studies have queried which childhood or adolescent diagnoses are associated with increased risk for later BD. One found that anxiety disorder at age 14 or 16 was associated with BD at age 22 (odds ratio [OR] 5.76; 95% confidence interval [CI], 1.44–22.95; Johnson, Cohen, Brook et al., 2000). Another found that mania at age 26 was associated with depression (OR 3.3; 95% CI, 1.2–9.2) and CD/ODD (OR 2.5; 95% CI, 1.1–5.4) at age 11–15, but not with ADHD (Kim-Cohen, Caspi, Moffitt et al., 2003); the association between adult mania and childhood anxiety was a statistical trend (OR 2.1; 95% CI, 0.9–4.8). Thus, epidemiological samples do not support the contention that ADHD is a risk factor for subsequent BD, although anxiety, depression and CD/ODD may be. Clinic-based followup studies of children with ADHD give somewhat more mixed results, although the bulk of the evidence is consistent with the epidemiological data (Biederman, Monuteaux, Mick et al., 2006; Hazell, Carr, Lewin et al., 2003; Mannuzza, Klein, Bessler et al., 1998). All eight clinical studies (n = 28–83) that followed depressed children into late adolescence or early adulthood find that prepubertal MDD is associated with increased risk for BD (Geller, Zimerman, Williams et al., 2001; Harrington, Fudge, Rutter et al., 1990; Kovacs, Akiskal, Gatsonis et al., 1994; McCauley, Myers, Mitchell et al., 1993; Rao, Ryan, Birmaher et al., 1995; Strober & Carlson, 1982; Strober, Lampert, Schmidt et al., 1993; Weissman, Wolk, Wickramaratne et al., 9781405145497_4_038.qxd 29/03/2008 02:52 PM Page 615

1999). However, the prevalence of BD ranged widely, perhaps because of small sample sizes. Positive family history, psychosis and rapid symptom onset may predict BD (Akiskal, Walker, Puzantian et al., 1983; Geller, Fox, & Clark, 1994; Strober & Carlson, 1982; Strober, Lampert, Schmidt et al., 1993). Preschoolers Controversy has surrounded recent American reports suggesting that BD may occur in preschool children (Dilsaver & Akiskal, 2004; Scheffer & Niskala Apps, 2004; Tumuluru, Weller, Fristad et al., 2003; Wilens, Biederman, Brown et al., 2002, 2003). These reports are of particular interest given data indicating a rapid rise in the percentage of US preschoolers receiving psychotropic medication (Zito, Safer, dosReis et al., 2000). The two largest samples of preschoolers diagnosed with BD (n = 44, Wilens, Biederman, Forkner et al., 2003; n = 31, Scheffer & Niskala Apps, 2004) report very high rates of ADHD (80–95%) and mixed states (i.e., co-occurring manic and depressive symptoms) in approximately 80%. Severe, impairing irritability is ubiquitous in preschoolers diagnosed with BD, and elated mood and grandiosity are also reported, with the caveat that the boundaries of these symptoms in controls or typical preschoolers with ADHD are not well defined, and many case descriptions of preschool mania do not identify the presence of distinct mood episodes. Preschoolers diagnosed with BD tend to have strongly positive family histories (e.g., 70%). Longitudinal follow-up of these children is essential to ascertain the extent to which they meet DSM-IVTR criteria for BD in adolescence and adulthood. Clinical Presentation: Summary The burgeoning research on BD in youth permits some preliminary conclusions about clinical presentation. Research groups who use adult assessment techniques find that children with BD have definable (albeit frequent) episodes that are typically characterized by euphoria mixed with irritability. Research groups using other techniques find either that euphoria is relatively rare, or that distinct episodes cannot be identified. Longitudinal studies will determine whether children ascertained using these alternative techniques develop into adults who fit neatly into the DSM-IV-TR category of BD, have bipolar spectrum illness, exhibit symptoms of another psychiatric illness or have a healthy outcome. As the number of genetic studies of PBD increase, it will be particularly important for investigators to specify precisely their phenotyping methods. Prevalence Cross-national epidemiological studies of adults find a lifetime prevalence rate of 1–3% for BD (Kessler, Chiu, Demler et al., 2005; Lasch, Weissman, Wickramaratne et al., 1990; ten Have, Vollebergh, Bijl et al., 2002; Weissman, Bland, Canino et al., 1996). In youth, community-based studies find low rates of BD. Lewinsohn et al. found that 1.1% of adolescents (n = 1507) met the criteria for BD, while 2.1% of a subset reassessed at age 24 (n = 893) did so (Lewinsohn, Klein, & Seeley, 1995, 2000; Lewinsohn, Seeley, Buckley et al., 2002). A second study (n = 1015, 9–13 years) found no manic cases and a 3-month prevalence of 0.10 ± 0.06% for hypomania (Costello, Angold, Burns et al., 1996), while a third (n = 717) found that the 12-month prevalence of BD was 1.9% in patients assessed at ages 14 ± 3 years and 16 ± 3 years ( Johnson, Cohen, & Brook, 2000). Finally, a twin sample enriched for ADHD (n = 1610, 7–18 years), found a BD prevalence of 0.2% (Reich, Neuman, Volk et al., 2005). Pathophysiology Behavioral Data Some behavioral paradigms assess traditional neuropsychological domains to determine a patient’s level of cognitive function or gain clues to pathophysiology. Such data indicate that youth with BD, like BD adults, have trait-related deficits in verbal memory and sustained attention (Doyle, Wilens, Kwon et al., 2005; McCarthy, Arrese, McGlashan et al., 2004; McClure, Treland, Snow et al., 2005a,b; Pavuluri, Schenkel, Aryal et al., 2006), although there are some negative studies of sustained attention (DelBello, Zimmerman, Mills et al., 2004b; McCarthy, Arrese, McGlashan et al., 2004; Robertson, Kutcher, & Lagace, 2003). Deficits have also been identified in working memory (Doyle, Wilens, Kwon et al., 2005; Pavuluri, Schenkel, Aryal et al., 2006) and mathematical skill (Lagace, Kutcher, & Robertson, 2003). Other behavioral studies are aimed at elucidating the neural circuitry mediating PBD. These paradigms assess emotional function (e.g., by measuring responses to reward, punishment or emotional faces) and find three specific deficits in BD youth. First, they have difficulty adapting their behavior to changes in reward contingencies (i.e., selecting a novel stimulus when the previously rewarded one begins to lose, rather than win, points; Dickstein, Treland, Snow et al., 2004; Gorrindo, Blair, Budhani et al., 2005; McClure, Treland, Snow et al., 2005b). This deficit is reminiscent of parents’ complaints that patients will not stop one activity and switch to another when appropriate. Deficits in response flexibility may be relevant to the pathophysiology of BD in that response inflexibility, present during euthymia, may be a forme fruste of the more marked response inflexibility seen when bipolar patients are acutely ill. That is, when patients with BD are depressed or manic, they have marked deficits in their ability to respond appropriately to emotional rewarding stimuli, as evidenced by the anhedonia present during depression and the hyperhedonia characteristic of mania. Second, youth with BD have difficulty labeling the emotion displayed on faces (McClure, Pope, Hoberman et al., 2003; McClure, Treland, Snow et al., 2005b). Deficits in face emotionly recognition may in turn be associated with these patients’ third abnormality (i.e., an inability to focus their attention when experiencing strong emotions; Rich, Schmajuk, Perez-Edgar CHAPTER 38 616 9781405145497_4_038.qxd 29/03/2008 02:52 PM Page 616

BIPOLAR DISORDER 617 et al., 2005). In patients with BD, the adverse impact of emotion on attention may contribute to their inability to label emotions properly. Future study will elucidate the neural circuitry of these deficits and possible associations between abnormal processing of emotional stimuli and core features of BD, such as switching mood states. Neuroimaging Structural Magnetic Resonance Imaging By far the most replicated structural magnetic resonance imaging (MRI) finding in PBD is significantly decreased amygdala volume compared to controls (Blumberg, Kaufman, Martin et al., 2003; Chang, Karchemskiy, Barnea-Goraly et al., 2005; DelBello, Zimmerman, Mills et al., 2004b; Dickstein, Milham, Nugent et al., 2005a). Because structural MRI studies of BD adults have reported both increased and unchanged amygdala volume (Altshuler, Bartzokis, Grieder et al., 1998; Altshuler, Bartzokis, Grieder et al., 2000; Brambilla, Harenski, Nicoletti et al., 2003; Pearlson, Barta, Powers et al., 1997; Strakowski, DelBello, Sax et al., 1999), decreased amygdala volume may represent a marker of childhood-onset BD, although further work is needed to determine the effects of development, gender, medications and comorbidity on amygdala size. Individual studies suggest possible differences between patients with PBD and controls in other brain regions (e.g., prefrontal cortex and striatum), but the literature is less consistent (for reviews see Blumberg, Charney, & Krystal, 2002; DelBello, Adler, & Strakowski, 2006a). Functional Magnetic Resonance Imaging Functional MRI (fMRI) allows investigators to quantify neural activation while subjects perform tasks engaging specific psychological processes. For example, investigators study the neural mechanisms mediating patients’ impulsivity and inattention by using fMRI tasks requiring motor inhibition or the ability to direct one’s attention away from distracting stimuli. These studies indicate striatal dysfunction in PBD. For example, Blumberg, Kaufman, Martin et al. (2003) found increased striatal activation in BD adolescents, compared to controls, during a Stroop paradigm of cognitive interference. Using a motor inhibition task, Leibenluft, Rich, Vinton et al. (2007) found that, compared to controls, PBD subjects had a reduced striatal “error signal” during failed motor inhibition (Leibenluft, Rich, Vinton et al., 2007), a deficit that might contribute to the patients’ inability to inhibit effectively. In an fMRI study building on the finding that children with PBD have face emotion identification deficits (McClure, Treland, Snow et al., 2005a), Rich, Vinton, Roberson-Nay et al. (2006) found that PBD subjects viewed neutral faces as more hostile and feared these faces more than did controls, and that these between-group differences in ratings were associated with increased amygdala and striatal activation in PBD versus control youth (Rich, Vinton, Roberson-Nay et al., 2006). Interestingly, whereas both children with PBD and those with anxiety disorders exhibit amygdala dysfunction during this fMRI task (relative to controls), the precise nature of that dysfunction varies among diagnoses (McClure, Monk, Nelson et al., 2007). It will be important for future work to compare the pathophysiology of PBD with that of other mood disorders, as well as with ADHD. Magnetic Resonance Spectroscopy Magnetic resonance spectroscopy (MRS) research in BD has focused on N-acetyl aspartate (NAA), an intraneuronal marker whose levels are decreased in neuropathology, and myoinositol (mI), an intracellular second messenger, thought to be overabundant in mania, whose levels are decreased by lithium (Moore, Bebchuk, Parrish et al., 1999; Silverstone, Wu, O’Donnell et al., 2002). Youth with familial BD (Chang, Adleman, Dienes et al., 2003), and adults with BD (Winsberg, Sachs, Tate et al., 2000), have significantly decreased NAA in the dorsolateral prefrontal cortex compared to controls and, in one study, lithium treatment was associated with increased NAA in a sample of adult controls and BP patients (Manji, Moore, & Chen, 2000; Moore, Bebchuk, Hasanat et al., 2000). In BD youth, olanzapine treatment resulted in significantly greater medial ventral prefrontal cortex NAA in remitters (n = 11, 58%) versus non-remitters (n = 8, 42%; DelBello, Cecil, Adler et al., 2006). Studies also indicate that PBD subjects have increased anterior cingulate coretex (ACC) mI compared to healthy controls or youth with intermittent explosive disorder (Davanzo, Yue, Thomas et al., 2003). Moreover, 7 days of lithium treatment significantly decreased mI in the ACC, and this decrease was more prominent in lithium responders than in nonresponders (Davanzo, Thomas, Yue et al., 2001). Together, these MRS studies suggest that PBD may be characterized by specific neurochemical alterations that respond to psychopharmacological treatment; future work in this area may ultimately inform such treatment. Diffusion Tensor Imaging Diffusion tensor imaging (DTI) is an emerging neuroimaging technique used to study the integrity of white matter tracts. A DTI study found that adolescents experiencing their first manic episode have less fractional anisotropy in the prefrontal cortex than controls, indicating disruption of white matter tracts (Adler, Adams, DelBello et al., 2006). Future DTI studies, in combination with MRS and structural and functional MRI studies, may allow investigators to define more precisely the causes of neural dysfunction in youth with PBD. Familial Risk and Genetics Children At Risk for Bipolar Disorder Compared to children without a first-degree relative with BD, those with such a relative are at an approximately 10-fold increased risk for BD (Hodgins, Faucher, Zarac et al., 2003; Kelsoe, 2003; Smoller & Finn, 2003). Twin studies suggest that the heritability of BD in adults is greater than 60%, with greater concordance for BD in monozygotic (60–70%) than dizygotic twins (20–30%) (Bertelsen, Harvald, & Hauge, 1977; Smoller & Finn, 2003). 9781405145497_4_038.qxd 29/03/2008 02:52 PM Page 617

The clinical status and neurocognitive function of children with a first-degree relative with BD are of considerable interest. Six studies with n > 50 have assessed children recruited through their parents with BD (Carlson & Weintraub, 1993; Chang, Steiner, & Ketter, 2000; Grigoroiu-Serbanescu, Christodorescu, Jipescu et al., 1989; Henin, Biederman, Mick et al., 2005; Hillegers, Reichart, Wals et al., 2005; Wals, Hillegers, Reichart et al., 2001). All find very high rates of psychopathology in these youth, with 44–63% meeting criteria for at least one DSM-IV-TR diagnosis, including ADHD, anxiety disorder, MDD and/or PBD. Molecular Genetics Currently, much research aims to identify genetic mechanisms underlying the increased familial risk for BD. Studies implicate a number of genetic regions in the transmission of adult BD (Hayden & Nurnberger, 2006; Kelsoe, 2003), with a locus on 6q21–q25 having perhaps the strongest evidence (McQueen, Devlin, Faraone et al., 2005). Candidate gene studies implicate the genes coding for brain-derived neurotrophic factor (BDNF) perhaps especially in rapid-cycling BD (Green, Raybould, Macgregor et al., 2006) and DAOA(G72)/G30. However, it is clear that all conclusions must be considered tentative in the absence of replication, because the genetics of BD are complex, with multiple genes involved and no one gene of main effect (Kelsoe, 2003). In addition, recent research indicates that there may be significant overlap between the genes conferring risk for BD and those implicated in schizophrenia (Craddock & Forty, 2006; Kelsoe, Spence, Loetscher et al., 2001). Other studies implicating dopaminergic genes (e.g., the dopamine transporter gene [DAT] on chromosome 5p; Keikhaee, Fadai, Sargolzaee et al., 2005) in both ADHD and BD may be of particular interest in PBD, given the strong association between ADHD and early-onset BD (Geller, Williams, Zimerman et al., 1998c; Wilens, Biederman, Forkner et al., 2003). In PBD, three genetic studies have been conducted, with one finding that the val66 allele of the BDNF gene on chromosome 11p was preferentially transmitted in PBD (n = 53 trios; Geller, Badner, Tillman et al., 2004a). Treatment Clinicians attempting to prescribe evidence-based treatment for PBD are confronted by a dearth of randomized placebocontrolled trials (RCTs) that precludes designating any psychopharmacological or psychotherapeutic treatment as having “strong” evidentiary support. RCTs are essential because placebo response rates range 10–50% in both acute and maintenance treatment trials of adult mania (Keck, Welge, McElroy et al., 2000a,b). In fact, fewer than 10 published placebo-controlled RCTs have been conducted in pediatric BD. Given the paucity of pediatric data, clinicians often rely on data from adult BD; hence, we summarize briefly the most relevant adult data. However, caution is urged in basing treatment on adult data, because youth sometimes respond differently from adults, as in major depression (Hazell, O’Connell, Heathcote et al., 1995). We discuss both psychopharmacological and psychotherapeutic approaches to PBD. Again, the lack of systematic data precludes firm recommendations as to how these two modalities should be prioritized, although it is likely that both modalities will ultimately prove to be important in the treatment of PBD. Our discussion focuses on children clearly meeting DSM-IV-TR criteria for bipolar disorder who, like adults with the illness, are typically too severely impaired to benefit from psychotherapeutic approaches without initial stabilization with pharmacotherapy. This is the population that is generally targeted in RCTs of medications. In children exhibiting the “broad phenotype” of PBD (see p. 615), whose major presenting problem is non-episodic irritability, psychosocial approaches, including interventions with the child, family and school environment, may be particularly important. Generally, clinicians should focus treatment on the most acute and disabling aspects of BD (e.g., acute mania, depression, psychosis, substance abuse, suicidality; Fig. 38.1). Later treatment addresses other problems (e.g., comorbid anxiety, ADHD, substance abuse, deficient social skills). Treatment decisions require collaboration among physicians, patients and families to identify target symptoms, educate about side-effects, and evaluate each treatment’s efficacy. Daily ratings of target symptoms by parents and/or patients allow treatment to be based upon prospective, rather than retrospective, data. Ideally, medication trials should be at least 6–8 weeks long, with only one new agent added at a time. However, this approach may not be feasible in acutely manic or psychotic patients. Physicians should assess continuously the need for each medication to determine whether any can be discontinued. Moreover, as noted above, symptoms do not typically resolve on medication alone; rather, comprehensive treatment usually requires both psychopharmacology and psychotherapy. Finally, treatment must develop in synchrony with a child’s illness, because acute and maintenance interventions differ. Psychopharmacology for Pediatric Bipolar Disorder Pharmacotherapy of Mania Mania should be the initial treatment focus in BD, because antimanic medications not only reduce manic symptoms but may also prevent activation secondary to antidepressants or psychostimulants. Currently available antimanic medications include: 1 Lithium; 2 Antiepileptic medications (AEDs, e.g. valproate and carbamazepine); and 3 Atypical antipsychotic medications (Fig. 38.1). In general, relatively weak support exists concerning the efficacy of any of these agents in PBD. This complicates efforts to select any one agent as a first-line treatment and again emphasizes the importance of thorough discussions with patients and their families concerning the available data on each agent’s efficacy and safety. In our discussion of each medication, we focus CHAPTER 38 618 9781405145497_4_038.qxd 29/03/2008 02:52 PM Page 618

on efficacy in BD, and only mention side-effects of particular interest; readers are also referred to other references for dosing guidelines and a more thorough discussion of sideeffects (Correll, Penzner, Parikh et al., 2006; Kowatch, Fristad, Birmaher et al., 2005a). Lithium Support for lithium’s utility in PBD is mixed. Among the three categories of medications typically used in PBD, efficacy data are stronger for lithium than for the AEDs but weaker than for the atypical antipsychotics. Similarly, in terms of safety data, lithium should probably also be placed in an intermediate category relative to these two other treatments. While lithium is the only medication with a US Food and Drug Administration (FDA) indication for the treatment of mania in patients as young as 12 years, this indication was granted at a time when FDA decisions for children were based largely on adult data. If lithium efficacy data were reviewed today, an FDA indication would not be granted because of the lack of two large placebo-controlled RCTs to demonstrate efficacy. Nevertheless, given the data from open trials, small studies, etc., and the extensive efficacy data in adults with BD, it is reasonable to prescribe lithium for youth with PBD. One small parallel-group placebo-controlled RCT examined the use of lithium in a heterogeneous group of 25 patients with substance abuse and either DSM-III-R BD, or MDD plus at least one feature associated with elevated risk for BD (e.g., BD in a first-degree relative; Geller, Cooper, Sun et al., 1998a). On global response ratings, 46.2% of patients responded to lithium versus 8.3% to placebo, but lithium had no specific benefit for mood symptoms (Geller, Cooper, Sun et al., 1998a). Another study (Kafantaris, Coletti, Dicker et al., 2004) used a discontinuation design, whereby acutely manic adolescents (n = 108) were treated with lithium openly before randomization to either continued lithium treatment or placebo. Consistent with other trials (Findling, Gracious, McNamara et al., 2001; Kafantaris, Coletti, Dicker et al., 2003; Kowatch, Suppes, Carmody et al., 2000), 42% of patients responded to open lithium treatment. However, the blinded discontinuation trial found no difference between lithium and placebo, with a relapse rate greater than 50% in both groups. In adults, there is robust evidence for the efficacy of lithium in adult acute mania (Bowden, Brugger, Swann et al., 1994, 2005; Small, Klapper, Milstein et al., 1991) and long-term prophylaxis (Bowden, Calabrese, Sachs et al., 2003). Longterm lithium treatment also appears to reduce suicide risk in adult BD (Cipriani, Pretty, Hawton et al., 2005; Goodwin, Fireman, Simon et al., 2003). Adult studies suggest that optimal lithium levels are between 0.6 and 1.0 mEq/L for acute mania and down to 0.4 mEq/L for maintenance treatment, but this has not been tested rigorously in youth (Gelenberg, Kane, Keller et al., 1989; Keller, Lavori, Kane et al., 1992; Stokes, Shamoian, Stoll et al., 1971). Of note, an MRS study showed that PBD youth (n = 9) had lower brain/serum lithium concentrations than BD adults (n = 18; Moore, Demopulos, Henry et al., 2002), suggesting that PBD BIPOLAR DISORDER 619 Fig. 38.1 Pediatric bipolar disorder psychopharmacology algorithm. After Kowatch et al. (2005a). Step 2: Assess and treat associated conditions • ADHD: Consider stimulants • Depression/anxiety: Consider SSRIs, lithium, lamotrigine, or atypical antipsychotic medications Re-evaluate response Step 1: Initiate antimanic agent First line*: lithium, valproate, carbamazepine, risperidone, olanzapine, quetiapine * 1st line agents based upon present data in pediatrican BD. Full response • Continue maintenance treatment (with medication-specific side-effect monitoring) • Proceed to Step 2 Partial response • Consider augmentation with second antimanic agent • Consider how associated/comorbid conditions are affecting response Non-response or not tolerated • Switch to other antimanic agent 9781405145497_4_038.qxd 29/03/2008 02:52 PM Page 619

patients, compared to adults with the illness, may require higher doses of lithium to achieve the same brain concentration of lithium. However, the clinical implications of this finding have not been studied systematically. Antiepileptic Drugs Relative to lithium or atypical antipsychotic medication, support for the therapeutic efficacy of the AEDs in PBD is weakest. However, because many AEDs are used in pediatric epilepsy, considerable data exist concerning long-term effects in children (de Silva, MacArdle, McGowan et al., 1996). The safety data for AEDs is generally strong, with the exception of questions regarding acute hepatic or pancreatic failure and possible adverse effects on female gonadal function (see below). Data from RCTs fail to demonstrate the benefits of AEDs in pediatric BPD. First, DelBello, Findling, Kushner et al. (2005) found no difference in reduction of manic symptoms in patients treated with topiramate (n = 29) versus placebo (n = 27), although secondary measures provided some suggestion of greater benefit from topiramate. Second, Wagner, Weller, Carlson et al. (2002) found no difference in efficacy between oxacarbazepine and placebo in more than 300 youth with PBD. While open-label trials, most of them small, document some evidence of benefit for carbamazepine, valproate or lamotrigine, in the absence of a placebo control these studies can provide only weak support for efficacy (Chang, Saxena, & Howe, 2006; Findling, McNamara, Youngstrom et al., 2005; Kowatch, Suppes, Carmody et al., 2000; Wagner, Weller, Carlson et al., 2002). In adult BD, acute antimanic efficacy has been demonstrated for valproate and a long-acting form of carbamazepine, leading to FDA indications for both in BD (Pope, McElroy, Keck et al., 1991, Weisler, Keck, Swann et al., 2005). Lamotrigine is another AED with an FDA indication for BD, although data suggest that it is more effective as a maintenance treatment, preventing depressive and manic relapse, than for acute mania (Bowden, Calabrese, Sachs et al., 2003; Bowden & Karren, 2006; Goodwin, Bowden, Calabrese et al., 2004; Ichim, Berk, & Brook, 2000). Valproate has a black-box FDA warning because of the possibility of acute life-threatening hepatic failure and pancreatitis (Grauso-Eby, Goldfarb, Feldman-Winter et al., 2003). Therefore, any patient taking valproate who develops the acute onset of nausea, vomiting or acute abdominal pain should have a prompt medical evaluation. In addition, irregular menses and polycystic ovary syndrome (i.e., polycystic ovarian morphology, increased serum testosterone or leutenizing hormone and irregular menses) may be associated with valproate use (McIntyre, Mancini, McCann et al., 2003). Regarding lamotrigine, the FDA issued a black-box warning for use in children younger than 16 because of the association between lamotrigine use and the development of two potentially life-threatening rashes, Stephens–Johnson syndrome and toxic epidermal necrolysis (TEN). More benign rashes are common, and a meta-analysis found that increased risk for such rashes was associated with patient age less than 12 years or coadministration of medications that inhibit hepatic metabolism (e.g., valproate; Calabrese, Sullivan, Bowden et al., 2002). Experts suggest that the risk of rash can be minimized by increasing the dose extremely slowly. If a rash occurs, the patient should be seen urgently by a physician to rule out Stephens– Johnson syndrome or TEN. Antipsychotic Medications Atypical antipsychotic agents have the strongest efficacy data in PBD; however, given the small number of trials, even here the evidence is moderate at best. Moreover, there are more safety concerns regarding this class of medications versus AEDs and probably also versus lithium. At present, two RCTs evaluate efficacy of quetiapine in PBD. First, a small 6-week double-blind placebo-controlled RCT in manic/mixed BD adolescents found that valproate plus quetiapine (n = 15) was significantly more effective than valproate plus placebo (n = 15) (DelBello, Schwiers, Rosenberg et al., 2002). The second showed similar efficacy for quetiapine (n = 25) versus valproate monotherapy (n = 25) (DelBello, Kowatch, Adler et al., 2006c), although quetiapine had advantages on secondary outcome measures. Additional open trials of atypical antipsychotics, including olanzapine, risperidone and aripiprazole, suggest efficacy (Barzman DelBello, Kowatch et al., 2004; Biederman, Mick, Hammerness et al., 2005b,c; Frazier, Meyer, Biederman et al., 1999, 2001; Pavuluri, Henry, Carbray et al., 2004b). Atypical antipsychotic medications that are FDA approved for the treatment of mania in adults include aripiprazole, olanzapine, quetiapine, risperidone and ziprasidone (Bowden, Grunze, Mullen et al., 2005; Calabrese, Keck, Macfadden et al., 2005; Hirschfeld, Keck, Kramer et al., 2004; Keck, Marcus, Tourkodimitris et al., 2003a,b; Khanna, Vieta, Lyons et al., 2005; McIntyre, Brecher, Paulsson et al., 2005; Tohen, Greil, Calabrese et al., 2005; Vieta, Bourin, Sanchez et al., 2005). A particular concern is the association of atypical antipsychotic medication with “metabolic syndrome” (i.e., extreme and rapid weight gain and endocrine abnormalities, including diabetes mellitus; Caballero, 2003). For example, BD youth gained an average of 5 kg in 8 weeks in an open-label study of olanzapine (Frazier, Biederman, Tohen et al., 2001). Patients should be monitored routinely for weight, height and body mass index, and possibly every 6 months for fasting glucose and lipid panel (Correll, Penzner, Parikh et al., 2006; Straker, Correll, Kramer-Ginsberg et al., 2005). Finally, for atypical antipsychotics, firm conclusions on the risk of tardive dyskinesia are not possible because of the lack of long-term data (Ghaemi, Hsu, Rosenquist et al., 2006). Pharmacotherapy of Depression or ADHD in PBD No RCT has targeted bipolar depression in children or adolescents. RCTs in adult bipolar depression demonstrate efficacy for lamotrigine, quetiapine and the combination of olanzapine plus fluoxetine (Altshuler, Suppes, Black et al., 2003; Calabrese, Bowden, Sachs et al., 1999, 2005; Tohen, Greil, Calabrese et al., 2005; Zornberg & Pope, 1993). Studies give conflicting CHAPTER 38 620 9781405145497_4_038.qxd 29/03/2008 02:52 PM Page 620

results as to whether selective serotonin reuptake inhibitor (SSRI) antidepressants or lithium are preferable in the treatment of adult bipolar depression (Amsterdam, Garcia-Espana, Fawcett et al., 1998; Nemeroff, Evans, Gyulai et al., 2001). No RCTs address this issue in youth. Of note, some evidence suggests that the risk of antidepressant-induced mania is higher in pre-pubertal children than in older adolescents or adults (Martin, Young, Leckman et al., 2004; Rey & Martin, 2006). One double-blind crossover RCT in children with PBD and ADHD found that, once mania remitted on valproate, the addition of amphetamine salts to valproate was more effective in reducing ADHD symptoms than was placebo plus valproate, and amphetamine salts did not exacerbate manic symptoms (n = 30) (Scheffer, Kowatch, Carmody et al., 2005). Thus, clinicians treating youth with BD and comorbid ADHD should treat the patient’s mania, and then consider psychostimulant treatment. Psychotherapy for Pediatric Bipolar Disorder While there are few trials of psychotherapy in youth or adults with BD, preliminary data suggest that any one of three types of psychotherapy, in combination with psychopharmacology, may reduce morbidity in BD. First, in families with BD offspring (n = 35), multifamily psycho-educational groups are associated with increased knowledge about BD and ability to obtain appropriate services (Fristad, Gavazzi, & Mackinaw-Koons, 2003). Second, in BD youth, open cognitive–behavioral therapy (n = 34) with family involvement was associated with significant symptom reduction (Pavuluri, Graczyk, Henry et al., 2004a). Third, in family-focused psycho-educational therapy (FFT), families participate in psycho-education, communication enhancement and problem-solving skills training. In PBD adolescents (n = 20), FFT resulted in a 12-month reduction of depression (38% improvement) and mania (46% improvement) ratings (Miklowitz, George, Axelson et al., 2004). In sum, these data suggest that the combination of psychotherapy plus psycho-pharmacotherapy may reduce the morbidity of BD in youth. However, there is a clear need for RCTs to document efficacy definitively. Conclusions We now know much more about PBD than we did as recently as a decade ago. Several conclusions can be drawn. BD occurs in children and adolescents, and when it does it tends to be severely impairing. Several studies implicate depression and anxiety as risk factors for PBD. The prevalence of BD in children and adolescents is 1% or less. PBD is associated with several neurocognitive deficits, consistent with functional and structural neuroimaging data implicating prefrontal cortex– amygdala–striatal circuitry in its pathophysiology. BD is clearly heritable, with high rates of psychopathology in the offspring of adults with BD. The hunt for susceptibility genes for BD is on, although the clearest findings at this time are that the genetics of the illness are likely to be complex, and there are likely to be susceptibility genes involved in the pathogenesis of both BD and schizophrenia. Finally, interest in the clinical presentation and pathophysiology of PBD has been accompanied by similar interest in its treatment. However, the rarity of the disease, the fact that the children tend to be severely impaired and the scarcity of trained investigators conspire to create a paucity of doubleblind placebo-controlled treatment trials. Because of the woefully limited data, strong recommendations cannot be made for any treatment. In the meantime, clinicians must strive to stay current with the literature while also extrapolating from the latest treatment research in adults with BD, bearing in mind that PBD patients do not respond to therapeutic interventions as “little adults.” Furthermore, the applicability of the adult treatment data is greatest to those children who have been assessed using techniques similar to those used in adults. It is to be hoped that the near future will bring great advances in the knowledge base about the treatment of PBD, just as the recent past has brought significant advances in the literature about the phenomenology and short-term course of the illness. References Adler, C. M., Adams, J., DelBello, M. P., Holland, S. K., Schmithorst, V., Levine, A., et al. (2006). Evidence of white matter pathology in bipolar disorder adolescents experiencing their first episode of mania: a diffusion tensor imaging study. American Journal of Psychiatry, 163, 322–324. Akiskal, H. S., Walker, P., Puzantian, V. R., King, D., Rosenthal, T. L., & Dranon, M. (1983). Bipolar outcome in the course of depressive illness. Phenomenologic, familial, and pharmacologic predictors. Journal of Affective Disorders, 5, 115–128. Altshuler, L., Suppes, T., Black, D., Nolen, W. A., Keck, P. E. Jr., Frye, M. A., et al. (2003). Impact of antidepressant discontinuation after acute bipolar depression remission on rates of depressive relapse at 1-year follow-up. American Journal of Psychiatry, 160, 1252–1262. Altshuler, L. L., Bartzokis, G., Grieder, T., Curran, J., Jimenez, T., Leight, K., et al. (2000). An MRI study of temporal lobe structures in men with bipolar disorder or schizophrenia. Biological Psychiatry, 48, 147–162. Altshuler, L. L., Bartzokis, G., Grieder, T., Curran, J., & Mintz, J. (1998). Amygdala enlargement in bipolar disorder and hippocampal reduction in schizophrenia: An MRI study demonstrating neuroanatomic specificity. Archives of General Psychiatry, 55, 663– 664. Amsterdam, J. D., Garcia-Espana, F., Fawcett, J., Quitkin, F. M., Reimherr, F. W., Rosenbaum, J. F., et al. (1998). Efficacy and safety of fluoxetine in treating bipolar II major depressive episode. Journal of Clinical Psychopharmacology, 18, 435–440. Axelson, D., Birmaher, B., Strober, M., Gill, M. K., Valeri, S., Chiappetta, L., et al. (2006). Phenomenology of children and adolescents with bipolar spectrum disorders. Archives of General Psychiatry, 63, 1139–1148. Barzman, D. H., DelBello, M. P., Kowatch, R. A., Gernert, B., Fleck, D. E., Pathak, S., et al. (2004). The effectiveness and tolerability of aripiprazole for pediatric bipolar disorders: A retrospective chart review. Journal of Child and Adolescent Psychopharmacology, 14, 593–600. Bellivier, F., Golmard, J. L., Henry, C., Leboyer, M., & Schurhoff, F. (2001). Admixture analysis of age at onset in bipolar I affective disorder. Archives of General Psychiatry, 58, 510–512. BIPOLAR DISORDER 621 9781405145497_4_038.qxd 29/03/2008 02:52 PM Page 621

Bellivier, F., Golmard, J. L., Rietschel, M., Schulze, T. G., Malafosse, A., Preisig, M., et al. (2003). Age at onset in bipolar I affective disorder: further evidence for three subgroups. American Journal of Psychiatry, 160, 999–1001. Bertelsen, A., Harvald, B., & Hauge, M. (1977). A Danish twin study of manic-depressive disorders. British Journal of Psychiatry, 130, 330–351. Biederman, J., Faraone, S. V., Chu, M. P., & Wozniak, J. (1999). Further evidence of a bidirectional overlap between juvenile mania and conduct disorder in children. Journal of the American Academy of Child and Adolescent Psychiatry, 38, 468–476. Biederman, J., Faraone, S. V., Wozniak, J., Mick, E., Kwon, A., Cayton, G. A., et al. (2005a). Clinical correlates of bipolar disorder in a large, referred sample of children and adolescents. Journal of Psychiatric Research, 39, 611–622. Biederman, J., Mick, E., Hammerness, P., Harpold, T., Aleardi, M., Dougherty, M., et al. (2005b). Open-label, 8-week trial of olanzapine and risperidone for the treatment of bipolar disorder in preschool-age children. Biological Psychiatry, 58, 589–594. Biederman, J., Mick, E., Wozniak, J., Aleardi, M., Spencer, T., & Faraone, S. V. (2005c). An open-label trial of risperidone in children and adolescents with bipolar disorder. Journal of Child and Adolescent Psychopharmacology, 15, 311–317. Biederman, J., Monuteaux, M. C., Mick, E., Spencer, T., Wilens, T. E., Silva, J. M., et al. (2006). Young adult outcome of attention deficit hyperactivity disorder: a controlled 10-year follow-up study. Psychological Medicine, 36, 167–179. Birmaher, B., Axelson, D., Strober, M., Gill, M. K., Valeri, S., Chiappetta, L., et al. (2006). Clinical course of children and adolescents with bipolar spectrum disorders. Archives of General Psychiatry, 63, 175–183. Blumberg, H. P., Charney, D. S., & Krystal, J. H. (2002). Frontotemporal neural systems in bipolar disorder. Seminars in Clinical Neuropsychiatry, 7, 243–254. Blumberg, H. P., Kaufman, J., Martin, A., Whiteman, R., Zhang, J. H., Gore, J. C., et al. (2003). Amygdala and hippocampal volumes in adolescents and adults with bipolar disorder. Archives of General Psychiatry, 60, 1201–1208. Bowden, C. L., Brugger, A. M., Swann, A. C., Calabrese, J. R., Janicak, P. G., Petty, F., et al. (1994). Efficacy of divalproex vs lithium and placebo in the treatment of mania. The Depakote Mania Study Group. Journal of the American Medical Association, 271, 918–924. Bowden, C. L., Calabrese, J. R., Sachs, G., Yatham, L. N., Asghar, S. A., Hompland, M., et al. (2003). A placebo-controlled 18- month trial of lamotrigine and lithium maintenance treatment in recently manic or hypomanic patients with bipolar I disorder. Archives of General Psychiatry, 60, 392–400. Bowden, C. L., Grunze, H., Mullen, J., Brecher, M., Paulsson, B., Jones, M., et al. (2005). A randomized, double-blind, placebo-controlled efficacy and safety study of quetiapine or lithium as monotherapy for mania in bipolar disorder. Journal of Clinical Psychiatry, 66, 111–121. Bowden, C. L., & Karren, N. U. (2006). Anticonvulsants in bipolar disorder. Australian and New Zealand Journal of Psychiatry, 40, 386–393. Brambilla, P., Harenski, K., Nicoletti, M., Sassi, R. B., Mallinger, A. G., Frank, E., et al. (2003). MRI investigation of temporal lobe structures in bipolar patients. Journal of Psychiatric Research, 37, 287–295. Caballero, E. (2003). Obesity, diabetes, and the metabolic syndrome: new challenges in antipsychotic drug therapy. CNS Spectrums, 8, 19–22. Calabrese, J. R., Bowden, C. L., Sachs, G. S., Ascher, J. A., Monaghan, E., & Rudd, G. D. (1999). A double-blind placebocontrolled study of lamotrigine monotherapy in outpatients with bipolar I depression. Lamictal 602 Study Group. Journal of Clinical Psychiatry, 60, 79–88. Calabrese, J. R., Keck, P. E. Jr., Macfadden, W., Minkwitz, M., Ketter, T. A., Weisler, R. H., et al. (2005). A randomized, double-blind, placebo-controlled trial of quetiapine in the treatment of bipolar I or II depression. American Journal of Psychiatry, 162, 1351– 1360. Calabrese, J. R., Sullivan, J. R., Bowden, C. L., Suppes, T., Goldberg, J. F., Sachs, G. S., et al. (2002). Rash in multicenter trials of lamotrigine in mood disorders: Clinical relevance and management. Journal of Clinical Psychiatry, 63, 1012–1019. Carlson, G. A., & Weintraub, S. (1993). Childhood behavior problems and bipolar disorder – relationship or coincidence? Journal of Affective Disorders, 28, 143–153. Chang, K., Adleman, N., Dienes, K., Barnea-Goraly, N., Reiss, A., & Ketter, T. (2003). Decreased N-acetylaspartate in children with familial bipolar disorder. Biological Psychiatry, 53, 1059–1065. Chang, K., Karchemskiy, A., Barnea-Goraly, N., Garrett, A., Simeonova, D. I., & Reiss, A. (2005). Reduced amygdalar gray matter volume in familial pediatric bipolar disorder. Journal of the American Academy of Child and Adolescent Psychiatry, 44, 565– 573. Chang, K., Saxena, K., & Howe, M. (2006). An open-label study of lamotrigine adjunct or monotherapy for the treatment of adolescents with bipolar depression. Journal of the American Academy of Child and Adolescent Psychiatry, 45, 298–304. Chang, K. D., Steiner, H., & Ketter, T. A. (2000). Psychiatric phenomenology of child and adolescent bipolar offspring. Journal of the American Academy of Child and Adolescent Psychiatry, 39, 453–460. Chengappa, K. N., Kupfer, D. J., Frank, E., Houck, P. R., Grochocinski, V. J., Cluss, P. A., et al. (2003). Relationship of birth cohort and early age at onset of illness in a bipolar disorder case registry. American Journal of Psychiatry, 160, 1636–1642. Christie, K. A., Burke, J. D. Jr., Regier, D. A., Rae, D. S., Boyd, J. H., & Locke, B. Z. (1988). Epidemiologic evidence for early onset of mental disorders and higher risk of drug abuse in young adults. American Journal of Psychiatry, 145, 971–975. Cipriani, A., Pretty, H., Hawton, K., & Geddes, J. R. (2005). Lithium in the prevention of suicidal behavior and all-cause mortality in patients with mood disorders: A systematic review of randomized trials. American Journal of Psychiatry, 162, 1805–1819. Correll, C. U., Penzner, J. B., Parikh, U. H., Mughal, T., Javed, T., Carbon, M., et al. (2006). Recognizing and monitoring adverse events of second-generation antipsychotics in children and adolescents. Child and Adolescent Psychiatric Clinics of North America, 15, 177–206. Costello, E. J., Angold, A., Burns, B. J., Erkanli, A., Stangl, D. K., & Tweed, D. L. (1996). The Great Smoky Mountains Study of Youth. Functional impairment and serious emotional disturbance. Archives of General Psychiatry, 53, 1137–1143. Craddock, N., & Forty, L. (2006). Genetics of affective (mood) disorders. European Journal of Human Genetics, 14, 660–668. Davanzo, P., Thomas, M. A., Yue, K., Oshiro, T., Belin, T., Strober, M., et al. (2001). Decreased anterior cingulate myo-inositol/ creatine spectroscopy resonance with lithium treatment in children with bipolar disorder. Neuropsychopharmacology, 24, 359–369. Davanzo, P., Yue, K., Thomas, M. A., Belin, T., Mintz, J., Venkatraman, T. N., et al. (2003). Proton magnetic resonance spectroscopy of bipolar disorder versus intermittent explosive disorder in children and adolescents. American Journal of Psychiatry, 160, 1442–1452. de Silva, M., MacArdle, B., McGowan, M., Hughes, E., Stewart, J., Neville, B. G., et al. (1996). Randomised comparative monotherapy trial of phenobarbitone, phenytoin, carbamazepine, or sodium valproate for newly diagnosed childhood epilepsy. Lancet, 347, 709– 713. DelBello, M. P., Adler, C. M., Amicone, J., Mills, N. P., Shear, P. K., Warner, J., et al. (2004a). Parametric neurocognitive task design: CHAPTER 38 622 9781405145497_4_038.qxd 29/03/2008 02:52 PM Page 622

a pilot study of sustained attention in adolescents with bipolar disorder. Journal of Affective Disorders, 82 (Supplement 1), S79– S88. DelBello, M. P., Adler, C. M., & Strakowski, S. M. (2006a). The neurophysiology of childhood and adolescent bipolar disorder. CNS Spectrums, 11, 298–311. DelBello, M. P., Cecil, K. M., Adler, C. M., Daniels, J. P., & Strakowski, S. M. (2006b). Neurochemical effects of olanzapine in first-hospitalization manic adolescents: A proton magnetic resonance spectroscopy study. Neuropsychopharmacology, 31, 1264– 1273. DelBello, M. P., Findling, R. L., Kushner, S., Wang, D., Olson, W. H., Capece, J. A., Fazzio, L., Rosenthal, N. R. (2005). A pilot controlled trial of topiramate for mania in children and adolescents with bipolar disorder. Journal of the American Academy of Child & Adolescent Psychiatry, 44, 539–547. DelBello, M. P., Kowatch, R. A., Adler, C. M., Stanford, K. E., Welge, J. A., Barzman, D. H., et al. (2006c). A double-blind randomized pilot study comparing quetiapine and divalproex for adolescent mania. Journal of the American Academy of Child and Adolescent Psychiatry, 45, 305–313. DelBello, M. P., Schwiers, M. L., Rosenberg, H. L., & Strakowski, S. M. (2002). A double-blind, randomized, placebo-controlled study of quetiapine as adjunctive treatment for adolescent mania. Journal of the American Academy of Child and Adolescent Psychiatry, 41, 1216–1223. DelBello, M. P., Zimmerman, M. E., Mills, N. P., Getz, G. E., & Strakowski, S. M. (2004b). Magnetic resonance imaging analysis of amygdala and other subcortical brain regions in adolescents with bipolar disorder. Bipolar Disorders, 6, 43–52. Dickstein, D. P., Milham, M. P., Nugent, A. C., Drevets, W. C., Charney, D. S., Pine, D. S., et al. (2005a). Frontotemporal alterations in pediatric bipolar disorder: results of a voxel-based morphometry study. Archives of General Psychiatry, 62, 734–741. Dickstein, D. P., Nelson, E. E., McClure, E. B., Grimley, M. E., Knopf, L., Brotman, M. A., et al. (2007). Cognitive flexibility in phenotypes of pediatric bipolar disorder. Journal of the American Academy of Child and Adolescent Psychiatry, 46, 341–355. Dickstein, D. P., Rich, B. A., Binstock, A. B., Pradella, A. G., Towbin, K. E., Pine, D. S., et al. (2005b). Comorbid anxiety in phenotypes of pediatric bipolar disorder. Journal of Child and Adolescent Psychopharmacology, 15, 534–548. Dickstein, D. P., Treland, J. E., Snow, J., McClure, E. B., Mehta, M. S., Towbin, K. E., et al. (2004). Neuropsychological performance in pediatric bipolar disorder. Biological Psychiatry, 55, 32–39. Dilsaver, S. C., & Akiskal, H. S. (2004). Preschool-onset mania: Incidence, phenomenology and family history. Journal of Affective Disorders, 82 (Supplement 1), S35–S43. Doyle, A. E., Wilens, T. E., Kwon, A., Seidman, L. J., Faraone, S. V., Fried, R., et al. (2005). Neuropsychological functioning in youth with bipolar disorder. Biological Psychiatry, 58, 540–548. Faraone, S. V., Biederman, J., Mennin, D., Wozniak, J., & Spencer, T. (1997). Attention-deficit hyperactivity disorder with bipolar disorder: A familial subtype? Journal of the American Academy of Child and Adolescent Psychiatry, 36, 1378–1387. Findling, R. L., Gracious, B. L., McNamara, N. K., Youngstrom, E. A., Demeter, C. A., Branicky, L. A., et al. (2001). Rapid, continuous cycling and psychiatric co-morbidity in pediatric bipolar I disorder. Bipolar Disorders, 3, 202–210. Findling, R. L., McNamara, N. K., Youngstrom, E. A., Stansbrey, R., Gracious, B. L., Reed, M. D., et al. (2005). Double-blind 18-month trial of lithium versus divalproex maintenance treatment in pediatric bipolar disorder. Journal of the American Academy of Child and Adolescent Psychiatry, 44, 409–417. Frazier, J. A., Biederman, J., Tohen, M., Feldman, P. D., Jacobs, T. G., Toma, V., et al. (2001). A prospective open-label treatment trial of olanzapine monotherapy in children and adolescents with bipolar disorder. Journal of Child and Adolescent Psychopharmacology, 11, 239–250. Frazier, J. A., Meyer, M. C., Biederman, J., Wozniak, J., Wilens, T. E., Spencer, T. J., et al. (1999). Risperidone treatment for juvenile bipolar disorder: A retrospective chart review. Journal of the American Academy of Child and Adolescent Psychiatry, 38, 960– 965. Fristad, M. A., Gavazzi, S. M., & Mackinaw-Koons, B. (2003). Family psychoeducation: An adjunctive intervention for children with bipolar disorder. Biological Psychiatry, 53, 1000–1008. Gelenberg, A. J., Kane, J. M., Keller, M. B., Lavori, P., Rosenbaum, J. F., Cole, K., et al. (1989). Comparison of standard and low serum levels of lithium for maintenance treatment of bipolar disorder. New England Journal of Medicine, 321, 1489–1493. Geller, B., Badner, J. A., Tillman, R., Christian, S. L., Bolhofner, K., & Cook, E. H. Jr. (2004a). Linkage disequilibrium of the brainderived neurotrophic factor Val66Met polymorphism in children with a prepubertal and early adolescent bipolar disorder phenotype. American Journal of Psychiatry, 161, 1698–1700. Geller, B., Cooper, T. B., Sun, K., Zimerman, B., Frazier, J., Williams, M., et al. (1998a). Double-blind and placebo-controlled study of lithium for adolescent bipolar disorders with secondary substance dependency. Journal of the American Academy of Child and Adolescent Psychiatry, 37, 171–178. Geller, B., Fox, L. W., & Clark, K. A. (1994). Rate and predictors of prepubertal bipolarity during follow-up of 6- to 12-year-old depressed children. Journal of the American Academy of Child and Adolescent Psychiatry, 33, 461–468. Geller, B., Tillman, R., Craney, J. L., & Bolhofner, K. (2004b). Fouryear prospective outcome and natural history of mania in children with a prepubertal and early adolescent bipolar disorder phenotype. Archives of General Psychiatry, 61, 459–467. Geller, B., Warner, K., Williams, M., & Zimerman, B. (1998b). Prepubertal and young adolescent bipolarity versus ADHD: Assessment and validity using the WASH-U-KSADS, CBCL and TRF. Journal of Affective Disorders, 51, 93–100. Geller, B., Williams, M., Zimerman, B., Frazier, J., Beringer, L., & Warner, K. L. (1998c). Prepubertal and early adolescent bipolarity differentiate from ADHD by manic symptoms, grandiose delusions, ultra-rapid or ultradian cycling. Journal of Affective Disorders, 51, 81–91. Geller, B., Zimerman, B., Williams, M., Bolhofner, K., & Craney, J. L. (2001). Bipolar disorder at prospective follow-up of adults who had prepubertal major depressive disorder. American Journal of Psychiatry, 158, 125–127. Ghaemi, S. N., Hsu, D. J., Rosenquist, K. J., Pardo, T. B., & Goodwin, F. K. (2006). Extrapyramidal side effects with atypical neuroleptics in bipolar disorder. Progress in NeuroPsychopharmacology and Biological Psychiatry, 30, 209–213. Goodwin, F. K., Fireman, B., Simon, G. E., Hunkeler, E. M., Lee, J., & Revicki, D. (2003). Suicide risk in bipolar disorder during treatment with lithium and divalproex. JAMA, 290, 1467–1473. Goodwin, G. M., Bowden, C. L., Calabrese, J. R., Grunze, H., Kasper, S., White, R., et al. (2004). A pooled analysis of 2 placebocontrolled 18-month trials of lamotrigine and lithium maintenance in bipolar I disorder. Journal of Clinical Psychiatry, 65, 432– 441. Gorrindo, T., Blair, R. J., Budhani, S., Dickstein, D. P., Pine, D. S., & Leibenluft, E. (2005). Deficits on a probabilistic responsereversal task in patients with pediatric bipolar disorder. American Journal of Psychiatry, 162, 1975–1977. Grauso-Eby, N. L., Goldfarb, O., Feldman-Winter, L. B., & McAbee, G. N. (2003). Acute pancreatitis in children from valproic acid: Case series and review. Pediatric Neurology, 28, 145–148. Green, E. K., Raybould, R., Macgregor, S., Hyde, S., Young, A. H., O’Donovan, M. C., et al. (2006). Genetic variation of brain-derived neurotrophic factor (BDNF) in bipolar disorder: Case–control BIPOLAR DISORDER 623 9781405145497_4_038.qxd 29/03/2008 02:52 PM Page 623

study of over 3000 individuals from the UK. British Journal of Psychiatry, 188, 21–25. Grigoroiu-Serbanescu, M., Christodorescu, D., Jipescu, I., Totoescu, A., Marinescu, E., & Ardelean, V. (1989). Psychopathology in children aged 10–17 of bipolar parents: psychopathology rate and correlates of the severity of the psychopathology. Journal of Affective Disorders, 16, 167–179. Harpold, T. L., Wozniak, J., Kwon, A., Gilbert, J., Wood, J., Smith, L., et al. (2005). Examining the association between pediatric bipolar disorder and anxiety disorders in psychiatrically referred children and adolescents. Journal of Affective Disorders, 88, 19– 26. Harrington, R., Fudge, H., Rutter, M., Pickles, A., & Hill, J. (1990). Adult outcomes of childhood and adolescent depression. I. Psychiatric status. Archives of General Psychiatry, 47, 465–473. Harrington, R. & Myatt, T. (2003). Is preadolescent mania the same condition as adult mania? A British perspective. Biological Psychiatry, 53, 961–969. Hayden, E. P., & Nurnberger, J. I. Jr. (2006). Molecular genetics of bipolar disorder. Genes, Brain, and Behavior, 5, 85–95. Hazell, P., O’Connell, D., Heathcote, D., Robertson, J., & Henry, D. (1995). Efficacy of tricyclic drugs in treating child and adolescent depression: a meta-analysis. British Medical Journal, 310, 897– 901. Hazell, P. L., Carr, V., Lewin, T. J., & Sly, K. (2003). Manic symptoms in young males with ADHD predict functioning but not diagnosis after 6 years. Journal of the American Academy of Child and Adolescent Psychiatry, 42, 552–560. Henin, A., Biederman, J., Mick, E., Sachs, G. S., Hirshfeld-Becker, D. R., Siegel, R. S., et al. (2005). Psychopathology in the offspring of parents with bipolar disorder: A controlled study. Biological Psychiatry, 58, 554–561. Hillegers, M. H., Reichart, C. G., Wals, M., Verhulst, F. C., Ormel, J., & Nolen, W. A. (2005). Five-year prospective outcome of psychopathology in the adolescent offspring of bipolar parents. Bipolar Disorders, 7, 344–350. Hirschfeld, R. M., Keck, P. E. Jr., Kramer, M., Karcher, K., Canuso, C., Eerdekens, M., et al. (2004). Rapid antimanic effect of risperidone monotherapy: A 3-week multicenter, double-blind, placebo-controlled trial. American Journal of Psychiatry, 161, 1057–1065. Hodgins, S., Faucher, B., Zarac, A., & Ellenbogen, M. (2002). Children of parents with bipolar disorder. A population at high risk for major affective disorders. Child and Adolescent Psychiatric Clinics of North America, 11, 533–553, ix. Ichim, L., Berk, M., & Brook, S. (2000). Lamotrigine compared with lithium in mania: a double-blind randomized controlled trial. Annals of Clinical Psychiatry, 12, 5–10. Johnson, J. G., Cohen, P., & Brook, J. S. (2000). Associations between bipolar disorder and other psychiatric disorders during adolescence and early adulthood: A community-based longitudinal investigation. American Journal of Psychiatry, 157, 1679–1681. Kafantaris, V., Coletti, D. J., Dicker, R., Padula, G., Kane, J. M. (2003). Lithium treatment of acute mania in adolescents: a large open trial. Journal of the American Academy of Child & Adolescent Psychiatry, 42, 1038–1045. Kafantaris, V., Coletti, D. J., Dicker, R., Padula, G., Pleak, R. R., Alvir, J. M. (2004). Lithium treatment of acute mania in adolescents: a placebo-controlled discontinuation study. Journal of the American Academy of Child & Adolescent Psychiatry, 43, 984–993. Keck, P. E. Jr., Marcus, R., Tourkodimitris, S., Ali, M., Liebeskind, A., Saha, A., et al. (2003a). A placebo-controlled, double-blind study of the efficacy and safety of aripiprazole in patients with acute bipolar mania. American Journal of Psychiatry, 160, 1651–1658. Keck, P. E. Jr., Versiani, M., Potkin, S., West, S. A., Giller, E., & Ice, K. (2003b). Ziprasidone in the treatment of acute bipolar mania: A three-week, placebo-controlled, double-blind, randomized trial. American Journal of Psychiatry, 160, 741–748. Keck, P. E. Jr., Welge, J. A., McElroy, S. L., Arnold, L. M., & Strakowski, S. M. (2000a). Placebo effect in randomized, controlled studies of acute bipolar mania and depression. Biological Psychiatry, 47, 748–755. Keck, P. E. Jr., Welge, J. A., Strakowski, S. M., Arnold, L. M., & McElroy, S. L. (2000b). Placebo effect in randomized, controlled maintenance studies of patients with bipolar disorder. Biological Psychiatry, 47, 756–761. Keikhaee, M. R., Fadai, F., Sargolzaee, M. R., Javanbakht, A., Najmabadi, H., & Ohadi, M. (2005). Association analysis of the dopamine transporter (DAT1)-67A/T polymorphism in bipolar disorder. American Journal of Medical Genetics. B Neuropsychiatric Genetics, 135, 47–49. Keller, M. B., Lavori, P. W., Kane, J. M., Gelenberg, A. J., Rosenbaum, J. F., Walzer, E. A., et al. (1992). Subsyndromal symptoms in bipolar disorder: A comparison of standard and low serum levels of lithium. Archives of General Psychiatry, 49, 371– 376. Kelsoe, J. R. (2003). Arguments for the genetic basis of the bipolar spectrum. Journal of Affective Disorders, 73, 183–197. Kelsoe, J. R., Spence, M. A., Loetscher, E., Foguet, M., Sadovnick, A. D., Remick, R. A., et al. (2001). A genome survey indicates a possible susceptibility locus for bipolar disorder on chromosome 22. Proceedings of the National Academy of Sciences of the USA, 98, 585–590. Kennedy, N., Everitt, B., Boydell, J., Van Os, J., Jones, P. B., & Murray, R. M. (2005). Incidence and distribution of first-episode mania by age: Results from a 35-year study. Psychological Medicine, 35, 855–863. Kessler, R. C., Chiu, W. T., Demler, O., Merikangas, K. R., & Walters, E. E. (2005). Prevalence, severity, and comorbidity of 12-month DSM-IV disorders in the National Comorbidity Survey Replication. Archives of General Psychiatry, 62, 617–627. Khanna, S., Vieta, E., Lyons, B., Grossman, F., Eerdekens, M., & Kramer, M. (2005). Risperidone in the treatment of acute mania: Double-blind, placebo-controlled study. British Journal of Psychiatry, 187, 229–234. Kim-Cohen, J., Caspi, A., Moffitt, T. E., Harrington, H., Milne, B. J., & Poulton, R. (2003). Prior juvenile diagnoses in adults with mental disorder: developmental follow-back of a prospectivelongitudinal cohort. Archives of General Psychiatry, 60, 709–717. Kovacs, M., Akiskal, H. S., Gatsonis, C., & Parrone, P. L. (1994). Childhood-onset dysthymic disorder: Clinical features and prospective naturalistic outcome. Archives of General Psychiatry, 51, 365– 374. Kowatch, R. A., Fristad, M., Birmaher, B., Wagner, K. D., Findling, R. L., & Hellander, M. (2005a). Treatment guidelines for children and adolescents with bipolar disorder. Journal of the American Academy of Child and Adolescent Psychiatry, 44, 213–235. Kowatch, R. A., Suppes, T., Carmody, T. J., Bucci, J. P., Hume, J. H., Kromelis, M., et al. (2000). Effect size of lithium, divalproex sodium, and carbamazepine in children and adolescents with bipolar disorder. Journal of the American Academy of Child and Adolescent Psychiatry, 39, 713–720. Kowatch, R. A., Youngstrom, E. A., Danielyan, A., & Findling, R. L. (2005b). Review and meta-analysis of the phenomenology and clinical characteristics of mania in children and adolescents. Bipolar Disorders, 7, 483–496. Lagace, D. C., Kutcher, S. P., & Robertson, H. A. (2003). Mathematics deficits in adolescents with bipolar I disorder. American Journal of Psychiatry, 160, 100–104. Lasch, K., Weissman, M., Wickramaratne, P., & Bruce, M. L. (1990). Birth-cohort changes in the rates of mania. Psychiatry Research, 33, 31–37. Leboyer, M., Bellivier, F., McKeon, P., Albus, M., Borrman, M., Perez-Diaz, F., et al. (1998). Age at onset and gender resemblance in bipolar siblings. Psychiatry Research, 81, 125–131. CHAPTER 38 624 9781405145497_4_038.qxd 29/03/2008 02:52 PM Page 624

Leibenluft, E., Charney, D. S., Towbin, K. E., Bhangoo, R. K., & Pine, D. S. (2003). Defining clinical phenotypes of juvenile mania. American Journal of Psychiatry, 160, 430–437. Leibenluft, E., Cohen, P., Gorrindo, T., Brook, J. S., & Pine, D. S. (2006). Chronic vs. episodic irritability in youth: A community-based, longitudinal study of clinical and diagnostic associations. Journal of Child and Adolescent Psychopharmacology, 16, 456–466. Leibenluft, E., Rich, B. A., Vinton, D. T., Nelson, E. E., Fromm, S. J., Berghorst, L. H., et al. (2007). Neural circuitry engaged during unsuccessful motor inhibition in pediatric bipolar disorder. American Journal of Psychiatry, 164, 52–60. Lewinsohn, P. M., Klein, D. N., & Seeley, J. R. (1995). Bipolar disorders in a community sample of older adolescents: Prevalence, phenomenology, comorbidity, and course. Journal of the American Academy of Child and Adolescent Psychiatry, 34, 454–463. Lewinsohn, P. M., Klein, D. N., & Seeley, J. R. (2000). Bipolar disorder during adolescence and young adulthood in a community sample. Bipolar Disorders, 2, 281–293. Lewinsohn, P. M., Seeley, J. R., Buckley, M. E., & Klein, D. N. (2002). Bipolar disorder in adolescence and young adulthood. Child and Adolescent Psychiatric Clinics of North America, 11, 461–75, vii. Lin, P. I., McInnis, M. G., Potash, J. B., Willour, V., MacKinnon, D. F., DePaulo, J. R., et al. (2006). Clinical correlates and familial aggregation of age at onset in bipolar disorder. American Journal of Psychiatry, 163, 240–246. Manji, H. K., Moore, G. J., & Chen, G. (2000). Lithium upregulates the cytoprotective protein Bcl–2 in the CNS in vivo: A role for neurotrophic and neuroprotective effects in manic depressive illness. Journal of Clinical Psychiatry, 61, 82–96. Mannuzza, S., Klein, R. G., Bessler, A., Malloy, P., & LaPadula, M. (1998). Adult psychiatric status of hyperactive boys grown up. American Journal of Psychiatry, 155, 493–498. Martin, A., Young, C., Leckman, J. F., Mukonoweshuro, C., Rosenheck, R., & Leslie, D. (2004). Age effects on antidepressantinduced manic conversion. Archives of Pediatrics and Adolescent Medicine, 158, 773–780. McCarthy, J., Arrese, D., McGlashan, A., Rappaport, B., Kraseski, K., Conway, F., et al. (2004). Sustained attention and visual processing speed in children and adolescents with bipolar disorder and other psychiatric disorders. Psychological Reports, 95, 39–47. McCauley, E., Myers, K., Mitchell, J., Calderon, R., Schloredt, K., & Treder, R. (1993). Depression in young people: initial presentation and clinical course. Journal of the American Academy of Child and Adolescent Psychiatry, 32, 714–722. McClure, E. B., Monk, C. S., Nelson, E. E., Parrish, J. M., Adler, A., Blair, R. J. R., et al. (2007). Abnormal attention modulation of fear circuit function in pediatric generalized anxiety disorder. Archives of General Psychiatry, 64, 97–106. McClure, E. B., Pope, K., Hoberman, A. J., Pine, D. S., & Leibenluft, E. (2003). Facial expression recognition in adolescents with mood and anxiety disorders. American Journal of Psychiatry, 160, 1172– 1174. McClure, E. B., Treland, J. E., Snow, J., Dickstein, D. P., Towbin, K. E., Charney, D. S., et al. (2005a). Memory and learning in pediatric bipolar disorder. Journal of the American Academy of Child and Adolescent Psychiatry, 44, 461–469. McClure, E. B., Treland, J. E., Snow, J., Schmajuk, M., Dickstein, D. P., Towbin, K. E., et al. (2005b). Deficits in social cognition and response flexibility in pediatric bipolar disorder. American Journal of Psychiatry, 162, 1644–1651. McElroy, S. L., Strakowski, S. M., West, S. A., Keck, P. E. Jr., & McConville, B. J. (1997). Phenomenology of adolescent and adult mania in hospitalized patients with bipolar disorder. American Journal of Psychiatry, 154, 44–49. McIntyre, R. S., Brecher, M., Paulsson, B., Huizar, K., & Mullen, J. (2005). Quetiapine or haloperidol as monotherapy for bipolar mania: A 12-week, double-blind, randomised, parallel-group, placebo-controlled trial. European Neuropsychopharmacology, 15, 573–585. McIntyre, R. S., Mancini, D. A., McCann, S., Srinivasan, J., & Kennedy, S. H. (2003). Valproate, bipolar disorder and polycystic ovarian syndrome. Bipolar Disorders, 5, 28–35. McQueen, M. B., Devlin, B., Faraone, S. V., Nimgaonkar, V. L., Sklar, P., Smoller, J. W., et al. (2005). Combined analysis from eleven linkage studies of bipolar disorder provides strong evidence of susceptibility loci on chromosomes 6q and 8q. American Journal of Human Genetics, 77, 582–595. Mick, E., Spencer, T., Wozniak, J., & Biederman, J. (2005). Heterogeneity of irritability in attention-deficit/hyperactivity disorder subjects with and without mood disorders. Biological Psychiatry, 58, 576–582. Miklowitz, D. J., George, E. L., Axelson, D. A., Kim, E. Y., Birmaher, B., Schneck, C., et al. (2004). Family-focused treatment for adolescents with bipolar disorder. Journal of Affective Disorders, 82 (Supplement 1), S113–S128. Moore, C. M., Demopulos, C. M., Henry, M. E., Steingard, R. J., Zamvil, L., Katic, A., et al. (2002). Brain-to-serum lithium ratio and age: An in vivo magnetic resonance spectroscopy study. American Journal of Psychiatry, 159, 1240–1242. Moore, G. J., Bebchuk, J. M., Hasanat, K., Chen, G., SerajiBozorgzad, N., Wilds, I. B., et al. (2000). Lithium increases N-acetylaspartate in the human brain: in vivo evidence in support of bcl-2’s neurotrophic effects? Biological Psychiatry, 48, 1–8. Moore, G. J., Bebchuk, J. M., Parrish, J. K., Faulk, M. W., Arfken, C. L., Strahl-Bevacqua, J., et al. (1999). Temporal dissociation between lithium-induced changes in frontal lobe myo-inositol and clinical response in manic-depressive illness. American Journal of Psychiatry, 156, 1902–1908. Nemeroff, C. B., Evans, D. L., Gyulai, L., Sachs, G. S., Bowden, C. L., Gergel, I. P., et al. (2001). Double-blind, placebo-controlled comparison of imipramine and paroxetine in the treatment of bipolar depression. American Journal of Psychiatry, 158, 906–912. National Institute of Mental Health (NIMH). (2001). National Institute of Mental Health research roundtable on prepubertal bipolar disorder. Journal of the American Academy of Child and Adolescent Psychiatry, 40, 871–878. Patel, N. C., DelBello, M. P., Keck, P. E. Jr., & Strakowski, S. M. (2006). Phenomenology associated with age at onset in patients with bipolar disorder at their first psychiatric hospitalization. Bipolar Disorders, 8, 91–94. Pavuluri, M. N., Graczyk, P. A., Henry, D. B., Carbray, J. A., Heidenreich, J., & Miklowitz, D. J. (2004a). Child- and familyfocused cognitive-behavioral therapy for pediatric bipolar disorder: Development and preliminary results. Journal of the American Academy of Child and Adolescent Psychiatry, 43, 528–537. Pavuluri, M. N., Henry, D. B., Carbray, J. A., Sampson, G., Naylor, M. W., & Janicak, P. G. (2004b). Open-label prospective trial of risperidone in combination with lithium or divalproex sodium in pediatric mania. Journal of Affective Disorders, 82 (Supplement 1), S103–S111. Pavuluri, M. N., Schenkel, L. S., Aryal, S., Harral, E. M., Hill, S. K., Herbener, E. S., et al. (2006). Neurocognitive function in unmedicated manic and medicated euthymic pediatric bipolar patients. American Journal of Psychiatry, 163, 286–293. Pearlson, G. D., Barta, P. E., Powers, R. E., Menon, R. R., Richards, S. S., Aylward, E. H., et al. (1997). Ziskind–Somerfeld Research Award 1996. Medial and superior temporal gyral volumes and cerebral asymmetry in schizophrenia versus bipolar disorder. Biological Psychiatry, 41, 1–14. Perlis, R. H., Miyahara, S., Marangell, L. B., Wisniewski, S. R., Ostacher, M., DelBello, M. P., et al. (2004). Long-term implications of early onset in bipolar disorder: Data from the first 1000 participants in the systematic treatment enhancement program BIPOLAR DISORDER 625 9781405145497_4_038.qxd 29/03/2008 02:52 PM Page 625

for bipolar disorder (STEP-BD). Biological Psychiatry, 55, 875– 881. Pope, H. G. Jr., McElroy, S. L., Keck, P. E. Jr., & Hudson, J. I. (1991). Valproate in the treatment of acute mania. A placebo-controlled study. Archives of General Psychiatry, 48, 62–68. Rao, U., Ryan, N. D., Birmaher, B., Dahl, R. E., Williamson, D. E., Kaufman, J., et al. (1995). Unipolar depression in adolescents: clinical outcome in adulthood. Journal of the American Academy of Child and Adolescent Psychiatry, 34, 566–578. Reich, W., Neuman, R. J., Volk, H. E., Joyner, C. A., & Todd, R. D. (2005). Comorbidity between ADHD and symptoms of bipolar disorder in a community sample of children and adolescents. Twin Research and Human Genetics, 8, 459–466. Rey, J. M., & Martin, A. (2006). Selective serotonin reuptake inhibitors and suicidality in juveniles: Review of the evidence and implications for clinical practice. Child and Adolescent Psychiatric Clinics of North America, 15, 221–237. Rich, B. A., Schmajuk, M., Perez-Edgar, K., Pine, D. S., Fox, N. A., & Leibenluft, E. (2007). Different psychophysiological and behavioral responses elicited by frustration in pediatric bipolar disorder and severe mood dysregulation. American Journal of Psychiatry, 164, 309–317. Rich, B. A., Schmajuk, M., Perez-Edgar, K. E., Pine, D. S., Fox, N. A., & Leibenluft, E. (2005). The impact of reward, punishment, and frustration on attention in pediatric bipolar disorder. Biological Psychiatry, 58, 532–539. Rich, B. A., Vinton, D. T., Roberson-Nay, R., Hommer, R. E., Berghorst, L. H., McClure, E. B., et al. (2006). Limbic hyperactivation during processing of neutral facial expressions in children with bipolar disorder. Proceedings of the National Academy of Sciences of the USA, 103, 8900–8905. Robertson, H. A., Kutcher, S. P., & Lagace, D. C. (2003). No evidence of attentional deficits in stabilized bipolar youth relative to unipolar and control comparators. Bipolar Disorders, 5, 330– 339. Scheffer, R. E., Kowatch, R. A., Carmody, T., & Rush, A. J. (2005). Randomized, placebo-controlled trial of mixed amphetamine salts for symptoms of comorbid ADHD in pediatric bipolar disorder after mood stabilization with divalproex sodium. American Journal of Psychiatry, 162, 58–64. Scheffer, R. E. & Niskala Apps, J. A. (2004). The diagnosis of preschool bipolar disorder presenting with mania: open pharmacological treatment. Journal of Affective Disorders, 82 (Supplement 1), S25–S34. Silverstone, P. H., Wu, R. H., O’Donnell, T., Ulrich, M., Asghar, S. J., & Hanstock, C. C. (2002). Chronic treatment with both lithium and sodium valproate may normalize phosphoinositol cycle activity in bipolar patients. Human Psychopharmacology, 17, 321–327. Small, J. G., Klapper, M. H., Milstein, V., Kellams, J. J., Miller, M. J., Marhenke, J. D., et al. (1991). Carbamazepine compared with lithium in the treatment of mania. Archives of General Psychiatry, 48, 915–921. Smoller, J. W., & Finn, C. T. (2003). Family, twin, and adoption studies of bipolar disorder. American Journal of Medical Genetics. C. Seminars in Medical Genetics, 123, 48–58. Stokes, P. E., Shamoian, C. A., Stoll, P. M., & Patton, M. J. (1971). Efficacy of lithium as acute treatment of manic-depressive illness. Lancet, 1, 1319–1325. Straker, D., Correll, C. U., Kramer-Ginsberg, E., Abdulhamid, N., Koshy, F., Rubens, E., et al. (2005). Cost-effective screening for the metabolic syndrome in patients treated with second-generation antipsychotic medications. American Journal of Psychiatry, 162, 1217–1221. Strakowski, S. M., DelBello, M. P., Sax, K. W., Zimmerman, M. E., Shear, P. K., Hawkins, J. M., et al. (1999). Brain magnetic resonance imaging of structural abnormalities in bipolar disorder. Archives of General Psychiatry, 56, 254–260. Strober, M., & Carlson, G. (1982). Bipolar illness in adolescents with major depression: Clinical, genetic, and psychopharmacologic predictors in a three- to four-year prospective follow-up investigation. Archives of General Psychiatry, 39, 549–555. Strober, M., Lampert, C., Schmidt, S., & Morrell, W. (1993). The course of major depressive disorder in adolescents. I. Recovery and risk of manic switching in a follow-up of psychotic and nonpsychotic subtypes. Journal of the American Academy of Child and Adolescent Psychiatry, 32, 34–42. ten Have, M., Vollebergh, W., Bijl, R., & Nolen, W. A. (2002). Bipolar disorder in the general population in The Netherlands (prevalence, consequences and care utilisation): results from The Netherlands Mental Health Survey and Incidence Study (NEMESIS). Journal of Affective Disorders, 68, 203–213. Tillman, R., & Geller, B. (2003). Definitions of rapid, ultrarapid, and ultradian cycling and of episode duration in pediatric and adult bipolar disorders: a proposal to distinguish episodes from cycles. Journal of Child and Adolescent Psychopharmacology, 13, 267–271. Tohen, M., Greil, W., Calabrese, J. R., Sachs, G. S., Yatham, L. N., Oerlinghausen, B. M., et al. (2005). Olanzapine versus lithium in the maintenance treatment of bipolar disorder: A 12-month, randomized, double-blind, controlled clinical trial. American Journal of Psychiatry, 162, 1281–1290. Tumuluru, R. V., Weller, E. B., Fristad, M. A., & Weller, R. A. (2003). Mania in six preschool children. Journal of Child and Adolescent Psychopharmacology, 13, 489–494. Vieta, E., Bourin, M., Sanchez, R., Marcus, R., Stock, E., McQuade, R., et al. (2005). Effectiveness of aripiprazole v. haloperidol in acute bipolar mania: double-blind, randomised, comparative 12-week trial. British Journal of Psychiatry, 187, 235–242. Wagner, K. D., Weller, E. B., Carlson, G. A., Sachs, G., Biederman, J., Frazier, J. A., et al. (2002). An open-label trial of divalproex in children and adolescents with bipolar disorder. Journal of the American Academy of Child and Adolescent Psychiatry, 41, 1224– 1230. Wals, M., Hillegers, M. H., Reichart, C. G., Ormel, J., Nolen, W. A., & Verhulst, F. C. (2001). Prevalence of psychopathology in children of a bipolar parent. Journal of the American Academy of Child and Adolescent Psychiatry, 40, 1094–1102. Weisler, R. H., Keck, P. E., Jr, Swann, A. C., Cutler, A. J., Ketter, T. A., Kalali, A. H. for the SPD417 Study Group. (2005). Extended-release carbamazepine capsules as monotherapy for acute mania in bipolar disorder: A multicenter, randomized, double-blind, placebo-controlled trial. Journal of Clinical Psychiatry, 66, 323– 330. Weissman, M. M., Bland, R. C., Canino, G. J., Faravelli, C., Greenwald, S., Hwu, H. G., et al. (1996). Cross-national epidemiology of major depression and bipolar disorder. Journal of the American Medical Association, 276, 293–299. Weissman, M. M., Wolk, S., Wickramaratne, P., Goldstein, R. B., Adams, P., Greenwald, S., et al. (1999). Children with prepubertalonset major depressive disorder and anxiety grown up. Archives of General Psychiatry, 56, 794–801. Wilens, T. E., Biederman, J., Brown, S., Tanguay, S., Monuteaux, M. C., Blake, C., et al. (2002). Psychiatric comorbidity and functioning in clinically referred preschool children and school-age youths with ADHD. Journal of the American Academy of Child and Adolescent Psychiatry, 41, 262–268. Wilens, T. E., Biederman, J., Forkner, P., Ditterline, J., Morris, M., Moore, H., et al. (2003). Patterns of comorbidity and dysfunction in clinically referred preschool and school-age children with bipolar disorder. Journal of Child and Adolescent Psychopharmacology, 13, 495–505. Wilens, T. E., Biederman, J., Kwon, A., Ditterline, J., Forkner, P., Moore, H., et al. (2004). Risk of substance use disorders in adolescents with bipolar disorder. Journal of the American Academy of Child and Adolescent Psychiatry, 43, 1380–1386. CHAPTER 38 626 9781405145497_4_038.qxd 29/03/2008 02:52 PM Page 626

Winsberg, M. E., Sachs, N., Tate, D. L., Adalsteinsson, E., Spielman, D., & Ketter, T. A. (2000). Decreased dorsolateral prefrontal N-acetyl aspartate in bipolar disorder. Biological Psychiatry, 47, 475–481. Wozniak, J., Biederman, J., Kiely, K., Ablon, J. S., Faraone, S. V., Mundy, E., et al. (1995). Mania-like symptoms suggestive of childhood-onset bipolar disorder in clinically referred children. Journal of the American Academy of Child and Adolescent Psychiatry, 34, 867–876. Zito, J. M., Safer, D. J., dosReis, S., Gardner, J. F., Boles, M., & Lynch, F. (2000). Trends in the prescribing of psychotropic medications to preschoolers. Journal of the American Medical Association, 283, 1025–1030. Zornberg, G. L., & Pope, H. G. Jr. (1993). Treatment of depression in bipolar disorder: New directions for research. Journal of Clinical Psychopharmacology, 13, 397–408. BIPOLAR DISORDER 627 9781405145497_4_038.qxd 29/03/2008 02:52 PM Page 627

628 The current chapter reviews five anxiety disorders: phobic disorders, separation anxiety disorder, social anxiety disorder, generalized anxiety disorder and panic disorder. It is organized around four themes. The first section focuses on diagnosis, nosology and assessment. The second summarizes data on prevalence, risk factors and outcome. The third reviews research on family genetics and psychobiology. Treatment is summarized in the final section. Clinical Presentation of Childhood Anxiety Disorders Diagnosis For phenomena that fall on a continuum, extremes have been viewed alternatively as severe expressions of continuously distributed traits or as distinct pathological entities. Controversy remains regarding the relative advantages and disadvantages in conceptualizing pediatric anxiety as a continuous or categorical phenomenon. A key reason for categorizing children presenting in the clinic as affected by anxiety disorders is to allocate services for those anxious children most in need. However, categorization of one or another group of children does not imply distinct etiology. Distinguishing normal anxiety from pathological anxiety can be problematic because childhood anxieties are not only common, but may be adaptive. Diagnostically, anxiety may be considered pathological at any age if it limits developmentally appropriate behavior and thus causes functional limitation. However, anxiety may be considered pathological even when the child’s activities are not affected if there is significant distress. Classification of disorders with little or no manifest impairment and only distress is often difficult, because the threshold for considering distress as clinically significant varies according to many factors, such as the child’s age, life circumstances or cultural background. Another guide for diagnosis is the child’s ability to recover from anxiety. As such, failure to adapt represents a hallmark of pathology. Disagreements on definitional boundaries between normal and pathological anxiety are likely to persist as long as clinical descriptors remain the exclusive basis for diagnosis. Other data may shed light, leading to nosological changes by identifying which syndromes carry long-term significance. As with definitions of hypertension, the definition of “abnormal” anxiety could change as longitudinal data identify factors that contribute to excessive long-term risk (Pine, Cohen, Gurley et al., 1998; Pine, Cohen, & Brook, 2001). Eventually, advances in genetics or neuroscience also may impact on nosology. However, considerable progress is needed before such approaches can provide clinical utility. Nosology of Childhood Anxiety Disorders Delimitating specific syndromes that facilitate communication among professionals is not a trivial accomplishment, but it represents a minimal standard for a useful nomenclature. While DSM-IV and ICD-10 meet this minimal goal, questions concerning the distinctiveness of anxiety disorders persist. These questions emerge as a result of comorbidity among anxiety disorders, coupled with inconsistent findings of distinct natural histories and factors used to validate diagnosis. The ICD-10 and DSM-IV have similar diagnoses for childhood anxiety disorders. The major difference concerns the handling of comorbidity: ICD-10 provides a single diagnosis for cooccurring anxiety and behavior disorders, whereas the DSMIV requires separate diagnoses for each condition. In addition, obsessive compulsive disorder (OCD) and post-traumatic stress disorder (PTSD) are classified as anxiety disorders in the DSM-IV, but not in ICD-10 (these are not considered in this chapter because they are clinically distinct from the disorders examined here). Finally, some differences exist in the definitions of childhood anxiety disorders between ICD-10 and DSMIV (Klein, 1994); however, this chapter focuses on common clinical features. Presentation of Specific Anxiety Disorders Phobic Disorder Phobic disorder is defined by marked unreasonable fear of a specific object that is not intrinsically dangerous, such as animals, or a situation, such as heights. The level of fear is considered extreme, and exposure invariably elicits extreme fear. In addition, the phobia must either cause clinically significant distress or impair the person’s well-being by leading to interference with ordinary activities because of avoidance. Phobic disorders may begin at any age, but typical onset is in childhood (Fyer, 1998; Pine, Cohen, Gurley et al., 1998). Anxiety Disorders 39 Daniel S. Pine and Rachel G. Klein 9781405145497_4_039.qxd 29/03/2008 02:52 PM Page 628 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

Phobias can be classified based on the nature of the feared object: animals, natural environments, blood infection; or specific situations, such as elevators. Most children with phobic disorders share a limited number of feared situations. Attempts to differentiate among phobias on pathophysiological grounds have not yielded divergent features, except for blood injury phobia (Fyer, 1998), whose distinct physiological signature consists of a sudden drop in blood pressure and heart rate, and fainting. Separation Anxiety Disorder Separation anxiety disorder represents the only anxiety diagnosis that must begin in childhood. In ICD-10, onset must be in early childhood, whereas in the DSM-IV, onset must occur any time before age 18. The onset is frequently in late childhood, before adolescence, and decreases as children mature into adolescence. As the name connotes, the disorder reflects anxiety at separation from home or caretakers that causes impairment by leading to avoidance. The terms “school phobia” and “school refusal” have been used to describe a pattern of school avoidance (Egger, Costello, & Angold, 2003). In preadolescents, refusal to attend school because of fears is most often related to separation anxiety disorder. Feared separations situations often seem illogical. For example, a child may have no difficulty going to school, but be highly anxious while visiting familiar friends’ homes. Difficulty sleeping alone is especially salient in children with separation anxiety disorder. As reviewed below, some evidence suggests relationships between childhood separation anxiety disorder and adult panic disorder. Social Phobia/Social Anxiety Disorder Social anxiety disorder is characterized by anxiety in a range of social situations because of fear of scrutiny, ridicule, humiliation or embarrassment. Some children may not articulate these concerns but feel uncomfortable in social settings. Children must experience discomfort with peers, not only with adults, and anxiety cannot be caused by impaired capacity for socialization, as evidenced by the fact that the children interact satisfactorily with those who are familiar to them. The diagnostic distinction between severe social anxiety disorder and mild pervasive developmental disorder can be problematic. Chronic avoidance of social interactions might limit development of social competence, contributing to similarities with mild pervasive developmental disorder. However, in general, children and adolescents with social anxiety desire social contacts, whereas those with pervasive developmental disorder typically lack interest in reciprocal relationships. The diagnostic qualifier, generalized social phobia, denotes anxiety in multiple social settings. There are no standard definitions for distinguishing it from the non-generalized form, leading to divergent interpretations. Some apply the nongeneralized label to individuals who experience social anxiety in only one or two situations, such as parties; others use the diagnosis for individuals who experience only performance anxiety, such as public speaking, eating in front of people, as well as test anxiety, but who do not have anxiety during social interactions. Performance anxiety may occur without significant anxiety in social situations, but the reverse is unusual. Epidemiological evidence supports the distinction between generalized and non-generalized social anxiety disorder. The generalized form has been reported to have earlier onsets, more chronicity, more comorbidity and more psychopathology in relatives (Wittchen, Stein, & Kessler, 1999). This work exemplifies how epidemiological studies can inform diagnostic validity. Generalized Anxiety Disorder Generalized anxiety disorder encompasses multiple worries about a variety of life circumstances, such as school work, one’s appearance or future. The age of onset is poorly understood, but typically it is not in early childhood. Prior to the DSMIV, “overanxious disorder” was used for children and adolescents with multiple worries. It remains unclear to what degree the outdated diagnosis of overanxious disorder overlaps with generalized anxiety disorder (Pine, Cohen, Gurley et al., 1998). Generalized anxiety disorder is the only anxiety disorder that requires somatic symptoms. However, there is no documentation that these occur preferentially in this anxiety disorder. Relative to other anxiety disorders, generalized anxiety disorder has very high rates of comorbidity, and it rarely presents on its own in clinic patients. Beyond comorbidity with other anxiety disorders, it has a strong relationship with major depressive disorder (Costello, Pine, Hammen et al., 2002; Kessler, Andrade, Bijl et al., 2002). This high comorbidity raises questions about whether the diagnosis identifies a unique syndrome as opposed to a complication of other associated disorders. Because the symptoms consist mostly of worries, the disorder is not usually characterized by avoidant behavior, although there are exceptions. For example, children with extreme worries about academic performance may miss school on testing days. Panic Disorder The essential clinical feature of panic disorder is the repeated experience of unprovoked spontaneous panic attacks, which may lead to limited independent travel or agoraphobia. The panic attacks are characterized by intense fear of impending doom, accompanied by physical symptoms, such as rapid heartbeat, shortness of breath, choking sensation, sweating, depersonalization or derealization. To some extent, these symptoms identify meaningful subtypes of panic disorder patients. Thus, patients who present with respiratory symptoms have been reported to differ from other panic disorder patients in treatment response and familial aggregation (Briggs, Stretch, & Brandon, 1993; Horwath, Adams, Wickramaratne et al., 1997). Usual onset begins with spontaneous panic attacks, typically during adolescence. Progression to full-blown panic disorder occurs in a minority, typically during early adulthood (Pine, Cohen, Gurley et al., 1998). Diagnostic confusion arises concerning panic disorder because panic reactions can occur in many anxiety states, including in various phobias during exposure to feared situations. The key ANXIETY DISORDERS 629 9781405145497_4_039.qxd 29/03/2008 02:52 PM Page 629

distinction is that, in panic disorder, panic attacks occur without cues, as prototypically exemplified by nocturnal panic attacks. Moreover, young children may display panic reactions, but whether they experience spontaneous, unprovoked panic attacks, the hallmark of panic disorder, remains controversial. Whether panic disorder occurs in pre-adolescents is still an unresolved issue, but if it does, it must be very rare (Costello, Egger, & Angold, 2004). This scarcity has limited systematic study. It has been suggested that, in keeping with the cognitive model of anxiety, children lack the cognitive resources for misinterpreting somatic experiences in a catastrophic fashion, and therefore do not have panic attacks. This conjecture seems unlikely, because panic reactions associated with terror occur in children. It is the sudden unprovoked aspect of panic that seems to be missing in childhood, not the catastrophic reaction. At the same time, it is possible that true panic attacks have age-related clinical variants. Comorbidity of Childhood Anxiety Disorders Comorbidity is an important clinical feature because it entails greater dysfunction than either condition alone. Two forms of diagnostic overlap are considered: comorbidity among anxiety disorders, and anxiety disorders with other disorders. Anxiety Comorbidity Children referred for treatment exhibit especially high comorbidity among anxiety disorders (Costello, Egger, & Angold, 2004). Such patterns likely reflect ascertainment biases. In a large treatment study, social anxiety, separation anxiety and generalized anxiety disorders were each diagnosed in about 60% of children (RUPP, 2001). Comorbidity was particularly elevated in children with generalized anxiety disorder who, in 90% of cases, also had another anxiety disorder. Clearly, comorbidity is less marked in community than clinical samples, but strong comorbidity across anxiety disorders, especially for generalized anxiety or overanxious disorder, is also found in population studies (Anderson, Williams, McGee et al., 1987; Bird, Canino, Rubio-Stipec et al., 1988; Essau, Conradt, & Petermann, 1999; Fergusson, Horwood, & Lynskey, 1993; McGee, Feehan, Williams et al., 1990; Verhulst, van der Ende, Ferdin-and et al., 1997). This high comorbidity has raised questions regarding the diagnostic separation of these three disorders. Non-Anxiety Disorders There is unanimous agreement that major depression is highly comorbid with anxiety disorders. The strength of this relationship rivals virtually all others in developmental psychopathology (Angold, Costello, & Erkanli, 1999; Costello, 2004; Costello, Pine, Hammen et al., 2002). Because depression is rarer than anxiety disorders, especially in pre-adolescents, it follows that among those with anxiety the overlap with depression is not as striking as when one selects those with depression, and that this comorbidity increases with age. Although some clinical reports indicate comorbidity between anxiety and attention deficit hyperactivity disorder (ADHD), population-based studies find weak relationships (Angold, Costello, & Erkanli, 1999). There is some evidence of comorbidity between anxiety disorders and substance abuse or conduct disorder (Kaplow, Curran, Angold et al., 2001; Rutter, Maughan, & Kim-Cohen, 2006). Assessment The assessment of pediatric anxiety has benefitted from a proliferation of instruments. They include paper-and-pencil rating scales for children, parents and teachers, clinician-rated scales, as well as child and parent interviews. Several reviews have appeared of self, parent and teacher rated anxiety scales for children (Brooks & Kutcher, 2003; Seligman, Ollendick, Langley et al., 2004; Silverman & Ollendick, 2005). Therefore, only an overview is provided. Rating Scales Rating scales serve diverse purposes. They may screen large groups to identify children most in need of assistance or to implement prevention programs. Scales may be used for economic reasons, as they provide an economical way for assessments in epidemiological or behavioral genetic studies (Topolski, Hewitt, Eaves et al., 1999). In clinical studies, scales may serve as indices of severity (RUPP, 2003). Rating scales that anteceded DSM-III and ICD-10 were not designed to reflect the current classification. They comprised factors such as worry, physiological anxiety and fear of bodily harm, as in the Revised Children’s Manifest Anxiety Scale (RCMA; Reynolds & Richmond, 1985), the State-Trait Anxiety Inventory for Children (STAIC; Speielberger, 1973) and the Revised Fear Survey Schedule for Children (FSSC-R; Ollendick, Yang, King et al., 1996). The widely used Children’s Behaviour Checklist (CBCL; Achenbach, 1991) generates a nonspecific factor of emotional disturbance, called “internalizing” factor. In general, these scales assess constructs distinct from those generated by newer scales. An important clinical challenge is to differentiate between anxiety and depression, a challenge reflected by the fact that a single unitary factor of the CBCL encompasses both dysfunctions. Many other scales that purport to differentiate anxiety from depression fail to do so (Klein, 1994). The meaning of scale ratings of anxiety is further complicated by the poor agreement between parent or child ratings with information obtained from clinical interviews (RUPP, 2003). It is beyond the purview of this chapter to provide comprehensive discussion of psychometric requirements for diagnostic indices. Growing interest spurred the development of more diagnostically relevant measures of childhood anxiety. Recent efforts reflect shifts in the classification of anxiety disorders, with greater relevance given to diagnostic groupings. Standardized scales include the Multidimensional Anxiety Scale for Children (MASC; March, Parker, Sullivan et al., 1997; March & Sullivan, 1999) and the Self Report for Child Anxiety Related Disorders (SCARED; Birmaher, Khetarpal, Brent et al., 1997). The MASC and SCARED stand out as promising clinically CHAPTER 39 630 9781405145497_4_039.qxd 29/03/2008 02:52 PM Page 630

relevant indices. Both measures demonstrate adequate test– retest reliability, divergent validity from depression measures, reasonable correlations with clinical ratings of anxiety severity, and sensitivity to treatment effects. Several anxiety scales are designed for clinicians. The Hamilton Anxiety Scale (HAS; Hamilton, 1969) developed for adults has had limited application in younger populations. In a controlled treatment study, it performed less well than another clinician-rated index, the Pediatric Anxiety Rating Scale (PARS), which taps diagnostic criteria and has good psychometric properties (RUPP, 2003). Diagnostic Interviews Diagnostic interviews serve different purposes. The highly structured DISC was developed for epidemiological studies, to be administered by individuals without clinical training or by computer (Shaffer, Fisher, Lucas et al., 2000). Support for the clinical utility of the DISC is mixed. Fair agreement between DISC diagnoses and clinical interviews conducted by the same clinicians led to the claim that the DISC had a role in clinical settings (Schwab-Stone, Shaffer, Dulcan et al., 1996). However, other data do not support the claim. For example, diagnostic rates are high in epidemiological studies using the DISC (Table 39.1). Moreover, other findings question the validity of anxiety diagnoses generated by the DISC (March, Swanson, Arnold et al., 2000). The Child and Adolescent Psychiatric Assessment (CAPA; Angold & Costello, 2000), highly structured and administered by non-clinicians, is also used in epidemiological studies. Relative to the DISC, the CAPA requires more training and more closely resembles the clinical interview. While CAPA appears promising, the unavailability of data concerning treatment sensitivity precludes endorsement of clinical relevance. The key issue is whether anxiety disorders generated by structured interviews are valid. Some evidence from longitudinal, family-based and imaging studies points towards validity. However, inconsistent findings concerning the predictive significance of childhood anxiety disorders among girls and boys studied epidemiologically (Costello, Angold, & Keeler, 1999; McGee, Feehan, Williams et al., 1992; Pine, Cohen, Gurley et al., 1998) raise questions about the validity of anxiety diagnoses in community samples. The Kiddie-Schedule for Affective Disorder and Schizophrenia (K-SADS) was developed for use by clinicians and allows full latitude of inquiry. Multiple versions exist, including a highly structured version administered by lay interviewers (Kaufman, Birmaher, Brent et al., 1997, 2000). The Diagnostic Interview for Children and Adolescents (DICA; Reich, 2000), also highly structured, has been used in semistructured format. The Anxiety Disorders Interview Schedule for Children (ADIS) allows full clinical inquiry (Silverman, Saavedra, & Pina, 2001). As with other clinically based semistructured interviews, the quality of data depends highly on interviewers’ training and qualifications. There is little to guide the selection of one instrument over another, in terms of better reliability or validity. All have demonstrated modest to adequate test–retest reliability, with anxiety disorders faring no better than mood disorders and slightly worse than behavioral disorders. The major factor informing selection concerns the availability of skilled clinicians for implementation. Although conceived for research purposes, diagnostic interviews may be useful to clinicians because they provide comprehensive coverage of symptomatic status (see chapter 19), and represent excellent teaching tools for training in clinical diagnosis. Epidemiology of Pediatric Anxiety Disorders Across several continents, well-executed epidemiological studies delineate key features of anxiety disorders, including prevalence, risk factors and longitudinal outcomes. These studies have the great advantage of avoiding clinical biases introduced by clinical samples. Prevalence of Childhood Anxiety Disorders Prevalence studies that have relied on interviews with parents and/or children are presented in Table 39.1. Most report the prevalence of broadly conceptualized anxiety disorders. Ongoing epidemiological studies are obtaining DSM-IV and ICD-10 diagnoses. However, most anxiety diagnoses have remained virtually unchanged, so that previous studies are relevant to the current nomenclature. Most epidemiological studies at all ages find anxiety disorders to be the most common mental disorders. The few population-based studies of panic disorder have found very low rates in children and adolescents, below 1% for lifetime and lower frequencies for the past 6 or 12 months (Pine, Cohen, Gurley et al., 1998; Reed & Wittchen, 1998; Verhulst, van der Ende, Ferdinand et al., 1997; Whitaker, Johnson, Shaffer et al., 1990). In pre-adolescents, separation anxiety disorder is probably the most prevalent diagnosis (Anderson, Williams, McGee et al., 1987; Costello, Angold, Burns et al., 1996, 1999; Costello, Egger, & Angold, 2005; Pine, Cohen, Brook et al., 1998), whereas social anxiety disorder, generalized anxiety disorder and what was previously termed overanxious disorder, increase in adolescence (Fergusson, Horwood, & Lynskey, 1993; McGee, Feehan, Williams et al., 1990; Pine, Cohen, Gurley et al., 1998; Verhulst, van der Ende, Ferdinand et al., 1997). All longitudinal epidemiological studies (Anderson, Williams, McGee et al., 1987; Costello, Angold & Keeler 1999; Kim-Cohen, Caspi, Moffitt et al., 2003; McGee, Feehan, Williams et al., 1992; Pine, Cohen, Gurley et al., 1998) find an increment in social phobia during adolescence, confirming that the disorder often emerges in adolescence. Rates of any anxiety disorder within the past 6 or 12 months range widely, from 1.8% in New Zealand (Anderson, Williams, McGee et al., 1987) to 23.5% in Holland (Verhulst, van der Ende, Ferdinand et al., 1997). Variation may reflect true differences as a result of cultural influences. However, disparate rates emerge even when site differences seem minimal. For ANXIETY DISORDERS 631 9781405145497_4_039.qxd 29/03/2008 02:52 PM Page 631

CHAPTER 39 632 Table 39.1 Prevalence (%) of anxiety disorders in children, adolescents, and adults followed prospectively. Rates (%) Location New Zealand Dunedin Christchurch Germany Manheim Munich Bremen UK London‡ Holland Puerto Rico USA Missouri Pennsylvania New York State Authors Anderson et al. (1987)a McGee et al. (1990)a Kim-Cohen et al. (2003)a Fergusson et al. (1993) Goodwin et al. (2004) Essau et al. (1999) Reed & Wittchen (1998)a Wittchen et al. (1999)a Essau et al. (1999) Kramer & Garralda (1998) Verhulst et al. (1997) Bird et al. (1988) Kashani et al. (1987) Costello et al. (1988)a Benjamin et al. (1990)a Pine et al. (1998) n 785 943 976 986 965 969 957 191 3021 925 1035 131 312/780k 386/777h 150 300/789k 300/789k 776 760 716 Age (years) 11 15 26 15 16–18 18–21 13 14–24 14–17 12–17 13–17 13–18 4–16 14–16 7–11 7–11 9–18 11–20 17–26 Interview DISC-Cb DISC-C DIS DISC-P DISC-C M-CIDIi,o M-CIDIi,o Graham/Rutter P/Cf,g,m M-CIDIh,i M-CIDIh,i M-CIDIh,i K-SADSi,j DISC-C DISC-P DISCl DISCm DISCm DICAi,n DISC-C DISC-P DISCe DISCe DISCe DISCe Time frame (months) 12c 12d 12e 12e 12e 12e 12e 12e 6 12 Lifetime 12 Lifetime Lifetime 12 6 6 12 12 12 12 12 12 12 Any 1.8–7.5 3.6* 10.7* 26.1* 3.9 10.8 18.4 14.6 5.8 – – – – – 5.3 10.5 16.5 23.5 5.3 4.4 7.0 8.7 10.5 6.5 15.4 – – – SiPh 0–2.4 1.7 3.6 7.1 1.3 5.1 9.6 6.5 – – – – – – – 4.5 9.2 12.7 – 2.6 1.3 – 6.7 3.0 9.1 11.6 5.9 22.1 SAD 0.06–3.5 1.9 2.0 – 0.1 0.5 – – – – – – – – – 1.4 0.6 1.8 – 4.7 2.1 – 4.1 0.4 4.1 8.6 3.7 – OAD 0.05–2.9 2.5 5.9 5.5 (GAD) 0.6 2.1 2.7 (GAD) 1.8 (GAD) – – – – – – 3.1 1.8 1.5 3.1 – – – – 2.0 2.8 4.6 14.3 8.0 5.0 (GAD) SoPh 0–0.9 0.4 1.1 10.7 0.7 1.7 7.5 6.7 – – – 3.0 4.0 1.6 1.5 3.7 6.3 9.2 – – – – 1.0 0 1.0 8.4 9.9 5.6 PD – – 3.9 – – – 0.6 0.8 – – – 0.8 0.2 0.3 0.4 – – – – – – – 0.0 0.0 0.1 9781405145497_4_039.qxd 29/03/2008 02:52 PM Page 632

example, two well-executed studies of adolescents, using similar interviews and both conducted in urban sites in Germany, Bremen (Essau, Conradt, & Petermann, 1999) and Munich (Wittchen, Stein, & Kessler, 1999), report lifetime rates for social phobia of 1.6% and 4%, respectively. As is evident in Table 39.1, another case in point are the New Zealand studies from Dunedin (McGee, Feehan, Williams et al., 1990) and Christchurch (Fergusson, Horwood, & Lynskey, 1993). No anxiety disorder is spared discrepancies in prevalence, even when diagnostic definitions are identical and sites appear indistinguishable. Table 39.1 illustrates clearly that diagnostic rates are reduced sharply if diagnoses are made irrespective of the “extreme distress” criterion, when only impairment is present. Not surprisingly, the one study that compared prevalence as a function of impairment (Shaffer, Fisher, Dulcan et al., 1996) found that applying an impairment criterion led to a dramatic lowering of prevalence estimates. Could secular changes affect rates of anxiety disorders? This possibility cannot be ruled out, but does not seem to account for discrepancies across studies, because results do not ANXIETY DISORDERS 633 New Jersey Nationwide North Carolina Georgia, New Haven New York Puerto Rico Oregon Virginia C-GAS, children’s global assessment scale; GAD, generalized anxiety disorder; OAD, overanxious disorder; P/C, parent/child; PD, panic disorder; SAD, separation anxiety disorder; SiPh, simple phobia; SoPh, social phobia. * Rates calculated from papers. ‡ Adolescents in primary care clinics. a Same cohort within site. b DISC-C and DISC-P, Diagnostic Interview Schedule for Children, Child and Parent Versions (Costello et al., 1984). c Rates vary depending on diagnostic criteria based on DISC-C, and parent and teacher ratings, e.g., diagnostic criteria met: (1) by two of three sources or by one source and symptoms confirmed by at least one other source; (2) by one source but no other source confirms symptoms; (3) by combining symptoms from all three sources. d Percentage meeting diagnostic criteria applying same standards as at age 15 in McGee et al. (1992). e Percent meeting criteria based on DISC-C plus parent ratings. f Interview by Graham & Rutter (1968). g Includes anxiety and mood disorders. h M-CIDI, Munich modification of CIDI (Wittchen et al., 1999). i Diagnosis based on interview with adolescent. j K-SADS, Kiddie Schedule for Affective Disorders and Schizophrenia (Ambrosini et al., 1989). k Two stage study: N in stage 2/N in Stage 1. l Percent meeting diagnostic criteria based on interview with parent or child. m Top line: percentage meeting diagnostic criteria on parent or child interview and had a C-GAS <61 (Shaffer et al., 1983). Bottom line: percentage meeting diagnostic criteria on parent or child interview and had a C-GAS of 61–70. n DICA, Diagnostic Interview for Children and Adolescents (Herjanic & Reich, 1982). o CIDI, Composite International Diagnostic Interview (Wittchen, 1994). p CAPA, Child and Adolescent Psychiatric Assessment (Angold & Costello, 2000). q DISC Version 2.3 (Shaffer et al., 1996). r Percentage meeting diagnostic criteria only for symptom number, age of onset and duration. s Percentage meeting diagnostic criteria and impairment linked to the specific disorder. t Top line: percentage meeting diagnostic criteria. Bottom line: percentage meeting diagnostic criteria and impairment criteria. Whittaker et al. (1990) Magee et al. (1996) Costello et al. (1996) Costello et al. (2003) Shaffer et al. (1996) Lewinsohn et al. (1998) Simonoff et al. (1997) 356/5596k 1765 1015 1420 1285 1709 2762 (twins) 13–18 15–24 9, 11, 13 9–16 9–17 15.5 8–16 Study interviewi CIDIi,o CAPAi,p CAPAi,p DISC-Pq,r DISC-Cr DISCm DISC K-SADS CAPAp,t Lifetime Lifetime 3 3 6 12 3 – – 5.7 2.4 21.0 23.7 18.5 13.9 20.5 2.8 – – 10.8 0.3 – 11.7 11.2 9.5 6.8 3.3 1.3 21.2 4.4 – – 3.5 – 2.5 3.1 4.1 3.5 5.8 0.2 7.2 1.5 3.7 – 1.4 – 4.3 5.4 8.0 6.5 7.7 0.5 10.8 4.4 – 14.9 0.6 – 7.9 8.5 8.2 6.6 7.6 0.9 8.4 2.5 0.6 – 0.03 – – – – 0.3 – 9781405145497_4_039.qxd 29/03/2008 02:52 PM Page 633

suggest time-dependent rates of anxiety disorders (Table 39.1). Similarly, could methods for combining informant information contribute to cross-study differences? The low rate of informant agreement in most studies makes this a reasonable possibility. Depending on their age, children contribute varyingly valuable levels of information, and prevalence of anxiety disorders varies as a function of the reporting source (Table 39.1). It is generally agreed that the answer regarding optimal approach to diagnosis will come from studies that examine the relative accuracy of diagnostic conventions in predicting course, as well as other features such as genetics and biological markers. One study reported that childhood anxiety disorders without impairment are not predictive of difficulties in adolescence, whereas the same is not true for disorders with impairment (Costello, Angold, & Keeler, 1999). However, these findings were not supported by another study (Pine, Cohen, & Brook, 2001). Further complicating diagnosis, impairment may occur in subthreshold syndromes (Reed & Wittchen, 1998). In conclusion, a fair estimate of current prevalence for any pediatric anxiety disorder accompanied by impairment appears to be 5–10%. Additionally, epidemiological studies have been important in confirming that child and adolescent anxiety disorders are associated with significant impairment in multiple functional domains. Risk Factors As a result of the impact of referral biases in clinical samples, epidemiological studies provide more precise identification of risk factors. The current section reviews a range of potential risk factors, including demographic factors, various forms of environmental insult or stress, pre-diagnostic manifestations and medical conditions. Because of inconsistent findings and very small numbers of anxiety disorder cases in epidemiological samples, we also review data from clinically based studies. Gender emerges as the most consistent risk factor for anxiety. Higher rates of most anxiety disorders have been found in females relative to males as early as age 6 (Lewinsohn, Gotlib, Lewinsohn et al., 1998). Anxiety in girls may also have greater predictive impact than in boys for later anxiety (Costello, Angold, & Keeler, 1999; McGee, Feehan, Williams et al., 1992), but findings are not unanimous (Pine, Cohen, Gurley et al., 1998). Little consensus exists regarding socio-environmental risk factors. Anxiety has been linked to various features, including economic disadvantage, school failure, stressful life events, family dysfunction, single home households, parental emotional problems and low parental education, but no consistent pattern has emerged. Using a quasi-experimental design, Costello, Compton, Keeler et al. (2003) did not find that changes in social welfare were associated with changes in rates of anxiety. Negative findings may reflect limitations of epidemiological studies. Although they have the advantage of minimizing referral biases, they typically study relatively small numbers of affected children, often with relatively mild disorders. For example, among 1035 adolescents in one study (Essau, Conradt, & Petermann, 1999), only 17 had social phobia. Inconsistent associations for socio-environmental risk factors also emerge in clinical or family-based studies. For example, a recent meta-analysis identified an association between pediatric anxiety and parenting behaviors (Wood, McLeod, Sigman et al., 2003). However, these are non-specific correlates of psychopathology that occur in multiple childhood disorders. Interest in the relationship between pediatric anxiety disorders and adverse social experiences emerges from at least two sets of findings. First, as reviewed below, rodents and non-human primates display developmental plasticity in behavioral and neural responses to threats (Gross & Hen, 2004), as shown by findings that alterations in social experiences produce long-term alterations in stress responses. These data generate questions concerning the degree to which adverse social experiences might shape humans’ responses to threats during childhood. Second, children who experienced trauma exhibited marked increases in various anxiety disorders, not exclusively PTSD (Pine & Cohen, 2002; Steinberg & Avenevoli, 2000). Associations between adverse life events and pediatric anxiety have not been found consistently (Eley & Stevenson, 2000; Hankin & Abramson, 2001; Williamson, Birmaher, Dahl et al., 2005). Because most studies are cross-sectional, it remains unclear whether life events represent correlates, as opposed to causes, of anxiety. However, in a longitudinal study, adverse life events in adolescence predicted incidence of future anxiety, with a particularly strong risk in females for generalized anxiety disorder (Pine, Cohen, Johnson et al., 2002). Similar associations have been found among adults, in that the same varieties of psychosocial risk exhibit associations with pediatric and adult anxiety disorders. Subclinical elevations on anxiety rating scales and personality style questionnaires, such as the Children’s Anxiety Sensitivity Index (CASI), have been considered risk factors for anxiety disorders (Pine, Cohen, & Brook, 2001). Whether such measures reflect current anxiety, as opposed to risk factors, remains controversial (Mannuzza, Klein, Moulton et al., 2002). So far, no data document an association between such scale ratings and future anxiety. Finally, risks associated with medical conditions have been reported. In the perinatal period, various adversities have been linked to risk for anxiety. These include neurological injury, febrile seizures, low birth weight, exposure to toxins and minor neurological findings (Breslau, 1995; Breslau & Chilcoat, 2000; Breslau, Chilcoat, Johnson et al., 2000; Shaffer, Schonfeld, O’Connor et al., 1985; Vasa, Gerring, Grados et al., 2002; Whitaker, Van Rossem, Feldman et al., 1997). However, as with other risk factors, no consistent findings emerge. The strongest medical risk factor appears to be respiratory dysregulation. Circumstances that produce recurrent dyspnea predict risk for pediatric anxiety disorders (Goodwin, Pine, & Hoven, 2003; Slattery, Klein, Pine et al., 2002); associations are particularly strong with asthma, which confers risk CHAPTER 39 634 9781405145497_4_039.qxd 29/03/2008 02:52 PM Page 634

for separation anxiety disorder and panic attacks. Cigarette smoking during adolescence also incurs risk for future panic attacks, but not for social anxiety disorder (Johnson, Cohen, Pine et al., 2000). Similar associations have not been found for illicit substances (Rutter, Maughan, & Kim-Cohen, 2006). Findings are consistent with other work implicating respiratory dysfunction in separation anxiety disorder and panic disorder. Kagan, Snidman, McManis et al. (2001) noted a relationship between what has been designated as inhibited childhood temperament and later anxiety disorders. Children with inhibited temperament are defined as high reactive during infancy, behaviorally inhibited and reacting with apprehension to novelty during toddlerhood. They are defined as in the top 15% in delay to speak and smile in novel settings. Altogether, associations between inhibition and psychopathology have been examined in thousands of children. Findings by Kagan (1994) suggest an association between behavioral inhibition and later anxiety, with distinct associations at different developmental periods. During school-age years, increased risk occurs for various anxiety disorders, including separation anxiety disorder and phobias. Others find that inhibition at age 3 predicts risk for depression but not anxiety at age 21 (Caspi, Moffitt, Newman et al., 1996). Associations with anxiety vary in strength, and correlations between inhibition and anxiety ratings cross-sectionally, let alone over time, are rarely greater than 0.20–0.40. Hence, the magnitude of associations is at best moderate. However, some evidence suggests particularly strong associations for measures of social anxiety in adolescence (Hayward, Killen, Kraemer et al., 1998; Schwartz, Snidman, & Kagan, 1999). Comparable associations also emerge with shyness in early childhood, and with anxiety in early adolescence, with odds ratios in the moderate range (Prior, Smart, Sanson et al., 2000), as well as for teacher or parent measures of anxious/withdrawn behavior in childhood and anxiety disorders in adulthood (Goodwin, Fergusson, & Horwood, 2004). Longitudinal Outcome The long-term consequences of childhood anxiety disorders take on special importance given the high proportion of affected children. The study of diagnostic stability has used community cases, high-risk children and clinic patients, using retrospective and prospective designs. Seven community-based studies have examined the course of specific anxiety disorders. The first, from Dunedin (Anderson, Williams, McGee et al., 1987), provides indirect evidence on outcome for individual anxiety disorders (Feehan, McGee, & Williams, 1993; Kim-Cohen, Caspi, Moffitt et al., 2003; McGee, Feehan, Williams et al., 1992; Poulton, Pine, & Harrington, in press). In the initial follow-up, from age 11 to 15, a composite index of any mood or anxiety disorder predicted later anxiety for girls, but not boys (McGee, Feehan, Williams et al., 1992). This sex difference was obtained in two other prospective studies (Costello, Angold, & Keeler, 1999; Rueter, Scaramella, Wallace et al., 1999). The latter also found that emotional symptoms predicted major depression. Further follow-up documents longitudinal associations in anxiety disorders, with little relationship between specific child and adult anxiety disorders. The results from two other community-based studies provide similar evidence of nonspecific risk for adult anxiety disorders among adolescents with a range of anxiety disorders (Bittner, Goodwin, Wittchen et al., 2004; Lewinsohn, Zinbarg, Seeley et al., 1997). Thus, five studies found that anxiety disorders during childhood or adolescence predicted risk for an array of mood or anxiety disorders during adulthood. None documented diagnostic specificity in outcome. Two other studies found evidence of specificity. A school-based study found specificity in the course of social phobia but not separation anxiety disorder across adolescence (Hayward, Killen, Kraemer et al., 1998). Perhaps the strongest evidence of longitudinal specificity derives from the New York longitudinal study (Pine, Cohen, Gurley et al., 1998). From childhood or adolescence to adulthood, specific phobias predicted specific phobias exclusively. Similarly, social phobia was predictive of social phobia exclusively. Separation anxiety disorder predicted no specific disorder, but tended to predict panic attacks, and overanxious disorder was associated with an array of adult disorders including anxiety disorders, but not overanxious disorder, and major depression. Beyond these community-based studies, evidence of specificity in course also emerged from a prospective high-risk study that followed children of parents with either major depression or panic disorder. Phobias and overanxious disorder, but not separation anxiety disorder, carried a two- to fourfold increase of major depression at follow-up (Weissman, Warner, Wickramaratne et al., 1997). The course of childhood anxiety disorders has also been reported for clinic samples. Two studies ascertained children with school refusal and prominent anxiety symptoms prior to the nosological system introduced in the early 1980s (Berg & Jackson, 1985; Flakerska-Praquin, Lindstoem, & Gillberg, 1997). The majority of children experienced relatively benign clinical courses into adulthood. Three other clinical studies (Aschenbrand, Kendall, Webb et al., 2003; Klein, 1995; Last, Hansen, & Franco, 1997) confirm a relatively low rate of later anxiety disorders in children with anxiety disorders. In the study by Klein (1995), separation anxiety disorder coupled with school phobia predicted panic disorder, as well as major depression, although panic disorder was not a frequent outcome (7% versus 0% in non-anxious comparisons). Another short-term follow-up found an elevated rate of panic disorder only among clinic children with “primary” separation anxiety disorder (Aschenbrand, Kendall, Webb et al., 2003). In conclusion, data from outcome studies support several observations. Although childhood anxiety disorders show considerable stability, most children with anxiety disorders do not have anxiety disorders or depression in adulthood. However, most adults with anxiety or mood disorders are likely to have a childhood history of anxiety. Evidence of specific risk for adult mood and anxiety disorders is not strong. ANXIETY DISORDERS 635 9781405145497_4_039.qxd 29/03/2008 02:52 PM Page 635

Pathophysiology Family Genetics Familial aggregation studies have relied on multiple designs, summarized below. Family Studies During the past 25 years, more than 20 studies have reported an association between various forms of parental psychopathology and childhood anxiety (Beidel & Turner, 1997; McClure, Brennan, Hammen et al., 2001; Merikangas, Avenevoli, Dierker et al., 1999; Middeldorp, Cath, Van Dyke et al., 2005; Rende, Wickramaratne, Warner et al., 1995; Turner, Beidel, & Costello, 1987; Warner, Mufson, & Weissman, 1995; Weissman, Leckman, Merikangas et al., 1984). These studies include so-called “top-down” studies, which evaluate children of parents with anxiety or depressive disorders, as well as a handful of so-called “bottom-up” studies, which ascertain parents of children with anxiety disorders. Multiple studies reported higher rates of anxiety disorders in children of parents with anxiety disorders, relative to children of non-ill parents, as shown in Table 39.2. Questions arising from these studies concern the specificity of parent– child concordance for anxiety disorders versus depression, and specificity of aggregation for distinct anxiety disorders (Middeldorp, Cath, Van Dyck et al., 2005). The weight of evidence from the studies in Table 39.2 suggests non-specificity in the associations between offspring anxiety disorders and parental anxiety and depression. Some work provides evidence of specificity for parent–child anxiety disorders aggregation. An association between panic disorder in parents and separation anxiety disorder in offspring is the most consistent finding (Biederman, Faraone, Hirshfeld-Becker et al., 2001, 2004; Capps, Sigman, Sena et al., 1996). Coupled with data implicating respiratory dysfunction in the two conditions, these data suggest that panic disorder and separation anxiety disorder share an underlying diathesis (Klein, 1993). An association between parental depression and separation anxiety disorder in offspring has also been noted (Biederman, Monuteaux, Faraone et al., 2004). Other data suggest that parental depression is associated with offspring social anxiety disorder, phobias and generalized anxiety disorder, but not separation anxiety disorder (Lieb, Isensee, Höfler et al. 2002; Merikangas, Avenevoli, Dierker et al., 1999). Finally, late adolescent rather than adult onset panic disorder may be particularly heritable (Goldstein, Wickram-aratne, Horwath et al., 1997). Genetic Studies In the light of consistent cross-generational transmission, attempts have been made to decompose familial transmission into environmental and genetic components. Few studies have been conducted in pediatric anxiety, none using an adoption design and most relying on symptom scales. Among adults, a growing literature suggests that genetic factors account for approximately 40% of the variability in risk for anxiety, with most of the remaining variance attributed to non-shared environmental factors (Hettema, Neale, & Kendler, 2001; Hettema, Prescott, Myers et al., 2005). These studies provide evidence of both unique and shared liabilities across distinct adult disorders. Generalized anxiety disorder and major depressive disorder appear to share a genetic substrate, and differ largely in contributions from non-shared environmental factors (Hettema, Neale, & Kendler, 2001). Studies in adolescents suggest similar genetic patterns, with common genes predisposing towards anxiety before puberty and depression after puberty (Silberg, Pickles, Rutter et al., 1999; Silberg, Rutter, & Eaves, 2001). Other anxiety disorders appear to have more disorder-specific genetic risk. For example, genetic risk for panic disorder appears distinct from the risk for phobias, generalized anxiety disorder and major depression (Hettema, Prescott, Myers et al., 2005). While not all twin data support specificity, the weight of evidence indicates that adult anxiety disorders are influenced by both disorderspecific and disorder-unique liability factors (Middeldorp, Cath, Van Dyck et al., 2005). Genetic influences on anxiety comorbidity have been examined in a large twin study (Hettema, Prescott, Myers et al., 2005). The study found genetic influences to separate two groups of anxiety disorders. One consisted of panic disorder and generalized anxiety disorder, the other of specific phobias. Based on these genetic findings, comorbidity between panic disorder and generalized anxiety disorder is to be expected. Other work in this sample suggests that shared liability to a range of anxiety states may be expressed through underlying personality factors, such as neuroticism (Hettema, Neale, Myers et al., 2006). Extending the search for possible explanations of comorbidity across anxiety disorders, the twin sample was used to test the contribution of neuroticism to the genetic variance in anxiety disorders (Hettema, Neale, Myers et al., 2006). In children, divergent estimates of heritability emerge from studies using scale scores (Bolton, Eley, O’Connor et al., 2006; Eley, Bolton, O’Connor et al., 2003; Eley & Stevenson, 1999; Eley, Stirling, Ehlers et al., 2004; Topolski, Hewitt, Eaves et al., 1999). Similar assessment methods have yielded divergent estimates for parent and child rated anxiety scales. Twin data in children are consistent in suggesting a modest genetic component to most forms of childhood anxiety, with heritabilities generally accounting for less than 40% of the variance. These relatively low heritabilities across the age range have led to the suggestion that genes confer a broad diathesis towards anxiety as opposed to a predilection for one or another specific disorder. Consistent with this possibility, heritabilities for temperamental factors, such as behavioral inhibition, have been somewhat higher than those for specific anxiety symptoms or disorders (Goldsmith & Lemery, 2000). Non-shared environmental factors account for much of the remaining variance in child-based twin studies of anxiety symptoms, much as they do in adults. Results in children show variability in genetic and environmental contributions to anxiety. This variability, which may reflect distinct genetic and environmental effects across age, sex and specific forms CHAPTER 39 636 9781405145497_4_039.qxd 29/03/2008 02:52 PM Page 636