ANXIETY DISORDERS 28
Table 28.1 A brief description of anxiety and related disorders Box 28.1 Patient testimonies (NICE, 2005a, 2005b)
Symptoms common Fear or worry, sleep disturbances, Symptoms described by a sufferer of posttraumatic stress disorder:
to all anxiety disorders concentration problems, dry mouth, I would feel angry at the way the crash happened and that
sweating, palpitations, GI discomfort,
restlessness, shortness of breath, avoid- there was nothing I could do to stop it or help. I was physically
ance behaviour exhausted, but was finding it hard to sleep. As soon as the bed-
room light went out at night a light would come on in my head
Generalised anxiety Persistent (free-floating), excessive and and all I could do was lie there and think. When I would eventu-
disorder (GAD) inappropriate anxiety on most days for ally fall asleep, I would wake up with nightmares of the crash. I
at least 6 months. The anxiety is not could not get away from it. It was all I could think about in the
restricted to a specific situation. day and all I would dream about at night.
Panic disorder (with or Recurrent, unexplained surges of severe Thoughts from a sufferer of obsessive-compulsive disorder:
without agoraphobia) anxiety (panic attack). Most patients I’ve just arrived home from work. Tired and tense, I’m
develop a fear of repeat attacks or the convinced my hands are contaminated with some hazardous
implications of an attack. Often seen in substance and my primary concern now is to ensure that I don’t
agoraphobia (fear in places or situations spread that contamination to anything that I, or others, may sub-
from which escape might be difficult). sequently touch. I will wash my hands, but first I will need to put a
hand in my pocket to get my door keys, contaminating these, the
Social anxiety disorder A marked, persistent and unreasonable pocket’s other contents, and everything else I touch on my way
(or social phobia) fear of being observed, embarrassed or to the sink. It will be late evening before I will have completed
humiliated in a social or performance the whole decontamination ritual.
situation (e.g. public speaking or eating A slow recovery described by a posttraumatic stress disorder
in front of others) and panic attack sufferer:
Slowly I gained ground and as each new insight came I was able
Specific phobia Marked and persistent fear that is exces- to see my symptoms diminish. The panic attacks tapered off, the
sive or unrealistic, precipitated by the intensity of the flashbacks dwindled, and my irritable bowel began
presence (or anticipation) of a specific to loosen some of its hold on me. I was able to breathe again.
object or situation (e.g. flying, spiders).
Sufferers avoid the feared object/subject of more than one anxiety disorder at the same time, which can
or endure it with intense anxiety. further complicate treatment. Anxiety disorders are the most
commonly reported mental disorders and as a whole have a life-
Posttraumatic stress Can occur after an exposure to a time prevalence of approximately 21% (Baldwin et al., 2014),
disorder (PTSD) traumatic event which involved actual with speciic phobias the most commonly reported.
or threatened death or serious injury or
threats to the physical integrity of self For all anxiety disorders together, the overall female-to-male
or others. The person responds with ratio is 2:1. The age of onset of most anxiety disorders is in young
intense fear, helplessness or horror. adulthood (20s and 30s), although the maximum prevalence of
Sufferers can re-experience symptoms generalised anxiety and agoraphobia in the general population is
(flashbacks) and avoid situations associ- in the 50- to 64-year-old age group.
ated with the trauma. Usually occurs
within 6 months of the traumatic event.
Obsessive-compulsive Persistent thoughts, impulses or images Pathophysiology
disorder (OCD) (obsessions) that are intrusive and cause
distress. The person attempts to get
rid of these obsessions by completing Anxiety occurs when there is a disturbance of the arousal systems
repetitive, time-consuming purposeful in the brain. Arousal is maintained by at least three interconnected
behaviours or actions (compulsions). systems: a general arousal system, an ‘emotional’ arousal system
Common obsessions include contamina- and an endocrine/autonomic arousal system (Fig. 28.3). The gen-
tion, and the compulsion may be repeti- eral arousal system, mediated by the brainstem reticular forma-
tive washing or cleaning. tion, thalamic nuclei and basal forebrain bundle, serves to link the
cerebral cortex with incoming sensory stimuli and provides a tonic
GI, Gastro-intestinal. inluence on cortical reactivity or alertness. Excessive activity in
this system, due to internal or external stresses, can lead to a state
are now considered to be separate illnesses. For completeness, of hyperarousal as seen in anxiety. Emotional aspects of arousal, 485
though, these will also be discussed here. Table 28.1 presents a such as fear and anxiety, are contributed by the limbic system,
brief description of anxiety and related disorders. Patient testimo- which also serves to focus attention on selected aspects of the envi-
nials are presented in Box 28.1. Approximately two-thirds of suf- ronment. There is evidence that increased activity in certain limbic
ferers of an anxiety disorder will have another psychiatric illness. pathways is associated with anxiety and panic attacks.
This is most commonly depression, and often successful treat-
ment of an underlying depression will signiicantly improve the These arousal systems activate physical responses to arousal,
symptoms of anxiety. Many patients also present with symptoms such as increased muscle tone, increased sympathetic activity
28 THERAPEUTICS
CORTEX
AROUSAL SYSTEMS SLEEP SYSTEMS
General SWS
REMS
(reticular (Brainstem,
basal forebrain,
Emotional formation, pons, etc.)
(limbic thalamic and
system) other nuclei)
Somatic
(hypothalamus
pituitary)
Motor, Inhibition
autonomic, Excitation
endocrine Inhibition or excitation
Incoming
sensory stimuli
Fig. 28.3 Diagram of arousal and sleep systems. Arousal systems receive environmental and internal
stimuli, cause cortical activation and mediate motor, autonomic and endocrine responses to arousal.
Reciprocally connected sleep systems generate slow-wave sleep (SWS) and rapid eye movement sleep
(REMS). Either system can be excited or inhibited by cognitive activity generated in the cortex.
and increased output of anterior and posterior pituitary hormones. linked to genetic factors. Many patients presenting for the irst
Inappropriate increases in autonomic activity are often associated time with anxiety symptoms have a long history of high anxiety
with anxiety states; the resulting symptoms (palpitations, sweating, levels going back to childhood. Anxiety may also be induced by
tremor, etc.) may initiate a vicious circle that increases the anxiety. central stimulant drugs (e.g. caffeine, amphetamines), withdrawal
from chronic use of central nervous system depressant drugs (e.g.
Several neurotransmitters have been implicated in the arousal alcohol, hypnotics, anxiolytics) and metabolic or endocrine dis-
systems. Acetylcholine is the main transmitter maintaining general turbances (e.g. hyperventilation, hypoglycaemia, thyrotoxicosis).
arousal, but there is evidence that heightened emotional arousal is Anxiety may form part of a depressive disorder or psychosis and
particularly associated with noradrenergic and serotonergic activ- may occur in temporal lobe lesions and in rare hormone-secreting
ity. Drugs which antagonise such activity have anxiolytic effects. tumours such as phaeochromocytoma or carcinoid syndrome.
In addition, the inhibitory neurotransmitter γ-aminobutyric acid
(GABA) exerts an inhibitory control on other transmitter pathways, Apart from the psychological symptoms of apprehension
and increased GABA activity may have a protective effect against and fear, somatic symptoms may be prominent in anxiety and
excessive stress reactions. Many drugs which increase GABA include palpitations, chest pain, shortness of breath, dizziness,
activity, such as the benzodiazepines, are potent anxiolytics. dysphagia, gastro-intestinal disturbances, loss of libido, head-
aches and tremor. Panic attacks are experienced as storms of
Aetiology and clinical increased autonomic activity combined with a fear of imminent
manifestations death or loss of control. If panic becomes associated with a par-
ticular environment, commonly a crowded place with no easy
Anxiety is commonly precipitated by stress or adverse life events, escape route, the patient may actively avoid similar situations
486 but vulnerability to stress and trait anxiety also appear to be and eventually become agoraphobic. When anxiety is precipi-
tated by a speciic cause, then behaviour can become altered to
ensure the sufferer avoids the cause. This avoidance behaviour
ANXIETY DISORDERS 28
can maintain the often-irrational fear and strengthen the desire In PTSD, CBT is trauma focused, with the therapist help-
to avoid the threat. ing patients confront their traumatic memories and people or
objects associated with the trauma. At the same time, patients are
Investigations and differential taught skills to help them cope with the emotional or physical
diagnosis response to the trauma. One such skill includes relaxation train-
ing, which may involve systematically relaxing major muscle
In patients presenting with symptoms and clinical signs of anxi- groups in a way that decreases anxiety. Another psychotherapy
ety, it is important to exclude organic causes such as thyrotoxi- sometimes recommended in PTSD is eye movement desensitisa-
cosis, excessive use of stimulant drugs such as caffeine and the tion and reprocessing (EMDR). This involves briely recounting
possibility of alcohol dependence or withdrawal effects from the trauma or objects associated with the trauma to the thera-
benzodiazepines. However, unnecessary investigations should pist, who will then simultaneously initiate another stimulus, for
generally be avoided if possible. Extensive gastroenterological, example, moving a inger continuously in front of the patient’s
cardiological and neurological tests may increase anxiety by rein- eyes or hand tapping. Over time, it enables the patient to focus
forcing the patient’s fear of a serious underlying physical disease. on alternative thoughts when associations with the trauma occur.
Routinely applied single- or multiple-session ‘debrieing’ follow-
Treatment ing a traumatic event is not thought effective to prevent PTSD
and, therefore, not recommended.
Treatment for anxiety disorders often requires multiple
approaches. The patient may need short-term treatment with an In OCD, CBT includes exposure and response prevention
anxiolytic, such as a benzodiazepine, to help reduce the imme- (ERP). This involves the therapist and the patient repeatedly
diate symptoms combined with psychological therapies and an facing the fears, beginning with the easiest situations and pro-
antidepressant for longer-term treatment and to prevent relapse gressing until all the fears have been faced. At the same time the
of symptoms. person must not perform any rituals or checks.
Psychological interventions Speciic phobias, illness anxiety disorder and separation anxi-
ety disorder are also almost exclusively treated using psychologi-
Psychological therapies (‘talking therapies’) are generally con- cal therapies. Only a few patients will require additional drug
sidered irst-line treatments in all anxiety disorders because therapy, which is usually a selective serotonin reuptake inhibitor
they may provide lower relapse rates than pharmacotherapy. (SSRI).
Psychotherapy, however, is less readily available, is more emo-
tionally demanding and takes longer to work than pharmacother- Other psychotherapies (excluding those based on CBT tech-
apy. If the patient is unable to tolerate the anxiety or associated niques) are occasionally tried, but these have a poorer evidence
distress, then medicines are often used before psychotherapy or base and are, therefore, not usually recommended. Self-help
while awaiting psychotherapy. The ideal treatment should be tai- approaches are recommended (National Institute for Health and
lored to the individual and optimised treatment may involve the Care Excellence [NICE], 2011) for GAD and panic disorder.
combination of psychotherapy and pharmacotherapy. The type They usually involve using materials either alone or in part under
of treatment should depend on symptoms, type of anxiety dis- professional guidance to learn skills to help cope with the anxi-
order, speed of response required, long-term goals and patient ety. The materials, such as books, tapes or computer packages,
preference. can be accessed at home and at the patient’s convenience. Some
self-help material, however, is of poor quality, so it is probably
The speciic psychotherapy with the most supporting evidence best used in those who have mild symptoms and who do not need
in anxiety disorders is cognitive behavioural therapy (CBT). CBT more intensive treatments.
focuses on the ‘here and now’ and explores how individuals feel
about themselves and others and how behaviour is related to Pharmacotherapy
these thoughts. Through individual therapy or group work, the
patient and therapist identify and question maladaptive thoughts Benzodiazepines 487
and help develop an alternative perspective. Individual goals and
strategies are developed and evaluated with patients, who are Benzodiazepines are often prescribed to provide an immediate
encouraged to practise what they have learned between sessions. reduction in the symptoms of severe anxiety. Various benzodiaz-
Therapy usually lasts for around 60–90 minutes every week for epines are available (Table 28.2). These drugs differ considerably
8–16 weeks, or longer in more resistant cases. Cognitive behav- in potency (equivalent dosage) and in the rate of elimination but
ioural therapists are usually health professionals such as mental only slightly in clinical effects. All benzodiazepines have seda-
health nurses, psychologists, primary care doctors, social work- tive/hypnotic, anxiolytic, amnesic, muscular relaxant and anti-
ers, counsellors or occupational therapists who have undertaken convulsant actions, with minor differences in the relative potency
speciic training and supervision. of these effects.
Pharmacokinetics. Most benzodiazepines are well absorbed
and rapidly penetrate the brain, producing an effect within half an
hour after oral administration. Rates of elimination vary, however,
with elimination half-lives from 8 to 35 hours (see Table 28.2). The
drugs undergo hepatic metabolism via oxidation or conjugation
and some form pharmacologically active metabolites with shorter
28 THERAPEUTICS
or even longer elimination half-lives. An example of this effect benzodiazepines bind to these sites, although with varying degrees
is diazepam, which has active metabolites including temazepam of afinity, and potentiate the inhibitory actions of GABA at these
and oxazepam. Oxidation of benzodiazepines is decreased in the sites. GABA is the most important inhibitory neurotransmitter in
elderly, in patients with hepatic impairment and in the presence the central nervous system (CNS). Neuronal activity in the CNS
of some drugs, including alcohol. Benzodiazepines are metabo- is regulated by the balance between GABA inhibitory activity
lised mostly through the cytochrome P450 3A4/3 enzyme system and excitatory neurotransmitters such as glutamate. If the bal-
in the liver, so signiicant enzyme inducers (e.g. carbamazepine) ance swings towards more GABA activity, sedation, ataxia and
may reduce levels, whereas enzyme inhibitors (e.g. erythromy- amnesia occur. Conversely, when GABA is reduced arousal, anxi-
cin) may increase levels (Bazire, 2014). ety and restlessness occur. GABAA receptors are multimolecular
complexes that control a chloride ion channel and contain speciic
Mechanism of action. Most of the effects of benzodiaz- binding sites for GABA, benzodiazepines and several other drugs,
epines result from their interaction with speciic binding sites including many nonbenzodiazepine hypnotics and some anticon-
associated with postsynaptic GABAA receptors in the brain. All vulsant drugs (Haefely, 1990) (Fig. 28.4). The various effects of
benzodiazepines (hypnotic, anxiolytic, anticonvulsant, amnesic,
Table 28.2 Profile of selected benzodiazepines (Bazire, 2014; muscle-relaxant) result from GABA potentiation in speciic brain
Taylor et al., 2015) sites and at different GABAA receptor types. There are multiple
subtypes of GABAA receptor which may contain different com-
Drug Usual daily Half-life Equivalent dose binations of at least 17 subunits (including α1–6, β1–3, γ1–3, and
Alprazolam dose (mg) hours to diazepam others), and the subtypes are differentially distributed in the brain
(range) 10 mg (Christmas et al., 2008). Benzodiazepines bind to two or more sub-
types, and it appears that combination with α2-containing subtypes
0.5–1.5 13 (12–15) Unknown mediates their anxiolytic effects and α1-containing subtypes their
sedative and amnesic effects. There is some evidence that patients
Chlordiazepoxide 30 12 (6–30) 30 mg with anxiety disorders have reduced numbers of benzodiazepine
receptors in key brain areas that regulate anxiety responses (Roy-
Clonazepam 2–4 35 (20–60) 1–2 mg Byrne, 2005). Secondary suppression of noradrenergic and/or
serotonergic and other excitatory systems may also be of impor-
Diazepam 5–30 32 (21–50) — tance in relation to the anxiolytic effects of benzodiazepines.
Lorazepam 1–4 12 (8–25) 1 mg Role in treating anxiety. Benzodiazepines have been used
for more than 50 years in the treatment of anxiety and can
Oxazepam 30 8 (5–15) 30 mg provide rapid symptomatic relief from acute anxiety states.
Temazepam 10–20 8 (5–11) 20 mg
Chloride ion channel
B Cl – Cl – B
Neuronal membrane Extracellular surface
Intracellular surface
Cl –
GABA activation of receptor opens channel gate, an effect
enhanced by benzodiazepine binding to receptor subunits
Fig. 28.4 Schematic diagram of the GABAA receptor. This consists of five subunits arranged around a
central chloride ion channel (one subunit has been removed in the diagram to reveal the ion channel,
shown in the closed position). Some of the subunits have binding sites for benzodiazepines (B) and
other hypnotics and anticonvulsants. Activation of the receptor by GABA opens the chloride channel,
allowing chloride ions (Cl–) to enter the cell, resulting in hyperpolarisation (inhibition) of the neuron.
Occupation of the benzodiazepine site, along with GABA, potentiates the inhibitory actions of GABA.
488
ANXIETY DISORDERS 28
Concerns about dependence and tolerance largely restrict use patients on long-term benzodiazepines complain of poor mem-
to short-term treatment (Baldwin et al., 2013a). Many clinical ory, and incidents of shoplifting have been attributed to memory
trials have shown short-term eficacy in patients with anxiety lapses associated with benzodiazepine use. In elderly patients,
disorders, although the eficacy shown is in part dependent on the amnesic effects may falsely suggest the development of
the year of publication of the study. Older randomised con- dementia. There is some evidence that benzodiazepines also
trolled trials appear to show a larger effect than more recent ones inhibit the learning of alternative stress-coping strategies, such
(Martin et al., 2007). Anxiolytic effects have also been reported as behavioural treatments for agoraphobia. Additive effects with
in normal volunteers with high trait anxiety and in patients with other CNS depressants, including alcohol, occur and may con-
anticipatory anxiety before surgery. However, in subjects with tribute to road trafic and other accidents.
low trait anxiety and in nonstressful conditions, benzodiazepines
may paradoxically increase anxiety and impair psychomotor Disinhibition, paradoxical effects. Rarely, benzodiaze-
performance. pines produce paradoxical stimulant effects. These effects are
most marked in impulsive individuals and include excitement,
Although useful for many anxiety disorders, benzodiazepines increased anxiety, irritability and outbursts of rage. Violent
are not generally recommended for those with panic disorder behaviour has sometimes been attributed to disinhibition by
(NICE, 2011). Some patients report worse panic attacks after the benzodiazepines. This behaviour is normally suppressed by
benzodiazepines are stopped. Benzodiazepines are also useful at social restraints, fear or anxiety. Increased daytime anxiety can
the start of SSRI treatment in OCD and as hypnotics in PTSD also occur with rapidly eliminated benzodiazepines and may be
(NICE, 2005a, 2005b). They should, however, be used at the low- a withdrawal effect.
est effective dose, prescribed intermittently where possible and
used for no longer than 2–4 weeks. Affective reactions. Chronic use of benzodiazepines can
worsen depression and may possibly provoke suicide attempts
Choice of benzodiazepine in anxiety. The choice of ben- in impulsive patients. Aggravation of depression is a particular
zodiazepine depends largely on pharmacokinetic characteris- risk in anxious patients who often have mixed anxiety/depres-
tics. Potent benzodiazepines such as lorazepam and alprazolam sion. Benzodiazepines are taken alone or in combination with
(Table 28.2) have been widely used for anxiety disorders but are other drugs in 40% of self-poisoning incidents. Although
probably inappropriate. Both are rapidly eliminated and need to relatively nontoxic in overdose, they can cause fatalities as
be taken multiple times a day. Declining blood concentrations a result of drug interactions and in those with respiratory
may lead to interdose anxiety as the anxiolytic effect of each disease.
tablet wears off. The high potency of lorazepam (∼10 times that
of diazepam), and the fact that it is available only in 1- and 2.5 Some patients on long-term benzodiazepines complain of
mg tablet strengths, has often led to excessive dosage. Similarly, ‘emotional anaesthesia’, the inability to experience either plea-
alprazolam (∼20 times more potent than diazepam) has often sure or distress. However, in some patients, benzodiazepines
been used in excessive dosage, particularly in the USA. Such induce euphoria, and they are occasionally used as drugs of
doses lead to adverse effects, a high probability of dependence abuse.
and dificulties in withdrawal.
Dependence. The greatest drawback of chronic benzodiaz-
A slowly eliminated benzodiazepine such as diazepam is epine use is the risk of drug dependence. It is generally agreed
more appropriate in most cases. Diazepam has a rapid onset of that the regular use of therapeutic doses of benzodiazepines as
action, and its slow elimination ensures a steady blood concen- hypnotics or anxiolytics for more than a few weeks (2–4 weeks)
tration. Clonazepam, although long acting, is more potent than can give rise to dependence, with withdrawal symptoms on ces-
diazepam and in practice is often dificult to withdraw from. It sation of drug use in around 40% of patients. It is estimated that
is only indicated for epilepsy in the UK but is commonly used as there are about 1 million long-term benzodiazepine users in the
an anxiolytic. UK, and many of these are likely to be dependent. People with
substance misuse histories or anxious or ‘passive-dependent’ per-
Parenteral administration of lorazepam or diazepam may occa- sonalities seem to be most vulnerable to dependence and with-
sionally be indicated for severely agitated patients. drawal symptoms. Such individuals make up a large proportion
of anxious patients in psychiatric practice, are often described
Adverse effects. Adverse effects include drowsiness, light- as suffering from ‘chronic anxiety’ and are the type of patient
headedness, confusion, ataxia, amnesia, a paradoxical increase for whom benzodiazepines are most likely to be prescribed. Such
in aggression, an increased risk of falls and of road trafic acci- patients often continue to take benzodiazepines for many years
dents. They are also widely acknowledged as addictive and because attempts at dosage reduction or drug withdrawal result
cause tolerance after more than 2–4 weeks of continuous use in intolerable abstinence symptoms. Nevertheless, these patients
(Taylor et al., 2015). Respiratory depression is rare but pos- continue to suffer from anxiety symptoms despite continued ben-
sible following high oral doses or parenteral use. Flumazenil, zodiazepine use, possibly because they have become tolerant
a benzodiazepine receptor antagonist, can reverse the effects of to the anxiolytic effects and may also suffer from other adverse
severe reactions but requires repeated dosing and close monitor- effects of long-term benzodiazepine use such as depression or
ing because of its short half-life. psychomotor impairment.
Psychomotor and cognitive impairment. Although overse- Abuse. Over the last 30 years, there has been much con-
dation is not usually a problem in anxious patients, there is cern about benzodiazepine abuse. Some patients escalate their
evidence that long-term use of benzodiazepines can result in prescribed dosage and may obtain prescriptions from several
psychomotor and memory impairment in some patients. Some
489
28 THERAPEUTICS
doctors. These tend to be anxious patients with ‘passive-depen- The eventual outcome does not appear to be inluenced by
dent’ personalities who may have a history of alcohol misuse; dosage, type of benzodiazepine, duration of use, psychiatric
they may combine large doses of benzodiazepines with excessive history, age, severity of withdrawal symptoms or rate of with-
alcohol consumption. In addition, a high proportion (30–90%) drawal. Hence, benzodiazepine withdrawal is worth attempt-
of illicit recreational drug abusers also use benzodiazepines, and ing in patients who are motivated to stop, and most patients
some take them as euphoriants in their own right. Recreational report that they feel better after withdrawal than when they
use of most benzodiazepines has been reported in various coun- were taking the benzodiazepine. Community pharmacists may
tries; in the UK, temazepam is the most commonly abused anx- be ideally suited to advise doctors and patients on the manage-
iolytic drug. Exceedingly large doses (over 1g) may be taken ment of benzodiazepine withdrawal. Leading a benzodiazepine
and sometimes injected intravenously. Benzodiazepines became withdrawal clinic may also be a useful role for non-medical
easily available due to widespread prescribing, which favoured prescribers.
their entrance into the illicit drug scene. Abusers can become
dependent and suffer the same adverse effects and withdrawal Drug interactions. In addition to the pharmacokinetic inter-
symptoms as prescribed-dose users. actions listed earlier, benzodiazepines have additive effects with
other CNS depressants. Combinations of benzodiazepines with
Benzodiazepine withdrawal. Many patients on long-term alcohol, other hypnotics, tricyclic antidepressants (TCAs), seda-
benzodiazepines seek help with drug withdrawal. Clinical expe- tive antipsychotics, antihistamines or opioids can cause marked
rience shows that withdrawal is feasible in most patients if car- sedation and may lead to accidents, collapse or severe respiratory
ried out with care. Abrupt withdrawal in dependent subjects is depression.
dangerous and can induce acute anxiety, psychosis or convul-
sions. However, gradual withdrawal, coupled where necessary Pregnancy and lactation. The regular use of benzodiaz-
with psychological treatments, can be successful in the major- epines is not recommended in pregnancy because the drugs are
ity of patients. The duration of withdrawal should be tailored to concentrated in fetal tissue where hepatic metabolism is mini-
individual needs and may last many months. Dosage reductions mal. They have been associated with an increased risk of oral
may be of the order of 1–2 mg of diazepam per month. Even with clefts following irst-trimester exposure, a low birth weight, neo-
slow dosage reduction, a variety of withdrawal symptoms may natal depression, feeding dificulties and withdrawal symptoms
be experienced, including increased anxiety, insomnia, hypersen- if given in late pregnancy. They also enter breast milk and may
sitivity to sensory stimuli, perceptual distortions, paraesthesia, cause sedation, lethargy and weight loss in the infant. Long-
muscle twitching, depression and many others (Box 28.2). These acting benzodiazepines should particularly be avoided during
may last for many weeks, although diminishing in intensity, but lactation because of the potential for the infant to accumulate the
occasionally, the withdrawal syndrome is protracted for a year or drug. Short- to medium-acting benzodiazepines are occasionally
more. Transfer to diazepam, because of its slow elimination and used with enhanced monitoring of the infant.
availability as a liquid and in low-dosage forms, may be indicated
for patients taking other benzodiazepines. Useful guidelines for Antidepressant drugs
benzodiazepine withdrawal are given in the British National
Formulary, and detailed withdrawal schedules are also available Antidepressants can provide a long-term treatment option for
(Lader et al., 2009). those with an anxiety disorder. They are generally recommended
for those who are unable to commit to or have not responded
Box 28.2 Benzodiazepine withdrawal symptoms to psychological therapies. In addition, antidepressants are con-
sidered irst-line treatment option either alone or in combina-
Symptoms common to Symptoms relatively specific to tion with CBT in patients suffering from OCD with moderate or
anxiety states benzodiazepine withdrawal severe impairment (NICE, 2005a). The number needed to treat
Anxiety, panic Perceptual distortions, sense of (NNT) to see one beneit with antidepressants is around ive in
Agoraphobia movement PTSD and GAD (NICE, 2005b, 2011).
Insomnia, nightmares Depersonalisation, derealisation
Depression, dysphoria Hallucinations The response rate to antidepressants in anxiety is often lower
Excitability, restlessness Distortion of body image and takes longer than that seen in depression. Initial worsening
Poor memory and Tingling, numbness, altered of symptoms can occur, and high therapeutic doses are often
concentration sensation required to improve response (Baldwin et al., 2014).
Dizziness, light-headedness Skin prickling (formication)
Weakness, ‘jelly legs’ Sensory hypersensitivity Selective serotonin reuptake inhibitors. The SSRIs have a
Tremor Muscle twitches, jerks broad anxiolytic effect and are considered the irst drug option
Muscle pain, stiffness Tinnitus in GAD, panic disorder, social anxiety disorder, PTSD and
Sweating, night sweats Psychosisa OCD (Baldwin et al., 2014; NICE, 2005a, 2005b, 2011, 2013).
Palpitations Confusion, deliriuma Individual SSRIs have varying licensed indications across the
Blurred or double vision Convulsionsa anxiety disorders, but this does not necessarily mean others have
Gastro-intestinal and urinary no supporting evidence. Where more than one SSRI is licensed
symptoms in a particular disorder, it is not possible to conclude which SSRI
would be more effective because of the lack of direct head-
490 aUsually only on rapid or abrupt withdrawal from high doses. to-head trials. The SSRIs differ in their interaction potential,
side-effect proile and ease of discontinuation. Initial worsen-
ing of symptoms is common when starting an SSRI in anxiety,
ANXIETY DISORDERS 28
so beginning with half the dose than that used in depression is the risk of symptoms returning, patients should be advised to con-
recommended, as is reassuring the patient that this is usually tinue the antidepressant for at least 6 months following improve-
only experienced for the irst few weeks of treatment. In view of ment of symptoms in panic disorder and for 12 months in GAD,
these concerns, the NICE guidelines for GAD and panic disor- PTSD, OCD and social anxiety disorder (Baldwin et al., 2014;
der recommend that patients are reviewed every 2 weeks for the NICE, 2005a, 2011). Those with an enduring and recurrent ill-
irst 6 weeks of treatment to monitor for eficacy and tolerabil- ness, however, may continue for many years, depending on the
ity (NICE, 2011). Although unlicensed, sertraline was recom- risk of relapse and severity of symptoms.
mended by NICE (2011) as the irst-line SSRI in GAD because it
was the most cost-effective drug. Sertraline and escitalopram are For a complete review of the antidepressants, including adverse
highlighted as appropriate irst-choice SSRIs in social anxiety effects and interactions, see Chapter 29.
disorder (NICE, 2013).
Other medications occasionally used in anxiety
Tricyclic antidepressants. Certain TCAs, such as clomip-
ramine, imipramine and amitriptyline, are eficacious in some Hydroxyzine, a sedating antihistamine, is licensed for the 491
anxiety disorders. They are, however, associated with a greater short-term treatment of anxiety in adults at a dose of 50–100
burden of adverse reactions, such as antimuscarinic effects, hypo- mg four times a day. The clinical evidence only supports its use
tension and weight gain. Of particular concern is the TCAs’ car- in GAD (for up to 4 weeks) if sedation is required (Baldwin
diac toxicity in overdose, which relegates their position to second et al., 2014).
line following the failure of an SSRI. They should be avoided in
any patient at risk of suicide or those with an underlying cardiac Antipsychotics have limited evidence and a high side effect
disease. TCAs commonly cause sedation, which occasionally burden when used in anxiety disorders. The first-generation
can prove useful in anxiety disorders. Clomipramine may also be (typical) antipsychotics are associated with movement dis-
slightly more effective in OCD compared with SSRIs. orders such as akathisia and tardive dyskinesia and so are
rarely used in anxiety. The second-generation (atypical)
Monoamine-oxidase inhibitors. The monoamine-oxi- antipsychotics are less likely to cause movement disorders
dase inhibitors (MAOIs) are rarely used in practice because but can have other physical health concerns. Antipsychotics
of their potentially severe interactions with other medicines (most commonly risperidone, olanzapine and quetiapine)
and tyramine in the diet. Moclobemide is a reversible MAOI, are occasionally used by specialists for those with resistant
so it causes fewer problematic interactions. Phenelzine and symptoms in OCD, GAD, PTSD and social anxiety disorder
moclobemide are occasionally used by specialists in social (Baldwin et al., 2014).
anxiety disorder following the failure of an SSRI. Phenelzine
is also recommended as a third-line treatment option in PTSD Pregabalin has robust evidence and is licensed for GAD and
(NICE, 2005b). has shown an anxiolytic effect over placebo after 1 week in
adults or 2 weeks in the elderly (Montgomery et al., 2008). Two
Other antidepressants. The selective and noradrenaline short-term studies in GAD (4 and 6 weeks) suggest that prega-
reuptake inhibitor (SNRI) venlafaxine has some evidence to balin 400–600 mg/day is as effective but better tolerated than
support its use in almost all the anxiety disorders but is only venlafaxine 75 mg/day XL or lorazepam 6 mg/day. Pregabalin
licensed for use in GAD, OCD and social anxiety disorder. is most commonly used in GAD in combination with an SSRI or
Discontinuation symptoms are common following venlafax- SNRI when initial treatments have failed (Baldwin et al., 2014).
ine withdrawal and can be experienced after missing a single Emerging evidence also supports pregabalin in social anxiety
dose. Patients prescribed venlafaxine should be reminded of the disorders. Adverse effects of pregabalin include dizziness,
importance of a slow withdrawal (over at least 4 weeks, some- somnolence and nausea, and there have been concerns raised
times longer) when discontinuation is necessary. Venlafaxine over its abuse potential (Baldwin et al., 2013b; Schnerning
can increase blood pressure at higher doses in some patients and et al., 2016).
so is contraindicated in patients with a high risk of cardiac ven-
tricular arrhythmia or uncontrolled hypertension. Duloxetine, Buspirone, a 5HT1A partial agonist, is licensed for short-term
another SNRI, is also licensed in GAD and can similarly use in anxiety. It is not a benzodiazepine and so does not treat
increase blood pressure; withdrawal symptoms are also reported or prevent benzodiazepine-withdrawal problems. In GAD, bus-
after abrupt discontinuation. pirone and other azapirones are superior to placebo in short-term
studies (4–9 weeks) but less effective or acceptable than benzodi-
Mirtazapine, an α2-adrenoreceptor antagonist, is recommended azepines (Chessick et al., 2006). Buspirone is occasionally used
as an option for PTSD if patients do not wish to participate in in GAD after nonresponse to the irst-line treatments.
trauma-focused CBT (NICE, 2005b). Mirtazapine has a lower
incidence of nausea, vomiting and sexual dysfunction than the Propranolol and oxprenolol are both licensed for anxiety
SSRIs but can commonly cause weight gain and sedation. symptoms but are probably only useful for physical symptoms
such as palpitations, tremor, sweating and shortness of breath.
Agomelatine, a melatonin agonist and speciic serotonin recep- Beta blockers do not have suficient evidence to support their
tor antagonist, has proven eficacy in the acute treatment and pre- inclusion in NICE guidelines, but intriguingly, small pilot studies
vention of relapse in GAD (Baldwin et al., 2014), although it is indicate that giving an immediate course of propranolol follow-
currently unlicensed for these conditions. ing a traumatic event may prevent emerging PTSD (Pitman et al.,
2002; Vaiva et al., 2003).
No other antidepressants are routinely recommended for anxi-
ety disorders, although some, such as vortioxetine, have been An overview of the recommended drug treatments in anxiety is
evaluated in GAD to investigate potential future uses. To reduce provided in Table 28.3.
28 THERAPEUTICS
Table 28.3 Overview of the recommended drug treatments in anxiety
Immediate Generalised anxiety Panic disorder Social anxiety Obsessive-compulsive Posttraumatic stress
management/ disorder disorder (social disorder disorder
short-term Benzodiazepines not phobia)
treatment Benzodiazepines recommended by Benzodiazepines Hypnotics may be
(2–4 weeks only) NICE Benzodiazepines (only to counter initial considered for
(2–4 weeks only) worsening of short-term use for
symptoms with SSRIs) insomnia
First-line SSRI SSRI SSRI SSRI SSRI
pharmacotherapya Escitalopram Citalopram Citalopram– Escitalopram Escitalopram
Paroxetine Escitalopram– Escitalopram– Fluoxetine Fluoxetine–
Paroxetine Paroxetine Sertralineb Fluvoxamine
Sertraline Paroxetine–Sertraline
Other drug Agomelatine Clomipramineb Moclobemidec Clomipramine Amitriptylinec
treatments with Buspirone Imipramineb Phenelzinec Augmentation
supporting Duloxetine Mirtazapine with aripiprazole, Augmentation
evidence Imipramine Moclobemide Venlafaxine quetiapine or
Pregabalinc Venlafaxine Pregabalinc risperidonec with olanzapine or
Venlafaxine risperidonec
Quetiapine
Vilazodone Imipramine
Vortioxetine Mirtazapineb
Phenelzinec
Venlafaxine
Prazosinc
aThe licensed SSRI is indicated but other SSRIs may also be beneficial.
bUnlicensed but recommended by NICE (2005a, 2005b, 20011, 2013).
cUsually prescribed by mental health specialists only.
SSRI, Selective serotonin reuptake inhibitor.
Case studies Answers
Case 28.1 1. Benzodiazepines are not recommended in OCD. The first choice is
CBT or an SSRI.
Mrs DW is a 32-year-old with a 10-year history of ‘emotional prob-
lems’. These have largely been dealt with by her primary care 2. Potential drug treatments include high-dose SSRIs or clomip-
doctor, who has prescribed low-dose TCAs for the last 3 years. ramine. Augmentation strategies (e.g. antipsychotics) would also
Mrs DW’s life is severely restricted by a number of rituals which be a possibility. Treatment may need to be continued for a year
she obsessively carries out. They include washing of sinks, baths before a dose reduction is tried.
and toilets; disinfection of kitchen surfaces; and vacuuming. These
activities occupy her up to 8 hours a day. 3. Because Mrs DW is on a dose of 30 mg diazepam daily, it would
be appropriate to consider reducing the diazepam by 2 mg/
Current prescribed medication: day every 1–2 weeks until a 20 mg/day dose is reached. Further
• diazepam 10 mg three times a day, reductions may need to be 1 mg every 1–2 weeks until stopped.
• amitriptyline 25 mg twice a day. Longer intervals between dose reduction may be necessary as the
dose reduces towards zero. The patient may wish to adopt faster
Both have been prescribed for 3 years. withdrawal and accept the consequences. All patients should be
Mrs DW is concerned about possible addiction to her medica- monitored for increased anxiety, restlessness, agitation and other
tion, as previous attempts to stop it have been unsuccessful. In effects, and may need slow withdrawal.
addition, both she and her family feel that more can be achieved
and are willing to work at solving the problems faced by Mrs DW. Case 28.2
Questions Mrs AB, a previously well 30-year-old woman, had been treated
with paroxetine 40 mg daily for anxiety/depression which had
1. Is this appropriate therapy for OCD, and if not, what would be a been precipitated by a traumatic marriage breakup. After taking
better first choice? paroxetine for 18 months, Mrs AB’s problems had mainly resolved,
and she was feeling well. She decided that she no longer needed
2. Suggest possible drug therapies for Mrs DW and indicate for how the drug and stopped taking it. Within 3 days, her anxiety/
long they should be continued. depression returned, with insomnia and nightmares. Her mood
lowered, and she became irritable and found herself weeping
3. Provided an alternative therapy is commenced, recommend an for no reason. A week later she returned to her doctor complain-
appropriate scheme for withdrawal of the diazepam. ing of these symptoms, as well as depersonalisation and electric
492
ANXIETY DISORDERS 28
shock sensations. The doctor thought the original depression had Answer
returned and reinstated paroxetine, which cleared up her symp-
toms within a few days. 1. A sedating antidepressant such as mirtazapine or amitriptyline
may be appropriate, ensuring adequate duration of therapy and
Questions effective dose. A short course of a benzodiazepine may prove use-
ful but for no longer than 2–4 weeks. Alternatively, augmenting
1. What alternative explanation could there be for Mrs AB’s symp- the antidepressant with a sedating antipsychotic such as olanzap-
toms, and what other decision could the doctor have made? ine may be useful. For prolonged symptom treatment and relapse
prevention, it is likely that the patient will need to fully engage
2. What would be a suitable withdrawal schedule for her paroxetine? with psychological therapies.
Answers Case 28.4
1. All antidepressants can cause a discontinuation reaction. Mrs AB’s Ms AC is a 32-year-old personal assistant to a director of a leading
symptoms are typical of SSRI withdrawal. This occurs most com- investment company. She has recently been promoted to this role
monly with paroxetine, perhaps partly due to its rapid rate of elimi- and is now expected to entertain potential clients by dining out
nation (half-life around 21 hours in chronic users). with the director at local restaurants. She has always preferred
eating alone in the comfort of her own home, and the thought of
2. In this previously well patient, who is no longer under marital eating in public while promoting the business fills her with dread,
stress, the doctor, after reinstating paroxetine, could have sup- which brings on palpitations and shortness of breath.
plied a gradual tapering schedule of drug withdrawal – that is,
reducing the dose by 10 mg/week, aiming to withdrawal in 4 Questions
weeks or longer depending on patient preference.
1. What drug therapy is available which may provide some immedi-
Case 28.3 ate relief of her anxiety symptoms?
Mr SB is a 22-year-old soldier. He has recently returned from his 2. What would be an appropriate choice of treatment for long-term
second active tour, where he was injured by a roadside bomb. Two control and prevention of symptoms?
of his squad were killed in the same blast, and although his physi-
cal injuries healed quickly, he has persistent and intense episodes Answers
of panic and flashbacks. He is especially aroused at night and has
great difficulty getting to sleep. An initial prescription of an SSRI 1. β-Blockers such as propranolol may help with the shortness of
has proved ineffective, and he is currently on the waiting list for breath and palpitations but will not treat the fear and dread.
psychological therapies. Benzodiazepines may be appropriate but may affect her perfor-
mance and cause other adverse reactions.
Question
2. For long-term control, a course of CBT including exposure tech-
1. What alternative drug treatment may be appropriate? niques is appropriate or treatment with an SSRI such as escitalo-
pram or sertraline.
References Martin, J., Sainz-Pardo, M., Furukawa, T., et al., 2007. Review: benzodiaz-
epines in generalized anxiety disorder: heterogeneity based on systematic
Baldwin, D., Ajel, K., Masdraskis, V., et al., 2013a. Pregabalin for the treat-
ment of generalized anxiety disorder: an update. Neuropsychiatr. Dis. review and meta-analysis of clinical trials. J. Psychopharmacol. 21,
Treat. 9, 883–892.
774–782.
Baldwin, D., Anderson, I., Nutt, D., et al., 2014. Evidence-based guidelines Montgomery, S.A., Chatamra, K., Pauer, L., et al., 2008. Eficacy and safety
for the pharmacological treatment of anxiety disorders, post-traumatic
stress disorder and obsessive-compulsive disorder: a revision of the 2005 of pregabalin in elderly people with generalised anxiety disorder. Br. J.
guidelines from the British Association for Psychopharmacology. J.
Psychopharmacol. 28, 403–439. Psychiatry 193, 389–394.
National Institute for Health and Care Excellence (NICE), 2005a. Obsessive
Baldwin, D.S., Aitchison, K., Bateson, A., et al., 2013b. Benzodiazepines:
risks and beneits. A reconsideration. J. Psychopharmacol 27 (11), compulsive disorder. Clinical Guideline 31. Available at: http://www.nice.
967–971.
org.uk/Guidance/CG31.
Bazire, S., 2014. Psychotropic Drug Directory. Lloyd-Reinhold Publica- National Institute for Health and Care Excellence (NICE), 2005b. Post
tions, Shaftesbury.
traumatic stress disorder (PTSD). Clinical Guideline 26. Available at:
Chessick, C.A., Allen, M.H., Thase, M.E., et al., 2006. Azapirones for
generalized anxiety disorder. Cochrane Database Syst. Rev. 2006 (3), http://www.nice.org.uk/CG26.
Art. No. CD006115. https://doi.org/10.1002/14651858.CD006115. National Institute for Health and Care Excellence (NICE), 2011. General-
Christmas, D., Hood, S., Nutt, D., 2008. Potential novel anxiolytic drugs. ised anxiety disorder and panic disorder in adults: management. Clinical
Curr. Pharm. Des. 14, 3534–3546.
Guideline 113. Available at: https://www.nice.org.uk/guidance/cg113/-
Haefely, W., 1990. Benzodiazepine receptor and ligands: structural and
functional differences. In: Hindmarch, I., Beaumont, G., Brandon, S. resources/generalised-anxiety-disorder-and-panic-disorder-in-adults-
(Eds.), Benzodiazepines: Current Concepts. John Wiley, Chichester, pp.
1–18. management-35109387756997.
National Institute for Health and Care Excellence (NICE), 2013. Social
Lader, M., Tylee, A., Donoghue, J., 2009. Withdrawing benzodiazepines in
primary care. CNS Drugs 23, 19–34. anxiety disorder: recognition, assessment and treatment. Clinical
Guideline 159. Available at: https://www.nice.org.uk/guidance/cg159.
Pitman, R., Sanders, K., Zusman, R., et al., 2002. Pilot study of secondary pre-
vention of posttraumatic stress disorder with propranolol. Biol. Psychiatry
51, 189–192.
493
28 THERAPEUTICS
Roy-Byrne, P.P., 2005. The GABA-benzodiazepine receptor complex: Taylor, D., Paton, C., Kapur, S., 2015. The Maudsley Prescribing Guidelines
structure, function and role in anxiety. J. Clin. Psychiatry 66 (Suppl. 2), in Psychiatry, twelfth ed. Wiley-Blackwell, Chichester.
14–20. Vaiva, G., Ducrocq, F., Jezequel, K., et al., 2003. Immediate treatment with
Schjerning, O., Rosenzweig, M., Pottegård, A., et al., 2016. Abuse potential propranolol decreases posttraumatic stress disorder two months after
trauma. Biol. Psychiatry 54, 947–949.
of pregabalin: a systematic review. CNS Drugs 30 (1), 9–25.
Further reading Garner, M., Mohler, H., Stein, D., et al., 2009. Research in anxiety disor-
ders: from the bench to the bedside. Eur. Neuropsychopharmacol. 19,
Baldwin, D., 2008. Room for improvement in the pharmacological treatment 381–390.
of anxiety disorders. Curr. Pharm. Des. 14, 3482–3491.
Bleakley, S., 2013. Anxiety disorders: clinical features and diagnosis. Clin
Pharmacist 5, 281–283.
Useful websites No Panic, a national charity offering support for suffers of panic attacks,
phobias, OCD and GAD: http://www.nopanic.org.uk
British Association for Behavioural and Cognitive Psychotherapies has a list
of therapists, training resources and general information for the public: College of Mental Health Pharmacy, a national charity supporting the work
http://www.babcp.com and education of pharmacy staff in mental health: http://www.cmhp.org.uk
Anxiety UK, a national charity for anyone affected by an anxiety disorder:
http://www.anxietyuk.org.uk
494
THERAPEUTICS
29 Affective Disorders
Alan Pollard
Key points Classification
• Diagnosis of affective disorders should be made using Depression
standardised criteria, for example, Diagnostic and Statistical
Manual of Mental Disorders, Fifth Edition, and International The term depression is often used by people to describe a gen-
Classification of Diseases, 10th Revision. eral feeling of being low in mood and negative, but in clinical
practice, depression is more than just sadness or unhappiness
• Target symptoms should be recorded and response to treat- in response to a life event. A diagnosis of depression is only
ment monitored against these symptoms. made when key signs and symptoms are present. International
Classiication of Diseases, 10th Revision (ICD 10; World Health
• In patients with mild depression, non-pharmacological strate- Organization [WHO]) and Diagnostic and Statistical Manual of
gies should be considered as first-line intervention. Mental Disorders, Fifth Edition (DSM-5; American classiica-
tion system) list their relevant diagnostic criteria. Much overlap
• The evidence base for determining the choice of a particular exists, and both require a cluster of presenting features to be pres-
antidepressant in an individual patient does not exist. For most ent for a deined period.
patients, when an antidepressant is indicated, a generic selec-
tive serotonin reuptake inhibitor should be considered as a Depression is subclassiied as mild, moderate or severe accord-
first-line treatment option. ing to the intensity of presenting symptoms. This classiica-
tion has implications for treatment options with milder forms
• Currently, all antidepressants are considered equally effective of depression amenable to psychological-based interventions,
but differ in their side effect profile, toxicity in overdose, need whereas more severe forms of depression are likely to require
for dose titration, and monitoring. more medically focused interventions, such as antidepressants or
at the most severe end electroconvulsive therapy (ECT).
• In the absence of a previous response or contraindication,
antidepressant choice should be guided by evidence-based Mania and hypomania
clinical guidelines and the clinician and patient’s perception of
the risks and benefits of available options. Resource implica- When mood becomes abnormally elated, the terms hypomania
tions should not be ignored. or mania may be applied. Mania is the more extreme form and is
often distinguished from hypomania by the presence of psychotic
• Emerging evidence and a greater understanding of the clinical symptoms (see Chapter 30 for further information on psychosis)
application of pharmacogenomics may lead to the ability to and the potential need for hospitalisation. In the early stages of
individualise treatments in the future. hypomania, irritability may be more evident than overt symptoms
of overactivity and elation.
• Comprehensive assessment, accurate diagnosis, adequate
duration of pharmacotherapy, and involvement of the patient Bipolar and unipolar disorders 495
in the treatment regimen are the cornerstones of effective
medicines management of affective disorders. Depression on its own is a unipolar disorder. Mania or hypoma-
nia on its own could also be deined as a unipolar disorder, but in
• Valproate, antipsychotics, and benzodiazepines, sometimes the UK the term bipolar disorder is used from the outset because
in combination, are the treatments of choice in acute at some point it is expected that a depressive episode will ensue.
mania. Bipolar I identiies mania as the irst episode that brought the
patient in for treatment. Bipolar II is applied when depressive
• Either lithium, valproate, or specific antipsychotics may be episodes dominate the presentation. Between episodes, patients
considered to be the first-line prophylactic agent of choice in may have a relatively level state of mood and can be clinically
bipolar I disorder. described as euthymic, although many will say that subjec-
tively they may feel on the subdued side. Mood cycles are very
The term affect relates to mood or emotional state, and this chap-
ter therefore analyses mood disorders. These consist in clini-
cal practice of depression and bipolar disorder. Within bipolar
disorder, mood swings predominate so at times the person may
present as ‘high’ or manic, which led to the historical description
of manic depression for this condition. The issues addressed in
this chapter relate to adults. Affective disorders in children and
adolescents are more complex and are beyond the scope of this
chapter.
29 THERAPEUTICS
Mania
Euthymia
Depression
Fig. 29.1 Mood swings in bipolar disorder.
individual and often asymmetric, with the majority of patients environmental, biochemical, hormonal and social factors all have
having far more depressive episodes than manic episodes. some role in determining an individual’s susceptibility to devel-
Fig. 29.1 shows a diagrammatic representation of a pattern of opment of the disorder, with major life events sometimes acting
mood swings in bipolar disorder. The time interval between as a trigger for a particular episode. Although pharmacological
mood episodes is also very variable, but to be identiied as a rapid treatments are clearly effective, there is no simple relationship
cycling as few as four episodes per year are needed. between biochemical abnormalities and affective disorders.
Bipolar disorder is a cyclical mood disorder. Abnormally ele- Genetic causes
vated mood or irritability alternates with depressed mood, but
mood luctuations are often asymmetric and for much of the time Evidence for a genetic component to mood disorders has been
patients are never truly ‘euthymic’. documented consistently using family, twin and adoption studies.
The irst genetic studies of mood disorders were conducted more
Epidemiology than 70 years ago and included assessment of concordance rates
for monozygotic and dizygotic twins with mood disorders. These
Nearly one-ifth of adults experience anxiety or depression, with early studies did not distinguish between bipolar depression and
the conditions affecting a higher proportion of women than men. unipolar depression. A review in 2000 of twin studies in recurrent
Reported in 2012, the World Mental Health Survey, conducted in unipolar depression estimated heritability at 37%, with a substan-
17 countries, found that on average about 1 in 20 people reported tial component of unique individual environmental risk but little
having an episode of depression in the previous year. Depressive shared environmental risk (Sullivan et al., 2000).
disorders may start at a young age; they reduce people’s function-
ing and often are recurring. For these reasons, depression remains In depression one theory suggests that a variant of the gene
the leading cause of disability worldwide. In contrast, bipolar dis- responsible for encoding the serotonin transporter protein could
order is quite different. The aggregate lifetime prevalence rates account for early childhood experiences being translated into an
have been identiied as 0.6% for bipolar I disorder, 0.4% for bipo- increased risk of depression through stress sensitivity in adult-
lar II disorder, 1.4% for subthreshold bipolar and 2.4% for bipo- hood. In bipolar disorder some genetic linkage has been pro-
lar spectrum disorder. Twelve-month prevalence rates were 0.4% posed, but a precise marker remains elusive.
for bipolar I, 0.3% for bipolar II, 0.8% for subthreshold bipolar
and 1.5% for bipolar spectrum disorder (Merikangas et al., 2011). Following a large, comparative study of bipolar patients and
healthy control subjects, ive DNA regions were identiied as risk
The incidence of bipolar I is generally reported to be the same for regions associated with bipolar disorder. Of particular interest is
both men and women, whereas some studies suggest that bipolar the ADCY2 region because it codes an enzyme that has a role in
II may be slightly more common in women. Although depression sending signals to nerve cells.
may occur at any age, including childhood, it is estimated that the
average age of onset of depression is in the mid-20s. Some earlier The discovery of the ADCY2 risk region provides new insight
studies found the incidence and prevalence of depression in women into the biological mechanisms involved in the development of
peaking at the age of 35–45 years. In bipolar disorder an earlier age bipolar disorder (Muhleisen et al., 2014).
of onset is suggested, perhaps in late adolescence, with most people
experiencing their irst episodes before 30 years of age. The incidence of affective disorder in irst-degree relatives
of someone with severe depression may be about 20%, which
Aetiology is almost three times the risk of relatives in control groups.
Comparisons of the risk of affective disorder in the children of
Like most other psychiatric disorders, the causes of affective dis- both parents with an affective disorder show a four times greater
496 orders remain unknown. In depression it is likely that genetic, risk, and the risk is doubled in children with one parent with an
affective disorder. Studies evaluating twins have found fairly
strong evidence for a genetic factor. Evidence of a genetic link has
also been found in studies of children from parents with affective
disorder who were adopted by healthy parents. A higher incidence
of affective disorder was found in the biological parents of adopted
children with affective disorder than in the adoptive parents.
AFFECTIVE DISORDERS 29
Noradrenaline Serotonin
Vigilance Anixiety Impulse
irritability
Mood emotion
cognitive
Motivation function Appetite sex
energy aggression
Euphoria
pleasure
Dopamine
Fig. 29.2 Amine transmitters and association with behavioural response.
Environmental factors serotonin system will impact on noradrenergic (norepinephrin-
ergic) and dopaminergic systems.
Although environmental stresses can often be identiied before
an episode of mania or depression, a causal relationship between Fig. 29.2 shows the actions of each monoamine transmitter
a major event in someone’s life and the development of an affec- and their inter-relationship. Because the transmitters do not work
tive disorder has not been irmly established. It may be that life in isolation, modiication of one transmitter will impact across
events described as ‘threatening’ are more likely to be associated numerous behavioural domains. The overlap between trans-
with depression. The lack of prospective studies makes it dificult mitters linked to discrete behaviours helps account for why a
to interpret data linking early life events, such as loss of a parent, single transmitter-focused antidepressant may produce a broad
to the development of an affective disorder. The fact that speciic improvement in a range of depressive symptoms. Although less
environmental stresses have not been identiied should not lead attention has been paid to dopaminergic activity, some studies
to the conclusion that the environment or lifestyle is irrelevant to have found reduced activity in patients with depression, and an
the course or development of affective disorders. Employment, overactivity has been postulated in mania. There remains no clear
higher socio-economic status and the existence of a close and biochemical model to explain mania.
coniding relationship have been consistently noted to offer some
protection against the development of an episode. Endocrine factors
Biochemical factors Stress triggers the hypothalamus to release corticotrophin-
releasing factor. Corticotrophin-releasing factor interacts with
In its simplistic form the biochemical theory of depression pos- the pituitary gland to release adrenocorticotrophic hormone.
tulates a deiciency of neurotransmitter amines in certain areas Adrenocorticotrophic hormone binds to adrenal glands on the
of the brain. This theory has been developed to suggest that kidney and releases stress hormones including cortisol. There
receptor sensitivity changes may be important. Alternative prop- is negative feedback under short-lived healthy conditions, but
ositions suggest a central role of acetylcholine arising from dys- chronic stress may damage the switch off process (Fig. 29.3).
regulation of the cholinergic and noradrenergic neurotransmitter
systems. Although many neurotransmitters may be implicated, Patients with depression often have higher baseline corti-
the theory focuses on an involvement of the neurotransmitters sol levels and larger adrenal glands (the source of cortisol).
noradrenaline (norepinephrine), serotonin (5-hydroxytryptamine Dexamethasone mimics cortisol, and it was postulated that this
[5-HT]) and dopamine. This theory emerged from the indings agent could provide a diagnostic marker for depression. Failure
that both monoamine oxidase inhibitors (MAOIs) and tricyclic of a test dose of dexamethasone to suppress cortisol levels in the
antidepressants (TCAs) appeared to increase neurotransmitter so-called dexamethasone suppression test was once thought to be
amines, particularly noradrenaline (norepinephrine), at impor- a robust marker of depression. However, all severe and enduring
tant sites in the brain. When it was found that reserpine, previ- mental health conditions chronically stress the hypothalamic–
ously used as an antihypertensive, caused both a depletion of pituitary–adrenal axis, switch off the negative feedback and can
neurotransmitter and also induced depression, this was taken as result in failure of dexamethasone to suppress cortisol production.
further evidence of the monoamine theory. Newer antidepres-
sants continue to pharmacologically promote serotonin and Physical illness and side effects of medication 497
noradrenaline activity, albeit in more subtle ways. However, the
amine transmitters do not work in isolation, and modifying the Disorders of mood, particularly depression, have been associ-
ated with several types of medication and a number of physical
29 THERAPEUTICS
+ Hypothalamus
Stress Corticotrophin-releasing factor (CRF)
factors
Anterior
− pituitary
−
Adenocorticotrophic hormone
(ACTH)
Adrenal −
glands
Metabolic Cortisol
effects
+
+ identifies a reinforcing or enhanced effect
− identifies an inhibitory or reduced effect
Fig. 29.3 The hypothalamic–pituitary–adrenal axis, key hormones and feedback mechanisms
involved in regulating the body’s response to stress.
illnesses (Box 29.1). Depression can affect the outcome in peo- and non-speciic aches and pains. In some cases, known as atypi-
ple with a range of physical problems. An increase in mortality cal depression, the biological symptoms are reversed and excessive
rates has been found in those patients with comorbid depression. eating and sleeping may occur. In contrast with anxiety and agita-
Many drugs can affect mood states and other risk factors such as tion, psychomotor retardation may be a presenting feature.
underlying physical health condition that contribute to a syndro-
mal episode. This is why in any patient assessment it is impor- The following mnemonic may be useful in helping to iden-
tant to always look for any organic factors that may contribute to tify the key signs and symptoms that present in depression.
an altered mental state. For many long-term physical conditions INSADCAGES describes the sense of being trapped in a prison
(e.g. diabetes), the incidence of depression is higher than in con- of sadness (Box 29.2).
trols. Altered or abnormal biochemistry may be another factor,
particularly as presentation is more acute in onset. When medica- Bipolar disorder
tion is a main driver for mood-related changes, then a few drugs
(e.g. interferon-alfa, corticosteroids and digoxin) can be identi- Standardised diagnostic criteria vary. For an ICD 10 diagnosis
ied as potentially more problematic with associated evidence to of bipolar disorder, at least two mood episodes must occur, one
support this risk (Preda, 2012). of which must be manic or hypomanic (Box 29.3). According to
DSM 5, at least one episode of mania must have occurred for a
Clinical manifestations diagnosis of bipolar I disorder to be made; depression may also
occur, but it is not essential.
Depression
Mania/Hypomania
A low mood is the central feature of depression. This is often
accompanied by a loss of interest or pleasure in normally enjoy- In hypomanic states the mood is described as elated or irritable,
able activities. Thinking is pessimistic and in some cases suicidal. and the accompanying overactivity is usually unproductive.
A depressed person may complain he or she has little or no energy. Disinhibition may result in excessive spending sprees, inappro-
In severe cases psychotic symptoms such as mood-congruent priate sexual activity and other high-risk behaviours. Driving
hallucinations or delusions may be present. Anxiety or agitation may be particularly dangerous. Manic people may describe their
frequently accompanies the disorder, and the so-called biological thoughts as racing, with ideas rapidly changing from one topic
features of sleep disturbances, weight loss and loss of appetite are to another. Speech may be very rapid or indeed stop as the rapid
often present. Sexual drive is often reduced, and some people may low of thoughts is not able to be vocalised. Ideas may become
lose interest in sex altogether. Depression in an older adult may grandiose, with patients embarking on expansive projects which
498 present with more somatic symptoms, particularly gastric problems, lead nowhere and usually their projects are left incomplete and
disjointed. Clothing may become lamboyant, and if makeup is
AFFECTIVE DISORDERS 29
Box 29.1 Physical illnesses and drugs implicated in disorders Box 29.2 Mnemonic describing the key signs and symptoms
of mood present in depression
Biochemical Effect on mental state Mental Insomnia – typically early morning wakening
change health link Neurotic symptoms – anxiety/agitation with ruminations
Hyperthyroid state Overactivity, poor sleep Suicidality – thoughts/plans around self-harm
Hypothyroid state Lethargy, reduced energy Hypomania Appetite ↓ – leading to weight loss
Hypoglycaemia levels Depression Depressed mood – tearfulness, feeling low
Confusion, disorientation, Concentration ↓ – reading and staying focused, retaining informa-
Drug group tremor and unsteadiness Alcohol
Anticonvulsants intoxication tion, concentrating on television more difficult
Anhedonia – loss of pleasure in usually rewarding pastimes
Antidepressants Comment Guilt/worthlessness – pessimistic around the future; may not
Antimalarials
β-Blockers More prone to induce depressive episodes, believe in being worthy of receiving help; exaggerated nega-
Corticosteroids but some agents can trigger a manic pres- tivity around past misdemeanours
entation and psychotic symptoms Energy ↓ – poor self-care, lack of motivation
HIV medicines In bipolar patients unopposed antidepres- Sex – loss of libido; amenorrhoea
Interferons sants may trigger a manic episode
Mefloquine carries a risk of depression, Box 29.3 ICD 10 diagnostic criteria for bipolar affective
Isotretinoin anxiety and psychosis disorder (WHO, 1992)
Propranolol and some other β-blockers
Methyldopa may contribute to depression Bipolar affective disorder is characterised by repeated (at least
Long-term treatment reported to contrib- two) episodes in which the patient’s mood and activity levels are
ute to depression but also known in short- significantly disturbed. This disturbance consists on some occa-
term and high doses to induce euphoria sions of an elevation in mood and increased energy and activity
and manic presentations (mania or hypomania), and on others of a lowering of mood and
Non-nucleoside reverse transcriptase inhib- decreased energy and activity (depression).
itors may increase the risk of depression
As many as 40% of people who are Manic episodes usually begin abruptly and last for between
receiving interferon-alfa may experience 2 weeks and 4–6 months (median 4 months). Depression tends
depression to last longer (median about 6 months). Episodes of both kinds
Has been associated with depression and often follow stressful life events or other mental trauma, but the
proactive monitoring for signs of depres- presence of such stress is not essential for the diagnosis.
sion recommended
An antihypertensive that may be used The social and inancial consequences can have a devastating
during pregnancy but has been associated effect on both the patient with mania or hypomania and his or
with depression her family. Depression may also contribute to poorer outcomes
of physical problems such as increased pain and worsening out-
worn it may become excessive and will often involve bright colours. comes from cardiac disease and diabetes.
Hypomania and mania are on a continuum, and in clinical prac-
tice mania is applied when the patient experiences psychotic Investigations
symptoms and cannot be managed outside of a hospital environ-
ment or equivalent intervention. No universally accepted biochemical or genetic tests exist that 499
will conirm the presence of an affective disorder. Various rat-
Severity ing scales have been developed that may help to demonstrate the
severity of depressive disorder or distinguish a predominantly
The severity of depression may vary from mild through mod- anxious patient from a depressed patient. In an older adult, dis-
erate to severe. In the UK more than 90% of depression cases tinguishing depression from early stages of dementia can also
are managed in primary care, and in most circumstances it is not pose a challenge (see Chapter 33). Within the limits of our cur-
necessary for people with milder forms of depression to be seen rent understanding of the technology, biochemical or genetic tests
by specialist services. In the absence of a risk of serious self- are unlikely to be helpful in determining the treatment plan or
harm, or other complex comorbidities, patients should be entirely management of affective disorders.
managed by the primary healthcare team. Guidelines advise that
a stepwise approach is taken on the management of depression; In the UK, mental and behavioural disorders are commonly
evidence supports antidepressant therapy as more effective in the classiied using the ICD 10 (WHO, 1992). The American
moderate-to-severe cases (National Institute of Health and Care Psychiatric Association (2013) has developed a precise system
Excellence [NICE], 2009a, 2009b). of diagnosis based on the description of symptoms in the DSM 5.
If left untreated, it is important to remember that affective dis- A systematic approach to the diagnosis of affective disorders
orders carry a risk of mortality. In addition to suicidal attempts is important when considering the effectiveness of medication.
by someone who is depressed, the lack of self-care and physical
exhaustion resulting from mania may become life-threatening.
29 THERAPEUTICS
Box 29.4 ICD 10 diagnostic criteria for depressive disorder low mood and other depression-related symptoms is acknowl-
(WHO, 1992) edged by NICE as signiicant enough to warrant intervention.
Usual symptoms National guidelines provide a sound framework for the man-
Depressed mood, loss of interest and enjoyment, and reduced agement of depression (NICE, 2009a, 2009b) and bipolar dis-
order (NICE, 2014). It is important that people with depression
energy leading to increased fatigability and diminished activity are identiied. A simple screening process for the presence of
depression could involve asking the patient two questions about
Common symptoms his or her mood and interest. For example, the patient could be
Reduced concentration and attention asked: ‘During the last month, have you often been bothered
Reduced self-esteem and self-confidence by feeling down, depressed or hopeless?’ and ‘During the last
Ideas of guilt and unworthiness (even in a mild type of episode) month, have you often been bothered by having little interest
Bleak and pessimistic views of the future or pleasure in doing things?’ If the answer to either question is
Ideas or acts of self-harm or suicide no, it is unlikely the patient will be considered to have a depres-
Disturbed sleep sive disorder. Patients who answer yes warrant further investi-
Diminished appetite gation. A follow-up question asking about any unusual periods
In a depressive episode the mood varies little from day to day of elation or overactivity is recommended to detect potential for
and is often unresponsive to circumstances, yet may show char- bipolar disorder.
acteristic diurnal variation as the day goes on. The clinical picture
shows marked individual variations, and atypical presentations Identiication of target symptoms may be useful in evaluating
are particularly common in adolescence. In some cases anxiety, the response to treatment. In routine clinical practice, antidepres-
distress and motor agitation may be more prominent at times sant medication should not generally be used to treat patients
than the depression. with mild depression. Non-pharmacological strategies are prefer-
able in this group.
For depressive episodes of all grades of severity, a duration
of 2 weeks is usually required for diagnosis, but shorter periods Rating scales
may be reasonable if symptoms are unusually severe and of rapid
onset. Various rating scales can be used to assist with the assessment
Mild depressive episode: For at least 2 weeks, at least two of of the severity of the disorder. Two of the more commonly used
the usual symptoms of a depressive episode plus at least two rating scales are the Beck Depression Inventory and the Hamilton
of the common symptoms listed earlier must be present. An Depression Rating Scale.
individual with a mild depressive episode is usually distressed by
the symptoms and has some difficulty in continuing with ordinary Beck depression inventory
work and social activities, but will probably not cease to function
completely. This is a self-reporting scale that evaluates 21 depressive symp-
Moderate depressive episode: For at least 2 weeks, at least two toms. Subjects are asked to read a series of statements and mark
or three of the usual symptoms of a depressive episode plus on a scale of 1–4 the severity of their symptoms. The higher the
at least three (preferably four) of the common symptoms listed score, the more severely depressed a person may be.
earlier must be present. An individual with moderately severe
depressive episode will have these symptoms to a marked Hamilton depression rating scale
degree, but this is not essential if a particularly wide variety
of symptoms are present overall. These individuals will usually This rating scale is used by a healthcare professional at the end
have considerable difficulties in continuing with social, work or of an interview to rate the severity of depression. It scores on
domestic activities. 17 items, although 21 items are listed. The higher the score is,
Severe depressive episode: For at least 2 weeks, all three the more severe the depression. Moderate depression starts at 14,
of the usual symptoms of a depressive episode plus at least with severe depression scoring greater than 19.
four of the common symptoms listed earlier, some of which
should be of severe intensity, must be present. An individual Treatment
with severe depressive episode may be unable or unwilling
to describe many symptoms in detail, but an overall grading The aim of treatment is to promote recovery, and in unipolar
of severe may still be justified. These individuals will usually depression a return to premorbid state is a realistic goal. In bipo-
show considerable distress or agitation, unless retardation is a lar disorder the focus shifts to reducing intensity and duration of
marked feature. Loss of self-esteem or feelings of uselessness mood swings. In all cases quality of life is an important consid-
or guilt are likely to be prominent. Suicide is a distinct danger, eration. Pharmacological interventions alongside psychological
particularly in severe cases. interventions will be utilised in most patients.
Most new clinical trials for antidepressants or antipsychotics Pharmacological management of unipolar depression, bipo-
require a DSM diagnosis as an entry criterion. In the UK the ICD lar disorder (including bipolar depression) and manic states are
10 classiication is commonly used, with the severity of depres- quite distinct. In some cases medication used will be outside
sion determined by the presence of the number of symptoms (see
Boxes 29.3 and 29.4 ). More recently, use of the symptom count
as a single factor upon which to base treatment decisions has been
cautioned against (NICE, 2009a, 2009b). Account should also be
taken of the extent of impairment and disability associated with
500 depression. Recognition of enduring subsyndromal symptoms of
AFFECTIVE DISORDERS 29
of its product licence but supported by a strong evidence base. Table 29.1 Different terms employed in reporting
Clinicians should be aware of the licensed indication of treat- interventions in depression management
ments, so that any off-label use is done knowingly and in line
with current best practice. Term Definition
Onset A 20% improvement in depressive symptoms
Treatment of depression
Response A 50% improvement in depressive symptoms
In moderate and severe depression, pharmacological intervention is
important, but this should never be considered in isolation from the Remission A return to premorbid baseline with minimal
social, cultural and environmental inluences on the patient. Non- or no residual symptoms
pharmacological therapies are effective, and in mild depression they
are considered preferable to drug treatment. Non-drug treatments Recovery Usually declared when the patient has been in
and antidepressant medication are not mutually exclusive, and in sustained remission for between 4 and 6 months
some cases it is preferable to use both in combination. Cognitive
behavioural therapy (CBT) is frequently employed to support weeks. In monitoring a patient’s progress, failure to see any onset 501
changes to unhelpful patterns of thinking that occur in depression. of beneit at week 2 should prompt a review of treatment, and
often this will be a change to an alternative agent. Patients may
The basis of CBT was developed more than 50 years ago also switch antidepressants because of tolerability issues. When
and subsequently reined into a speciic therapy in the 1970s. considering an antidepressant for a particular patient, many fac-
This type of treatment helps patients to address their unhelpful tors are likely to inluence the choice of agent.
thoughts and actions associated with depression. Over a series of • Previous experience or response to treatment: If this is not the
up to 20 sessions, the CBT therapist works with the patient either
alone or in groups, to replace negative or self-critical thoughts irst occasion of taking an antidepressant, then it is useful to
and actions with more positive and helpful ones. CBT is not a explore past outcomes with treatment, and if positive consider
‘quick ix’ solution to depression; patients are often given ‘home- a previously successful antidepressant as irst line.
work’ between sessions to try and put their positive actions into • Dosing regimen: A big advantage of SSRIs is the once-daily
practice. Interpersonal psychotherapy is another form of psycho- dosing which often requires no further titration.
therapy which may help patients deal with more social aspects of • Other medications or comorbidities: Patients with epilepsy
their depression. This type of therapy explores relationships and and receiving anticonvulsant medication may be exposed to
their effect on mental health and well-being. interactions with some antidepressants. All antidepressants
lower seizure threshold, but this per se is not usually a prob-
Drug treatment lem in clinical practice for patients well stabilised on their
anticonvulsant treatment. Those at risk of QTc prolongation
In the treatment of depression all of the antidepressants currently may need to avoid antidepressants that carry a larger impact
available in the UK may be considered to be equally effective. on QT prolongation. Any signiicant renal or hepatic impair-
Table 29.1 deines terminology often used when reporting out- ment may also need to be taken into consideration.
comes of antidepressant treatment in the literature. A strong • Formulary constraints: The local health economy may add its
response to placebo is found in most of the studies of antide- own additional formulary and prescribing restrictions.
pressants. Tolerability is, therefore, an important factor in the • Cost: Resource implications are important because the vol-
choice of drug; patients who are unable to tolerate the side effects ume of prescribing in depression means that small price dif-
of antidepressants are likely to discontinue taking these drugs. ferences can equate with signiicant savings.
Overall, the selective serotonin reuptake inhibitors (SSRIs) anti- For patients who obtain a partial response to a chosen anti-
depressants appear to be better tolerated than tricyclics, and their depressant, augmentation options, as opposed to a switch to an
improved safety proile in overdose may be an important consid- alternative treatment, are available. The most common and uni-
eration for use. versal antidepressant treatment used in augmentation is lithium.
Evidenced-based antidepressant combinations have also been
For most patients irst-line treatment is a generic SSRI. For identiied (NICE, 2009a, 2009b) and also included in the updated
these agents the starting dose is often the treatment dose because evidence based British Association for Psychopharmacology
these agents have a lat dose–response curve. This means increas- 2015 guidelines for treating depressive disorders with antide-
ing the dose serves only to increase adverse effects. Patients pressants (Cleare et al., 2015). Specialist texts such as Maudsley
should notice some discernible improvement in symptoms by Prescribing Guidelines and Bazire’s Psychotropic Drug Directory
week 2, although full beneit is often not seen until 4–6 weeks provide details of less commonly prescribed combinations.
into treatment. This delay is probably due to adaptive neurochem- Once a patient is in remission, then the question of when to
ical changes that need to take place but are not fully understood. stop treatment is likely to arise. For a irst episode of depres-
Some effects which are directly linked to primary transmitter sion, where the patient is well supported psychosocially, the evi-
effects will occur quickly. These are often side effects. Some dence-based recommendation is to continue for a minimum of
such as increased sedation may be helpful, particularly if poor 6 months. Where patient support is less favourable or this is not
sleep is improved, whereas others such as dry mouth, blurred the patient’s irst episode of depression, maintenance treatment
vision and constipation will not be welcome. In older adults and
with MAOIs, this full beneit time frame may be extended to 12
29 THERAPEUTICS
should continue for 2 years. Any patient who has experienced Of the three drugs in this category, tranylcypromine carries
three or more episodes within a 5-year period is likely to beneit the highest risk of hypertensive crisis, whereas isocarboxazid is
from ongoing antidepressant treatment. the weakest and safest. Although tranylcypromine is a reversible
inhibitor of MAO and enzyme recovery may be seen in as little
Given these time frames many patients express concerns about as 5 days following cessation of treatment, in clinical practice
becoming addicted to antidepressants. It can be accurately stated MAOI precautions should be maintained for a full 2 weeks after
that antidepressants are not addictive. Antidepressants do not stopping treatment regardless of which MAOI has been taken.
cause the cravings associated with drugs of addiction. In addi-
tion the dose does not need to be increased to preserve ongoing Reversible inhibitors of monoamine oxidase. Monoamine
beneit. Patients are also unlikely to become preoccupied with oxidase exists in two forms, MAO-A and MAO-B. MAO-A is
where the next dose is obtained, so addiction criteria are unmet. the major form found in monoamine neurones. MAO-A inhibi-
However, abrupt cessation of a course of antidepressant treat- tion appears necessary for an antidepressant response. MAO-B
ment can lead to unpleasant discontinuation effects. Patients may inhibition helps preserve dopamine and has an anti-parkinso-
interpret such discontinuation effects as withdrawal. However, nian effect. MAO-A is also found in the gut and liver, where it
healthcare professionals can advise that a 4-week dose reduction acts to metabolise ingested tyramine. Moclobemide is a com-
strategy should minimise any adverse events resulting from dis- petitive reversible inhibitor of MAO-A and is displaced by large
continuation of treatment. amounts of tyramine. There is therefore little risk of a poten-
tially fatal hypertensive crisis, and the need for dietary caution
Monoamine oxidase inhibitors or the avoidance of other medicines is reduced. MAO-B can also
Traditional monoamine oxidase inhibitors. The traditional compensate physiologically for some loss of MAO-A activity.
MAOI group contains the earliest recognised antidepressants Moclobemide was introduced into clinical practice in the early
comprising isocarboxazid, phenelzine and tranylcypromine. 1990s as a safer option over traditional MAOIs. Patients can be
Their antidepressant effect is understood to come about from reassured that dietary and medicinal restrictions associated with
promoting levels of biogenic amines serotonin, noradrenaline original MAOIs are not required. If an MAOI antidepressant is
(norepinephrine) and dopamine, by blocking enzyme breakdown initiated, this is likely to be the agent of choice. In terms of clini-
of these transmitters in key brain synapses. These agents are no cal eficacy, timescales and unwanted effects, it shares many of
longer early choices in depression for several reasons. Clinically the traditional MAOI characteristics.
they can be slow to provide noticeable beneit and do not pro-
vide any early symptom relief of associated anxiety or poor sleep. Tricyclic antidepressants. Pharmacologically, tricyclic agents
However, the main concern is the risk they introduce alongside act as serotonin, noradrenaline (norepinephrine) reuptake inhibi-
tyramine-containing foods and medicines that may similarly tors, but with the additional property of blocking acetylcholine
release noradrenaline (norepinephrine) from peripheral nerve at muscarinic receptors. This additional antimuscarinic property
terminals, that is, indirectly acting sympathomimetics. These tra- is not believed to confer any therapeutic beneit but accounts for
ditional MAOI agents block both MAO-A and MAO-B enzyme many predictable unwanted effects of this class of drugs.
subtypes, rendering the patient vulnerable to the pressor effects
of such compounds. MAO enzyme is present in many areas of the Predictable antimuscarinic side effects are:
body including the gut, and normally tyramine found in cheese • Dry mouth: Caused by reduced saliva production. This is best
would be broken down by MAO in the gut. With no gut MAO
available, the tyramine passes unhindered in to the circulation, countered by sips of cool water, chewing sugar-free gum or
where it displaces noradrenaline on to peripheral target sites. The the application of saliva-enhancing sprays.
cardiovascular system is most at risk, increasing heart rate with • Blurred vision: Accommodation is impaired early on in treat-
a vasoconstriction which leads to a dramatic rise in blood pres- ment, and patients should be reassured that this will settle and
sure. This hypertensive crisis, sometimes referred to as a ‘cheese’ is not an indication of sight problems.
reaction, is a medical emergency and is one of the few situations • Constipation: Reduced peristalsis may occur. Most patients
where hypertension produces key symptoms for the patient. are likely to require a laxative early on in treatment and this
Symptoms of a hypertensive crisis are likely to include pain and should be proactively managed. Depression itself caused by
stiffness in the neck, an occipital headache and angina-like chest reduced mobility and poor diet may separately contribute.
pain. In an emergency department, treatment is likely to involve • Dificulty passing urine: Reducing sphincter activity. Male
the administration of a noradrenergic (norepinephergic) α recep- patients with enlarged prostate may ind this problematic, and
tor blocker such as phentolamine or phenoxybenzamine. in rare instances urinary retention may ensue.
Therefore, patients should be aware of the dietary precautions • Confusion: Confusion is a central antimuscarinic effect.
and need to avoid purchasable medicines that carry similar risk. Older adults are more overtly vulnerable, but subtler effects
MAOI warning cards were produced, but these have now been in other patients may lead to reduced reaction times and
discontinued. However, the patient lealet contained with the pose increased driving risks. Depression itself will already
medicines provides this written advice. Most patients receiving have lowered reaction time. Doses of tricyclics should be
these treatments are likely to have been receiving them for some titrated over several days to full treatment dose with these
time and will be fully aware of food restrictions and the need to factors in mind.
check the safety of any bought medicines with the pharmacist. As A number of TCAs are in current clinical use. The basic chemi-
well as being used for depression, these agents may be in place as cal structures of these compounds are similar, but there are dif-
502 part of treatment for phobic disorders. ferences between them. All of the TCAs require dose titration
to achieve optimum antidepressant dose. Most are signiicantly
sedating and with central antimuscarinic effects; therefore,
AFFECTIVE DISORDERS 29
starting a patient on the full treatment dose would predict- effects, but there are variations in the intensity or duration. The 503
ably induce a confusional state alongside unwanted sedation. degree of speciicity for serotonin reuptake differs between the
Furthermore, the common property of postural hypotension SSRIs, but this does not correlate with clinical eficacy. When
and blurred vision further adds to an unpleasant experience and given in adequate doses for an adequate period of time, all of
increases the risk of falls or other accidents. the drugs in this class appear to be equally effective. The two
main clinical issues with SSRIs are nausea and their early alerting
Tricyclics can be taken as single daily doses because of their effects whereby patients are likely to feel more anxious or on edge
long half-lives and often at night so that peak levels occur dur- during the irst 2 weeks of treatment. Nausea is best addressed by
ing sleep. Tricyclics are toxic in overdose. The antimuscarinic advising patients to take their daily dose after breakfast. Nausea
effects on the vagus nerve can lead to the development of car- should decline within a few days, but for some patients it remains
diac arrhythmias and these, in turn, may prove fatal. Children and an intolerable adverse event and an alternative class of agent is
older adults are especially vulnerable. required. Alerting effects may be addressed by exploring non-
pharmacological strategies to promote relaxation (e.g. yoga or
In low doses some tricyclics have other uses in clinical practice. music). Alternatively, a short course (maximum 2 weeks) of a
For example, those with signiicant noradrenergic (norepinephri- benzodiazepine such as diazepam could be prescribed. A hyp-
nergic) reuptake properties may be used to help with neuropathic notic agent such as zopiclone or zolpidem could be prescribed if
pain. Low doses of particularly sedating agents are sometimes alerting effects occur at nighttime.
used for hypnotic purposes. This should not be supported because
it represents unlicensed use and is employing an agent with many Some years ago the SSRI paroxetine was subject to media
adverse properties to substitute for a single need. attention in the UK, and this led to the identiication of three
important medicines management issues with use of antidepres-
Amitriptyline. Amitriptyline is one of the more sedating sants: unpleasant events occurring on abrupt cessation of treat-
agents and in low doses is often employed to manage neuro- ment, sexual dysfunction and increased risk of suicide.
pathic pain. Its use in depression continues to decline because it
is no longer a recommended irst-line treatment option. It has now become standard practice to stop antidepressant
treatment over a 4-week period by gradually reducing the dose.
Imipramine. Imipramine is similar to amitriptyline, but Patients who abruptly stop antidepressants may feel acutely quite
less sedating. This agent may be employed in children to help unwell, and this should not be taken to indicate a recurrence of
manage nocturnal enuresis or again in children as part of atten- the depression. Left unchecked, symptoms will remit after some
tion-deicit/hyperactivity disorder treatment. Again use as an days, but a short-term reinstatement of dose and review of the
antidepressant is declining for the same reasons as amitriptyline. discontinuation strategy is often all that is required.
Clomipramine. Pharmacologically clomipramine is a potent Sexual dysfunction has now been identiied as a feature of
serotonin reuptake inhibitor with minimal noradrenergic (nor- many other classes of antidepressant, linked to agonist effect on
epinephrinergic) reuptake inhibition, and this leads to some serotonin 5-HT2 receptors. There are various pharmacological
differences in clinical application outside of depression. For strategies identiied in the literature to manage this, and some of
example, it has little or no value in neuropathic pain manage- the newer antidepressants carry less sexual dysfunction. It should
ment, but as a serotonin-rich drug it has an established role in also be remembered that depression itself reduces libido, but anti-
the management of obsessive-compulsive disorder (OCD). depressant impairment is more often associated with ejaculatory
ability.
Dosulepin. Formerly known as dothiepin (British Approved
Name), dosulepin is the most cardiotoxic of the tricyclic agents Self-harm and suicide are aspects of depression itself, and the
and should now not be initiated in any new patients. Patients suggestion that this class of antidepressants actually contributed
already established on this agent should not be automatically to this mortality outcome was subject to much debate and review
switched to another antidepressant. Instalment dispensing (i.e. of evidence. The early alerting effects of SSRIs may allow a
dispensing only small quantities at a time) may be put in place if patient to carry out a suicidal intent. With the older TCAs, many
there are concerns about self-harming through overdosing. patients receiving treatment experience signiicant sedation and
are unable to act on these impulses. As the depression remits, the
Lofepramine. Within the tricyclic group, lofepramine carries suicidal ideation reduces with effective treatment.
a much-reduced toxicity proile. Antimuscarinic effects do occur
with lofepramine, but these are less severe than with other tri- Since their launch as antidepressants, SSRIs have become
cyclics. Lofepramine does not have a signiicant sedative effect. treatment options for a range of anxiety-based disorders (e.g.
For new patients who require a TCA to manage their depression, panic disorder, OCD, general anxiety disorder, eating disorders,
this is likely to be the drug of choice. post-traumatic stress disorder), but generally the doses required
are much higher than those employed in depression.
Selective serotonin reuptake inhibitors. In the mid-1980s
these agents were developed in an attempt to reduce some of the Fluvoxamine. The irst SSRI launched in the mid-1980s, lu-
problems associated with the TCAs. Overall, the SSRIs are better voxamine was marketed at a high dose requiring a three times a
tolerated by most patients, and they are considerably less toxic in day dosing. Many patients experienced severe nausea, and the
overdose; this means that they should be the irst-line choice for drug has many interactions because it is a potent inhibitor of the
the pharmacological management of moderate or severe depres- cytochrome P450 drug metabolising system. It is unlikely to be
sion (NICE, 2009a, 2009b). Compared with TCAs, they have less seen very often in clinical practice today.
impairment on reaction time and there is less additional sedation
if alcohol is consumed. Because generic versions of the drugs are Fluoxetine. The main difference between luoxetine and the
available, the inancial impact of using SSRIs irst line is consid- other SSRIs is its long half-life. In the initial stages of treatment, some
erably reduced. The SSRIs have a broadly similar range of side
29 THERAPEUTICS
patients may experience a greater feeling of nervousness with Venlafaxine. Venlafaxine possesses minimal antimuscarinic
luoxetine than with the other SSRIs. The long half-life of luox- properties and greatly reduced toxicity compared with TCAs.
etine, mediated through its major metabolite norluoxetine, can At low doses the drug behaves more like an SSRI, but as the
be a problem if severe side effects develop. In other situations, dose is increased venlafaxine adopts its serotonin noradrena-
the long half-life means that the risk of a patient experienc- line reuptake inhibitor (SNRI) proile. Across all doses there
ing discontinuation symptoms is minimal. This SSRI may be is weak dopamine reuptake inhibition. Dose titration therefore
abruptly stopped because it will take about 5 weeks to clear is indicated. There is a low potential for postural hypotension,
from the body. Formulations of luoxetine that can be taken on although the drug carries a risk of hypertension at higher doses.
a weekly basis are available in some parts of the world. Discontinuation effects can be problematic, and careful gradual
dosage reduction is required when stopping treatment.
Paroxetine. In contrast with luoxetine, paroxetine has a rela-
tively short half-life and no active metabolites. Therefore, this Duloxetine. The SNRI proile of duloxetine remains constant
drug requires gradual dose reduction prior to stopping. It has and equal between the two transmitters, serotonin and noradren-
some inhibitory activity at CYP4502D6, which may need to be aline (norepinephrine). This means that dose titration is not rou-
considered in patients who are taking other medications. tinely indicated.
Sertraline. The SSRI sertraline is preferred where a patient Medicine management issues including adverse events closely
has comorbid cardiac disease because it does not increase the resemble SSRIs. In the UK duloxetine is also licensed separately
burden of the underlying condition and has very few drug inter- for neuropathic pain and stress incontinence; this latter indication
actions. It is also a popular choice within perinatal mental health is under a different brand.
because it does not independently add to any baseline risk of
taking SSRIs. In pregnancy all SSRIs carry a slightly increased Reboxetine. Reboxetine is indicated for more reclusive and
risk of neonatal septal heart defect. From week 20 there is an presentations where the patient is particularly lacking energy. The
increased risk of the respiratory syndrome persistent pulmo- main side effects are dry mouth and insomnia. The drug is con-
nary hypertension of the neonate. However, the absolute risk sidered to have a low evidence base of independent effectiveness.
remains small at 0.3%, although subsyndromal respiratory states
are more common. Exposure to SSRIs during the third trimester Mirtazapine. Compared with SSRIs, the antidepressant mir-
is likely to produce mild neonatal withdrawal reactions (e.g. irri- tazapine represents an agent with reduced alerting effects, mini-
tability or tremor). These are minimal with sertraline but may be mal nausea and low incidence of sexual dysfunction. However,
more problematic with paroxetine. both sedation, which is more prominent at lower dose, and
weight gain are signiicant. Use of mirtazapine has superseded
Citalopram and Escitalopram. Citalopram is a racemic mix- mianserin to which it is chemically related.
ture of R- and S-citalopram and predates escitalopram, the active
S enantiomer of citalopram. Escitalopram was launched on the Agomelatine. Advantages of agomelatine include restoration
basis that the R enantiomer has no antidepressant effect, and it of sleep pattern without residual sedation and impaired reaction
may even counteract some of the antidepressant effects of the S time, as well as minimal weight gain, gastro-intestinal upset and
enantiomer of escitalopram. Citalopram carries a greater risk of sexual dysfunction. Abnormal liver function tests are common
clinically signiicant QT prolongation, prompting restrictions to and require regular liver function monitoring in accordance with
be placed on doses especially in older adults. The QT prolonga- the Summary of Product Characteristics. Variable eficacy has
tion effect is much less with escitalopram. In clinical practice sev- been seen in clinical trials.
eral patients do ind escitalopram much more tolerable, and now
that escitalopram is available generically, the economic pressure Vortioxetine. The mechanism of action of vortioxetine is
to avoid using this SSRI as irst-line treatment is much less. described descriptively, but the focus is on promoting serotonin
activity. Nausea is the most common adverse effect. Sexual dys-
Other Antidepressants function is present but only at higher doses. Early alerting effects
Trazodone. Trazodone is a little used antidepressant which are likely to be less pronounced, and in remission patients appear
requires adult dosages of 300 mg daily and above to treat to be less residually cognitively impaired with this agent. There
depression. It is rapidly absorbed on an empty stomach, leading is no evidence of QT prolongation. Patients show minimal weight
to profound dizziness, so it should always be taken with food. Its gain and no evidence of signiicant discontinuation symptoms
mechanism of action remains unclear. It does have some help- following abrupt cessation of treatment. NICE (2015) supports
ful anxiolytic properties and occasionally is used in older adults its use as a third-line option for the treatment of major depression.
more for this property than to manage depression. Compared
with the tricyclics it is much safer in overdose and lacks signii- Other treatments
cant antimuscarinic properties. Priapism has also been noted as
a rare but distressing side effect. This is almost certainly due to Electroconvulsive therapy. When urgent intervention is
its potent α receptor–blocking properties. indicated to manage severe depression, ECT may be considered.
In an attempt to improve on the beneits gained with SSRIs ECT involves inducing a seizure under controlled conditions.
over TCAs, newer antidepressants were introduced from the late Unless a patient lacks capacity it requires their agreement and
1990s onward. These antidepressants include venlafaxine, dulox- is prescribed by a psychiatrist. ECT involves the administration
etine, reboxetine, mirtazapine, agomelatine and vortioxetine. of an anaesthetic and muscle relaxant before the application of
Table 29.2 summarises the key practice points associated with the treatment and thus is carried out under theatre-like conditions
504 these newer agents. with full resuscitation facilities present. ECT is often delivered
twice weekly as a course of six to eight treatments and for some
patients provides a rapid resolution of the most severe symptoms,
AFFECTIVE DISORDERS 29
Table 29.2 Newer antidepressants and key practice points
Name Type Practice points
Venlafaxine SNRI
• Reduced toxicity compared with TCAs
• At low doses, drug behaves like SSRI, adopting SNRI profile as dose increases;
across all doses there is additional dopamine reuptake inhibition
• Dose titration applicable
• Low risk of postural hypotension, but risk of hypertension at high dose
• Marked discontinuation effects
Duloxetine SNRI • A fixed ratio of serotonin to noradrenaline (norepinephrine) reuptake inhibition
• Dose titration rarely indicated
• Resembles SSRIs in clinical practice
• Also licensed for neuropathic pain and for stress incontinence; in the UK duloxetine
is marketed under a different brand name when prescribed for stress incontinence
Reboxetine NARI • Indicated for more reclusive and anergic presentations
• Key side effects are dry mouth and insomnia
• Low evidence base of independent effectiveness
Mirtazapine NaSSA • Reduced alerting effects
• Minimal nausea
• Low incidence of sexual dysfunction
• Sedation is more prominent at lower dose
• Weight gain is significant
Agomelatine MT1 MT2 agonist • Restoration of sleep pattern without residual sedation and impaired reaction time
5-HT2c antagonist • Minimal weight gain, GI upset and sexual dysfunction
• Abnormal LFTs are common and require regular monitoring
• Variable efficacy in trials
Vortioxetine Direct modulation of receptor • Nausea is most common adverse effect
activity and inhibition of the • Sexual dysfunction present at higher doses only
serotonin transporter • Alerting effects less pronounced
• Less residual cognitive impairment
• No evidence of QT prolongation
• Minimal weight gain
• No significant discontinuation symptoms
GI, Gastro-intestinal; LFT, liver function test; NARI, noradrenaline reuptake inhibitor; NaSSA, noradrenaline-specific serotonin agonist; SNRI, serotonin noradrena-
line reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic antidepressant.
promoting enough improvement to provide ongoing treatment responsible for oral contraceptive failure, breakthrough seizures 505
via pharmacological and non-pharmacological means. Although and reducing the effectiveness of antirejection medication. Mental
the treatment itself is very safe, patients must be risk assessed health stigma may lead some patients to self-medicate for ano-
for safe receipt of an anaesthetic, and many patients experience nymity of treatment. St John’s wort is readily accessible, but
short-term memory loss following treatment. information provided with the herbal medication will not provide
speciic information about use in depression. As a herbal product
ECT remains controversial, but its speed of effect is not cur- there is some variance in the quality and content of various active
rently matched by any antidepressant medication. This situa- ingredients, which indicates inconsistency of dosing is likely. As
tion may change because recently the immediate and beneicial with prescription antidepressants, treatment should continue for 6
effects of ketamine in treating depression have been identiied. months to minimise the risk of relapse. Once a patient is feeling
better this may prove inancially challenging if he or she is buy-
St John’s wort (Hypericum perforatum). In the UK herbal ing the product. Encouraging people to be aware of mental health
remedies such as St John’s wort do not feature in prescribing guide- issues together with the signs and symptoms of depression is ben-
lines, but this agent has become a popular option for self-medica- eicial. However, management of depression without professional
tion. Extracts of hypericum have been shown to be as effective support severely limits the options for other interventions (e.g.
as standard antidepressants in the management of major depres- psychological support) and also objective monitoring.
sion (Linde et al., 2008). Herbal remedies can appear attractive
because they sound and feel ‘natural’, and some patients assume Ketamine. Ketamine predominantly exerts its effect through
that this exempts them from the serious side effects or interac- an antagonist action on the glutamate N-methyl-d-aspartate recep-
tions that characterise prescribed medicines. In reality St. John’s tor. Researchers are now looking for an alternative oral preparation
wort has been identiied as a cytochrome P450 enzyme inducer
29 THERAPEUTICS
with the same therapeutic effect but fewer of the adverse effects, introduced into the UK in the 1970s, remains licensed only for
less abuse potential and fewer problems of administration seen the management of epilepsy.
with ketamine. It also means that antidepressants of the future
may depart from the traditional biogenic amines and focus on the Valproate semisodium is a 1:1 molar combination of sodium
glutamate pathway. valproate and valproic acid. Following administration, valpro-
ate ion is released and subsequently absorbed. Any meaningful
Treatment of mania therapeutic differences between sodium valproate and valpro-
ate semisodium have not been established. The mechanism of
The treatment of acute mania often requires urgent intervention to action of valproate in mania is unclear but may be related to
reduce high arousal states and associated risks. Pharmacological increased levels of γ-aminobutyric acid. The antimanic effects
agents employed include benzodiazepines, valproate, antipsy- of valproate are seen within 3 days, but the full beneit of treat-
chotics and lithium. Combinations of these agents may be used ment may not be apparent for up to 3 weeks. Doses should be
in the early management of such episodes. Lithium is now rarely rapidly titrated to between 1000 and 2000 mg/day. Routine
used in the management of acute mania because it has a slow valproate serum levels are not necessary, but levels between
onset of effect and the dose required can result in high levels 50 and 100 mg/L have been reported to be associated with
which are close to toxic. From a patient perspective, an early optimal response in some patients. Although the risks for liver
unpleasant experience with lithium is likely to deter a patient to damage are greater in young children, liver function tests
agree to this agent being used as a longer-term strategy to help should be performed prior to initiation of therapy and periodi-
protect against further mood swings. At the same time any agents cally thereafter in all patients. In addition, the patient must be
that could be exacerbating a manic episode should be reviewed. instructed to report any problems, such as unexplained bruis-
Depression associated with bipolar disorder should not be man- ing, that may indicate abnormalities in coagulation. Although
aged by using antidepressants in isolation because there is valproate is well established as a prophylactic treatment to
a risk of prompting a switch to a manic episode. Agents such prevent relapse, this is an off-label use across all formula-
as quetiapine or lamotrigine with or without lithium represent tions. Valproate should not be used in women of childbear-
evidence-based preferred options. Therefore, antidepressants in ing potential because of its high risk of teratogenicity. These
bipolar patients should be urgently reviewed and strong consid- warnings have been strengthened in the UK through amended
eration given to their withdrawal. Sometimes non-psychotropic NICE guidance.
drugs such as high-dose steroids (e.g. prednisolone) may pre-
cipitate an episode. Prescribing prednisolone in divided doses, Antipsychotics
as well as reducing the overall daily dose, may help mitigate the
situation. All antipsychotics are acknowledged as being intrinsically anti-
manic, although not all have this utility formally listed within
Benzodiazepines their licensed indications. Most of the second-generation (atypi-
cal) antipsychotics, for example, olanzapine, risperidone, que-
Lorazepam, because of its high potency and availability in tiapine, aripiprazole and asenapine, are licensed for use in the
both tablet and injection form, is often the agent of choice for management of acute mania and in most cases prevention of new
prompt sedation. As with other members of this group it works manic episodes.
quickly to lower high arousal states and on its own may be
enough to interrupt an emergent episode. Some patients have Haloperidol is still commonly prescribed as part of the acute
small quantities of benzodiazepine, or related agents, available management of mania. It is less sedating than other antipsychot-
to self-manage any early signs of such mood swings. In more ics, but because of its potent dopamine D2 receptor blockade it
urgent cases lorazepam may need to be given parenterally to carries a much higher risk of inducing acute extrapyramidal side
a patient by a healthcare professional to effect treatment. In effects. See Chapter 30 for more details around management of
the UK this may be under the provision of the Mental Health extrapyramidal side effects.
Act legislation if the patient does not consent and there are
clear risks of not treating the episode. An alternative paren- Longer-term management
teral agent to lorazepam is midazolam, which has the advan-
tage of not requiring refrigeration or dilution 1:1 with water for Second-generation antipsychotics also have an established
injection prior to intramuscular injection. However, in the UK role in the longer-term management of bipolar disorder.
midazolam is a Schedule 3 Controlled Drug, and this requires Quetiapine in particular is now recognised as an evidence-
additional processes relating to ordering, recording and audit- based choice for management of bipolar depression. This
ing of stock levels. paradox of an antipsychotic playing a key role in managing
depression associated with bipolar disorder is linked to the
Valproate semisodium limited understanding of the pharmacological mechanisms
of newer antipsychotics in the management of affective
Valproate semisodium (divalproate) is licensed in the UK as a disorders.
speciic treatment for mania associated with bipolar disorder.
506 This distinguishes it from the original sodium valproate which, Continuation therapy with a prophylactic mood stabiliser
should be considered in all bipolar patients who have had two or
more acute episodes within 2–4 years. It may also be reasonable
to consider prophylaxis in any patient following a severe manic
AFFECTIVE DISORDERS 29
episode. Because treatment is long-term the cooperation of the whether lithium is being used in unipolar depression or within 507
patient is essential; therefore, a thorough explanation of the risks bipolar disorder management. The majority of a dose of lith-
and beneits of the treatment is vital. ium is excreted unchanged in the urine, making renal func-
tion the primary determinant of the treatment dose. The target
Lithium. Lithium has two distinct roles within affective range for prophylaxis should be routinely around 0.6 mmol/L,
disorders: and so a dosage of around 600 mg daily for adult patients is
• In unipolar depression it can augment the partial effect of appropriate. Older adults, who will invariably have some age-
related reduced renal function, may be initiated at 200 mg
an antidepressant. Adding lithium to the regimen can lead to daily, but target levels are the same, so under-dosing should
remission within a few weeks. be avoided.
• In bipolar disorder lithium remains for the UK the irst-choice
mood stabiliser. When initiating lithium, or making a dose adjustment, it takes
It has a greater impact on manic episodes, but in bipolar around 7 days for a revised steady state to develop. Therefore,
depression its effectiveness can be improved when used along- unless assessment is required for toxicity, blood levels should
side lamotrigine. Lithium has a signiicant impact on reduc- not be measured any sooner because dosing adjustments would
ing suicide rates in bipolar disorder. The mechanism of action be based on inaccurate levels. Dose adjustments with lithium
remains to be fully elucidated, but since its discovery lithium are straightforward because at steady-state lithium levels vary in
has been shown to act upon various neurotransmitter systems direct proportion to dose; that is, a doubling of dose will double
at multiple levels of signalling in the brain. It is suggested that the blood level. However, should this empirical dosing lead to
lithium restores the balance among faulty signalling pathways predictive doses above 1600 mg daily, adherence should be thor-
in critical brain regions. Such effects are thought to trigger long- oughly assessed.
term changes in neuronal signalling patterns that account for the
prophylactic properties of lithium in the treatment of bipolar Doses are likely to need adjusting during the early stages of
disorder. Through its inhibitory effects on glycogen synthase treatment according to patient response and measured serum
kinase-3beta (GSK-3β) and β-arrestin-2, lithium may alter the levels. A number of predictable and unwanted effects can occur,
level of phosphorylation of cytoskeletal proteins, which leads to such as polydipsia (increased thirst), polyuria (increased urine
neuroplastic changes associated with mood stabilisation (Malhi output of up to 3 L/day), mild stomach discomfort with some
et al., 2013). looseness of the bowels and ine tremor of the hands.
Lithium has a number of medicines management issues
because it has a narrow therapeutic range, a low therapeutic However, with the exception of polyuria, these early adverse
index, a wide range of unpleasant side effects and may be effects usually resolve within 1–2 weeks. Patients usually adapt
involved in several clinically signiicant drug interactions. to the increased urine output. Monitoring should initially include
It is potentially very toxic, with a clear correlation between routine lithium levels on a 3 monthly basis which may be reduced
serum levels and eficacy, as well as toxicity. It was made to 6 monthly after a year in patients who continue with stable lev-
the subject of a national patient safety alert in 2009 requiring els and have no other comorbidities that could affect the body’s
all healthcare services to implement a ive-point action plan. handling of lithium. Assessment of renal function and thyroid sta-
Before initiating treatment with lithium, certain tests should tus should be carried out 6 monthly or at least annually. A lithium
be performed: treatment pack (National Patient Safety Agency [2009] lithium
• Check serum urea and electrolytes to identify luid and salt resource pack) should be made available to all patients who are
balance. prescribed lithium.
• Measure serum creatinine to generate an estimate of glomeru-
lar iltration rate and assess renal function. Some patients may notice a swelling in the neck (goitre).
• Undertake thyroid function test and measure calcium lev- Lithium can reduce the output of thyroid hormone, but this is
els to check on baseline activity of thyroid and parathyroid easily corrected with levothyroxine. Often any reduction in thy-
glands. roid activity is identiied in blood tests before the patient notices
• Where clinically indicated, perform a full blood count. This any discomfort. Weight gain is a signiicant side effect of lithium
would include patients with a history of blood disorders therapy.
because lithium is likely to induce a benign increase in white
cells. Lithium toxicity. When lithium levels exceed 1.5 mmol/L
• Conduct an electrocardiogram if cardiovascular risk fac- signs of lithium toxicity begin to develop. Lithium toxicity is
tors are present or the patient has existing cardiovascular characterised by severe shaking of the hands, giddiness or loss
disease. of balance, slurred speech, unusual drowsiness or sleepiness,
If no abnormalities are found in these parameters, lithium can vomiting and/or diarrhoea. These symptoms should be seen as
then be initiated based on the premise that 1 g lithium carbonate a medical emergency. Lithium levels may become high uninten-
produces a steady-state level of around 1.0 mmol/L. tionally and usually because of dehydration, diet and drugs. It
Serum levels. At steady state, which is usually 7 days fol- is important to educate the patient on recognising and avoiding
lowing initiation of treatment, blood samples are taken 12 lithium toxicity.
hours after the last dose. The 12-hour standard lithium level
range is routinely 0.4–1.0 mmol/L. For prophylaxis a plasma Dehydration arising from extreme luid loss because of fever-
lithium level of 0.6–0.8 mmol/L is considered optimum ish illness, sickness and diarrhoea should prompt a stopping
of the lithium until the situation is improved. This will avoid
high concentrations of lithium developing. In relation to diet,
extreme changes to salt intake, particularly the exclusion of salt
from the diet, may lead to the body retaining more lithium to
29 THERAPEUTICS
compensate for the salt loss. Some medicines taken alongside Patient care
lithium may interact. Patients should be advised to ask their
pharmacist before purchasing any over-the-counter medicines. Adherence to medication in patients with affective disorders may
Some medications may push lithium levels into the toxic range. prove challenging. A patient with severe depression may feel that
This applies not just to prescription drugs, where the diuretic no treatment can help. At the height of a manic episode anything
bendrolumethiazide is a classic example, but also to some that will subdue great elation and well-being may be resisted. In
over-the-counter medications such as ibuprofen; this analgesic these circumstances patients may be described as lacking insight,
is best avoided unless there is good access to close monitoring and in the UK their choice to refuse treatment overridden by the
of the lithium. processes within the Mental Health Act. However, outside of
an acute phase, good therapeutic discussions around treatment
Formulation. As the absorption and bioavailability of lithium options can take place. Pharmacists are ideally placed to present
may vary from brand to brand, it is important that patients do balanced information on the medicines available to help patients
not inadvertently change brands or dosage forms without lev- identify treatments and regimens.
els being checked. Failing to correctly convert a tablet dose to
the correct equivalent of the liquid formulations can also lead to It is good practice to provide written information about
dosing errors. The poor aqueous solubility of lithium carbonate the medicines. One source is the Choice and Medication web-
(soluble 1 part in 100 parts water) compared with lithium citrate site (http://www.choiceandmedication.org/cms/?lang=en) which
means that the citrate salt is used in all liquid formulations of provides access via subscription to independent medicines
lithium. information on psychotropic agents. It is not restricted by
licensed indications and is a resource for both healthcare profes-
When converting from citrate formulations to carbonate, it sionals and patients.
should be noted that:
In any patient consultation it should be remembered that con-
520 mg of lithium citrate = 200 mg of lithium carbonate. cerns around stigma associated with a mental health condition and
adherence to treatment may need to be addressed. During treatment
Other anticonvulsants in bipolar disorder. Carbamazepine selection shared decision making is likely to be much more suc-
is a second-line prophylactic treatment which is likely to be cessful than a unilateral decision made by a healthcare professional.
prescribed when lithium is ineffective, contraindicated or not The nature of bipolar disorder means that some patients value the
tolerated. The medicines management issues that apply when option of advance decisions. This is encouraged as best practice
carbamazepine is employed as an anticonvulsant are the same as with patients identifying and recording their preference(s) and
when it is used as an anticonvulsant. However, there is no robust dislikes for acute intervention which allow, unless circumstances
evidence to conirm that such carbamazepine target serum levels dictate otherwise, their preferences to be honoured in a relapse situ-
are applicable for use in bipolar disorder. ation. Exploring with patients their hopes and expectations around
medication and actively listening to their concerns about treatment
There is a good evidence base to support the use of lamotrigine should help to ensure that rewarding conversations take place.
in bipolar depression. Speciic drug-related monitoring is also
not required. Lamotrigine should always be initiated slowly and Many of the drugs used in the treatment of affective disorders
at half the standard incremental regimen when valproate is also have the potential to interact with other drugs that have been
being taken. This is because valproate elevates lamotrigine levels prescribed or purchased. Some of these are summarised in Table
and through this process increases the risk of development of 29.3. Common therapeutic problems in the management of affec-
serious skin reactions to lamotrigine. The use of lamotrigine in tive disorder are outlined in Table 29.4.
bipolar disorder remains unlicensed in the UK.
Table 29.3 Examples of important drug interactions with drugs used in the management of affective disorders
Drug group Interacting drugs Effects
Tricyclics
Adrenaline (epinephrine) and other directly Increased risk of hypertension and arrhythmias
acting sympathomimetics
Alcohol Enhanced sedation
Antiarrhythmics Risk of ventricular arrhythmias
Anticonvulsants Lowered seizure threshold and possible lowered tricyclic levels
MAOIs Severe hypertension, although some combinations are relatively safe
and have been used in augmentation strategies
Fluoxetine Increased tricyclic serum levels
Paroxetine Increased tricyclic serum levels
SSRIs Anticoagulants Enhanced anticoagulant effects
MAOIs Central nervous system effects of SSRIs increased and risk of serotonin
508 syndrome
Lithium Possible serotonin syndrome
AFFECTIVE DISORDERS 29
Table 29.3 Examples of important drug interactions with drugs used in the management of affective disorders—cont’d
Drug group Interacting drugs Effects
MAOIs Fermented beverages, tyramine-rich foods Hypertensive crisis; nonfermented alcoholic beverages will not induce
hypertensive event
Antihypertensives Increased hypotensive effect
Anticonvulsants Lowered seizure threshold
Levodopa Hypertensive crisis
Sympathomimetics Hypertensive crisis
Antipsychotics Anaesthetic agents Hypotension
Anticonvulsants Lowered seizure threshold
Drugs that prolong QT interval Risk of ventricular arrhythmias
Lithium Non-steroidal anti-inflammatory drugs Enhanced lithium serum levels
SSRIs Possible serotonin syndrome
Diuretics Enhanced lithium serum levels particularly with thiazides
Angiotensin-converting enzyme inhibitors Enhanced lithium serum levels
Sumatriptan Possible central nervous system toxicity; notably, some other triptans
are cautioned alongside SSRIs and MAOIs for the same reason
St John’s wort Induces cytochrome P450 enzymes, particularly
1A2, 2C9 and 3A4
Indinavir Reduced indinavir serum concentration (avoid)
Warfarin Reduced anticoagulant effect (avoid)
SSRIs Increased serotonergic effect (avoid)
Carbamazepine (and other anticonvulsants) Reduced serum concentrations (avoid)
Digoxin Reduced digoxin serum concentration (avoid)
Oestrogens and progestogens Reduced contraceptive effect (avoid)
Theophylline Reduced theophylline serum concentration (avoid)
Ciclosporin Reduced ciclosporin serum concentration (avoid)
Always check latest British National Formulary or other reference source for specific drug interaction information.
MAOI, Monoamine oxidase inhibitor; SSRI, selective serotonin reuptake inhibitor.
Table 29.4 Common therapeutic problems in the management of affective disorder
Problem Possible solution
Antidepressants
Treatment failure (30–40% of patients will Ensure adequate dose and duration of treatment
not respond to first antidepressant) Check adherence, engage the patient and develop therapeutic alliance
Reassess response against target symptoms
Risk of self-harm Reconfirm diagnosis and identify other risk factors, e.g. high levels of alcohol
consumption in unsupervised situations
Discontinuation reactions Re-introduce antidepressant and adopt slower tapering of dose
True relapse which develops much later Consider long-term treatment
than acute discontinuation events
Intolerance Consider changing to a different class
Antimanic agents
Treatment failure Ensure adequate dose, check serum levels and adherence; consider drug combinations
Toxicity adverse effects Determine dose by clinical response, guided by serum levels
Ensure patient is well informed and able to recognise impending toxicity and adverse effects
of treatment
Problematic weight gain Dietary advice; structured exercise programmes; consider alternative pharmacotherapy, 509
noting that most drugs used in affective disorders will cause some degree of weight gain
Lithium levels Ensure serum levels are 12 h post-dose. This is facilitated by single night time dosing and a
blood sample taken the following morning
29 THERAPEUTICS
Case studies records showed that on his last admission he had been treated with
haloperidol. He was not keen to take any medication offered and it
Case 29.1 was decided that admission to hospital was appropriate.
Ms PS is a 21-year-old woman who presented to her primary care Question
doctor with a 2-month history of difficulty in getting to sleep. She
described herself as feeling generally unhappy. She was socialis- What treatment is appropriate for Mr DD?
ing much less but was able to perform most of her usual daily
routines. She sometimes felt as though she had little energy and Answer
was spending more time just watching the television.
Although Mr DD has an established psychiatric diagnosis, it is still
Question important to rule out any organic or physical causes or drivers for his
presentation. Following a thorough physical and psychiatric examina-
What other questions would you want to ask of Ms PS before a diag- tion, it was established that Mr DD had been relatively well since com-
nosis is made? What treatment options are indicated? mencing treatment with lithium almost 4 years previously. However, it
was identified that a few months ago he decided to stop taking lithium.
Answer It is important that symptoms of mania are promptly brought under
control. Haloperidol would be a suitable choice, in view of his pre-
Firstly, it is important to explore with the patient if there are any other vious response. However, a review of Mr DD’s medication history
changes, especially with regard to signs and symptoms that present in revealed that he had experienced several acute dystonic reactions to
depression. In a discussion with Ms PS it would be important to look for haloperidol during previous admissions. His daughter also reported
other symptoms of anxiety such as worrying thoughts, appetite changes that her father had commented on how awful it felt being given halo-
and associated weight loss, suicidality, reduced concentration, loss of peridol during his last admission. Mr DD was, therefore, given the
interest in hobbies and reduced libido (see mnemonic in main text). option to discuss alternative antipsychotic treatment. He agreed to
On further questioning by her primary care doctor, Ms PS does not take olanzapine which was prescribed at a dosage of 15 mg daily.
reveal any indicators of self-harm. She does not identify any signifi- When Mr DD’s manic symptoms are controlled, prophylactic treat-
cant weight loss, and her appetite has not reduced significantly. She ment should be discussed with him. This should include a discussion
does not demonstrate any signs of poor self-care, is in a supportive about why he had discontinued lithium several months earlier. The
relationship, and although she has some financial concerns, these are opportunity should be taken to provide written information with the
not excessive. offer of a further discussion that should include his daughter.
It is likely that her depression is subthreshold or of mild severity. Mr DD had stopped lithium because he felt he no longer needed it,
Referral to specialist services is not appropriate. Ms PS could be given but after discussion he was prepared to restart treatment. In line with
advice on sleep hygiene. Sleep hygiene strategies include ensuring results from renal and thyroid function tests, lithium carbonate may be
that the sleeping environment is comfortable and at an acceptable re-introduced. A suitable starting dose is likely to be of the order 400
temperature and not too bright. Ms PS herself should be advised to mg lithium carbonate at night.
avoid heavy meals, excessive exercise and stimulant (e.g. caffeine- One week later, a 12-hour standard serum lithium level should be per-
based drinks) prior to bedtime. Associating bed with sleep and formed and the dose of lithium adjusted to achieve the same lithium
avoiding reading, watching TV or listening to the radio in bed is also levels as before (0.6 mmol/L).
recommended. The side effects and signs of impending toxicity from lithium should
Active monitoring should be adopted and Ms PS asked to attend for be explained to Mr DD and, if possible, his daughter. They should
a follow-up appointment in around 2 weeks. be provided with the National Patient Safety Agency lithium resource
At this stage antidepressants are not indicated. Non-pharmacological booklet or any local hospital equivalent publication. In the UK this
interventions to consider would be a structured group exercise pro- resource is used to provide important safety information around med-
gramme, guided self-help based on the principles of CBT or comput- icines management of lithium and includes the importance of regular
erised CBT. The specific intervention should be guided by Ms PS’s lithium levels and other blood tests such as kidney and thyroid func-
preferences. tion, signs and symptoms of lithium toxicity, and actions that can be
taken to avoid lithium toxicity. Once Mr DD is more settled, the olan-
Case 29.2 zapine can be reduced with a view to discontinuation. This may take
several weeks and can be done after he has been discharged from
510 Mr DD is a 50-year-old unemployed man with a long-standing his- hospital. Further discussion with the patient and prescriber about hav-
tory of bipolar disorder. He has been prescribed lithium for some ing a supply of medication to help with any breakthrough symptoms
time. His admission into hospital was prompted by a short period of that may occur in the future would be helpful and promote insight into
increasingly disturbed behaviour. Mr DD’s daughter had contacted the condition. This medication might be olanzapine or could be an
the mental health services when she discovered that her father had agreed benzodiazepine or related sedative agent.
just spent over £5000 on scientific instruments from an Internet
auction site. Over the same period she had noticed that her father Case 29.3
had lost interest in his self-care and become elated at the prospect
of being on the verge of developing a special formula to solve the Mr MA is a 49-year-old unemployed man. He was admitted to a
fuel crisis. On assessment Mr DD said he felt ‘fine, fine all the time’. psychiatric unit as an emergency admission. Mr MA had been pre-
He told the visiting team that he did not need to be in hospital and it scribed fluoxetine 20 mg daily 2 months ago, and after no appar-
would keep him away from his top-secret mission. He also said that ent response the prescriber had changed this to citalopram 20 mg
they could not admit him. Mr DD’s speech was sometimes very rapid, daily 4 weeks earlier. On admission he was noted to be withdrawn,
and it was sometimes difficult to understand what he was saying. His lacking motivation and just gave yes or no in response to ques-
tioning. He reported no interests in his life, and it was noted that
he had attempted to harm himself in the past. Two weeks after
AFFECTIVE DISORDERS 29
admission there was no significant improvement in his symptoms. Answer
Mr MA is a non-smoker and takes no other medications. He has
lost some weight but remains still mildly obese with a body mass Cautions around the use of valproate in pregnancy have recently
index of 32 kg/m2. been strengthened in national guidance (NICE, 2016). However, in
any perinatal mental health situation the wellness of the mother and
Question the treatment(s) needed must be balanced against individualised risks
of effective treatment. The fetal malformation risk of valproate use in
What treatment options would you consider for Mr MA? pregnancy is dose dependent and non-linear (Eadie, 2016). Valproate
semisodium at a dose of 1500 mg daily has a risk of around 18%.
Answer The risk is fetal malformation. At higher valproate doses of around
2000 mg/day the incidence of spina bifida is increased. The risk to
Mr MA demonstrates symptoms of severe depression with some risk Ms YS could be reduced by identifying a lower effective dose; for
factors, and ECT may be considered an early intervention pending example, at 1000 mg daily the risk is around 10%.
review of antidepressant treatment. Mr MA must give his consent to Alternative agents for managing manic episodes include lithium, car-
this treatment because he is an informal patient and retains capacity bamazepine and antipsychotics. Carbamazepine is inherently less tera-
to make treatment decisions. togenic, and at a dosage of 1000 mg daily fetal malformation risk is
Before considering a change in antidepressant treatment, previous around 8%. However, because Ms YS has not previously been prescribed
adherence should be checked. Review of the medicine charts and this drug its effectiveness for her bipolar management is unknown.
discussion with nursing staff, relatives, key workers and the patient For both carbamazepine and valproate, supplementary high-dose
should enable a reasonable judgement to be reached. A dose folate (5 mg folic acid daily) might help mitigate some of the risk to
increase is unlikely to be helpful unless the patient is a fast metabo- the developing foetus including development of neural tube defect,
liser or smoker because SSRIs have a flat dose–response curve. In but the protective effect of folate has recently been questioned if
this case, the patient had taken the majority of prescribed doses, is used pre-conception (Eadie, 2016).
a non-smoker, and having received no apparent benefit, a change in Lithium, outside of first-trimester use, where there is a risk of around
treatment is warranted. 1 in 1000 of causing a heart defect (Ebstein’s anomaly), is now con-
An in-depth review of his physical condition and previous medica- sidered a suitable option with careful medicines management. Ms YS
tion should be undertaken. This should include discussion about any stopped treatment because of weight gain, not because of lack of
previous antidepressant treatment found to be particularly effective, efficacy, and her priorities may now be different. As part of pregnancy
or troublesome. planning lithium is sometimes stopped during a low-risk period of
This review revealed that Mr MA had received several different antide- relapse and this is timed to coincide with first trimester. For Ms YS and
pressants over the past 20 years. Three years ago he was treated with her hypomanic state, re-establishing lithium may take too long.
venlafaxine modified release 75 mg twice daily. The medical records Second-generation antipsychotics with a license for use in and pre-
confirmed Mr MA’s view that this medication had helped him in the vention of further manic episodes remain another option. There is
past, but on further questioning he stated that he had not taken medi- no one particular agent to recommend and in line with the US Food
cation for long after discharge from hospital because he did not want and Drug Administration category C classification, benefits are con-
to get ‘hooked’ on it. sidered to outweigh risks when used in pregnancy. If this option is
The importance of long-term treatment and the proposed treat- selected, then choice of agent is best determined by consideration of
ment plan should be discussed with Mr MA. Particular issues to be other properties of each agent. Drugs that may be considered include
addressed include an assessment of physical health including base- aripiprazole, olanzapine and risperidone.
line blood pressure and the need for ongoing periodic monitoring. Benzodiazepines may also be considered as a short-term adjunct if
In view of Mr MA’s concerns about dependence, particular attention additional sedation is required.
should be given to discussion around ‘antidepressant addiction’.
Based on Mr MA’s agreement to the treatment plan, his previous Case 29.5
response, the lack of any physical contraindication and the ability to
organise ongoing, periodic blood pressure monitoring, venlafaxine Ms AB is a 55-year-old unemployed lady with a long-standing
would be an appropriate treatment option. history of depression. She has been treated with several antide-
pressants over the years and is currently under the care of the
Case 29.4 community mental health team. The only treatment that appears
to have had any effect on her depressive episodes has been dosu-
Ms YS is a 28-year-old student with a history of bipolar disorder. lepin. She has taken several overdoses in the past, and her psy-
She recently moved to the area in the hope of continuing her stud- chiatrist is reluctant to prescribe this drug.
ies. She was urgently assessed at the request of her key worker,
who reported that Ms YS had recently become increasingly elated Question
and her partner was very concerned about the increased credit
card bills she was incurring. In the past Ms YS had been prescribed What measures could be taken to enable Ms AB to be treated ef-
lithium but had refused to continue with it because of significant fectively?
weight gain. She had been switched to valproate. Prescribed med-
ication was valproate semisodium 1500 mg daily. However, Ms YS Answer
had become aware that this agent was very toxic in pregnancy.
Being keen to start a family with her partner, Ms YS had stopped Ms AB does not have treatment-resistant depression. She has been 511
taking this treatment. successfully treated with dosulepin in the past, but seemingly impul-
sively takes an overdose from time to time. This case requires man-
Question agement of the overdose risk and exploring any triggers that prompt
such action, or moving to an alternative untried regimen which carries
Describe the treatment options available for Ms YS. a lower toxicity profile.
29 THERAPEUTICS
Although current guidelines (NICE, 2009a, 2009b) now advocate that for only a few days’ treatment at a time. An instalment dispensing
no new patients should be commenced on dosulepin, this is not the arrangement requires good communication among all those involved
same as switching patients for whom the drug is effective to an alter- in her care. When individualising the supply of medication in this
native agent. way, all of those involved must be alert to the possibility that the
If Ms AB is going to continue to take dosulepin, then practical mea- system of supply may break down. In this case, an apparently rou-
sures for controlling the quantities of medication should be intro- tine prescription for 1 month’s supply of medication may have fatal
duced. This could be ensuring she receives sufficient medication consequences.
References National Institute for Health and Care Excellence (NICE), 2009b.
American Psychiatric Association, 2013. Diagnostic and Statistical Manual Depression. The treatment and management of depression in adults.
of Mental Disorders, ifth ed. American Psychiatric Publishing Inc.,
Washington, DC. Clinical Guidelines 91. NICE, London. Available at: http://www.nice.
org.uk/guidance/CG91.
Cleare, A., Pariante, C.M., Young, A.H., et al., 2015. Evidence-based guide- National Institute for Health and Care Excellence (NICE), 2014. Bipolar
lines for treating depressive disorders with antidepressants: a revision disorder. The management of bipolar disorder in adults, children and
of the 2008 British Association for Psychopharmacology guidelines. J.
Psychopharmacol. 29 (5), 459–525. adolescents in primary and secondary care. Clinical Guideline 185. NICE,
London. Available at: https://www.nice.org.uk/guidance/cg185.
Eadie, M.J., 2016. Antiepileptic drug safety in pregnancy. Clin. Pharm. 8 National Institute for Health and Care Excellence (NICE), 2015. Vortioxetine
(1), 24–31. for treating major depressive episodes. Technology appraisal guidance TA
Linde, K., Berner, M.M., Kriston, L., 2008. St John’s wort for major depres- 367. NICE, London. Available at: https://www.nice.org.uk/guidance/ta367.
sion. Cochrane Database Syst. Rev. 2008 (4), CD000448. https://doi. National Institute for Health and Care Excellence (NICE), 2016. Bipolar
org/10.1002/14651858.CD000448.pub3.
disorder: assessment and management: update to CG 185. Supporting the
Malhi, G., Tanious, M., Das, P., et al., 2013. Potential mechanisms of action toolkit on the risks of valproate medicines in female patients. Available at:
of lithium in bipolar disorder. Current understanding. CNS Drugs 27 (2),
135–153. http://www.medicines.org.uk/emc/RMM.421.pdf.
National Patient Safety Agency, 2009. Safer lithium therapy. Available at:
Merikangas, K.R., Jin, R., Jian-Ping, H., et al., 2011. Prevalence and cor-
relates of bipolar spectrum disorder in the. World Mental Health Survey http://www.nrls.npsa.nhs.uk/EasySiteWeb/getresorce.axd?Asset
Initiative. Arch. Gen. Psychiatry 68 (3), 241–251. ID=65428&.
Preda, A., 2012. Substance induced mood disorder. Available at: http://www.
Muhleisen, T.W., Leber, M., Schulze, T.G., et al., 2014. Genome wide asso- nrls.npsa.nhs.uk/EasySiteWeb/getresource.axd?AssetID=65428&....
ciation study reveals two new risk loci for bipolar disorder. Nat. Commun. Sullivan, P.F., Neale, M.C., Kendler, K.S., 2000. Genetic epidemiology of
5, 3339. https://doi.org/10.1038/ncomms4339. Available at: http://www.
nature.com/ncomms/2014/140311/ncomms4339/full/ncomms4339.html. major depression: review and meta-analysis Am. J. Psychiatry 157 (10),
National Institute for Health and Care Excellence (NICE), 2009a. Depres- 1552–1562.
sion. The treatment and management of depression in adults. Clinical World Health Organization (WHO), 1992. International Classiication of
Guidelines 90. NICE, London. Available at: http://www.nice.org.uk/guid
ance/CG90. Diseases and related health problems, 10th Revision (ICD 10). World
Health Organization, Geneva.
Further reading Gelder, M., Andreasen, N., Lopez-Ibor, J., et al., 2012. New Oxford Text-
Bazire, S., 2016. Psychotropic Drug Directory 2016. Lloyd-Reinhold Com- book of Psychiatry, second ed. Oxford University Press, Oxford.
munications, Cheltenham, UK.
Goodwin, G., 2009. Evidence-based guidelines for treating bipolar disorder:
Cipriani, A., Furukawa, T.A., Salanti, G., et al., 2009. Comparative eficacy and
acceptability of 12 new-generation antidepressants: a multiple-treatments revised second edition – recommendations from the British Association
meta-analysis. Lancet 373, 746–758. for Psychopharmacology. J. Psychopharmacol. 23, 346–388.
Halverson, J.L., 2016. Depression clinical presentation. Available at: http://e
Cipriani, A., Pretty, H., Hawton, K., et al., 2005. Lithium in the preven- medicine.medscape.com/article/286759-clinical.
tion of suicidal behaviour and all-cause mortality in patients with mood Kasper, S., Hamon, M., 2009. Beyond the monoaminergic hypothesis: ago-
disorders: a systematic review of randomised trials. Am. J. Psychiatry
162, 1805–1819. melatine, a new antidepressant with an innovative mechanism of action.
World J. Biol. Psychiatry 10, 117–126.
Fournier, J., DeRubeis, R.J., Hollon, S., et al., 2010. Antidepressant drug ef- Shiloh, R., Stryjer, R., Weizman, A., et al., 2006. Atlas of Psychiatric Phar-
fects and depression severity: a patient-level meta-analysis. J. Am. Med. macotherapy, second ed. Informa Healthcare, Abingdon, UK.
Assoc. 303, 47–53.
Taylor, D., Paton, C., Kapur, S., 2015. The Maudsley Prescribing Guidelines
Geddes, J.R., Burgess, S., Hawton, K., et al., 2004. Long-term lithium
therapy for bipolar disorder: systematic review and meta-analysis of rand- in Psychiatry, twelfth ed. Wiley-Blackwell, Oxford.
omized controlled trials. Am. J. Psychiatry 161, 217–222. Walden, J., Heinz, G. (Eds.), 2014. Bipolar Affective Disorders: Etiology
and Treatment. Thieme Publishing Group, Stuttgart.
Useful website
Choice and Medication: http://www.choiceandmedication.org/cms/subscrib
ers/?lang=en
512
THERAPEUTICS
30 Schizophrenia
Caroline Parker
Key points Classification
• Schizophrenia is a complex chronic illness which varies greatly Since the late 19th century there have been frequent attempts to
in presentation (positive and negative symptoms). deine the illness we now call schizophrenia. Kraepelin, in the
late 1890s, coined the term ‘dementia praecox’ (early madness) to
• Positive symptoms such as hallucinations, delusions and describe an illness where there was a deterioration of the person-
thought disorder, which commonly occur in the acute phase of ality at a young age. Kraepelin also coined the terms ‘catatonic’
the illness, usually respond to treatment with antipsychotics. (where motor symptoms are prevalent and changes in activity
vary), ‘hebephrenic’ (silly, childish behaviour, affective symptoms
• Negative symptoms such as apathy, social withdrawal and lack and thought disorder prominence) and ‘paranoid’ (clinical picture
of drive, which occur commonly in the chronic phase of the dominated by paranoid delusions). A few years later Bleuler, a
illness, are more resistant to medication. Swiss psychiatrist, introduced the term ‘schizophrenia’, derived
from the Greek words skhizo (‘to split’) and phren (‘mind’), mean-
• The term ‘atypical’ or ‘second generation’ is used to describe ing the split between the emotions and the intellect.
the newer antipsychotics that generally do not cause the extra-
pyramidal side effects (EPSE) or hyperprolactinaemia. Two systems for the classiication of schizophrenia are widely
used: Diagnostic and Statistical Manual of Mental Disorders, Fifth
• However, the second generation antipsychotics are associated Edition (DSM 5) (American Psychiatric Association, 2013) and
with a range of metabolic side effects including weight gain the International Classiication of Diseases and Related Health
and diabetes, which in turn may have long-term effects on Problems, 10th Edition (ICD 10) (World Health Organization, 1992).
morbidity and mortality.
Symptoms and diagnosis
• The older ‘typical’ or ‘first generation’ antipsychotics are often
associated with anticholinergic, sedative and cardiovascular Schizophrenia is a chronic illness; the exact nature of the symp-
side effects, in addition to EPSE. toms varies greatly in presentation between individuals. It com-
prises ‘positive’ and ‘negative’ symptoms. Positive symptoms
• Long-term treatment with first generation antipsychotics is include hallucinations (these may be auditory, visual or visceral),
associated with the development of the movement disorder delusions, thought disorder (including thought insertion or dele-
tardive dyskinesia. tion), paranoia, and grandiosity. Negative symptoms include apa-
thy, social withdrawal and lack of drive and interest.
• Most first generation and second generation antipsychotics
have similar efficacy in the treatment of schizophrenia. The The intensity of an individual’s positive and negative symp-
exception is clozapine, which has greater efficacy than all other toms may vary over time. As with most chronic illness, a person
antipsychotics and is therefore indicated for treatment-resistant with schizophrenia may always have some of these symptoms
schizophrenia. Its use is hampered by the mandatory require- to some degree, but during an acute relapse they will be worse,
ment for regular full blood count checkups. and it is usually the positive symptoms that are more obvious to
other people and may be problematic. During periods of remis-
• Decisions about which antipsychotic to use should be a shared sion between acute episodes, it is often the negative symptoms
decision between patient and the prescriber, based on an that are more problematic, and these are generally less responsive
informed discussion involving individual preference, previous to treatment with antipsychotics.
efficacy of medication and potential side effects.
Acute psychotic illness 513
The concept of schizophrenia can be dificult to understand.
People who do not suffer from schizophrenia can have little idea An acute psychotic episode may occur in a number of disease
of what the experience of hallucinations and delusions is like. states and for a range of reasons, and a single psychotic episode
The presentation of schizophrenia can be extremely varied, with
a great range of possible symptoms. It is a chronic disorder with a
lifetime prevalence of 1 in 100 people. There are also many mis-
conceptions about the condition of schizophrenia that have led
to prejudice against sufferers of the illness. People with schizo-
phrenia are commonly thought to have low intelligence and to be
dangerous. In fact, only a minority shows violent behaviour, with
social withdrawal being a more common picture. Up to 10% of
people with schizophrenia commit suicide.
30 THERAPEUTICS
does not constitute the disease schizophrenia. Symptoms which their goal in fetal development and when supernumerary neural
commonly occur in an acute psychotic episode include: cells slough off at adolescence. This model is supported by neu-
• awkward social behaviour, appearing preoccupied, perplexed roimaging studies which show structural brain abnormalities in
patients with schizophrenia.
and withdrawn, or showing unexpected changes in behaviour;
• initial vagueness in speech which can progress to disorders of Environmental factors
the stream of thought or poverty of thought; Multiple external environmental factors may inluence the
• abnormality of mood such as anxiety, depression, irritability development of the disorder including the social, cultural
and family environments; the population density; living in
or euphoria; an urban environment; individual space; family dysfunction;
• auditory hallucinations, the most common of which are socio-economic status; social isolation; racial status; immi-
gration; substance misuse; and prenatal stressors. Childhood
referred to as ‘voices’; such voices can give commands to trauma, death of a parent, and being bullied or abused also
patients or may discuss the person in the third person, or com- increase the risk of psychosis.
ment on their actions;
• delusions, of which those relating to control of thoughts are Genetic model
the most diagnostic; for example, patients feel that thoughts
are being inserted into or withdrawn from their mind; There is undoubtedly a genetic component to schizophrenia,
• lack of insight (understanding or self-awareness) into the with a higher incidence in the siblings of people with schizo-
illness. phrenia and in those with a irst-degree relative with schizo-
These symptoms are commonly called positive symptoms and phrenia. However, even in monozygotic twins there are many
generally respond to treatment with antipsychotics. cases where schizophrenia developed in only one sibling. It
can often be dificult to separate the effects of genetics and the
Factors that affect diagnosis and prognosis environment.
A deinite diagnosis of schizophrenia is established according to Transmitter abnormality model
the diagnostic criteria in either DSM 5 or ICD 10. It would not
generally be made after a single psychotic episode, especially if Based on the research that shows that all effective antipsychotics
it is brief. It is more likely to be made after a repeated psychotic are active at dopamine receptors and, in particular, D2 receptors,
episode. A number of features aid prediction of whether an acute the hypothesis is that schizophrenia is due to an overactivity of
illness will become chronic. These features include: dopamine (the dopamine hypothesis). However, such a theory
• age of onset, which, typically for schizophrenia, is late teenage is increasingly being questioned as newer research emerges
regarding eficacy of antipsychotics relating to activity at other
to 30 years; receptors.
• reports of a childhood which indicate the individual did not
Vulnerability model
mix or was a rather shy and withdrawn personality;
• a poor work record; The vulnerability model postulates that the persistent character-
• a desire for social isolation; istic of schizophrenia is not the acute episode itself, but the vul-
• being single and not seeming to have sexual relationships; nerability to the development of such episodes. The episodes are
• a gradual onset of the illness and deterioration from the previ- time limited, but the vulnerability remains, awaiting the trigger
such as stress. The vulnerability can depend on the premorbid
ous level of functioning; personality, the individual’s social network or the environment.
• grossly disorganised behaviour. Manipulation and avoidance of stress can abort a potential psy-
chotic episode.
A person with schizophrenia may well have periods of relapse
with acute psychotic symptoms, and in between there may be Other factors
a general underlying trend towards ‘negative’ symptoms, for
example, lack of drive, social withdrawal and emotional apa- Numerous other factors have been implicated in the development
thy. Unfortunately negative symptoms respond poorly to most and cause of schizophrenia. These include perinatal insult, infec-
antipsychotics. tions, season of birth (people with schizophrenia are more likely
to have been born in winter or spring, at least in the northern
Causes of schizophrenia hemisphere), viruses and toxins.
Although the cause of schizophrenia remains unknown, there are In reality, all of the above factors may inluence both the devel-
many theories and models. opment and the progression of schizophrenia. Social, familial and
biological factors may lead to premorbid vulnerability and subse-
Developmental model quently inluence both the acute psychosis and the progression to
The developmental model postulates that there are critical peri-
ods in the development of neuronal cells which, if adversely
affected, may result in schizophrenia. Two such critical periods
514 are postulated to occur when migrant neural cells do not reach
SCHIZOPHRENIA 30
chronic states. What is then likely is that the illness will feed back antipsychotics have a more speciic effect on D2 receptors alone,
to inluence social, familial and biological factors, thus leading to yet they do not appear to have superior antipsychotic effect when
future vulnerability. compared with other agents.
Pharmacological treatment Even today, all the known antipsychotics have an effect via the
D2 receptors. However, additionally most second generation anti-
Antipsychotics psychotics also target serotonin (5-HT2A) receptors, and the bal-
ance between the activity at these two receptors types is thought
Antipsychotics have been widely available in the UK since the to be important to their mechanism of action.
1950s. They are an essential treatment for most individuals with
schizophrenia and are considered irst-line pharmacotherapy. ‘Typical’ or ‘first generation’ and ‘atypical’ or
Antipsychotics can help treat acute symptoms and maintain ‘second generation’ antipsychotics
remission from the illness. In fact, the main aim of antipsychotic
treatment is to prevent acute relapse and to help keep the person The antipsychotics that were irst available were known to
well and stable. Although antipsychotics are a core treatment in commonly cause extrapyramidal movement disorders. It was
the management of schizophrenia, they are just one part of the not until the development of clozapine in the 1980s that it was
package of care that contributes towards this aim. established that antipsychotic eficacy could be achieved without
inducing extrapyramidal side effects (EPSE). Thereafter, devel-
A wide range of antipsychotics is available. Overall most anti- opment of antipsychotics aimed to ensure antipsychotic eficacy
psychotics are equally effective for the treatment of psychotic without EPSE.
symptoms (Leucht et al., 2013); however, some individuals
respond much better to one than another and they are not effec- The older antipsychotics developed before clozapine and
tive in all cases. There is no way of predicting to which antipsy- which ‘typically’ caused EPSE became known as ‘typical’ anti-
chotic an individual person will respond. psychotics, with the new antipsychotics developed after clozap-
ine, which caused no or fewer EPSE, termed ‘atypical’. These
Mode of action of antipsychotics two groups are now more often termed ‘irst’ and ‘second’ gener-
ation antipsychotics, as in the British National Formulary (BNF).
Although the cause of schizophrenia is the subject of controversy, Although there are no deinitive criteria for this classiication, it
an understanding of the mode of action of antipsychotics has led is generally accepted that when used at therapeutic doses sec-
to the dopamine hypothesis of schizophrenia. This postulates that ond generation antipsychotics tend not to cause EPSE and tend
the psychotic symptoms in schizophrenia are caused by an altera- not to raise prolactin. Importantly this is not without exception,
tion in the level of dopamine activity in the brain. It is known that because some second generation antipsychotics (e.g. risperidone,
dopamine receptor antagonists are often effective at treating psy- amisulpride) can cause EPSE and hyperprolactinaemia even at
chotic symptoms, whilst drugs which increase dopamine activity, therapeutic doses. Therefore, these two classiications are better
such as amphetamine, can either induce psychosis or exacerbate viewed as principles, and it is helpful not to consider antipsychot-
schizophrenia. ics as being in two discrete groups, but rather on a continuum
(refer to Fig. 30.1).
At least six dopamine receptors exist in the brain, with much
interest being focused on antagonism of the D2 receptor as Although the reason for the superiority of clozapine in
being responsible for the antipsychotic effect. However, some schizophrenia treatment remains an enigma, a variety of the-
ories have led to the development of newer antipsychotics.
Oil-based depots First generation or
Haloperidol [1958] ‘Typical’ antipsychotics
Trifluoperazine [1958] EPSE is common, raised
Chlorpromazine [1952] prolactin
Sulpiride [1983]
Amisulpride [1997] Second generation or
Risperidone [1996] = Paliperidone [2007] ‘Atypical’ antipsychotics
Asenapine [2014] EPSE uncommon
Olanzapine [1996] Generally prolactin sparing
Quetiapine [1997] Greater metabolic disorders
Lurasidone [2015]
Aripiprazole [2004]
Clozapine [1989]
Fig. 30.1 Classification of antipsychotics. EPSE, Extrapyramidal side effects. 515
30 THERAPEUTICS
Some mimic the impact of clozapine on a wide range of dopa- Sedation. Of the commonly used antipsychotics, sedation
mine and serotonin receptors (e.g. olanzapine), some mimic is most prominent with olanzapine and clozapine, even when
the impact on particular receptors (e.g. 5-HT2/D2 recep- used at moderate doses. However, it is seen to a lesser extent
tor antagonists such as risperidone), others focus on limited with many other antipsychotics. Patients may become accus-
occupancy of D2 receptors (e.g. quetiapine), and still others tomed to the sedation after the initial period (i.e. the irst few
focus on alternative theories such as partial agonism (e.g. weeks of treatment), although for some individuals it may
aripiprazole). make that particular antipsychotic an unfeasible maintenance
option.
Selecting an antipsychotic and dose
Weight gain and diabetes. Weight gain was a common fea-
Despite a wide selection of antipsychotics with different chemi- ture with the irst generation phenothiazine antipsychotics, but is
cal structures, different suggested variation in mechanisms of now seen to a greater extent with certain second generation anti-
action and different safety proiles, a number of studies and meta- psychotics, particularly olanzapine and clozapine. Weight gain
analyses in recent years have demonstrated that all antipsychotics is generally related to increased food intake driven by increased
are of similar eficacy for the treatment of positive symptoms of appetite and lack of satiation. In addition to weight gain, these
schizophrenia, with the exception of clozapine which has supe- two second generation antipsychotics have also been associated
rior eficacy, being effective for people with schizophrenia who with increased incidence of diabetes and hyperlipidaemia. This
did not successfully respond to treatment with other antipsychot- is seen with some other second generation antipsychotics (e.g.
ics (Kane et al., 1988; Lieberman et al., 1994). There is no clear quetiapine), but to a much lesser extent.
advantage of a second generation antipsychotic over a irst gen-
eration antipsychotic (Hartling et al., 2012; Jones et al., 2006; Schizophrenia itself is associated with increased incidence
Leucht et al., 2009, 2013; Lieberman et al., 2005; Stroup et al., of diabetes and cardiovascular disease; therefore, any addi-
2007). They do, however, vary signiicantly in terms of potential tional effect from an antipsychotic on increasing weight gain,
side effects. lipids and adversely affecting glucose control is a signifi-
cant concern. People with schizophrenia often suffer poorer
The choice of antipsychotic should always be informed by a physical health in addition to poor mental health and require
patient’s previous response to treatment, past experiences, includ- regular and often proactive monitoring of physical health risk
ing side effects, and preference, as well as any concurrent medi- factors.
cal comorbidity and medication (National Institute for Health and
Care Excellence [NICE], 2014). Cardiac side effects and QT prolongation. Postural hypo-
tension may be relatively common with a number of antipsychot-
Side effects ics. This is part of the rationale for slow-dose titrations when
initiating treatment (e.g. olanzapine, risperidone, quetiapine, clo-
A large number of adverse effects are associated with antipsy- zapine, chlorpromazine).
chotic medicines. In general the frequent or troublesome side
effects of the older irst generation antipsychotics include EPSE, Some antipsychotics, particularly haloperidol, are associated
tardive dyskinesia (TD), anticholinergic effects, cardiac effects with changes to the QTc interval measured on the electrocardio-
and hypotension, hyperprolactinaemia and sexual dysfunction. In gram (ECG) and, if given in high doses, may increase the risk of
contrast, in general the frequent or troublesome side effects of sudden cardiac death. Although overall the risk is very low, moni-
the newer second generation antipsychotics, including metabolic toring the ECG has become part of normal practice. Maximum
changes such as diabetes, weight gain and sexual dysfunction, licensed doses should not be exceeded.
can affect adherence in many patients. Sedation remains a factor
for many antipsychotics. Extrapyramidal side effects and tardive dyskinesia. The
Beyond these generalisations there is great variation in side EPSE such as akathisia, dystonia and parkinsonian symptoms
effects with each antipsychotic. Some effects, such as sedation are frequently associated with irst generation antipsychotics,
and weight gain, may be beneicial for particular patients, but particularly triluoperazine, luphenazine and haloperidol (see
not for others. The susceptibility of individual patients to such Box 30.1). They are also seen with certain second generation
adverse effects can vary signiicantly and is often a major factor antipsychotics, especially at higher doses (e.g. risperidone,
in determining the choice of antipsychotic. When deciding on the amisulpride). These side effects can be managed by dosage
most suitable antipsychotic for an individual patient, the relative reduction or by giving anticholinergics such as procyclidine or
potential of the individual antipsychotics to cause speciic side orphenadrine.
effects such as EPSE, akathisia, metabolic side effects, weight
gain and other unpleasant subjective experiences should be con- Attempts to treat TD have been many and varied. These strate-
sidered (NICE, 2014). gies are rarely successful and the focus should be on avoiding
development rather than treatment. Currently, the most success-
Extensive prescribing guidelines are available (Barnes et al., ful strategies involve a gradual withdrawal of the causal irst gen-
2011; Bazire, 2016; Procyshyn et al., 2015; Taylor et al., 2015) eration antipsychotic and replacement with a second generation
providing detailed comparisons of the relative likelihood of side antipsychotic.
effects with the various antipsychotics. The major side effects are
516 set out below. Anticholinergics may be prescribed to counter the EPSE of
antipsychotics. A number of studies have investigated the discon-
tinuation of anticholinergic agents and reported re-emergence of
the EPSE. The anticholinergics are not without problems, having
their own range of side effects including dry mouth, constipa-
tion and blurred vision. They can cause euphoria and, therefore,
SCHIZOPHRENIA 30
Box 30.1 Movement disorders associated with antipsychotics However, it was noted even at an early stage in trials that it was
completely free from causing the debilitating extrapyramidal
Extrapyramidal symptoms consist of: symptoms frequently seen with all the other existing antipsychot-
• Parkinsonian symptoms (usually present as tremor, rigidity, ics. In the 1980s, clozapine was demonstrated to have a greater
eficacy than other antipsychotics because it was effective for
bradykinesia, stooping gait and poverty of facial expression): some patients for whom other antipsychotics had failed (Kane
may appear gradually. These may remit if the antipsychotic et al., 1988; Lieberman et al., 1994). It was subsequently rein-
is withdrawn and may be suppressed by the administration troduced into clinical practice but with mandatory routine blood
of anticholinergics; however, routine co-administration of monitoring.
anticholinergics is not justified because not all patients are
affected. Anticholinergics are also associated with adverse Clozapine is now established as the antipsychotic of choice
effects and may unmask or worsen tardive dyskinesia. in treatment-resistant schizophrenia (NICE, 2014), but it is
• Acute dystonic reactions (abnormal face and body move- not without problems (Bleakley and Taylor, 2013). Treatment-
ments as a result of sustained muscle contraction) and resistant schizophrenia is generally deined as a failure to respond
dyskinesia: occurs more commonly in children or young adults to two antipsychotics used (in succession) at therapeutic doses
and may appear after only a few doses. These are acute and for a reasonable period of time. The use of clozapine should not
painful and need immediate treatment with an anticholinergic, be delayed or viewed as a treatment option of ‘last resort’. The
often in the parenteral form. earlier it is used the better is the patient’s prognosis.
• Akathisia (inner restlessness): patients may pace up and down,
constantly shifting their leg position or tapping their feet. In addition to neutropenia, clozapine is associated with a
• Tardive dyskinesia (rhythmic, involuntary movements that greater risk of seizures, particularly at higher dosages (>600
usually affect the tongue, face, neck and jaw muscles, but can mg daily); therefore, careful dose titration is required, as well
also affect extremities): usually develops after long-term use as regular adherence to the daily doses. Other problematic side
of antipsychotics or with high doses. It is of particular concern effects include initial hypotension and sedation. Later, sig-
because it may be irreversible and there is no effective treat- niicant weight gain, mediated through increased food intake
ment. Withdrawal of the causal antipsychotic at the earliest driven by food craving, disturbed glucose control, and poten-
signs may halt its full development. tially the development of diabetes and excessive drooling can
also present.
have the potential for misuse. Withdrawal problems can include
cholinergic rebound. One of the beneits of most second genera- A regimen of gradual dose titration starting at 12.5 mg twice
tion antipsychotics is the reduced need for co-prescription of daily aiming to reach 300 mg in 2–3 weeks is normally recom-
anticholinergics. mended. If the titration is too rapid, tachycardia, sedation and sei-
zures may be problems. Although tachycardia is a common and
Hormonal effects and sexual dysfunction. The side effects of usually benign problem during the initiation, if it is associated
hormonal effects and sexual dysfunction are primarily inluenced with fever, chest pain or hypotension this may indicate a high
by the effect of antipsychotics on inhibiting prolactin regulation risk of myocarditis, and clozapine should be stopped (Bleakley
leading to hyperprolactinaemia. This may become symptomatic; and Taylor, 2013).
symptoms include amenorrhoea, galactorrhoea, gynaecomastia
and loss of libido. Such effects are relatively common with the When treatment with clozapine is perceived to be inadequate,
older irst generation antipsychotics, as well as with certain sec- or dose optimisation is limited due to side effects, the treatment
ond generation antipsychotics such as risperidone, paliperidone plan can become complex. The theory behind the addition of a
and amisulpride. further medication is either to enhance the plasma concentration
of clozapine, or for the second medication to enhance a par-
Neuroleptic malignant syndrome. The neuroleptic malig- ticular receptor blockade which may be considered necessary
nant syndrome is a rare but serious idiosyncratic adverse effect in a speciic patient (Barber et al., 2017; Paton et al., 2007).
that can occur with any antipsychotic and with a few other related The augmentation strategy with the best evidence to support
medicines (e.g. metoclopramide). The primary symptoms are its use is the addition of sulpiride or amisulpride to clozapine.
related to loss of autonomic control (e.g. rigidity, fever, diapho- Other strategies include the addition of risperidone, lamotrigine
resis, confusion and luctuating consciousness). There may also or omega-3 fatty acids. However, many of the trials that support
be a signiicant rise in creatinine kinase, although this is not a these augmentation strategies are small scale. A meta-analysis
speciic diagnostic indicator. Although unpredictable, the onset concluded that no single strategy was superior to another (Paton
is particularly associated with the use of high-potency irst gen- et al., 2007).
eration antipsychotics such as haloperidol, recent and rapid-dose
increases, and abrupt withdrawal of anticholinergics. Treatment Using antipsychotics 517
usually requires urgent admission to a medical ward and immedi-
ate withdrawal of all antipsychotics. As a general rule, a patient should be prescribed only one antipsy-
chotic at a time. Exceptions would include the short periods of
Clozapine and refractory illness time when changing from one antipsychotic to another, because
an antipsychotic should not be stopped abruptly, and the new
Clozapine was developed as an antipsychotic during the 1960s. one is likely to require titration to a therapeutic dose; therefore,
Unfortunately, it was associated with a 1–2% incidence rate there will often be a period of a few weeks of crossover. Another
of neutropenia, and this initially resulted in its withdrawal. exception is augmentation of clozapine as described earlier.
30 THERAPEUTICS
If a person is being treated with an antipsychotic and it is swallowing problems. For such patients a ‘depot’ intramuscu-
not thought to be working suficiently the following steps are lar formulation may be an alternative strategy for maintenance
recommended: treatment (Fig. 30.2). Some patients also prefer to have a depot
• consider the patient’s adherence to the prescribed dose; because this avoids the daily routine of taking oral medicines.
• optimise the dose; Non-adherence with oral medicines is a major problem in patients
• review the symptoms and diagnosis in case it has changed; with any long-term illness, and the administration of a depot for-
• consider changing to another antipsychotic; mulation guarantees drug delivery.
• consider using clozapine if the patient has not responded suc-
Antipsychotics have been available in depot formulations
cessfully to two antipsychotics. since the 1960s; there are now a number available and they are
Prescribers should not keep increasing the dose of the existing widely used. Despite this increasing range of options in terms
antipsychotic beyond the BNF maximum or simply add a second of treatment eficacy and overall adverse effects, there is min-
antipsychotic for use alongside the irst. imal discernable difference between the depot formulations;
however, there are notable practical differences (Shajahan
Maximum and equivalent doses et al., 2010).
The consensus is that higher than licensed doses of antipsychotics Disadvantages of depots include reduced lexibility of dosage
do not improve the overall level of response which tends to pla- because it may be necessary to wait a few weeks until the next
teau. Higher doses only increase the number and severity of side dose is due before any dose amendment can be made. Other
effects, because many are dose related; therefore, both acute and disadvantages are the potentially painful nature of intramus-
longer-term risks are increased (Royal College of Psychiatrists, cular injections and, for some antipsychotics, a high incidence
2014). of EPSE. In addition, risperidone long-acting injection has a
considerable delay in onset, because there is no release of the
If more than one antipsychotic is used regularly, then prescrib- active drug from the microsphere formulation until 3 weeks
ers should consider the total cumulative daily dose of antipsy- after injection. The olanzapine depot is associated with a post-
chotics and the BNF maximum should not be exceeded. injection syndrome consistent with olanzapine overdose; there
is a requirement for patients to be observed for 3 hours after
Antipsychotics vary in potency of D2 receptor activity. every injection.
However, this is known to be only part of the explanation for
their eficacy. There is no deinitive list of equivalent doses in Most long-acting (depot) formulations are esters which are
terms of eficacy, but in terms of safety a standardised con- lipophilic and soluble. These are dissolved in an oily vehicle such
cept has been developed for calculating maximum doses. This as sesame oil or a thin vegetable oil (Viscoleo). Once injected
widely accepted method is to calculate what proportion the into muscle it is slowly released from the oil vehicle. Active drug
current dose is of the maximum dose stated in the BNF. For becomes available following hydrolysis for distribution to the
example, a daily dose of 15 mg of olanzapine is 75% of the site of the action.
maximum dose of 20 mg a day. This method is not without its
drawbacks because it generally relects the maximum doses Although the ideal long-acting antipsychotic formulation
manufacturers used in trials, but not all manufacturers con- should release the drug at a constant rate so that plasma level
ducted dose ranging trials to establish the maximum beneicial luctuations are kept to a minimum, all of the available products
dose. produce signiicant variations. This can result in increased side
effects at the time of peak plasma concentrations, usually after
Onset of effect 5–7 days for oil-based depots after which plasma concentrations
decline.
The full antipsychotic effect is not evident immediately. For the
more sedating antipsychotics the sedating effects may be evident Four irst generation and four second generation antipsychotics
within hours and generally wears off after 2–3 weeks (Kapur are currently licensed in the UK as long-acting depot formula-
et al., 2005). The actual antipsychotic effects on thought disorder, tions for intramuscular injection. The irst generation depots are
hallucinations and delusions may begin to be noticed within a oily injections given every 1–5 weeks; the second generation
week, but it may take several more weeks for full effects to be depots (or long-acting injections) are aqueous suspensions, given
seen. If there has been no response at all within 2–3 weeks of every 2–4 weeks (Table 30.1).
adherence, then a change of antipsychotic or change of dose is
probably indicated. Interactions and antipsychotics
Long-acting formulations of antipsychotics There are claimed to be many interactions involving antipsychot-
ics, but few appear to be clinically signiicant. Carbamazepine
Oral antipsychotic medication should be offered to people with accelerates the metabolism of haloperidol, risperidone and olan-
newly diagnosed schizophrenia. There may be circumstances zapine, and should not be used with clozapine because of the
where oral formulations of antipsychotics may not be suitable additional risk of neutropenia. Most antipsychotics increase
for an individual patient, for example, for those who struggle the sedative effect of alcohol. The selective serotonin reuptake
to remember to take medicines regularly and for those with inhibitors luoxetine, paroxetine and luvoxamine interact with
518 clozapine, resulting in increases in clozapine plasma concen-
tration. Smoking tobacco increases the rate of metabolism of
SCHIZOPHRENIA 30
Iliac crest Iliac crest
Injection site Anterior
superior
Posterior iliac spine
superior
iliac spine Injection site
Greater Greater
trochanater trochanater
of femur
Sciatic nerve
Femoral
A B artery and
vein
Scapula Acromion
process Sciatic
Clavicle nerve
Deltoid muscle Greater Deep
Injection site trochanater femoral
Axilla of femur artery
Rectus
Humerus Vastus lateralis femoris
(Outer middle injection
Deep brachial third) site
artery (Injection site)
Radial nerve
Lateral femoral
condyle
CD
Fig. 30.2 Location of intramuscular injection site (deltoid and gluteal). A and B are both gluteal in-
jection sites, viewed from different angles. C is a deltoid injection site. D is vastus lateralis and rectus
femoris injection sites.
olanzapine and clozapine, and regular doses may need to be of drug concentrations is not a part of routine clinical practice
reduced if a person stops smoking. Clozapine levels should also except with clozapine, although even with clozapine there is
be checked if a patient changes his or her smoking habits. only a weak correlation between plasma levels and clinical
effect. The general guidance is that individuals who have not
Therapeutic drug monitoring adequately responded to clozapine and have a plasma level less
than 350–500 micrograms/L may beneit from a dose increase.
Therapeutic drug monitoring is only of value if there is a reliable Those who suffer side effects and have a plasma level above
laboratory assay and a correlation exists between the concentra- this range may beneit from a dose reduction. Those with a
tion of the drug in any particular body compartment, usually plasma level greater than 1000 micrograms/L are more likely to
blood/plasma, and its clinical effectiveness. Unfortunately, this suffer seizures, and antiepileptic cover using sodium valproate
is not the case for most antipsychotics, and the measurement should be considered.
519
30 THERAPEUTICS
Table 30.1 Depot antipsychotics available in the UK
Formulation and Administration (intramuscular) Time to Half-life Available
vehicle since
Trade name Generic name and comments peak (days) (days) 1978
First generation 1972
1982
Clopixol Zuclopenthixol Thin vegetable oil Upper outer buttock 4–7 19 1968
decanoate (gluteal) or upper lateral 2002
thigh, every 1–4 weeks
2015
Depixol Flupentixol Thin vegetable oil Upper outer buttock 7 17
decanoate (gluteal) or upper lateral 2011
thigh, every 1–4 weeks 2010
Haldol Haloperidol Sesame oil Gluteal, every 4 weeks 3–9 21
decanoate
Modecate Fluphenazine Sesame oil Gluteal, every 2–5 weeks 0.3–1.5 6–9
decanoate
Second generation
Risperdal Consta Risperidone Powder for reconsti- Gluteal or deltoid, 32 8–9
tution with aqueous every 2 weeks
solution in a prefilled Requires refrigeration
syringe, forms a
suspension
Abilify Maintena Aripiprazole Prefilled syringe of Gluteal or deltoid, 7 after 47
aqueous prolonged- every month gluteal,
release suspension and 4 after
deltoid
administra-
tion
Xeplion Paliperidone Prefilled syringe of Gluteal or deltoid, every 13 25–49
palmitate aqueous prolonged-
release suspension month (no refrigeration), active
metabolite of risperidone
ZypAdhera Olanzapine Powder for reconsti- Gluteal, every 2 or 4 weeks 3 10
pamoate tution with aque- Observe patient carefully for
ous fluid, forms a symptoms of post-injection
suspension syndrome for 3 h after
each dose
Case studies raves. Police were called to his flat after a violent disturbance. They
found Mr LT living in squalor. He was surrounded by pieces of paper
Case 30.1 containing incomprehensible messages and was incoherent. He sat
with a fixed stare, appearing quite inaccessible. He kept laughing
Mr LT is a 20-year-old man. His childhood was disrupted by constant and responding to imaginary people. He was very resistant to hospi-
changes to family membership. From an early age his behaviour tal admission, and had to be admitted under a section of the Mental
was difficult, but despite such changes at school he coped and per- Health Act 1983. On the ward he has remained quiet but appears to
formed academically well. At age 15 he started using cannabis and be in conversation with people who are not there.
increasingly lost interest in his studies at school. His parents became
concerned as he appeared to undergo a change of personality, com- Questions
municating with them very little. He eventually dropped out of school
and briefly took various short-term jobs. He was unable to sustain any 1. Outline the medicine(s) of choice for Mr LT and the rationale for
long-term employment. When he was 17 he moved into a flat and your selection.
seemed to live a twilight existence involving illicit drugs and all-night
2. What factors in his presentation are likely to influence his
prognosis?
520
SCHIZOPHRENIA 30
3. Outline the medicine(s) of choice if there is a short-term, immedi- 3. What would you recommend if Mr GL relapsed and was admitted
ate need to control aggressive behaviour. again?
Answers Answers
1. The choice of medicine used (or not) will be influenced by the 1. Mr GL has been treated with three oral second generation antipsy-
working diagnosis. So the first need is to ascertain whether Mr LT’s chotics all with good effect. The initial treatment was with a fairly
behaviour results from abuse of cannabis and other illicit sub- large dose of risperidone (8 mg). If this was his first episode and if
stances, or whether it is the onset of a psychotic illness such as he was antipsychotic naive, the dose was titrated straight up to this
schizophrenia. If the former, he would be expected to recover dose quite quickly, and it may well be considered excessive. The
within a few days with little or no medication. If, however, this usual treatment dosage is 4–6 mg/day. EPSE are dose related and
is the first presentation of a schizophrenic illness, the symptoms could be expected at a dosage of 8 mg/day. The second choice of
are likely to persist and it would be appropriate to prescribe an olanzapine, another second generation antipsychotic was appro-
antipsychotic. For first episode psychosis an oral antipsychotic priate, because this rarely causes EPSE. The third choice of amis-
should be offered. The exact choice will partly depend on which is ulpride was unlikely to cause weight gain (unlike olanzapine) but is
tolerable to the patient, the likelihood of certain side effects, the quite likely to cause EPSE. Choosing a third oral antipsychotic was
patient’s age (there are additional considerations if the patient is not addressing the potential issue of adherence.
aged <18 years) and the balance and risk of side effects. It would
usually be a second generation antipsychotic such as aripiprazole 2. Mr GL has no insight into his illness or the need for continu-
or risperidone. Olanzapine may not be such a suitable choice ing treatment. Repeatedly stopping antipsychotics and having
because of the high likelihood of significant weight gain and meta- relapses leads to a worse prognosis. Therefore, it is really impor-
bolic symptoms. If there are concerns that he may not swallow the tant to properly address Mr GL’s repeated discontinuation of anti-
medications, then an orodispersible formulation may be useful. psychotic medication, which could be for a number of reasons
These formulations are available for aripiprazole and risperidone including:
and some other medicines. • His lack of insight into the nature of his illness, and its need
for treatment, is part of the illness itself, and his failure to gain
2. A number of factors in Mr LT’s history indicate a poor prognosis: insight is a sign of his incomplete recovery, which in turn drives
• there has been a deterioration in his overall functioning; poor adherence to medicines, and so a poorer response.
• his age (quite young), which is typical for a first breakdown; • He needs a more supportive home environment with help to
• his poor work record; remind, encourage and prompt him to take his antipsychotic
• his substance misuse history; medication daily.
• his grossly disorganised behaviour; • He is suffering from side effects that deter him from taking the
• a number of positive symptoms such as hallucinations. antipsychotic regularly.
Mr GL’s opinion and preferences about medication should be
3. If whilst in hospital Mr LT becomes acutely aggressive because sought, and the next antipsychotic should be selected accordingly.
of the psychosis, other medicines may be needed in addition to He should also be educated (again) about the need for ongoing
the prescribed regular antipsychotic, to control his aggression to treatment, as per any chronic illness.
protect both him and other people. A decision would have to be
made about whether to use antipsychotics or benzodiazepines 3. If Mr GL were to relapse again it would be important to establish
in the short-term. This decision is separate from the longer-term the reason. Repeated relapses will adversely affect his longer-
treatment plan. Each hospital should have their own protocol for term prognosis. Therefore, a depot formulation of antipsychotic
the management of such emergencies. The NICE guidelines on should be considered. In most cases, the use of a depot anti-
the management of violence (NICE, 2015) recommend that if a psychotic injection would be the easiest way to ensure adher-
person will not take oral medicines, then use lorazepam injection ence in the short-term although if Mr GL is determined to
or haloperidol plus promethazine injections (at the same time). avoid treatment, then this strategy is unlikely to be successful,
because he simply would not attend the appointments for the
Case 30.2 depot injection. In his case, the response to each antipsychotic
bodes well, and he is therefore fairly likely to respond to the
Mr GL, aged 32 years, has relapsed for the third time this year. next antipsychotic if given as a depot. However, because he
The pattern for the last two psychotic relapses is the same as this has had EPSE with high doses of risperidone this may influence
presentation, and both required brief admissions. On both previ- the choice of depot. He should be involved in the decision as
ous occasions his positive symptoms responded rapidly to antipsy- to which depot. It could be worth trying a risperidone depot
chotics. The first antipsychotic, risperidone, was titrated up to 8 but at a moderate dose (not as high as the oral dosage of 8
mg/day and he suffered distressing EPSE. This was subsequently mg daily). Alternatively, paliperidone, the active metabolite of
changed to olanzapine, and he was stabilised and discharged on risperidone, may be appropriate, although this too can induce
a dosage of 15 mg daily. However, he stopped taking this within EPSE in a dose-related manner. However, the patient may prefer
a couple of weeks of discharge, claiming not to be ill and having this option because it is a monthly, rather than fortnightly, injec-
gained notable weight. During his second relapse and admission tion. Alternatively, it may be appropriate to try a first genera-
he was successfully treated with amisulpride 400 mg twice daily tion antipsychotic with a lower propensity to cause EPSE such
but again stopped taking it soon after discharge. as flupenthixol decanoate or zuclopenthixol decanoate. These
also have great dose flexibility. Therefore, they could be started
Questions very gently at low doses to establish whether they are tolerated,
before increasing the dose.
1. Was Mr GL’s medication treatment appropriate?
2. What strategies could be adopted to maintain Mr GL’s treatment? 521
30 THERAPEUTICS
Case 30.3 • She is suffering severe weight gain. This is more likely to be
caused by olanzapine by increasing her appetite, rather than
Ms SW, aged 28 years, has a 5-year history of schizophrenia with by the zuclopenthixol decanoate.
many admissions to hospital. Throughout the period of her illness
she has received a range of different oral antipsychotics including 2. Because Ms SW has not fully responded to (more than) two anti-
risperidone, olanzapine, quetiapine, amisulpride, as well as the psychotics taken at proper therapeutic doses for reasonable
depot formulations of flupenthixol and zuclopenthixol decanoate. periods of time, she meets the definition of treatment-resistant
For most of this time she has had fixed beliefs that she is being schizophrenia. Trying yet further alternative antipsychotics is not
watched and spied on by gangs of men who want to sexually likely to be any more successful than the current treatment regi-
assault her when she is asleep and tarnish her name and reputa- men, and clozapine is therefore indicated.
tion to everyone she knows. When she is ill these beliefs torment
her and she rarely goes out of her flat, preferring to stay hid- 3. The preparation for starting treatment with clozapine involves a
den at home. Until recently she has been treated with zuclopen- number of steps. These include:
thixol decanoate 500 mg by intramuscular injection every week • First, discussing the potential treatment plan with Ms SW.
at her home, plus olanzapine 10 mg at night, fluoxetine 20 mg This includes explaining that it is indicated for treatment-
daily, and procyclidine 5 mg three times daily. She was admitted resistant schizophrenia and is more likely to be effective than
to hospital 3 months ago. There is no sign of improvement in her any other antipsychotic. The need to have regular manda-
mental state; however, she has greatly increased in weight, now tory blood tests, initially weekly, to assess the full blood
approaching 127 kg. counts to monitor for any signs of neutropenia must be
clearly explained.
Questions • We would need to consider that until now the use of a depot
formulation has been considered necessary. Presumably she
1. Comment on Ms SW’s current treatment plan. has had a history of problems with adherence to oral antipsy-
2. What would you recommend next? chotics (this would be the indication for choosing a depot).
3. The team wishes to consider clozapine for Ms SW. What should be Therefore, because clozapine is available only as an oral for-
mulation, the team would need to review whether anything
done before Ms SW can receive clozapine? would now need to be put in place to support her long-term
adherence with oral clozapine, as regular adherence is particu-
Answers larly important with this option; erratic compliance is particu-
larly risky, increasing the likelihood of hypotension (potentially
522 1. Although sometimes polypharmacy (the use of more than one casing syncope), severe sedation and seizures. This may mean
antipsychotic) is used for patients when there has been poor or planning for additional services and support for Ms SW when
inadequate response, the practice is not evidence based and is she is discharged from hospital and reviewing her living accom-
potentially risky. Additional medicines are often added in a crisis modation arrangement (i.e. whether she has staff living with
or in the hope of achieving a greater degree of response. As in her or visiting who can support her adherence).
this case, the strategy is often unsuccessful. The particular issues • Ideally the team would want to get Ms SW’s consent to hav-
of note with this patient’s treatment regimen are: ing regular blood tests and starting an oral medicine. However,
• The combination of two antipsychotics exceeds the BNF maxi- if she is very unwell she may not currently have capacity to
mum dose. The maximum dose of zuclopenthixol decanoate agree to these things. If she does not agree and is detained
depot is 600 mg/week; therefore, 500 mg weekly is 83% of the in hospital under the Mental Health Act 1983, although it is
maximum dose. The maximum dose of olanzapine is 20 mg; legal to enforce blood tests this can be very traumatic and not
therefore, 10 mg is 50% of the maximum dose. 83% + 50% = favourable for the patient’s therapeutic relationship with the
133%. Doses greater than 100% confer greater risks for side care team. In addition it is not practically possible to force a
effects, and the Royal College of Psychiatrists monitoring guid- patient to take oral tablets.
ance should be followed. This includes a regular review of the • All patients prescribed clozapine and their consultant psy-
dosage and regular blood tests and ECGs. chiatrist and the dispensing pharmacy service must be regis-
• There is a combination of a first generation (zuclopenthixol tered with a clozapine monitoring scheme (i.e. ZTAS [Zaponex
decanoate) and a second generation (olanzapine) antipsy- Treatment Access System], CPMS [Clozaril Patient Monitoring
chotic; this reduces the potential benefit of using a second Service] or DMS [Denzapine Monitoring System]). Only then
generation antipsychotic with a very low incidence of EPSE may the clozapine be legally dispensed.
because the patient is still suffering with EPSE to the extent • Once registered with a clozapine monitoring scheme and
that she requires the anticholinergic, procyclidine. before starting clozapine a baseline full blood count and back-
• The use of a depot formulation suggests that there has been ground checks are required to ensure that the patient is not
an issue with poor/incomplete/erratic adherence; however, the already suffering from neutropenia or another blood disorder.
concurrent use of oral olanzapine means that she is expected Once these have been checked, clozapine can be prescribed.
to be adherent with this oral formulation. Therefore, the logic • The Summary of Product Characteristics for clozapine says that
for this combination of formulations needs to be reviewed and depot antipsychotics are contraindicated with it because of the
her adherence assessed. small risk of neutropenia. This is compounded by the nature of
• She is at risk of development of TD by being on an antipsy- the formulation, meaning that the depot antipsychotic remains
chotic long term that is causing EPSE. present in the patient for some time (weeks). Therefore, further
• This regular dose of the anticholinergic procyclidine is likely to doses of this should be stopped before clozapine is started.
cause its own side effects. • The prescriber should be aware of the interaction between
• The need for such frequent dosing of the intramuscular depot fluoxetine and clozapine, noting that this causes an increase
might not be necessary; administration at 2-weekly intervals in clozapine’s levels. It may be appropriate to continue the
would normally be appropriate. fluoxetine, but the patient may need lower doses of clozapine.
Serum levels of clozapine can be checked to optimise the dose
and avoid unnecessarily high levels, which are associated with
toxicity.
SCHIZOPHRENIA 30
• Once the depot is stopped, which was the cause of the EPSE, clozapine has notable anticholinergic effects, which would be
then the associated prescription for the anticholinergic pro- compounded by concurrent procyclidine.
cyclidine can also be gradually stopped. This should not be • Ideally all other treatments would be stopped and clozapine pre-
done immediately or abruptly, because the EPSE may continue scribed alone. However, sometimes this is simply not practica-
for some time, and the depot antipsychotic may take weeks ble, because the patient would then be left untreated whilst the
to no longer have effects. Furthermore stopping procycli- clozapine is titrated, which routinely takes 2–3 weeks. Therefore,
dine abruptly can lead to symptoms of cholinergic rebound. the final steps of gradually withdrawing other medicines may
However, the prescribing team should also be aware that occur alongside the gradual initial titration phase with clozapine.
References Leucht, S., Cipriani, A., Spineli, L., et al., 2013. Comparative eficacy and tol-
erability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments
American Psychiatric Association, 2013. Diagnostic and Statistical Manual metaanalysis. Lancet 382, 951–962.
of Mental Disorders, ifth ed. American Psychiatric Association, Wash-
ington, DC. Lieberman, J.A., Safferman, A.Z., Pollack, S., et al., 1994. Clinical effects of
clozapine in chronic schizophrenia: response to treatment and predictors
Barber, S., Olotu, U., Corsi, M., et al., 2017. Clozapine combined of outcome. Am. J. Psychiatry 15, 1744–1752.
with different antipyschotic drugs for treatment-resistant schizo-
phrenia. Cochrane Database Syst. Rev. 3, CD006324. https://doi. Lieberman, J., Stroup, T.S., McEvoy, J., et al., 2005. Clinical Antipsychotics
org/10.1002/14651858.CD006324.pub3. Trials of Intervention Effectiveness (CATIE) Investigators. Effectiveness
of antipsychotic drugs in patients with chronic schizophrenia N. Engl. J.
Barnes, R.E., 2011. Schizophrenia Consensus Group of the British As- Med. 353 (12), 1209–1223.
sociation for Psychopharmacology, evidence-based guidelines for the
pharmacological treatment of schizophrenia: recommendations from the National Institute for Health and Care Excellence (NICE), 2014. Clinical
British Association for Psychopharmacology. J. Psychopharmacol. 25 guideline: CG178 psychosis and schizophrenia in adults: treatment and
(5), 567–620. management. Available at: https://www.nice.org.uk/guidance/cg178.
Bazire, S., 2016. Psychotropic Drug Directory: The Professionals’ National Institute for Health and Care Excellence (NICE), 2015. NICE guid-
Pocket Handbook and Aide Memoire. Lloyd-Reinhold Publications, ance: NG10. violence and aggression: short-term management in mental
Shaftesbury, UK. health, health and community settings. Available at: https://www.nice.org.
uk/guidance/ng10.
Bleakley, S., Taylor, D., 2013. Clozapine handbook. Lloyd-Reinhold Publi-
cations, Shaftesbury, UK. Paton, C., Whittington, C., Barnes, T., 2007. Augmentation with a second
antipsychotic in patients with schizophrenia who partially respond to
Hartling, L., Abou Setta, A.M., Dursun, S., et al., 2012. Antipsychotics in clozapine: a meta-analysis. J. Clin. Psychopharmacol. 27, 198–204.
adults with schizophrenia: comparative effectiveness of irst-generation
versus second-generation medications. Ann. Intern. Med. 157 (7), Procyshyn, R.M., Bezchlibnyk-Butler, K.Z., Jeffries, J.J. (Eds.), 2015.
498–511. Clinical Handbook of Psychotropic Drugs, twenty irst ed. Hogrefe
Publishing, Gottingen.
Jones, P.B., Barnes, T.R., Davies, L., et al., 2006. Randomised controlled
trial of the effect on quality of life of second- vs. irst-generation Royal College of Psychiatrists (RCP), 2014. Consensus Statement on High-
antipsychotic drugs in schizophrenia. Cost utility of the latest Dose Antipsychotic Medication. CR190. RCP, London.
antipsychotic drugs in schizophrenia study (CUtLASS-1). Arch. Gen.
Psychiatry 63, 1079–1087. Shajahan, P., Spence, E., Taylor, M., et al., 2010. Comparison of the
effectiveness of depot antipsychotics in routine clinical practice. The
Kane, J., Honigield, G., Singer, J., Meltzer, H., 1988. Clozapine for the Psychiatrist 34, 273–279.
treatment-resistant schizophrenic. A double-blind comparison with chlor-
promazine. Arch. Gen. Psychiatry 45, 789–796. Stroup, T.S., Lieberman, J.A., McEvoy, J., et al., 2007. Effectiveness
of olanzapine, quetiapine, and risperidone in patients with chronic
Kapur, S., Arenovich, T., Agid, O., et al., 2005. Evidence for onset of schizophrenia after discontinuing perphenazine: a CATIE study. Am. J.
antipsychotic effects within the irst 24 hours of treatment. Am. J. Psychiatry 164 (3), 415–427.
Psychiatry 162 (5), 939–946.
Taylor, D., Paton, C., Kapuar, S., 2015. The Maudsley Prescribing Guidelines,
Leucht, S., Komossa, K., Rummel-Kluge, C., et al., 2009. A meta- twelfth ed. Wiley-Blackwell, Chichester, UK.
analysis of head-to-head comparisons of second-generation
antipsychotics in the treatment of schizophrenia. Am. J. Psychiatry World Health Organization, 1992. International Classiication of Diseases
166, 152–163. and Related Health Problems, tenth ed. (ICD 10). World Health Organi-
zation, Geneva.
Further reading National Institute for Health and Care Excellence (NICE), 2016. Clinical
guideline CG155. Psychosis and schizophrenia in children and young
National Institute for Health and Care Excellence (NICE), 2016. Clinical people: recognition and management. Available at: https://www.nice.org.
guideline CG185. Bipolar disorder: assessment and management. Available uk/guidance/cg155.
at: https://www.nice.org.uk/guidance/cg185.
Scottish Intercollegiate Guidelines Network (SIGN), 2013. Management of
National Institute for Health and Care Excellence (NICE), 2011. Clini- schizophrenia: SIGN publication number 131. Available at: http://www.
cal guideline CG120. Coexisting severe mental illness (psychosis) and sign.ac.uk/guidelines/fulltext/131/.
substance misuse: assessment and management in healthcare settings.
Available at: https://www.nice.org.uk/guidance/cg120.
National Institute for Health and Care Excellence (NICE), 2015. NICE
guideline NG10. Violence and aggression: short-term management in
mental health, health and community settings. Available at: https://www.
nice.org.uk/guidance/ng10.
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THERAPEUTICS
31 Epilepsy
Gonçalo Cação and Josemir W. Sander
Key points Epidemiology
• An epileptic seizure is a transient paroxysm of uncontrolled There are problems in establishing precise epidemiological
neuronal discharges causing an event which is discernible by information for a heterogeneous condition such as epilepsy.
the person experiencing the seizure and/or an observer. Unlike most ailments, epilepsy is episodic; between seizures,
individuals may be perfectly normal and have normal inves-
• Epilepsy is a brain disorder characterised by an enduring pre- tigations. Thus, the diagnosis is essentially clinical, relying
disposition to generate epileptic seizures. heavily on eyewitness descriptions of the events. There are
also a number of other conditions in which consciousness
• The annual incidence of epileptic seizures is around 50 cases may be transiently impaired and which may be confused with
per 100,000 of the population. epilepsy. Another problem is that of case identification,
because sometimes the person may be unaware of the nature
• About 60–70% of those who develop epilepsy will become sei- of the attacks and so may not seek medical help. People with
zure free on treatment, and about 50% will eventually withdraw milder epilepsy may also not be receiving ongoing medi-
their medication successfully. cal care and so may be missed in epidemiological surveys.
Because there is some degree of stigma attached to epilepsy,
• Generalised seizures present immediate involvement of both people may sometimes be reluctant to admit their condition.
hemispheres and include different types of seizures: tonic- In today’s society, in high- and low-income countries, fear,
clonic, absence, myoclonic, clonic, tonic and atonic. misunderstanding, discrimination and social stigma still exist.
These affect the quality of life for people with the disorder
• Focal seizures arise from an area limited to one hemisphere and their families.
and may evolve into a bilateral convulsive seizure.
Epilepsy does impact on an individual’s human rights; for
• Treatment of epilepsy is usually for at least 3 years and, example, access to health and life insurance is often affected.
depending on circumstances, sometimes for life. A person who suffers from epilepsy may not be able to obtain a
driving license, and it has an impact on the choice of career.
• Treatment aims to control seizures using one drug without A global campaign has been established to raise awareness about
causing side effects and minimising the use of polypharmacy. epilepsy, provide information and highlight the need to improve
care and reduce the disorder’s impact through public and private
• Management of epilepsy requires empowering the person to collaboration. This is supported through a partnership estab-
understand his or her condition and medication, and help- lished between World Health Organization (WHO), ILAE and the
ing the person to develop effective partnerships with health International Bureau for Epilepsy.
professionals.
Epilepsy is recognised as a priority in effective healthcare
An epileptic seizure is a transient occurrence of signs and/or delivery, and there are still a number of issues that health profes-
symptoms due to abnormal excessive or synchronous neuronal sionals should consider (WHO, 2015):
activity in the brain, causing an event that is discernible by the • Epilepsy is a chronic neurological disorder that affects people
person experiencing the seizure and/or by an observer. Epilepsy is
a disorder of the brain characterised by an enduring predisposition of all ages.
to generate epileptic seizures and by the associated neurobiologic, • More than 50 million people worldwide have epilepsy.
cognitive, psychological, and social consequences. According to • Nearly 80% of people with epilepsy are found in resource-
the International League Against Epilepsy (ILAE) (Fisher et al.,
2014), epilepsy is deined by any of the following conditions: poor settings.
1. at least two unprovoked (or relex) seizures occurring more • Epilepsy responds to treatment 70% of the time. Despite this,
than 24 hours apart; approximately more than two-thirds of people affected in poor
2. one unprovoked seizure (or relex) and a probability of fur- countries are not treated.
• People with epilepsy and their families suffer from stigma and
ther seizures similar to the general recurrence risk (at least discrimination in many parts of the world.
60%) after two unprovoked seizures, occurring over the next
10 years;
3. diagnosis of an epilepsy syndrome.
A person with epilepsy will show recurrent epileptic seizures that
occur unexpectedly and stop spontaneously.
524
EPILEPSY 31
Incidence and prevalence cerebrovascular disease, pneumonia, iatrogenic accidents and
Epileptic seizures are common. The incidence (number of new suicide. Sudden unexpected death in epilepsy (SUDEP) is
cases per given population per year) in high-income countries deined as a sudden unexpected, witnessed or unwitnessed, non-
is estimated between 40 and 70 cases per 100,000 persons, and traumatic and non-drowning death in people with epilepsy, with
the cumulative incidence rate (the risk of having the condition at or without evidence for a seizure, and excluding documented
some point in life) is 2–5%. The incidence is higher in the irst status epilepticus, in which postmortem examination does not
two decades of life but falls over the next few decades, only to reveal a toxicological or anatomic cause for death. This entity
increase again in late life, mainly because of cerebrovascular
diseases. Currently, the elderly are the group in the population remains unexplained, but identiied risk factors are younger age
with the highest incidence of epilepsy. Most studies of the prev- at onset, frequent convulsions, long duration of epilepsy and
alence of active epilepsy (the number of cases in the population
at any given time) in high-income countries provide igures in refractory epilepsy. Its incidence is about 0.35 cases per 1000
the range of 4–10 per 1000, with a rate of 5 per 1000 popula- person-years in a population-based incidence cohort of epilepsy
tion most commonly quoted. In England, epilepsy has been esti-
mated to affect between 362,000 and 415,000 people (National (Tomson et al., 2005).
Institute for Health and Care Excellence [NICE], 2012).
Aetiology
In low-income countries, the prevalence is higher with rates of
10 per 1000 population cited and reported annual new cases twice Epileptic seizures are produced by abnormal discharges of neu-
those seen in high-income countries, presumably because of the rones that may be caused by any pathological process which
higher risk of experiencing conditions that can lead to permanent affects the cortical layer of the brain. The idiopathic or genetic
brain damage. Overall, nearly 80% of epilepsy cases worldwide epilepsies are those in which there is a clear genetic component,
are found in resource-poor settings. and they probably account for a third of all new cases of epi-
lepsy. In a signiicant proportion of cases, however, no cause can
Prognosis be determined, and these are termed as unknown or cryptogenic
epilepsies. Possible explanations for unknown epilepsy include
Up to 5% of all people will suffer at least one seizure in their as yet unexplained metabolic or biochemical abnormalities and
lifetime. The prevalence of active epilepsy is, however, much
lower, and most people who experience seizures have a very microscopic lesions in the brain resulting from brain malforma-
good prognosis as about 60–70% of all will eventually become
seizure free. About half will successfully withdraw their tion or trauma during birth or other injury. The term ‘symptom-
medication. Once a substantial period of remission has been
achieved, the risk of further seizures is greatly reduced. The atic’ or structural/metabolic epilepsy indicates that a probable
probability of seizure freedom is particularly high in those with cause has been identiied.
generalised epilepsy and a normal neurological examination.
A minority of people (up to a third) will experience chronic epi- The likely aetiology depends upon age of onset and seizure
lepsy and in such cases, treatment is more dificult. People with type. The commonest causes in young infants are hypoxia or
symptomatic epilepsy, more than one seizure type, associated
learning disabilities, or neurological or psychiatric disorders are birth asphyxia, intracranial trauma during birth, metabolic dis-
more likely to have a poor outcome. For those who continue to
have seizures, in appropriate candidates epilepsy surgery may turbances, congenital malformations of the brain and infection.
render seizure freedom more than continued antiepileptic drugs
(AEDs) alone. Of people with chronic epilepsy, fewer than 5% In young children and adolescents, genetic epilepsies account
will be unable to live in the community or will depend on oth-
ers for their day-to-day needs. Most people with epilepsy are for the majority, although trauma and infection also play a
entirely normal between seizures, but a small minority of peo- role. In this age group, particularly in children aged between
ple with severe epilepsy may suffer physical and intellectual 6 months and 5 years, seizures may occur in association with
deterioration. febrile illness. These are usually short convulsions that occur
Mortality during the early phase of a febrile disease. They must be dis-
People with epilepsy, especially the young and those with severe tinguished from seizures that are triggered by central nervous
epilepsy, are at an increased risk of premature death. Most stud- system infections which produce fever, for example, meningitis
ies have given overall standardised mortality ratios between two or encephalitis. Unless febrile seizures are prolonged, focal and
and three times that of the general population (Thurman et al., recurrent, or there is a background of neurological handicap,
2017). Common causes of death include accidents (drowning, the prognosis is excellent and it is unlikely that the child will
head injury, road trafic accidents), status epilepticus, tumours, develop epilepsy.
The range of causes of adult-onset epilepsy is very wide.
Both genetic epilepsies and those due to perinatal causes may
also begin in early adulthood. Other important causes are
trauma, developmental disorders (e.g. cortical dysplasias), brain
tumours, cerebrovascular diseases, immunological disorders and
degenerative conditions. Brain tumours are responsible for the
development of epilepsy in up to a third of those between the
ages of 30 and 50 years. Over the age of 50 years, cerebrovascu-
lar disease is the commonest risk factor for epilepsy and may be
present in up to half of people developing the condition in this
age group.
525
31 THERAPEUTICS
Pathophysiology Box 31.1 Classification of seizures (Fisher et al., 2017)
Epilepsy differs from other neurological conditions because it Focal onset
has no pathognomonic lesion. A variety of different electrical or Aware/Impaired awareness
chemical stimuli can easily give rise to a seizure in any normal Motor onset: automatisms, atonic, clonic, epileptic spasms,
brain. The hallmark of epilepsy is a rather rhythmic and repeti- hyperkinetic, myoclonic, tonic
tive hyper-synchronous discharge of neurones, either localised Non-motor onset: autonomic, behaviour arrest, cognitive, emo-
in an area of the cerebral cortex or generalised throughout the tional, sensory
cortex, which can be observed on an electroencephalogram
(EEG). Generalised onset
Motor: tonic-clonic, clonic, tonic, myoclonic, myoclonic-tonic-clonic,
Neurones are interconnected in a complex network in which myoclonic-atonic, atonic, epileptic spasms
each individual neurone is linked through synapses with hun- Non-motor (absence): typical, atypical, myoclonic, eyelid
dreds of others. A small electrical current is discharged by neu- myoclonia
rones to release neurotransmitters at synaptic levels to permit
communication with each other. Neurotransmitters fall into two Unknown onset
basic categories: inhibitory or excitatory. Therefore, a neurone Motor: tonic-clonic, epileptic spasms
discharging can either excite or inhibit neurones connected to it. Non-motor: behaviour arrest
An excited neurone will activate the next neurone, whereas an
inhibited neurone will not. In this manner, information is con- Generalised seizures
veyed, transmitted and processed throughout the central nervous
system. Generalised seizures are subdivided in motor and non-motor
(absence) types. The motor includes tonic-clonic, clonic, tonic,
A normal neurone discharges repetitively at a low baseline fre- myoclonic, myoclonic-tonic-clonic, myoclonic-atonic, atonic
quency, and it is the integrated electrical activity generated by the and epileptic spasms. The non-motor includes typical absence,
neurones of the supericial layers of the cortex that is recorded atypical absence and absence with special features (myoclonic,
in a normal EEG. If neurones are damaged, injured or suffer a eyelid myoclonia).
chemical or metabolic insult, a change in the discharge pattern
may develop. In the case of epilepsy, regular low-frequency Tonic-clonic seizures
discharges are replaced by bursts of high-frequency discharges
usually followed by periods of inactivity. A single neurone dis- Tonic-clonic seizures often begin with bilateral myoclonic
charging in an abnormal manner usually has no clinical signii- jerks, followed by a tonic contraction of the extremities and
cance. It is only when a whole population of neurones discharge trunk sustained by a short period. Then contractions become
synchronously in an abnormal way that an epileptic seizure may progressively longer and interrupted, resulting in clonic
be triggered. This abnormal discharge may remain localised or jerking. Cyanosis, incontinence and tongue biting may occur.
it may spread to adjacent areas, recruiting more neurones as it The seizure ceases after a few minutes and may often be fol-
expands. It may also generalise throughout the brain via corti- lowed by a period of drowsiness, confusion, headache and
cal and subcortical routes, including callosal and thalamocortical sleep.
pathways. The area from which the abnormal discharge origi-
nates is known as the epileptic focus. An EEG recording carried Typical absence seizures
out during one of these abnormal discharges may show a vari-
ety of atypical signs, depending on which area of the brain is Typical absence seizures happen almost exclusively in child-
involved, its progression and how the discharging areas project hood and early adolescence, and are characterised by behav-
to the supericial cortex. ioural arrest for a few seconds. The child goes blank and
stares; fluttering of the eyelids and flopping of the head may
Clinical manifestations occur. The attacks last only a few seconds and afterwards
normal activity is resumed as if nothing had happened. They
The clinical manifestation of a seizure will depend on the loca- are seen in developmentally normal people and are associ-
tion of the focus and the pathways involved in its spread. ILAE ated with a typical rhythmic 3-Hz spike and wave complexes
has recently published a revised classiication of seizure types on the EEG.
(Fisher et al., 2017). It divides seizures into three main groups
according to its onset (Box 31.1). If it involves initial activation Atypical absence seizures
of both hemispheres of the brain simultaneously, the seizures are
termed ‘generalised’. If a discharge starts in a localised area of Atypical absence seizures differ from the previous types because
the brain, the seizure is termed ‘focal’. Lastly seizures are clas- they are mostly seen in people with developmental delay, the
siied as ‘unknown onset’ if it is not possible to classify as focal behavioural arrest may be longer, the EEG shows background
526 or generalised. abnormalities (diffuse slowing), and the spike and wave com-
plexes are less than 3 Hz in frequency.
EPILEPSY 31
Absence seizures with special features also seen in children with structural lesions conined to one hemi-
sphere and where surgical treatment can often be curative. They
Absence seizures with special features are absence seizures asso- occur in early infancy and are characterised by tonic lexion of the
ciated with other characteristics such as eyes myoclonic (Jeavons head, neck and trunk, with circumlexion of the upper extremities.
syndrome) or myoclonic movements.
Myoclonic seizures Diagnosis
Myoclonic seizures are abrupt, very brief, involuntary, shocklike Diagnosing epilepsy can be dificult because it is irst necessary 527
jerks, which may involve the extremities and/or axial trunk muscles. to demonstrate a tendency to recurrent epileptic seizures. The
They usually happen in the morning, shortly after waking. They
may sometimes cause the person to fall, but recovery is immediate. one feature that distinguishes epilepsy from other conditions is
There are non-epileptic myoclonic jerks that occur in a variety of
other neurological diseases and may also occur in healthy people, its unpredictability and transient nature. The diagnosis is clinical
particularly when they are just going off to sleep (hypnic jerks).
and depends on a reliable account of what happens during the
Tonic seizures events, if possible, from the individual and from an eyewitness.
Investigations may help and the EEG is usually one of them.
Tonic seizures occur during sleep with a duration of approxi-
mately 20 seconds. They usually involve all or most of the brain, These investigations, however, cannot conclusively conirm or
affecting both sides of the body. If the person is standing when refute the diagnosis.
the seizure starts, they may fall.
Other conditions may cause impairment or loss of conscious-
Clonic seizures ness which can be misdiagnosed as epilepsy; these include
syncope, breath-holding attacks, transient ischaemic attacks
Clonic seizures are rare alone, but most often are part of a tonic- and psychogenic attacks. People may also present with acute
clonic seizure. They are characterised by a rapidly alternating symptomatic seizures or provoked seizures as a result of other
contraction and relaxation of a muscle – clonus. Brief and infre- problems such as drugs, metabolic dysfunction, infection, head
quent clonic seizures in infants usually disappear on their own
within a short time. trauma or lashing lights (photosensitive seizures). These condi-
tions have to be clearly ruled out before a diagnosis of epilepsy
Atonic seizures
is made. Epilepsy must only be diagnosed when at least one of
Atonic seizures comprise a sudden loss of muscle tone, caus- the three deining ILAE conditions given at the beginning of this
ing the person to collapse to the ground. Recovery afterwards is chapter is present. The diagnosis must be accurate because the
quick. They are rare, accounting for less than 1% of the epilep-
tic seizures seen in the general population, but more common in label ‘suffering with epilepsy’ carries a social stigma that has
people with severe epilepsy starting in infancy. great implications.
Focal seizures An EEG recording is often the only examination required in
In focal seizures, discharges are localised, and manifestations often typical generalised epilepsies, and it aims to record abnormal
relect activation of the underlying cortical areas. They are primar-
ily divided according to awareness in focal aware and focal with neuronal discharges. EEGs have, however, limitations that should
impaired awareness. Then subdivided according to motor or non- be clearly understood. Up to 5% of people without epilepsy may
motor onset. The motor onset includes automatism (e.g. chewing, have non-speciic abnormalities in their EEG recording, while up
lip smacking, fumbling), atonic, clonic, epileptic spasms, hyperki- to 40% of people with epilepsy may have a normal recording
netic, myoclonic and tonic seizures. The non-motor onset includes between seizures. The diagnosis of epilepsy needs to be strongly
autonomic (e.g. pallor, tachycardia), behaviour arrest, cognitive, supported by a bona ide history of unprovoked seizures. The
emotional and sensory seizures. Symptoms may vary widely from EEG is, however, invaluable in classifying epilepsy.
person to person but will normally be stereotyped in one person.
The chance of recording the discharges of an actual seizure
This seizure may progress into a bilateral tonic-clonic seizure,
which is termed as focal to bilateral tonic-clonic. during a routine EEG, which usually takes 20–30 minutes,
is slight and because of this, ambulatory EEG monitoring and
Epileptic spasms
EEG video-telemetry are sometimes required. Ambulatory EEG
Previously considered a type of generalised epilepsy, it is now
placed under both focal and generalised seizures because they are allows recording in day-to-day circumstances using a small
recorder. EEG video-telemetry is useful in the assessment of dif-
icult cases, particularly if surgery is considered. The individual
is usually admitted and remains under continuous monitoring.
This is only helpful in a very few cases and best suited for people
who have frequent seizures.
Neuroimaging with magnetic resonance imaging (MRI) is the
most valuable investigation when structural abnormalities (e.g.
stroke, tumour, developmental abnormalities, hydrocephalus) are
suspected. MRI does not need to be done routinely in generalised
epilepsy, but is particularly important in people who develop epi-
lepsy before the age of 2 years or in adulthood, in those with any
suggestion of focal onset and in those who continue with seizures
despite irst-line medication.
31 THERAPEUTICS
Other diagnostic investigations, such as functional MRI, mag- seldom necessary, but the person should, however, be made as
netic resonance spectroscopy, single-photon emission comput- comfortable as possible, preferably lying down (ease to the loor
erised tomography and positron emission tomography studies, if sitting), cushioning the head and loosening any tight clothing
are normally performed only in speciic cases, particularly when or neckwear. During seizures, the individual should not be moved
evaluating for surgical treatment. unless he or she is in a dangerous place, for example, in a road, by
a ire or hot radiator, at the top of stairs or by the edge of water.
Treatment No attempt should be made to open the person’s mouth or force
anything between the teeth. This usually results in damage and
In 2004 the NICE issued guidance on the diagnosis and treat- broken teeth or other objects may be inhaled, causing second-
ment of epilepsy in adults and children in primary and secondary ary lung damage. When the seizure stops, the person should be
care, which was updated in 2014 (NICE, 2014). This guidance turned over into the recovery position and the airway checked for
covers issues such as when a person with epilepsy should be any blockage.
referred to a specialist centre, the special considerations con-
cerning the care and treatment of women, and the management Focal seizures are usually less dramatic. During automatisms,
of people with learning disabilities. The key points of the guid- people may behave in a confused manner and should gener-
ance are summarised in Box 31.2. ally be left undisturbed. Gentle restraint may be necessary if
the automatism leads to dangerous wandering. Attempts at
Treatment during seizures irm restraint, however, may increase agitation and confusion.
No drinks should be given after the seizure, nor should extra
Convulsive seizures may look frightening, but the person is not AEDs be given. It is commonly felt that seizures may be life-
in pain, will usually have no recollection of the event afterwards threatening, but this is seldom the case. After a seizure, it is
and is usually not seriously injured. Emergency treatment is important to stay with the person and offer reassurance until
the confused period has completely subsided and the person has
Box 31.2 Key points on the diagnosis and management of fully recovered.
epilepsy (NICE, 2012, 2014)
Status epilepticus
Diagnosis
• Diagnosis is to be made urgently by a specialist with an Status epilepticus is traditionally deined as ongoing seizure
interest in epilepsy. activity for ≥30 minutes, but from a pragmatic point of view, a
seizure that lasts longer than 5 minutes warrants pharmacological
Management intervention. Initial management of status epilepticus is support-
• The individual with epilepsy, and their family and/or carers, ive and may include:
should participate in all decisions, taking into account any • secure airway and resuscitate,
specific need. • administer oxygen,
• All should have a comprehensive agreed-upon care plan. • assess cardiorespiratory function,
• Treatment should be individualised according to seizure • establish intravenous access.
type, epilepsy syndrome, co-medication and comorbidity,
the individual’s lifestyle and personal preferences. Buccal midazolam (10 mg) is irst-line treatment in the com-
munity. Rectal diazepam is an alternative if preferred or if buc-
Prolonged or repeated seizures and convulsive status cal midazolam is not available. If intravenous access is already
epilepticus established and resuscitation facilities are available, intravenous
lorazepam is administered.
• Prescribe buccal midazolam or rectal diazepam for use in
the community. First-line AED for hospital management of status epilepticus
is intravenous lorazepam. If unavailable, then intravenous diaz-
• Buccal midazolam is first-line treatment. Rectal diazepam is epam should be administered or buccal midazolam if immedi-
prescribed if the previous is not available or if it is preferred. ate intravenous access cannot be secured. If seizures continue,
Intravenous lorazepam is prescribed if intravenous access is intravenous phenytoin or valproate or phenobarbital should be
established and resuscitation facilities are available. administered as second-line treatment. In the refractory status,
general anaesthesia with propofol, midazolam or thiopentone
Women and girls of childbearing potential may be necessary.
• They must be given accurate information and counselling
about contraception, conception, pregnancy, caring for Febrile convulsions
children, breastfeeding and menopause.
Febrile convulsions may occur in the young without epilepsy.
Review and referral Brief events are managed conservatively with the primary aim
• Regular structured review should occur at least once a year. of reducing the child’s temperature. Tepid sponging and use of
• Individuals should be given all required information and paracetamol is usual. Prolonged febrile convulsions lasting ≥10–
referral if necessary. 15 minutes or in a child with risk factors, active management is
• Individuals should be referred back to tertiary care if required to avoid brain damage. The drug of choice is diazepam
seizures are not controlled, uncertainty of diagnostic or
treatment failure.
528
EPILEPSY 31
by intravenous or rectal administration. Prophylactic manage- classiication are essential. Table 31.1 lists the main indications
ment of febrile convulsions may be required in some children, for the more commonly used AEDs, and Table 31.2 summarises
such as those with pre-existing risk factors or a history of previ- the clinical use of the newer AEDs.
ous prolonged seizures.
Initiation of therapy in newly diagnosed epilepsy
Long-term treatment
A irst-line AED suitable for the person’s seizure type should
In most cases, epilepsy can only be treated by regular, long- be introduced slowly, starting with a small dose. A hasty intro-
term drug treatment aiming at suppressing seizures. Full seizure duction may induce side effects that may challenge the person’s
control can be obtained in most cases, and in others drugs may conidence. For most drugs, a gradual introduction will produce
reduce seizure frequency or severity. a therapeutic effect just as fast as a rapid introduction, and the
person should be reassured about this.
Initiating treatment with an AED is a major event in a person’s
life, and the diagnosis should be unequivocal. Treatment options Maintenance dosage
must be considered with careful evaluation of all relevant factors,
including the number and frequency of seizures, the presence of There is no single optimum dose of any AED that will suit
precipitants such as alcohol, drugs or lashing lights, and the pres- all because the required dose varies from person to person
ence of other medical conditions. Single seizures do not require
treatment unless they are associated with a structural abnormal- Table 31.1 Antiepileptic drugs for different seizure types
ity in the brain, a progressive brain disorder or there is a clearly
abnormal EEG recording. If there are long intervals between Seizure type First-line treatment Adjunctive anti-
seizures (>2 years), there is a case for not starting treatment. If Focal seizures epileptic drugs
there are more than two attacks that are clearly associated with a Carbamazepine
precipitating factor, fever or alcohol, for instance, then treatment Lamotrigine Brivaracetam
may not be necessary. Levetiracetam Clobazam
Oxcarbazepine Eslicarbazepine
Therapy is long-term, usually for at least 3 years and, depend- Sodium valproate Gabapentin
ing on circumstances, sometimes for life. A full explanation of all Lacosamide
of the implications must be given to the person, and the individ- Generalised seizures Perampanel
ual must be involved in all stages of the treatment plan. It is vital Phenytoin
that the person fully understands the implications and agrees with Tonic-clonic Carbamazepine Pregabalin
the treatment goals. Empowerment of the person with epilepsy to Topiramate
be actively involved in the decision-making process will encour- Lamotrigine Zonisamide
age adherence and is essential for effective clinical management.
Support for people so that they understand the implications of the Oxcarbazepine Clobazam
condition and why drug therapy is important is crucial to ensure Levetiracetam
effective clinical management. Sodium valproate Topiramate
Health professionals have a key role in supporting people Tonic or atonic Sodium valproate Lamotrigine
with epilepsy to ensure they are able to manage their medicines Rufinamide
appropriately. AED treatment will fail unless the person fully Absence Ethosuximide Topiramate
understands the importance of regular therapy. Poor adher- Lamotrigine Clobazam
ence is still a major factor which results in hospital admissions Sodium valproate Clonazepam
and poor seizure control, and leads to the clinical use of mul- Levetiracetam
tiple AEDs. Myoclonic Levetiracetam Topiramate
Sodium valproate Clonazepam Zonisamide
General principles of treatment Topiramate Piracetam Clobazam
Zonisamide
The primary aim of epilepsy treatment is to control seizures using
one drug, with the lowest effective dose causing the fewest side
effects possible. The established AEDs, those licensed before
2000, are still an important part of the antiepileptic armamen-
tarium, and include carbamazepine, clobazam, clonazepam, eth-
osuximide, gabapentin, lamotrigine, phenobarbital, phenytoin,
piracetam, primidone, sodium valproate, tiagabine, topiramate
and vigabatrin. Since 2000, new AEDs such as eslicarbazepine
acetate, brivaracetam, felbamate, lacosamide, levetiracetam,
oxcarbazepine, perampanel, pregabalin, stiripentol, ruinamide
and zonisamide have been introduced. The choice of drugs
depends largely on the seizure type, and so correct diagnosis and
529
31 THERAPEUTICS
Table 31.2 Summary of newer antiepileptic agents achieve optimal control. The Medicines and Healthcare prod-
ucts Regulatory Agency (MHRA) has classiied AEDs into three
Antiepileptic Clinical use Available formulation categories (MHRA, 2013):
drugs • Category 1: phenytoin, carbamazepine, phenobarbital and
Adjunctive for focal Tablets: 10, 25, 50, 75,
Brivaracetam seizures 100 mg primidone. People receiving these drugs should be maintained
Oral solution: 10 mg/mL on a speciic manufacturer’s product.
Injection solution: 10 • Category 2: valproate, lamotrigine, perampanel, ruinamide, clo-
mg/mL bazam, clonazepam, oxcarbazepine, eslicarbazepine, zonisamide
and topiramate. The need for continued supply of a particular
Eslicarbazepine Adjunctive for focal Tablets: 800 mg manufacturer’s product is based on clinical judgement and con-
sultation with the patient/carer, taking into account factors such
acetate seizures as seizure frequency and treatment history.
• Category 3: levetiracetam, lacosamide, tiagabine, gabapentin,
Lacosamide Adjunctive for focal Tablets: 50, 100, 150, pregabalin, ethosuximide and vigabatrin. It is usually unnec-
seizures 200 mg essary to maintain the patient on a speciic manufacturer’s
Syrup: 10 mg/mL product.
Infusion: 200 mg/20 mL
Altering drug regimens
Levetiracetam Monotherapy and Tablets: 250, 500, 750,
adjunctive therapy 1000 mg If the maximal tolerated dose of a drug does not control sei-
for focal and Syrup: 100 mg/mL zures or if it is not tolerated, the irst drug should be replaced
generalised seizures Injection: 500 mg/5 mL with another irst-line AED. To do this, the second drug
Granules: 250 mg, 500 should be added gradually to the irst. Once a good dose of the
mg, 1 g new drug is established, the irst drug should then slowly be
withdrawn.
Oxcarbazepine Monotherapy and Tablets: 150, 300, 600
adjunctive therapy mg Withdrawal of drugs
for focal and Syrup: 60 mg/mL
generalised tonic- AEDs should not be withdrawn abruptly. Withdrawal of indi-
clonic seizures vidual AEDs should be carried out in a slow, stepwise fashion
to avoid the precipitation of rebound seizures (e.g. over 2–3
Perampanel Adjunctive for focal Tablets: 2, 4, 6, 8, 10, months). This risk is particularly great with barbiturates (phe-
nobarbital and primidone) and benzodiazepines (clobazam and
seizures 12 mg clonazepam). If a drug needs to be withdrawn rapidly, for exam-
ple, if there are life-threatening side effects, a benzodiazepine can
Pregabalin Adjunctive for focal Tablets: 25, 50, 75, be used to cover the withdrawal phase.
seizures 100, 150, 200, 225,
300 mg Examples of withdrawal regimens are given below.
Syrup: 20 mg/mL • Carbamazepine
Zonisamide Monotherapy and Capsule: 25, 50, 100 mg 100–200 mg every 2 weeks (as part of a drug change)
adjunctive for focal 100–200 mg every 4 weeks (total withdrawal)
seizures • Phenobarbital
15–30 mg every 2 weeks (as part of a drug change)
and from drug to drug. Drugs are introduced slowly and then 15–30 mg every 4 weeks (total withdrawal)
increased incrementally to an initial target dose. Seizure con- • Phenytoin
50 mg every 2 weeks (as part of a drug change)
trol should then be assessed, and the dose of drug changed if 50 mg every 4 weeks (total withdrawal)
• Sodium valproate
necessary. For most AEDs, dosage increments are constant 200–400 mg every 2 weeks (as part of a drug change)
over a wide range. More care is, however, needed with phe- 200–400 mg every 4 weeks (total withdrawal)
nytoin because the serum level–dose relationship is not linear • Ethosuximide
125–250 mg every 2 weeks (as part of a drug change)
and small dose changes may result in considerable serum level 125–250 mg every 4 weeks (total withdrawal)
changes. Phenytoin is, however, currently rarely used. Generic Variations in the earlier regimens may be used in different set-
prescribing for epilepsy remains controversial. Most special- tings. People must be monitored closely for any change in seizure
ists would prefer people to remain on the same brand because frequency. The pace of withdrawal may be slower if the person
it provides consistency. This is also preferred by the majority is within the higher end of the quoted dose range and faster if the
of people with epilepsy and is recommended by NICE (2014). person is an in-patient.
Different preparations of some AEDs may vary in bioavailabil-
ity or pharmacokinetic proiles. This is obviously important in
those people in whom the dosage has been carefully titrated to
530
EPILEPSY 31
When to make dose changes Intractable epilepsy. It is important to realise that there are
Some AEDs have long half-lives and it may take time, normally limits to AED treatment and that in some people, albeit a small
ive half-lives, before a change in dose results in a stable blood group, seizure control is not possible with the drugs currently
level. For example, phenobarbital has a half-life of up to 6 days available. In such cases the goal of drug treatment changes, and
and will take more than 4 weeks to produce a stable blood level.
For this reason an assessment of the effectiveness of any dose the objectives are to reduce medication to minimise toxicity
change should be undertaken several weeks after the dose change while providing partial control. The sedative drugs, for example,
has been made and be informed by knowledge of the half-life of barbiturates or benzodiazepines, should be used only where abso-
the drug. lutely necessary. In these persons, surgical treatment or the use of
experimental antiepileptic agents may be considered. However,
Newer antiepileptic drugs only a relatively small number of people with focal epilepsy are
suitable for curative surgical treatment.
The newer AEDs are generally used as second-line drugs when
treatment with established irst-line drugs has failed. Exceptions Stopping treatment
to this are levetiracetam and oxcarbazepine. Overall, newer AEDs
are not more effective than the established drugs but seem to be Withdrawing therapy should be considered in people who have
better tolerated. Notwithstanding, the chronic side effect proile been seizure free for a considerable period. In no individual case,
of the new AEDs has not yet been fully established. however, can the safety of drug withdrawal be guaranteed, and
the risk of relapse on withdrawal of medication in a person who
Follow-up and monitoring of treatment has been seizure free for more than 2 years is about 40%. The
longer the person has been free of seizures, the lower the risk of
It is essential to follow up people in whom AED treatment has seizure recurrence when drugs are withdrawn. If a person has a
been started. The reason for this is essentially to monitor the efi- learning disability, focal seizures or symptomatic epilepsy, neu-
cacy and side effects of treatment, upon which drug dosage will rological signs or other evidence of cerebral damage, this risk is
depend, but also to encourage good adherence. This follow-up is much higher, and in such cases it may be best to continue drug
particularly important in the early stages of treatment, when an treatment indeinitely. Drug withdrawal should be carried out
effective maintenance dose may not have been fully established, only very slowly in staged decrements, and only one drug at a
when the importance of adherence may not have been recognised time should be withdrawn.
by the person and when the psychological adjustment to regular
treatment may not be resolved. The risks of drug withdrawal should be clearly explained to the
person, and the possible medical and social implications taken
Chronic epilepsy into account. There may be serious social or domestic conse-
quences if seizures recur, and the attacks may be subsequently
The drug treatment of people with uncontrolled epilepsy despite dificult to control, even if the original AED regimen is re-estab-
initial attempts is much more dificult than that of those newly lished. In the inal analysis, the decision to withdraw therapy is an
diagnosed. Prognosis is worse, drug resistance may have devel- individual one, and the person should be made aware of the risks
oped, and there may be additional neurological, psychological or and beneits of withdrawal.
social problems.
Monitoring antiepileptic therapy
Assessment. The diagnosis of epilepsy should be reassessed
before assuming seizures are intractable because misdiagnosis Therapeutic drug monitoring (TDM) involves the measurement
is common. Progressive neurological conditions should also of serum drug levels and their pharmacokinetic interpretation. It
be ruled out. A treatment history should be obtained and note is an integral component in the management of people who are
made of previous drugs used which were helpful, unhelpful or of taking phenytoin and carbamazepine but is less useful in people
uncertain beneit. Serum level measurements should be obtained receiving other AEDs. Indeed, TDM has a very limited use for
where appropriate, and drugs not previously tried should be new AEDs, except in people who are acutely unwell, pregnant
identiied. or in the elderly. It is also very useful to document AED side
effects and in managing drug interactions. Adherence may also
Choice of drug and dosage. Treatment should always be be a problem in these people, and hence TDM may be useful to
started with one AED appropriate for seizure type and suitable for establish treatment adherence.
the individual. Only when attempts at monotherapy fail should
a combination of two AEDs be tried. In the majority of people, TDM is indicated:
there is no place for therapy with more than two drugs. The • at the onset of therapy,
choice of drugs should be made according to seizure type and • if seizure control is poor or sudden changes in seizure control
previous treatment history. Drugs that were helpful in the past
or found to be of uncertain beneit, or which have not been used occur,
before, should be tried if appropriate to seizure type. The use of • if toxicity is suspected,
sedative AEDs should be minimised where possible. • if poor or non-adherence is suspected,
• to monitor the timescale of drug interactions,
• when changing AED therapy or making changes to other aspects
of a person’s drug regimen that may interact with the AED.
531
31 THERAPEUTICS
The frequency of undertaking TDM varies. Those with stabi- Unlike most of the older agents, levetiracetam, lacosamide,
lised epilepsy may require their serum levels to be checked only pregabalin and zonisamide are devoid of clinically signiicant
once a year. TDM may be used more often in some people, for enzyme-inhibiting or enzyme-inducing properties. Oral contra-
one or more of the above indications. A number of the newer ceptives may increase the metabolism of lamotrigine and topira-
AEDs do not require routine TDM. However, because most are mate, and oxcarbazepine may induce cytochrome P450 CYP3A4
used as adjuvant therapy, it is useful to establish baseline levels of which is responsible for the metabolism of oral contraceptives
existing drugs before the new agent is introduced. Clinical effects (Sabers and Gram, 2000).
should be monitored and TDM, where appropriate, carried out at
6- to 12-month intervals. Antiepileptic drug profiles
Drug development and action The maintenance doses for the used AEDs are given in Table 31.3,
whereas pharmacokinetic proiles of some AEDs are presented in
Some of the established AEDs were developed in animal models Table 31.4. Drug interactions are summarised in Table 31.5, and
in which the potential drugs were assessed in terms of their ability common side effects in Table 31.6.
to raise seizure threshold or prevent spread of seizure discharge.
The animals involved in these tests would not have epilepsy but Acetazolamide
would have seizures induced by, for instance, maximal electro-
shock or subcutaneous pentylenetetrazole. As a consequence the Acetazolamide is occasionally used as an AED. It can be pre-
relevance of these models to epilepsy can be questioned. scribed as a second-line drug for most types of seizures, but
particularly for focal seizures, absence seizures and myoclonic
Established AEDs such as phenytoin, phenobarbital, sodium seizures. Its intermittent use in catamenial seizures has also been
valproate, carbamazepine, ethosuximide, clonazepam and diaz- suggested. Acetazolamide has only limited use as long-term ther-
epam are effective but have poor side-effect proiles, are involved apy because of the development of tolerance in the majority of
in many interactions and have complex pharmacokinetics. Over people. Side effects include skin rash, weight loss, paraesthesia,
the past 15 years, there has been renewed interest in the develop- drowsiness and depression. Routine TDM is not available for
ment of new AEDs, based on a better understanding of excitatory this drug.
and inhibitory pathways in the brain. The main mechanisms of
the available drugs are thought to involve: Brivaracetam
• voltage-gated sodium channels: most common mechanism of
Brivaracetam is a new AED, recently approved by the European
action, shared by carbamazepine, eslicarbazepine, felbamate, Medicines Agency and launched in the UK in 2016. It is indi-
lacosamide, lamotrigine, oxcarbazepine, phenytoin, ruin- cated as adjunctive therapy in the treatment of focal epilepsy in
amide, topiramate, valproate and zonisamide; adult and adolescents from 16 years of age. The initial dosage is
• voltage-gated calcium channels: ethosuximide, lamotrigine, 25–50 mg twice daily, with a usual maintenance dose of 25–100
gabapentin, pregabalin, valproate and zonisamide; mg twice daily. The most common side effects are somnolence,
• enhancement of the inhibitory γ-aminobutyric-acid (GABA)- dizziness and fatigue. The clinical experience with this AED in
ergic system (Fig. 31.1): benzodiazepines, barbiturates, stirip- the “real world” is still small, but initial experience suggests
entol, tiagabine and vigabatrin; that it is effective for some people who had not beneitted from
• attenuation of glutamate-mediated excitatory neurotransmis- other AEDs.
sion: perampanel;
• synaptic vesicle protein 2A: levetiracetam and brivaracetam.
Inhibition of axonal
transmission
(e.g. carbamazepine,
oxcarbazepine,
phenytoin, lamotrigine)
Inhibition of Glutamate Inhibition of GABA GABA
release
breakdown (e.g. vigabatrin)
(e.g. gabapentin)
Inhibition of glutamate Inhibition of GABA Potentiation of GABA
receptors (e.g. topiramate)
uptake (e.g. tiagabine) receptors (e.g. benzodiazepines,
phenobarbitone)
532 Fig. 31.1 Action of antiepileptic drugs. GABA, γ-Aminobutyric acid. (From Duncan et al., 2006.)
EPILEPSY 31
Carbamazepine adverse reactions including ataxia, dizziness, blurred vision and
Carbamazepine is a irst-line drug for generalised tonic-clonic diplopia are common. Idiosyncratic reactions, such as skin rash,
seizures and focal seizures. It is not effective in absence sei- occur in up to 10%, but rarely cause severe skin eruptions as ery-
zures and myoclonic seizures, where it may even be deleterious. thema multiform and Stevens–Johnson syndrome. Others seri-
Carbamazepine acts through blockage of voltage-gated sodium ous adverse events including hepatic failure and bone marrow
channel. Tolerance to its beneicial effect does not usually depression are extremely uncommon.
develop. Adverse events may occur in up to a third of people
treated with carbamazepine, but only about 5% of these events Carbamazepine exhibits auto-induction, that is, induces its
will require drug withdrawal, usually because of skin rash,
gastro-intestinal disturbances or hyponatraemia. Dose-related own metabolism as well as inducing the metabolism of other
drugs (see Table 31.7). It should, therefore, be introduced at low
Table 31.3 Commonly used starting and maintenance doses of dosage, and this should be steadily increased over a period of a
antiepileptic drugs for adults
month. The target serum concentration therapeutic range is 4–12
Average main-
micrograms/mL. In addition, a number of clinically important
Starting tenance (total
Antiepileptic drug dose (mg) pharmacokinetic interactions may occur, and caution should be
mg/day) Doses/day exercised when co-medication is instituted (see Table 31.5). The
slow-release preparation of carbamazepine has distinct advan-
Acetazolamide 250 500–1500 2 tages, allowing twice-daily ingestion and avoiding high peak
serum concentrations. A ‘chewtab’ formulation is also available,
Carbamazepine 200 800–2000 2–4 (retard 2) and pharmacokinetic studies have shown that it performs well
even if inadvertently swallowed whole. Carbamazepine retard
reduces luctuations of serum levels and allows a twice-daily
regimen, which can assist adherence.
Clobazam 10 10–40 1–2
Clonazepam 1 2–8 1–2 Clobazam
Eslicarbazepine 400 800–1200 1 Clobazam is a 1,5-benzodiazepine that is said to be less seda-
tive than 1,4-benzodiazepine drugs such as clonazepam and
Ethosuximide 250 500–2000 2 diazepam. As with other benzodiazepines, it acts through acti-
vation of the ionotropic γ-aminobutyric acid (GABAA) recep-
Gabapentin 300 1800–3600 3 tor. The development of tolerance is common, but clobazam is
used as an adjunctive therapy for focal and generalised seizures
Lacosamide 50 200–400 2 that have proved unresponsive to other medication. Its inter-
mittent use in catamenial epilepsy has also been suggested; it
Lamotrigine 25 200–400a 1–2 is also used in people with seizure clusters as a single dose of
20–30 mg because it can have a prophylactic action. Clobazam
Levetiracetam 250 1500–3000 2 may produce less sedation than other benzodiazepines, but
otherwise its adverse effects are similar, including dizziness,
Oxcarbazepine 300 600–2400 2–3 behavioural disturbances and dry mouth. Withdrawal may be
dificult.
Perampanel 2 4–12 1–2
Phenobarbital 60 60–240 1–2 Clonazepam
Phenytoin 200 200–500 1–2 Clonazepam, a 1,4-benzodiazepine, is a second-line drug for
generalised tonic-clonic seizures, absences, myoclonic seizures
Pregabalin 25 150–600 2–3 and as adjunctive therapy for focal seizures, but as with cloba-
zam, effectiveness often wears off with time as tolerance devel-
Primidone 250 250–1500 1–2 ops. It has limited use in epilepsy management and is almost
restricted to refractory myoclonic seizures. It has an adverse
Rufinamide 200 400–1200 2 effect proile similar to that of clobazam, but may be more
sedating.
Sodium valproate 500 1000–2500 2–4
Tiagabine 5b 30–45 2–3
Topiramate 25 100–500 2 Diazepam
Vigabatrin 500 1000–3000 2 Diazepam is used mainly in the treatment of status epilepticus,
Zonisamide 50 200–500 2 intravenously or in the acute management of febrile convulsions
as a rectal solution. Absorption from suppositories or following
aReduce by 50% if receiving sodium valproate. intramuscular injection is slow and erratic. The rectal solution 533
bIf taking enzyme inducer. may also be useful in status epilepticus if it is not possible to give
the drug intravenously.
31 THERAPEUTICS
Table 31.4 Pharmacokinetic data of antiepileptic drugs
Absorption Elimination
Renal excretion (%) Active metabolite
Drug F (%) Tpeak (h) Vd (L/kg) Protein binding T½ (h) <1 Yes
(% bound)
Carbamazepine 75–85 1–5 (chronic dose) 0.8–1.6 24–45 (single),
70–78 8–24 (chronic)
Diazepam 90 1–2 1–2 96 20–95 2 Yes
Clonazepam 80–90 1–2 2.1–4.3 80–90 19–40 2 –
Gabapentin 51–59 2–3 57.7 0 5–7 100 No
Lamotrigine 100 2–3 0.92–1.22 55 24–35 <10 No
(induces its own
metabolism)
Ethosuximide 90–95 3–7 0.6–0.9 0 20–60 10–20 No
Phenobarbital 95–100 1–3 0.6 40–50 50–144 20–40 No
Phenytoin 85–95 4–7 0.5–0.7 90–95 9–40 (non- <5 No
linear kinetics)
Primidone 90–100 1–3 0.4–1.1 20–30 3–19 40 Yes
Sodium valpro- 100 0.5–1.0 0.1–0.5 88–92 7–17 <5 No
ate
Vigabatrin 60–80 2 0.6–1.0 0 5–7 100 No
Zonisamide 100 2–4 1.1–1.7 40 52–69 30 Yes
F, Bioavailability; Tpeak, time to peak; Vd, volume of distribution.
Eslicarbazepine acetate The therapeutic range commonly quoted is 1–1.5 g daily in two
divided doses, increased if necessary up to 2 g daily. The initial
Eslicarbazepine acetate is a drug which is similar to oxcarbaze- dosage is 500 mg daily in two divided doses and increased in
pine and which is licensed as a second-line treatment for focal sei- steps of 250 mg every 5–7 days. The absorption of ethosuximide
zures. As with oxcarbazepine, its mode of action is thought to be is complete, and the bioavailability of the syrup and capsule for-
by interacting with voltage-gated sodium channels. Currently, it is mulations is equivalent. An increase in daily dose may lead to
available only as a 800 mg tablet. It has a long half-life and can be disproportionately higher increases in average serum concentra-
used once per day. The recommended starting dosage is 400 mg tions; therefore, careful monitoring is indicated at high doses.
once daily for 1–2 weeks, then increased to 800 mg once daily. The
maximum dosage is 1200 mg daily. Its pharmacokinetic proile and Felbamate
side effects are also similar to those of oxcarbazepine.
Felbamate may be used as a drug of last resort in people with
Ethosuximide intractable epilepsy, particularly in those within the Lennox–
Gastaut spectrum. It is licensed in the USA and most countries
Ethosuximide is a drug of irst choice for generalised absence of the European Union, but not in the UK. Its mechanism of
seizures, and it has no useful effect against any other seizure type. action is unknown. The usual dosage is between 2400 and 3600
It mechanism of action is through blockage of low-voltage acti- mg/day. Felbamate exhibits signiicant pharmacokinetic inter-
vated calcium channel. Tolerance does not seem to be a problem. actions with phenytoin, carbamazepine and valproic acid. Side
The most commonly encountered adverse effects are gastro- effects include diplopia, insomnia, dizziness, headache, ataxia,
intestinal symptoms, which occur frequently at the beginning anorexia, nausea and vomiting. A major limiting problem is its
of therapy. Behaviour disorders, anorexia, fatigue, sleep distur- potential to cause aplastic anaemia and liver failure. It, there-
bances and headaches may also occur. Idiosyncratic side effects fore, seems prudent to limit use to specialist centres and severe
include rash, Stevens–Johnson syndrome and aplastic anaemia. intractable cases.
534
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