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Paediatric bipolar disorder – an update
CLINICAL SYNDROMES
Paediatric bipolar disorder – an update
(no more than 2 months symptom-free) with clinical distress or functional impairment. None of the above disorders are diagnosed if symptoms are better accounted for by schizoaffective disorder, schizophrenia, schizophreniform disorder, delusional disorder, or psychotic disorder not otherwise specified, or are due to drugs or a medical condition. Subtypes include: • bipolar I disorder – at least one manic or mixed episode • bipolar II disorder – one or more episodes of major depression and hypomania, but no manic or mixed episodes • rapid cycling – at least 4 episodes of mood disturbance (major depression, mania, mixed, hypomania) over 12 months • seasonal pattern represents a course of illness where the episodes occur consistently at a particular time of year.
Paramala J Santosh
Paediatric bipolar disorder is a serious condition that affects a child’s ability to function normally during important developmental stages. Developmental variations in presentation, symptomatic overlap with other disorders and lack of awareness have all contributed to its under-diagnosis or misdiagnosis.
Clinical assessment and symptom thresholds History should be obtained from the child, parent and school. Collateral history from family members or close friends may be the key to uncovering a more complete history. Prospective mood charting is very helpful in clarifying bipolar presentations. The Young Mania Rating Scale is increasingly used to monitor changes in bipolar symptoms while the Kiddie Schedule for the Affective Disorders and Schizophrenia (K-SADS) is used to assist diagnosis. When assessing the presence or absence of manic symptoms, it is recommended that clinicians use the FIND (frequency, intensity, number and duration) strategy to make this determination. FIND guidelines for the diagnosis of paediatric bipolar disorder suggest: • frequency – symptoms should occur most days of the week • intensity – symptoms should be severe enough to cause extreme disturbance, in 1 domain, or moderate disturbance in 2 • number – symptoms should occur 3 or 4 times a day • duration – symptoms should occur 4 or more hours a day. It is, however, important to note that these FIND thresholds have yet to be validated and have been presented as clinically useful thresholds only by the expert panel for paediatric bipolar disorder.2
Clinical features The current DSM-IV criteria, developed for adults, are difficult to apply to children. Manic episode requires: • a distinct period of abnormally and persistently elevated, expansive, and/or irritable mood, lasting at least one week (or any duration of hospitalization) is necessary • during the period of mood disturbance, the patient must display at least three (four if the mood is only irritable) symptoms of: grandiosity, decreased sleep, pressured speech, racing thoughts, distractibility, increased goal-directed activity, and/or excessive involvement in reckless activities • the mood disturbance causes marked impairment – this may indicate hospitalization or presence of psychotic symptoms • the mood disturbance is not part of a mixed manic depressive episode, which is diagnosed separately. Hypomanic episode has similar symptoms as a manic episode but differs in the severity and duration criteria. Symptoms must be present for at least 4 days and produce an unequivocal change in the patient’s functioning that is observable by others, without marked deterioration in functioning, need for hospitalization, or psychotic symptoms; otherwise a manic episode is diagnosed.1 Mixed episode is when the patient meets criteria for both manic and major depressive episodes over at least a 1-week period. Bipolar depressive episode meets all the criteria for a depressive episode but occurs during the course of bipolar disorder. Bipolar disorder not otherwise specified is diagnosed when subjects have a mood disorder but do not have clearly defined episodes. They may have mixed presentations, too few manic symptoms or their episodes do not meet the DSM-IV duration criteria. Cyclothymic disorder – children and adolescents who have had for 1 year or more (2 years or more for adults) numerous hypomanic or depressive symptoms that do not meet full criteria for either a major depressive disorder, manic episode, or mixed episode. Symptoms must be present for much of the defined period
Symptom description Children might present with seemingly manic symptoms for a variety of reasons. Symptoms should be considered as abnormal only if they cannot be understood in the context in which they are occurring in and if they are out of keeping with what would be expected at that developmental level. Symptoms that discriminate paediatric bipolar disorder are: • euphoric or expansive mood – children with paediatric bipolar disorder become extremely happy or excited without obvious reason, for sustained periods of time • grandiosity – they often have exaggerated ideas about their abilities, tell tall tales, or exaggerate things. Children act on their belief when their insight is impaired • decreased need for sleep – to meet the manic criteria, the child’s sleep should be decreased by 2 or more hours per night for their age, without evidence of daytime fatigue. Children with other forms of insomnia often lie in bed trying to sleep, whereas manic children are full of energy. They often get up and wander the house in the middle of the night • pressured speech or flight of ideas – speech may be loud, intrusive, difficult to interrupt, and jump from one topic to another • racing thoughts – this requires asking the child whether their thoughts are going too fast. Racing thoughts are impairing when
Paramala J Santosh is Honorary Senior Lecturer at the Institute of Child Health, University College London, UK and Consultant in Developmental Neuropsychiatry and Neuropharmacology in the Department of Child and Adolescent Mental Health at Great Ormond Street Hospital, London, UK.
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they prevent the child from keeping daily activities on track • increase in goal-directed activity – is specific to mania. Those who are hypomanic may be fairly productive, but if their mania progresses, they may become disorganized and non-productive • excessive involvement in pleasurable or risky activities – children with paediatric bipolar disorder often display precocious sexual curiosity and are hypersexual. This hypersexual behaviour frequently has an erotic, flirtatious, pleasure-seeking quality to it that would be appropriate if done in private between consenting adults. In contrast, hypersexual behaviour of children who have been sexually abused is often anxious and compulsive in nature. It is, however, important to rule out sexual abuse or exposure to sexually explicit materials or behaviour as a possible cause for hypersexual behaviour in any child • psychotic symptoms, in addition to the core symptoms of mania, including hallucinations and delusions, are frequently seen. Other symptoms to consider in paediatric bipolar disorder: • irritable mood and explosive temper tantrums – the tantrums during manic irritability are qualitatively different, being episodic, extremely severe, often with an explosive quality, occurring suddenly, peaking very quickly, and lasting for long periods, with parents often reporting that they are unable to predict their child’s responses. Extreme rages over trivial matters (e.g. one- to two-hour tantrums after being asked to brush their teeth) are common. • psychomotor agitation – they often display periods of high energy and motor activation during certain parts of the day (e.g. evenings). Agitation is more often seen during mixed episodes. • relentlessly pursuing own needs – they often do not understand the other person’s perspective and can be very demanding. They often argue with adults and are very bossy towards them. • distractibility – needs to be in conjunction with a manic mood shift, and should not be accounted for exclusively by another disorder, especially attention deficit hyperactivity disorder (ADHD). • suicidality – although not a core symptom of mania, children with paediatric bipolar disorder are at very high risk of suicide plans and attempts, during a depressed, mixed or psychotic episode. To improve the diagnostic sensitivity for bipolar depression, every patient who presents with a depressive syndrome should be asked about past history of mania or hypomania.
being considered as a categorical diagnosis, it can be viewed as a spectrum (similar to autism spectrum disorders), with affective dysregulation with impairment being the mildest form and typical bipolar disorder with psychotic symptoms being its severe presentation. The older the adolescent is at first presentation, the greater the likelihood of it being atypical bipolar disorder, while young children are likely to have co-existing ADHD. Studies suggest that bipolar NOS is the most frequent label given to children and adolescents with paediatric bipolar disorder. As the bipolar NOS label is used by clinicians for different reasons (e.g. lack of clearly defined episodes, mixed presentations, having fewer manic symptoms than accepted by DSM-IV criteria for mania, or when episodes do not meet the DSM-IV duration criteria), it automatically makes paediatric bipolar disorder very heterogeneous, fuelling the debate about its relevance and nosological status as an entity. The current confusion arises from the lumping of the above spectrum into a single diagnostic category of paediatric bipolar disorder. The above re-conceptualization may increase the acceptance of paediatric bipolar disorder as a genuine disorder with a spectrum of presentations. Epidemiology and course Paediatric bipolar disorder is rare, although up to 60% of adult cases of bipolar disorder are reported to have an early onset. The peak age of onset is 15 to 19 years with a lifetime prevalence of 1 to 3%. Both sexes are affected equally, although boys are more often affected before the age of 13 years. Bipolar disorder is shown to be a familial disorder especially in early-onset cases and life-time rates are approximately 15% in first-degree relatives. Compared with the adult form, paediatric bipolar disorder may have a prolonged early course and be less responsive to treatment. Mixed features, psychotic symptoms, and/or comorbid behaviours, which are a frequent presentation in children, predict a more refractory response to lithium therapy.3 Premorbid characteristics (e.g. intellectual functioning) strongly predict outcome. Adolescents with bipolar disorder are at increased risk of suicide, especially depressed boys. Fifty percent of children with major depression and 90% with mania continue to have adult recurrences. Differential diagnosis and comorbidity ADHD is commonly associated with paediatric bipolar disorder, with those with a history of stimulant exposure being reported to have an earlier age at onset of paediatric bipolar disorder than those without prior stimulant exposure.4 It has been suggested that ADHD treatment with anti-ADHD agents is efficacious only after mood stabilization.5 Elation, grandiosity, hypersexuality, decreased need for sleep, with increased goal directed activity, high energy levels and psychotic symptoms appear to differentiate paediatric bipolar disorder from ADHD. Paediatric bipolar disorder is suspected if: • ADHD symptoms are absent in early years (before 7 years) • symptoms occur episodically and resolve without treatment • symptoms that were well controlled become suddenly worse for no reason and continue to be resistant to usual treatment • unexplained increase of ADHD symptoms at particular times of day (e.g. evening worsening not related to medication). • stimulant-induced worsening of behaviour, especially increasing mood lability and explosive behaviour. Longitudinal follow-up often helps clarify whether paediatric bipolar disorder and ADHD co-exist. Presence of ADHD has implications for
Re-conceptualized model Synthesizing the existing literature and clinical experience it appears that one can view paediatric bipolar disorder as a spectrum disorder, conceptualized as: • a large number of children in whom, since early childhood, impairment results from ‘affective dysregulation’ or ‘developmental disorder of affect regulation’, which may arise due to a developmental delay/disorder, or temperamental characteristic (many cyclothymic or hyperthymic), or neglect • a smaller group who have what could be loosely termed ‘bipolar disorder not otherwise specified (NOS)’, where the subjects have features of bipolar disorder but do not meet the typical criteria for bipolar disorder, especially the duration criteria • at the extreme, a small group who would meet all the DSM-IV criteria for typical ‘bipolar disorder’. Apart from this, many children will have some affective dysregulation without impairment. Instead of paediatric bipolar disorder
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treatment; use of stimulants in the absence of mood stabilization can lead to rapid cycling of paediatric bipolar disorder. Bipolar depression is often misdiagnosed as unipolar depression. Eliciting information about past hypomania or mania from a depressed patient may be extremely difficult. In some cases, the presenting depression is the index episode of bipolar disorder, so there will be no hypomania or mania to elicit. Twenty to thirty percent of youth with major depressive disorder go on to have manic episodes. Risk factors predicting mania include a depressive episode characterized by rapid onset, presence of psychomotor retardation, psychotic symptoms, a family history of mood disorders, a history of antidepressant-induced mania or hypomania, and a history of ADHD with affective instability. Unfortunately, the ramifications of a missed diagnosis can be severe. Patients whose disease is incorrectly assessed as unipolar depression are likely to be prescribed antidepressant monotherapy, which can cause mood destabilization; this has been reported to occur in approximately 25% to 40% of patients with bipolar disorder.6 Misdiagnosis may also lead to delayed initiation of a mood stabilizer – this may increase the risk of suicide, impair psychosocial functioning, and reduce the likelihood of a response to lithium.7,8 Schizophrenia – bipolar disorder with onset during adolescence commonly presents with ‘schizophrenic-like’ symptoms and, in the past, has been misdiagnosed as schizophrenia in up to 50% of cases. Factors that favour a diagnosis of schizophrenia include premorbid schizotypal personality, family history of schizophrenia, and early-onset psychosis. Schizoaffective disorder – there must be at least a 2-week period where hallucinations and delusions persist without mood symptoms while mood symptoms must be present for a substantial portion of the overall illness. Agitated depression may be confused with a mixed episode due to symptoms of increased psychomotor activity and anxiety. Post-traumatic stress disorder (PTSD) the presence of significant trauma, hypervigilance, flashbacks and high arousal help differentiate PTSD. Borderline personality disorder – adolescents with affective instability, poor impulse control and erratic behaviours may be misdiagnosed as bipolar disorder. Organic mood disorders – neurological disorders (e.g. brain tumours, temporal lobe seizures, Kleine-Levin syndrome) as well as systemic conditions (e.g. hyperthyroidism, uraemia, porphyria) can all present with symptoms of mania. Also, prescribed medications (e.g. antidepressants, sympathomimetics, steroids) and substances of abuse (e.g. cocaine, ecstasy) can induce mania.1
monitoring arrangements are among the many difficult issues for those with paediatric bipolar disorder and those caring for them, and management by a specialist is essential. In acute illness, the patient can progress through the stages of mania and then depression, before recovery. Multiple changes to drug therapy are unnecessary and a minimum of four to six weeks of therapeutic blood level and an adequate dose for each medication trial (eight weeks for lithium) is recommended for assessing effectiveness before switching medication. Figure 1 provides the treatment algorithms for acute-phase bipolar disorder with and without features of psychosis. It is important to emphasize that these algorithms are only guidelines that have been arrived at by the consensus group and not necessarily backed up by the best evidence base, as very little is available in this area.2
Treatment algorithm for acute phase of bipolar I disorder, manic or mixed episodes Without features of psychosis • Stage 1: monotherapy with either a mood stabilizer (e.g. valproate, carbamazepine, lamotrigine, lithium), or an atypical antipsychotic (e.g. risperidone, olanzapine, quetiapine). • Stage 2: if there is no response, then switch to another drug (either mood stabilizer or atypical antipsychotic). • Stage 3: if there is no response, then switch monotherapy agent to a drug class not tried in stage 1 or 2. • Stage 4a: if no response, combine an atypical antipsychotic with a mood stabilizer. • Stage 4b: if no response, combine two mood stabilizers and an atypical antipsychotic. • Stage 5: if no response, try alternate monotherapy with aripiprazole, oxcarbazepine or ziprazidone. • Stage 6: if these strategies fail, then clozapine or ECT (in adolescents) may be considered. It is increasingly accepted that clinicians may choose to try an alternate monotherapy, with aripiprazole, oxcarbazepine or • ziprazidone before combining two mood stabilizers and an atypical antipsychotic or before considering clozapine. Partial response at any stage is managed by combining a mood stabilizer and an atypical antipsychotic (add drug from class not being used). With features of psychosis • Stage 1: involves combination of a mood stabilizer (e.g. valproate, carbamazepine, lamotrigine, lithium) and an atypical antipsychotic (e.g. risperidone, quetiapine). • Stage 2: if there is no response, then switch to another mood stabilizer and an atypical antipsychotic. • Stage 3: if there is no response, then switch to a different mood stabilizer and atypical antipsychotic agent. • Stage 4: if no response, a combination treatment of two mood stabilizers (e.g. lithium and valproate) and an atypical antipsychotic is to be tried, and if it fails • Stage 5: a combination of aripiprazole or ziprazidone or oxcarbazepine plus an atypical antipsychotic is to be tried. • Stage 6: if these strategies fail, then ECT (in adolescents) or clozapine may be considered. Partial response at any stage is managed by using a combination of mood stabilizers and atypical antipsychotics.
Treatment guidelines for paediatric bipolar disorder A treatment plan that combines pharmacological and psychological interventions, as well as psychoeducation, is required. The goal of intervention is to ameliorate symptoms and prevent relapse; with the ultimate aim of reducing long-term morbidity and promoting development. Despite the guidelines below, the clinician must make the final judgement regarding a particular treatment plan, using the clinical data presented by the patient. Acute-phase medication: very few clinical trials of drug treatment have been conducted in children and adolescents. As a rule, treatment along the same lines as an adult is accepted practice. Decisions about long-term treatment, adherence to treatment and
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Acute-phase treatment of bipolar depression: treatment options in bipolar depression are especially limited as tricyclic antidepressants are not recommended, and selective serotonin-reuptake inhibitors (SSRIs) (apart from fluoxetine) have been contraindicated by the UK Committee on Safety of Medicine. Non-pharmacological interventions, such as cognitive–behavioural therapy (CBT) and interpersonal therapy (IPT), are recommended for depression in paediatric bipolar disorder, but if all else fails, fluoxetine can be tried, after mood stabilization has been achieved using a mood stabilizer (e.g. lamotrigine, valproate, lithium or carbamazepine). As with adults, it is recommended that an antidepressant medication be continued for at least 8 weeks after depressive symptom remission. Lamotrigine has been shown to have good antidepressant action in bipolar depression. Gabapentin or bupropion may be used to manage anxiety in bipolar disorder, as they will at least not worsen the manic state.
principle of treating ADHD is to obtain mood stabilization, first using a mood stabilizer, and subsequently, if ADHD symptoms persist, using a low dose of stimulant, and monitoring carefully to see whether one can manage the ADHD effectively without worsening the paediatric bipolar disorder. Pervasive developmental disorders (PDD) – patients with paediatric bipolar disorder and PDD should be initially treated with an atypical antipsychotic (e.g. risperidone), and mood stabilizers should be added as necessary. The use of other medication to target other PDD symptoms should be considered, taking into account that some medications may destabilize mood. Patients should be referred to an appropriate PDD programme when available. Migraine or epilepsy – for those with paediatric bipolar disorder and seizures or migraines, the mood stabilizer chosen should be an anti-migraine agent (eg. carbamazepine, valproate). Medication used in paediatric bipolar disorder Anticonvulsant mood stabilizers – indications for use of anticonvulsants include rapid cycling and mixed episodes. Valproate, carbamazepine and lamotrigine are commonly used. Divalproex sodium is frequently used in children and adolescents as a first-line agent for mania. Common side-effects of valproate include sedation, nausea and vomiting. Rare, but potential serious side effects include fatal hepatic toxicity, haematological side-effects and polycystic ovary disease. Transient side-effects of carbamazepine may include drowsiness, dizziness, nausea and mild ataxia. Carbamazepine has been reported to cause agranulocytosis (within 3 months of initiating therapy, although it may occur as late as 5 years after starting treatment) and aplastic anaemia. Leucopenia may occur in children but is not significant unless total white blood count falls below 3000/mm3. Hepatic toxicity and cognitive and behavioural effects including impaired performance on learning and memory tasks, irritability, insomnia and emotional lability rarely occur. Lamotrigine appears to have antidepressant as well as mood-stabilizing properties. Lamotrigine is used to manage depressive symptoms in paediatric bipolar disorder in acute phase as well as at follow up, as a mood stabilizer including in those with rapid cycling, as maintenance treatment, and as a prophylactic agent to decrease depressive episodes. However, serious rash occurs in 1 in 10,000 children taking lamotrigine, and hence the escalation of dose should be very gradual. Serious rashes are more likely to occur between 2 and 8 weeks of treatment and typically involve systemic disturbances, often manifesting with blistering on soft mucocutaneous tissues (e.g. oral-buccal mucosa) or the palms and soles. To reduce the risk of rash, gradual titration of lamotrigine is recommended (e.g. 12.5 mg/day for 2 weeks, followed by 25 mg/day for 2 weeks, with further gradual dosage increases to 100 mg/day or target dose). Starting doses should be adjusted downward for patients on cytochrome P450 inhibitors and upward for patients on inducing agents. Oxcarbazepine is a promising agent for acute mania in adults, but no data is available in childhood. Atypical antipsychotics – weight gain and possibility of metabolic syndrome (hyperglycaemia and hypercholesterolaemia) are risks with all atypical antipsychotics and require monitoring. Clozapine, olanzapine, risperidone, amisulpiride, quetiapine, aripiprazole and ziprazidone gives the drugs in descending order of potential to increase weight. Hyperprolactinaemia is especially a problem with risperidone. Clozapine should not be combined
Treatment of maintenance and continuation phases: it is generally accepted that treatment with a maintenance agent should continue for at least 18 months after stabilization of a manic episode. However, there are no clear answers to definitively inform clinicians regarding how long treatment should continue. It is generally suggested that treatment should continue for a minimum of 12 to 24 consecutive months after achieving symptom remission. Recently, lithium and valproate were reported to be equally effective in maintenance treatment.9 The risk associated with the potential relapse should be compared with the risk associated with continued pharmacotherapy. Treatment discontinuation should be attempted with great caution in those with a history of suicidal behaviour, severe aggression, and/or psychosis. Many patients may need long-term or even life-long pharmacotherapy. Special considerations Rapid cycling affective disorder – up to half of all adult patients with bipolar disorder develop rapid cycling at some point. This is sometimes triggered or worsened by the use of antidepressants, which should be stopped if rapid cycling develops. Patients should be assessed for alcohol and substance misuse, thyroid dysfunction, and temporal lobe epilepsy, use of prescription drugs (e.g. steroids and certain antibiotics). Anticonvulsant mood stabilizers are recommended as first-line treatment, but in practice, many children and adolescents will require a combination of drugs. Suicide – suicide prevention is a critical objective in the treatment of bipolar disorder.10 Suicide attempts are highly prevalent in bipolar patients and are related to drug abuse, family history of affective disorders, and severe depressive episodes. Problemsolving strategies combined with intensive rehearsal of cognitive, social, emotional labelling, and distress-tolerance skills have been found to be effective therapeutic strategies.11 Treatment of comorbid psychiatric disorders Before treating the comorbid disorder, it is important to first stabilize the symptoms of bipolar disorder. If the symptoms of the comorbidity are negatively affecting the child’s psychosocial or academic functioning, then treatment is warranted. Whenever appropriate, using psychosocial therapies to treat co-existing disorders is recommended (e.g. using CBT to manage depression). ADHD – medications used to treat ADHD can lead to rapid cycling if mood stabilization has not already been achieved. The
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Conclusions Paediatric bipolar disorder is a severe and complex illness that seriously disrupts the lives of those afflicted. However there has been confusion because paediatric bipolar disorder is a very heterogeneous condition as currently conceptualized. This review suggests that paediatric bipolar disorder can be viewed as a spectrum, with ‘developmental disorder of affect regulation’ at one end and typical bipolar disorder (fulfilling all DSM-IV criteria) at the other, with the majority of those currently being diagnosed as paediatric bipolar disorder lying in between. Although the early course of paediatric bipolar disorder in adolescents is more chronic and refractory to treatment, the long-term prognosis is probably similar to that of adults. Guidelines and algorithms for treatment of paediatric bipolar disorder have emerged through expert consensus rather than an evidence base, the lack of which needs to be rectified urgently through well-planned studies with the phenotype being clearly specified.
with Carbamazepine because of the risk of agranulocytosis. Aripiprazole and ziprazidone are promising agents for acute mania in adults, but no data is available in childhood. Lithium has been shown to be effective for treatment of acute mania and depressive episodes, prevention of recurrent mania and depressive episodes and reduction of mood instability between episodes. Although lithium has been found to be effective for paediatric bipolar disorder, the overall response may be less than that of adults. However, a recent study shows that it is as effective as valproate.9 Children have a higher glomerular filtration rate than adults and since lithium is excreted almost entirely by the kidneys, the required therapeutic dose may need to be higher in this age group. The recommended therapeutic serum levels for the acute phase range from 0.6 to 1.2 mEq/L, and for prophylaxis 0.4 to 0.8 mEq/L. Lithium levels should be monitored regularly. Younger children are more prone to side-effects than older children. Sideeffects include nausea, diarrhoea, vomiting, tremor, weight gain, headache, polyuria, polydipsia, enuresis, fatigue, ataxia, hypothyroidism, goitres, and reversible diabetes insipidus. Lithium toxicity manifests with tremors, ataxia, vomiting and other neurological symptoms and requires emergency treatment. Benzodiazepines are useful for acute agitated manic states particularly in conjunction with anti-manic agents (atypical antipsychotics, lithium or anticonvulsants). However, their long term use should be discouraged, due to potential dependency problems. Omega-3 fatty acid has been shown to be of benefit as an adjunct in adults with bipolar disorder. Electroconvulsive therapy (ECT) is the treatment of choice for bipolar disorder in pregnancy, catatonia, neuroleptic malignant syndrome and any other condition where standard medication is contraindicated. Case reports indicate that ECT is beneficial for children and adolescents with paediatric bipolar disorder.
REFERENCES 1 McClellan J, Werry J S, Ayres W et al. Practise parameters for the assessment and treatment of children and adolescents with bipolar disorder. J Am Acad Child Adolesc Psychiatry 1997; 36: 157S–176S. 2 Kowatch R A, Fristad M, Birmaher B, Wagner K D, Findling R L, Hellander M. Child psychiatric workgroup on bipolar disorder. Treatment guidelines for children and adolescents with bipolar disorder. J Am Acad Child Adolesc Psychiatry 2005; 44: 213–35. 3 Carlson G A, Bromet E J, Driessens C, Mojtabai R, Schwartz J E. Age at onset, childhood psychopathology, and 2-year outcome in psychotic bipolar disorder. Am J Psychiatry 2002; 59: 307–9. 4 DelBello M P, Soutullo C A, Hendricks W, Niemeier R T, McElroy S L, Strakowski S M. Prior stimulant treatment in adolescents with bipolar disorder: association with age at onset. Bipolar Disord 2001; 3: 53–7. 5 Biederman J. Resolved: mania is mistaken for ADHD in prepubertal children. J Am Acad Child Adolesc Psychiatry 1998; 37: 1091–9. 6 Goldberg J F, Truman C J. Antidepressant-induced mania: an overview of current controversies. Bipolar Disor 2003; 5: 407–20. 7 Goldberg J F, Ernst C L. Features associated with the delayed initiation of mood stabilizers at illness onset in bipolar disorder. J Clin Psychiatry 2002; 63: 985–91. 8 Franchini L, Zanardi R, Smeraldi E, Gasperini M. Early onset of lithium prophylaxis as a predictor of good long-term outcome. Eur Arch Psychiatry Clin Neurosci 1999; 249: 227–30. 9 Findling R L, McNamara N K, Youngstrom E A et al. Double-blind 18month trial of lithium versus divalproex maintenance treatment in pediatric bipolar disorder. J Am Acad Child Adolesc Psychiatry 2005; 44: 409–17. 10 Sachs G S, Yan L J, Swann A C, Allen M H. Integration of suicide prevention into outpatient management of bipolar disorder. J Clin Psychiatry 2001; 62: 3–11. 11 Gray S M, Otto M W. Psychosocial approaches to suicide prevention: applications to patients with bipolar disorder. J Clin Psychiatry 2001; 62: 56–64. 12 Mackinow-Koons B, Fristad M A. Children with bipolar disorder: how to break down barriers and work effectively together. Prof Psychol 2004; 35: 481–4. 13 Rosenfarb I S, Miklowitz D J, Goldstein M J, Harmon L, Nuechterlein K H, Rea M M. Family transactions and relapse in bipolar disorder. Fam Process 2001; 40: 5–14.
Psychoeducation/psychosocial treatments While drug therapy is crucial, support and education for the patient and carers and psychological therapy are integral for optimizing outcomes in paediatric bipolar disorder. In the process of diagnosing the child, clinicians frequently discover untreated, and sometimes undiagnosed, mood disorders or other conditions in immediate family members. Referring these individuals for treatment can greatly reduce stress in the household, thereby providing more resources for managing the child’s bipolar disorder. The families need to become educated about bipolar disorder and its effects on the family regarding the nature of the disorder, treatment options, potential impact on psychosocial and family functioning and heritability; relapse prevention that aims at education on impact of non-compliance with medication, early recognition of relapse symptoms and other factors that promote relapse. The willingness of the patient to adhere to the regimen and monitoring, the availability of support from family and friends, and factors such as stress, sleep disruption, or misuse of alcohol or drugs should also be identified and managed. When psychosocial therapies are being used, it is important for the therapist to have good working knowledge of paediatric bipolar disorder and other childhood psychiatric disorders, otherwise it is very easy to fall into therapeutic traps (e.g. being disappointed when a behavioural plan backfires and the child becomes manic).12 A bi-directional, interactional relationship between patients’ symptoms and relatives’ coping style seems to capture best the role of the family in predicting relapse.13
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(no more than 2 months symptom-free) with clinical distress or functional impairment. None of the above disorders are diagnosed if symptoms are better accounted for by schizoaffective disorder, schizophrenia, schizophreniform disorder, delusional disorder, or psychotic disorder not otherwise specified, or are due to drugs or a medical condition. Subtypes include: • bipolar I disorder – at least one manic or mixed episode • bipolar II disorder – one or more episodes of major depression and hypomania, but no manic or mixed episodes • rapid cycling – at least 4 episodes of mood disturbance (major depression, mania, mixed, hypomania) over 12 months • seasonal pattern represents a course of illness where the episodes occur consistently at a particular time of year.
Paramala J Santosh
Paediatric bipolar disorder is a serious condition that affects a child’s ability to function normally during important developmental stages. Developmental variations in presentation, symptomatic overlap with other disorders and lack of awareness have all contributed to its under-diagnosis or misdiagnosis.
Clinical assessment and symptom thresholds History should be obtained from the child, parent and school. Collateral history from family members or close friends may be the key to uncovering a more complete history. Prospective mood charting is very helpful in clarifying bipolar presentations. The Young Mania Rating Scale is increasingly used to monitor changes in bipolar symptoms while the Kiddie Schedule for the Affective Disorders and Schizophrenia (K-SADS) is used to assist diagnosis. When assessing the presence or absence of manic symptoms, it is recommended that clinicians use the FIND (frequency, intensity, number and duration) strategy to make this determination. FIND guidelines for the diagnosis of paediatric bipolar disorder suggest: • frequency – symptoms should occur most days of the week • intensity – symptoms should be severe enough to cause extreme disturbance, in 1 domain, or moderate disturbance in 2 • number – symptoms should occur 3 or 4 times a day • duration – symptoms should occur 4 or more hours a day. It is, however, important to note that these FIND thresholds have yet to be validated and have been presented as clinically useful thresholds only by the expert panel for paediatric bipolar disorder.2
Clinical features The current DSM-IV criteria, developed for adults, are difficult to apply to children. Manic episode requires: • a distinct period of abnormally and persistently elevated, expansive, and/or irritable mood, lasting at least one week (or any duration of hospitalization) is necessary • during the period of mood disturbance, the patient must display at least three (four if the mood is only irritable) symptoms of: grandiosity, decreased sleep, pressured speech, racing thoughts, distractibility, increased goal-directed activity, and/or excessive involvement in reckless activities • the mood disturbance causes marked impairment – this may indicate hospitalization or presence of psychotic symptoms • the mood disturbance is not part of a mixed manic depressive episode, which is diagnosed separately. Hypomanic episode has similar symptoms as a manic episode but differs in the severity and duration criteria. Symptoms must be present for at least 4 days and produce an unequivocal change in the patient’s functioning that is observable by others, without marked deterioration in functioning, need for hospitalization, or psychotic symptoms; otherwise a manic episode is diagnosed.1 Mixed episode is when the patient meets criteria for both manic and major depressive episodes over at least a 1-week period. Bipolar depressive episode meets all the criteria for a depressive episode but occurs during the course of bipolar disorder. Bipolar disorder not otherwise specified is diagnosed when subjects have a mood disorder but do not have clearly defined episodes. They may have mixed presentations, too few manic symptoms or their episodes do not meet the DSM-IV duration criteria. Cyclothymic disorder – children and adolescents who have had for 1 year or more (2 years or more for adults) numerous hypomanic or depressive symptoms that do not meet full criteria for either a major depressive disorder, manic episode, or mixed episode. Symptoms must be present for much of the defined period
Symptom description Children might present with seemingly manic symptoms for a variety of reasons. Symptoms should be considered as abnormal only if they cannot be understood in the context in which they are occurring in and if they are out of keeping with what would be expected at that developmental level. Symptoms that discriminate paediatric bipolar disorder are: • euphoric or expansive mood – children with paediatric bipolar disorder become extremely happy or excited without obvious reason, for sustained periods of time • grandiosity – they often have exaggerated ideas about their abilities, tell tall tales, or exaggerate things. Children act on their belief when their insight is impaired • decreased need for sleep – to meet the manic criteria, the child’s sleep should be decreased by 2 or more hours per night for their age, without evidence of daytime fatigue. Children with other forms of insomnia often lie in bed trying to sleep, whereas manic children are full of energy. They often get up and wander the house in the middle of the night • pressured speech or flight of ideas – speech may be loud, intrusive, difficult to interrupt, and jump from one topic to another • racing thoughts – this requires asking the child whether their thoughts are going too fast. Racing thoughts are impairing when
Paramala J Santosh is Honorary Senior Lecturer at the Institute of Child Health, University College London, UK and Consultant in Developmental Neuropsychiatry and Neuropharmacology in the Department of Child and Adolescent Mental Health at Great Ormond Street Hospital, London, UK.
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they prevent the child from keeping daily activities on track • increase in goal-directed activity – is specific to mania. Those who are hypomanic may be fairly productive, but if their mania progresses, they may become disorganized and non-productive • excessive involvement in pleasurable or risky activities – children with paediatric bipolar disorder often display precocious sexual curiosity and are hypersexual. This hypersexual behaviour frequently has an erotic, flirtatious, pleasure-seeking quality to it that would be appropriate if done in private between consenting adults. In contrast, hypersexual behaviour of children who have been sexually abused is often anxious and compulsive in nature. It is, however, important to rule out sexual abuse or exposure to sexually explicit materials or behaviour as a possible cause for hypersexual behaviour in any child • psychotic symptoms, in addition to the core symptoms of mania, including hallucinations and delusions, are frequently seen. Other symptoms to consider in paediatric bipolar disorder: • irritable mood and explosive temper tantrums – the tantrums during manic irritability are qualitatively different, being episodic, extremely severe, often with an explosive quality, occurring suddenly, peaking very quickly, and lasting for long periods, with parents often reporting that they are unable to predict their child’s responses. Extreme rages over trivial matters (e.g. one- to two-hour tantrums after being asked to brush their teeth) are common. • psychomotor agitation – they often display periods of high energy and motor activation during certain parts of the day (e.g. evenings). Agitation is more often seen during mixed episodes. • relentlessly pursuing own needs – they often do not understand the other person’s perspective and can be very demanding. They often argue with adults and are very bossy towards them. • distractibility – needs to be in conjunction with a manic mood shift, and should not be accounted for exclusively by another disorder, especially attention deficit hyperactivity disorder (ADHD). • suicidality – although not a core symptom of mania, children with paediatric bipolar disorder are at very high risk of suicide plans and attempts, during a depressed, mixed or psychotic episode. To improve the diagnostic sensitivity for bipolar depression, every patient who presents with a depressive syndrome should be asked about past history of mania or hypomania.
being considered as a categorical diagnosis, it can be viewed as a spectrum (similar to autism spectrum disorders), with affective dysregulation with impairment being the mildest form and typical bipolar disorder with psychotic symptoms being its severe presentation. The older the adolescent is at first presentation, the greater the likelihood of it being atypical bipolar disorder, while young children are likely to have co-existing ADHD. Studies suggest that bipolar NOS is the most frequent label given to children and adolescents with paediatric bipolar disorder. As the bipolar NOS label is used by clinicians for different reasons (e.g. lack of clearly defined episodes, mixed presentations, having fewer manic symptoms than accepted by DSM-IV criteria for mania, or when episodes do not meet the DSM-IV duration criteria), it automatically makes paediatric bipolar disorder very heterogeneous, fuelling the debate about its relevance and nosological status as an entity. The current confusion arises from the lumping of the above spectrum into a single diagnostic category of paediatric bipolar disorder. The above re-conceptualization may increase the acceptance of paediatric bipolar disorder as a genuine disorder with a spectrum of presentations. Epidemiology and course Paediatric bipolar disorder is rare, although up to 60% of adult cases of bipolar disorder are reported to have an early onset. The peak age of onset is 15 to 19 years with a lifetime prevalence of 1 to 3%. Both sexes are affected equally, although boys are more often affected before the age of 13 years. Bipolar disorder is shown to be a familial disorder especially in early-onset cases and life-time rates are approximately 15% in first-degree relatives. Compared with the adult form, paediatric bipolar disorder may have a prolonged early course and be less responsive to treatment. Mixed features, psychotic symptoms, and/or comorbid behaviours, which are a frequent presentation in children, predict a more refractory response to lithium therapy.3 Premorbid characteristics (e.g. intellectual functioning) strongly predict outcome. Adolescents with bipolar disorder are at increased risk of suicide, especially depressed boys. Fifty percent of children with major depression and 90% with mania continue to have adult recurrences. Differential diagnosis and comorbidity ADHD is commonly associated with paediatric bipolar disorder, with those with a history of stimulant exposure being reported to have an earlier age at onset of paediatric bipolar disorder than those without prior stimulant exposure.4 It has been suggested that ADHD treatment with anti-ADHD agents is efficacious only after mood stabilization.5 Elation, grandiosity, hypersexuality, decreased need for sleep, with increased goal directed activity, high energy levels and psychotic symptoms appear to differentiate paediatric bipolar disorder from ADHD. Paediatric bipolar disorder is suspected if: • ADHD symptoms are absent in early years (before 7 years) • symptoms occur episodically and resolve without treatment • symptoms that were well controlled become suddenly worse for no reason and continue to be resistant to usual treatment • unexplained increase of ADHD symptoms at particular times of day (e.g. evening worsening not related to medication). • stimulant-induced worsening of behaviour, especially increasing mood lability and explosive behaviour. Longitudinal follow-up often helps clarify whether paediatric bipolar disorder and ADHD co-exist. Presence of ADHD has implications for
Re-conceptualized model Synthesizing the existing literature and clinical experience it appears that one can view paediatric bipolar disorder as a spectrum disorder, conceptualized as: • a large number of children in whom, since early childhood, impairment results from ‘affective dysregulation’ or ‘developmental disorder of affect regulation’, which may arise due to a developmental delay/disorder, or temperamental characteristic (many cyclothymic or hyperthymic), or neglect • a smaller group who have what could be loosely termed ‘bipolar disorder not otherwise specified (NOS)’, where the subjects have features of bipolar disorder but do not meet the typical criteria for bipolar disorder, especially the duration criteria • at the extreme, a small group who would meet all the DSM-IV criteria for typical ‘bipolar disorder’. Apart from this, many children will have some affective dysregulation without impairment. Instead of paediatric bipolar disorder
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treatment; use of stimulants in the absence of mood stabilization can lead to rapid cycling of paediatric bipolar disorder. Bipolar depression is often misdiagnosed as unipolar depression. Eliciting information about past hypomania or mania from a depressed patient may be extremely difficult. In some cases, the presenting depression is the index episode of bipolar disorder, so there will be no hypomania or mania to elicit. Twenty to thirty percent of youth with major depressive disorder go on to have manic episodes. Risk factors predicting mania include a depressive episode characterized by rapid onset, presence of psychomotor retardation, psychotic symptoms, a family history of mood disorders, a history of antidepressant-induced mania or hypomania, and a history of ADHD with affective instability. Unfortunately, the ramifications of a missed diagnosis can be severe. Patients whose disease is incorrectly assessed as unipolar depression are likely to be prescribed antidepressant monotherapy, which can cause mood destabilization; this has been reported to occur in approximately 25% to 40% of patients with bipolar disorder.6 Misdiagnosis may also lead to delayed initiation of a mood stabilizer – this may increase the risk of suicide, impair psychosocial functioning, and reduce the likelihood of a response to lithium.7,8 Schizophrenia – bipolar disorder with onset during adolescence commonly presents with ‘schizophrenic-like’ symptoms and, in the past, has been misdiagnosed as schizophrenia in up to 50% of cases. Factors that favour a diagnosis of schizophrenia include premorbid schizotypal personality, family history of schizophrenia, and early-onset psychosis. Schizoaffective disorder – there must be at least a 2-week period where hallucinations and delusions persist without mood symptoms while mood symptoms must be present for a substantial portion of the overall illness. Agitated depression may be confused with a mixed episode due to symptoms of increased psychomotor activity and anxiety. Post-traumatic stress disorder (PTSD) the presence of significant trauma, hypervigilance, flashbacks and high arousal help differentiate PTSD. Borderline personality disorder – adolescents with affective instability, poor impulse control and erratic behaviours may be misdiagnosed as bipolar disorder. Organic mood disorders – neurological disorders (e.g. brain tumours, temporal lobe seizures, Kleine-Levin syndrome) as well as systemic conditions (e.g. hyperthyroidism, uraemia, porphyria) can all present with symptoms of mania. Also, prescribed medications (e.g. antidepressants, sympathomimetics, steroids) and substances of abuse (e.g. cocaine, ecstasy) can induce mania.1
monitoring arrangements are among the many difficult issues for those with paediatric bipolar disorder and those caring for them, and management by a specialist is essential. In acute illness, the patient can progress through the stages of mania and then depression, before recovery. Multiple changes to drug therapy are unnecessary and a minimum of four to six weeks of therapeutic blood level and an adequate dose for each medication trial (eight weeks for lithium) is recommended for assessing effectiveness before switching medication. Figure 1 provides the treatment algorithms for acute-phase bipolar disorder with and without features of psychosis. It is important to emphasize that these algorithms are only guidelines that have been arrived at by the consensus group and not necessarily backed up by the best evidence base, as very little is available in this area.2
Treatment algorithm for acute phase of bipolar I disorder, manic or mixed episodes Without features of psychosis • Stage 1: monotherapy with either a mood stabilizer (e.g. valproate, carbamazepine, lamotrigine, lithium), or an atypical antipsychotic (e.g. risperidone, olanzapine, quetiapine). • Stage 2: if there is no response, then switch to another drug (either mood stabilizer or atypical antipsychotic). • Stage 3: if there is no response, then switch monotherapy agent to a drug class not tried in stage 1 or 2. • Stage 4a: if no response, combine an atypical antipsychotic with a mood stabilizer. • Stage 4b: if no response, combine two mood stabilizers and an atypical antipsychotic. • Stage 5: if no response, try alternate monotherapy with aripiprazole, oxcarbazepine or ziprazidone. • Stage 6: if these strategies fail, then clozapine or ECT (in adolescents) may be considered. It is increasingly accepted that clinicians may choose to try an alternate monotherapy, with aripiprazole, oxcarbazepine or • ziprazidone before combining two mood stabilizers and an atypical antipsychotic or before considering clozapine. Partial response at any stage is managed by combining a mood stabilizer and an atypical antipsychotic (add drug from class not being used). With features of psychosis • Stage 1: involves combination of a mood stabilizer (e.g. valproate, carbamazepine, lamotrigine, lithium) and an atypical antipsychotic (e.g. risperidone, quetiapine). • Stage 2: if there is no response, then switch to another mood stabilizer and an atypical antipsychotic. • Stage 3: if there is no response, then switch to a different mood stabilizer and atypical antipsychotic agent. • Stage 4: if no response, a combination treatment of two mood stabilizers (e.g. lithium and valproate) and an atypical antipsychotic is to be tried, and if it fails • Stage 5: a combination of aripiprazole or ziprazidone or oxcarbazepine plus an atypical antipsychotic is to be tried. • Stage 6: if these strategies fail, then ECT (in adolescents) or clozapine may be considered. Partial response at any stage is managed by using a combination of mood stabilizers and atypical antipsychotics.
Treatment guidelines for paediatric bipolar disorder A treatment plan that combines pharmacological and psychological interventions, as well as psychoeducation, is required. The goal of intervention is to ameliorate symptoms and prevent relapse; with the ultimate aim of reducing long-term morbidity and promoting development. Despite the guidelines below, the clinician must make the final judgement regarding a particular treatment plan, using the clinical data presented by the patient. Acute-phase medication: very few clinical trials of drug treatment have been conducted in children and adolescents. As a rule, treatment along the same lines as an adult is accepted practice. Decisions about long-term treatment, adherence to treatment and
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Acute-phase treatment of bipolar depression: treatment options in bipolar depression are especially limited as tricyclic antidepressants are not recommended, and selective serotonin-reuptake inhibitors (SSRIs) (apart from fluoxetine) have been contraindicated by the UK Committee on Safety of Medicine. Non-pharmacological interventions, such as cognitive–behavioural therapy (CBT) and interpersonal therapy (IPT), are recommended for depression in paediatric bipolar disorder, but if all else fails, fluoxetine can be tried, after mood stabilization has been achieved using a mood stabilizer (e.g. lamotrigine, valproate, lithium or carbamazepine). As with adults, it is recommended that an antidepressant medication be continued for at least 8 weeks after depressive symptom remission. Lamotrigine has been shown to have good antidepressant action in bipolar depression. Gabapentin or bupropion may be used to manage anxiety in bipolar disorder, as they will at least not worsen the manic state.
principle of treating ADHD is to obtain mood stabilization, first using a mood stabilizer, and subsequently, if ADHD symptoms persist, using a low dose of stimulant, and monitoring carefully to see whether one can manage the ADHD effectively without worsening the paediatric bipolar disorder. Pervasive developmental disorders (PDD) – patients with paediatric bipolar disorder and PDD should be initially treated with an atypical antipsychotic (e.g. risperidone), and mood stabilizers should be added as necessary. The use of other medication to target other PDD symptoms should be considered, taking into account that some medications may destabilize mood. Patients should be referred to an appropriate PDD programme when available. Migraine or epilepsy – for those with paediatric bipolar disorder and seizures or migraines, the mood stabilizer chosen should be an anti-migraine agent (eg. carbamazepine, valproate). Medication used in paediatric bipolar disorder Anticonvulsant mood stabilizers – indications for use of anticonvulsants include rapid cycling and mixed episodes. Valproate, carbamazepine and lamotrigine are commonly used. Divalproex sodium is frequently used in children and adolescents as a first-line agent for mania. Common side-effects of valproate include sedation, nausea and vomiting. Rare, but potential serious side effects include fatal hepatic toxicity, haematological side-effects and polycystic ovary disease. Transient side-effects of carbamazepine may include drowsiness, dizziness, nausea and mild ataxia. Carbamazepine has been reported to cause agranulocytosis (within 3 months of initiating therapy, although it may occur as late as 5 years after starting treatment) and aplastic anaemia. Leucopenia may occur in children but is not significant unless total white blood count falls below 3000/mm3. Hepatic toxicity and cognitive and behavioural effects including impaired performance on learning and memory tasks, irritability, insomnia and emotional lability rarely occur. Lamotrigine appears to have antidepressant as well as mood-stabilizing properties. Lamotrigine is used to manage depressive symptoms in paediatric bipolar disorder in acute phase as well as at follow up, as a mood stabilizer including in those with rapid cycling, as maintenance treatment, and as a prophylactic agent to decrease depressive episodes. However, serious rash occurs in 1 in 10,000 children taking lamotrigine, and hence the escalation of dose should be very gradual. Serious rashes are more likely to occur between 2 and 8 weeks of treatment and typically involve systemic disturbances, often manifesting with blistering on soft mucocutaneous tissues (e.g. oral-buccal mucosa) or the palms and soles. To reduce the risk of rash, gradual titration of lamotrigine is recommended (e.g. 12.5 mg/day for 2 weeks, followed by 25 mg/day for 2 weeks, with further gradual dosage increases to 100 mg/day or target dose). Starting doses should be adjusted downward for patients on cytochrome P450 inhibitors and upward for patients on inducing agents. Oxcarbazepine is a promising agent for acute mania in adults, but no data is available in childhood. Atypical antipsychotics – weight gain and possibility of metabolic syndrome (hyperglycaemia and hypercholesterolaemia) are risks with all atypical antipsychotics and require monitoring. Clozapine, olanzapine, risperidone, amisulpiride, quetiapine, aripiprazole and ziprazidone gives the drugs in descending order of potential to increase weight. Hyperprolactinaemia is especially a problem with risperidone. Clozapine should not be combined
Treatment of maintenance and continuation phases: it is generally accepted that treatment with a maintenance agent should continue for at least 18 months after stabilization of a manic episode. However, there are no clear answers to definitively inform clinicians regarding how long treatment should continue. It is generally suggested that treatment should continue for a minimum of 12 to 24 consecutive months after achieving symptom remission. Recently, lithium and valproate were reported to be equally effective in maintenance treatment.9 The risk associated with the potential relapse should be compared with the risk associated with continued pharmacotherapy. Treatment discontinuation should be attempted with great caution in those with a history of suicidal behaviour, severe aggression, and/or psychosis. Many patients may need long-term or even life-long pharmacotherapy. Special considerations Rapid cycling affective disorder – up to half of all adult patients with bipolar disorder develop rapid cycling at some point. This is sometimes triggered or worsened by the use of antidepressants, which should be stopped if rapid cycling develops. Patients should be assessed for alcohol and substance misuse, thyroid dysfunction, and temporal lobe epilepsy, use of prescription drugs (e.g. steroids and certain antibiotics). Anticonvulsant mood stabilizers are recommended as first-line treatment, but in practice, many children and adolescents will require a combination of drugs. Suicide – suicide prevention is a critical objective in the treatment of bipolar disorder.10 Suicide attempts are highly prevalent in bipolar patients and are related to drug abuse, family history of affective disorders, and severe depressive episodes. Problemsolving strategies combined with intensive rehearsal of cognitive, social, emotional labelling, and distress-tolerance skills have been found to be effective therapeutic strategies.11 Treatment of comorbid psychiatric disorders Before treating the comorbid disorder, it is important to first stabilize the symptoms of bipolar disorder. If the symptoms of the comorbidity are negatively affecting the child’s psychosocial or academic functioning, then treatment is warranted. Whenever appropriate, using psychosocial therapies to treat co-existing disorders is recommended (e.g. using CBT to manage depression). ADHD – medications used to treat ADHD can lead to rapid cycling if mood stabilization has not already been achieved. The
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Conclusions Paediatric bipolar disorder is a severe and complex illness that seriously disrupts the lives of those afflicted. However there has been confusion because paediatric bipolar disorder is a very heterogeneous condition as currently conceptualized. This review suggests that paediatric bipolar disorder can be viewed as a spectrum, with ‘developmental disorder of affect regulation’ at one end and typical bipolar disorder (fulfilling all DSM-IV criteria) at the other, with the majority of those currently being diagnosed as paediatric bipolar disorder lying in between. Although the early course of paediatric bipolar disorder in adolescents is more chronic and refractory to treatment, the long-term prognosis is probably similar to that of adults. Guidelines and algorithms for treatment of paediatric bipolar disorder have emerged through expert consensus rather than an evidence base, the lack of which needs to be rectified urgently through well-planned studies with the phenotype being clearly specified.
with Carbamazepine because of the risk of agranulocytosis. Aripiprazole and ziprazidone are promising agents for acute mania in adults, but no data is available in childhood. Lithium has been shown to be effective for treatment of acute mania and depressive episodes, prevention of recurrent mania and depressive episodes and reduction of mood instability between episodes. Although lithium has been found to be effective for paediatric bipolar disorder, the overall response may be less than that of adults. However, a recent study shows that it is as effective as valproate.9 Children have a higher glomerular filtration rate than adults and since lithium is excreted almost entirely by the kidneys, the required therapeutic dose may need to be higher in this age group. The recommended therapeutic serum levels for the acute phase range from 0.6 to 1.2 mEq/L, and for prophylaxis 0.4 to 0.8 mEq/L. Lithium levels should be monitored regularly. Younger children are more prone to side-effects than older children. Sideeffects include nausea, diarrhoea, vomiting, tremor, weight gain, headache, polyuria, polydipsia, enuresis, fatigue, ataxia, hypothyroidism, goitres, and reversible diabetes insipidus. Lithium toxicity manifests with tremors, ataxia, vomiting and other neurological symptoms and requires emergency treatment. Benzodiazepines are useful for acute agitated manic states particularly in conjunction with anti-manic agents (atypical antipsychotics, lithium or anticonvulsants). However, their long term use should be discouraged, due to potential dependency problems. Omega-3 fatty acid has been shown to be of benefit as an adjunct in adults with bipolar disorder. Electroconvulsive therapy (ECT) is the treatment of choice for bipolar disorder in pregnancy, catatonia, neuroleptic malignant syndrome and any other condition where standard medication is contraindicated. Case reports indicate that ECT is beneficial for children and adolescents with paediatric bipolar disorder.
REFERENCES 1 McClellan J, Werry J S, Ayres W et al. Practise parameters for the assessment and treatment of children and adolescents with bipolar disorder. J Am Acad Child Adolesc Psychiatry 1997; 36: 157S–176S. 2 Kowatch R A, Fristad M, Birmaher B, Wagner K D, Findling R L, Hellander M. Child psychiatric workgroup on bipolar disorder. Treatment guidelines for children and adolescents with bipolar disorder. J Am Acad Child Adolesc Psychiatry 2005; 44: 213–35. 3 Carlson G A, Bromet E J, Driessens C, Mojtabai R, Schwartz J E. Age at onset, childhood psychopathology, and 2-year outcome in psychotic bipolar disorder. Am J Psychiatry 2002; 59: 307–9. 4 DelBello M P, Soutullo C A, Hendricks W, Niemeier R T, McElroy S L, Strakowski S M. Prior stimulant treatment in adolescents with bipolar disorder: association with age at onset. Bipolar Disord 2001; 3: 53–7. 5 Biederman J. Resolved: mania is mistaken for ADHD in prepubertal children. J Am Acad Child Adolesc Psychiatry 1998; 37: 1091–9. 6 Goldberg J F, Truman C J. Antidepressant-induced mania: an overview of current controversies. Bipolar Disor 2003; 5: 407–20. 7 Goldberg J F, Ernst C L. Features associated with the delayed initiation of mood stabilizers at illness onset in bipolar disorder. J Clin Psychiatry 2002; 63: 985–91. 8 Franchini L, Zanardi R, Smeraldi E, Gasperini M. Early onset of lithium prophylaxis as a predictor of good long-term outcome. Eur Arch Psychiatry Clin Neurosci 1999; 249: 227–30. 9 Findling R L, McNamara N K, Youngstrom E A et al. Double-blind 18month trial of lithium versus divalproex maintenance treatment in pediatric bipolar disorder. J Am Acad Child Adolesc Psychiatry 2005; 44: 409–17. 10 Sachs G S, Yan L J, Swann A C, Allen M H. Integration of suicide prevention into outpatient management of bipolar disorder. J Clin Psychiatry 2001; 62: 3–11. 11 Gray S M, Otto M W. Psychosocial approaches to suicide prevention: applications to patients with bipolar disorder. J Clin Psychiatry 2001; 62: 56–64. 12 Mackinow-Koons B, Fristad M A. Children with bipolar disorder: how to break down barriers and work effectively together. Prof Psychol 2004; 35: 481–4. 13 Rosenfarb I S, Miklowitz D J, Goldstein M J, Harmon L, Nuechterlein K H, Rea M M. Family transactions and relapse in bipolar disorder. Fam Process 2001; 40: 5–14.
Psychoeducation/psychosocial treatments While drug therapy is crucial, support and education for the patient and carers and psychological therapy are integral for optimizing outcomes in paediatric bipolar disorder. In the process of diagnosing the child, clinicians frequently discover untreated, and sometimes undiagnosed, mood disorders or other conditions in immediate family members. Referring these individuals for treatment can greatly reduce stress in the household, thereby providing more resources for managing the child’s bipolar disorder. The families need to become educated about bipolar disorder and its effects on the family regarding the nature of the disorder, treatment options, potential impact on psychosocial and family functioning and heritability; relapse prevention that aims at education on impact of non-compliance with medication, early recognition of relapse symptoms and other factors that promote relapse. The willingness of the patient to adhere to the regimen and monitoring, the availability of support from family and friends, and factors such as stress, sleep disruption, or misuse of alcohol or drugs should also be identified and managed. When psychosocial therapies are being used, it is important for the therapist to have good working knowledge of paediatric bipolar disorder and other childhood psychiatric disorders, otherwise it is very easy to fall into therapeutic traps (e.g. being disappointed when a behavioural plan backfires and the child becomes manic).12 A bi-directional, interactional relationship between patients’ symptoms and relatives’ coping style seems to capture best the role of the family in predicting relapse.13
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