Until relatively recently, the concept of diagnosing bipolar affective disorder in children and adolescents was controversial. The prevailing wisdom in the early part of this century was that prepubertal onset of manic depression did not occur (1). Furthermore, according to some psychoanalytic theories, depression was not possible in children because of a lack of the development of necessary psychological structures. Over the past 20 years, there has been a significant shift toward recognizing the existence of bipolar disorder in children and adolescents. Since 1980, the Diagnostic and Statistical Manual of Mental Disorders, Third Edition: DSM-III, (2), the Diagnostic and Statistical Manual of Mental Disorders, Third Edition, Revised: DSM-III-R (3), and the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition: DSM-IV (4) have applied adult criteria to diagnose mania in children, with some modifications to take into account differences in developmental stages (5). Despite the recognition of the existence of bipolar disorder in this age group, difficulty in clearly delineating the clinical characteristics of the presentation of this illness in paediatric patients relative to adult patients continues (6).
There also exists a debate about the relationship between attention deficit/hyperactivity disorder (ADHD) and bipolar disorder in the paediatric population (7). This debate reflects the difficulty in distinguishing bipolar disorder from other psychiatric disorders. Bipolar disorder has been reported to be underdiagnosed and misdiagnosed (8). These diagnostic difficulties are of clinical significance because it is critically important to diagnose this disorder as early as possible to prevent the clinical sequelae that occur with untreated bipolar disorder (9). The recognition of the deficiency in clinical knowledge in diagnosing bipolar disorder has prompted the initiation of research to delineate the epidemiology of this illness, its phenomenology in paediatric patients, clinical course and the outcome of various treatment modalities.
To date, no comprehensive epidemiological study had been conducted to determine the prevalence of paediatric bipolar disorder. Prepubertal onset of mania as defined by DSM-IV (4) is estimated to be rare. If severity and duration criteria are not required for diagnosis, lifetime prevalence estimates rise significantly (10). Thus, when reading the literature, it is important to notice that DSMIII-Revised (3) removed the duration criteria, and, consequently, prevalence estimates using these criteria are substantially higher than those using either DSM-III (2) or DSM-IV (4). The studies that have been conducted, taken together with information gathered from other sources, suggest that the rate of paediatric bipolar disorder is on the rise (6).
The types of studies that have been reported essentially consist of retrospective reporting or local, community-based surveys. Lish et al (11) conducted a retrospective survey of adult patients with bipolar disorder and asked them to report at what age their symptoms began. Fifty-nine per cent of these adults reported that they had the onset of their symptoms in childhood or adolescence. In a local, community-based school survey of adolescents aged 14 to 18 years, Lewinsohn et al (12) found a combined lifetime prevalence rate of approximately 0.8% for bipolar types I and II, with 85% of these adolescents having had bipolar type II. For the patients with bipolar disorder, initial episodes of illness were generally reported to be depression (11), with a relatively high rate of patients (approximately 30%) ‘switching’ to mania during the episode (13,14). In comparison, the lifetime prevalence of adult bipolar disorder (including both types I and II) is approximately 1.4% of the general population.
There appear to be neurodevelopmental antecedents to paediatric bipolar disorder. Sigurdsson et al (15) found that patients with bipolar disorder (compared with those with depression alone) are more likely to have experienced delayed language, social or motor development. As well, patients with paediatric bipolar disorder often have initial manifestations of ADHD and/or conduct disorder (16-18). However, studies have found that, in general, over 90% of patients with paediatric bipolar disorder have normal intelligence quotients (13,16).
The diagnosis of child and adolescent bipolar disorder is complex, and there is substantial uncertainty and disagreement among child and adolescent psychiatrists as to what constitutes its diagnostic criteria (6,7). This diagnostic uncertainty is especially true for patients with prepubertal symptomatology. There are many factors to consider in identifying symptoms and making a diagnosis. The importance of an accurate diagnosis is profound given the consequences of either making a falsely positive diagnosis or missing the diagnosis. An incorrect diagnosis of bipolar disorder can lead to the long term use of medications for which the long-lasting effects on the central nervous system are unknown. However, the lack of treatment of individuals with bipolar disorder may substantially worsen their prognosis (9).
One of the major reasons for difficulties in clearly delineating the clinical characteristics of paediatric bipolar disorder is that the symptoms of the disorder may manifest themselves differently according to the developmental stage of the patient. DSM-IV (4) identifies two types of bipolar disorders. Type I involves patients who have had at least one manic (Table 1) or mixed episode. A mixed episode occurs when a patient meets criteria over a oneweek period for both a manic episode and a major depressive episode (Table 1). Type II involves patients who have had at least one episode of major depression and one episode of hypomania, but no manic or mixed episodes. The criteria for hypomania are the same as for mania; the difference in diagnosis depends on the duration and severity of the episode. In a hypomanic episode, symptoms must have been present for at least four days (as opposed to seven days for mania) and be a significant change of functioning from the baseline of the patient. However, the episode does not lead to marked deterioration in functioning, a need for hospitalization or psychotic symptoms; if it does, a manic episode is diagnosed. For a bipolar diagnosis to be made, the manic symptoms must not be due to the direct effects of a substance or to a general medical condition (4).
Children and adolescents with bipolar disorder tend to present with what is considered to be atypical features in adults. Mixed features; rapid (more than four episodes per year), ultrarapid (episodes lasting a few days to a few weeks) or ultradian (variation occurring within a 24 h period) cycling; psychotic features; high rates of comorbidity, especially with disruptive behaviour disorders; and significant psychosocial impairment are common (5).
Geller et al (19), in the first controlled phenomenological study of paediatric bipolar disorder, reported on symptom differences between patients with paediatric bipolar disorder and those with ADHD. Patients with bipolar disorder (age seven to 16 years) had symptoms of grandiosity, elated mood, daredevil acts, a flight of ideas, racing thoughts, hypersexuality, a decreased need for sleep, increased goal-directed activity, increased productivity, irritable mood and accelerated speech at statistically significantly greater rates than matched patients with ADHD. There were no significant differences in the symptoms of being hyperenergetic or distractible. Thus, the symptomatology of paediatric bipolar disorder did not differ substantially from adult bipolar symptoms. However, the paediatric bipolar patients tended to present with a chronic, nonepisodic manic episode (average duration three years) that featured very rapid mood swings multiple times per day (ultradian cycling 75%), and 60% of the patients had psychotic symptoms. The study combined pre- and postpubertal patients because there were a limited number of differences between the two groups.
In considering the symptomatology of paediatric bipolar disorder, it is critical to recognize that the symptoms manifest in developmentally appropriate ways. In fact, certain authors have proposed that bipolar disorder presents differently in prepubertal and postpubertal patients. It has been proposed that adolescent onset bipolar disorder more closely resembles adult onset bipolar disorder. However, as described above, in the only controlled phenomenological study of paediatric bipolar disorder, there were no significant differences in the clinical presentations between the two age groups. Nevertheless, although the symptoms are the same, they manifest differently at different ages. For example, grandiose delusions in a child may manifest as continual harassment of teachers about how to teach the class or intentionally failing tests because of the firm belief that the material was taught incorrectly (6). Another example is the sixyear-old child who is restrained by a 99 kg policeman and firmly believes that when the policeman ‘lets go’, he is going to `kick his a- - . Alternatively, an adolescent may express grandiose delusions such as the fixed belief that he is the star of the football team, even though he did not make the starting line-up. Furthermore, hypersexuality is expressed according to the cognitive knowledge of the child. It is the preoccupation with sexuality and not the knowledge level that is characteristic of bipolar disorder.
The differential diagnosis of mania is both extensive and complex, consisting of both psychiatric and nonpsychiatric medical conditions. Nonpsychiatric medical conditions that can present in a similar manner include the following: neurological disorders, such as brain tumours and central nervous system infections (including human immunodeficiency virus), multiple sclerosis, temporal lobe seizures and Kleine-Levin syndrome; systemic conditions such as hyperthyroidism, uremia, Wilson’s disease and porphyria; prescribed medications that lead to bipolar symptoms, including antidepressant agents, sympathomimetics, bromocriptine, stimulants and steroids; and the abuse of substances, including amphetamines, cocaine, phencyclidine, inhalants and 3,4-methylenedioxymethamphetamine (Ecstasy) (1). Consequently, patients presenting with manic symptoms should have a thorough physical examination, including a neurological examination. Decisions regarding further laboratory and neuroimaging examinations should be made based on the clinical findings of the psychiatric, paediatric and neurological examinations (1).
The psychiatric differential diagnosis of manic symptoms varies according to the age of the patient. In children, it is particularly important to ensure that the child is not a victim of sexual abuse (6). This is particularly true if hypersexuality is a part of the clinical presentation. As well, language disorders and disruptive behaviour disorders (ADHD, oppositional-defiant disorder, conduct disorder) are part of the differential diagnosis. As described above, Geller et al’s study (19) has begun to delineate the hallmark symptomatology of paediatric bipolar disorder such that distinction between these diagnostic entities should, hopefully, become clearer. The presence of a family history of bipolar disorder in the immediate family is a critical part of considering the diagnosis of prepubertal onset bipolar disorder, and without it, the clinician should be extremely cautious.
In adolescence, with the exception of language disorders, the differential diagnosis includes disorders that are present in childhood, but schizophrenia and substance abuse become more prevalent. Substance abuse is an important part of the differential diagnosis but is also frequently comorbid (20).
Wilens et al (20) found that approximately 40% of patients with adolescent onset bipolar disorder had a comorbid substance use disorder and that their risk for substance abuse was 8.8 times greater than those with childhood onset bipolar disorder. In contrast, conduct disorder appears to be more common in bipolar children than in bipolar adolescents (22% versus 18%, respectively) (21). Finally, multiple comorbid anxiety conditions are more frequent in prepubertal bipolar children than in bipolar adolescents (33% versus 12%, respectively) (21).
To date, there are no systematic follow-up data on preschool or prepubertal school-aged children with bipolar disorder (5). Strober et al (9), in a five-year, prospective, naturalistic follow-up study of 54 adolescents with bipolar disorder who were admitted to an inpatient service, found that 96% recovered from that episode of the illness sometime during the study. Patients with depressive presentations took significantly longer to recover from the episode than those with manic symptoms only. However, 44% of those who recovered during the study experienced a relapse of a major affective disorder during the five years of the study, and 21% had two episodes. Suicide attempts of sufficient severity as to require medical attention occurred in 20% of participants. Interestingly, among study participants (9), substance use disorders were relatively uncommon (9%) in contrast with the studies mentioned above (19,20).
A multimodal treatment plan that combines pharmacological treatments with psychosocial treatments is required (1). The psychosocial treatment consists of psychotherapeutic interventions to address the psychological aspects of bipolar disorder that confound development and biological treatment, and intervention to address the social and culturally relevant consequences of bipolar disorder. This may include the psychoeducation of family and school personnel in the pertinent issues surrounding bipolar disorder, and in particular, addressing the disorder’s symptoms and course, treatment options, and potential impact on peer and family functioning. Relapse prevention discussions on the importance of medication compliance and early recognition of symptoms are also an important part of this aspect of treatment (1,22). The goal of these interventions is to ameliorate symptoms and prevent relapse, while also reducing long term morbidity, and promoting normal growth and development (1).
Before initiating pharmacotherapy for the treatment of bipolar disorder, it is necessary to ensure that an adequate premedication work-up has been performed. This includes obtaining informed consent, and addressing the rationale for treatment, as well as the potential risks and benefits of the treatment (1). Furthermore, before initiating medications and after a thorough psychiatric examination, a physical examination that includes any clinically indicated laboratory studies to provide baseline assessments for monitoring specific medications is warranted (1).
The discussion of pharmacotherapy below focuses on the treatment of mania, and readers are referred to Fleisher and Katz (pages 444 to 448 of the present issue) for a discussion of the treatment of depression. The selection of medications should be based on evidence of efficacy (eg, the Geller et al trial [23, see below] and data from controlled treatment trials of adults with bipolar disorder), the phase of the illness (see below), the presence of confounding presentations (eg, rapid cycling, psychotic symptoms), the agent’s side effect spectrum, the patient’s history of medication response, and the preferences of the patient and family (1). The paucity of controlled trials of medications for child and adolescent bipolar disorder places the clinician in a very difficult position because extrapolation from adult data is not necessarily valid (eg, children and adolescents with major depressive disorder do not necessarily respond to the same antidepressants as adults).
The treatment of bipolar disorder consists of acute symptom stabilization, maintenance treatment and prophylactic treatment. Acute symptom stabilization for manic symptoms varies, depending on whether psychotic features are a part of the presentation. If psychotic symptoms are present, then antipsychotic medications are frequently a part of the initial medication regimen. This regimen is based on studies from the adult literature and juvenile chart reviews (24,25). Other medications that can be considered include anxiolytics (eg, the benzodiazepines), and some authors have reported the use of stimulants to address symptoms of ADHD that may be present. The use of stimulants in the treatment of bipolar disorder remains a highly contentious issue because the diagnosis of ADHD in the presence of bipolar disorder is confounded by collinearity, and, at the present time, there are no controlled outcome studies on the use of stimulants in the presence of bipolar disorder.
Although medications, such as antipsychotics, stimulants and anxiolytics, may be a part of acute symptom stabilization (24,25), mood stabilizers are the mainstays of treatment of paediatric bipolar disorder (26). This is especially true with regard to maintenance and prophylactic treatment. Although a rapidly growing number of medications are available, three mood stabilizers are commonly prescribed. Lithium, valproic acid and carbamazepine have the most experience supporting their use. Gabapentin, lamotrigine and topiramate are on the market, and case reports are beginning to appear. Currently, Geller and colleagues’ study (23) on the use of lithium in adolescents with bipolar disorder and secondary substance dependency is the only controlled study. Geller and colleagues (23) found lithium to be efficacious in reducing substance use (P=0.028) and in improving the overall level of functioning, as assessed on a global assessment of functioning scale (P=0.046). This response occurred in 46% of the treated adolescents. Aside from the study by Geller and colleagues (23), there is a paucity of data examining the efficacy of lithium in early onset bipolar disorder (1,5,27).
There are no placebo controlled trials of anticonvulsant medications for the treatment of bipolar disorder. The use of valproic acid and carbamazepine is supported by the adult literature; case reports and small series support their use in paediatric bipolar disorder. With regard to valproic acid, a number of worrying side effects warrant caution in prescribing this medication for bipolar disorder. In addition to concerns regarding hepatotoxicity and teratogenicity, recent reports suggest a possible association of valproic acid with polycystic ovarian disease and other endocrinological abnormalities in females with seizure disorders (28,29). All of the mood stabilizing medications carry a significant risk with regard to adverse effects, the potential for toxicity and a significant risk of overdose. A thorough review of the case reports and small series data that inform the psychopharmacology of paediatric bipolar disorder is beyond the scope of this review, and the reader is referred elsewhere for more detailed reviews (1,6,23,26,27,30).
Paediatric bipolar disorder is increasingly being recognized as a major health problem that is associated with substantial morbidity and mortality. The evaluation and management of this disorder are multimodal. The early recognition and appropriate management of patients and their families will, hopefully, help to reduce the complications of this chronic disorder. There is a desperate need for further research in almost all aspects of this disorder because there is a paucity of controlled data available for review.
References| Table 1: Criteria for mania and major depression in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Ediditon: DSM-IV (4) | |
| Mania episode | Major depressive episode |
More than a one-week period of an elevated, irritable or expansive mood that represents a significant change in the patient's baseline mental status accompanied by at least three of the following symptome:
|
More than a two-week period characterized by a depressed or irritable mood, or diminished interest or loss of pleasure in most activities accompanied by at least four of the following:
|