Treatment Guidelines


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Treatment Guidelines

  1. 1. Practice Parameters for the Assessment and Treatment of Children and Adolescents With Bipolar Disorder Reprinted with permission of the American Academy of Child & Adolescent Psychiatry andLipincott Williams & Wilkins, publishers. 1. Abstract, including: Introduction and Historical Review Diagnosis 2. Treatment 3. Practice Parameters 4. References ABSTRACT These practice parameters describe the assessment and treatment of early-onset bipolar disorder based on scientific evidence regarding diagnosis and effective treatment and on the current state of clinical practice. Given the paucity of research on bipolar disorder in children and adolescents, many of the treatment recommendations are drawn from the adult literature. Although the same diagnostic criteria are used as for adults, youth may differ with regard to the developmental presentation of symptoms and comorbid psychiatric disorders. Treatment involves the combination of pharmacotherapy and adjunctive psychosocial interventions. Antimanic agents (primarily lithium or valproic acid) are the mainstays of pharmacotherapy. The treatment focuses on (1) amelioration of acute symptoms; (2) the prevention of relapse; (3) the reduction of long- term morbidity; and (4) the promotion of long-term growth and development. These parameters were approved by Council of the American Academy of Child and Adolescent Psychiatry on June 5, 1996. J. Am. Acad. Child Adolesc. Psychiatry, 1997, 36(l):138-157. Principal Authors: Jon McClellan. M.D., and John Werry, M.D. These parameters were developed by the Work Group on Quality Issues: William Ayres, M.D., and John Dunne, MD., Chairs; Members: Elissa Benedek, M. D., Gail Bernstein, M.D., Richard L. Gross, M.D., Robert King, M. D., Henrietta Leonard, M. D., and William Licamele, M. D. AACAP Staff: Mary Graham, Leslie Seigle, Carolyn A. Heier, Michelle E. Wright, and Diane Wiegand, R. N. A draft of these parameters was distributed to the entire AACAP membership for comments. The parameters were approved by the AACAP Council on June 15, 1996. © 1997 by the American Academy of Child and Adolescent Psychiatry. Republished on the BPSO Public Pages with the permission of the Academy. INTRODUCTION Bipolar disorder was once thought to occur only rarely in youth. However, approximately 20% of all bipolar patients have their first episode during adolescence, with a peak age of onset between 15 and 19 years of age. Developmental variations in presentation, symptomatic overlap with other disorders, and lack of clinician awareness have all led to underdiagnosis or misdiagnosis in children and adolescents. Therefore, clinicians need to be aware of some unique clinical characteristics associated with the early-onset form. HISTORICAL REVIEW
  2. 2. Childhood-onset mania generally went unrecognized over the first part of this century, despite Kraepelin's (1921) observations that mania occurred rarely in children and that the onset of first episodes increased significantly after puberty. Anthony and Scott (1960) reached similar conclusions by using criteria derived from the adult literature to review reported cases of manic- depressive psychosis in children. They established a basis for further research by separating childhood onset from that during adolescence and by applying a criterion-based diagnostic schema to youth (Carlson, 1990). The clinical biases that mania did not occur in adolescents persisted until large-scale studies of bipolar adults indicated that approximately one fifth of cases presented prior to age 19 (Carlson et al., 1977; Winokur et al., 1969). Subsequent studies have confirmed these findings (Joyce, 1984; Loranger and Levine, 1978). Another previously held clinical bias, that schizophrenia was more common in youth, was complicated by the fact that manic adolescents frequently present with psychotic symptoms (McGlashan et al., 1988). Carlson and Strober (1978) reported on six bipolar adolescents originally misdiagnosed as schizophrenic, a diagnostic tendency further noted in subsequent studies (Bashir et al., 1987; Joyce, 1984; McClellan et al., 1993; Werry et al., 1991). Although clinicians have become increasingly aware of the confusion between early-onset bipolar disorder and schizophrenia, bipolar disorder in youth continues to be underrecognized and misdiagnosed (Carlson et al., 1994). Historically considered rare, childhood-onset bipolar disorder is now being reported more often, although its frequency remains an area of some controversy (Carlson, 1990). Further research is needed to establish the specificity of symptoms distinguishing childhood mania from behavior disorders. Furthermore, if severity and duration are not included in the diagnostic criteria, estimated lifetime prevalence rates are greatly increased (Carlson and Kashani, 1988). This is an important issue when reviewing the literature since DSM-III-R (APA, 1987) removed the 7-day duration requirement specified in DSM-III (APA, 1980). Thus, studies reporting on early-onset mania using DSM-III-R (APA, 1987) criteria may have overdiagnosed mania. With DSM-IV (APA, 1994b) the 7-day duration criterion has been reinstituted, and a severity requirement has been added. The existing research examining early-onset bipolar disorder is limited. Methodological problems include small sample sizes, lack of comparison groups, retrospective designs, and tack of standardized measures. More research is clearly needed in all aspects of this disorder but especially in examining the efficacy of various modes of treatment, longitudinal course, and diagnostic issues. Given these limitations, some of the information presented in this review had to be drawn from the adult literature. When discussing aspects of the disorder in relation to age of onset, we refer to early onset as prior to 18 years of age and very early onset as prior to 13 years of age. The literature has referred to the latter group as prepubescent but often on the basis of age rather than actual physiological development. DIAGNOSIS Children and adolescents are diagnosed with bipolar disorder based onthe same criteria used for adults as outlined in DSM-IV (American Psychiatric Association [APA], 1994b). The existing data are sufficient to suggest that bipolar disorder with onset before the age of 18 years is essentially the same disorder as that in adults, but further studies are needed to clarify the long-term course and outcome of the early-onset forms, especially for those with very early onset. The following definitions should be used: I. Manic Episode. A manic episode, the hallmark feature of this disorder, is described by the following DSM-IV (APA, 1994b) criteria:
  3. 3. A. A distinct period of abnormally and persistently elevated, expansive, and/or irritable mood. This represents a significant change in the patient's baseline mental status, and must last for at least 1 week (or any duration if hospitalization is necessary). B. During the period of mood disturbance, the patient must display at least three (four if the mood is only irritable) of the following symptoms: grandiosity, decreased sleep, pressured speech, racing thoughts, distractibility, increased goal-directed activity, and/or excessive involvement in reckless activities. C. The mood disturbance is not part of a mixed manic-depressive episode, which is diagnosed separately. D. The mood disturbance must cause marked impairment in occupational/social functioning. This may include the need for hospitalization or the presence of psychotic symptoms. E. The symptoms are not due to the direct effects of a substance (e.g., drug abuse, antidepressant medications) or to a general medical condition. II. Mixed Episode. A mixed episode is diagnosed when the patient meets criteria for both a manic episode and a major depressive episode over at least a 1-week period. The requirement for significant impairment and the exclusion of organic causes are the same as for a manic episode. III. Hypomanic Episode. A hypomanic episode has similar symptoms as a manic episode but differs in the severity and duration criteria. The symptoms must be present for at least 4 days and must produce an unequivocal change in the patient's functioning that is observable by others. However, by definition, there is no marked deterioration in functioning, need for hospitalization, or psychotic symptoms; otherwise, a manic episode is diagnosed. DSM-IV (APA, 1994b) has outlined several subtypes of bipolar disorder, including: 1. Bipolar I Disorder. To have bipolar I disorder, the patient must have experienced at least one manic or mixed episode. 2. Bipolar II Disorder. Patients with bipolar II disorder have had one or more episodes of both major depression and hypomania, but no manic or mixed episodes. 3. Cyclothymic Disorder. For children and adolescents, cyclothymia is described as periods of 1 year or more (2 years or more for adults) where there are numerous hypomanic and 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 (no more than 2 consecutive months symptom-free) and must cause clinically significant distress or impairment of functioning. COURSE SPECIFIERS Whether there is either a seasonal pattern or rapid cycling should be specified for both bipolar I and II. A seasonal pattern represents a course of illness where the major depressive episodes occur consistently at a particular time of year. Rapid cycling is diagnosed when the patient has at least four episodes of a mood disturbance (major depression, mania, mixed, or hypomania) over a 12-month period. EXCLUSION CRITERIA None of the above three disorders is diagnosed if the symptoms are either better accounted for, or superimposed on, schizoaffective disorder, schizophrenia, schizophreniform disorder, delusional disorder, or a psychotic disorder not otherwise specified. DIAGNOSTIC ISSUES
  4. 4. The diagnostic assessment needs to incorporate both current and past history regarding symptomatic presentation, treatment response, and psychosocial stressors. Cross-cultural issues may influence the expression or interpretation of symptoms and/or treatment response; therefore, they must be assessed (APA, 1994a). It is helpful to organize the clinical information using a life chart to characterize the course of illness, patterns of episodes, severity, and treatment response (APA, 1994a). Using such a longitudinal perspective to conceptualize the disorder helps with diagnostic accuracy, since the presenting symptoms during the acute phases often can be confused with other disorders. Similarly, it is important to recognize the various phases and patterns of episodes associated with bipolar disorder. Youth may first present with either manic or depressive episodes. Twenty to thirty percent of youth with major depressions go on to have manic episodes (Geller et al., 1994; Rao et al., 1995; Strober and Carlson, 1982). Risk factors predicting eventual mania include: (1) a depressive episode characterized by rapid onset, psychomotor retardation, and psychotic features; (2) a family history of affective disorders, especially bipolar disorder; and (3) a history of mania or hypomania after treatment with antidepressants (Strober and Carlson, 1982). The same risk factors are also noted in the adult literature (Goodwin and Jamison, 1990). Similarly, psychotic depression, a family history of bipolar disorder, and a history of attention-deficit hyperactive disorder (ADHD) with associated affective instability are factors associated with youth switching to mania on antidepressant therapy (Venkataraman et al., 1992). In children with major depressive disorder, Geller et al. (1994) found that 31.7% (n = 25) went on to develop either mania or hypomania; 80 percent of them were 12 years old or younger (mean age 11.1 years) at the time of onset. Neither exposure to antidepressants, nor atypical features, were predictive in this sample. In studies of adults, characteristic stages of mania have been described: stage I includes euphoria, increased psychomotor activity, and mood lability. This evolves into stage II, with symptoms of irritability, racing thoughts, dysphoria, and disorganization. Finally, in stage III, the patient's cognitive status deteriorates, with significant confusion and florid psychosis (Carlson and Goodwin, 1973). Significant depressive symptoms may either precede, occur conjointly (mixed episodes), and/or follow those of mania within the same episode. Depressive episodes in bipolar disorder are typically characterized by psychomotor retardation and hypersomnia, significant suicide attempts, and often psychotic symptoms (Goodwin and Jamison, 1990). Severe cases may progress to catatonia. Children with mania frequently present with symptoms that are considered a typical (Bowring and Kovacs, 1992). The changes noted in mood, level of psychomotor agitation, and mental excitement are often markedly labile and erratic, rather than persistent. Irritability, belligerence, and mixed manic-depressive features are more common than euphoria. The types of reckless behaviors seen are constrained by the child's developmental and social boundaries, and thereby limited to typical childhood behavior problems, such as school failure, fighting, dangerous play, and inappropriate sexualized activity. Thus, hallmark manic symptoms, such as grandiosity, psychomotor agitation, and reckless behavior, must be differentiated from those of other more common childhood disorders, as well as from the normal childhood phenomena of boasting, imaginary play, overactivity, and youthful indiscretions. The incidence and validity of the diagnosis in children remains controversial (Carlson, 1990). Dating back to Kraepelin (1921), large surveys have found that onset prior to age 10 occurs in only 0.3% to 0.5% of bipolar patients (Goodwin and Jamison, 1990; Kraepelin, 1921; Loranger and Levine, 1978). Since the estimated lifetime prevalence in the general population is 0.8% (APA, 1994a), it has generally been accepted that childhood-onset bipolar disorder is rare. However, more recent case reports question these estimates, noting that many seriously emotionally disturbed children meet criteria for mania by virtue of their problems with irritability, emotional lability, increased energy and reckless/dangerous behaviors (Weller et al., 1986b; Wozniak et al., 1995). These symptoms, which often have a chronic and, at times, rapidly
  5. 5. fluctuating course, may represent the child's baseline state, rather than a marked change in functioning (Wozniak et al., 1995). Such presentations differ from the episodic course classically ascribed to the illness and are more typical of childhood behavioral disorders (Bowring and Kovacs, 1992). Further research is needed to clarify whether these reflect "true cases" of mania, or are, rather, a nonspecific collection of behavioral and emotional difficulties. Of particular importance will be longitudinal studies following these youth into adolescence/adulthood to determine if their symptoms evolve into the more typical presentation of the disorder (Goodwin and Jamison, 1990). Adolescents with mania frequently have complicated presentations, including: (1) psychotic symptoms, including mood-incongruent hallucinations, paranoia, and marked thought disorder; (2) markedly labile moods, with mixed manic and depressive features; and (3) severe deterioration in their behavior (Akiskal et al., 1985; Goodwin and Jamison, 1990). These varying presentations have led to underdiagnosis of bipolar disorder in teenagers (Carlson et al., 1994), including very high rates of misdiagnosis as schizophrenia (Carlson, 1990; McClellan et al., 1993; Werry et al., 1991). Although the early course of bipolar disorder in adolescents is often more chronic and refractory to treatment, the long-term prognosis is probably similar to that of adults (Carlson, 1990; McClellan et al., 1993; McGlashan, 1988; Werry et al., 1991). A diagnosis of bipolar disorder should be considered for any youth with a marked deterioration in functioning associated with either mood or psychotic symptoms. Since diagnostic accuracy does improve if DSM criteria are reliably applied (Carlson et al., 1994), using the available structured and semistructured diagnostic interviews may be warranted. However, even with these instruments, there is still a risk of overdiagnosis in youth with conduct disorder and ADHD (Weller et al., 1995). The Mania Rating Scale (Fristad et al., 1992) and subscales on the Child Behavior Checklist (Achenbach and Edelbrock, 1983; Biederman et al., 1995) have been used to distinguish manic children from those with ADHD. DIFFERENTIAL DIAGNOSIS Youth presenting with symptoms suggestive of bipolar disorder need to have a thorough psychiatric evaluation, including any necessary pediatric and neurological assessments. In this section, we highlight the most pertinent diagnostic conditions that need to be considered. Schizophrenia. Early-onset bipolar disorder is frequently misdiagnosed (rates of 50% or more) as schizophrenia, especially in patients with onset during adolescence (Carlson, 1990; McClellan et al., 1993; Werry et al., 1991). Adolescents with mania more often have "schizophrenic-like" symptoms (i.e., hallucinations and delusions), and are more likely to be diagnosed as having schizophrenia or schizoaffective disorder than patients with adult-onset bipolar disorder (Bashir et al., 1987; McGlashan, 1988). Using standardized diagnostic techniques improves accuracy, although differentiation can still be problematic (Carlson et al., 1994). Schizoaffective Disorder. The diagnosis of schizoaffective disorder requires a period of illness in which the patient has both a significant mood disorder (either major depression, mania, or a mixed episode) and psychotic symptoms fulfilling the requirements for schizophrenia (APA, 1994b). During the same period of illness, there also must be at least a 2-week period where hallucinations and delusions persist in the absence of predominant mood symptoms. Finally, the mood symptoms must be present for a substantial portion of the overall illness. Schizoaffective disorder has not been well defined in youth. Eggers (1989) found that 28% of patients with early-onset schizophrenia had schizoaffective psychoses at follow-up. This is an ICD-9 diagnosis that overlaps with DSM-III-R (APA, 1987) diagnoses of bipolar disorder and schizoaffective disorder. Other follow-up studies of psychotic youth have found that the diagnosis
  6. 6. of schizoaffective disorder was made infrequently, was associated with the most severe impairment, and was somewhat unreliable (McClellan et al., 1993; Werry et al., 1991). Agitated Depression. An agitated depression may be confused with a mixed episode due to symptoms of increased psychomotor activity and anxiety. Ratings of manic symptoms have been used to differentiate the two conditions in adults (Swann et al., 1993). Conversely, patients with agitated depressions may eventually develop bipolar disorder. Posttraumatic Stress Disorder. Youth with significant histories of trauma, including childhood maltreatment, often present with mood instability, hypervigilance, irritability, dissociative symptoms, and sleep disturbances. These symptoms may be confused with mania/mixed episodes. Some youth will have both disorders (Borchardt and Bernstein, 1995). Borderline Personality Disorder. The affective instability, poor impulse control, and erratic behaviors associated with borderline personality disorder may be misdiagnosed as bipolar disorder. To differentiate, the traits of a personality disorder should be pervasive and persistent, whereas the symptoms of bipolar disorder represent a marked change in the patient's baseline mental status and global functioning. However, patients with bipolar disorder may have chronic symptoms of irritability, cyclothymia, and/or dysthymia, and are, therefore, at risk of being misdiagnosed as borderline (Akiskal, 1981). Some youth may have both (Kutcher et al., 1990). An additional problem is that a diagnosis of borderline personality disorder in adolescents may lack specificity (Garnet et al., 1994). Childhood Disruptive Behavioral Disorders. The impulsivity, hyperactivity and irritability of ADHD or the antisocial and provocative behaviors of conduct disorder may all be confused with mania. Many of the symptoms overlap, including aggression, school failure, psychomotor agitation, restless sleep, distractibility, and sexually inappropriate behaviors. Although historically, mania was undoubtedly underdiagnosed in youth felt to be behaviorally disordered, the increased recognition of the phenomenon may now be leading to overdiagnosis, especially in preadolescents. Adding to this confusion is the fact that many youth with bipolar disorder have comorbid ADHD and/or conduct disorder (Carlson, 1990). However, the reverse does [not (bpso ed.)] seem to be true, since longitudinal follow-up studies of ADHD have not shown an increased ncidence of bipolar disorder (Gittelman et al., 1985). Finally, Wozniak et al. (1994) found that first- degree relatives of children who meet DSM-III-R (APA, 1987) criteria for mania (94% also had ADHD) had high rates of both ADHD and bipolar disorder, and relatives of children with only ADHD had high rates of ADHD but not bipolar disorder. Differentiating between these conditions can usually be done via history and mental status examination (Bowring and Kovacs, 1992). Both ADHD and conduct disorder are chronic persistent disorders of impulse control and behavioral regulation, and they represent stable patterns of functioning. ADHD begins before age 7 and may evolve into conduct disorder during late childhood or early adolescence. Bipolar disorder is usually episodic, with onset usually after age 12. It is a disorder of affect regulation characterized by abnormal mood and mental excitement usually presenting as a marked change in a youth's baseline functioning. Cross-Cultural Issues and Culture-Bound Syndromes. Ethnic minorities and individuals from lower socioeconomic settings have had a greater risk of misdiagnosis of schizophrenia (Goodwin and Jamison, 1990). Ki1gus et al. (1995) found that psychiatrically hospitalized African-American adolescents were more often diagnosed with organic/psychotic disorders and less often diagnosed with affective/anxiety disorders than Caucasian teenagers. Culture-bound syndromes represent recurrent patterns of maladaptive behaviors and/or troubling experiences specifically associated with different cultures or localities (APA, 1994b). Clinicians should refer to DSM-IV for a glossary of the best-studied culture-bound syndromes (APA, 1994b).
  7. 7. These syndromes may be confused with bipolar disorder, and in many cases, the clinician will need to obtain consultation from a professional familiar with the particular cultural issues involved. Mood Disorder Due to a Medical Condition. Symptoms of mania can be produced by a variety of different medical conditions (Cummings, 1985), including: (1) neurological disorders, such as brain tumors and CNS infections, including human immunodeficiency virus (HIV), multiple sclerosis, temporal lobe seizures, and Klein-Levin syndrome; (2) systemic conditions, such as hyperthyroidism, uremia, Wilson's disease, and porphyra; (3) prescribed medications, including antidepressant agents, sympathomimetics, bromocriptine, stimulants, and steroids; and (4) substances of abuse, including amphetamines, cocaine, phencyclidine, inhalants, and methylenedioxymethamphetamine (ecstasy). Youth presenting with manic symptoms need to have a thorough physical evaluation. Decisions regarding more extensive laboratory and neuroimaging studies should be made based on the clinical findings of the psychiatric, pediatric, and neurological examinations. ASSOCIATED CLINICAL FEATURES Although the number of studies examining early-onset bipolar disorder is limited, the data are sufficient to outline some of the associated features of the disorder: Prevalence and Age of Onset. Epidemiological surveys of childhood psychiatric disorders have generally not addressed bipolar disorder (Costello, 1989a). A community school survey of older adolescents (14 to 18 years of age) found the lifetime prevalence rate to be approximately 1% (Lewinsohn et al., 1995). Most of the patients identified had bipolar II disorder. An additional 5.7% had subthreshold symptomatology. Carlson and Kashani (1988), in an epidemiological survey of 14- to 16-year-old youth, found that the estimated lifetime prevalence of mania varied from 0.6% to 13.3%, depending on whether duration and severity criteria were applied; for comparison, the lifetime prevalence in adults is estimated to be 0.8% (APA, 1994a). The incidence appears to increase after onset of puberty. Despite anecdotal reports of onset prior to 6 years of age, further research is needed to establish whether such cases represent true bipolar disorder. Subtypes of Bipolar Disorder. Manic symptoms in youth frequently do not persist long enough to meet the 1-week duration criteria required by DSM-IV (APA, 1994b) for a manic episode (Akiskal, 1995; Akiskal et al., 1985; Carlson and Kashani, 1988;Lewinsohn et al., 1995). This is especially true for children. Therefore, youth are more likely to have a diagnosis of either bipolar II or cyclothymic disorder, rather than bipolar I disorder. Children and adolescents may also be more likely than adults to present with rapid-cycling episodes. Geller et al. (1995) found that in 26 patients with early-onset bipolar disorder (ages 7 to 18 years), 81% had a rapid-cycling course. Gender Ratio. 0verall, bipolar disorder affects both sexes equally. However, in studies of early- onset cases, males seem to be more often affected, especially in those with onset before the age of 13 years. Females are more likely overall to have depressive disorders, although for children younger than 12 years of age, boys again appear to be at greater risk (Costello, 1989b). Rapidity of Onset. Studies of the rapidity of onset have found that the majority of youth have either an acute (less than 2 weeks) or subacute (less than 3 months) prodromal course (McClellan et al., 1993; Werry et al., 1991). Premorbid Functioning. Many youth with bipolar disorder have normal premorbid histories. However, preexisting behavioral problems, including ADHD and/or conduct disorder, are also found in a significant number (Carlson, 1990; McClellan et al., 1993; Werry et al., 1991). Premorbid anxiety and emotional problems are also common, including among those whose first affective episode is a depressive disorder. Dysthymic, cyclothymic, or hyperthymic (irritable, driven) temperaments may presage eventual bipolar disorder (Akiskal, 1995).
  8. 8. Intellectual Functioning. Studies have generally reported that over 90% of youth with bipolar disorder have normal IQs (Geller et al., 1994; McClellan et al., 1993; Werry et al., 1991). However, bipolar disorder, including rapid cycling, has been reported in patients with moderate to severe mental retardation, autism, and trisomy 21 (Carlson, 1990). Family History. Bipolar disorder definitely has been shown to be a familial disorder (Rice et al., 1987; Strober, 1992b). The degree of familiarity is increased in early-onset cases, with reported lifetime rates of bipolar disorder of approximately 15% in first-degree relatives (Strober, 1992b; Todd et al., 1993, 1994). Comorbid Conditions. A significant number of youth displays comorbid ADHD and/or conduct disorder (Borchardt and Bernstein, 1995; Carlson, 1990; Kovacs and Pollock, 1995; West et at., 1995). High rates of substance abuse are also noted in some samples (Borchardt and Bernstein, 1995; Carlson, 1990; McClellan et al., 1993). The presence of comorbid behavioral disorders and/ or substance abuse negatively influences prognosis and treatment response (Carlson, 1990; Kovacs and Pollock, 1995; Strober, 1992a). Course and Prognosis. In adults, bipolar disorder is generally an episodic disorder with a variable course (APA, 1994a). The majority of patients will have multiple episodes, usually 10 or more in untreated patients (Goodwin and Jamison, 1990). Episodes tend to come more frequently over time, until the cycle length stabilizes after the fourth or fifth episode (Goodwin and Jamison, 1990). In a 5-year naturalistic prospective follow-up study of 54 adolescents with bipolar disorder, two patients never achieved complete remission (Strober et al., 1995). Of the remaining patients, 44% had a relapsing course (either major depression or mania), and 21% had two or more further episodes (Strober et al., 1995). Recovery from the index episode took longer for patients with depression (median time to recovery, 26 weeks) than for either mania or mixed episodes (median time, 9 and 11 weeks, respectively) (Strober et al., 1995). Compared with adults, adolescents with bipolar disorder may have a more prolonged early course and less responsiveness to treatment (McGlashan, 1988; Strober et al., 1995). This may be due to the fact that adolescents with bipolar disorder frequently present with either mixed features, psychotic symptoms, and/or comorbid behavior/substance abuse problems, all of which predict a more refractory response to lithium therapy. However, the few available studies suggest that the long-term prognosis of early-onset bipolar disorder is similar to that of adult onset; with approximately one half of patients showing significant functional impairment compared with their premorbid state (McClellan et al., 1993; McGlashan, 1988; Werry et al., 1991). Premorbid characteristics, including intellectual functioning, also strongly influence outcome (Werry et al., 1992). Further research is needed to examine how bipolar disorder affects evolving developmental processes, given the disruptive impact of the episodes on academic, social, and family functioning. Adolescents with bipolar disorder are at increased risk for completed suicides (Brent et al., 1988, 1993, 1994; Welner et al., 1979). Strober et al. (1995) found that 20% of their adolescent patients made at least one medically significant suicide attempt. In the adult literature, a large review of studies examining depressive and manic depressive disorders found the mean rate of completed suicides to be 19% (Goodwin and Jamison, 1990). Patients who are male or who are in the depressed phase of their illness are at the highest risk. TREATMENT A multimodal treatment plan, combining medications with psychotherapeutic interventions, is needed to address the symptomatology and confounding psychosocial factors in children and
  9. 9. adolescents with bipolar disorder. Cultural issues must be appropriately incorporated into the treatment plan. The goal of therapy is to ameliorate symptoms and prevent relapse, while also reducing long-term morbidity and promoting normal growth and development. This guideline will focus primarily on the treatment of mania and mixed episodes. The treatment of bipolar depression will be more thoroughly addressed in a practice parameter that is being developed for the assessment and treatment of depression in children and adolescents. PHARMACOLOGICAL TREATMENTS Psychopharmacological intervention is necessary to effectively treat early-onset bipolar disorder. The literature regarding medication treatment for children and adolescents with bipolar disorder is limited. Many of the current recommendations are, therefore, based on studies of adults. Pharmacotherapy is usually instituted to address manic (or mixed) symptoms and depressive symptoms or to prevent relapse of the disorder. Regardless of medication choice, the procedures that need to be followed when initiating pharmacotherapy include: Informed Consent. Informed consent (addressing the rationale for treatment, as well as the potential risks and benefits of the therapy) should be obtained from both the youth and the youth's parents/guardians. If the mental status of the patient precludes this or if therapy is refused, invoking the relevant statutory mechanisms for involuntary treatment may become necessary. For patients under the legal age of consent, basic information regarding treatment should be provided in a developmentally appropriate manner. Examinations. Prior to medication therapy, a thorough psychiatric evaluation is needed. The symptoms for which treatment is targeted should be documented. A thorough physical examination is also necessary, including any clinically indicated laboratory and/or neuroimaging studies to evaluate potential organic etiologies and to provide baseline assessments for monitoring specific medications. Phase of the Illness. The clinician must assess which phase of the patient's illness (i.e., manic, depressed, mixed, or in remission) to effectively intervene. As patients are effectively treated for mania, they will frequently progress through the stages of the disorder. Thus, they may appear to be worsening when, in fact, they are undergoing a natural progression of symptoms. Some patients with mania will have a depressive phase before their mood returns to its baseline state. Similarly, mania often progresses from a euphoric/hyperexcited condition to a more disorganized state before showing clinical improvement. Recognition of these changes is important when considering the addition of other medications or a change in the primary antimanic agent. Length of Treatment. Short-term, an antimanic agent needs to be given at an adequate dose for at least 4 to 6 weeks before its efficacy can be determined. Clinicians should avoid multiple medication changes/additions, since doing so frequently confuses the clinical picture and generally does not improve efficacy. Long-term, the evidence to date shows that the relapse rate is quite high for early-onset bipolar disorder. Strober et al. (1990) prospectively followed 37 adolescents with bipolar disorder over 18 months and found that more than 90% of those who were noncompliant with their lithium treatment relapsed (12 of 13 cases). The relapse rate for those compliant with treatment was 37.5%. This study suggests that prophylactic therapy is needed for at least 18 months. However, further research is needed.
  10. 10. In the adult literature, over 80% of patients with a manic episode will have at least one episode of relapse (APA, 1994a). Withdrawal of maintenance lithium therapy has been associated with an increased risk of relapse, especially within the 6-month period following lithium discontinuation (APA, 1994a). In addition, there are reports of patients whose symptoms were well managed long-term on lithium, but after the lithium was discontinued, the patients relapsed and no longer responded adequately to lithium therapy (Post et al., 1992). The indications for, and the overall duration of, long-term maintenance therapy need further study. Clinically, however, some individuals may need lifelong prophylaxis. Since no definitive studies address the long-term treatment of early-onset bipolar disorder, the clinician must balance the potential deleterious impact of relapse versus that of the side effects of the medications. Any attempts to taper prophylactic therapy must be closely monitored for symptoms of relapse. Further, patients and families must be thoroughly educated as to the signs and symptoms of relapse to provide for resumption of treatment as soon as possible, if necessary. Finally, the patient's diagnostic status must be reassessed over time, given the high rate of misdiagnosis in youth, to ensure that the course of medication therapy is appropriate. Medication Choice. The choice of medication(s) should be made based on: (1) evidence of efficacy, (2) the phase of illness (see above), (3) the presence of confounding presentations (e.g., rapid-cycling mood swings, psychotic symptoms), (4) the agent's side effect spectrum, (5) the patient's history of medication response, and (6) the preferences of family/patients. In addition, different ethnic groups may vary in their pharmacokinetic response to lithium, antidepressants, and the other psychotropic agents, with a potential impact on side effects, blood levels, and efficacy (Lin et al., 1995). ultiple agents are often required, but care should be taken to avoid unnecessary polypharmacy. A discussion of the individual agents follows. LITHIUM Lithium, traditionally the agent of first choice in the treatment of bipolar disorder, has the largest database supporting its efficacy (APA, 1994a). In adults, lithium has been shown to be effective for: (1) the treatment of acute manic and depressive episodes, (2) prevention of recurrent manic and depressive episodes, and (3) reduction of mood instability between episodes (Goodwin and Jamison, 1990). Approximately 80% of patients with bipolar disorder respond to lithium, both for acute mania and depression (APA, 1994a). However, the response rate for mania is quicker (2 weeks versus 6 to 8 weeks for depression). Lithium also helps recurrent episodes of both mania and major depression. Discontinuation of long-term lithium therapy increases the risk of relapse, at least in the short term (APA, 1994a). Some patients may develop a more treatment-resistant form of the illness after previously effective lithium prophylaxis has been discontinued (Post et al., 1992). A paucity of data examines the efficacy of lithium for early-onset bipolar disorder (Alessi et al., 1994; Kafantaris, 1995; Strober, 1992a; Viesselman et al., 1993). The few double-blind placebo- controlled studies are limited by either small sample size and/or mixed diagnostic status, including more broadly defined psychotic disorders and/or the combination of manic symptoms and disruptive behavior disorders (Carlson et al., 1992; Delong and Aldershof, 1987; Gram and Rafaelsen, 1972; McKnew et al., 1981). These studies, plus case series and individual case reports, have found lithium to be effective (Alessi et al., 1994; Carlson and Strober, 1978; Hassanyeh and Davison, 1980; Horowitz, 1977; Hsu and Starzynski, 1986; Strober et al., 1988), with greater evidence published for those with adolescent onset (Alessi et al., 1994). However, the overall response may be less than that for adults, possibly because youth, especially adolescents, with mania often have either mixed manic-depressive syndromes and/or a predominance of psychotic symptoms, both of which are generally more refractory to treatment. 1. Pharmacology. Lithium, an alkali metal similar to sodium, is prescribed as one of two salt preparations, lithium carbonate or citrate (Viesselman et al., 1993). It has multiple complex
  11. 11. neurochemical effects, with impact on ion channels, serotonin, dopamine, and norepinephrine neurotransmitter systems, as well as on second messenger systems (e.g., adenylate cyclase) (Alessi et al., 1994). How these neurochemical effects influence mania is not clearly understood (Viesselman et al., 1993). Lithium is excreted almost entirely by the kidneys without undergoing hepatic metabolism (Viesselman et al., 1993). Serum levels increase linearly with dose, and steady-state levels are usually reached after approximately 1 week of administration. Since children generally have a higher glomerular filtration rate than adults, the required dose to weight ratio is usually higher for this age group (Viesselman et al., 1993). 2. Blood Levels. As in adults, the recommended therapeutic serum levels for the acute phase range from 0.6 to 1.2 mEq/ L (Viesselman et al., 1993). However, if manic symptoms persist, the serum levels may be carefully increased beyond this range, as long as the side effects are tolerated. In adults, maintenance serum levels generally have been in the range of 0.6 to 0.8 mEq/L, although this has not been adequately studied (APA, 1994a). Patients maintained on lower prophylactic levels (0.4 to 0.6 mEq/L) have fewer side effects but higher rates of relapse than those maintained on higher dosages (0.8 to 1.0 mEq/L) (Gelenberg et al., 1989). For some patients, the necessary acute phase and maintenance phase serum levels will be the same (APA, 1994a). To achieve therapeutic levels, clinicians may choose to initiate a reasonable starting dose and monitor blood levels over time. Lithium levels are often needed at least weekly when starting treatment. Serum levels are assessed 12 hours after the last dose. Generally, starting dosages range from 300 mg to 900 mg per day, depending on the size of the child. Weller et al. (1986a) found that, for children, a starting dose of 900 mg/m2 (approximately 30 mg/kg daily) generally produced a therapeutic serum level within 5 days, although some children may develop levels greater than 1.4 mEq/L (Alessi et al., 1994). Also, published nomograms used to calculate dosages based on blood levels after single test doses (Alessi et al., 1994; Geller and Fetner, 1989) may be helpful in avoiding excessive dosages in children who are slow metabolizers and may permit more rapid dosage adjustments. Several studies have examined the possibility of using saliva levels in children to avoid blood draws. However, methodological problems have limited the utility of this technique. Saliva levels are more variable than serum, and to establish an accurate serum-saliva ratio for a given patient, several blood draws are needed (Alessi et al., 1994). Therefore, serum levels remain the standard of care. 3. Side Effects. Youth generally tolerate lithium well and may have fewer side effects than adults (Alessi et al., 1994). Younger children may be more prone to side effects than older children (Campbell et al., 1991). Commonly reported adverse reactions include nausea, diarrhea, vomiting, tremor, weight gain, headache, polyuria, polydipsia, enuresis, fatigue, and ataxia (Alessi et al., 1994; Silva et al., 1992; Viesselman et al., 1993). Although the spectrum of lithium side effects in youth is similar to that in adults, there are few studies regarding its long-term effects in youth. Therefore, the potential side effects outlined below are primarily derived from the literature on adults: Endocrine. Lithium has been associated with the development of hypothyroidism, goiters, and thyroid autoantibodies, including reported cases in children (Alessi et al., 1994). Thyroid stimulating hormone is elevated in lithium-induced hypothyroidism and, therefore, conducting the laboratory test for its level is useful in monitoring lithium therapy. Renal. Lithium inhibits the action of antidiuretic hormone on the distal tubules and collecting ducts, leading to the common side effects of polyuria and polydipsia. This may evolve into
  12. 12. diabetes insipidus, which is usually reversible if the lithium is discontinued (Gelenberg and Schoonover, 1991). In adults, structural changes in the kidney, including focal glomerular atrophy, interstitial fibrosis, and impaired tubular functioning, have been reported with long-term lithium therapy (Gelenberg and Schoonover, 1991). However, the risk of significant glomerular damage with long-term lithium therapy appears to be minimal (Gelenberg and Schoonover, 1991; Hetmar, 1991; Meyers, 1989). Other reported renal problems include nephrotic syndrome, proteinuria, and renal failure with acute intoxication (Alessi etal., 1994; Gelenberg and Schoonover, 1991). Cardiovascular. Lithium can have significant effects on cardiac conduction, including first-degree atrioventricular block, irregular sinus rhythms, and increased premature ventricular contractions. However, serious adverse reactions are rare (Gelenberg and Schoonover, 1991). In children, reversible conduction abnormalities have been reported (Campbell et al., 1972). Hematological. Benign mild leukocytosis is commonly noted (Viesselman et al., 1993). Dermatological. Lithium can induce or exacerbate dermatological problems, including acne, which may be a significant concern to adolescent patients (Viesselman et al., 1993). Neurological. Lithium may produce a variety of neurological effects, including muscle weakness, tremor (which can be treated with propranolol), lethargy, cognitive blunting, and headaches (Gelenberg and Schoonover, 1991; Viesselman et al., 1993). These are often time-limited and remit quickly. Serious neurotoxicity may develop with higher blood levels, including ataxia, dysarthria, nystagmus, and confusion. With blood levels above 3.0 mEq/L, patients may develop more devastating neurological impairments, including seizures, coma, and death (Gelenberg and Schoonover, 1991). In children, lithium has been reported to alter EEG patterns and to decrease performance on cognitive testing (Portteus Mazes test) (Alessi et al., 1994). However, at therapeutic blood levels, the impact on overall cognitive functioning does not appear to be significant (Viesselman et al., 1993). Osseous. Given lithium's interaction with calcium metabolism, it theoretically might cause long- term problems with skeletal growth. However, it does not seem to increase the risk for osteoporosis in adults (Viesselman et al., 1993). How lithium potentially interacts with the developmental maturation of a child needs to be further researched. Teratogenic. In utero exposure to lithium has been associated with various congenital abnormalities, especially cardiac anomalies (Ebstein's anomaly) (Jacobson et al., 1992). However, when examined prospectively in a multicenter study, women who used lithium during the first trimester of pregnancy had no greater risk of mania or congenital malformations in their offspring than controls (one out of 148 cases with in utero exposure to lithium developed Ebstein's anomaly) (Jacobson et al., 1992). It is generally recommended that lithium be avoided during pregnancy, especially during the first trimester (Green, 1995). If lithium is used, adequate monitoring for fetal congenital anomalies, including ultrasound and fetal echocardiography, is needed (Jacobson et al., 1992). Adolescent females should be evaluated for unsuspected pregnancies prior to making medication decisions. Drug-Drug Interactions. Lithium is commonly used with antipsychotic agents without significant problems. However, there are reports of patients developing an encephalopathic syndrome or neuroleptic malignant syndrome with concomitant use of lithium and neuroleptics (Green, 1995). This may be dose-related. Many agents influence lithium levels. For example, carbamazepine,
  13. 13. nonsteroidal antiinflammatory agents, some antibiotics (tetracycline), and thiazide diuretics all may raise lithium levels (Green, 1995). 4. General Medical Evaluation. Prior to initiating lithium therapy, a thorough psychiatric and pediatric evaluation is warranted, including inquiring about any history of renal, endocrine, and/or cardiovascular problems. Whether or not the patient is on a low-salt diet or diuretic therapy should also be noted, since these will influence lithium levels. Baseline laboratory assessment should include: blood counts, thyroid functions, urinalysis, blood urea nitrogen, creatinine, and a pregnancy test in adolescent females (Rosenberg et al., 1994). When clinically indicated, an electrocardiogram and a 24-hour creatinine clearance should also be obtained. Once a stable lithium dose is obtained, lithium levels, renal and thyroid functions, and urinalyses need to be regularly monitored (every 3 to 6 months) (Rosenberg et al., 1994). ANTICONVULSANT MOOD STABILIZERS In the adult literature, both open and controlled studies have supported the efficacy of the anticonvulsants carbamazepine and valproate for the acute treatment of bipolar disorder (APA, 1994a; McElroy et al., 1992). Greater evidence supports the use of valproate, which was recently approved as a treatment for mania by the U.S. Food and Drug Administration. Some patients who do not respond to, or are intolerant of, lithium, may respond to the anticonvulsants. These agents have been used by themselves, together, or in combination with lithium. Indications for their use include rapid cycling and dysphoric (or mixed) mania (both of which are associated with poor response to lithium) (APA, 1994a; McElroy et al., 1992). Some evidence supports their use as prophylactic agents during the maintenance phase of therapy, but controlled studies are lacking (APA, 1994a). The anticonvulsants are probably less effective for acute depressive symptoms than lithium, although valproate has been reported beneficial for the depressive phases of bipolar II disorder (Puzynski and Klosiewicz, 1984). Only a few case reports examine the efficacy of anticonvulsant agents for early-onset bipolar disorder, but none is placebo-controlled (Pataki and Carlson, 1992; Viesselman et al., 1993). Therefore, the justification for their use is derived primarily from the adult literature. Valproate has been reported to be effective for treating mania in adolescents (West et al., 1994). However, the patients in these reports were also receiving adjunctive psychotropic agents (primarily neuroleptics). Carbamazepine has been reported to be effective in manic adolescents nonresponsive to lithium (Hsu, 1986). Since these agents have been widely used in children and adolescents with seizure disorders, there is considerable information regarding side effects in youth (Carpenter and Vining, 1993). Valproate. Valproate, a commonly used anticonvulsant in youth, is effective for a wide variety of seizure disorders (Carpenter and Vining, 1993). Its antiepileptic effects are believed to be due to its increasing brain levels of (-aminobutyric acid (GABA) (Viesselman et al., 1993). It is hepatically metabolized and highly protein-bound (APA, 1994a). Valproate tends to inhibit the metabolism of other agents and, therefore, may cause an increase in the plasma levels of concurrent medications (APA, 1994a; Viesselman et al., 1993). The relationship between valproate serum levels and its effectiveness for mania has not been adequately defined (APA, 1994a). Thus, the recommended therapeutic levels are the same as for treating seizure disorders -– 50 to 100 (g/mL (Viesselman et al., 1993). The usual dose for children is 10 to 60 mg/kg daily, and for adolescents, 1,000 to 3,000 mg daily (Pedley et al., 1995). Most youth tolerate valproate well. Common side effects include sedation, nausea, and vomiting (Viesselman et al., 1993). Although rare, potentially serious side effects are reported. Valproate
  14. 14. has been associated with fatal hepatic toxicity. Those at highest risk are very young children (less than 2 years old) during the first 6 months of therapy, especially those on multiple anticonvulsants: and/or with severe seizure disorders/organic impairment (PDR, 1994). Hematological side effects have been noted, including reported cases of coagulopathies, thrombocytopenia, neutropenia, pancytopenia, and/or aplastic anemia (PDR, 1994; Viesselman et al., 1993). Increased rates of polycystic ovary disease in adult women with seizure disorders have also been reported (Isojarvi,et al., 1993). Finally, valproate has been associated with neural tube defects when exposure occurred during the first trimester (PDR, 1994). Prior to treatment, baseline liver functions, blood cell counts, and coagulation tests are recommended (Visselman et al., 1993). Once a stable therapeutic valproate level is obtained, serum valproate levels, plus hepatic and hematological measures, should then be periodically monitored every 3 to 6 months (Papatheodorou and Kutcher, 1993). However, periodic monitoring does not ensure that abnormalities will be identified; it is also important to advise patients and families about presenting symptoms of these side effects. Carbamazapine. Carbamazapine is chemically related to tricyclic antidepressants. Its dosing kinetics are linear. However, it causes induction of hepatic metabolic enzymes, which accelerates its own metabolism, as well as that of other hepatically metabolized agents. This autoinduction often results in decreased blood levels over time without any change in dosage. Similar to valproate, the therapeutic range for serum levels has not been established for treating mania. The recommended range is the same as that used for seizure disorders–4 to 12 (g/mL (Rosenberg et al., 1994). The dosage for children generally is 10 to 20 mg/kg daily (200 to 600 mg per day), and for adolescents, dosages may go as high as 1,200 mg per day or more (Pedley et al., 1995; Viesselman et al., 1993). When initiating a trial of Carbamazapine, starting dosages begin at 100 to 300 mg per day and are increased as tolerated while monitoring blood levels. Daily dosages are usually divided in b.i.d. or t.i.d. schedules. Upon initiation of therapy, transient side effects may include drowsiness, dizziness, nausea, and mild ataxia (Viesselman et al., 1993). Leukopenia occurs in children but is generally not clinically significant unless the total white blood count drops below 3,000/mm3. Carbamazapine has been reported to cause agranulocytosis and aplastic anemia (PDR, 1994). The greatest risk for agranulocytosis occurs within 3 months of initiating therapy, although it has been reported as late as 5 years after starting treatment (PDR, 1994). Finally, there are also reports of hepatic toxicity. In children with seizure disorders, reported cognitive and behavior effects include impaired performance on learning and memory tasks, irritability, agitation, insomnia, and emotional lability (Carpenter and Vining, 1993). However, Stores et al. (1992) found no significant cognitive or behavior effects after 1 year of therapy with either Carbamazapine or valproate. Prior to initiating therapy, baseline blood counts and liver functions should be obtained. Carbamazapine blood levels are obtained frequently (once per week or more) at first to adjust the dose. Once the dosage is stabilized, periodic monitoring of serum levels, blood counts, and liver functions is needed (every 3 to 6 months) (Rosenberg et al., 1994). Since periodic monitoring does not ensure detection of granulocytosis, the patient and family need to be advised of presenting symptoms (e.g., fever, easy bruising). If significant bone marrow suppression occurs, the Carbamazapine should be stopped and the blood counts closely monitored, with referral for specialized pediatric care. Finally, Carbamazapine may have teratogenic effects (especially with first trimester exposure) and has been associated with neural tube defects (Rosa, 1991). BENZODIAZEPINES Benzodiazepines may be useful for treating agitated manic states (APA, 1994a; Viesselman et al., 1993). These agents, used in conjunction with antimanic agents (i.e., lithium or anticonvulsants) and in place of neuroleptics, are helpful for psychomotor agitation, irritability, and insomnia in acutely manic patients (APA, 1994a; Viesselman et al., 1993). In adults, clonazepam
  15. 15. and lorazepam have been most often studied, but no literature is available on their use in children and adolescents with mania (Werry and Arnan, 1993). The evidence is mixed as to whether benzodiazepines have any specific antimanic activity or whether their therapeutic effects are due solely to sedation (APA, 1994a). The few studies to date have had small sample sizes, and some were confounded by the coadministration of neuroleptics (APA, 1994a). No controlled studies examine the use of benzodiazepines for maintenance therapy or bipolar depression. Although alprazolam has been reported to be helpful for major depression, it also can induce mania (APA, 1994a). Thus, benzodiazepines can be useful adjuncts to antimanic agents for patients with acute mania. However, their long term use in children and adolescents with bipolar disorder should be discouraged, given the lack of supporting research and potential dependency problems. NEUROLEPTICS No studies examine the efficacy of neuroleptics for early-onset bipolar disorder (although they are commonly used in clinical practice). In the adult literature, neuroleptics have been shown to be effective for the treatment of acute mania (Goodwin and Jamison, 1990). However, it is not clear whether the effects of neuroleptics are actually antimanic or due to sedation (Goodwin and Jamison, 1990). Since their effects occur more rapidly than mood stabilizers, they may be useful during the initial phases when patients are highly agitated or psychotic (APA, 1994a). Little evidence indicates that neuroleptics, by themselves, should be used for maintenance treatment of bipolar disorder (APA, 1994a). Some patients whose symptoms do not respond adequately to antimanic agents alone may benefit from a combination of a mood stabilizer with an antipsychotic (APA, 1994a). The side-effect spectrum of neuroleptics dictates close monitoring of their use and periodic reassessment of their ongoing use over the course of therapy (Campbell et al., 1993). Patients with mood disorders may be at greater risk to develop tardive yskinesia (APA, 1991). In addition, the combination of lithium and neuroleptics has been associated with an increased risk of extrapyramidal side effects and neurotoxicity (Alessi et al., 1994). OTHER ANTIMANIC AGENTS Clozapine and the other atypical antipsychotic agents (e.g., risperidone), may have mood stabilizing effects in patients with bipolar disorder, including those with psychotic features, mixed episodes, and/or rapid cycling (APA, 1994a). Clozapine was reported to be effective in an adolescent with bipolar disorder (Fuchs, 1994). Other agents with reported efficacy in the adult literature include calcium channel blockers and thyroid hormones (usually as an adjunct to other antimanic agents) (APA, 1994a). However, these agents have not been studied for the treatment of early-onset bipolar disorder, and their use in this population should only be considered after more standard regimens have been tried. ANTIDEPRESSANT MEDICATIONS No studies with youth and only a few studies in the adult literature examine the efficacy of tricyclic antidepressants for the treatment of bipolar depression (Zornberg and Pope, 1993). They are more effective than placebos, but their usefulness either compared or used in conjunction with antimanic agents, such as lithium, has not been systematically studied (Zornberg and Pope, 1993). There are even fewer studies examining monoamine oxidase inhibitors and selective serotonin uptake inhibitors (Zornberg and Pope, 1993). Some evidence indicates that the antidepressant bupropion may be less likely than other antidepressants to induce mania in patients with bipolar disorder, although further study is needed (APA, 1994a; Haykal and Akiskal, 1990; Sachs et al., 1994). One case has been reported of the use of light therapy as an adjunct to antimanic agents for treating depressive symptoms in seven young adults, aged 16 to 22 years (Papatheodorou and Kutcher, 1995).
  16. 16. A major risk of antidepressant use in bipolar patients is the induction of mania and/or rapid cycling. This risk has been noted with all classes of antidepressant agents (APA, 1994a). Thus, they are generally used only as adjuncts to antimanic therapy for persistent depressive symptoms. PSYCHOSTIMULANTS Psychostimulants may exacerbate or induce psychosis/mania (Waters and Mitch, 1993). However, there are case reports of stimulants having antimanic effects (Max et al., 1995). There are two reports of using lithium and methylphenidate together in treating preadolescent children (eight patients, total) with a combination of mood and disruptive behavior problems (Carlson et al., 1992; Licamele and Goldberg, 1989). Some improvements were noted, without significant side effects. Although the patients in these reports had some manic symptoms, none met the criteria for mania. Psychostimulants must be used with caution in patients with bipolar disorder and are best avoided during acute manic phases. ELECTROCONVULSIVE THERAPY In adults, electroconvulsive therapy (ECT) is as effective as lithium for the treatment of mania (APA, 1994a; Welch, 1989). Furthermore, it is the most effective therapy available for depression, particularly for patients with psychotic depression or for those nonresponsive or intolerant of medication therapy (APA, 1994a; Welch, 1989). Many patients with bipolar disorder respond quickly to ECT. It is extremely safe as long as modern methods are used (i.e., appropriate anesthesia, alterations in the delivery of the electrical stimulus, the selected use of unilateral treatment, and cardiopulmonary monitoring) (APA, 1994a). For a more thorough review of standard guidelines for the proper use and techniques, please see the APA Task Force on ECT report (APA, 1990). ECT is generally considered the treatment of choice for bipolar disorder in the following clinical situations: (1) pregnancy; (2) catatonia; (3) neuroleptic malignant syndrome; and (4) any other medical condition where more standard medication regimens are contraindicated (APA, 1990). Although the literature is sparse, case reports indicate that ECT is beneficial for children and adolescents with bipolar disorder, including mania, rapid cycling, and depressed phases (Bertagnoli and Borchardt, 1990). Potential side effects include short-term cognitive impairment, anxiety reactions, disinhibition, and altered seizure threshold (Bertagnoli and Borchardt, 1990). Despite its potential efficacy, many centers do not use ECT for patients with early-onset bipolar disorder due to a lack of experience and concern about its associated social stigma. Since ECT may be the most appropriate treatment for some patients, it should not be denied because of these barriers. TREATMENT OF MIXED EPISODES AND RAPID CYCLING Based on the adult literature, the treatment of mixed episodes is basically the same as that for mania, although lithium may be less often effective (APA, 1994a; Prien and Potter, 1990). Antidepressants are best avoided. The anticonvulsants may be particularly effective for mixed episodes, but further research is needed (APA, 1994a; Prien and Potter, 1990). Similar to patients with mixed episodes, those with rapid cycling may be less responsive to lithium (APA, 1994a; Prien and Potter, 1990). Clinical experience suggests that antidepressants be avoided and that a combination of antimanic agents is often necessary to relieve symptoms (APA, 1994a). It is also important that patients with rapid cycling mania undergo a thorough medical evaluation to rule out potential medical conditions (e.g., thyroid disorder, substance abuse) that may be exacerbating the affective instability (APA, 1994a).
  17. 17. PSYCHOSOCIAL TREATMENTS A comprehensive multimodal treatment approach combining psychopharmacology with adjunctive psychosocial therapies is almost always indicated for early-onset bipolar disorder. Medications help with the core symptoms of the illness, but they do not necessarily address the associated functional impairment. Preexisting behavioral disorders, substance abuse disorders, learning problems, and confounding psychosocial issues may all require additional treatment once the affective episode is stabilized. Furthermore, psychotherapeutic interventions are needed to promote medication compliance and avoid relapse. Despite these clinical needs, the available research examining psycho social interventions for bipolar disorder is quite limited, and there is essentially no literature regarding children and adolescents (Kafantaris, 1995). No psychotherapy specific for the treatment of mania has been defined, although some pilot work is examining cognitive therapy interventions in adult patients (Kahn, 1990; Prien and Potter, 1990). A large literature addresses the effectiveness of cognitive behavioral and interpersonal psychotherapist for the treatment of depression in adults (APA, 1989). The use of these psychotherapies with children and adolescents will be reviewed in a separate practice parameter. Extrapolating from the adult literature and clinical experience with this population suggests several areas where psychotherapeutic interventions should be directed: Psychoeducational Therapy. Information should be provided to both the patients and their families on the disorder's symptoms and course, treatment options, potential impact on psychosocial and family functioning, and heritability (Goodwin and Jamison, 1990; Kahn, 1990; Prien and Potter, 1990). Relapse Prevention. Education should be provided to the patient and family on the impact of noncompliance with medications, the recognition of emergent relapse symptoms, and other factors that may promote relapse (e.g., sleep deprivation, substance abuse). Medication noncompliance is a major contributor to relapse. Estimates of noncompliance in adults range from 25% to 50% (Prien and Potter, 1990). In a study of adolescents with bipolar disorder, 90% of those who were noncompliant with lithium relapsed over an 18-month period (Scrober et al., 1990). Thus, efforts must be made to educate both the patient and family of the importance of ongoing treatment. Establishing a strong therapeutic relationship and providing regular follow-up assessments are important in maintaining compliance (Kahn, 1990). Reports of supportive group therapies indicate that they are helpful for adult patients, but this modality has not been systematically studied (Prien and Potter, 1990). Similar to schizophrenia, measures of family patterns of expressed emotion and interactional style are predictive of relapse in bipolar patients (Miklowitz et al., 1988). Preliminary evidence in studies of adults with bipolar disorder suggests that psychoeducational therapies with both the patient and family can effectively decrease relapse rates and improve overall functioning when used in conjunction with pharmacotherapy (APA, 1994a; Clarkin et al., 1990; Miklowitz and Goldstein, 1990; Prien and Potter, 1990). In these models, psychotherapeutic interventions are directed at stress reduction, problem-solving skills, and family functioning. Miklowitz and Goldstein (1990) modified the Behavioral Family Management program, a home- based intervention designed for patients with schizophrenia (Falloon et al., 1984), to use with adult patients who have bipolar disorder. This program utilizes psychoeducation and training to enhance problem-solving and communication skills. Although further study is needed, use of this program, in conjunction with pharmacotherapy, does appear to decrease relapse rates (APA, 1994a).
  18. 18. Reduction of Morbidity. Bipolar disorder significantly affects social, family, academic, and developmental functioning. Therefore, in addition to efforts directed at reducing further episodes, psychosocial interventions are needed to address the myriad of disruptions that emerge in the wake of the disorder. There is a dearth of systematic research regarding the efficacy of standard psychotherapeutic interventions with this population. Therefore, the use of these interventions is based solely on clinical consensus. Individual (usually supportive) and family psychotherapies may be indicated to deal with the various interpersonal, intrapsychic, and social conflicts that arise during the course of the disorder. Cultural issues must be taken into account when devising psychotherapeutic strategies. The use of more intensive forms of psychotherapy may be contraindicated insome patients with bipolar disorder because they cannot tolerate the affect generated (Bemporad, 1989). The educational needs of youth with bipolar disorder must be adequately addressed to help promote long-term academic growth, especially given the high rates of comorbid disruptive behavior disorders. School consultation is often necessary to help develop an appropriate educational environment. Consultation with the school system and personnel can also be helpful to alert them to early warning signs of mania or depression. Some youth will need specialized educational programs, including day treatment/partial hospitalization programs. Consultation may be needed with other involved community, juvenile justice, and/or social welfare programs. Some youth, either because of the severity of the symptoms or confounding environmental stressors, will need referral for intensive community-based services to continue living in heir homes. Alternatively, some patients will need either foster care and/or residential services. Finally, patients and families often benefit from participation with community support and advocacy programs. Bipolar disorder may first present during childhood and adolescence; therefore, clinicians working with youth should be familiar with its diagnosis and treatment. Although the same diagnostic criteria are used as for adults, issues regarding the developmental presentation of symptoms and the co-occurrence of other psychiatric disorders must be recognized. Treatment involves the combination of pharmacotherapy and adjunctive psychosocial therapies. As in adults, early onset bipolar disorder may represent a lifelong condition that requires longitudinal assessment, medication monitoring, and ongoing psychosocial interventions. Treatment varies according to the phase of the disorder, with an overall focus on (1) amelioration of acute symptoms, (2) prevention of relapse, (3) reduction of long-term morbidity, and (4) promotion of long-term growth and development. PRACTICE PARAMETERS I. Diagnostic assessment. A. Premorbid history. 1. Cognitive, motor, sensory, social, or other developmental problems. 2. Premorbid personality characteristics; i.e., temperament, mood, anxiety, and/or behavioral problems. B. History of present illness. 1. Document DSM-IV (APA, 1994b) target symptoms (both manic and depressive symptoms), as well as associated phenomena (e.g., psychotic symptoms, suicidality). The symptoms should represent a significant change from baseline functioning, with associated changes in the child's mental status. Rapidity of onset and any precipitating stressors should be noted.
  19. 19. 2. Examine the longitudinal course of illness. It is often helpful to create a life chart to identify cyclical and/or seasonal patterns. 3. Assessment for associated or confounding symptoms, especially substance abuse, organic factors, and/or behavioral disorders. C. Family history. 1. Obtain a thorough family history of mood, anxiety and psychotic disorders, suicidality, impulse control disorders, neurological and medical conditions, and substance abuse. 2. Family emotional, communicative, interactional, and coping styles and resources. D. School information. 1. Obtain information about school functioning, both premorbid and subsequent to the onset of symptoms, either directly or from written reports from appropriate staff, such as the principal, school psychologist/ counselor, teacher, and/or nurse after release of information is granted. E. Neuropsychological functioning. 1. Suspected disabilities in either intellectual functioning, communication abilities, and/or motor skills should be evaluated to help with the differential diagnosis and/or to identify comorbid problems. Assessments to consider include psychological testing (IQ, neuropsychological testing, adaptive functioning, and/or academic testing), speech and language assessment, and/ or an occupational/physical therapy evaluation. F. Consultation and collaboration with other mental health and/or social service providers as necessary. G. Physical evaluation of the child. A thorough evaluation is needed to rule out organic conditions. 1. A pediatric examination is needed, including a thorough neurological evaluation, especially in the presence of either psychotic symptoms and/ or catatonia, with consideration of neurological consultation, EEG, and computed tomographic and magnetic resonance imaging head scans. This may be done in collaboration with the primary family physician or other health care providers. 2. Medical conditions that mimic either mania or depression, such as metabolic, endocrine, infectious disorders, or acute intoxication/withdrawal, need to be evaluated as indicated. Routine laboratory tests (i.e., blood counts, renal and liver functions, thyroid functions, toxicology screen, pregnancy test, and urinalysis) are usually indicated, both as part of the organic workup and also as baseline assessments for medication therapy. If the risk factors are present, testing for HIV should be done, with appropriate informed consent. II. Diagnostic formulation. A. A diagnosis of bipolar disorder is made when the required DSM-IV (APA, 1994b) target symptoms for mania/mixed state are present, either currently or by history, and other disorders, such as schizophrenia or organic affective disturbances, have been adequately ruled out. Once the diagnosis has been established, it should be reassessed longitudinally to ensure accuracy. B. In the assessment of children and adolescents presenting with symptoms suggestive of bipolar disorder, evaluation includes consideration of: 1. Recent onset of biopsychosocial stresses. 2. Educational and vocational potential, disabilities, and achievement. 3. Peer, sibling, family, and sociocultural problems and strengths. 4. Environmental factors, including disorganized home, presence of child abuse/neglect, and/or mental illness in parents or guardians. 5. Developmental abnormalities (motor and language delays). 6. Child/adolescent interpersonal strengths, especially the ability to form adult and peer relationships.
  20. 20. C. Differential diagnosis. 1. The following conditions may be misdiagnosed as bipolar disorder: a. Schizophrenia. b. Schizoaffective disorder or other psychotic disorders (delusional disorders, schizophreniform disorder, psychosis not otherwise specified). c. Organic affective disorders. d. Childhood disruptive behavior disorders. e. Borderline personality disorder (or other personality disorders/traits that present with affective instability and erratic behavior). f. Posttraumatic stress disorder. 2. The following conditions often occur comorbidly with bipolar disorder: a. Substance abuse disorders. b. Childhood disruptive behavioral disorders. c. Anxiety disorders. 3. The following medical conditions may mimic bipolar disorder: a. Organic mania: i. Organic mania due to substance abuse or withdrawal (amphetamines, cocaine, phencyclidine, inhalants, methylenedioxymethamphetamine). ii. Organic mania due to prescribed medications, such as antidepressant agents (induced mania), sympathomimetics, bromocriptine, stimulants, and/or corticosteroids. b. Neurological disorders (e.g., brain tumors, posttrauma, CNS infections, including HIV, multiple sclerosis, temporal lobe seizures, Kleine-Levin syndrome). c. Metabolic conditions (e.g., hyperthyroidism, urermia, Wilson's disease, collagen vascular disorders, delirium). III. Treatment. A. Substantial scientific evidence suggests that the only specific treatment of bipolar disorder is medication therapy using a mood stabilizer. However, medications need to be used in conjunction with a multimodal treatment model that also includes psychoeducational services, individual and family supportive and psychotherapeutic interventions, educational programs, and community support services. Psychotherapeutic interventions must be sensitive to cultural issues. Most of the treatment recommendations are based on studies of adults. However, the limited available research on early-onset bipolar disorder, plus clinical consensus within the field, suggests that these findings can be applied to youth as long as pertinent developmental factors are incorporated into the treatment plan. The following elements are necessary to develop a multimodal treatment formulation: 1. Thorough diagnostic assessment. Acute mania or severe depression (especially psychotic depression) may require hospitalization, depending on the severity and potential danger of the symptomatology, as well as the social supports of the family. Hospitalization may be necessary because of the extensive array of psychiatric and neurological evaluation resources required to complete the initial assessment, and the need for a more structured, safe environment in which to evaluate the patient.
  21. 21. 2. Assessment for suicide potential, since this population is at significant risk for attempting/completing suicide. 3. Identification of other pertinent issues, i.e., family dysfunction, school difficulties, and premorbid and/or comorbid disorders, requiring ongoing treatment. 4. Evaluation and initiation of medication therapy. 5. Education of the patient and family as to the nature of the illness, potential prognostic issues, and treatment needs. 6. Development of a long-term treatment plan, including medication management, appropriate psychotherapy and psychoeducational services for the patient, supportive services for the family (advocacy groups, support groups), appropriate educational and vocational services, and residential services when indicated. 7. Designation of a case manager for chronically disabled individuals because of the wide range of services needed. 8. Provisions for long-term periodic diagnostic reassessments to ensure accuracy of diagnosis. B. Psychopharmacology. The phase of the illness needs to be considered when making decisions on medication therapy. 1. Acute mania/mixed mania. a. Prior to initiating medications, a thorough psychiatric evaluation is needed, including documentation of the symptoms targeted for therapy. Informed consent is needed from the parents and adolescent patients, and assent, when possible, should be obtained from preadolescents. b. In adults, lithium has been the most extensively researched antimanic agent, and its efficacy has been documented. The anticonvulsants valproate and carbamazepine are also used, with greater evidence supporting the efficacy of valproate. During the acute phase, it may be necessary to augment the antimanic agent with either an antipsychotic agent or a benzodiazepine to address the associated psychomotor agitation and/or psychotic symptoms. c. To determine whether or not an antimanic medication is effective, it must be used for at least 4 to 6 weeks at adequate dosages and blood levels. If no effects are seen at that point, consideration should be given to either adding or changing to a different antimanic medication. d. As the acute manic symptoms stabilize, the patient may cycle through a period of confusion and disorganization. These symptoms may also progress into a depressive episode. It is important to recognize these as phases of the disorder; otherwise, the tendency may be to make significant changes in the medication regimen that may, in fact, only prolong recovery. The antimanic agent should be maintained through this phase, with modifications in dosage or augmenting agents to further ameliorate the presenting symptomatology. 2. Depressed phase. a. Care must be taken in using antidepressant agents because they may induce a manic episode. Patients with established bipolar disorder should be maintained on an antimanic agent prior to initiating antidepressant therapy. b. As patients recover from mania, it is common for them to cycle through a depressive phase. This phase often resolves with continued antimanic treatment; therefore, the addition of an
  22. 22. antidepressant may not be necessary unless the depressed phase persists or becomes severe. 3. Remission. a. Long-term maintenance therapy with an antimanic agent is indicated to prevent relapse. Data are inadequate to specify how long prophylactic treatment should be maintained. However, one study of youth suggests at least 18 months of therapy is necessary, and, undoubtedly, some patients will need lifelong treatment. b. If multiple psychotropic agents were needed to treat the patient's acute symptoms, attempts to taper adjunctive agents (e.g., antipsychotic agents, benzodiazepines) should be made once remission has been achieved and the patient is clinically stable. Patients with bipolar disorder may be at increased risk for tardive dyskinesia with long-term neuroleptic use. Similarly, if more than one antimanic agent has been used to control manic symptoms, an assessment is needed to determine if remission can be maintained with a single agent. Close monitoring for relapse is necessary during these changes. 4. Relapse of symptoms. a. When symptoms relapse, it should first be determined whether or not the patient was compliant with prophylactic therapy. If nor, resumption of the antimanic medication should occur. If the patient was compliant and had been previously responding to the agent (without significant side effects), an increase in the medication dose may stabilize the symptoms (keeping in mind the standard dosage ranges and blood levels). b. If symptoms relapse and the patient is not adequately responding to the current antimanic agent (at adequate dosages), a trial of a different antimanic, either alone or in addition, should then be undertaken. Adjunctive agents (e.g., antipsychotics, benzodiazepines, antidepressants) may also be indicated, depending on the symptom presentation. c. Patients who relapse may require acute hospitalization. This decision should be based on the severity of affective and psychotic symptoms, potential danger to self or others, degree of impairment in the patient's ability to maintain basic self care, and availability of supportive services in the community. 5. Patients who do not respond to standard therapy. a. Before it is decided that the patient is a nonresponder, the patient should receive at least two adequate trials of different antimanic agents, one of which should be lithium. An adequate trial is defined both by duration (4 to 6 weeks) and dosage (using maximal levels if necessary and tolerated). b. In adults, other agents with reported antimanic activity include clozapine, benzodiazepines, calcium channel blockers, and thyroid hormones. However, these have not been studied in children and adolescents. If clozapine is to be used, close monitoring for potential seizures, agranulocytosis (with periodic blood cell counts), and weight gain is necessary. C. ECT. 1. The efficacy of ECT for bipolar disorder, both mania and depression, is well established for adults. There is also some literature supporting its use in youth with bipolar disorder. It is generally used only for medication-resistant cases. However, it may be considered as an Initial treatment for severe psychotic depression and/or catatonia.
  23. 23. D. Psychosocial therapy. 1. Psychoeducational therapy for the patient, including ongoing education about the illness, medication effects, social skills training, problem- solving skills strategies, and basic life skills training. Part of the focus should be on relapse prevention, including compliance with medications. 2. Psychoeducational therapy for the family, focusing on increasing the understanding of the illness, treatment options and prognosis, relapse prevention, and effective coping and parenting intervention strategies. 3. Specialized education programs and/or vocational training programs. 4. Individual (usually supportive rather than insight-oriented), group, or family psychotherapy to address associated psychosocial problems that increase morbidity. E. Treatment of associated disorders or symptoms, such as substance abuse disorders, disruptive behavior disorders, and/or suicidality. F. Partial hospitalization or day treatment programs. 1. Many patients will need the specialized educational and psychiatric services available in either a partial hospitalization or day treatment program to be maintained at home within their community. G. Residential treatment. 1. In some cases, the severity of the individual's illness or lack of effective response to treatment (often in conjunction with chaotic social situations) may necessitate long-term hospitalization or residential treatment. This option should only be considered after less restrictive alternatives have been unsuccessful. Once in a long-term residential setting, the patient's status needs to be reassessed at regular intervals, with the goal of returning to a less restrictive setting when possible. H. Flexible models of care. 1. Many youth with bipolar disorder will be chronically impaired, with complicated clinical and social needs, and may need an integrated continuum of services, including: case management, intensive community and family support, in-home services, out-of-home care (including respite and specialized foster care), and specialized educational/vocational services. CONFLICT OF INTEREST In keeping with the requirement that practice parameters be developed by experienced clinicians and researchers, some of the contributors to these practice parameters are in active clinical practice. Through theirpractices, it is likely that most of these child and adolescentpsychiatrists have received income related to treatments discussed inthese parameters. Some contributors are primarily involved in research or other academic endeavors; it is possible that through such activities,many of them have also received income related to treatments discussed inthese parameters. A number of mechanisms are in place to minimize thepotential for producing biased recommendations due to conflicts ofinterest. First, the development process calls for extensive review of thedocument before it is finalized. All members of the Academy have theopportunity to comment on the parameters before they are approved. Comments have been solicited and received from a broad group of reviewers in child and adolescent psychiatry. Second, the contributors and reviewershave all been asked to base their recommendations on an objectiveevaluation of the available evidence. Third, we ask that contributors orreviewers who believe that they have conflicts of interest that may biasor appear to bias their work notify the Academy. LITERATURE REVIEW PROCESS
  24. 24. A National Library of Medicine search was initially done in May 1994, covering the preceding 5- year period. The following topics were reviewed: bipolar disorder and adolescents (39 articles), bipolar disorder and children (105 articles), and bipolar disorder and early onset (21 articles). This search was updated periodically (most recently in December 1995) to identify new articles. Searches were also undertaken to review specific topics (e.g., the use of lithium, valproate, and carbamazepine in children and adolescents). The abstracts generated by these MEDLINE searches were reviewed to identify articles relevant to early-onset bipolar disorder. Pertinent papers published before the 5-year search period were also reviewed, as were review articles and texts addressing the larger adult literature. Finally, the authors also drew from their own research in this area. Articles most often used are marked with an asterisk in the reference section. This literature review was used to develop the initial draft of the manuscript. After review by the Committee on Quality Issues, this draft was then distributed to a panel of experts for comment. The panel of experts included Hagop S. Akiskal, M.D., William Arroyo, M.D., Joseph Biederman, M.D., Kelly Botteron, M.D., Charles Bowden, M.D., Stacy Bower, R.N., Ian Canino, M.D., Magda Campbell, M.D., Gabrielle Carlson, M.D., Debbie Carter, M.D., Mark DeAntonio, M.D., Mina Dulcan, M.D., Norbert Enzer, M.D., Robert Freeman, R.N., Mary A. Fristad, Ph.D., Barbara Geller, M.D., Peter S. Jensen, M.D., Vivian Kafantaris, M.D., P. Keck, M.D., Wun Jung Kim, M.D., Maria Kovacs, Ph.D., Carlyn Lampert, M.S.W., Benjamin C.P. Lee, M.D., S. McElroy, M.D., Editha D. Nottelmann, Ph.D., Kambiz Pahlavan, M.D., Myrna Pollack, M.S.W., Elva Poznanski, M.D., Andres Pumariega, M.D., David Rue, M.D., Neal Ryan, M.D., Susan Schmidt-Lackner, M.D., Jeanne Spurlock, M.D., Michael Strober, Ph.D., Richard D. Todd, M.D., Ph.D., Michael W. Vannier, M.D., Elizabeth Weller, M.D., Ronald Weller, M.D., and Deborah Zarin, M.D. Their comments were then incorporated into the manuscript, which was then reviewed by the Academy members at large, with a public forum at the Annual Meeting in New Orleans, October 19, 1995. After incorporating the membership's input, a final draft was reviewed and adopted by the Academy's Council June 15, 1996. REFERENCES Achenbach TM, Edelbrock C (1983), Manual for the Child Behavior Checklist and Revised Child Behavior Profile. Burlington: University of Vermont Department of Psychiatry *Alessi N, Baylor MW, Ghaziuddin M, Zubieta JK (1994), Update on lithium carbonate therapy in children and adolescents. J Am Acad Child Adolesc Psychiatry 33:291-304 Akiskal HS (1981), Subaffecrive disorders: dysthymic, cyclothymic and bipolar II disorders in the "borderline realm." Psychiatr Clin North Am 4:25-46 Akiskal HS (1995), Developmental pathways to bipolarity: are juvenile-onset depressions pre- bipolar? J Am Acad Child Adolesc Psychiatry 34:754-763 Akiskal HS, Downs J, Jordan P, Watson S, Daugherty D, Pruitt D (1985), Affective disorders in referred children and younger siblings of manic depressives: mode of onset and prospective course. Arch Gen Psychiatry 42:996-1003 American Psychiatric Association (1989), Treatment f Psychiatric Disorders: A Task Force Report of the American Psychiatric ssociation, Vol 3. Washington, DC: American Psychiatric Association American Psychiatric Association (1991), Tardive yskinesia: A Task Force Report of the American Psychiatric Association. /I>Washington, DC: American Psychiatric Association
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