Treatment of Bipolar Disorder in Children and Adolescents
Volume 34(6) June 1995 pp 732-741
Kafantaris, Vivian MD
Objective: To evaluate the current status of research in the treatment of bipolar disorder in children and adolescents.
Method: A Medline search was conducted for articles on pharmacological or psychosocial treatment of bipolar disorder in children and adolescents.
Results: There are no controlled studies with adequate sample size of the efficacy of lithium (or any other treatments) in bipolar children and adolescents. Two large open studies suggest that, overall, lithium is beneficial, but there also are reports of lithium resistance in bipolar children and adolescents. Small open studies suggest that mood-congruent delusions and hallucinations may be treated successfully with lithium alone. Data on adjuncts or alternatives to lithium in bipolar children and adolescents are sparse. Several controlled studies have been published on psychosocial treatment of child and adolescent depression, but none on mania.
Conclusions: Pharmacological and psychosocial treatments of bipolar disorder in children and adolescents are understudied. There is a need for well-designed, controlled studies of lithium and alternative medications as well as adjunctive psychosocial treatments. J. Am. Acad. Child Adolesc. Psychiatry, 1995, 34, 6:732-741.
Key Words: bipolar, mania, treatment, child, adolescent.
The most crucial issue in treating mania is recognizing it.
-Dunner and Clayton (1987) .
The relative neglect of the treatment of bipolar disorder in children and adolescents may have arisen from difficulties in the diagnosis of mania in these age groups (Bowring and Kovacs, 1992; also see Weller et al., 1995) [11,105]. Misdiagnosis may lead to ineffective or inappropriate treatment. It may also deny a child or adolescent possibly effective prophylaxis against future episodes and, potentially, protection against ensuing complications, such as substance abuse, conduct disorder, or suicidal behavior. The aim of this review is to evaluate the current status of pharmacological and psychosocial treatment research of bipolar disorder in children and adolescents.
Lithium remains the treatment of choice for acute mania and prophylaxis in adults. The efficacy of lithium in adult mania was established by four placebo-controlled crossover studies with treatment duration of 7 to 14 days (Goodwin et al., 1969; Maggs, 1963; Schou et al., 1954; Stokes et al., 1971) [46,65,92,97]. Response rates of approximately 75% to lithium and 40% to placebo were reported (Stokes et al., 1971) . A recent large study, the first to use lithium in a parallel groups design, reported a response rate of 49% to lithium and 25% to placebo (Bowden et al., 1994) . Spurred by a significant (and possibly increasing) rate of nonresponse to lithium among bipolar adults, placebo-controlled studies of alternative medications such as carbamazepine, valproate, clonazepam, and clonidine were undertaken. There also have been parallel group comparisons of lithium with neuroleptics (for review see Goodwin and Zis, 1979) , of carbamazepine with neuroleptics or lithium (for review see Small, 1990) , and of valproate and lithium (Bowden et al., 1994; Freeman et al., 1992) [10,34].
In contrast with the research on adults, there are no methodologically sound, controlled studies on which to base treatment decisions for bipolar children and adolescents. Efficacy in adults cannot be taken as evidence of efficacy in children and adolescents. Tricyclic antidepressants, for example, were not superior to placebo in the treatment of childhood or adolescent depression (reviewed by Ambrosini et al., 1993) .
The only two comparisons of lithium and placebo in bipolar children (DeLong and Nieman, 1983; McKnew et al., 1981) [26,68] were based on very small samples in crossover designs. McKnew and colleagues (1981)  studied lithium response in six children with heterogeneous diagnoses who had a lithium-responding parent in a double-blind multiple crossover study lasting 16 to 18 weeks. Lithium, at serum levels of 0.8 to 1.2 mEq/L, was superior to placebo only in the two children, aged 8 and 12 years, who met adult criteria for bipolar disorder, mixed phase, by modified Research Diagnostic Criteria (RDC). DeLong and Nieman (1983)  studied lithium response in 11 children, aged 6.3 to 13.5 years, "with symptoms suggesting manic-depressive illness" in a double-blind, placebo-controlled crossover study lasting 3 weeks. For inclusion in the study, the child had to be a known lithium responder with more than two previous episodes in 2 years. A family history of major affective disorder also was required. Doses of lithium ranged from 600 to 1,200 mg/day with blood levels from 0.3 to 1.3 mEq/L (mean, 0.6 mEq/L). Subjects tended to improve when they were taking lithium and deteriorate while they were taking placebo. Parental ratings were the sole outcome measure.
In adolescents, the only placebo-controlled trials of lithium are ongoing. Two involve outpatients, one inpatients. A preliminary report from one study, of lithium in substance-dependent bipolar adolescents, is encouraging (Geller et al., 1992) . However, the main focus of this study, which is sponsored by the National Institute on Drug Abuse, is on whether lithium treatment will reduce substance use in this population, although effect on mood is measured also. Subjects may be bipolar (in a manic or depressed phase), or unipolar with "purported predictors" of bipolarity. The other outpatient study, funded by the National Institute of Mental Health (NIMH), is a multicenter, double-blind, placebo-controlled discontinuation study in bipolar adolescents on lithium maintenance (principal investigators: M. Keller, N. Ryan, and M. Strober). The NIMH-funded inpatient study addresses the treatment of acute mania (principal investigator: V. Kafantaris).
Two large open lithium treatment studies suggest that lithium is efficacious in bipolar children and adolescents. DeLong and Aldershof (1987)  reported on long-term treatment of bipolar outpatients, the majority of whom were under age 14 years. They found that 45 (73.7%) of the 59 bipolar children who continued to take lithium for more than 2 months were treated successfully, a rate similar to that reported in early studies of adults. Over the long run, 39 (66%) of 59 bipolar children benefited. The response rate did not differ for the 48 children under age 14 years (mean 9.4 years, range 3.1 to 13.9 years) from that for the 11 older adolescents (mean age, 16.4 years, range 14.3 to 20 years). The other large open treatment study involved 50 hospitalized, acutely manic adolescents, aged 13 to 17 years (Strober et al., 1988) . Although its main focus was to examine the family history of adolescent bipolar probands, response to lithium treatment was reported. Dosage of lithium was titrated to achieve a serum lithium level in the range of 0.9 to 1.5 mEq/L. Psychoactive medications, including carbamazepine and neuroleptics, were administered concurrently with lithium in some patients. Overall, 34 (68%) of the 50 subjects showed a good response after 6 weeks of treatment. It is not known how many might have responded to lithium alone. Of interest is a decreased response rate in those with an Axis I diagnosis before the age of 12 years. Only 6 (40%) of 15 improved, in contrast with 28 (80%) of 35 in the group who first exhibited psychiatric symptoms in adolescence. The childhood diagnoses in 12 of the 15 subjects were attention deficit disorder with hyperactivity plus conduct disorder. The issue of whether these disorders are actually part of a bipolar prodrome remains unresolved (see Akiskal, 1995; Carlson, 1995) [1,17]. The group with the earlier psychiatric diagnoses also tended to have a greater familial loading for bipolar disorder, but did not differ from the others in lithium dosage or plasma concentration, baseline severity ratings, including psychotic symptoms, or use of supplementary neuroleptics.
The only effort on the efficacy of lithium prophylaxis was a naturalistic study of 37 bipolar adolescents who were stabilized while taking lithium and told to continue to take the medication throughout adolescence (Strober et al., 1990) . During the 18-month follow-up period, 13 (35%) of the 37 adolescents were no longer compliant with lithium treatment, as determined by subtherapeutic serum lithium levels. Of those 13, 12 (92.3%) had a relapse compared to 9 (37.5%) of 24 who continued to take lithium (Strober et al., 1990) . The relapse rate, despite good compliance, is similar to the 33% failure rate in adults (Prien and Potter, 1990) . No systematic studies address the treatment of such breakthrough episodes.
The lithium resistance associated with mixed and rapid cycling mania in adults (reviewed by Prien and Potter, 1990)  also has been reported in children and adolescents, but all reports are based on uncontrolled studies. Himmelhoch and Garfinkel (1986)  found 23 of 46 lithium-resistant patients to be between the ages of 12 and 19 years. They noted an association between neuropsychiatric disorders, mixed mania, and lithium resistance in these bipolar adolescents; a majority required "complex pharmacologic treatment programs" consisting of adjunct treatment with carbamazepine and/or other medications. Hsu (1986)  reported that three of seven first-episode bipolar adolescents failed to respond to lithium after 28 days of treatment; their serum lithium levels were greater than 1.0 mEq/L. Carbamazepine proved useful in two of these patients. Clinical descriptions gave no indication of mixed mania. Rapid cycling (more than four mood episodes per year) was described in four children, aged 11 to 12 years, all with a mild mental handicap (Full Scale IQs 68 to 80). Only two responded to treatment with lithium. The two nonresponders had more frequent mixed episodes (Jones and Berney, 1987) .
Comorbidity with personality disorder also has been associated with decreased responsiveness to lithium in adolescents and increased likelihood of postdischarge neuroleptic treatment (Kutcher et al., 1990) . None of the 7 bipolar adolescents with a comorbid personality disorder, but 6 (46%) of 13 without a personality disorder, were lithium responders. The two groups did not differ in age at onset, presence of rapid cycling, substance abuse, alcohol abuse, or suicide attempts. However, other factors such as severity of illness, which could account for the differential response, were not assessed. Furthermore, the authors acknowledge some difficulty with distinguishing borderline personality disorder from incomplete recovery from a manic episode. There is no well-established correlation between the presence of a personality disorder and response to lithium in adult mania (Goodwin and Jamison, 1990) .
Substance dependence and conduct disorder are common comorbid conditions in bipolar children and adolescents. As noted above, the ongoing work of Geller et al. (1992)  on lithium treatment of bipolar adolescents with comorbid substance dependence is promising. Lithium also is an effective treatment for children with conduct disorder characterized by explosiveness and aggression (Campbell et al., 1984b, 1990, 1995) [15,16,12], so comorbidity with this particular profile of conduct disorder is unlikely to decrease responsiveness to lithium.
Lithium carbonate has been used to treat a variety of childhood disorders (for review see Alessi et al., 1994, and Campbell et al., 1984a) [2,13]. In large placebo-controlled studies of children with conduct disorder with a profile of aggressiveness and explosiveness, for example, lithium has been used safely with careful monitoring. No changes in renal, thyroid, or cardiac function or other side effects were observed in short-term or long-term (more than 6 months) lithium administration (Campbell et al., 1984b, 1990, 1991, 1995) [15,16,14,12]. One case of mild thyroid enlargement without hypothyroidism was reported after 4 years of treatment in an 11-year-old boy (DeLong and Aldershof, 1987) . Weight gain, stomachache, vomiting, headache, and tremor were the most common untoward effects associated with short-term administration of lithium in children, as they are in adults (Campbell et al., 1984a,b, 1990, 1991; Reisberg and Gershon, 1979) [13,15,16,14,84]. All untoward effects disappeared with decrease of dosage or discontinuation of lithium. Within the age range of 6 to 12 years, however, the younger children tended to have more side effects than the older children (Campbell et al., 1991) .
There is little information about untoward effects of lithium in adolescents. From the larger studies of lithium (DeLong and Aldershof, 1987; Strober et al., 1988) [25,100] there are no reports of side effects. Long-term effects of lithium on kidney function are of concern (for review, see Reisberg and Gershon, 1979) . However, renal function was reportedly unimpaired in four adolescents who received lithium for 3 to 5 years (Khandelwal et al., 1984) . Also, a concern for females of childbearing age is the risk of cardiovascular and other anomalies in infants with lithium exposure in utero during the first trimester (Weinstein and Goldfield, 1975) . A recent review found this risk to be much lower than previously reported, but still several times greater than in the general population (Cohen et al., 1994) .
Adverse effects of medication on cognitive functioning are of great concern in children and adolescents. Lithium has been reported to lower qualitative performance scores on the Porteus mazes in children with aggressive conduct disorder (Platt et al., 1984) . However, this effect may have been due to lithium-induced tremor. Carlson and colleagues (1992)  studied lithium effects in a heterogeneous group of children, most of whom were comorbid for bipolar disorder and a disruptive behavior disorder. They found no evidence of impaired attention, cognitive functioning, or learning.
It has been suggested that adolescents with mania may have more psychotic and "schizophreniform" symptoms than adults (Ballenger et al., 1982; Joyce, 1984; Rosen et al., 1983) [5,54,90]. Coadministration of neuroleptic medication and lithium is safe (Baastrup et al., 1976; Goldney and Spence, 1986) [4,43] and common in clinical practice. Despite early case reports suggesting the presence of a toxic interaction between lithium and neuroleptics (Cohen and Cohen, 1974; Spring, 1979) [22,95], large, comparative (albeit retrospective) studies found no greater incidence of adverse effects from their concurrent administration than from either drug alone (Baastrup et al., 1976; Goldney and Spence, 1986) [4,43].
However, there is no definitive evidence that the addition of neuroleptics is necessary to treat psychotic symptoms associated with mania in children and adolescents. From small open trials there is preliminary evidence that lithium alone is effective in treating hallucinations and delusions. Full resolution of mood-congruent delusions and hallucinations within a mean of 11 days was reported from an open trial of lithium alone in 10 psychotic manic children, aged 6 to 12 years (Varanka et al., 1988) . Horowitz (1977)  reported on lithium response in eight manic-depressive adolescents, aged 15 to 18 years. All eight had delusions and five had hallucinations. All symptoms responded to lithium alone within 5 to 14 days. There also is evidence that psychotic symptoms in adult mania, and schizoaffective-mania, respond to lithium alone (reviewed by Goodnick and Meltzer, 1984) , though, in some studies, achievement of "comparable remission" may take significantly longer for schizoaffective than manic patients (4 weeks or more, as compared to 2 weeks, respectively).
There is an increased risk of tardive dyskinesia in mood-disordered patients treated with neuroleptics (Kane, 1988, 1991; Mukherjee et al., 1986) [56,57,74]. Due to longer lifetime neuroleptic exposure, children with bipolar disorder may be especially vulnerable. In a prospective long-term study, autistic children, aged 3.4 to 6.7 years, were given individualized doses of haloperidol for 6 months and then switched to placebo for 1 month (Malone et al., 1991) . Twenty-nine (27.9%) of 104 children experienced a dyskinesia, most upon drug withdrawal, but all dyskinesias were reversible (the longest in duration was 7.5 months.) There is no information on the long-term use of neuroleptics in older children with other diagnoses.
The anticonvulsants carbamazepine and valproic acid are used frequently as alternatives or adjuncts to lithium treatment in clinical practice. It has been suggested that anticonvulsants may be more effective than lithium in mixed mania and rapid cycling (Himmelhoch and Garfinkel, 1986) , but no studies in adults have yet demonstrated their superiority (McElroy et al., 1992) . Garfinkel and colleagues (1985)  reported on a series of 19 treatment-resistant bipolar adolescent patients (11 with acute mania and 8 with mixed disorder) with excellent response to the combination of lithium and carbamazepine. Valproic acid has been used in open studies of hospitalized manic adolescents in conjunction with other psychoactive medications (Papatheodorou and Kutcher, 1993; West et al., 1994) [77,106].
Carbamazepine has been used to treat behavioral disorders in a large number of children and adolescents (Remschmidt, 1976; for review, see Evans et al., 1987) [86,30], including conduct disorder with a profile of explosiveness and aggression (Kafantaris et al., 1992) . Behavioral toxicity (Pleak et al., 1988)  and hematological adverse effects in children have been reported (Evans et al., 1989) . Valproic acid is less well-studied for behavioral disorders in children, possibly because of its association with fatal hepatotoxicity (Dreifuss et al., 1987) . As with lithium, an increased incidence of congenital anomalies has been reported in the offspring of women who took carbamazepine (Jones et al., 1989)  or valproate (Lindhout and Schmidt, 1986; Robert and Guibaud, 1982) [64,89] during pregnancy.
The high-potency benzodiazepines have been studied in adults as alternatives to neuroleptics for the acute management of agitation and insomnia in mania (Lenox et al., 1986, 1992; Modell et al., 1985; Pope et al., 1991) [61,62,70,80] and psychotic agitation (Battaglia et al., 1992; Bodkin, 1990) [6,9]. Lorazepam has been the best-studied. Two recent controlled studies with large samples found no difference between lorazepam and haloperidol in magnitude of response or time to response when used as an adjunct to lithium treatment (Lenox et al., 1992)  or used to reduce psychotic agitation in the emergency room (Battaglia et al., 1992) . Lorazepam administration is considered safe in children and adolescents (Relling et al., 1989) .
Electroconvulsive therapy (ECT) is rarely used in children and adolescents. The recent literature on the use of ECT to treat mood disorders in children and adolescents consists of case reports (for review see Bertagnoli and Borchardt, 1990) . ECT was reported to be successful for eight of nine patients, aged 5 to 15 years, treated for mania; for two rapid cycling adolescents, aged 15 and 18 years, and all 11 depressed adolescents, aged 12 to 18 years. The renewed interest in ECT to treat adult mania (Small et al., 1988)  may encourage systematic research on the safety and efficacy of ECT, particularly for the acute treatment of severe mania, in children and adolescents.
Open and controlled studies of psychosocial treatments for depression in children and adolescents have begun to appear in the literature, but none for mania. Behavior in mania tends to be much more disruptive and judgment to be more severely impaired than in depression. Consequently, unless a child is hospitalized, psychosocial treatments of mania are used adjunctly in acute episodes and, after their resolution, as part of maintenance treatment. Interpersonal psychotherapy (Klerman et al., 1984)  has been adapted for use in adult bipolar patients (Frank et al., 1990)  and depressed adolescents (Moreau et al., 1991; Mufson et al., 1993, 1994) [71,72,73]. It will have to be modified further for use with bipolar adolescents.
The high recurrence rate of mood disorder (37.5%), despite adherence to a regimen of lithium prophylaxis (Strober et al., 1990) , makes adjunctive psychosocial treatments, which may reduce the risk of recurrence, very attractive. Family factors in adult bipolar patients have been shown to influence rate of relapse (Miklowitz et al., 1988)  and level of social support to influence long-term outcome (O'Connell et al., 1985) . Psycho-educational family intervention that focuses on stress reduction and provides follow-up care, developed for families of hospitalized adults with mood disorders (Clarkin et al., 1990) , could be modified for use with families of children and adolescents with mania.
Group therapy has been reported to decrease relapse and rehospitalization rates in adult mania (Prien and Potter, 1990) , but there are no controlled studies of its use in any age group. Given the importance of peer groups to young people, this approach deserves exploration. Adjunct psychosocial treatments that help these young patients and their families to cope with the disruptiveness of bipolar illness, improve social functioning after the episode remits, and maintain and prolong remissions warrant study.
No data are available on the treatment of depression in children or adolescents who are bipolar or at high risk for bipolar disorder. A bipolar course ensues in 8.6% to 20% of depressed adolescents (Strober and Carlson, 1982; Strober et al., 1993) [98,99]. Predictors of bipolarity in adolescents include rapid onset of the episode, psychosis, psychomotor retardation, multigenerational family history of affective disorders, and hypomanic response to treatment with tricyclics (Strober and Carlson, 1982) . In a 24-month follow-up of 58 adolescents (18 psychotic, 40 nonpsychotic) who were hospitalized because of major depression, 5 (28%) of 18 psychotics, but none of the nonpsychotics, had switched into mania. In a nortriptyline study of prepubertal depression, 34% of the subjects had a family member with mania (Geller et al., 1989) . During follow-up of the prepubertal sample, it was noted that the 8 (14.8%) of 54 children who developed mania did so during or after treatment with a tricyclic antidepressant (Geller et al., 1993) . It is still not known whether tricyclic use increases the risk of switching into mania or developing rapid cycling. ECT is an effective, but little-used alternative treatment (Bertagnoli and Borchardt, 1990) , particularly for severe, delusional depressions. Geller and colleagues are currently conducting the first study that specifically evaluates the treatment of prepubertal bipolar depression, comparing lithium to placebo for the treatment of depression in outpatient children, aged 6 to 12 years, who are bipolar or have a multigenerational family history of bipolar disorder. However, preliminary results from the first 20 subjects (12 assigned to active treatment, 8 to placebo) showed no difference in improvement between the two treatment groups as measured by the Children's Global Assessment Scale (Geller et al., 1994) .
Brief, reproducible psychosocial treatment, including individual, group, and family treatment, deserves further study. The development of psychosocial therapy for depressed children and adolescents is very important, given the lack of proven efficacy for pharmacotherapy in this population and the tremendous impact of family and peers on children's functioning. Robbins and colleagues (1989)  reported that 47% of 38 hospitalized adolescents with major depression responded to 6 weeks of psychosocial treatment alone. Predictors of response to psychosocial treatment alone included nonmelancholic subtype and suppression on the dexamethasone suppression test.
Interpersonal psychotherapy (Klerman et al., 1984)  and cognitive therapy (Beck et al., 1979) , developed for the treatment of depression in adults, have been adapted for depressed adolescents (Moreau et al., 1991; Mufson et al., 1993, 1994; Wilkes and Rush, 1988) [71,72,73,107]. For bipolar depressed children and adolescents, who have a higher incidence of delusional thinking and psychomotor retardation than unipolar depressed children, this form of therapy may need additional modifications for use during acute episodes.
Controlled studies of psychosocial treatment of childhood and adolescent depression have shown significant improvement relative to the wait list controls, but little difference in efficacy between active treatments. For example, self-control and behavioral problem-solving therapy were equally efficacious in 29 moderately to severely depressed children, aged 9 to 12 years (Stark et al., 1987) . Both cognitive-behavioral therapy and relaxation training were effective treatments for 30 adolescent outpatients with symptoms of moderate depression (Reynolds and Coats, 1986) . A shortcoming of these early studies is that subjects were not given standardized diagnoses.
A recent open clinical trial of interpersonal psychotherapy for adolescents with 14 depressed adolescents (12 with major depression) used a structured interview for diagnosis and repeated assessments with other commonly used rating instruments for depression. The results were promising, and a randomized, controlled trial is planned (Mufson et al., 1994) .
Comparisons of two types of group therapy, social skills training and therapeutic support, in 66 adolescent outpatients (83% female) with major depression (88%) or dysthymia (12%) found an unexpected short-term advantage for therapeutic support, but no differences at 9-month follow-up (Fine et al., 1991) . In a well-designed study of 59 depressed adolescent outpatients (49% with DSM-III major depression, 7% RDC minor depression, and 44% RDC intermittent depression), two versions of a cognitive-behavioral group intervention, the "Coping with Depression Course" (one version involved an additional group for parents of the depressed adolescent), were superior to the wait list controls, and improvement was maintained at 2-year follow-up (Lewisohn et al., 1990) . However, at the end of the treatment protocol, a significant number of adolescents continued to meet entry criteria for the study (52.4% with parent groups and 57.1% adolescent only). From the wait list condition, however, 94.7% remained ill. There was a trend for greater efficacy when a parent was involved in treatment, and further studies that include joint sessions for the depressed teenager and their parents are planned.
Systematic study of family therapy in childhood and adolescent depression is sorely lacking. A brief family treatment model for adolescent suicide attempters and their families called Successful Negotiation Acting Positively (SNAP) has been described and is being tested in a large open trial (Rotheram-Borus et al., 1994) .
To delineate the "active ingredient" in psychosocial therapy, studies should include a control condition with therapist contact, so that a "placebo" response can be ruled out. It may be that much larger sample sizes will be required to detect differences between active treatments.
In summary, there are no controlled studies with adequate sample size of pharmacological or psychosocial treatments of bipolar disorder in children and adolescents. Ongoing studies of pharmacological treatment of bipolar disorder include two placebo-controlled trials of lithium in adolescent outpatients and one study of lithium in prepubertal depressed children who are bipolar or have a strong family history of bipolar disorder. Response rates to lithium of manic children and adolescents in open studies overall appear similar to the 75% rate reported in the early adult studies of lithium. Factors reported to contribute to lithium resistance in this age group include the presence of an Axis I diagnosis before the age of 12 years (Strober et al., 1988) , mixed states (Himmelhoch and Garfinkel, 1986) , and the presence of a personality disorder when euthymic (Kutcher et al., 1990) . Case reports suggest that ECT may be effective for treating mania and depression in children and adolescents.
Psychosocial treatments are necessary to address problems in functioning within the family, at school, and with peers (Puig-Antich et al., 1993) . Individual and group therapies are being developed and tested for children and adolescents with depression, but not for mania. The development and study of family therapy in this population lags behind other psychosocial treatment modalities.
Clearly, there is a great need for the critical assessment of currently available treatments for bipolar disorder in children and adolescents. As a first step, the efficacy of lithium, widely used in clinical practice, needs to be assessed under double-blind and placebo-controlled conditions. Subsequently, alternatives and adjuncts to lithium need to be explored for the patients who do not respond to lithium alone. A placebo arm also remains important in this episodic disorder, because one must control for the possibility of spontaneous remission of symptoms, reported to range from 22% (Janicak et al., 1989)  to as high as 40% in adult mania (Stokes et al., 1971) . No information is available about spontaneous or placebo-induced remission of mania in children or adolescents.
It is important to explore the possibility that lithium alone may be adequate to treat all symptoms, including delusions and hallucinations, associated with mania in children and adolescents. The report from the NIMH Workshop on Treatment of Bipolar Disorder that focused on adults stated that ". . . while it is clear that neuroleptics are helpful in managing acute mania, it would be helpful if there were research-generated guidelines for identifying patients who can be treated with lithium alone. Such guidelines would protect patients from unnecessary risks associated with neuroleptic treatment" (Prien and Potter, 1990, p. 410) .
There is an increased risk of tardive dyskinesia in mood-disordered patients treated with neuroleptics (Kane, 1988, 1991; Mukherjee et al., 1986) [56,57,74], and patients with childhood onset of bipolar disorder may be especially vulnerable because of longer lifetime neuroleptic exposure.
The methodology for clinical trials of medications in bipolar children and adolescents has advanced in recent years. For subject selection, structured diagnostic interviews have identified previously undiagnosed bipolar disorder in 5 (29%) of 17 adolescent inpatients (Gammon et al., 1983)  and 3 of 10 consecutively hospitalized adolescents with psychotic features during the Diagnostic Interview Schedule for Children (DISC 2.1) field trial (Fisher et al., 1993; Kafantaris, unpublished data) . Comorbidity with other Axis I diagnoses could also be identified with standardized diagnostic instruments such as the Schedule for Affective Disorders and Schizophrenia for Children-Present Episode (Chambers et al., 1985; Puig-Antich and Ryan, 1986) [19,83] and Epidemiologic Version (Orvaschel and Puig-Antich, 1987) . The Mania Rating Scale (Young et al., 1978)  has been studied for its ability to differentiate prepubertal mania from attention-deficit hyperactivity disorder (Fristad et al., 1992) . Dose prediction tools are available for the rapid and safe attainment of therapeutic lithium levels based on the child's weight (Weller et al., 1986)  or serum level 24 hours after a single 600-mg dose (Cooper et al., 1973; Cooper and Simpson, 1976; Geller and Fetner, 1989) [23,24,41]. Suggested predictors of a decreased probability of response to lithium also need to be examined. However, to ensure representative samples of prepubertal or adolescent mania, subjects with mixed mania and rapid cycling should be included in initial studies. Appropriate measures to capture any special features (e.g., depressive symptoms) during the episode should be included. If controlled data from these subgroups suggest decreased lithium responsiveness, subsequent studies would be warranted to evaluate this question further and to test adjunct and alternative treatments. Promising adjunct and alternative treatments from the adult literature include carbamazepine and valproic acid. The role of neuroleptics and high-potency benzodiazepines needs to be further defined.
The methodology for controlled study of psychosocial treatments in this population has been advanced by the development of treatment manuals, procedures to ensure the therapist's compliance with the treatment protocol, the use of standard diagnostic practices, and the use of contact-control conditions. Adjunct psychosocial treatments to help patients and their families cope with the disruptiveness of bipolar illness, improve functioning between episodes, and maintain and prolong remissions need to be studied. Finally, studies defining the efficacies of various psychosocial and pharmacological approaches, separately and in combination, are needed. In summary, much work remains to be done to address the treatment needs of children and adolescents with bipolar disorder.
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Accession Number: 00004583-199506000-00013