- Email: [email protected]
Risperidone Treatment for Juvenile Bipolar Disorder: A Retrospective Chart Review
Risperidone Treatment for Juvenile Bipolar Disorder: A Retrospective Chart Review JEAN A. FRAZIER, M.D., MICHELE C. MEYER, M.D., JOSEPH BIEDERMAN, M.D., JANET WOZNIAK, M.D., TIMOTHY E. WILENS, M.D., THOMAS J. SPENCER, M.D., GRACE S. KIM, MAR., AND STEPHANIE SHAPIRO, B.A.
ABSTRACT Objective: To investigate the effectiveness and tolerability of the atypical neuroleptic risperidone in the treatment of juvenile mania. Method: This is a retrospective chart review of outpatients with the diagnosis of bipolar disorder (DSM-/V) treated with risperidone at a university center. Response to treatment was evaluated using the Clinical Global Impression Scale (CGI) with separate assessments of mania, psychosis, aggression, and attention-deficit/hyperactivity disorder (ADHD). Results: Twenty-eight youths (mean ± SD age, 10.4 ± 3.8 years) with bipolar disorder (25 mixed and 3 hypomanic) who had been treated with risperidone were identified. These children received a mean dose of 1.7 ± 1.3 mg over an average period of 6.1 ± 8.5 months. Using a CGllmprovement score of:;:;2 (very much/much improved) to define robust improvement, 82% showed improvement in both their manic and aggressive symptoms, 69% in psychotic symptoms, but only 8% in ADHD symptoms. Conclusions: Although limited by its retrospective nature, this study suggests that risperidone may be effective in the treatment of manic young people and indicates the need for controlled clinical trials of risperidone and other atypical neuroleptics in juvenile mania. J. Am. Acad. Child Ado/esc. Psychiatry, 1999, 38(8):960-965. Key Words: juvenile, bipolar disorder, risperidone.
In a series of studies, our group extended previous work documenting the severity and chronicity of juvenile mania (Biederman et al., 1996; Wozniak and Biederman, 1996; Wozniak et al., 1995). However, because of the controversy regarding pediatric mania, little research has been done on the treatment of the disorder. In an effort to gain some understanding of the therapeutics of juvenile mania, our group conducted a systematic chart review aimed at capturing our clinical experience with this disorder (Biederman et al., in press). This chart review documented that mood stabilizers (lithium carbonate, carbamazepine, and valproic acid) were helpful in controlling manic symptoms in children; however, they had a slow onset of action and a high rate of relapse (Biederman et al., in press). These results prompted the search for alternative agents for the treatment of juvenile mania.
Accepted February 10, 1999. From the Child Psychiatry Department, Massachusetts General Hospital, Harvard Medical School, Boston. Reprint requests to Dr. Frazier, Massachusetts General Hospita4 ACC 725, 15 Parkman Street, Boston, MA 02114; e-maiL·[email protected]. 0890-8567/99/3808-0960©1999 by the American Academy of Child and Adolescent Psychiatry.
960
Although typical neuroleptics have been used in the acute and long-term management of adults and children with mania, concerns about neuroleptic side effects have limited their use (Campbell et al., 1988; Gelenberg and Hopkins, 1996). The atypical neuroleptics, with their combined dopaminergic and serotonergic action, have held the promise of a unique pharmacological profile that could be advantageous in the management of bipolar children with a less adverse side effect profile. Because recent reports suggested that risperidone was associated with improved mood stabilization in adult bipolar patients with incomplete response to mood stabilizers (Ghaemi et al., 1997; Goodnick, 1995; McIntyre et al., 1997; Tohen et al., 1996; Vieta et al., 1995, 1998), we evaluated the effectiveness of this agent in treating juvenile mania. We now report the findings of a systematic chart review of our clinical experience with risperidone in the treatment of children and adolescents with bipolar disorder. We hypothesized that risperidone would be effective and safe in this population. METHOD Subjects were ascertained through referrals to an outpatient pediatric psychopharmacology program at a major university center. The
]. AM. ACAD. CHILD ADOLESC. PSYCHIATRY, 38:8, AUGUST 1999
RISPERIDONE TREATMENT FOR JUVENILE MANIA
records of the first 28 children and adolescents with DSM-N bipolar disorder treated with risperidone were reviewed. The data obtained through the chart review included age, symptoms at presentation, the presence of comorbid conditions, previous and concurrent medication trials, adverse effects, and response to treatment as recorded by the treating clinicians. All diagnoses were made by the treating child psychiatrist using DSM-N criteria based on clinical interviews with the parents and the child and upon review of all available ancillary information including previous records. The overall severity of symptoms before risperidone treatment and the improvement of symptoms during risperidone treatment were evaluated using the National Institute of Mental Health Clinical Global Impression Scale (CGI) (CGI Severity [1 = not ill; 7 = extremely ill] and CGI Improvement [1 = very much improved; 7 = very much worse] scales) (National Institute of Mental Health, 1985). To differentiate the effects of treatment on various components of the clinical picture of juvenile mania, separate ratings were obtained for mania, psychosis, aggression, and attention-deficit! hyperactivity disorder (ADHD) using a syndrome-specific approach to coding CGI ratings as previously used by our group (Spencer et al., 1995). The first author .A. F.) , a board-certified child and adolescent psychiatrist, completed all ratings. Mania and ADHD were defined by DSM-N criteria. Psychosis was defined by positive symptoms (hallucinations, delusions, bizarre behavior, and thought disorder). Aggression was defined as physical assaultiveness or destruction of property. Because the cases were selected for review on the basis of the patients' having the diagnosis of bipolar disorder and receiving treatment with risperidone, blindness was not possible. Children were rated according to their follow-up appointment chart notes, which were writreri by the treating physician. The majority of children (n = 19) were seen at monthly intervals for their psychopharmacology appointments. The remainder of patients were seen every other week (n = 3) and every other month (n = 6). Final CGI ratings were compared with baseline ratings (prior to the initiation of risperidone). The CGI ratings before and during treatment with risperidone were analyzed using the signed rank statistic (p < .01 as significant [2-tailed]).
a
RESULTS
The mean (±SD) age of the sample was 10.4 years ± 3.8 (range 4-17 years); 17 (61 %) were children (<12 years) and 11 (39%) were adolescents (~12 years). All but one subject were male. Of the 28 youths with bipolar disorder, 25 (89%) were in the midst of a mixed episode and 3 (11 %) were in the midst of a hypomanic episode at the time of treatment with risperidone. The average number of comorbid diagnoses was 2.6 ± 0.8; 25 children (89%) had a comorbid diagnosis of ADHD and 8 (29%) had a comorbid diagnosis of pervasive developmental disorder (PDD) (Table 1). Thirteen (46%) of the 28 children had psychotic features (thought disorder, n = 9; auditory hallucinations, n = 3; visual hallucinations, n = 2; paranoia, n = 7; thought insertion, n = 1). The majority of bipolar youths had numerous previous medication trials, including stimulants (n = 20; 71 %), a-agonists and B-blockers (n = 20; 71 %), mood
J.
AM. ACAD. CHILD ADOLESC. PSYCHIATRY, 38:8, AUGUST 1999
TABLE 1 Clinical Characteristics of the Sample (N = 28) Age (years)a Gender, % male No. of comorbid diagnoses a Comorbid diagnoses, n (%) Attention-deficit/hyperactivity disorder Oppositional defiant disorder Pervasive developmental disorder Language disorder Anxiety disorders Conduct disorder Obsessive-compulsive disorder Posttraumatic stress disorder Tics a
10.4 ± 3.8
96.4 2.6 ± 0.8 25 10 8 7 7 6
(89.3) (35.7) (28.6) (25.0) (25.0) (21.4)
3 (l0.7) 2 (7.1) 2 (7.1)
Mean ± SD.
stabilizers (n = 18; 64%), serotonin reuptake inhibitors (SRIs) (n = 12; 43%), tricyclic antidepressants (TCAs) (for ADHD) (n = 12; 43%), atypical antidepressant (bupropion) (n = 6; 21 %), typical antipsychotics (n = 9; 32%) alone or in combination, and benzodiazepines (n = 2; 7%). The average number of previous medication trials was 3.6 ± 1.7. Only 1 patient had been medicationnaive and 2 had received another atypical neuroleptic (olanzapine) . The dose of risperidone was adjusted by the treating clinician based on response and side effects with the aim of using the lowest dose that achieved acceptable clinical response. The mean daily dose of risperidone at optimal response was 1.7 ± 1.3 mg. The average length of treatment and follow-up for this sample was 6.1 ± 8.5 (range 0.25-34) months. Concurrent medications were used with risperidone in 27 patients (96%). The average number of concurrent medications was 1.8 ± 1.1. These included mood stabilizers (n = 18; 64%), anti-ADHD treatments (n = 16; 57%) (stimulants [n = 8; 28%], a-agonists [n = 7; 25%], TCAs [n = 3; 11 %]) (I patient required 3 different anti-ADHD medications), SRIs (n = 7; 25%), other antipsY-
961
FRAZIER ET AL.
A.
CGI Severity Extremely 7 Severe Severe 6 Marked
5
Moderate
4
Mild
3
~:=J
p<. .01
p<. .01
Borderline 2
1
Nonnal
Mlnia
ADHD
Psychosis
(N=28)
(N=25)
(N=13)
Aggression (N=28)
B. CGllmprovement (Mean Improvement) Very 1 Much Improved Much 2 Improved
3 MinirreKy Improved
No Change 4
c.
Mania
ADHD
Psychosis
Aggression
(N=28)
(N=25)
(N=13)
(N=28)
Percent Improved (CGllmp $ 2) .90 80 70
60 50
observed in the ratings of severity of ADHD symptoms prior to and during risperidone treatment (ADHD CGI Severity score = 5.0 ± 0.8 at baseline versus 4.3 ± 0.8 on risperidone; p < .01) (Fig. 1A). Consistent with CGI Severity scores were the CGI Improvement scores. These also showed a marked overall improvement of mania (mean Mania CGI Improvement = 2.0 ± 1.3), aggression (mean Aggression CGI Improvement = 1.7 ± 0.9), and psychosis ratings (mean Psychosis CGI Improvement = 2.2 ± 0.8), but not for ADHD (mean ADHD CGI Improvement = 3.4 ± 0.8) (Fig. 1B). Using a categorical definition of improvement of a CGI of $2, 82% were considered improved for mania, 82% were considered improved for aggression, 69% for psychosis, and 8% for ADHD (Fig. 1C) as reflected in the very modest global improvement scores (mean ADHD CGI Improvement = 3.4 ± 0.8 [minimally improved]) (Fig. 1C). Treatment with risperidorie was very well tolerated; no serious adverse effects were observed (Table 2). Common side effects included weight gain (n = 5; 18%), sedation (mild in all cases) (n = 5; 18%), and drooling (n = 2; 7%). None of the patients had any evidence of delirium. Only one patient had increased aggression while taking risperidone. No child developed tardive dyskinesia (TD) during the follow-up period. Prolactin levels were available in 11 subjects, and they were elevated in all but 2 children (82%) (mean prolactin level 32.8 ng/mL ± 12.05 [normal range 0-15]). No baseline prolactin levels were available for comparison. Electrocardiograms (ECGs) were available in 4 patients, and all were within normal limits.
%40 30
TABLE 2
20
Risperidone Treatment in Juvenile Bipolat Disorder
10
o Mania (N=28)
ADHD (N=25)
Psychosis (N=13)
Aggression (N=28)
Fig. 1 CGI Severity ratings (A), ImptOvemenc ratings (B), and percentage imptOved (e) in youths with juvenile mania treated with risperidone. CGI = Clinical Global Impression Scale; ADHD = attention-deficit/hyperactivity disorder.
was a robust improvement in aggression in these children as noted by the significant reduction of the Aggression CGI Severity score (5.1 ± 1.2 at baseline and 3.0 ± 1.2 on risperidone; p < .01). CGI Severity ratings of psychotic symptoms also significantly declined from 3.6 ± 0.4 at baseline to 1.5 ± 0.24 on risperidone (p < .01). Despite statistical significance, much more modest effects were
962
Mean daily dosage (mg) Average time to optimal response (months) Average length of treatment (months) Mean no. of concurrent medications Adverse effects Weight gain Sedation Drooling Night terrors Headache Increased aggressiveness Galactorrhea Delayed ejaculation4 Weight loss Increased fearfulness
1.7 ± 1.9 ± 6.1 ± 1.8 ± 5 5 2 I 1 1 1 1 1 1
1.3 1.0 8.5 1.I
(17.9) (17.9) (7.1) (3.6) (3.6) (3.6) (3.6) (3.6) (3.6) (3.6)
Note: Values represent mean ± SD or n (%). a Reported by a I7-year-old male.
J. AM. ACAD. CHILD ADOLESC. PSYCHIATRY, 38:8, AUGUST 1999
RISPERIDONE TREATMENT FOR JUVENILE MANIA
Case Vignette
A 5?i-year-old boy presented to the clinic with a history of severe behavioral disturbances since age 2 years. He was hyperactive, impulsive, highly dysphoric, and explosive. The symptoms had increased in severity and intensity over the years. He had had multiple medication trials including various stimulants which all exacerbated the child's symptoms of agitation, disturbed sleep, and racing thoughts. He was hospitalized 4 times during the year prior to presentation to our outpatient clinic. Other medication trials included fluoxetine, which resulted in increased agitation and irritability, and clonidine, lithium, and valproate, all of which led to worsening of symptoms. In addition, he was tried on a combination of mood stabilizers and selective serotonin reuptake inhibitors and a combination of mood stabilizers and bupropion without success. Upon presentation to our clinic, he was taking 25 mg of sertraline every other day and guanfacine 0.5 mg b.i.d. He continued to be agitated, with daily unprovoked temper outbursts, impulsiveness, loud speech, aggressiveness, labile affect, limited eye contact, and impaired concentration. This patient had an unremarkable medical history. His developmental history was normal, except that he had a history of a mild speech delay. Because of his behavioral difficulties, he required special education and a one-to-one aide in the classroom. Family history was positive for ADHD in 2 older brothers and for depression in the mother. Evaluation at our center led to the diagnosis of juvenile bipolar disorder. Risperidone treatment was initiated at 0.75 mg/day. The patient had a remarkable response to risperidone within weeks, with a dramatic decrease in aggression and manic symptoms with no side effects. He continued to receive sertraline and guanfacine as before. DISCUSSION
In a systematic chart review of all children and adolescents with a clinical diagnosis of bipolar disorder treated with risperidone at our center, we found that risperidone treatment was associated with a rapid, robust, and sustained response in controlling manic, psychotic, and aggressive symptoms in a majority of these children. This positive response to risperidone was particularly striking considering that all but one child had been aggressively medicated before with limited success. These encouraging initial results suggest that risperidone
]. AM. ACAD. CHILD ADOLESC. PSYCHIATRY, 38:8, AUGUST 1999
may be a promising agent in the management of manic young people and indicate the need for controlled clinical trials of this compound and other atypical neuroleptics in the treatment of juvenile mania. The rapid and sustained response to risperidone treatment stands in sharp contrast to previous, much more modest results on mood stabilizers in the same population (Biederman et al., in press). Our previous work evaluating treatment approaches to juvenile mania revealed that although mood stabilizers were efficacious in improving manic symptoms, their effects took many months and were associated with high levels of relapse (Biederman et al., in press). Our results of responsivity to risperidone in juvenile mania are consistent with previous reports in the adult literature (Tohen et al., 1996; Vieta et al., 1995, 1998). For example, a similarly positive response to ours has been reported by Tohen and colleagues (1996) and by Vieta and colleagues (1998). As in our series, many of these adults had treatment-refractory or dysphoric mania and had limited previous success with mood stabilizers. It is noteworthy that the improvement observed in our sample was not secondary to tranquilization or sedation. Although sedation was noted in 18% of subjects treated with risperidone, improvement observed in our sample was not due to excessive sedation. Instead clinical improvement in mood and behavior was noted by the children, parents, and clinicians and was considered to be of high quality. Although it remains unclear why risperidone treatment has been so impressive in juvenile bipolar disorder, the improvement may be due to the unique pharmacological profile of risperidone with its high ratio of 5-HTzA antagonism to its D2-receptor antagonism, which may account for its efficacy in treating the dysphoric and manic mood components (Tohen et al., 1996) that characterize juvenile bipolar disorder (Wozniak et al., 1995). The decrease in aggression with risperidone in our series is consistent with an emerging body of literature in pediatric psychopharmacology documenting the effectiveness of risperidone in the treatment of aggression in young people. For example, a recent report documented that risperidone was useful in treating severe aggression in children and adolescents with conduct disorder (Fras and Major, 1995). An additional case series reported rapid, moderate to marked improvement in 8 of 11 children (age range 5.5-16 years) with affective symptoms (suggestive of bipolar disorder), aggression, and marked
963
FRAZIER ET AL.
behavioral problems when treated with risperidone either alone (n = 1) or in conjunction with mood stabilizers (n = 7) (Schreier, 1998). Inasmuch as juvenile mania is frequently comorbid with conduct disorder, risperidone could be effective in treating the dysphoric aggression displayed by manic children (Wozniak et al., 1995). In sharp contrast to the positive effects of risperidone in the treatment of manic symptoms, its effects on ADHD symptomatology were minimal. There was a need for additional anti-ADHD medication (e.g., TCAs, a-agonists, stimulants) in 57% (n = 16) of patients because they had persistent symptoms of ADHD. One of these children required 3 anti-ADHD medications. These results are not entirely surprising considering that dopaminergic activation and not suppression underlie the treatment of ADHD, providing support for the notion that mania and ADHD are independent syndromes (Wozniak and Biederman, 1995). These findings suggest that children with comorbid bipolar disorder and ADHD require treatment for both disorders (Biederman et al., in press; Wozniak et al., 1995). Twenty-nine percent of the sample had comorbid PDD. These findings are consistent with our previous work and several case reports supporting the overlap between PDD and BPD (Komoto et al., 1984; Sovner, 1989; Steingard and Biederman, 1987; Wozniak et al., 1997). Considering the severity of mania, the identification and treatment of bipolarity in youths with PDD is of important clinical significance. Treatment with risperidone in our series was well tolerated, and no child experienced serious adverse effects. In our series, the most common adverse effects were weight gain and sedation, each observed in 18% of cases. Sedation was considered mild and well tolerated. Weight gain on risperidone can be a concerning side effect in some children and adults (Brecher and Geller, 1997). Although weight gain was noted in a substantial minority of children (18%), it was not adequately quantified. The weight gain associated with risperidone is generally modest in adult patients, but it can be marked in some individuals (Brecher and Geller, 1997). Given that weight gain was noted in 18% of our subjects and the health hazards associated with excessive weight gain, clinicians should consider weight gain in the risk versus benefit analysis when using risperidone in the management of bipolar young people. It is noteworthy that one child (4%) became more aggressive during risperidone treatment,
964
suggesting that risperidone may also be activating (or perhaps not effective) in a minority of manic youths. No cases of extrapyramidal side effects (EPS) were observed. The absence of EPS in our series is consistent with 3 previous reports in children which failed to observe EPS with risperidone treatment used for various psychiatric conditions (McDougle et al., 1997; Quintana and Keshava, 1995). Although Armenteros and colleagues (1997) reported that 4 of 10 schiwphrenic children developed EPS that required concomitant benztropine, that study used high doses of risperidone (4-10 mg) and a rapid titration schedule over a 3-week period, which may account for the number of cases experiencing EPS. In addition, none of our 28 patients, treated with risperidone for an average of 6.1 ± 8.5 months (range 0.25-34 months), developed TD. These results are encouraging, yet uncertainties remain as to whether risperidone will be associated with TD in children with long-term use, particularly because TD has been associated with risperidone treatment in adults (Haberfeliner, 1997). Although atypical neuroleptics may have a lesser risk for TD than typical agents, more information is needed to evaluate the risk for TD with risperidone and other atypical neuroleptics in children. ECG and prolactin data were available in only a minority of subjects. All available ECGs were within normal limits, and all but one available prolactin level was elevated. In the adult and pediatric literature, elevated prolactin levels have been associated with galactorrhea and amenorrhea in females and gynecomastia in males (Goff and Shader, 1995; McDougle et al., 1997). In our series, one adolescent girl developed galactorrhea and amenorrhea. Since the long-term implications of elevated prolactin levels in children remain unknown, more work is needed to evaluate the clinical implications of hyperprolactinemia in developing young people. The findings discussed in this report should be viewed against their methodological limitations. Although ours represents the largest series of children reported to date with juvenile bipolar disorder who were treated with risperidone, the data presented were derived from retrospective chart reviews and as such are subject to observation and assessment bias. Given the retrospective nature of this study, syndrome-specific ratings were used. Future studies can benefit from using instruments such as the Young Mania Rating Scale (Fristad et al., 1992). Nonetheless, these preliminary results are encouraging and indicate the need for prospective controlled clinical trials
J.
AM. ACAD. CHILD ADOLESC. PSYCHIATRY, 38:8, AUGUST 1999
RISPERIDONE TREATMENT FOR JUVENILE MANIA
with risperidone and other atypical neuroleptics in the treatment of juvenile mania. Despite the inherent limitations of chart reviews and open series, such data are needed to begin to formulate hypotheses regarding potential therapeutic uses of novel compounds and new treatment approaches to a severe disorder such as juvenile bipolar disorder. Inasmuch as the majority of the children in this study received multiple medications, our results cannot help clarify whether risperidone will be effective as monotherapy or in combination with other psychotropics. However, because the average daily doses of risperidone used were relatively low, it remains to be seen whether more aggressive treatment regimens with risperidone will obviate the need for mood stabilizers. In addition, more work is needed to establish the optimal duration of treatment with risperidone in children with bipolar disorder. Summary and Clinical Implications
Despite these considerations, this retrospective chart review of a large series of children with bipolar disorder treated naturalistically showed that risperidone provided rapid and sustained treatment of manic, psychotic, and aggressive symptoms in these children. These initial encouraging results indicate the need for additional short- and long-term controlled trials of risperidone and other atypical neuroleptics in the treatment of juvenile bipolar disorder, either as monotherapy or in combination with mood stabilizers, with careful assessment of its associated risks.
REFERENCES Armenteros JL, Whitaker AH, Welikson M, Stedge DJ, Gorman J (1997), Risperidone in adolescents with schiwphrenia: an open pilot smdy.] Am
Acad ChildAdolesc Psychiatry 36:694-700 Biederman J, Faraone S, Mick E et al. (1996), Accention-deficit hyperactivity disorder and juvenile mania: an overlooked comorbidity?] AmAcad Child
Adolesc Psychiatry 35:997-1008 Biederman J, Mick E, Bostic Jet al. (in press), Pharmacologic treatment of ADHD in youth with severe mood instability: a systematic chart review.
] Child Adolesc Psychopharmacol Brecher M, Geller W (1997), Weight gain with risperidone (leccer).] Clin
PsychopharmacoI17:435-436 Campbell M, Adams P, Perty R, Spencer EK, Overall JE (1988), Tardive and withdrawal dyskinesia in autistic children: a prospective smdy. Psychopharmacol Bull 24:251-255
]. AM. ACAD. CHILD ADOLESC. PSYCHIATRY, 38:8, AUGUST 1999
Fras I, Major LF (1995), Clinical experience with risperidone (leccer).] Am
Acad ChildAdolesc Psychiatry 34:833 Fristad MA, Weller EB, Weller RA (1992), The mania rating scale: can it be used in children? A preliminary report.] Am Acad ChildAdolesc Psychiatry 31:252-257 Gelenberg AJ, Hopkins HS (1996), Antipsychotics in bipolat disorder.] Clin
Psychiatry 57:49-52 Ghaemi SN, Sachs GS, Baldassano CF, Truman CJ (1997), Acute treatment of bipolar disorder with adjunctive risperidone in outpatients. Can] Psychiatry 42: 196-199 Goff D, Shader R (1995), Non-neurological side effects of anti-pSychotic agents. In: Schizophrenia, Hirsch S, Weinberger D, eds. Oxford, England: Blackwell Science, pp 566-586 Goodnick P (1995), Risperidone treatment of refractoty acute mania.] Clin
Psychiatry 56:431-432 Haberfellner EB (1997), Tardive dyskinesia during treatment with risperidone. Pharmacopsychiatry 30:271 Komoto J, Seigo U, Hirata J (1984), Infantile autism and affective disorder.
] Autism Dev Disord 14:81-84 McDougle C, Holmes J, Bronson M et al. (1997), Risperidone treatment of children and adolescents with pervasive developmental disorders: a prospective, open-label smdy.] Am Acad ChildAdolesc Psychiatry 36:685-693 McIntyre R, Young L, Hasey G, Patelis-Siotis I, Jones B (1997), Risperidone treatment of bipolar disorder. Can] Psychiatry 42:88-90 National Instimte of Meneal Health (1985), CGI (Clinical Global Impression) Scale-NIMH. Psychopharmacol Bull 21 :839-844 Quintana H, Keshava M (1995), Case study: risperidone in children and adolescents with schizophrenia. ] Am Acad Child Adolesc Psychiatry 34: 1292-1296 Schreier HA (1998), Risperidone for young children with mood disorders and aggressive behavior.] Child Adolesc PsychopharmacoI8:49-59 Sovner R (1989), The use of valproate in the treatment of mentally retarded persons with typical and atypical bipolar disorders. ] Clin Psychiatry 50:40-43 Spencer T, Wilens TE, Biederman J, Faraone SV; Ablon S, Lapey K (1995), A double-blind, crossover comparison of methylphenidate and placebo in adults with childhood-onset attention deficit hyperactivity. Arch Gen
Psychiatry 52:434-443 Steingard R, Biederman J (1987), Lithium responsive manic-like symptoms in two individuals with autism and mental retardation. ] Am Acad Child
Adolesc Psychiatry 26:932-935 Tohen M, Zarate C Jr, Centorrino F, Hegarty J, Froeschl M, Zarate S (1996), Risperidone in the treatment of mania.] Clin Psychiatry 57:249-253 Vieta E, Gasto C, Colom F, Martinez A, Otero A, Vallejo J (1998), Treatment of refractoty rapid cycling bipolar disorder with risperidone.] Clin
PsychopharmacoI18:172-174 Vieta E, Gasto C, Escobar R (1995), Treatment of dysphoric mania with risperidone. Hum PsychopharmacoI1O:491-492 Wozniak J, Biederman J (1995), Childhood mania exists (and coexists) with ADHD. American Society of Clinical Psychopharmacology Progress Notes 6:4-5 Wozniak J, Biederman J (1996), A pharmacological approach to the quagmire of comorbidicy in juvenile mania.]Am Acad ChildAdolesc Psychiatry 35:826-828 WozniakJ, BiedermanJ, Faraone S et al. (1997), Mania in children with pervasive developmental disorder revisited. ] Am Acad Child Adolesc Psychiatry 36: 1552-1559 Wozniak J, Biederman J, Kiely K et al. (1995), Mania-like symptoms suggestive of childhood onset bipolar disorder in clinically referred children. ]
Am Acad ChildAdolesc Psychiatry 34:867-876
965
ABSTRACT Objective: To investigate the effectiveness and tolerability of the atypical neuroleptic risperidone in the treatment of juvenile mania. Method: This is a retrospective chart review of outpatients with the diagnosis of bipolar disorder (DSM-/V) treated with risperidone at a university center. Response to treatment was evaluated using the Clinical Global Impression Scale (CGI) with separate assessments of mania, psychosis, aggression, and attention-deficit/hyperactivity disorder (ADHD). Results: Twenty-eight youths (mean ± SD age, 10.4 ± 3.8 years) with bipolar disorder (25 mixed and 3 hypomanic) who had been treated with risperidone were identified. These children received a mean dose of 1.7 ± 1.3 mg over an average period of 6.1 ± 8.5 months. Using a CGllmprovement score of:;:;2 (very much/much improved) to define robust improvement, 82% showed improvement in both their manic and aggressive symptoms, 69% in psychotic symptoms, but only 8% in ADHD symptoms. Conclusions: Although limited by its retrospective nature, this study suggests that risperidone may be effective in the treatment of manic young people and indicates the need for controlled clinical trials of risperidone and other atypical neuroleptics in juvenile mania. J. Am. Acad. Child Ado/esc. Psychiatry, 1999, 38(8):960-965. Key Words: juvenile, bipolar disorder, risperidone.
In a series of studies, our group extended previous work documenting the severity and chronicity of juvenile mania (Biederman et al., 1996; Wozniak and Biederman, 1996; Wozniak et al., 1995). However, because of the controversy regarding pediatric mania, little research has been done on the treatment of the disorder. In an effort to gain some understanding of the therapeutics of juvenile mania, our group conducted a systematic chart review aimed at capturing our clinical experience with this disorder (Biederman et al., in press). This chart review documented that mood stabilizers (lithium carbonate, carbamazepine, and valproic acid) were helpful in controlling manic symptoms in children; however, they had a slow onset of action and a high rate of relapse (Biederman et al., in press). These results prompted the search for alternative agents for the treatment of juvenile mania.
Accepted February 10, 1999. From the Child Psychiatry Department, Massachusetts General Hospital, Harvard Medical School, Boston. Reprint requests to Dr. Frazier, Massachusetts General Hospita4 ACC 725, 15 Parkman Street, Boston, MA 02114; e-maiL·[email protected]. 0890-8567/99/3808-0960©1999 by the American Academy of Child and Adolescent Psychiatry.
960
Although typical neuroleptics have been used in the acute and long-term management of adults and children with mania, concerns about neuroleptic side effects have limited their use (Campbell et al., 1988; Gelenberg and Hopkins, 1996). The atypical neuroleptics, with their combined dopaminergic and serotonergic action, have held the promise of a unique pharmacological profile that could be advantageous in the management of bipolar children with a less adverse side effect profile. Because recent reports suggested that risperidone was associated with improved mood stabilization in adult bipolar patients with incomplete response to mood stabilizers (Ghaemi et al., 1997; Goodnick, 1995; McIntyre et al., 1997; Tohen et al., 1996; Vieta et al., 1995, 1998), we evaluated the effectiveness of this agent in treating juvenile mania. We now report the findings of a systematic chart review of our clinical experience with risperidone in the treatment of children and adolescents with bipolar disorder. We hypothesized that risperidone would be effective and safe in this population. METHOD Subjects were ascertained through referrals to an outpatient pediatric psychopharmacology program at a major university center. The
]. AM. ACAD. CHILD ADOLESC. PSYCHIATRY, 38:8, AUGUST 1999
RISPERIDONE TREATMENT FOR JUVENILE MANIA
records of the first 28 children and adolescents with DSM-N bipolar disorder treated with risperidone were reviewed. The data obtained through the chart review included age, symptoms at presentation, the presence of comorbid conditions, previous and concurrent medication trials, adverse effects, and response to treatment as recorded by the treating clinicians. All diagnoses were made by the treating child psychiatrist using DSM-N criteria based on clinical interviews with the parents and the child and upon review of all available ancillary information including previous records. The overall severity of symptoms before risperidone treatment and the improvement of symptoms during risperidone treatment were evaluated using the National Institute of Mental Health Clinical Global Impression Scale (CGI) (CGI Severity [1 = not ill; 7 = extremely ill] and CGI Improvement [1 = very much improved; 7 = very much worse] scales) (National Institute of Mental Health, 1985). To differentiate the effects of treatment on various components of the clinical picture of juvenile mania, separate ratings were obtained for mania, psychosis, aggression, and attention-deficit! hyperactivity disorder (ADHD) using a syndrome-specific approach to coding CGI ratings as previously used by our group (Spencer et al., 1995). The first author .A. F.) , a board-certified child and adolescent psychiatrist, completed all ratings. Mania and ADHD were defined by DSM-N criteria. Psychosis was defined by positive symptoms (hallucinations, delusions, bizarre behavior, and thought disorder). Aggression was defined as physical assaultiveness or destruction of property. Because the cases were selected for review on the basis of the patients' having the diagnosis of bipolar disorder and receiving treatment with risperidone, blindness was not possible. Children were rated according to their follow-up appointment chart notes, which were writreri by the treating physician. The majority of children (n = 19) were seen at monthly intervals for their psychopharmacology appointments. The remainder of patients were seen every other week (n = 3) and every other month (n = 6). Final CGI ratings were compared with baseline ratings (prior to the initiation of risperidone). The CGI ratings before and during treatment with risperidone were analyzed using the signed rank statistic (p < .01 as significant [2-tailed]).
a
RESULTS
The mean (±SD) age of the sample was 10.4 years ± 3.8 (range 4-17 years); 17 (61 %) were children (<12 years) and 11 (39%) were adolescents (~12 years). All but one subject were male. Of the 28 youths with bipolar disorder, 25 (89%) were in the midst of a mixed episode and 3 (11 %) were in the midst of a hypomanic episode at the time of treatment with risperidone. The average number of comorbid diagnoses was 2.6 ± 0.8; 25 children (89%) had a comorbid diagnosis of ADHD and 8 (29%) had a comorbid diagnosis of pervasive developmental disorder (PDD) (Table 1). Thirteen (46%) of the 28 children had psychotic features (thought disorder, n = 9; auditory hallucinations, n = 3; visual hallucinations, n = 2; paranoia, n = 7; thought insertion, n = 1). The majority of bipolar youths had numerous previous medication trials, including stimulants (n = 20; 71 %), a-agonists and B-blockers (n = 20; 71 %), mood
J.
AM. ACAD. CHILD ADOLESC. PSYCHIATRY, 38:8, AUGUST 1999
TABLE 1 Clinical Characteristics of the Sample (N = 28) Age (years)a Gender, % male No. of comorbid diagnoses a Comorbid diagnoses, n (%) Attention-deficit/hyperactivity disorder Oppositional defiant disorder Pervasive developmental disorder Language disorder Anxiety disorders Conduct disorder Obsessive-compulsive disorder Posttraumatic stress disorder Tics a
10.4 ± 3.8
96.4 2.6 ± 0.8 25 10 8 7 7 6
(89.3) (35.7) (28.6) (25.0) (25.0) (21.4)
3 (l0.7) 2 (7.1) 2 (7.1)
Mean ± SD.
stabilizers (n = 18; 64%), serotonin reuptake inhibitors (SRIs) (n = 12; 43%), tricyclic antidepressants (TCAs) (for ADHD) (n = 12; 43%), atypical antidepressant (bupropion) (n = 6; 21 %), typical antipsychotics (n = 9; 32%) alone or in combination, and benzodiazepines (n = 2; 7%). The average number of previous medication trials was 3.6 ± 1.7. Only 1 patient had been medicationnaive and 2 had received another atypical neuroleptic (olanzapine) . The dose of risperidone was adjusted by the treating clinician based on response and side effects with the aim of using the lowest dose that achieved acceptable clinical response. The mean daily dose of risperidone at optimal response was 1.7 ± 1.3 mg. The average length of treatment and follow-up for this sample was 6.1 ± 8.5 (range 0.25-34) months. Concurrent medications were used with risperidone in 27 patients (96%). The average number of concurrent medications was 1.8 ± 1.1. These included mood stabilizers (n = 18; 64%), anti-ADHD treatments (n = 16; 57%) (stimulants [n = 8; 28%], a-agonists [n = 7; 25%], TCAs [n = 3; 11 %]) (I patient required 3 different anti-ADHD medications), SRIs (n = 7; 25%), other antipsY-
961
FRAZIER ET AL.
A.
CGI Severity Extremely 7 Severe Severe 6 Marked
5
Moderate
4
Mild
3
~:=J
p<. .01
p<. .01
Borderline 2
1
Nonnal
Mlnia
ADHD
Psychosis
(N=28)
(N=25)
(N=13)
Aggression (N=28)
B. CGllmprovement (Mean Improvement) Very 1 Much Improved Much 2 Improved
3 MinirreKy Improved
No Change 4
c.
Mania
ADHD
Psychosis
Aggression
(N=28)
(N=25)
(N=13)
(N=28)
Percent Improved (CGllmp $ 2) .90 80 70
60 50
observed in the ratings of severity of ADHD symptoms prior to and during risperidone treatment (ADHD CGI Severity score = 5.0 ± 0.8 at baseline versus 4.3 ± 0.8 on risperidone; p < .01) (Fig. 1A). Consistent with CGI Severity scores were the CGI Improvement scores. These also showed a marked overall improvement of mania (mean Mania CGI Improvement = 2.0 ± 1.3), aggression (mean Aggression CGI Improvement = 1.7 ± 0.9), and psychosis ratings (mean Psychosis CGI Improvement = 2.2 ± 0.8), but not for ADHD (mean ADHD CGI Improvement = 3.4 ± 0.8) (Fig. 1B). Using a categorical definition of improvement of a CGI of $2, 82% were considered improved for mania, 82% were considered improved for aggression, 69% for psychosis, and 8% for ADHD (Fig. 1C) as reflected in the very modest global improvement scores (mean ADHD CGI Improvement = 3.4 ± 0.8 [minimally improved]) (Fig. 1C). Treatment with risperidorie was very well tolerated; no serious adverse effects were observed (Table 2). Common side effects included weight gain (n = 5; 18%), sedation (mild in all cases) (n = 5; 18%), and drooling (n = 2; 7%). None of the patients had any evidence of delirium. Only one patient had increased aggression while taking risperidone. No child developed tardive dyskinesia (TD) during the follow-up period. Prolactin levels were available in 11 subjects, and they were elevated in all but 2 children (82%) (mean prolactin level 32.8 ng/mL ± 12.05 [normal range 0-15]). No baseline prolactin levels were available for comparison. Electrocardiograms (ECGs) were available in 4 patients, and all were within normal limits.
%40 30
TABLE 2
20
Risperidone Treatment in Juvenile Bipolat Disorder
10
o Mania (N=28)
ADHD (N=25)
Psychosis (N=13)
Aggression (N=28)
Fig. 1 CGI Severity ratings (A), ImptOvemenc ratings (B), and percentage imptOved (e) in youths with juvenile mania treated with risperidone. CGI = Clinical Global Impression Scale; ADHD = attention-deficit/hyperactivity disorder.
was a robust improvement in aggression in these children as noted by the significant reduction of the Aggression CGI Severity score (5.1 ± 1.2 at baseline and 3.0 ± 1.2 on risperidone; p < .01). CGI Severity ratings of psychotic symptoms also significantly declined from 3.6 ± 0.4 at baseline to 1.5 ± 0.24 on risperidone (p < .01). Despite statistical significance, much more modest effects were
962
Mean daily dosage (mg) Average time to optimal response (months) Average length of treatment (months) Mean no. of concurrent medications Adverse effects Weight gain Sedation Drooling Night terrors Headache Increased aggressiveness Galactorrhea Delayed ejaculation4 Weight loss Increased fearfulness
1.7 ± 1.9 ± 6.1 ± 1.8 ± 5 5 2 I 1 1 1 1 1 1
1.3 1.0 8.5 1.I
(17.9) (17.9) (7.1) (3.6) (3.6) (3.6) (3.6) (3.6) (3.6) (3.6)
Note: Values represent mean ± SD or n (%). a Reported by a I7-year-old male.
J. AM. ACAD. CHILD ADOLESC. PSYCHIATRY, 38:8, AUGUST 1999
RISPERIDONE TREATMENT FOR JUVENILE MANIA
Case Vignette
A 5?i-year-old boy presented to the clinic with a history of severe behavioral disturbances since age 2 years. He was hyperactive, impulsive, highly dysphoric, and explosive. The symptoms had increased in severity and intensity over the years. He had had multiple medication trials including various stimulants which all exacerbated the child's symptoms of agitation, disturbed sleep, and racing thoughts. He was hospitalized 4 times during the year prior to presentation to our outpatient clinic. Other medication trials included fluoxetine, which resulted in increased agitation and irritability, and clonidine, lithium, and valproate, all of which led to worsening of symptoms. In addition, he was tried on a combination of mood stabilizers and selective serotonin reuptake inhibitors and a combination of mood stabilizers and bupropion without success. Upon presentation to our clinic, he was taking 25 mg of sertraline every other day and guanfacine 0.5 mg b.i.d. He continued to be agitated, with daily unprovoked temper outbursts, impulsiveness, loud speech, aggressiveness, labile affect, limited eye contact, and impaired concentration. This patient had an unremarkable medical history. His developmental history was normal, except that he had a history of a mild speech delay. Because of his behavioral difficulties, he required special education and a one-to-one aide in the classroom. Family history was positive for ADHD in 2 older brothers and for depression in the mother. Evaluation at our center led to the diagnosis of juvenile bipolar disorder. Risperidone treatment was initiated at 0.75 mg/day. The patient had a remarkable response to risperidone within weeks, with a dramatic decrease in aggression and manic symptoms with no side effects. He continued to receive sertraline and guanfacine as before. DISCUSSION
In a systematic chart review of all children and adolescents with a clinical diagnosis of bipolar disorder treated with risperidone at our center, we found that risperidone treatment was associated with a rapid, robust, and sustained response in controlling manic, psychotic, and aggressive symptoms in a majority of these children. This positive response to risperidone was particularly striking considering that all but one child had been aggressively medicated before with limited success. These encouraging initial results suggest that risperidone
]. AM. ACAD. CHILD ADOLESC. PSYCHIATRY, 38:8, AUGUST 1999
may be a promising agent in the management of manic young people and indicate the need for controlled clinical trials of this compound and other atypical neuroleptics in the treatment of juvenile mania. The rapid and sustained response to risperidone treatment stands in sharp contrast to previous, much more modest results on mood stabilizers in the same population (Biederman et al., in press). Our previous work evaluating treatment approaches to juvenile mania revealed that although mood stabilizers were efficacious in improving manic symptoms, their effects took many months and were associated with high levels of relapse (Biederman et al., in press). Our results of responsivity to risperidone in juvenile mania are consistent with previous reports in the adult literature (Tohen et al., 1996; Vieta et al., 1995, 1998). For example, a similarly positive response to ours has been reported by Tohen and colleagues (1996) and by Vieta and colleagues (1998). As in our series, many of these adults had treatment-refractory or dysphoric mania and had limited previous success with mood stabilizers. It is noteworthy that the improvement observed in our sample was not secondary to tranquilization or sedation. Although sedation was noted in 18% of subjects treated with risperidone, improvement observed in our sample was not due to excessive sedation. Instead clinical improvement in mood and behavior was noted by the children, parents, and clinicians and was considered to be of high quality. Although it remains unclear why risperidone treatment has been so impressive in juvenile bipolar disorder, the improvement may be due to the unique pharmacological profile of risperidone with its high ratio of 5-HTzA antagonism to its D2-receptor antagonism, which may account for its efficacy in treating the dysphoric and manic mood components (Tohen et al., 1996) that characterize juvenile bipolar disorder (Wozniak et al., 1995). The decrease in aggression with risperidone in our series is consistent with an emerging body of literature in pediatric psychopharmacology documenting the effectiveness of risperidone in the treatment of aggression in young people. For example, a recent report documented that risperidone was useful in treating severe aggression in children and adolescents with conduct disorder (Fras and Major, 1995). An additional case series reported rapid, moderate to marked improvement in 8 of 11 children (age range 5.5-16 years) with affective symptoms (suggestive of bipolar disorder), aggression, and marked
963
FRAZIER ET AL.
behavioral problems when treated with risperidone either alone (n = 1) or in conjunction with mood stabilizers (n = 7) (Schreier, 1998). Inasmuch as juvenile mania is frequently comorbid with conduct disorder, risperidone could be effective in treating the dysphoric aggression displayed by manic children (Wozniak et al., 1995). In sharp contrast to the positive effects of risperidone in the treatment of manic symptoms, its effects on ADHD symptomatology were minimal. There was a need for additional anti-ADHD medication (e.g., TCAs, a-agonists, stimulants) in 57% (n = 16) of patients because they had persistent symptoms of ADHD. One of these children required 3 anti-ADHD medications. These results are not entirely surprising considering that dopaminergic activation and not suppression underlie the treatment of ADHD, providing support for the notion that mania and ADHD are independent syndromes (Wozniak and Biederman, 1995). These findings suggest that children with comorbid bipolar disorder and ADHD require treatment for both disorders (Biederman et al., in press; Wozniak et al., 1995). Twenty-nine percent of the sample had comorbid PDD. These findings are consistent with our previous work and several case reports supporting the overlap between PDD and BPD (Komoto et al., 1984; Sovner, 1989; Steingard and Biederman, 1987; Wozniak et al., 1997). Considering the severity of mania, the identification and treatment of bipolarity in youths with PDD is of important clinical significance. Treatment with risperidone in our series was well tolerated, and no child experienced serious adverse effects. In our series, the most common adverse effects were weight gain and sedation, each observed in 18% of cases. Sedation was considered mild and well tolerated. Weight gain on risperidone can be a concerning side effect in some children and adults (Brecher and Geller, 1997). Although weight gain was noted in a substantial minority of children (18%), it was not adequately quantified. The weight gain associated with risperidone is generally modest in adult patients, but it can be marked in some individuals (Brecher and Geller, 1997). Given that weight gain was noted in 18% of our subjects and the health hazards associated with excessive weight gain, clinicians should consider weight gain in the risk versus benefit analysis when using risperidone in the management of bipolar young people. It is noteworthy that one child (4%) became more aggressive during risperidone treatment,
964
suggesting that risperidone may also be activating (or perhaps not effective) in a minority of manic youths. No cases of extrapyramidal side effects (EPS) were observed. The absence of EPS in our series is consistent with 3 previous reports in children which failed to observe EPS with risperidone treatment used for various psychiatric conditions (McDougle et al., 1997; Quintana and Keshava, 1995). Although Armenteros and colleagues (1997) reported that 4 of 10 schiwphrenic children developed EPS that required concomitant benztropine, that study used high doses of risperidone (4-10 mg) and a rapid titration schedule over a 3-week period, which may account for the number of cases experiencing EPS. In addition, none of our 28 patients, treated with risperidone for an average of 6.1 ± 8.5 months (range 0.25-34 months), developed TD. These results are encouraging, yet uncertainties remain as to whether risperidone will be associated with TD in children with long-term use, particularly because TD has been associated with risperidone treatment in adults (Haberfeliner, 1997). Although atypical neuroleptics may have a lesser risk for TD than typical agents, more information is needed to evaluate the risk for TD with risperidone and other atypical neuroleptics in children. ECG and prolactin data were available in only a minority of subjects. All available ECGs were within normal limits, and all but one available prolactin level was elevated. In the adult and pediatric literature, elevated prolactin levels have been associated with galactorrhea and amenorrhea in females and gynecomastia in males (Goff and Shader, 1995; McDougle et al., 1997). In our series, one adolescent girl developed galactorrhea and amenorrhea. Since the long-term implications of elevated prolactin levels in children remain unknown, more work is needed to evaluate the clinical implications of hyperprolactinemia in developing young people. The findings discussed in this report should be viewed against their methodological limitations. Although ours represents the largest series of children reported to date with juvenile bipolar disorder who were treated with risperidone, the data presented were derived from retrospective chart reviews and as such are subject to observation and assessment bias. Given the retrospective nature of this study, syndrome-specific ratings were used. Future studies can benefit from using instruments such as the Young Mania Rating Scale (Fristad et al., 1992). Nonetheless, these preliminary results are encouraging and indicate the need for prospective controlled clinical trials
J.
AM. ACAD. CHILD ADOLESC. PSYCHIATRY, 38:8, AUGUST 1999
RISPERIDONE TREATMENT FOR JUVENILE MANIA
with risperidone and other atypical neuroleptics in the treatment of juvenile mania. Despite the inherent limitations of chart reviews and open series, such data are needed to begin to formulate hypotheses regarding potential therapeutic uses of novel compounds and new treatment approaches to a severe disorder such as juvenile bipolar disorder. Inasmuch as the majority of the children in this study received multiple medications, our results cannot help clarify whether risperidone will be effective as monotherapy or in combination with other psychotropics. However, because the average daily doses of risperidone used were relatively low, it remains to be seen whether more aggressive treatment regimens with risperidone will obviate the need for mood stabilizers. In addition, more work is needed to establish the optimal duration of treatment with risperidone in children with bipolar disorder. Summary and Clinical Implications
Despite these considerations, this retrospective chart review of a large series of children with bipolar disorder treated naturalistically showed that risperidone provided rapid and sustained treatment of manic, psychotic, and aggressive symptoms in these children. These initial encouraging results indicate the need for additional short- and long-term controlled trials of risperidone and other atypical neuroleptics in the treatment of juvenile bipolar disorder, either as monotherapy or in combination with mood stabilizers, with careful assessment of its associated risks.
REFERENCES Armenteros JL, Whitaker AH, Welikson M, Stedge DJ, Gorman J (1997), Risperidone in adolescents with schiwphrenia: an open pilot smdy.] Am
Acad ChildAdolesc Psychiatry 36:694-700 Biederman J, Faraone S, Mick E et al. (1996), Accention-deficit hyperactivity disorder and juvenile mania: an overlooked comorbidity?] AmAcad Child
Adolesc Psychiatry 35:997-1008 Biederman J, Mick E, Bostic Jet al. (in press), Pharmacologic treatment of ADHD in youth with severe mood instability: a systematic chart review.
] Child Adolesc Psychopharmacol Brecher M, Geller W (1997), Weight gain with risperidone (leccer).] Clin
PsychopharmacoI17:435-436 Campbell M, Adams P, Perty R, Spencer EK, Overall JE (1988), Tardive and withdrawal dyskinesia in autistic children: a prospective smdy. Psychopharmacol Bull 24:251-255
]. AM. ACAD. CHILD ADOLESC. PSYCHIATRY, 38:8, AUGUST 1999
Fras I, Major LF (1995), Clinical experience with risperidone (leccer).] Am
Acad ChildAdolesc Psychiatry 34:833 Fristad MA, Weller EB, Weller RA (1992), The mania rating scale: can it be used in children? A preliminary report.] Am Acad ChildAdolesc Psychiatry 31:252-257 Gelenberg AJ, Hopkins HS (1996), Antipsychotics in bipolat disorder.] Clin
Psychiatry 57:49-52 Ghaemi SN, Sachs GS, Baldassano CF, Truman CJ (1997), Acute treatment of bipolar disorder with adjunctive risperidone in outpatients. Can] Psychiatry 42: 196-199 Goff D, Shader R (1995), Non-neurological side effects of anti-pSychotic agents. In: Schizophrenia, Hirsch S, Weinberger D, eds. Oxford, England: Blackwell Science, pp 566-586 Goodnick P (1995), Risperidone treatment of refractoty acute mania.] Clin
Psychiatry 56:431-432 Haberfellner EB (1997), Tardive dyskinesia during treatment with risperidone. Pharmacopsychiatry 30:271 Komoto J, Seigo U, Hirata J (1984), Infantile autism and affective disorder.
] Autism Dev Disord 14:81-84 McDougle C, Holmes J, Bronson M et al. (1997), Risperidone treatment of children and adolescents with pervasive developmental disorders: a prospective, open-label smdy.] Am Acad ChildAdolesc Psychiatry 36:685-693 McIntyre R, Young L, Hasey G, Patelis-Siotis I, Jones B (1997), Risperidone treatment of bipolar disorder. Can] Psychiatry 42:88-90 National Instimte of Meneal Health (1985), CGI (Clinical Global Impression) Scale-NIMH. Psychopharmacol Bull 21 :839-844 Quintana H, Keshava M (1995), Case study: risperidone in children and adolescents with schizophrenia. ] Am Acad Child Adolesc Psychiatry 34: 1292-1296 Schreier HA (1998), Risperidone for young children with mood disorders and aggressive behavior.] Child Adolesc PsychopharmacoI8:49-59 Sovner R (1989), The use of valproate in the treatment of mentally retarded persons with typical and atypical bipolar disorders. ] Clin Psychiatry 50:40-43 Spencer T, Wilens TE, Biederman J, Faraone SV; Ablon S, Lapey K (1995), A double-blind, crossover comparison of methylphenidate and placebo in adults with childhood-onset attention deficit hyperactivity. Arch Gen
Psychiatry 52:434-443 Steingard R, Biederman J (1987), Lithium responsive manic-like symptoms in two individuals with autism and mental retardation. ] Am Acad Child
Adolesc Psychiatry 26:932-935 Tohen M, Zarate C Jr, Centorrino F, Hegarty J, Froeschl M, Zarate S (1996), Risperidone in the treatment of mania.] Clin Psychiatry 57:249-253 Vieta E, Gasto C, Colom F, Martinez A, Otero A, Vallejo J (1998), Treatment of refractoty rapid cycling bipolar disorder with risperidone.] Clin
PsychopharmacoI18:172-174 Vieta E, Gasto C, Escobar R (1995), Treatment of dysphoric mania with risperidone. Hum PsychopharmacoI1O:491-492 Wozniak J, Biederman J (1995), Childhood mania exists (and coexists) with ADHD. American Society of Clinical Psychopharmacology Progress Notes 6:4-5 Wozniak J, Biederman J (1996), A pharmacological approach to the quagmire of comorbidicy in juvenile mania.]Am Acad ChildAdolesc Psychiatry 35:826-828 WozniakJ, BiedermanJ, Faraone S et al. (1997), Mania in children with pervasive developmental disorder revisited. ] Am Acad Child Adolesc Psychiatry 36: 1552-1559 Wozniak J, Biederman J, Kiely K et al. (1995), Mania-like symptoms suggestive of childhood onset bipolar disorder in clinically referred children. ]
Am Acad ChildAdolesc Psychiatry 34:867-876
965