randomized controlled trials of antipsychotics for bipolar disorder


(Updated 6/14/05; note that placebo-controlled trials have been placed in the right column.)

Tohen M, Goldberg JF, Gonzalez-Pinto Arrillaga AM, Azorin JM, Vieta E, Hardy-Bayle MC, Lawson WB, Emsley RA, Zhang F, Baker RW, Risser RC, Namjoshi MA, Evans AR, Breier A.
Lilly Research Laboratories, Indianapolis, Ind 46225, USA. m.tohen@lilly.com
A 12-week, double-blind comparison of olanzapine vs haloperidol in the treatment of acute mania.
Arch Gen Psychiatry. 2003 Dec;60(12):1218-26.
"BACKGROUND: This randomized controlled trial compares the efficacy and safety of olanzapine vs haloperidol, as well as the quality of life of patients taking these drugs, in patients with bipolar mania. METHODS: The design consisted of 2 successive, 6-week, double-blind periods and compared flexible dosing of olanzapine (5-20 mg/d, n = 234) with haloperidol (3-15 mg/d, n = 219). RESULTS: Rates of remission (Young-Mania Rating Scale score of < or =12 and 21-item Hamilton Rating Scale for Depression score of < or =8 at week 6) were similar for olanzapine- and haloperidol-treated patients (52.1% vs 46.1%, respectively; P =.15). For the subgroup of patients whose index episode did not include psychotic features, rates of remission were significantly greater for the olanzapine group compared with the haloperidol group (56.7% vs 41.6%, P =.04). Relapse into an affective episode (mania and/or depression) occurred in 13.1% and 14.8% of olanzapine- and haloperidol-treated patients, respectively (P =.56). Switch to depression occurred significantly more rapidly with haloperidol than with olanzapine when using survival analysis techniques (P =.04), and significantly more haloperidol-treated patients experienced worsening of extrapyramidal symptoms, as indicated by several measures. Weight gain was significantly greater in the olanzapine group compared with the haloperidol group (2.82 vs 0.02 kg, P<.001). The olanzapine group had significant improvement in quality of life on several dimensions compared with the haloperidol group. CONCLUSIONS: These data suggest that olanzapine does not differ from haloperidol in achieving overall remission of bipolar mania. However, haloperidol carries a higher rate of extrapyramidal symptoms, whereas olanzapine is associated with weight gain." [Abstract]

Shi L, Namjoshi MA, Zhang F, Gandhi G, Edgell ET, Tohen M, Breier A, Haro JM.
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA. shi_lizheng@lilly.com
Olanzapine versus haloperidol in the treatment of acute mania: clinical outcomes, health-related quality of life and work status.
Int Clin Psychopharmacol. 2002 Sep;17(5):227-37.
"We aimed to compare clinical outcomes, health-related quality of life (HRQOL) and work status associated with olanzapine and haloperidol treatment in patients with bipolar disorder. This double-blind, randomized controlled trial, comparing flexible dosing of olanzapine (5-20 mg/day, n = 234) to haloperidol (3-15 mg/day, n = 219), consisted of a 6-week acute phase, followed by a 6-week continuation phase. Symptomatic remission rates were similar for olanzapine- and haloperidol-treated patients at weeks 6 and 12. At week 6, significant changes in five dimensions of the Medical Outcomes Study 36-Item Short Form Health Survey (SF-36) [general health (P = 0.010), physical functioning (P < 0.001), role limitations due to physical problems (P < 0.001), social functioning (P < 0.05) and vitality (P < 0.01)] and the SF-36 physical components summary score were found in favour of olanzapine compared to haloperidol. At week 12, olanzapine treatment maintained the significantly favourable HRQOL changes. At the end of week 12, patients on olanzapine showed significantly greater improvement than haloperidol in work activities impairment and household activities impairment scores on the Streamlined Longitudinal Interview Clinical Evaluation from the Longitudinal Interval Follow-up Evaluation (SLICE/LIFE) activities impairment scores. Subgroup analyses revealed that olanzapine treatment significantly increased a proportion of employed patients and their weekly paid working hours. In conclusion, compared to haloperidol, olanzapine treatment was comparably effective in the remission of bipolar mania and significantly improved HRQOL and work status in patients with bipolar I disorder." [Abstract]

Bahk WM, Shin YC, Woo JM, Yoon BH, Lee JS, Jon DI, Chung SK, Choi SK, Paik IH, Pae CU
Topiramate and divalproex in combination with risperidone for acute mania: a randomized open-label study.
Prog Neuropsychopharmacol Biol Psychiatry. 2005 Jan;29(1):115-21.
Mood stabilizers and atypical antipsychotics are commonly combined for the treatment of bipolar mania. The aim of this study was to compare the effectiveness and tolerability of topiramate and divalproex in combination with risperidone for treating acute mania patients in a naturalistic treatment setting. Seventy-four patients who met the DSM-IV criteria for bipolar mania were enrolled in this study. In order to assess the efficacy and the extrapyramidal symptoms (EPS), the Young Mania Rating Scale (YMRS), Clinical Global Impression (CGI) and Simpson-Angus Rating Scale (SARS) were measured at the baseline and at weeks 1, 3 and 6. From the baseline to the endpoint, the YMRS and CGI scores were reduced by 67.9% and 56.6% in the topiramate plus risperidone group (TPMG). The YMRS and CGI scores were also reduced by 63.7% and 58.2% in the divalproex plus risperidone group (DVPG). The weight and body mass index (BMI) increased significantly by 3.6% and 3.3% from the baseline to the endpoint in the DVPG, while they decreased by 0.5% and 0.4%, respectively, with no significant difference in the TPMG. There were no serious adverse events in either group. Despite the methodological limitations, topiramate was effective and tolerable for treating acute mania and may also be a promising alternative to a weight-gain liable mood stabilizer (MS) such as divalproex. [Abstract]

Segal J, Berk M, Brook S.
Department of Psychiatry, University of the Witwatersrand Medical School, Johannesburg, South Africa.
Risperidone compared with both lithium and haloperidol in mania: a double-blind randomized controlled trial.
Clin Neuropharmacol. 1998 May-Jun;21(3):176-80.
"Case reports and studies of other neuroleptics suggest the efficacy of risperidone in the treatment of mania. Forty-five inpatients with DSM-IV mania were studied in a 28-day randomized, controlled, double-blind trial of either 6 mg daily of risperidone, 10 mg daily of haloperidol, or 800 to 1200 mg daily of lithium. The patients in all three groups showed a similar improvement on the total score for all rating scales at day 28 (Brief Psychiatric rating scale; lithium 9.1, haloperidol 4.9, risperidone 6.5, F = 1.01, df = 2, p = 0.37; Mania rating scale; lithium 15.7, haloperidol 10.2, risperidone 12.4, F = 1.07, df = 2, p = 0.35 [analysis of variance]). The Global Assessment of Functioning and Clinical Global Impression data showed a similar pattern of improvement. This study suggests that risperidone is of equivalent efficacy to lithium and haloperidol in the management of acute mania. The extrapyramidal side effects of risperidone and haloperidol were not significantly different." [Abstract]

McElroy SL, Keck PE, Stanton SP, Tugrul KC, Bennett JA, Strakowski SM.
Department of Psychiatry, University of Cincinnati College of Medicine, Ohio, 45267, USA.
A randomized comparison of divalproex oral loading versus haloperidol in the initial treatment of acute psychotic mania.
J Clin Psychiatry. 1996 Apr;57(4):142-6.
"BACKGROUND: Uncontrolled evidence suggests that divalproex administered via the oral loading strategy of 20 mg/kg/day may produce clinically significant antimanic response within 3 days of treatment in some patients. We conducted a prospective study to compare the antimanic response of divalproex oral loading with that of haloperidol in the initial treatment of acute psychotic mania. METHOD: After a < or = 1-day screening period, 36 consecutive hospitalized patients with bipolar disorder, manic or mixed phase and with psychotic features, were randomly assigned to receive either divalproex 20 mg/kg/day or haloperidol 0.2 mg/kg/day for 6 full days, without other psychotropic agents except lorazepam up to 4 mg/day for management of agitation. Serum valproate concentrations were measured after 1 day of treatment. Response was measured daily by a blind rater using the Young Mania Rating Scale and the Scale for Assessment of Positive Symptoms. RESULTS: Divalproex oral loading and haloperidol were equally effective in acutely reducing manic and psychotic symptoms. The greatest rate of improvement for both drug regimens occurred over the first 3 full days of treatment. Side effects were infrequent and minor for both treatments, except for extrapyramidal side effects which were significantly more common with haloperidol. CONCLUSION: Divalproex oral loading may produce rapid onset of antimanic and antipsychotic response comparable to that of haloperidol and with minimal side effects in the initial treatment of acute psychotic mania in a subset of bipolar patients." [Abstract]

Small JG, Klapper MH, Marhenke JD, Milstein V, Woodham GC, Kellams JJ.
Indiana University School of Medicine, Department of Psychiatry, Larue D. Carter Memorial Hospital, Indianapolis, IN 46202, USA.
Lithium combined with carbamazepine or haloperidol in the treatment of mania.
Psychopharmacol Bull. 1995;31(2):265-72.
"Hospitalized manic patients were withdrawn from psychoactive medications for 2 weeks after which they were randomized to double-blind treatment with carbamazepine plus lithium [CBZ-Li] or haloperidol plus lithium [HAL-Li] with benztropine. Unit dosages of Li 300 mg, CBZ 200 mg and HAL 2 mg were titrated to therapeutic plasma levels and maintained for 8 weeks. No rescue medications were permitted after 3 weeks. Standard ratings of psychopathology and side effects were accomplished weekly. Sixty patients entered the study but only 33 remained for randomization after drug washout. By 8 weeks both groups were improved from baseline without statistically reliable differences between them. However HAL-Li patients had more extrapyramidal side effects that were major reasons for dropout, whereas CBZ-Li patients were more often noncompliant and initially required more rescue medications. We conclude that either combination treatment can be beneficial but CBZ-Li has the advantage because of fewer neurologic side effects." [Abstract]

Suppes T, Webb A, Paul B, Carmody T, Kraemer H, Rush AJ.
Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas 75235-9070, USA.
Clinical outcome in a randomized 1-year trial of clozapine versus treatment as usual for patients with treatment-resistant illness and a history of mania.
Am J Psychiatry. 1999 Aug;156(8):1164-9.
"OBJECTIVE: Case series and follow-up studies suggest that clozapine may have mood-stabilizing properties in addition to antipsychotic action in patients with schizoaffective disorder, bipolar type, and bipolar I disorder, but the generalizability of these findings is limited. This article describes a randomized, open study of clozapine add-on therapy versus treatment as usual for patients with treatment-resistant illness and a history of mania. METHOD: Thirty-eight patients meeting the DSM-IV criteria for schizoaffective or bipolar disorder that was deemed treatment-resistant were randomly assigned to clozapine add-on treatment (N = 19) or treatment as usual (no clozapine) (N = 19) and followed up for 1 year. Patients received monthly ratings on the Brief Psychiatric Rating Scale, Clinical Global Impression scale, Bech-Rafaelsen Mania Scale, Hamilton Depression Rating Scale, Scale for the Assessment of Positive Symptoms, Scale for the Assessment of Negative Symptoms, Abnormal Involuntary Movement Scale, and a 40-item side effect checklist. Differences between treatment groups were assessed according to a pattern-mix random-regression model. An additional analysis compared group differences in rating scale scores against relative time in the study. RESULTS: Significant between-group differences were found in scores on all rating scales except the Hamilton depression scale. Total medication use over 1 year significantly decreased in the clozapine group. No significant differences between groups in somatic complaints were noted. The subjects with nonpsychotic bipolar I disorder who received clozapine showed a degree of improvement similar to that of the entire clozapine-treated group. Clozapine dose was significantly higher for the patients with schizoaffective illness than for those with bipolar disorder. CONCLUSIONS: The results of this study support clozapine's independent mood-stabilizing property. They demonstrate that clozapine use was associated with significant clinical improvement relative to treatment as usual." [Abstract]

Barbini B, Scherillo P, Benedetti F, Crespi G, Colombo C, Smeraldi E.
I.R.C.C.S. Istituto Scientifico Ospedale San Raffaele, Department of Neuropsychiatric Sciences, University of Milan, School of Medicine, Italy.
Response to clozapine in acute mania is more rapid than that of chlorpromazine.
Int Clin Psychopharmacol. 1997 Mar;12(2):109-12.
"The purpose of the present study was to compare the efficacy of clozapine with that of chlorpromazine in an open label manner (both given in association with lithium salts) in the treatment of acute mania. Thirty hospitalized manic patients were entered into the study. All patients met DSM-IV criteria for bipolar disorder, Manic Episode; 27 patients completed the study and three patients dropped for noncompliance. The duration of the study was 3 weeks. Patients were randomly assigned to two treatment groups; group 1 (n = 15) was treated with clozapine at a mean dose of 166 mg/day and group 2 (n = 12) was treated with chlorpromazine at a mean dose of 310 mg/day. Manic symptomatology was rated on Young Rating Scale for Mania (YRSM) each week; side effects were recorded on dosage records and treatment emergent symptoms; extrapyramidal acute side effects were rated on the Simpson-Angus Rating Scale performed at the beginning of the study and after 3 weeks of treatment. A two-way repeated measures analysis of variance on YRMS scores showed a significant time effect (p < 0.0001) and a significant time-group interaction (p < 0.0001). Post-hoc comparison between the two groups showed a significant difference after 2 weeks of treatment (p = 0.0001), with clozapine treated patients showing lower YRSM scores than chlorpromazine treated patients. YRSM scores at the end of the study were not significantly different. Patients treated with clozapine showed a more rapid trend toward amelioration. No clinically relevant side effect was observed during the study." [Abstract]

Sikdar S, Kulhara P, Avasthi A, Singh H.
Postgraduate Institute of Medical Education and Research, Chandigarh, India.
Combined chlorpromazine and electroconvulsive therapy in mania.
Br J Psychiatry. 1994 Jun;164(6):806-10.
"We report the efficacy of combined chlorpromazine and electroconvulsive therapy (ECT) in the treatment of mania. Two groups of 15 manic patients received eight ECT sessions either actual or simulated, in a double-blind, controlled study. All patients also received 600 mg of chlorpromazine daily until the sixth session. Results indicate that the group receiving the combination of chlorpromazine and ECT did significantly better than the other group." [Abstract]

Keck PE Jr, Marcus R, Tourkodimitris S, Ali M, Liebeskind A, Saha A, Ingenito G; Aripiprazole Study Group.
Biological Psychiatry Program, Department of Psychiatry, University of Cincinnati College of Medicine, PO Box 670559, Cincinnati, OH 45267-0559, USA. paul.keck@uc.edu
A placebo-controlled, double-blind study of the efficacy and safety of aripiprazole in patients with acute bipolar mania.
Am J Psychiatry. 2003 Sep;160(9):1651-8.
"OBJECTIVE: The authors compared the efficacy and safety of aripiprazole, a novel antipsychotic, to placebo for treatment of patients in an acute manic or mixed episode of bipolar disorder. METHOD: This 3-week, multicenter, double-blind study randomly assigned 262 bipolar disorder patients in an acute manic or mixed episode to aripiprazole, 30 mg/day (reduced to 15 mg/day if needed for tolerability), or placebo. Patients remained hospitalized for at least 2 of the weeks. The primary efficacy measure was mean change from baseline in total score on the Young Mania Rating Scale; response was defined as a decrease in score of > or =50%. RESULTS: Aripiprazole produced statistically significant mean improvements in total score on the Young Mania Rating Scale compared with placebo (-8.2 versus -3.4, respectively) and produced a significantly higher response rate (40% versus 19%). For key efficacy variables (response per Young Mania Rating Scale; Clinical Global Impression-Bipolar Version scores for severity of illness [mania] and change from preceding phase [mania]), aripiprazole separated from placebo by day 4. The completion rate was significantly higher with aripiprazole than with placebo (42% versus 21%). Discontinuations due to adverse events did not differ significantly between the aripiprazole and placebo groups. There were no significant changes in body weight versus placebo, and aripiprazole was not associated with elevated serum prolactin or QTc prolongation. CONCLUSIONS: Aripiprazole had significantly greater efficacy than placebo for the treatment of bipolar disorder patients in acute manic or mixed episodes and was safe and well tolerated in this randomized controlled trial." [Abstract]

Keck PE Jr, Versiani M, Potkin S, West SA, Giller E, Ice K; Ziprasidone in Mania Study Group.
Department of Psychiatry, University of Cincinnati College of Medicine, OH 45627-0559, USA. keckpe@email.uc.edu
Ziprasidone in the treatment of acute bipolar mania: a three-week, placebo-controlled, double-blind, randomized trial.
Am J Psychiatry. 2003 Apr;160(4):741-8.
"OBJECTIVE: The study evaluated the efficacy and tolerability of ziprasidone, compared with placebo, in the treatment of adult patients with acute bipolar mania. METHOD: Patients with a primary DSM-IV diagnosis of bipolar I disorder and a current manic or mixed episode (confirmed by the Structured Clinical Interview for DSM-IV Axis I Disorders, Patient Edition) (N=210) were randomly assigned in a 2:1 ratio to 3 weeks of double-blind treatment with ziprasidone (40-80 mg twice daily) or placebo. Efficacy was assessed with the Schedule for Affective Disorders and Schizophrenia, Change Version (which contains the Mania Rating Scale), Positive and Negative Syndrome Scale, Clinical Global Impression (CGI) severity scale, CGI improvement scale, and Global Assessment of Functioning Scale. Primary efficacy variables were differences from baseline to endpoint (last observation carried forward) in mean Mania Rating Scale and CGI severity scale scores between the ziprasidone and placebo groups. Safety evaluations included monitoring of adverse events, vital signs, electrocardiogram results, and clinical laboratory values and assessment of movement disorders and akathisia. RESULTS: Ziprasidone produced rapid, sustained improvements relative to baseline and placebo on all primary and most secondary efficacy measures at endpoint. Significant improvements were typically observed within 2 days after treatment commenced and were maintained throughout the 3 weeks. Ziprasidone was well tolerated and associated with a low rate of extrapyramidal symptoms; neither weight gain nor clinically significant changes in vital signs or other safety parameters were observed with ziprasidone. CONCLUSIONS: Ziprasidone monotherapy was significantly superior to placebo in reducing symptoms of acute mania in patients with bipolar I disorder. Onset of action was rapid, and tolerability of ziprasidone was generally comparable to that of placebo." [Abstract]

Smulevich AB, Khanna S, Eerdekens M, Karcher K, Kramer M, Grossman F
Acute and continuation risperidone monotherapy in bipolar mania: a 3-week placebo-controlled trial followed by a 9-week double-blind trial of risperidone and haloperidol.
Eur Neuropsychopharmacol. 2005 Jan;15(1):75-84.
In a randomized, double-blind trial, patients with acute bipolar mania received 1-6 mg/day of risperidone, 2-12 mg/day of haloperidol, or placebo for 3 weeks, followed by double-blind risperidone or haloperidol for 9 weeks. Of 438 patients, 154 were randomized to risperidone, 144 to haloperidol, and 140 to placebo. The mean+/-S.D. modal doses were 4.2+/-1.7 mg/day of risperidone and 8.0+/-3.6 mg/day of haloperidol during the initial 3-week phase and 4.1+/-1.8 and 7.4+/-3.7 mg/day during the 12-week period. At week 3, mean Young Mania Rating Scale (YMRS) score reductions from baseline were significantly greater in patients receiving risperidone than placebo (p<0.001). Differences between risperidone and haloperidol on this efficacy measure were not significant. Further reductions in YMRS scores were seen in patients receiving risperidone or haloperidol during the subsequent 9 weeks. No unexpected adverse events were reported. Extrapyramidal disorder and hyperkinesias, the most commonly reported adverse events with antipsychotic use, occurred less frequently with risperidone than haloperidol. We conclude that risperidone monotherapy was an effective and well-tolerated treatment for bipolar mania and that efficacy was maintained over the long term. [Abstract]

Shelton RC, Stahl SM
Risperidone and paroxetine given singly and in combination for bipolar depression.
J Clin Psychiatry. 2004 Dec;65(12):1715-9.
BACKGROUND: Bipolar depression is a major clinical problem that remains under-researched. The current study was intended to evaluate the effects of the novel antipsychotic risperidone, the selective serotonin reup-take inhibitor (SSRI) paroxetine, and the combination in patients with bipolar disorder. METHOD: Thirty patients with DSM-IV bipolar (I or II) disorder, depressed phase, who were receiving a stable dose of a mood stabilizer were randomly assigned to 12 weeks of double-blind treatment with risperidone (plus placebo), paroxetine (plus placebo), or the combination of risperidone and paroxetine. Data were gathered from August 1999 to September 2001. RESULTS: All 3 groups experienced significant reductions in depression ratings from baseline to endpoint; there were no significant differences in outcome between groups. There were statistically significant differences in paroxetine dose contrasting paroxetine plus placebo against the combined condition. The switch rate into mania or hypomania was very low, with only 1 patient in the paroxetine plus placebo condition experiencing mild hypomania. CONCLUSION: These results suggest that risperidone, paroxetine, and the combination of risperidone and paroxetine are equally but modestly effective when added to a mood stabilizer in bipolar depression. The paroxetine dose differed between groups, possibly because of drug-drug interactions. Using another SSRI in the combined condition could have produced a more robust effect and should be tested. [Abstract]

Hirschfeld RM, Keck PE Jr, Kramer M, Karcher K, Canuso C, Eerdekens M, Grossman F.
Department of Psychiatry and Behavioral Sciences, University of Texas Medical Branch, Galveston, TX 77555, USA.
Rapid antimanic effect of risperidone monotherapy: a 3-week multicenter, double-blind, placebo-controlled trial.
Am J Psychiatry. 2004 Jun;161(6):1057-65.
OBJECTIVE: This study evaluated the efficacy and safety of risperidone monotherapy in the treatment of acute bipolar mania. METHOD: Patients with DSM-IV bipolar I disorder experiencing an acute manic episode (baseline Young Mania Rating Scale score >/==" BORDER="0">20) were randomly assigned to 3 weeks of treatment with risperidone (flexible dose: 1-6 mg/day) or placebo. The primary efficacy measure was the mean baseline-to-endpoint change in total score on the Young Mania Rating Scale. Secondary efficacy measures included the Clinical Global Impression (CGI) severity rating and scores on the Montgomery-Asberg Depression Rating Scale, Positive and Negative Syndrome Scale, and Global Assessment Scale (GAS). Safety assessments consisted of monitoring adverse events, vital signs, electrocardiogram and laboratory results, and scores on the Extrapyramidal Symptom Rating Scale. RESULTS: Subjects (N=259) received treatment with either risperidone (N=134) or placebo (N=125). The mean modal dose of risperidone was 4.1 mg/day. Improvement in mean Young Mania Rating Scale total score (adjusted for covariates) was significantly greater in the risperidone than in the placebo group at endpoint (mean change=-10.6 [SD=9.5] versus -4.8 [SD=9.5], respectively), with significant between-group differences seen as early as 3 days after start of treatment (change with risperidone: mean=-6.8 [SD=5.8]; change with placebo: mean=-4.0 [SD=5.8]) and continuing throughout all time points. Improvements in CGI severity ratings and scores on the Montgomery-Asberg Depression Rating Scale, Positive and Negative Syndrome Scale, and GAS were also significantly greater among patients receiving risperidone than those given placebo. The most common adverse event reported among risperidone patients was somnolence. While Extrapyramidal Symptom Rating Scale scores were significantly greater in patients receiving risperidone, mean total and subscale scores were low. CONCLUSIONS: Risperidone monotherapy was significantly more efficacious than placebo in the treatment of acute mania and demonstrated a rapid onset of action. Risperidone was well tolerated by patients in this study. [Abstract]

Bowden CL, Myers JE, Grossman F, Xie Y.
University of Texas Health Science Center, San Antonio, TX 78229, USA.
Risperidone in combination with mood stabilizers: a 10-week continuation phase study in bipolar I disorder.
J Clin Psychiatry. 2004 May;65(5):707-14.
BACKGROUND: Combination therapy (risperidone and a mood stabilizer) for patients with a history of bipolar disorder (DSM-IV) and hospitalized for treatment of a manic episode was assessed in a 13-week study. METHOD: Subjects received flexible doses of a mood stabilizer (lithium or divalproex) plus placebo, risperidone, or haloperidol in a 3-week double-blind study. They could then enter a 10-week open-label study during which they received risperidone combined with a mood stabilizer. RESULTS: Of the 156 patients enrolled in the 3-week study, 85 entered the 10-week open-label extension, of whom 48 completed 10 weeks of treatment. The mean +/- SE doses of risperidone were 3.8 +/- 0.3 mg/day during the 3-week study and 3.1 +/- 0.2 mg/day during the 10-week study. At double-blind endpoint, mean reductions in Young Mania Rating Scale (YMRS) scores were significantly greater in patients receiving risperidone plus mood stabilizer than in those receiving placebo plus mood stabilizer (-14.3 vs. -8.2, p <.001). Further significant (p <.001) reductions were seen during the 10 weeks of treatment with risperidone plus mood stabilizer. Symptom remission (YMRS score <or= 12) was seen in 38 patients (79%) at the end of the 10-week study. Scores on the Brief Psychiatric Rating Scale, Hamilton Rating Scale for Depression, and Clinical Global Impressions scale improved significantly (p <.05) during both the 3-week and 10-week studies. Treatment was well tolerated, and modest weight gain was observed during the 13-week study period. CONCLUSION: The combination of risperidone and a mood stabilizer was efficacious and well tolerated in the continuation treatment of patients initially hospitalized for the management of an acute manic episode. [Abstract]

Yatham LN, Grossman F, Augustyns I, Vieta E, Ravindran A.
University of British Columbia, Vancouver, Canada. yatham@interchange.ubc.ca
Mood stabilisers plus risperidone or placebo in the treatment of acute mania. International, double-blind, randomised controlled trial.
Br J Psychiatry. 2003 Feb;182:141-7.
"BACKGROUND: Few double-blind trials have examined the efficacy of a combination of a mood stabiliser and an atypical antipsychotic in acute mania. AIMS: To determine the efficacy of risperidone in combination with a mood stabiliser in acute mania. METHOD: Patients taking a mood stabiliser were randomised to 3 weeks' treatment with risperidone (n=75) or placebo (n=76). RESULTS: Young Mania Rating Scale (YMRS) scores improved rapidly with significantly greater reductions at week 1 in the risperidone group compared with the placebo group. At end-point YMRS scores decreased by 14.5 and 10.3 points in the risperidone and placebo groups, respectively. Significant improvements v. placebo (P<0.05) were noted in the risperidone group on several other clinically meaningful measures. Additionally, a post hoc analysis excluding carbamazepine-treated patients (plasma concentrations of risperidone active moiety were 40% lower in this group) revealed significantly greater reductions (P=0.047) in YMRS scores in the risperidone group than in the placebo group. Incidence of adverse events was similar in both groups. CONCLUSIONS: Risperidone is superior to placebo when used in combination with lithium or divalproex in acute mania." [Abstract]

Sachs GS, Grossman F, Ghaemi SN, Okamoto A, Bowden CL.
Bipolar Research Program, Department of Psychiatry, Massachusetts General Hospital, 50 Staniford Street, Suite 580, Boston, MA 02114, USA. sachsg@aol.com
Combination of a mood stabilizer with risperidone or haloperidol for treatment of acute mania: a double-blind, placebo-controlled comparison of efficacy and safety.
Am J Psychiatry. 2002 Jul;159(7):1146-54.
"OBJECTIVE: The study assessed the efficacy and safety of risperidone as an adjunctive agent to mood stabilizers in the treatment of acute mania. METHOD: This 3-week randomized, double-blind, placebo-controlled study included 156 bipolar disorder patients with a current manic or mixed episode who received a mood stabilizer (lithium or divalproex) and placebo, risperidone, or haloperidol. The primary efficacy measure was the Young Mania Rating Scale. Other assessments used the Brief Psychiatric Rating Scale, the Clinical Global Impression scale, and safety measures. RESULTS: The trial was discontinued by 25 (49%) of the 51 placebo group patients, 18 (35%) of the 52 risperidone group patients, and 28 (53%) of the 53 haloperidol group patients. Mean modal doses were 3.8 mg/day (SD=1.8) of risperidone and 6.2 mg/day (SD=2.9) of haloperidol. Significantly greater reductions in Young Mania Rating Scale scores at endpoint and over time were seen in the risperidone group and in the haloperidol group, compared with the placebo group. Young Mania Rating Scale total scores improved with risperidone and with haloperidol both in patients with psychotic features and in those without psychotic features at baseline. Extrapyramidal Symptom Rating Scale total scores at endpoint were significantly higher in the haloperidol patients than in the placebo patients. Antiparkinsonian medications were received by 8%, 17%, and 38% of patients in the placebo, risperidone, and haloperidol groups, respectively. CONCLUSIONS: Risperidone plus a mood stabilizer was more efficacious than a mood stabilizer alone, and as efficacious as haloperidol plus a mood stabilizer, for the rapid control of manic symptoms and was well tolerated." [Abstract]

Bowden CL, Grunze H, Mullen J, Brecher M, Paulsson B, Jones M, Vågerö M, Svensson K
A randomized, double-blind, placebo-controlled efficacy and safety study of quetiapine or lithium as monotherapy for mania in bipolar disorder.
J Clin Psychiatry. 2005 Jan;66(1):111-21.
OBJECTIVE: To evaluate the efficacy and tolerability of quetiapine monotherapy versus placebo for the treatment of mania associated with bipolar disorder. METHOD: In an international, multicenter, double-blind, parallel-group, 12-week study, patients with a DSM-IV diagnosis of bipolar I disorder (manic episode) were randomly assigned to treatment with quetiapine (flexibly dosed up to 800 mg/day), placebo, or lithium. The primary efficacy measure was change from baseline in Young Mania Rating Scale (YMRS) score at day 21. Data were gathered from April 2001 to May 2002. RESULTS: More patients in the quetiapine (72/107) and lithium (67/98) groups completed the study compared with the placebo group (35/97). Improvement (reduction) in YMRS score was significantly greater for quetiapine than placebo at day 7 (-8.03 vs. -4.89; p < .01), and the difference between groups continued to increase over time to day 21 (-14.6 vs. -6.7; p < .001) and to endpoint at day 84 (-20.3 vs. -9.0; p < .001). Significantly more quetiapine patients compared with placebo patients fulfilled YMRS response criteria at day 21 (53.3% vs. 27.4%; p < .001) and at day 84 (72.0% vs. 41.1%; p < .001). Quetiapine was also superior to placebo in efficacy at day 21 and day 84 by all secondary measures. Lithium-treated patients improved significantly compared with placebo patients and similarly to quetiapine-treated patients on the primary efficacy measure. The most common adverse events for quetiapine were dry mouth, somnolence, and weight gain, while lithium was associated with tremor and insomnia. The quetiapine and placebo groups had similar, low levels of extrapyramidal symptom-related adverse events. CONCLUSIONS: Quetiapine demonstrated superior efficacy to placebo in patients with bipolar mania and was well tolerated. [Abstract]

Sachs G, Chengappa KN, Suppes T, Mullen JA, Brecher M, Devine NA, Sweitzer DE.
Harvard Bipolar Research Program, Massachusetts General Hospital, Boston, 02114, USA.
Quetiapine with lithium or divalproex for the treatment of bipolar mania: a randomized, double-blind, placebo-controlled study.
Bipolar Disord. 2004 Jun;6(3):213-23.
OBJECTIVE: Evaluate the efficacy and tolerability of quetiapine (QTP) combined with lithium (Li) or divalproex (DVP) in the treatment of acute mania. METHODS: Patients were randomized to 21 days of double-blind treatment with QTP plus Li/DVP, or placebo (PBO) plus Li/DVP. QTP was rapidly dosed up to a maximum of 800 mg/day; Li was dosed to 0.7-1.0 mEq/L; or DVP to 50-100 microg/mL. RESULTS: Fifty-six of 91 (61.5%) individuals in the QTP + Li/DVP group compared with 49 of 100 (49%) taking PBO + Li/DVP completed the study. A significantly greater mean reduction in total Young Mania Rating Scale (YMRS) score was observed at end-point in patients receiving QTP + Li/DVP compared with those in the PBO + Li/DVP group (-13.76 versus -9.93; p = 0.021). The response rate (> or =50% YMRS improvement) was significantly higher in the QTP + Li/DVP group than in PBO + Li/DVP-treated patients (54.3% versus 32.6%; p = 0.005), as was the proportion of patients achieving clinical remission (YMRS < 12) (45.7% versus 25.8%; p = 0.007). Patients receiving QTP + Li/DVP also had a significantly greater improvement in Clinical Global Impressions-Bipolar (CGI-BP) Severity of Illness scores (-1.38 versus -0.78; p = 0.001). The mean last-week dose of QTP was 584 mg/day in patients meeting response criteria. Common adverse events (at least 10% and twice the rate of Li/DVP) in the QTP + Li/DVP group included somnolence, dry mouth, asthenia, and postural hypotension. CONCLUSIONS: Quetiapine combined with either Li or DVP has superior efficacy compared with Li or DVP monotherapy for treating patients with bipolar mania. Combination therapy was well-tolerated and most adverse events were mild, withdrawal because of adverse events being only 5% compared with 6% on Li or DVP monotherapy. [Abstract]

Delbello MP, Schwiers ML, Rosenberg HL, Strakowski SM.
Bipolar and Psychotic Disorders Research Program, Department of Psychiatry, University of Cincinnati College of Medicine, Cincinnati, OH 45267-0559, USA. delbelmp@email.uc.edu
A double-blind, randomized, placebo-controlled study of quetiapine as adjunctive treatment for adolescent mania.
J Am Acad Child Adolesc Psychiatry. 2002 Oct;41(10):1216-23.
"OBJECTIVES: This randomized, double-blind, placebo-controlled study examined the efficacy and tolerability of quetiapine in combination with divalproex (DVP) for acute mania in adolescents with bipolar disorder. It was hypothesized that DVP in combination with quetiapine would be more effective than DVP alone for treating mania associated with adolescent bipolar disorder. Furthermore, it was hypothesized that quetiapine would be well tolerated. METHOD: Thirty manic or mixed bipolar I adolescents (12-18 years) received an initial DVP dose of 20 mg/kg and were randomly assigned to 6 weeks of combination therapy with quetiapine, which was titrated to 450 mg/day (n = 15) or placebo (n = 15). Primary efficacy measures were change from baseline to endpoint in Young Mania Rating Scale (YMRS) score and YMRS response rate. Safety and tolerability were assessed weekly. RESULTS: The DVP + quetiapine group demonstrated a statistically significantly greater reduction in YMRS scores from baseline to endpoint than the DVP + placebo group (F(1,27) = 5.04, p =.03). Moreover, YMRS response rate was significantly greater in the DVP + quetiapine group than in the DVP + placebo group (87% versus 53%; Fisher exact test, p =.05). No significant group differences from baseline to endpoint in safety measures were noted. Sedation, rated as mild or moderate, was significantly more common in the DVP + quetiapine group than in the DVP + placebo group. CONCLUSIONS: The findings of this study indicate that quetiapine in combination with DVP is more effective for the treatment of adolescent bipolar mania than DVP alone. In addition, the results suggest that quetiapine is well tolerated when used in combination with DVP for the treatment of mania." [Abstract]

Chou JC, Czobor P, Charles O, Tuma I, Winsberg B, Allen MH, Trujillo M, Volavka J.
Nathan Kline Institute, Orangeburg, New York 10962, USA. chou@nki.rfmh.org
Acute mania: haloperidol dose and augmentation with lithium or lorazepam.
J Clin Psychopharmacol. 1999 Dec;19(6):500-5.
"Antipsychotic dosing for acute mania has not been well studied. Combined treatment with lithium and an antipsychotic is the most common treatment, but additional antimanic efficacy of a lithium-antipsychotic combination beyond that of an antipsychotic alone has not been well demonstrated. Furthermore, the possibility that lithium could affect antipsychotic dose requirement is believed to have never been studied. In this study, 63 acutely psychotic bipolar manic inpatients were randomly assigned to receive double-blind treatment with 1 of 2 haloperidol doses, 25 mg/day or 5 mg/day, for 21 days. In addition to haloperidol, subjects were randomly assigned to receive concomitant treatment with placebo, standard lithium, or lorazepam 4 mg/day. The high haloperidol dose produced greater improvement and more side effects than did the low dose. Lithium added to the low dose produced a markedly greater clinical response than did the low dose alone. Lorazepam did not improve the outcome for the patients receiving low-dose haloperidol. The clinical response produced by high-dose haloperidol was not enhanced by adding either lithium or lorazepam. All treatment effects emerged by the fourth day of treatment and persisted. Used alone, a haloperidol dose of 5 mg/day is too low for most manic patients, but concomitant lithium produces a dose-dependent enhancement of haloperidol response. Lorazepam 4 mg/day was insufficient to produce an advantage when added to low-dose haloperidol." [Abstract]

Zarate CA Jr, Tohen M.
Consolidated Department of Psychiatry, McLean Hospital, Harvard Medical School, Belmont, Mass, USA. zaratec@intra.nimh.nih.gov
Double-blind comparison of the continued use of antipsychotic treatment versus its discontinuation in remitted manic patients.
Am J Psychiatry. 2004 Jan;161(1):169-71.
"OBJECTIVE: The goal of this study was to determine the benefits of the continued use of a typical antipsychotic agent following remission from an acute manic episode. METHOD: Immediately following remission of a manic episode treated with the combination of a typical antipsychotic (perphenazine) and a mood stabilizer (lithium, carbamazepine, or valproate), 37 patients were randomly assigned to 6 months of double-blind treatment in which in addition to the mood stabilizer they received either continued perphenazine treatment or placebo. RESULTS: Patients randomly assigned to continue perphenazine treatment, relative to those who discontinued it, were more likely to have a shorter time to depressive relapse, discontinue the study, and have increased rates of dysphoria, depressive symptoms, and extrapyramidal symptoms. CONCLUSIONS: There were no short-term benefits with the continued use of a typical antipsychotic after achieving remission from an episode of acute mania. In fact, its continued use was associated with detrimental effects." [Abstract]

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Recent Antipsychotic RCT Results

1) Camm AJ, Karayal ON, Meltzer H, Kolluri S, O'Gorman C, Miceli J, Tensfeldt T, Kane JM
Ziprasidone and the corrected QT interval: a comprehensive summary of clinical data.
CNS Drugs. 2012 Apr 1;26(4):351-65.
[PubMed Citation] [Order full text from Infotrieve]

2) Swartz HA, Frank E, Cheng Y
A randomized pilot study of psychotherapy and quetiapine for the acute treatment of bipolar II depression.
Bipolar Disord. 2012 Mar;14(2):211-6.
[PubMed Citation] [Order full text from Infotrieve]

3) McElroy SL, Winstanley E, Mori N, Martens B, McCoy J, Moeller D, Guerdjikova AI, Keck PE
A randomized, placebo-controlled study of zonisamide to prevent olanzapine-associated weight gain.
J Clin Psychopharmacol. 2012 Apr;32(2):165-72.
Weight gain is commonly observed with olanzapine treatment. Zonisamide is an antiepileptic drug associated with weight loss. This study examined the effectiveness of zonisamide in preventing weight gain in 42 patients beginning olanzapine for bipolar disorder or schizophrenia. Each patient had a body mass index of 22 mg/kg or greater and was randomized to taking olanzapine with either zonisamide (n = 20) or placebo (n = 22) for 16 weeks. The primary outcome measure was change in body weight in kilograms from baseline. In the primary analysis using longitudinal regression, patients who received zonisamide had a significantly slower rate of weight gain and increase in body mass index than those who received placebo. The patients treated with zonisamide gained a mean (SD) of 0.9 (3.3) kg, whereas those treated with placebo gained a mean (SD) of 5.0 (5.5) kg; P = 0.01. None of the patients in the zonisamide group, compared with 7 patients (33%) in the placebo group, gained 7% of body weight or greater from baseline (Fisher exact test, P = 0.009). The zonisamide group, however, reported significantly more cognitive impairment as an adverse event than the placebo group (25% vs 0, respectively; P = 0.02). Zonisamide was effective for mitigating weight gain in patients with bipolar disorder or schizophrenia initiating treatment with olanzapine but was associated with cognitive impairment as an adverse event. [PubMed Citation] [Order full text from Infotrieve]

4) Carlson BX, Ketter TA, Sun W, Timko K, McQuade RD, Sanchez R, Vester-Blokland E, Marcus R
Aripiprazole in combination with lamotrigine for the long-term treatment of patients with bipolar I disorder (manic or mixed): a randomized, multicenter, double-blind study (CN138-392).
Bipolar Disord. 2012 Feb;14(1):41-53.
[PubMed Citation] [Order full text from Infotrieve]

5) Kwentus J, Riesenberg RA, Marandi M, Manning RA, Allen MH, Fishman RS, Spyker DA, Kehne JH, Cassella JV
Rapid acute treatment of agitation in patients with bipolar I disorder: a multicenter, randomized, placebo-controlled clinical trial with inhaled loxapine.
Bipolar Disord. 2012 Feb;14(1):31-40.
[PubMed Citation] [Order full text from Infotrieve]

6) Thase ME, Bowden CL, Nashat M, Eudicone JM, Marcus R, McQuade RD, Carlson BX
Aripiprazole in bipolar depression: a pooled, post-hoc analysis by severity of core depressive symptoms.
Int J Psychiatry Clin Pract. 2012 Jun;16(2):121-31.
[PubMed Citation] [Order full text from Infotrieve]

7) Pavuluri MN, Passarotti AM, Fitzgerald JM, Wegbreit E, Sweeney JA
Risperidone and divalproex differentially engage the fronto-striato-temporal circuitry in pediatric mania: a pharmacological functional magnetic resonance imaging study.
J Am Acad Child Adolesc Psychiatry. 2012 Feb;51(2):157-170.e5.
[PubMed Citation] [Order full text from Infotrieve]

8) Citrome L
Inhaled loxapine for agitation revisited: focus on effect sizes from 2 Phase III randomised controlled trials in persons with schizophrenia or bipolar disorder.
Int J Clin Pract. 2012 Mar;66(3):318-25.
[PubMed Citation] [Order full text from Infotrieve]

9) Szegedi A, Calabrese JR, Stet L, Mackle M, Zhao J, Panagides J
Asenapine as adjunctive treatment for acute mania associated with bipolar disorder: results of a 12-week core study and 40-week extension.
J Clin Psychopharmacol. 2012 Feb;32(1):46-55.
In a 12-week randomized, placebo-controlled study evaluating the efficacy and safety of adjunctive asenapine, bipolar I disorder patients experiencing manic or mixed episodes despite pretreatment with lithium or valproate monotherapy were treated with flexible-dose, twice-daily asenapine 5 or 10 mg (n = 158) or placebo (n = 166). The primary efficacy end point was change from baseline Young Mania Rating Scale (YMRS) total score at week 3. Secondary outcomes included YMRS response and remission and Clinical Global Impression for Bipolar Disorder and Montgomery-Asberg Depression Rating Scale score changes. Patients completing the core study were eligible for a 40-week double-blind extension assessing safety and tolerability. Adjunctive asenapine significantly improved mania versus placebo at week 3 (primary end point) and weeks 2 to 12. The YMRS response rates were similar at week 3 but significantly better with asenapine at week 12. The YMRS remission rates and changes from baseline on Clinical Global Impression for Bipolar Disorder for mania and overall illness were significantly better with asenapine at weeks 3 and 12. No other statistically significant differences on secondary outcomes were observed. Only a small number of patients entered the extension, making firm statistical conclusions on efficacy difficult. Treatment-emergent adverse events reported by 5% or more of asenapine patients and at twice the incidence of placebo were sedation, somnolence, depression/depressive symptoms, oral hypoesthesia, and increased weight in the 12-week core study. Adjunctive asenapine to lithium or valproate was more effective than mood stabilizer monotherapy in the core study and was well tolerated for up to 52 weeks. [PubMed Citation] [Order full text from Infotrieve]

10) Findling RL, Youngstrom EA, McNamara NK, Stansbrey RJ, Wynbrandt JL, Adegbite C, Rowles BM, Demeter CA, Frazier TW, Calabrese JR
Double-blind, randomized, placebo-controlled long-term maintenance study of aripiprazole in children with bipolar disorder.
J Clin Psychiatry. 2012 Jan;73(1):57-63.
[PubMed Citation] [Order full text from Infotrieve]

11) West AE, Weinstein SM, Celio CI, Henry D, Pavuluri MN
Co-morbid disruptive behavior disorder and aggression predict functional outcomes and differential response to risperidone versus divalproex in pharmacotherapy for pediatric bipolar disorder.
J Child Adolesc Psychopharmacol. 2011 Dec;21(6):545-53.
[PubMed Citation] [Order full text from Infotrieve]

12) Chiesa A, Chierzi F, De Ronchi D, Serretti A
Quetiapine for bipolar depression: a systematic review and meta-analysis.
Int Clin Psychopharmacol. 2012 Mar;27(2):76-90.
Quetiapine has been proposed for depression in bipolar patients but a quantitative analysis is lacking. In the present paper, we review and meta-analyze available data about the short-term and long-term efficacy and tolerability of quetiapine for the depressive phase of bipolar disorder or bipolar depression. A literature research was carried out using three electronic databases. Studies providing measures of efficacy and tolerability of quetiapine, either as monotherapy or as augmentation, for bipolar depression were considered. Seven short-term studies and four maintenance studies were included. Short-term studies suggested that patients treated with quetiapine monotherapy were significantly more likely than patients treated with placebo and further active comparators to achieve higher response and remission rates as well as more clinical improvements at the endpoint. Such benefits were significant from the first weeks of treatment onward. Maintenance studies suggested that the combination of quetiapine and mood stabilizers was significantly better than placebo plus mood stabilizers for the prevention of both depressive and manic relapses. Quetiapine was generally well tolerated. Furthermore, several clinical variables moderated outcomes under investigation. In conclusion, quetiapine could have some advantages over traditional treatments for the treatment of bipolar depression. [PubMed Citation] [Order full text from Infotrieve]

13) Cutler AJ, Datto C, Nordenhem A, Minkwitz M, Acevedo L, Darko D
Extended-release quetiapine as monotherapy for the treatment of adults with acute mania: a randomized, double-blind, 3-week trial.
Clin Ther. 2011 Nov;33(11):1643-58.
[PubMed Citation] [Order full text from Infotrieve]

14) Weisler RH, Nolen WA, Neijber A, Hellqvist A, Paulsson B
Continuation of quetiapine versus switching to placebo or lithium for maintenance treatment of bipolar I disorder (Trial 144: a randomized controlled study).
J Clin Psychiatry. 2011 Nov;72(11):1452-64.
[PubMed Citation] [Order full text from Infotrieve]

15) Pavuluri MN, Ellis JA, Wegbreit E, Passarotti AM, Stevens MC
Pharmacotherapy impacts functional connectivity among affective circuits during response inhibition in pediatric mania.
Behav Brain Res. 2012 Jan 15;226(2):493-503.
[PubMed Citation] [Order full text from Infotrieve]

16) Gentile S
Clinical usefulness of second-generation antipsychotics in treating children and adolescents diagnosed with bipolar or schizophrenic disorders.
Paediatr Drugs. 2011 Oct 1;13(5):291-302.
The onset of severe, chronic or recurrent psychiatric illnesses, such as schizophrenia-spectrum and bipolar disorders, is a dramatic clinical event often detectable during adolescence and even in childhood. At any age, pharmacotherapy, along with enhancement of social skills and family support, is the mainstay for the management of such disorders. The aim of this review is to critically analyze findings from randomized controlled trials (RCTs) that have investigated the clinical utility of second-generation antipsychotics (SGAs) for the treatment of early-onset schizophrenia and bipolar disorders. Eighteen studies were considered, all of which were unfortunately impaired by methodologic limitations, such as the paucity of long-term data and lack of a three-arm comparison (SGA vs SGA vs placebo). Nevertheless, the results of this review allow us to suggest the effectiveness of three SGAs (aripiprazole, olanzapine, and risperidone) in the short-term treatment of both early-onset schizophrenia and bipolar mania, although such agents show different safety profiles. The use of clozapine should be strictly limited to patients with non-affective, psychotic symptoms who do not respond to any of these three SGAs. In contrast, the use of quetiapine and ziprasidone in young patients with either affective or non-affective psychosis is not yet supported by evidence-based information. Given our findings, further studies are urgently required to identify the best treatment option(s) for pediatric bipolar disorder (especially the depressive phase) and the long-term management of early-onset schizophrenia. [PubMed Citation] [Order full text from Infotrieve]

17) Cipriani A, Barbui C, Salanti G, Rendell J, Brown R, Stockton S, Purgato M, Spineli LM, Goodwin GM, Geddes JR
Comparative efficacy and acceptability of antimanic drugs in acute mania: a multiple-treatments meta-analysis.
Lancet. 2011 Oct 8;378(9799):1306-15.
[PubMed Citation] [Order full text from Infotrieve]

18) Costa RT, Cheniaux E, Rosaes PA, Carvalho MR, Freire RC, Versiani M, Rangé BP, Nardi AE
The effectiveness of cognitive behavioral group therapy in treating bipolar disorder: a randomized controlled study.
Rev Bras Psiquiatr. 2011 Jun;33(2):144-9.
[PubMed Citation] [Order full text from Infotrieve]

19) Mankoski R, Zhao J, Carson WH, Mathew SJ, Forbes RA
Young mania rating scale line item analysis in pediatric subjects with bipolar I disorder treated with aripiprazole in a short-term, double-blind, randomized study.
J Child Adolesc Psychopharmacol. 2011 Aug;21(4):359-64.
[PubMed Citation] [Order full text from Infotrieve]

20) Meltzer HY, Bonaccorso S, Bobo WV, Chen Y, Jayathilake K
A 12-month randomized, open-label study of the metabolic effects of olanzapine and risperidone in psychotic patients: influence of valproic acid augmentation.
J Clin Psychiatry. 2011 Dec;72(12):1602-10.
[PubMed Citation] [Order full text from Infotrieve]