Acute Treatment of Mania: An Update on New Medications Prashant Gajwani, MD, David E. Kemp, MD, David J. Muzina, MD, Guohua Xia, MD, PhD, Keming Gao, MD, PhD, and Joseph R. Calabrese, MD
Corresponding author Prashant Gajwani, MD Assistant Professor of Psychiatry, Case School of Medicine, Clinical Director, Mood Disorders Program, University Hospitals Case Medical Center, 11400 Euclid Avenue, Suite 200, Cleveland, OH 44106, USA. E-mail:
[email protected] Current Psychiatry Reports 2006, 8:504–509 Current Science Inc. ISSN 1523-3812 Copyright © 2006 by Current Science Inc.
Acute mania is frequently a medical emergency requiring hospitalization for behavioral control, rapid resolution of irritability, agitation, de-escalation of mood, and decreasing of risk-taking behavior. Lithium efficacy in the management of acute mania was reported in 1949 and approved by the US Food and Drug Administration (FDA) in 1970. Chlorpromazine, from the class of typical antipsychotics, was approved for treatment of bipolar disorder in 1973. Typical antipsychotics were frequently used alone and as adjunct for the treatment of bipolar mania for the next 2 decades. Divalproex was approved by the FDA for the treatment of acute mania in 1994. Since the approval of olanzapine in 2000, all five atypical antipsychotics, namely risperidone (2003), quetiapine (2004), ziprasidone (2004), and aripiprazole (2004), have been approved by the FDA for the management of acute mania. Clozapine is the only atypical antipsychotic not FDA approved for any phase of bipolar disorder. This article will systematically review some of the major studies published, randomized controlled monotherapy, and adjunct therapy trials involving five atypical antipsychotics and newer anticonvulsants for the treatment of acute bipolar mania.
Introduction Bipolar disorder is a form of severe, cyclical mental illness whose core features include abnormal elevation of mood lasting 4 to 7 days and depression. It is prevalent in 3% to 7% [1,2] of the adult population in the United States. The elevated mood state (hypomania and mania) can
be associated with numerous negative consequences, including risks of occupational [3] and legal [4] problems. Therefore, it is imperative that the high moods be managed in an appropriate and timely manner. The initial goal of treatment is to stabilize mood. Hospitalization may be warranted for a majority of patients to ameliorate acute symptoms and to prevent relapse during the maintenance period. This article will focus on the pharmacologic agents used in the management of acute manic symptoms in adult patients with bipolar disorder. Most of the studies reviewed in this article have defined response as a greater than or equal to 50% improvement in symptom severity from baseline to endpoint using either the Young Mania Rating Scale (YMRS) or the Mania Rating Scale (MRS). The majority of the randomized clinical trials have employed the YMRS; some have employed the MRS. Typical antipsychotics had been widely used for the treatment of acute bipolar mania prior to approval of mood-stabilizing medications such as divalproex and carbamazepine (CBZ). Since 2000, however, greater evidence has been published in scientific literature to support the efficacy of atypical antipsychotics in the management of acute bipolar mania; consequently, there has been greater use of atypical antipsychotics in clinical practice. One of the main factors limiting the use of typical antipsychotic medications is the development of extrapyramidal side effects (EPS) and irreversible tardive dyskinesia (TD). Atypical antipsychotics are proven to have more benign side effect profiles when compared with typical antipsychotics in regard to EPS and TD. However, more information is now available regarding the potential risks of weight gain, risk of diabetes, and induction of dyslipidemias with the use of atypical antipsychotic medications. In a recently published meta-analysis of atypical antipsychotics in the treatment of mania, Perlis et al. [5••] concluded that differences in acute efficacy between the five atypical antipsychotics are likely to be small. Due to rapid advances in the treatment of bipolar mania, management options for clinicians
Acute Treatment of Mania: An Update on New Medications
have expanded. Practice guidelines [6,7•] also recommend initiating treatment with either a mood stabilizer (MS) or atypical antipsychotic followed by a combination of medications from the previously mentioned two classes. Clozapine [8] has been used in the management of bipolar illness based upon small, open-label trials but has not been proven effective in large, double-blind, placebo-controlled, randomized trials.
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Table 1. FDA-approved indications for treatment of mania For mania
For mixed
Lithium
1970
No FDA indication
Valproate
1995
No FDA indication
Divalproex ER
2005
2005
Approved
Randomized placebo-controlled trials—acute mania (3 to 4 week)
Olanzapine
2000
2004
Approved
Randomized, placebo-controlled trials [9–16] have demonstrated efficacy of all five atypical antipsychotics (olanzapine, risperidone, quetiapine, ziprasidone, aripiprazole), all of which have earned US Food and Drug Administration (FDA) approval, for the management of acute bipolar manic states (Table 1). Olanzapine has demonstrated efficacy in two trials. In a 3-week trial [9], olanzapine, 10 mg/d, produced response rates of 48.6% as compared with 24% produced in the placebo group. In a 4-week trial [10], olanzapine, 15 mg/d, produced a response rate of 65% as compared with 43% in the placebo group. Reported adverse events included somnolence and weight gain (+1.65 kg in olanzapine vs -0.44 kg with placebo in first trial; +2.10 kg with olanzapine vs +0.45 kg with placebo in second trial). Risperidone [11] at a mean dose of 4.1 mg (range 1.0 to 6.0 mg) produced response rates of 43% as compared with 24% on placebo. In a trial completed in India [12], risperidone (mean modal dose 5.6 mg) produced response in 73% of patients as compared with 36% observed in the placebo group. Risperidone’s reported adverse effects included EPS, tremors, and weight gain (+1.6 kg vs -0.25 kg with placebo in the first trial). Aripiprazole [13] at a mean dose of 27.9 mg produced response rate of 40% as compared with 19% on placebo. In another 3-week trial [14], aripiprazole at a mean dose of 28 mg produced a response rate of 53% as compared with 32% on placebo. Aripiprazole’s adverse effects included headache, dyspepsia, and akathisia. Ziprasidone monotherapy [15] with dose range of 80 to 160 mg/d (mean daily dose of 130 mg) produced a response rate of 50% as compared with 35% produced by placebo. In a second 3-week trial, ziprasidone [16] with a mean daily dose of 112 mg produced a response rate of 46% as compared with 29% on placebo. Ziprasidone’s adverse effects included somnolence, headache, dizziness, and akathisia. In a recent meta-analysis of randomized, placebocontrolled monotherapy and adjunctive therapy of atypical antipsychotics in acute bipolar mania, Perlis et al. [5••] performed analysis on 12 placebo-controlled monotherapy and six placebo-controlled adjunctive therapy trials involving a total of 4304 subjects. The authors completed multiple comparisons (pair-wise comparisons
Risperidone
2003
2003
Approved
Quetiapine
2004
No FDA indication
Approved
Ziprasidone
2004
2004
Approved
Aripiprazole
2004
2004
Approved
Carbamazepine ER 2004
2004
No FDA indication
Atypical Antipsychotics
Medication
With or without psychotic features
ER—extended release; FDA—US Food and Drug Administration.
of individual effects) and found no difference in efficacy among atypical antipsychotics. They concluded that the magnitude of improvement was similar whether the antipsychotics were used as monotherapy or adjunctive therapy in management of acute bipolar mania.
Randomized placebo-controlled trials—acute mania and continuation for up to 12 weeks Quetiapine monotherapy was compared with haloperidol [17] and lithium [18] in two separate 12-week, doubleblind, randomized, placebo-controlled trials. These trials, unlike other acute mania trials, excluded patients experiencing mixed states, and consequently, quetiapine is FDA approved only for the treatment of acute manic states associated with bipolar disorder. McIntyre et al. [17] reported a 12-week randomized trial with quetiapine (dose range up to 800 mg), placebo, and haloperidol (dose range up to 8 mg). Quetiapine treatment produced a response rate of 43.6% as compared with placebo’s 35.0% at day 21. By day 84, the response rate in the quetiapine-treated group was 61.4% as compared with 39.0% with placebo. Quetiapine yielded more weight gain as compared with placebo (+0.9 kg vs -0.3 kg) and caused more postural hypotension and somnolence. Haloperidol response rate at day 21 was 56.1% versus 35.0% with placebo, and at day 84, haloperidol was 70.4% compared with placebo at 39.0%. Adverse events in the haloperidol group included EPS, akathisia, and tremor. Overall, both quetiapine and haloperidol were found to be superior to placebo at treating symptoms of mania. Bowden et al. [18] reported a 12-week randomized trial with quetiapine, placebo, or lithium. At day 21, response rates in quetiapine-treated patients were 53.3% versus 27.4% in placebo; at day 84, quetiapine response rate was 72.0% versus 41.1% for placebo. Similar adverse events were reported (weight
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gain of +2.63 kg with quetiapine, -0.08 kg with placebo). Quetiapine also caused greater somnolence and dizziness. Lithium treatment yielded response rate of 53.1% at day 21, improving to 75.5% on day 84. Vieta et al. [19] reported a combined analysis of the previously mentioned two studies with a total of 407 patients. The effect size of quetiapine treatment was 0.18 at day 4, 0.39 at day 21, and it continued to increase, reaching 0.49 at day 84. Risperidone monotherapy was compared with haloperidol in a 12-week, double-blind, placebo-controlled trial [20]. Risperidone in the dose range of 1 to 6 mg/d produced a response rate of 48%, similar to the response rate of 47% achieved with haloperidol at a dose range of 2 to 12 mg/d. Reported adverse events in the risperidone group included EPS, hyperkinesias, and somnolence, whereas adverse events in the haloperidol group included EPS, hyperkinesias, tremor, and hypetonia. The mean increase in weight at week 12 was 1.4 ± 4.6 kg in the risperidone group and 0.8 ± 3.5 kg in the haloperidol group. The authors concluded that changes from baseline in the risperidone group were significantly greater than placebo, and no significant difference was noted between the risperidone and haloperidol groups. Olanzapine was compared with haloperidol in a 12-week, double-blind, randomized clinical trial [21]. Olanzapine at a dose range of 5 to 20 mg/d and haloperidol at a dose range of 3 to 15 mg/d produced a comparable remission rate of 47% at week 6. Rates of relapse at week 12 in patients achieving remission at week 6 also were not different (13.1% in the olanzapine group, 14.8% in the haloperidol group). Olanzapine yielded fewer EPS but greater weight gain as compared with haloperidol (+2.82 kg vs +0.02 kg). Aripiprazole was compared with haloperidol in a double-blind, randomized, 12-week, controlled trial [22]. At week 12, significantly more patients taking aripiprazole achieved response (49.7%) as compared with haloperidol (28.4%). The haloperidol group yielded higher EPS and akathisia as compared with aripiprazole. Common adverse events reported in both groups included tremors, headache, and insomnia.
addition was significantly superior to placebo, as evidenced by the reduction of YMRS total scores and responder rates (67.7% vs 44.7%, P < 0.001). Adverse events reported more frequently in the co-therapy group included somnolence, dry mouth, weight gain, increased appetite, and tremors. In a 3-week, randomized, double-blind, placebocontrolled trial [24] involving bipolar patients in manic or mixed states who were inadequately responding to MS, risperidone (mean modal dose 3.8 mg/d), haloperidol (mean modal dose 6.2 mg/d), or placebo was added. Improvement was evident in risperidone plus MS and haloperidol plus MS as compared with placebo with MS (mean decrease in YMRS scores were -15.7, -14.9, and -7.4, respectively). Yatham et al. [25] reported efficacy of combination of MS with risperidone or placebo. At study endpoint (3 weeks), 59% of patients in the risperidone group met response criteria as compared with 41% in the placebo group. Adverse events such as EPS and use of antiparkinsonian medication were higher in the haloperidol plus MS group as compared with the risperidone plus MS group. The mean weight change was 0.3 lb in haloperidol plus MS, 5.3 lb in risperidone plus MS, and 1.1 lb in placebo plus MS. Quetiapine or placebo was added to lithium or divalproex in patients experiencing an acute manic episode [26]. The addition of quetiapine produced a response rate of 54.3% as compared with a 32.6% response rate with addition of placebo to MS. The incidence of adverse events reported in quetiapine plus MS was higher than placebo plus MS and included somnolence, headache, dry mouth, asthenia, postural hypotension, and dizziness. Ketter et al. [27••] have published pooled data from 20 acute mania studies that include 15 monotherapy and five combination therapy trials. Lithium, divalproex, CBZ, and atypical antipsychotics monotherapy trials have demonstrated response rates of 50% as compared with 29% in placebo. The combination of atypical antipsychotics with lithium or divalproex yielded a response rate of 62% as compared with 42% when placebo was added to lithium or divalproex.
Atypical antipsychotics as adjunct to MS in management of acute mania
MS
Olanzapine, risperidone, or quetiapine as adjunct to MS such as lithium or Depakote (Abbott Laboratories, Abbott Park, IL) have also been studied in patients who were either partially responsive or naïve to MS and were experiencing manic episode [23–26,27••]. The FDA also has approved these compounds for the adjunct indication in the treatment of mania. In the olanzapine combination with MS study [23], patients who were manic and inadequately responsive (YMRS score ≥ 16) after completing at least 2 weeks of lithium or valproate (VPA) monotherapy were randomly assigned to receive the addition of flexible doses of olanzapine (5 to 20 mg/d) or placebo for 6 weeks. Olanzapine
The FDA approved lithium for the treatment of manic episode in 1970. Despite methodological limitations, early studies [28,29] evaluating lithium in the treatment of acute mania demonstrated response in approximately 80% of patients. In recent years, lithium has been used as an active comparator in large, multicenter, randomized, double-blind clinical trials. In 2005, Bowden et al. [18] reported a higher response rate in manic patients treated with quetiapine or lithium (53%) as compared with placebo-treated patients (27%). Lithium has several adverse events, such as tremors, polyuria, polydipsia, nausea, vomiting, and drowsiness, which can occur with therapeutic serum level.
Lithium, divalproex, and CBZ
Acute Treatment of Mania: An Update on New Medications
The anticonvulsants CBZ and VPA were first developed for the treatment of epilepsy. Subsequent studies have demonstrated their efficacy in management of acute manic episode. Pivotal studies [30] demonstrating efficacy of divalproex sodium recruited bipolar manic patients intolerant or nonresponsive to lithium. VPA-treated patients demonstrated a mean decrease of 54% in the YMRS scores as compared with 5% in the placebo arm. In a larger, randomized, double-blind, multicenter, 21-day, parallelgroup study, Bowden et al. [31] reported a response rate of 48% in patients taking VPA as compared with 25% in the placebo arm. Efficacy assessments were based upon changes in MRS scores as opposed to the YMRS. A single, unblinded investigator at each site reviewed VPA serum concentration (mean value 93 μg/mL) and adjusted the dosage. Adverse events included vomiting, somnolence, and dry mouth. CBZ also has been evaluated in the treatment of acute manic states associated with bipolar disorder. The efficacy of CBZ has consistently been found to be similar to that of lithium [32]. Evaluations of CBZ studies were limited due to design and methodological issues. Recently, however, a large, controlled clinical trial has demonstrated efficacy of extended-release capsule formulation of CBZ (E-CBZ). In the pivotal trial [33], 204 bipolar patients in manic or mixed states were treated with E-CBZ or placebo for 3 weeks. CBZ was started at 200 mg twice daily and titrated by 200 mg/d, with mean daily dose of 756 mg and a mean final serum concentration of 8.9 μg/mL. Patients receiving E-CBZ demonstrated a response rate of 43% as compared with 22% in patients receiving placebo. The reported adverse events include dizziness, nausea, and somnolence. Oxcarbazepine, a congener of CBZ, has structural similarities to the parent compound CBZ. It has a more favorable adverse effect and drug interaction profile but very little evidence for efficacy in bipolar manic patients. In two small, multicenter, active comparator, 15-day, acute mania studies [34], oxcarbazepine (mean daily dose of 2400 mg) has been compared with haloperidol and oxcarbazepine (mean daily dose of 1400 mg) to lithium. The degree of improvement was similar in both arms, but studies were confounded by small sample size and lack of a placebo arm.
Topiramate Topiramate, an anticonvulsant, is effective in controlling seizures and migraine headaches. It is distinguished from its predecessor employed in bipolar disorder due to low risk of weight gain or even weight loss in some patients. In small, open-label studies, the addition of topiramate was associated with a reduction in manic symptoms. However, large trials in acutely manic patients did not support the efficacy of topiramate in acute mania or mixed episodes in adults with bipolar disorder. Kushner et al. [35] published results of four double-blind, placebo-controlled trials. Topiramate (target dose 200 to 600 mg/d) was compared with placebo in two trials and to lithium in the
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other two trials. Changes in YMRS scores during 3 weeks were not statistically different for topiramate versus placebo. Mean YMRS score reduction in the lithiumtreated group was significantly greater (P ≤ 0.001 vs placebo and topiramate).
Zonisamide Zonisamide is a novel anticonvulsant with documented efficacy as adjunctive treatment for refractory partial seizures. Preliminary open-label reports suggest efficacy of zonisamide in treatment of bipolar disorder when added to other psychotropic medications [36]. McElroy et al. [37] reported a larger open-label adjunctive zonisamide prospective trial in bipolar patients that involved an 8-week acute trial, followed by a 48-week continuation trial. Thirtyfour patients with bipolar mania received zonisamide (dose started at 100 mg/d with maximum up to 800 mg/ d) and showed a significant decrease in the YMRS score (F = 10.14, df = 5227; P < 0.001). Nineteen patients participated in a subsequent continuation trial and demonstrated that the YMRS score reduction achieved over an acute 8-week trial was maintained over the continuation phase. The authors also noted that zonisamide treatment was associated with statistically significant weight loss, which all patients identified as favorable.
Lamotrigine Unlike divalproex and CBZ, lamotrigine does not have efficacy in treatment of acute bipolar mania. In two large, multicenter, randomized, placebo-controlled trials, lamotrigine was no more effective than placebo in treatment of acute mania [38].
Gabapentin Early open-label case reports of gabapentin use in bipolar disorder were encouraging; later monotherapy [39] and augmentation [40] trials did not differentiate gabapentin from placebo-level effect in treatment of acute bipolar mania.
Conclusions A number of FDA-approved treatment options exist for the treatment of manic episode associated with bipolar disorder. It is evident from this review that FDA-approved agents provide significant benefit as compared with placebo in reducing the severity of manic symptoms. Pooled analysis of data [26] from trials involving patients with acute mania suggests that each FDA-approved agent yields a clinical response (ie, a reduction of ≤ 50% in mania severity relative to baseline) in 45% to 60% of patients. Therefore, clinicians are frequently presented with equally effective treatment options in management of bipolar mania, and appropriateness of treatment option is based on safety and tolerability, which may differ from one agent to another. Patients with bipolar disorder often do not have adequate response to monotherapy. Add-on therapy
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[5••] with atypical antipsychotics confers an additional benefit over monotherapy with MS in treatment of acute manic states associated with bipolar disorder. Practice guidelines published by the American Psychiatric Association [6] recommend use of combination therapy with a traditional MS and an atypical antipsychotic agent in the management of manic phase of bipolar disorder. Clinically combining MS with atypical antipsychotics can possibly result in faster resolution of symptoms of mania, which could translate into early discharge from the hospital. The FDA has stipulated changes in product information on all atypical antipsychotics to reflect risk of hyperglycemia and diabetes mellitus. A report of a recent consensus development conference [41•] suggested that the risk of obesity, diabetes, and hyperlipidemias is highest with clozapine and olanzapine, moderate with risperidone and quetiapine, and lowest with ziprasidone and aripiprazole. Thus, clinical and laboratory monitoring for obesity, diabetes, and hyperlipidemia appear prudent for patients being treated with atypical antipsychotics. However, there are several limitations to the acute mania trials. Most of the trials are short in duration (3 weeks). Bipolar disorder is a lifetime illness with reoccurrence rates as high as 90%. Also, traditionally, 50% reduction in symptom severity is defined as “response,” whereas in clinical practice, severely ill patients may still have residual manic symptoms. Therefore, studies evaluating 3 weeks linked with maintenance of efficacy to 3 months may better predict efficacy of a compound. In addition, most of the trials excluded comorbidities and treatment-refractory patients, which limits generalizability. Lastly, there still may be an undefined supporting role of compounds that have failed to demonstrate efficacy in treatment of acute mania based on their long-term benefits, such as lack of weight gain or even weight loss, that may occur with combination of medications.
Acknowledgments Dr. Gajwani has received research grants from Pfizer, Inc., Bristol-Myers Squibb, and Cyberonics, Inc. and served on the speakers’ bureau for Forest Laboratories, Inc., Abbott Laboratories, AstraZeneca International, Pfizer, Inc., and Cyberonics, Inc. Dr. Kemp has received educational grants from Bristol-Myers Squibb and Abbott Laboratories. Dr. Muzina has served as a speaker for AstraZeneca International (consultant also), Pfizer, Inc., and GlaxoSmithKline and has received research support from Abbott Laboratories, GlaxoSmithKline, and Repligen Corp. Dr. Calabrese has received research funding from Abbott Laboratories, AstraZeneca International, the Cleveland Foundation, the Department of Defense, GlaxoSmithKline, the Health Resources and Services Administration, Janssen Pharmaceutica, Eli Lilly and Co., NARSAD, the National Institute of Mental Health, Pfizer, Inc., and the Stanley Medical
Research Institute; he has served as a consultant, on the advisory board, and/or received honoraria from Abbott Laboratories, AstraZeneca International, Bristol-Myers Squibb, Otsuka America Pharmaceutical, Inc., Eli Lilly and Co., GlaxoSmithKline, Janssen Pharmaceutica, Servier Laboratories, Solvay Pharmaceuticals, Inc., and Wyeth.
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