Professor of Psychiatry/Director
Bipolar Disorders Programme
University of Barcelona Hospital Clinic
Department of Psychiatry
Bipolar disorder is a common, severe long-term condition and an important cause of disability among young adults.(1) Manic and depressive episodes alternate with periods of remission, and prophylactic treatment is needed in order to avoid relapse. Nowadays mood stabilisers are still the main treatment for bipolar patients. Although drugs such as lithium, anticonvulsants, traditional neuroleptics and antidepressants are still available and may be an option, their side-effect profile, the need for monitoring in some cases and the existence of treatment-refractory cases have encouraged the search for alternative options. Atypical antipsychotics are established as the main treatment for schizophrenia, but recently a growing number of trials have turned them into an option for bipolar patients, both as an alternative and adjuncts to so-called traditional mood stabilisers.(2) Mania is the most studied phase, but there is increasing evidence of the efficacy and safety of these drugs in the treatment of bipolar depression and maintenance of bipolar disorder.(3)
In addition to traditional first-line treatments for acute mania, such as lithium, divalproex, carbamazepine and conventional antipsychotics, Practical Guidelines of the American Psychiatry Association support the use of atypical antipsychotics.(4) The US Food and Drug Administration (FDA) has already approved five atypical antipsychotics for the treatment of acute mania: olanzapine, risperidone, quetiapine, ziprasidone and aripiprazole. Criteria for FDA approval include two multicentre, randomised, double-blind, placebo-controlled trials with adequate sample sizes supporting the safety and efficacy of these agents. These drugs are also approved for the treatment of mania in most European countries.
Several double-blind, placebo-controlled trials have demonstrated the safety and efficacy of risperidone as an antimanic agent.
When used as monotherapy, risperidone significantly improved YMRS (Young Mania Rating Scale) compared with placebo in three trials.(5–7) It has also been studied as adjunct treatment to lithium, valproate semisodium or carbamazepine.
Two double-blind, randomised controlled trials studied mood stabilisers plus risperidone or placebo in the treatment of acute mania and gave further support to the use of this atypical antipsychotic.(8,9) The main downsides of risperidone are the risk of dose-related extrapyramidal symptoms and hyper‑prolactinaemia.(6)
Olanzapine is the most studied of all the atypical antipsychotics.(10) It has been studied as monotherapy for acute mania with positive results in two randomised, double-blind, placebo-controlled trials.(11,12) Compared with haloperidol, both drugs were equally effective in improving manic symptoms, but patients randomised to haloperidol switched more frequently to depression.(13)
Olanzapine has also been compared with lithium and divalproex in the treatment of mania. Olanzapine was at least as effective as lithium in a double-blind trial,(14) and provided a higher decrease in YMRS scores than divalproex.(15)
Combinations of olanzapine plus lithium or valproate are more effective in the treatment of acute mania than lithium or valproate alone.(16) The main adverse events of olanzapine are weight gain and its complications, as well as somnolence.
Quetiapine was effective and safe in trials that compared it with haloperidol, lithium and placebo.(17,18) Haloperidol was more efficacious but also not so well tolerated. When added to lithium or divalproex in the treatment of acute mania, the quetiapine–mood stabiliser group had a significantly greater reduction in the YMRS score when compared with the placebo–mood stabiliser group, but somnolence and dry mouth were significantly higher as well.(18) The main adverse events of quetiapine are somnolence and hypotension.(19)
Two three-week double-blind trials evaluated the efficacy and tolerability of ziprasidone compared with placebo. (20,21) Ziprasidone improved relative to baseline and placebo on all primary and most secondary efficacy measures at endpoint. Somnolence and akathisia were more frequent in the ziprasidone group. A 12-week placebo-controlled trial confirmed the efficacy of ziprasidone, although, as happened with quetiapine, haloperidol was more efficacious but worse tolerated.(22) An add-on trial failed to yield positive results.(23)
Two three-week placebo-controlled trials showed aripiprazole to be effective and one failed.(24,25) One also demonstrated response rate superior to that of haloperidol in patients remaining on treatment in a 12-week comparative trial.(26)
Akathisia was significantly higher with aripiprazole when compared with placebo.(24,25)
There are no controlled trials on aripiprazole as adjunct treatment of mood stabilisers as yet.
Amisulpride, clozapine and zotepine
No double-blind clinical trials are available on the utility of these agents in bipolar patients, but several open studies suggest they may be an option.27–29 Clozapine should be considered in treatment-refractory cases.(30)
It is the most common phase of bipolar disorder.(31) Atypical antipsychotics are now conceived as a promising option for treating bipolar depression,(31,32) although only three controlled trials, none as adjunct therapy to mood stabilisers, are available so far.
A double-blind, randomised placebo-controlled trial was developed with 833 patients suffering bipolar I depression. They were divided into three groups that would receive placebo, olanzapine or olanzapine plus fluoxetine. Olanzapine, but especially the olanzapine–fluoxetine combination, significantly improved MADRS (Montgomery– Asberg Depression Rating Scale) scores compared with placebo, and treatment-induced mania was similar for the three arms of the trial.(33)
Quetiapine significantly improved MADRS total scores compared with placebo when treating bipolar patients going through a major depressive episode. Depressive symptoms, suicidal thoughts, anxiety, sleep quality and global quality of life improved in the quetiapine group, but rates of switches to mania were similar for both.(34)
A second trial has replicated these findings. The antidepressant activity identified in olanzapine and quetiapine might be related to their 5-HT(2A) antagonist properties. An advantage for both molecules would be their simultaneous D(2) antagonism, which would also give them mood stabiliser properties.(35)
There is growing evidence of second-generation antipsychotics having mood-stabilising properties.
No controlled trials are available with risperidone beyond 12 weeks, but bipolar and schizoaffective bipolar patients going through any sort of relapse were followed during six months in an open, multicentre study with add-on risperidone (mean dose of 3.9mg/day). No new-emergent tardive dyskinesia cases were identified. Although extrapyramidal symptoms and weight gain were the most reported side-effects, they were not very frequent.(36) Only 1.8% of switches to mania were found.
Olanzapine has been widely studied and is approved by the FDA and the European Medicines Agency (EMEA) for maintenance treatment. Several trials support its use in the maintenance phase of bipolar disorder, not only as adjunctive therapy with mood stabilisers but also as monotherapy, after successful treatment of mania.
This agent was compared with lithium and divalproex in two double-blind trials. Olanzapine significantly reduced YMRS scores at endpoint. No difference in relapse rates between divalproex and olanzapine was noted. Nausea and nervousness were more frequent in divalproex-treated patients. Lithium and olanzapine were similar in preventing depressive episodes, but olanzapine was superior in preventing manic relapses.
The efficacy of olanzapine in relapse prevention was tested again in a double-blind, placebo-controlled, 12-month clinical trial. Olanzapine was superior to placebo in preventing any kind of bipolar relapse. In these trials, somnolence, dry mouth, increased appetite, weight gain, akathisia and high alanine aminotransferase levels were reported in some patients when olanzapine was prescribed.(37–39)
When combined with a mood stabiliser, median time to bipolar symptomatic relapse was significantly higher than in the mood stabiliser alone group, but there were no differences in time to bipolar syndromic relapse.(40)
Two small open-label prospective trial have demonstrated that quetiapine could potentially be used in patients who are inadequate responders to mood stabilisers alone. Weight gain has been reported.(41,42)
A double-blind, placebo-controlled trial showed that aripiprazole could prevent manic relapses but not the depressive ones.(43) Aripiprazole is approved by the FDA for maintenance treatment.
An open-label trial suggests that ziprasidone could be helpful as augmentation therapy; the drug is relatively well tolerated, but this needs to be confirmed in future trials.(44) There are only series of cases regarding clozapine as a maintenance treatment.(45)
There is growing evidence of the utility of second-generation antipsychotics in bipolar disorder. Their role in mania is widely documented. In addition, quetiapine and olanzapine may also have a role in bipolar depression.
Some atypical agents are now being regarded as having mood-stabilising properties, and therefore a broader use of these drugs for bipolar disorder is anticipated in the near future.
- World Health Organization. World Health Report: Mental Health: New Understanding, New Hope. Geneva: World Health Organization; 2001.
- Vieta E. Goikolea JM. Bipolar Disord 2005;7 Suppl 2:1-13.
- Vieta E. Expert Rev Neurother 2004; 4 Suppl 2:35-42.
- American Psychiatric Association Work Group On Bipolar Disorder, Practice guideline for the treatment of patients with bipolar disorder (revision). Am J Psychiatry 2002;159 Suppl:1-50.
- Hirschfeld RM, Kramer M, Karcher K, et al. Am J Psychiatry 2004;161:1057-65.
- Khanna S, Vieta E, Lyons B, et al. Br J Psychiatry 2005;187:229-34.
- Smulevich AB, Khanna S, Eerdekens M, et al. Eur Neuropsychopharmacol 2005;15:75-84.
- Yatham LN, Grossman F, Augustyns I, et al. Br J Psychiatry 2003;182:141-7.
- Sachs GS, Grossman F, Ghaemi SN, et al. Am J Psychiatry 2002;159:1146-54.
- Vieta E. Expert Opin Pharmacother 2004;5:1613-9.
- Tohen M, Sanger TM, McElroy SL, et al. Am J Psychiatry 1999;156:702-9.
- Tohen M, Jacobs TG, Grundy SL, et al. Arch Gen Psychiatry 2000;57:841-9.
- Tohen M, Goldberg JF, Gonzalez-Pinto Arrillaga AM, et al. Arch Gen Psychiatry 2003;60:1218-26.
- Berk M, Ichim L, Brook S. Int Clin Psychopharmacol 1999;14:339-43.
- Tohen M, Baker RW, Altshuler LL, et al. Am J Psychiatry 2002;159:1011-7.
- Tohen M, Chengappa KNR, Suppes T, et al. Arch Gen Psychiatry 2002;59:62-9.
- McIntyre RS, Brecher M, Paulsson B, et al. Eur Neuropsychopharmacol 2005;15:573-85.
- Sachs G, Chengappa KNR, Suppes T, et al. Bipolar Disord 2004;6 :213-23.
- Vieta E, Mullen J, Brecher M, et al. Curr Med Res Opin 2005;21:923-34.
- Keck Jr PE, Versiani M, Potkin S, et al. Am J Psychiatry 2003;160:741-8.
- Potkin SG, Keck Jr PE, Segal S, et al. J Clin Psychopharmacol 2005;25:301-10.
- Dunn J, Ramey TS, Giller EL, et al. Efficacy and tolerability of ziprasidone in acute bipolar mania: twelve-week, double-blind study. Presented at the 13th Association of European Psychiatrists Congress, April 2–5 2006, Munich, Germany.
- Weisler R, Dunn J, English P. Ziprasidone in adjunctive treatment of acute bipolar mania: randomized, double-blind, placebo-controlled trial. 16th European College of Neuropsychopharmachology Congress, Prague, Czech Republic, 20–24 September 2003.
- Keck Jr PE, Marcus R, Tourkodimitris S, et al. Am J Psychiatry 2003;160:1651-8.
- Yocca F, McQuade RD, Sanchez R, et al. Efficacy of aripiprazole in acute mania. A new acute, placebo-controlled study. American College of Neuropsychopharmacology, San Juan, Puerto Rico, 2003.
- Vieta E, Bourin M, Sanchez R, et al. Br J Psychiatry 2005;187:235-42.
- Vieta E, Ros S, Goikolea JM, et al. J Clin Psychiatry 2005;66:575-8.
- McElroy SL, Dessain DC, Pope HG Jr, et al. J Clin Psychiatry 1991;52:411-4.
- Amann B, Sterr A, Mergi R, et al. Bipolar Disord 2005;7:471-6.
- Calabrese JR, Kimmel SE, Woyshville MJ, et al. Am J Psychiatry 1996;153:759-64.
- Judd LL, Akiskal HS, Schetter PJ, et al. Arch Gen Psychiatry 2002;59:530-7.
- Keck Jr PE. Bipolar Disord Supplement 2005;7:34-40.
- Tohen M, Vieta E, Calabrese J, et al. Arch Gen Psychiatry 2003;60:1079-88.
- Calabrese JR, Keck Jr PE, Macfadden W, et al. Am J Psychiatry 2005;162:1351-60.
- Yatham LN, Goldstein JM, Vieta E, et al. J Clin Psychiatry 2005;66:40-8.
- Vieta E, Goikolea JM, Corbella B, et al. J Clin Psychiatry 2001;62:818-25.
- Tohen M, Ketter TA, Zarate CA, et al. Am Psychiatry 2003;160:1263-71.
- Tohen M, Marneros A, Bowden CL. Bipolar Disord 2003;5:89.
- Tohen M, Bowden C, Calabrese JR, et al. Olanzapine’s efficacy for relapse prevention in bipolar disorder: a randomized double-blind placebo-controlled 12-month clinical trial. 5th International Conference on Bipolar Disorder (poster abstract), 2003.
- Tohen M, Chengappa KNR, Suppes T, et al. Br J Psychiatry 2004;184:337-45.
- Sajatovic M, Brescan DW, Perez DE, et al. J Clin Psychiatry 2001;62: 728-32.
- Vieta E, Parramon G, Padrell E, et al. Bipolar Disord 2002;4:335-40.
- McQuade RD, Sanchez R, Marcus R, et al. Int J Neuropsychopharmacol 2004;7:s161.
- Weisler R, Warrington L, Dunn J, et al. Adjunctive ziprasidone in bipolar mania: short and long-term data. Program and abstracts of the American Psychiatric Association 2004 Annual Meeting; May 1–6, 2004; New York, NY. Abstract NR358.
- Hummel B, Dittmann S, Forsthoff A, et al. Neuropsychobiology 2002;45:37-42.