Skip to main content
PMC home page
Neuroscience Bulletin logoLink to Neuroscience Bulletin
. 2015 May 30;31(5):572–588. doi: 10.1007/s12264-014-1534-0

Important clinical features of atypical antipsychotics in acute bipolar depression that inform routine clinical care: a review of pivotal studies with number needed to treat

Keming Gao 1,✉, Chengmei Yuan 2, Renrong Wu 3, Jun Chen 2, Zuowei Wang 4, Yiru Fang 2, Joseph R Calabrese 1
PMCID: PMC5563672  PMID: 26024955

Abstract

English-language literature cited in MEDLINE from January, 1980 to October 30, 2014 was searched by using terms of antipsychotic, generic and brand names of atypical antipsychotics, “bipolar depression/bipolar disorder”, “placebo”, and “trial”. The parameters of response (≥50% improvement on MADRS, Montgomery-Asberg Depression Rating Scale total score), remission (either ≤12 or 8 on MADRS total score at endpoint), discontinuation due to adverse events (DAEs), somnolence, ≥7% weight gain, overall extrapyramidal side-effects (EPSs), and akathisia, were extracted from originally published primary outcome papers. The number needed to treat to benefit (NNT) for response and remission or harm (NNH) for DAEs or other side effects relative to placebo were estimated and presented with the estimate and 95% confidence interval. Olanzapine monotherapy, olanzapine-fluoxetine combination (OFC), quetiapine-IR monotherapy, quetiapine-XR monotherapy, lurasidone monotherapy, and lurasidone adjunctive therapy were superior to placebo with NNTs for responses of 11–12, 4, 7–8, 4, 4–5, and 7, and NNTs for remission of 11–12, 4, 5–11, 7, 6–7, and 6, respectively. There was no significant difference between OFC and lamotrigine, and between aripiprazole or ziprasidone and placebo in response and remission. Olanzapine monotherapy, quetiapine-IR, quetiapine-XR, aripiprazole, and ziprasidone 120–160 mg/day had significantly increased risk for DAEs with NNHs of 24, 8–14, 9, 12, and 10, respectively. For somnolence, quetiapine-XR had the smallest NNH of 4. For ≥7% weight gain, olanzapine monotherapy and OFC had the smallest NNHs with both of 5. For akathisia, aripiprazole had the smallest NNH of 5. These findings suggest that among the FDA-approved agents including OFC, quetiapine-IR and -XR, lurasidone monotherapy and adjunctive therapy to a mood stabilizer, the differences in the NNTs for response and remission are small, but the differences in NNHs for DAEs and common side-effects are large. Therefore, the selection of an FDA-approved atypical antipsychotic for bipolar depression should be based upon safety and tolerability.

Keywords: bipolar depression, atypical antipsychotic, number needed to treat, efficacy, tolerability, weight gain, somnolence, extrapyramidal side-effects, akathisia

References

  • [1].Judd LL, Akiskal HS, Schettler PJ, Endicott J, Maser J, Solomon DA, et al. The long-term natural history of the weekly symptomatic status of bipolar I disorder. Arch Gen Psychiatry. 2002;59:530–537. doi: 10.1001/archpsyc.59.6.530. [DOI] [PubMed] [Google Scholar]
  • [2].Judd LL, Akiskal HS, Schettler PJ, Coryell W, Endicott J, Maser JD, et al. A prospective investigation of the natural history of the long-term weekly symptomatic status of bipolar II disorder. Arch Gen Psychiatry. 2003;60:261–269. doi: 10.1001/archpsyc.60.3.261. [DOI] [PubMed] [Google Scholar]
  • [3].Calabrese JR, Hirschfeld RM, Reed M, Davies MA, Frye MA, Keck PE, et al. Impact of depressive symptoms compared with manic symptoms in bipolar disorder: Results of a U.S. community-based sample. J Clin Psychiatry. 2004;65:1499–1504. doi: 10.4088/JCP.v65n1109. [DOI] [PubMed] [Google Scholar]
  • [4].Gao K, Gajwani P, Elhaj O, Calabrese JR. Typical and atypical antipsychotics in bipolar depression. J Clin Psychiatry. 2005;66:1376–1385. doi: 10.4088/JCP.v66n1106. [DOI] [PubMed] [Google Scholar]
  • [5].Gao K, Wu R, Grunze H, Calabrese JR. Pharmacological Treatment of Acute Bipolar Depression. In: Yildiz A, Ruiz P, Nemeroff C (Eds.). Bipolar Book: History, Neurobiology, and Treatment. New York: Oxford University Press (in press).
  • [6].Gao K, Kemp DE, Wu R, Calabrese JR. Mood stabilizers. In: Tasman AJ, Lieberman J, Kay J, First M, Riba M (Eds.). Psyschiatry. 4th Ed. Chichester, West Sussex, UK: Wiley-Blackwell (in press).
  • [7].Gao K, Ganocy SJ, Gajwani P, Muzina DJ, Kemp DE, Calabrese JR. A review of sensitivity and tolerability of antipsychotics in patients with bipolar disorder or schizophrenia: focus on somnolence. J Clin Psychiatry. 2008;69:302–309. doi: 10.4088/JCP.v69n0217. [DOI] [PubMed] [Google Scholar]
  • [8].Gao K, Kemp DE, Ganocy SJ, Gajwani P, Xia G, Calabrese JR. Antipsychotic-induced extrapyramidal side effects in bipolar disorder and schizophrenia: a systematic review. J Clin Psychopharmacol. 2008;28:203–209. doi: 10.1097/JCP.0b013e318166c4d5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [9].Wang Z, Kemp DE, Chan PK, Fang Y, Ganocy SJ, Calabrese JR, et al. Comparisons of the tolerability and sensitivity of quetiapine-XR in the acute treatment of schizophrenia, bipolar mania, bipolar depression, major depressive disorder, and generalized anxiety disorder. Int J Neuropsychopharmacol. 2011;14:131–142. doi: 10.1017/S146114571000101X. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [10].Gao K, Kemp DE, Fein E, Wang Z, Fang Y, Ganocy SJ, et al. Number needed to treat to harm for discontinuation due to adverse events in the treatment of bipolar depression, major depressive disorder, and generalized anxiety disorder with atypical antipsychotics. J Clin Psychiatry. 2011;72:1063–1071. doi: 10.4088/JCP.09r05535gre. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [11].Citrome L, Ketter TA, Cucchiaro J, Loebel A. Clinical assessment of lurasidone benefit and risk in the treatment of bipolar I depression using number needed to treat, number needed to harm, and likelihood to be helped or harmed. J Affect Disord. 2014;155:20–27. doi: 10.1016/j.jad.2013.10.040. [DOI] [PubMed] [Google Scholar]
  • [12].Carmody TJ, Rush AJ, Bernstein I, Warden D, Brannan S, Burnham D, et al. The Montgomery Asberg and the Hamilton ratings of depression: a comparison of measures. Eur Neuropsychopharmacol. 2006;16:601–611. doi: 10.1016/j.euroneuro.2006.04.008. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [13].McQuay HJ, Moore RA. Using numerical results from systematic reviews in clinical practice. Ann Intern Med. 1997;126:712–720. doi: 10.7326/0003-4819-126-9-199705010-00007. [DOI] [PubMed] [Google Scholar]
  • [14].Wu R, Kemp DE, Sajatovic M, Zhao J, Calabrese JR, Gao K. Communication of potential benefits and harm to patients and payers in psychiatry: a review and commentary. Clin Ther. 2011;33:B62–76. doi: 10.1016/j.clinthera.2011.11.013. [DOI] [PubMed] [Google Scholar]
  • [15].Cohen LS. Statistical Power Analysis for the Behavioral Sciences. Hillsdale, NJ: Erlbaum; 1988. [Google Scholar]
  • [16].Tohen M, Vieta E, Calabrese J, Ketter TA, Sachs G, Bowden C, et al. Efficacy of olanzapine and olanzapine-fluoxetine combination in the treatment of bipolar depression. Arch Gen Psychiatry. 2003;60:1079–1088. doi: 10.1001/archpsyc.60.11.1079. [DOI] [PubMed] [Google Scholar]
  • [17].Tohen M, McDonnell DP, Case M, Kanba S, Ha K, Fang YR, et al. Randomised, double-blind, placebo-controlled study of olanzapine in patients with bipolar I depression. Br J Psychiatry. 2012;201:376–382. doi: 10.1192/bjp.bp.112.108357. [DOI] [PubMed] [Google Scholar]
  • [18].Katagiri H, Tohen M, McDonnell DP, Fujikoshi S, Case M, Kanba S, et al. Efficacy and safety of olanzapine for treatment of patients with bipolar depression: Japanese subpopulation analysis of a randomized, double-blind, placebo-controlled study. BMC Psychiatry. 2013;13:138. doi: 10.1186/1471-244X-13-138. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [19].Brown EB, McElroy SL, Keck PE, Jr, Deldar A, Adams DH, Tohen M, et al. A 7-week, randomized, double-blind trial of olanzapine/fluoxetine combination versus lamotrigine in the treatment of bipolar I depression. J Clin Psychiatry. 2006;67:1025–1033. doi: 10.4088/JCP.v67n0703. [DOI] [PubMed] [Google Scholar]
  • [20].Calabrese JR, Keck PE, Jr, Macfadden W, Minkwitz M, Ketter TA, Weisler RH, et al. A andomized, double-blind, placebocontrolled trial of quetiapine in the treatment of bipolar I or II depression. Am J Psychiatry. 2005;162:1351–1360. doi: 10.1176/appi.ajp.162.7.1351. [DOI] [PubMed] [Google Scholar]
  • [21].Thase ME, Macfadden W, Weisler RH, Chang W, Paulsson B, Khan A, et al. Efficacy of quetiapine monotherapy in bipolar I and II depression: a double-blind, placebo-controlled study (the BOLDER II study) J Clin Psychopharmacol. 2006;26:600–609. doi: 10.1097/01.jcp.0000248603.76231.b7. [DOI] [PubMed] [Google Scholar]
  • [22].Suppes T, Datto C, Minkwitz M, Nordenhem A, Walker C, Darko D. Effectiveness of the extended release formulation of quetiapine as monotherapy for the treatment of acute bipolar depression. J Affect Disord. 2010;121:106–115. doi: 10.1016/j.jad.2009.10.007. [DOI] [PubMed] [Google Scholar]
  • [23].Young AH, McElroy SL, Bauer M, Philips N, Chang W, Olausson B, et al. A double-blind, placebo-controlled study of quetiapine and lithium monotherapy in adults in the acute phase of bipolar depression (EMBOLDEN I) J Clin Psychiatry. 2010;71:150–162. doi: 10.4088/JCP.08m04995gre. [DOI] [PubMed] [Google Scholar]
  • [24].McElroy SL, Weisler RH, Chang W, Olausson B, Paulsson B, Brecher M, et al. A double-blind, placebo-controlled study of quetiapine and paroxetine as monotherapy in adults with bipolar depression (EMBOLDEN II) J Clin Psychiatry. 2010;71:163–174. doi: 10.4088/JCP.08m04942gre. [DOI] [PubMed] [Google Scholar]
  • [25].Thase ME, Jonas A, Khan A, Bowden CL, Wu X, McQuade RD, et al. Aripiprazole monotherapy in nonpsychotic bipolar I depression: results of 2 randomized, placebo-controlled studies. J Clin Psychopharmacol. 2008;28:13–20. doi: 10.1097/jcp.0b013e3181618eb4. [DOI] [PubMed] [Google Scholar]
  • [26].Lombardo I, Sachs G, Kolluri S, Kremer C, Yang R. Two 6-week, randomized, double-blind, placebo-controlled studies of ziprasidone in outpatients with bipolar I depression: did baseline characteristics impact trial outcome? J Clin Psychopharmacol. 2012;32:470–478. doi: 10.1097/JCP.0b013e31825ccde5. [DOI] [PubMed] [Google Scholar]
  • [27].Gao K, Pappadopulos E, Karayal ON, Kolluri S, Calabrese JR. Risk for adverse events and discontinuation due to adverse events of ziprasidone monotherapy relative to placebo in the acute treatment of bipolar depression, mania, and schizophrenia. J Clin Psychopharmacol. 2013;33:425–431. doi: 10.1097/JCP.0b013e3182917f3f. [DOI] [PubMed] [Google Scholar]
  • [28].Sachs GS, Ice KS, Chappell PB, Schwartz JH, Gurtovaya O, et al. Efficacy and safety of adjunctive oral ziprasidone for acute treatment of depression in patients with bipolar I disorder: a randomized, double-blind, placebo-controlled trial. J Clin Psychiatry. 2011;72:1413–1422. doi: 10.4088/JCP.09m05934. [DOI] [PubMed] [Google Scholar]
  • [29].Loebel A, Cucchiaro J, Silva R, Kroger H, Hsu J, Sarma K, et al. Lurasidone monotherapy in the treatment of bipolar i depression: a randomized, double-blind, placebo-controlled study. Am J Psychiatry. 2014;171:160–168. doi: 10.1176/appi.ajp.2013.13070984. [DOI] [PubMed] [Google Scholar]
  • [30].Loebel A, Cucchiaro J, Silva R, Kroger H, Sarma K, Xu J, et al. Lurasidone as adjunctive therapy with lithium or valproate for the treatment of bipolar i depression: a randomized, double-blind, placebo-controlled study. Am J Psychiatry. 2014;171:169–177. doi: 10.1176/appi.ajp.2013.13070985. [DOI] [PubMed] [Google Scholar]
  • [31].Citrome L, Kantrowitz J. Antipsychotics for the treatment of schizophrenia: likelihood to be helped or harmed, understanding proximal and distal benefits and risks. Expert Rev Neurother. 2008;8:1079–1091. doi: 10.1586/14737175.8.7.1079. [DOI] [PubMed] [Google Scholar]
  • [32].Tohen M, Katagiri H, Fujikoshi S, Kanba S. Efficacy of olanzapine monotherapy in acute bipolar depression: a pooled analysis of controlled studies. J Affect Disord. 2013;149:196–201. doi: 10.1016/j.jad.2013.01.022. [DOI] [PubMed] [Google Scholar]
  • [33].Gao K, Mackle M, Cazorla P, Zhao J, Szegedi A. Comparison of somnolence associated with asenapine, olanzapine, risperidone, and haloperidol relative to placebo in patients with schizophrenia or bipolar disorder. Neuropsychiatr Dis Treat. 2013;9:1145–1157. doi: 10.2147/NDT.S41333. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [34].Suppes T, Dennehy EB, Hirschfeld RM, Altshuler LL, Bowden CL, Calabrese JR, et al. The Texas implementation of medication algorithms: update to the algorithms for treatment of bipolar I disorder. J Clin Psychiatry. 2005;66:870–886. doi: 10.4088/JCP.v66n0710. [DOI] [PubMed] [Google Scholar]
  • [35].Bowden CL, Calabrese JR, Sachs G, Yatham LN, Asghar SA, Hompland M, et al. A placebo-controlled 18-month trial of lamotrigine and lithium maintenance treatment in recently manic or hypomanic patients with bipolar I disorder. Arch Gen Psychiatry. 2003;60:392–400. doi: 10.1001/archpsyc.60.4.392. [DOI] [PubMed] [Google Scholar]
  • [36].Calabrese JR, Bowden CL, Sachs G, Yatham LN, Behnke K, Mehtonen OP, et al. A placebo-controlled 18-month trial of lamotrigine and lithium maintenance treatment in recently depressed patients with bipolar I disorder. J Clin Psychiatry. 2003;64:1013–1024. doi: 10.4088/JCP.v64n0906. [DOI] [PubMed] [Google Scholar]
  • [37].van der Loos ML, Mulder PG, Hartong EG, Blom MB, Vergouwen AC, de Keyzer HJ, et al. Efficacy and safety of lamotrigine as add-on treatment to lithium in bipolar depression: a multicenter, double-blind, placebo-controlled trial. J Clin Psychiatry. 2009;70:223–231. doi: 10.4088/JCP.08m04152. [DOI] [PubMed] [Google Scholar]
  • [38].Wu R, Gao K, Calabrese JR, Grunze H. Treatment induced mood instability: treatmentemergent affective switches and cycle acceleration. In: Yildiz A, Ruiz P, Nemeroff C (Eds.). Bipolar Book: History, Neurobiology, and Treatment. New York, USA: Oxford University Press (in press).
  • [39].Chen J, Fang Y, Kemp DE, Calabrese JR, Gao K. Switching to hypomania and mania: differential neurochemical, neuropsychological, and pharmacologic triggers and their mechanisms. Curr Psychiatry Rep. 2010;12:512–521. doi: 10.1007/s11920-010-0157-z. [DOI] [PubMed] [Google Scholar]
  • [40].Pacchiarotti I, Bond DJ, Baldessarini RJ, Nolen WA, Grunze H, Licht RW, et al. The International Society for Bipolar Disorders (ISBD) task force report on antidepressant use in bipolar disorders. Am J Psychiatry. 2013;170:1249–1262. doi: 10.1176/appi.ajp.2013.13020185. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [41].Merikangas KR, Akiskal HS, Angst J, Greenberg PE, Hirschfeld RM, Petukhova M, et al. Lifetime and 12-month prevalence of bipolar spectrum disorder in the National Comorbidity Survey replication. Arch Gen Psychiatry. 2007;64:543–552. doi: 10.1001/archpsyc.64.5.543. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [42].Zimmerman M, Martinez JA, Attiullah N, Friedman M, Toba C, Boerescu DA, et al. Why do some depressed outpatients who are in remission according to the Hamilton Depression Rating Scale not consider themselves to be in remission? J Clin Psychiatry. 2012;73:790–795. doi: 10.4088/JCP.11m07203. [DOI] [PubMed] [Google Scholar]
  • [43].Turner EH, Matthews AM, Linardatos E, Tell RA, Rosenthal R. Selective publication of antidepressant trials and its influence on apparent efficacy. N Engl J Med. 2008;358:252–260. doi: 10.1056/NEJMsa065779. [DOI] [PubMed] [Google Scholar]
  • [44].FoodDrug Administration Center for Drug EvaluationResearch CDER. Review Guidance . Conducting a Clinical Safety Review of a New Product Application and Preparing a Report on the Review. Rockville, Maryland, USA: Food and Drug Administration; 2005. [Google Scholar]

Articles from Neuroscience Bulletin are provided here courtesy of Springer

RESOURCES