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Antipsychotic Monotherapy for Major Depressive Disorder: A Systematic Review and Meta-Analysis
Although several randomized controlled trials (RCTs) have compared the effectiveness, efficacy, and safety of antipsychotic monotherapy (APM) versus placebo in patients with major depressive disorder (MDD), no meta-analysis has examined this topic. We conducted a systematic literature search using MEDLINE and Embase to identify relevant RCTs and performed a meta-analysis to compare the following outcomes between APM and placebo: response and remission rates, study discontinuation due to all causes, lack of efficacy, and adverse events, changes in total scores on depression severity scales, and individual adverse event rates. A total of 13 studies were identified, with 14 comparisons involving 3,197 participants that met the eligibility criteria. There were significant differences between APM and placebo in response and remission rates and changes in the primary depression severity scale in favor of APM, and study discontinuation due to adverse events and several individual adverse events in favor of placebo. No significant difference was observed in discontinuation due to all causes. APM could have antidepressant effects in the acute phase of MDD, although clinicians should be aware of an increased risk of some adverse events.
Key wordsmajor depressive disorder - antipsychotics - monotherapy - meta-analysis - systematic review
* Both authors contributed equally
Received: 21 June 2022
Received: 18 August 2022
Accepted: 13 August 2022
Article published online:
18 October 2022
© 2022. Thieme. All rights reserved.
Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany
- 1 Bayes AJ, Parker GB. Comparison of guidelines for the treatment of unipolar depression: A focus on pharmacotherapy and neurostimulation. Acta Psychiatr Scand 2018; 137: 459-471 DOI: 10.1111/acps.12878.
- 2 Rush JA, Trivedi MH, Wisniewski SR. et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: A STAR*D report. Am J Psychiatry 2006; 163: 1905-1917
- 3 Gartlehner G, Hansen RA, Morgan LC. et al. Comparative benefits and harms of second-generation antidepressants for treating major depressive disorder: An updated meta-analysis. Ann Intern Med 2011; 155: 772-785 DOI: 10.7326/0003-4819-155-11-201112060-00009.
- 4 Cohen S. TP-21, a new phenothiazine. Am J Psychiatry 1958; 115: 358 DOI: 10.1176/ajp.115.4.358.
- 5 Overall JE, Hollister LE, Meyer F. et al. Imipramine and thioridazine in depressed and schizophrenic patients. JAMA 1964; 189 DOI: 10.1001/jama.1964.03070080011002.
- 6 Robertson MM, Trimble MR. Major tranquillisers used as antidepressants. J Affect Disord 1982; 4: 173-193 DOI: 10.1016/0165-0327(82)90002-7.
- 7 Jenner P, Marsden CD. The mode of action of sulpiride as an atypical antidepressant agent. Adv Biochem Psychopharmacol 1982; 32: 85-103
- 8 Peselow ED, Stanley M. Clinical trials of benzamides in psychiatry. Adv Biochem Psychopharmacol 1982; 35: 163-194
- 9 Lecrubier Y, Boyer P, Turjanski S. et al. Amilsulpride versus imipramine and placebo in dysthymia and major depression. J Affect Disord 1997; 43: 95-103 DOI: 10.1016/S0165-0327(96)00103-6.
- 10 Kennedy SH, Giacobbe P, Placenza F. et al. Depression treatment by withdrawal of short-term low-dose antipsychotic, a proof-of-concept randomized double-blind study. J Affect Disord 2014; 166: 139-143 DOI: 10.1016/j.jad.2014.04.014.
- 11 Suppes T, Silva R, Cucchiaro J. et al. Lurasidone for the treatment of major depressive disorder with mixed features: A randomized, double-blind, placebo-controlled study. Am J Psychiatry 2016; 173: 400-407 DOI: 10.1176/appi.ajp.2015.15060770.
- 12 Rothschild AJ, Williamson DJ, Tohen MF. et al. A double-blind, randomized study of olanzapine and olanzapine/fluoxetine combination for major depression with psychotic features. J Clin Psychopharmacol 2004; 24: 365-373 DOI: 10.1097/01.jcp.0000130557.08996.7a.
- 13 Chaput Y, Magnan A, Gendron A. The co-administration of quetiapine or placebo to cognitive-behavior therapy in treatment refractory depression: A preliminary trial. BMC Psychiatry 2008; 8: 1-8 DOI: 10.1186/1471-244X-8-73.
- 14 Weisler R, Joyce M, McGill L. et al. Extended release quetiapine fumarate monotherapy for major depressive disorder: Results of a double-blind, randomized, placebo-controlled study. CNS Spectr 2009; 14: 299-313
- 15 Cutler AJ, Montgomery SA, Feifel D. et al. Extended release quetiapine fumarate monotherapy in major depressive disorder: A placebo- and duloxetine-controlled study. J Clin Psychiatry 2009; 70: 526-539
- 16 Bortnick B, El-Khalili N, Banov M. et al. Efficacy and tolerability of extended release quetiapine fumarate (quetiapine XR) monotherapy in major depressive disorder: A placebo-controlled, randomized study. J Affect Disord 2011; 128: 83-94 DOI: 10.1016/j.jad.2010.06.031.
- 17 Katila H, Mezhebovsky I, Mulroy A. et al. Randomized, double-blind study of the efficacy and tolerability of extended release quetiapine fumarate (quetiapine XR) monotherapy in elderly patients with major depressive disorder. Am J Geriatr Psychiatry 2013; 21: 769-784 DOI: 10.1016/j.jagp.2013.01.010.
- 18 McIntyre A, Paisley D, Kouassi E. et al. Quetiapine fumarate extended-release for the treatment of major depression with comorbid fibromyalgia syndrome: A double-blind, randomized, placebo-controlled study. Arthritis Rheumatol 2014; 66: 451-461 DOI: 10.1002/art.38228.
- 19 Wang G, McIntyre A, Earley WR. et al. A randomized, double-blind study of the efficacy and tolerability of extended-release quetiapine fumarate (quetiapine XR) monotherapy in patients with major depressive disorder. Neuropsychiatr Dis Treat 2014; 10: 201-216 DOI: 10.2147/NDT.S50248.
- 20 Rüther E, Degner D, Munzel U. et al. Antidepressant action of sulpiride. Results of a placebo-controlled double-blind trial. Pharmacopsychiatry 1999; 32: 127-135 DOI: 10.1055/s-2007-979218.
- 21 Papakostas GI, Vitolo OV, Ishak WW. et al. A 12-week, randomized, double-blind, placebo-controlled, sequential parallel comparison trial of ziprasidone as monotherapy for major depressive disorder. J Clin Psychiatry 2012; 73: 1541-1547 DOI: 10.4088/JCP.12m07670.
- 22 Komossa K, Depping AM, Gaudchau A. et al. Second-generation antipsychotics for major depressive disorder and dysthymia. Cochrane Database Syst Rev 2010; CD008121 DOI: 10.1002/14651858.cd008121.pub2.
- 23 Weisler RH, Montgomery SA, Earley WR. et al. Efficacy of extended release quetiapine fumarate monotherapy in patients with major depressive disorder: A pooled analysis of two 6-week, double-blind, placebo-controlled studies. Int Clin Psychopharmacol 2012; 27: 27-39 DOI: 10.1097/YIC.0b013e32834d6f91.
- 24 Maneeton N, Maneeton B, Srisurapanont M. et al. Quetiapine monotherapy in acute phase for major depressive disorder: A meta-analysis of randomized, placebo-controlled trials. BMC Psychiatry 2012; 12: 1-9 DOI: 10.1186/1471-244X-12-160.
- 25 Vieta E, Bauer M, Montgomery S. et al. Pooled analysis of sustained response rates for extended release quetiapine fumarate as monotherapy or adjunct to antidepressant therapy in patients with major depressive disorder. J Affect Disord 2013; 150: 639-643 DOI: 10.1016/j.jad.2013.01.052.
- 26 Moher D, Liberati A, Tetzlaff J. et al. Preferred reporting items for systematic reviews and meta-analyses: The PRISMA statement. BMJ 2009; 339: 332-336 DOI: 10.1136/bmj.b2535.
- 27 Hamilton M. Development of a rating scale for primary depressive illness. Br J Soc Clin Psychol 1967; 6: 278-296 DOI: 10.1111/j.2044-8260.1967.tb00530.x.
- 28 Åsberg M, Montgomery SA, Perris C. et al. A comprehensive psychopathological rating scale. Acta Psychiatr Scand 1978; DOI: 10.1111/j.1600-0447.1978.tb02357.x.
- 29 Sheehan DV, Harnett-Sheehan K, Raj BA. The measurement of disability. Int Clin Psychopharmacol 1996; 11: 89-95 DOI: 10.1097/00004850-199606003-00015.
- 30 Endicott J, Nee J, Harrison W. et al. Quality of Life Enjoyment and Satisfaction Questionnaire: a new measure. Psychopharmacol Bull 1993; 29: 321-326
- 31 Zimmerman M, Martinez JH, Young D. et al. Severity classification on the Hamilton depression rating scale. J Affect Disord 2013; 150: 384-388 DOI: 10.1016/j.jad.2013.04.028.
- 32 Müller MJ, Szegedi A, Wetzel H. et al. Moderate and severe depression - gradations for the Montgomery-Asberg Depression Rating Scale. J Affect Disord 2000; 60: 137-140 DOI: 10.1016/S0165-0327(99)00162-7.
- 33 Müller MJ, Himmerich H, Kienzle B. et al. Differentiating moderate and severe depression using the Montgomery-Åsberg depression rating scale (MADRS). J Affect Disord 2003; 77: 255-260 DOI: 10.1016/S0165-0327(02)00120-9.
- 34 Papakostas GI, Fava M. Does the probability of receiving placebo influence clinical trial outcome? A meta-regression of double-blind, randomized clinical trials in MDD. Eur Neuropsychopharmacol 2009; 19: 34-40 DOI: 10.1016/j.euroneuro.2008.08.009.
- 35 Cipriani A, Furukawa TA, Salanti G. et al. Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: A systematic review and network meta-analysis. Lancet 2018; 391: 1357-1366 DOI: 10.1016/S0140-6736(17)32802-7.
- 36 Kinoshita T. A double-blind, placebo controlled study of a new antidepressant, mirtazapine, in depressed patients. J Clin Psychopharmacol 2009; 12: 289-306
- 37 Hewett K, Chrzanowski W, Schmitz M. et al. Eight-week, placebo-controlled, double-blind comparison of the antidepressant efficacy and tolerability of bupropion XR and venlafaxine XR. J Psychopharmacol 2009; 23: 531-538
- 38 Hewett K, Gee MD, Krishen A. et al. Double-blind, placebo-controlled comparison of the antidepressant efficacy and tolerability of bupropion XR and venlafaxine XR. J Psychopharmacol 2010; 24: 1209-1216 DOI: 10.1177/0269881109106953.
- 39 Oakes T, Myers A, Marangell L. et al. Assessment of depressive symptoms and functional outcomes in patients with major depressive disorder treated with duloxetine versus placebo: Primary outcomes from two trials conducted under the same protocol. Hum Psychopharmacol 2012; 27: 47-56
- 40 Boulenger JP, Loft H, Olsen CK. Efficacy and safety of vortioxetine (Lu AA21004), 15 and 20 mg/day: A randomized, double-blind, placebo-controlled, duloxetine-referenced study in the acute treatment of adult patients with major depressive disorder. Int Clin Psychopharmacol 2014; 29: 138-149 DOI: 10.1097/YIC.0000000000000018.
- 41 Robinson M, Oakes TM, Raskin JL. et al. Acute and long-term treatment of late-life major depressive disorder: Duloxetine versus placebo. Am J Geriatr Psychiatry 2014; 22: 34-45 DOI: 10.1016/j.jagp.2013.01.019.
- 42 Higuchi T, Kamijima K, Nakagome K. et al. A randomized, double-blinded, placebo-controlled study to evaluate the efficacy and safety of venlafaxine extended release and a long-term extension study for patients with major depressive disorder in Japan. Int Clin Psychopharmacol 2016; 31: 8-19 DOI: 10.1097/YIC.0000000000000105.
- 43 Cassano GB, Jori MC. Efficacy and safety of amisulpride 50 mg versus paroxetine 20 mg in major depression: A randomized, double-blind, parallel group study. Int Clin Psychopharmacol 2002; 17: 27-32 DOI: 10.1097/00004850-200201000-00004.
- 44 Wang Z, Kemp DE, Chan PK. 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.
- 45 Gao K, Kemp DE, Ganocy SJ. et al. 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.
- 46 Gao K, Ganocy SJ, Gajwani P. et al. 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.
- 47 Fang F, Sun H, Wang Z. et al. Antipsychotic drug-induced somnolence: Incidence, mechanisms, and management. CNS Drugs 2016; 30: 845-867 DOI: 10.1007/s40263-016-0352-5.
- 48 Keck PE, McElroy SL, Strakowski SM. et al. Antipsychotics in the treatment of mood disorders and risk of tardive dyskinesia. J Clin Psychiatry 2000; 61: 33-38
- 49 Solmi M, Pigato G, Kane JM. et al. Clinical risk factors for the development of tardive dyskinesia. J Neurol Sci 2018; 389: 21-27 DOI: 10.1016/j.jns.2018.02.012.
- 50 MacCallum RC, Zhang S, Preacher KJ. et al. On the practice of dichotomization of quantitative variables. Psychol Methods 2002; 7: 19-40 DOI: 10.1037/1082-989x.7.1.19.