Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2017 Jul 1;74(7):675-684.
doi: 10.1001/jamapsychiatry.2017.0624.

Efficacy of 42 Pharmacologic Cotreatment Strategies Added to Antipsychotic Monotherapy in Schizophrenia: Systematic Overview and Quality Appraisal of the Meta-analytic Evidence

Christoph U Correll  1 , Jose M Rubio  2 , Gabriella Inczedy-Farkas  2 , Michael L Birnbaum  1 , John M Kane  1 , Stefan Leucht  3
Affiliations
Review

Efficacy of 42 Pharmacologic Cotreatment Strategies Added to Antipsychotic Monotherapy in Schizophrenia: Systematic Overview and Quality Appraisal of the Meta-analytic Evidence

Christoph U Correll et al. JAMA Psychiatry. .

Abstract

Importance: Limited treatment responses in schizophrenia prompted the testing of combining an antipsychotic drug treatment with a second psychotropic medication. A comprehensive evaluation of the efficacy of multiple medication combinations is missing.

Objective: To summarize and compare the meta-analytically determined efficacy of pharmacologic combination strategies of antipsychotic drugs in adults with schizophrenia.

Data sources: Systematic search of PubMed and PsycInfo until May 13, 2016.

Study selection: Meta-analyses of randomized clinical trials comparing the efficacy of antipsychotic drugs combined with other antipsychotic or nonantipsychotic medications vs placebos or antipsychotic monotherapy among adults with schizophrenia.

Data extraction and synthesis: Independent reviewers extracted the data and assessed the quality of the methods of the included meta-analyses using A Measurement Tool to Assess Systematic Reviews (AMSTAR), adding 6 new items to rate their quality. Effect sizes, expressed as standardized mean difference /Hedges g or risk ratio, were compared separately for combinations with any antipsychotic drug and for combinations with clozapine.

Main outcomes and measures: The primary outcome was total symptom reduction. Secondary outcomes included positive and negative symptoms, treatment recommendations by authors, study-defined inefficacies, cognitive and depressive symptoms, discontinuation of treatment because of any cause, and inefficacies or intolerabilities.

Results: Of 3397 publications, 29 meta-analyses testing 42 combination strategies in 381 individual trials and among 19 833 participants were included. For total symptom reductions, 32 strategies that augmented any antipsychotic drug and 5 strategies that augmented clozapine were examined. Fourteen combination treatments outperformed controls (standard mean difference/Hedges g, -1.27 [95% CI, -2.35 to -0.19] to -0.23 [95% CI, -0.44 to -0.02]; P = .05). No combination strategies with clozapine outperformed controls. The quality of the methods of the meta-analyses was generally high (mean score, 9 of a maximum score of 11) but the quality of the meta-analyzed studies was low (mean score, 2.8 of a maximum score of 8). Treatment recommendations correlated with the effect size (correlation coefficient, 0.22; 95% CI, 0.35-0.10; P < .001), yet effect sizes were inversely correlated with study quality (correlation coefficient, -0.06; 95% CI, 0.01 to -0.12; P = .02).

Conclusions and relevance: Meta-analyses of 21 interventions fully or partially recommended their use, with recommendations being positively correlated with the effect sizes of the pooled intervention. However, the effect sizes were inversely correlated with meta-analyzed study quality, reducing confidence in these recommendations. Higher-quality trials and patient-based meta-analyses are needed to determine whether subpopulations might benefit from combination treatment, as no single strategy can be recommended for patients with schizophrenia based on the current meta-analytic literature.

PubMed Disclaimer

Conflict of interest statement

Conflict of Interest Disclosures: Dr Correll has received consulting and advisorial fees and honoraria from Alkermes, Forum, Gerson Lehrman Group, IntraCellular Therapies, Janssen/J&J, Lundbeck, Medavante, Medscape, Otsuka, Pfizer, ProPhase, Sunovion, Supernus, Takeda, and Teva. He has provided expert testimony for Bristol-Myers Squibb, Janssen, and Otsuka. He served on a Data Safety Monitoring Board for Lundbeck and Pfizer. He received grant support from Takeda. Dr Kane has received honoraria for lectures and/or consulting from Alkermes, Bristol Myers Squibb, Eli Lilly, Forrest Labs, Forum, Genentech, Intracellular Therapies, Janssen, Johnson and Johnson, Lundbeck, Merck, Novartis, Otsuka, Pfizer, Reviva, Roche, and Sunovion. He has received grant support from Genentech, Johnson and Johnson, the National Institute of Mental Health, and Otsuka. He is a shareholder of MedAvante and Vanguard Research Group. Dr Leucht has received honoraria for lectures from EliLilly, Lundbeck, Pfizer, Janssen, BMS, Johnson and Johnson, Otsuka, Roche, SanofiAventis, ICON, Abbvie, AOP Orphan, and Servier; for consulting/advisory boards from Roche, Janssen, Lundbeck, Eli Lilly, Otsuka, and TEVA; and for preparing educational material and publications for Lundbeck and Roche. Eli Lilly provided medication for a clinical trial led by Dr Leucht as the principal investigator. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Meta-analysis–Based Effect Sizes of Psychopharmacologic Augmentation of Any Antipsychotic Drug for Total Psychopathology
Ach indicates acetylcholine; AchEsterase inhib, acetylcholinesterase inhibitors; AMSTAR, A Measurement Tool to Assess Systematic Reviews; AP, antipsychotic; DHEA, dehydroepiandrosterone; MAO, monoamine oxidase; N, number of studies; n, number of patients; NaSSA, noradrenergic and specific serotonergic antidepressant; NMDA, n-methyl-d-aspartate; NSAID, nonsteroidal anti-inflammatory drugs; NRI, norepinephrine reuptake inhibitor; PUFA, polyunsaturated fatty acids; Rec Ant, receptor antagonist; SARI, serotonin antagonist and reuptake inhibitor; SNRI, serotonin-norepinephrine reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor; TCA, tricarboxylic acid.
Figure 2.
Figure 2.. Meta-analysis–Based Effect Sizes of Psychopharmacologic Augmentation of Any Antipsychotic Drug for Study-Defined Inefficacy (Nonreponse)
AMSTAR indicates A Measurement Tool to Assess Systematic Reviews; AP, antipsychotic; rec ant, receptor antagonist.
Figure 3.
Figure 3.. Meta-analysis–Based Effect Sizes of Psychopharmacologic Augmentation of Any Antipsychotic Drug For Positive Symptoms
Ach indicates acetylcholine; AchEsterase inhib, acetylcholinesterase inhibitors; AMSTAR, A Measurement Tool to Assess Systematic Reviews; AP, antipsychotic; DHEA, dehydroepiandrosterone; MAO, monoamine oxidase; N, number of studies; n, number of patients; NaSSA, noradrenergic and specific serotonergic antidepressant; NMDA, n-methyl-d-aspartate; NSAID, nonsteroidal anti-inflammatory drugs; NRI, norepinephrine reuptake inhibitor; PUFA, polyunsaturated fatty acids; Rec Ant, receptor antagonist; SARI, serotonin antagonist and reuptake inhibitor; SNRI, serotonin-norepinephrine reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor.
Figure 4.
Figure 4.. Meta-analysis–Based Effect Sizes of Psychopharmacologic Augmentation of Any Antipsychotic Drug for Negative Symptoms
Ach indicates acetylcholine; AchEsterase inhib, acetylcholinesterase inhibitors; AMSTAR, A Measurement Tool to Assess Systematic Reviews; AP, antipsychotic; DHEA, dehydroepiandrosterone; MAO, monoamine oxidase; N, number of studies; n, number of patients; NaSSA, noradrenergic and specific serotonergic antidepressant; NMDA, n-methyl-d-aspartate; NSAID, nonsteroidal anti-inflammatory drugs; NRI, norepinephrine reuptake inhibitor; PUFA, polyunsaturated fatty acids; Rec Ant, receptor antagonist; SARI, serotonin antagonist and reuptake inhibitor; SNRI, serotonin-norepinephrine reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor.
See this image and copyright information in PMC

Comment in

  • A Meta View on Meta-analyses.
    Fleischhacker WW. Fleischhacker WW. JAMA Psychiatry. 2017 Jul 1;74(7):684-685. doi: 10.1001/jamapsychiatry.2017.1167. JAMA Psychiatry. 2017. PMID: 28514464 No abstract available.

References

    1. Robinson DG, Woerner MG, Alvir JM, et al. . Predictors of treatment response from a first episode of schizophrenia or schizoaffective disorder. Am J Psychiatry. 1999;156(4):544-549. - PubMed
    1. Lieberman JA, Stroup TS, McEvoy JP, et al. ; Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Investigators . Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med. 2005;353(12):1209-1223. - PubMed
    1. Leucht S, Cipriani A, Spineli L, et al. . Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis. Lancet. 2013;382(9896):951-962. - PubMed
    1. Hasan A, Falkai P, Wobrock T, et al. ; World Federation of Societies of Biological Psychiatry (WFSBP) Task Force on Treatment Guidelines for Schizophrenia . World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for biological treatment of schizophrenia, part 1: update 2012 on the acute treatment of schizophrenia and the management of treatment resistance. World J Biol Psychiatry. 2012;13(5):318-378. - PubMed
    1. Lehman AF, Lieberman JA, Dixon LB, et al. ; American Psychiatric Association; Steering Committee on Practice Guidelines . Practice guideline for the treatment of patients with schizophrenia, second edition. Am J Psychiatry. 2004;161(2)(suppl):1-56. - PubMed

MeSH terms