Efficacy of 42 Pharmacologic Cotreatment Strategies Added to Antipsychotic Monotherapy in Schizophrenia: Systematic Overview and Quality Appraisal of the Meta-analytic Evidence | Psychiatry | JAMA Psychiatry | JAMA Network
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Figure 1.  Meta-analysis–Based Effect Sizes of Psychopharmacologic Augmentation of Any Antipsychotic Drug for Total Psychopathology
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.  Meta-analysis–Based Effect Sizes of Psychopharmacologic Augmentation of Any Antipsychotic Drug for Study-Defined Inefficacy (Nonreponse)
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.  Meta-analysis–Based Effect Sizes of Psychopharmacologic Augmentation of Any Antipsychotic Drug For Positive Symptoms
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.  Meta-analysis–Based Effect Sizes of Psychopharmacologic Augmentation of Any Antipsychotic Drug for Negative Symptoms
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.

Supplement.

eTable 1. Characteristics of the Included Meta-analyses.

eTable 2. Rating Criteria for A Measurement Tool to Assess Systematic Reviews (AMSTAR), and an Additional Newly Proposed Content Score (AMSTAR-Plus Content Score).

eTable 3. Quality Assessment of 37 Strategies With Data for the Primary Outcome (Total Psychopathology PANSS/BPRS).

eFigure 1. Included and Excluded Studies With Reasons.

eFigure 2. Meta-analysis-Based Effect Sizes of Psychopharmacologic Augmentation of Clozapine for Total, Positive and Negative Symptoms.

eFigure 3. Meta-analysis-Based Effect Sizes of Psychopharmacologic Agents for Cognitive Symptoms.

eFigure 4. Meta-analysis-Based Effect Sizes of Psychopharmacologic Agents for Depressive Symptoms.

eFigure 5. Meta-analysis-Based Effect Sizes of Psychopharmacologic Agents for All-Cause Discontinuation.

eFigure 6. Meta-analysis-Based Effect Sizes of Psychopharmacologic Agents for Discontinuation due to Inefficacy.

eFigure 7. Meta-analysis-Based Effect Sizes of Psychopharmacologic Agents for Discontinuation due to Side Effects.

eFigure 8. Meta-regression of Total Psychopathology scores in AMSTAR Score.

eFigure 9. Meta-regression of Total Psychopathology scores in AMSTAR-Plus Content Score.

eFigure 10. Meta-regression of Total Psychopathology in Recommendation by Author.

eFigure 11. Meta-regression of Positive Symptoms in AMSTAR Score.

eFigure 12. Meta-regression of Positive Symptoms in AMSTAR-Plus Content Score.

eFigure 13. Meta-regression of Negative Symptoms in AMSTAR Score.

eFigure 14. Meta-regression of Negative Symptoms in AMSTAR-Plus Content Score.

eFigure 15. Meta-regression of Total Psychopathology in Sample Size.

eFigure 16. Meta-regression of Positive Symptoms in Sample Size.

eFigure 17. Meta-regression of Negative Symptoms in Sample Size.

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Original Investigation
Meta-analysis
July 2017

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

Author Affiliations
  • 1The Zucker Hillside Hospital, Psychiatry Research, Northwell Health, Glen Oaks, New York
  • 2Hofstra Northwell School of Medicine, Hempstead, New York
  • 3The Feinstein Institute for Medical Research, Manhasset, New York
  • 4Department of Psychiatry and Psychotherapy, Klinikum rechts der Isar der Technischen Universität München, Munich, Germany
JAMA Psychiatry. 2017;74(7):675-684. doi:10.1001/jamapsychiatry.2017.0624
Key Points

Question  What are effective medication strategies that can be added to an antipsychotic drug treatment to improve the suboptimally responsive global or specific symptom domains among adults with schizophrenia?

Findings  In this overview of methodologically sound meta-analyses, 14 combination strategies significantly improved the overall symptoms of schizophrenia compared with antipsychotic monotherapy. Although the meta-analytically based recommendation to use a given combination strategy was correlated with the effect sizes favoring the combination treatment, these effect sizes were inversely correlated with the frequently low quality of the meta-analyzed trials, seriously lowering the confidence in the affirmative recommendation of any combination strategy.

Meaning  Based on a review of the meta-analytic evidence, aided by a structured evaluation of the quality of meta-analyzed studies, none of the 42 combinations of an antipsychotic drug treatment with a second psychotropic medication had consistent support for its recommendation for treating an unselected population with schizophrenia.

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.

Introduction

Although antipsychotic drugs are the cornerstone of treatment for schizophrenia, their effectiveness is limited, leaving many patients symptomatic despite ongoing antipsychotic therapy.1-3 As a result, alternative strategies, including switching antipsychotic drug treatments, dosage increases, and combination treatments, are often used in schizophrenia.4-6 While adding medications to antipsychotic drug treatments is common when managing partial responses or treatment resistance in schizophrenia,7-9 no pharmacologic combination has been approved for this indication.

Numerous randomized clinical trials examined several pharmacological combination strategies in schizophrenia, yielding a complex evidence base that requires careful examination across different strategies.4,5 However, most studies have been small and the overall results have remained mixed or inconclusive.10 Several systematic reviews, usually treatment guidelines,2,4,6 have summarized efficacy data for multiple combination strategies, yet these reviews have not quantitatively compared different strategies. Increasingly, meta-analyses have been conducted that have provided efficacy and safety data for specific combination strategies. This form of evidence is more comparable between agents than individual trial data, as it uses similar outcome measures (pooled effect sizes, such as standardized mean differences or risk ratios), derived from all randomized clinical trials, and can be systematically reviewed for the risk of bias. Currently, the meta-analytic efficacy literature for combination strategies of antipsychotic drugs has led to evidence-based recommendations for or against dozens of combination options, yet, to our knowledge, there is no direct quantitative comparison of the evidence across all individual combination strategies vs antipsychotic monotherapy in schizophrenia. Moreover, the quality of these meta-analyses and the included studies has not been evaluated, which is an indispensable step before treatment recommendations can confidently be made. The current systematic review of meta-analytic reviews aimed to fill these gaps in the literature.

Methods
Search Strategy

We conducted a computer-based search without language restrictions, using PubMed and PsycINFO until May 13, 2016, to find meta-analyses of pharmacologic treatment strategies added to antipsychotic drug treatments compared with antipsychotic monotherapy using the following search terms: “(schizophrenia OR schizoaffective OR schizoaffective OR psychosis OR psychotic) and (meta-analy* OR metaanaly* OR systematic review).” We applied search filters for systematic reviews and meta-analyses. Meta-analyses were screened out if they did not meet the inclusion criteria listed later, first at the title/abstract level, and later at the methods section level if necessary. Reference lists of retrieved studies and pertinent reviews were hand-searched for additional relevant meta-analyses. At least 2 authors (M.B., G.I.-F., and J.M.R.) independently double-checked the inclusion and exclusion criteria of the identified meta-analyses, extracted and synthesized the data, and conducted a quality assessment as explained later. Discrepancies were resolved by a consensus.

Inclusion and Exclusion Criteria

Included were meta-analyses of randomized clinical trials that reported effect sizes for the efficacy of combinations of any pharmacological agent added on to antipsychotic drug treatments compared with controls (a placebo or antipsychotic monotherapy in open studies) that reported at least 1 of the included outcomes listed later in patients with schizophrenia, or related conditions (psychosis not otherwise specified, schizophreniform disorder, schizoaffective disorder).

Meta-analyses meeting the inclusion criteria were removed if there was a more recently updated meta-analysis for that same combination strategy and outcome as long as more than 50% of the meta-analyzed trials overlapped and the pooled sample was larger.

Data Extraction, Outcomes, and Data Synthesis

Data for effect sizes of continuous outcomes were extracted as standardized mean difference (SMD) or Hedges g, which express the mean difference between the intervention and control groups in standard deviation units, with 95% confidence intervals. Generally, an effect size of an SMD less than 0.2 is considered negligible, an SMD between 0.2 and less than 0.5 is small, an SMD between 0.5 and 0.8 is medium, and an SMD more than 0.8 is large.11 Risk ratios were used for categorical outcomes. For both types of outcomes, we followed the decisions of the original authors concerning fixed- vs random-effects models. To yield unified effect size measures, we recalculated the nonstandardized continuous outcome and weighted mean difference into SMD and the categorical measure odds ratio into risk ratio using RevMan, version 5.3.5 (Cochrane Collaboration).

The primary outcome was total psychopathology using the Positive and Negative Syndrome Scale or Brief Psychiatric Rating Scale. Key secondary outcomes were positive and negative symptoms subscale scores. Because meta-analyses of randomized clinical trials are considered the highest level of evidence12 and the recommendations of clinicians are often based on meta-analyses,13 we included the recommendation for or against the combination treatment over monotherapy made by the authors of the meta-analysis as another key secondary outcome. We operationalized this outcome as “no recommendation” (ie, there was no conclusion made about a possible efficacy of the combination treatment), “partial recommendation” (ie, the combination was described as at least somewhat beneficial or promising), and “complete” (ie, there was an explicit recommendation or stating of an advantage over monotherapy). Other secondary outcomes were depressive and cognitive symptoms assessed with a validated scale, study-defined inefficacies, all-cause discontinuations, and discontinuations because of inefficacy or intolerability.

To determine whether the trials included in the meta-analyses did not primarily target total symptom reduction, which could introduce heterogeneity into our overview of meta-analyses, we recorded whether the primary outcome was different from total psychopathology and whether the selection of trials for each meta-analysis was performed based on the specific treatment target of the augmenting agent.

Data for combination strategies of any antipsychotic drug, and specifically of clozapine, were extracted and analyzed separately, as clozapine is the only approved antipsychotic drug for treatment-refractory schizophrenia.

Quality Assessment of the Meta-analyzed Studies

Included meta-analyses were assessed using A Measurement Tool to Assess Systematic Reviews (AMSTAR)14 (range, 0-11). While AMSTAR is a reliable and valid tool for measuring the methodological quality of meta-analyses,14 its score does not capture quality indicators of the meta-analyzed trials, which could bias pooled results. Thus, a meta-analysis that meets all methodological quality criteria but that meta-analyzes potentially biased studies would have a good methodological quality but poor content quality. For a more comprehensive assessment of the content validity of the results from the included meta-analyses, we developed a set of 6 additional quality items, each ranging between 0 and 1 or 2, that capture the content quality of the meta-analyzed trials (“AMSTAR-Plus Content,” range, 0-8) (eTable 1 in the Supplement).

Statistical Analysis

We analyzed data as they were directly extracted from the published meta-analyses, or, if necessary, after they had been converted to standardized outcomes. To compare the effect sizes of combination treatments vs monotherapy, we conducted separate random-effects meta-analyses for each variable using Comprehensive Meta Analysis, version 3.0 (Biostat). The AMSTAR and AMSTAR-Plus Content scores and sample size (n) were used in meta-regression analyses of total psychopathology (primary outcome) and positive and negative symptoms (key secondary outcomes). We also added to the meta-regression analysis of total psychopathology “recommendation by author” as a covariate to test the relationship of this variable with the effect size along with the AMSTAR-Plus Content score.

Results
Systematic Search Results

Of 3397 search engine hits, 29 meta-analyses were included, creating a total of 381 meta-analyzed trials and 19 321 study participants and providing meta-analytic data for antipsychotic drug treatments combined with 42 different psychotropic medications. Among these combinations, 37 were of any antipsychotic drug (not excluding clozapine) with a second psychotropic medication15-39 and 5 were specifically of combinations with clozapine (eFigure 1 in the Supplement).40-42 All included meta-analyses designated the primary outcome as total psychopathology except for 2 (glutamate positive modulator and varenicline), and none of them selected trials based on the specific treatment target for the agent added to the antipsychotic drug. A mean (SD) of 8.2 ([6.8] range, 1-40) studies were included in the meta-analyses, with 49.9 ([20.5] range, 12-107) patients per study, that lasted 12.6 ([8.1] range, 3-52) weeks. The mean (SD) age of participants was 37.8 (4.2) years, 64.6% (7.8%) were men, and the mean (SD) illness duration was 13.3 (4.1) years (eTable 2 in the Supplement).

Symptom Change, Study-Defined Inefficacy, Discontinuation, and Concluding Recommendation by Authors of the Meta-analyses

For total psychopathology, 14 of 32 agents combined with antipsychotic drugs were found to be significantly superior to controls. The magnitude of the differences comparing combination treatments with controls for those significantly different combinations ranged between SMDs of −1.27 (95% CI, −2.35 to −0.19) for serotonin-noradrenaline reuptake inhibitors to −0.23 (95% CI, −0.44 to −0.02) for modafinil/armodafinil (Figure 1). None of the 5 pharmacological combinations with clozapine outperformed controls (eFigure 2 in the Supplement). Regarding study-defined inefficacy (equal to response rates), none of the agents with data outperformed controls (Figure 2).

For positive symptoms, 6 of 25 strategies significantly outperformed controls, with differences between combination treatments and controls ranging from an SMD of −0.69 (95% CI, −1.20 to −0.18) for lamotrigine to an SMD of −0.19 (95% CI, −0.37 to −0.01) for nonsteroidal anti-inflammatory drugs (Figure 3). For combinations with clozapine, only glycine had a significant benefit compared with controls (SMD, −0.64 [95% CI, −1.11 to −0.17]) (eFigure 2 in the Supplement).

Regarding negative symptoms, 12 of 26 strategies significantly outperformed controls, with differences between combination treatments and controls ranging from an SMD of −1.40 (95% CI, −2.44 to −0.36) for serotonin-noradrenaline reuptake inhibitors to an SMD of −0.26 (95% CI, −0.50 to −0.02) for selective serotonin reuptake inhibitors (Figure 4). None of the 5 pharmacological combination strategies with clozapine outperformed placebos (eFigure 2 in the Supplement).

Cognitive symptoms were not improved with combination strategies compared with controls, except for n-methyl-d-aspartate receptor antagonists (SMD, −0.77 [95% CI, −1.26 to −0.28]) and pooled antidepressants (SMD, −0.10 [95% CI, −0.17 to −0.02]). Similarly, no significant difference in depressive symptoms was observed for any of the 16 combination strategies, except for serotonin agonist and reuptake inhibitors (SMD, −0.99 [95% CI, −1.81 to −0.17]) (eFigures 3 and 4 in the Supplement).

Of 18 combination strategies, only azapirones were associated with significantly less all-cause discontinuations vs controls (risk ratio, 0.71; 95% CI, 0.57-0.88). Combinations did not differ from controls for discontinuation because of inefficacies or intolerabilities (eFigures 5-7 in the Supplement).

Altogether, 1 of the 42 included augmentation strategies was explicitly recommended by the authors, and 20 were at least partially recommended. There were 3 strategies (ie, nonsteroidal anti-inflammatory drugs, lithium, and lamotrigine)18,19,28 that were not recommended, despite having significant effect sizes favoring the combination treatment, because of methodological limitations. Also, there were 12 strategies that were at least partially recommended by authors of the meta-analyses despite their lack of significant differences between combination treatments and controls (ie, selective serotonin reuptake inhibitors, serotonin-noradrenaline reuptake inhibitors, tricyclic antidepressants, norepinephrine reuptake inhibitors, dopamine and norepinephrine reuptake inhibitors, monoamine-oxydase-B inhibitors, acetylcholinesterase inhibitors, and n-methyl-d-aspartate antagonists combined with any antipsychotic drug, as well as a second antipsychotic drug, topiramate, lamotrigine, or glycine combined with clozapine)16,33,36,40,41 (eTable 1 in the Supplement).

Quality Assessment and Meta-Regression Analyses

The quality assessment of the methods of the meta-analyses was conducted for the 37 meta-analyses that provided data toward the primary outcome or key secondary outcomes (total psychopathology, positive and negative symptoms subscore on the Positive and Negative Syndrome Scale/Brief Psychiatric Rating Scale). Among these, 33 combinations (89.2%) had AMSTAR scores of 8 or higher and 18 had the maximum AMSTAR score of 11 (48.6%).

The AMSTAR-Plus Content mean score was 2.8 of a maximum 8. Only 1 of the 37 examined strategies had a score that was more than 4 (nonsteroidal anti-inflammatory drugs). Thirty-three of the 37 strategies (89.2%) included only double-blind, placebo-controlled trials. However, the evidence for most of the meta-analytically studied combinations was exposed to potential inconsistencies. Thirty-three meta-analyses (89.6%) did not reach a total pooled sample of more than 500 cases, none had a total sample of more than 1000 participants, and none of the positive results were confirmed by a trial with more than 200 participants. Furthermore, 29 meta-analyses (78.4%) did not exclude data derived from observed cases analyses. Finally, a significant heterogeneity was found for 24 meta-analytically studied combinations (64.9%), and 20 (54.1%) could not disprove the presence of a publication bias (eTable 3 in the Supplement).

Further, we examined the relationship between the effect size for a given combination treatment vs a control regarding total psychopathology, positive and negative symptoms scores, the quality assessment measures (AMSTAR and AMSTAR-Plus Content), and the concluding recommendation made by the authors of the meta-analysis. The effect sizes for total psychopathology were positively correlated with the recommendation of the authors (correlation coefficient, 0.22; 95% CI, 0.35-0.10; P < .001) but inversely correlated with the content quality of the meta-analysis, as measured by AMSTAR-Plus Content (correlation coefficient, −0.06; 95% CI, 0.01 to −0.12; P = .02). No other correlations were significant between the effect sizes in positive or negative symptoms and the quality of the meta-analysis (AMSTAR), or its content (AMSTAR-Plus Content) (eFigures 7-17 in the Supplement).

Discussion

To our knowledge, this overview of meta-analyses is the first one to systematically and quantitatively compare the multiple pharmacologic combination strategies that have been studied for suboptimal treatment responses in schizophrenia, and its aim was to facilitating decision making. Across 37 pharmacologic combination strategies with any antipsychotic drug, 14 outperformed controls for the primary outcome of total psychopathology, mostly with large to medium effect sizes. Conversely, none of the 5 combinations with clozapine outperformed controls regarding total psychopathology. The recommendation to clinicians by the authors of each meta-analysis favoring using the combination treatment was correlated with the effect size produced by each meta-analysis. However, when all this meta-analytic literature was compared regarding the quality of its meta-analyzed content, the effect sizes were inversely correlated with the study quality, reducing confidence in these affirmative recommendations.

This overview advances the field by providing a clinically meaningful revision of previous affirmative recommendations for specific combination treatments with antipsychotic drugs among patients with schizophrenia with insufficient symptom responses. In this overview, we appraised the quality of how the meta-analysis was conducted (AMSTAR score) and the content quality of the meta-analyzed studies (AMSTAR-Plus Content Score). While the quality of the methods of the meta-analyses was generally good/very good, the content lacked quality, suggesting a low evidence level for all combination interventions, except for nonsteroidal anti-inflammatory drugs. Although the risk of bias in the meta-analyzed trials was minimized by most of them being double-blind placebo-controlled trials, the newly added AMSTAR-Plus Content score was limited in all 5 other areas, questioning the validity of the results. Most trials included in the meta-analyses were small, or the results were not confirmed by a larger trial. Also, most trials did not exclude results based on observed cases, which introduces attrition and survivor biases.40,41 Moreover, the heterogeneity remained significant across most meta-analyzed trials. Also, publication bias was problematic for many meta-analyses, potentially overestimating the pooled effect sizes. Furthermore, our finding that the newly developed AMSTAR-Plus Content score was inversely correlated with the effect size for total psychopathology underscores the need to evaluate meta-analyses beyond the rigor of their methods and further calls into question the positive results of individual combination strategies. Only the results for cognitive and depressive symptoms, study-defined inefficacies, and treatment discontinuations were consistent, showing no differences between cotreatment and monotherapy.

The preponderance of studies with small sample sizes in which only large effects are statistically significant presents a challenge, introducing a bias, as trials with positive results are more likely to be published than trials with negative results,43 especially if the latter were small. The inverse correlation between the effect size and the quality of the meta-analyzed studies (but not the quality of the meta-analysis) reverberates with the previously expressed concern about a “garbage in, garbage out” phenomenon in meta-analyses.43 Based on our results, we strongly recommend concurrently evaluating the quality of the meta-analysis and its content. We further recommend to critically reevaluate the current strong reliance of treatment recommendations in all areas of medicine on meta-analyses of many studies that are often of poor quality. Qualitatively excellent and sufficiently large individual randomized clinical trials are essential, not only because when meta-analyzed they can overcome the bias introduced by poor-quality studies, but also because their results should be used as a measure to assess the consistency of the results derived from otherwise easily accessible meta-analytic results that might be based on mostly poor-quality studies. Thus, we propose the AMSTAR-Plus Content Score as a mechanism to potentially correct the meta-analytically suggested recommendations, with one item being the lack of or inconsistency with results from larger, well-conducted trials. Additionally, the field should advance by moving from study-level to patient-level meta-analyses, as this would provide a more fine-grained and ultimately more personalized picture of treatment effects derived from adequately powered moderator, mediator, and subgroup analyses.44 This level of detail is unachievable with individual studies, and is especially valuable when head-to-head trials among different strategies are negligible. For instance, a patient-based meta-analysis comparing a combination strategy with monotherapy might have been able to identify specific patient subgroups who responded to the combination treatment in adequately powered moderator and subgroup analyses. For example, the finding that some patients experience symptomatic worsening/relapse when an antipsychotic polypharmacy is discontinued and only monotherapy is maintained45 suggests that a subgroup of responders to specific combinations might exist, even when the results of pooled analyses are negative.17 Given our results of an absent high-quality efficacy signal in study-based meta-analyses for the entire studied population with schizophrenia, patient-based meta-analyses should be performed to identify moderators and subgroups of responders. Furthermore, patient-level meta-analyses could also disentangle the heterogeneity introduced by poor-quality trials from the true variation in treatment responses around a “mean” effect by allowing for such powered moderator and subgroup analyses. The move toward developing a platform that allows for the exchange of individual patient data for patient-level meta-analyses will require standardizing methods, data elements and database structures, and funding or incentives to build a data repository, but the initial examples already exist (http://yoda.yale.edu/).

As a result of the advanced methods, our findings resulted in a revision of clinical recommendations for the combination treatment of schizophrenia. However, our results should be related to the literature about the strategies for managing suboptimal responses to antipsychotic monotherapy: dosage escalation or switching to another agent or combination treatment.10 To our knowledge, only 1 randomized clinical trial compared these strategies head-to-head and found no conclusive differences between these practices.46 Dosage escalation is advised against in all treatment guidelines of national and international psychiatric societies given its limited evidence of success.4,5,47 Switching to another antipsychotic drug has not been supported by conclusive evidence, except for switching to clozapine.10,48 Although the superiority of clozapine over other second-generation antipsychotic drugs has been challenged by a recent network meta-analysis,49 dosages of clozapine may have been insufficiently high and subgroups of patients may not have been truly treatment resistant.50 Moreover, mirror-image trials51 and cohort studies that enrolled more generalizable patients52 consistently showed an advantage of treatment with clozapine.

However, our overview indicates that combination treatments are the most studied strategy. Although some combination strategies had medium to large effect sizes for total, positive, and negative symptoms, no pharmacological combination treatment had sufficiently high-quality or consistent efficacy results to support recommending them over antipsychotic monotherapy for clinical care or guidelines for any of the measured schizophrenia outcomes, which contrasts with the recommendations that emerged from those meta-analyses. Although 21 strategies had some level of affirmative recommendation, and although the recommendations were positively correlated with the meta-analytic effect size, this effect size was inversely correlated with the content quality of the meta-analyzed trials. Therefore, based on our critical review of the evidence, there are no grounds for recommending any pharmacologic combination treatment for the population with schizophrenia. Nevertheless, as noted earlier, we cannot exclude that certain patient subgroups might respond to specific combination treatments, but future trials targeting clinically or biologically defined subgroups are needed to clarify this possibility. Notwithstanding this caveat, our findings suggesting the lack of high-quality support for any pharmacologic combination strategy should be considered by forthcoming schizophrenia treatment guidelines.

Given the lack of data directly comparing dosage escalation, switching the antipsychotic drug treatment, and pharmacologic combination strategies, switching to treatment with clozapine remains the option that is most solidly supported by the literature, although obviously potential risks should also be incorporated in medical decision making.53,54 For patients insufficiently responding to clozapine, our results suggest that a combination with an additional psychotropic drug will not consistently improve any domain of psychopathology.

Limitations

Several limitations should be considered when interpreting our results. Although the included meta-analyses were the most updated for each specific agent and outcome, individual studies published since the last search date of the latest meta-analyses are not included. The duration of the meta-analyzed trials was short and the longer-term effects of combination strategies cannot be ascertained from the present results. Also, because of limited data for psychopathologic or sociodemographic variables, conducting meta-regression analyses for these variables was not possible. Meta-analyses generally included studies that augmented antipsychotic drugs with a second agent after a nonresponse to the baseline medication, but they often also mixed in trials in which 2 agents were started at baseline and compared against antipsychotic monotherapy. Since these 2 strategies are clinically incompatible, the results may be difficult to interpret, and future meta-analyses should perform at least subgroup analyses of these categorically different strategies. Population heterogeneity introduced by various indications for cotreatment was possible. However, we believe that this risk was low because only data for 2 of 42 interventions were derived from meta-analyses with outcomes other than total psychopathology, and none of the meta-analyses selected trials based on specific indications for a given combination treatment, suggesting that the 381 meta-analyzed trials were homogeneously unselected rather than mixed homogeneous subgroups. The efficacy of the studied interventions and the control conditions is likely dependent on the degree of refractoriness and rigor with which the degree and persistence of prior nonresponses was assessed.55 However, no information was available to systematically assess this variable or conduct subgroup or meta-regression analyses. Finally, while AMSTAR9 is a validated rating tool, the development of AMSTAR-Plus Content was based on expert opinion only, which while having good face validity has not yet been validated.

Conclusions

Meta-analyses of some combinations of an antipsychotic drug with a second psychotropic agent resulted in significant differences favoring their use over controls, but virtually all of the meta-analyzed study content revealed a high risk of bias. Therefore, none of the studied interventions had consistent empirical evidence for its use among an unselected population of patients with schizophrenia, yet future high-quality randomized clinical trials and patient-level meta-analyses could provide much needed clarity about moderators and mediators as well as patient subgroups that might benefit from specific pharmacologic combination strategies.

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Article Information

Corresponding Author: Christoph U. Correll, MD, Department of Psychiatry, The Zucker Hillside Hospital, 75-59 263rd St, Glen Oaks, NY 11004 (ccorrell@northwell.edu).

Accepted for Publication: February 25, 2017.

Published Online: May 17, 2017. doi:10.1001/jamapsychiatry.2017.0624

Author Contributions: Drs Correll and Rubio had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Drs Correll and Rubio contributed equally to the authorship of this article.

Concept and design: Correll, Rubio, Birnbaum, Kane, Leucht.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Correll, Rubio, Birnbaum, Kane.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Correll, Rubio, Inczedy-Farkas, Birnbaum, Kane.

Supervision: Correll, Leucht.

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.

Funding/Support: This study was supported by the Zucker Hillside Hospital and award MH 074543-01 from the National Institute of Mental Health Advanced Center for Intervention and Services Research for the Study of Schizophrenia.

Role of the Funder/Sponsor: The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

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