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. Author manuscript; available in PMC: 2015 Nov 1.
Published in final edited form as: Schizophr Res. 2014 Sep 18;159(0):385–394. doi: 10.1016/j.schres.2014.08.015

Antidepressants for Cognitive Impairment in Schizophrenia – A Systematic Review and Meta-analysis

Jeffrey A Vernon 1, Eugene Grudnikoff 2, Andrew J Seidman 2, Thomas W Frazier 3, Mani Sandhya Vemulapalli 4, Priyanki Pareek, Terry E Goldberg 2,5,6, John M Kane 2,5,6,7, Christoph U Correll 2,5,6,7
PMCID: PMC4252251  NIHMSID: NIHMS626362  PMID: 25240772

1. Introduction

Cognitive symptoms are amongst the earliest in schizophrenia. They often develop in the prodromal period (Lencz, Smith, & McLaughlin, 2006; Kane & Lencz, 2008) and can be significant by the time of the first episode (Mesholam-Gately et al., 2009). Specific deficits have been found in all cognitive domains, including executive function, memory, and attention, and are between 0.5 and 1.5 standard deviations below matched control subjects (Velligan et al., 2000; Mohamed et al., 1999; Buchanan et al., 2005; Green, 2006; Zanelli et al., 2010; Bilder et al., 2000). Cognitive symptoms are highly disabling, having a strong correlation with functional outcome (Green, Kern, & Heaton, 2004; Green, Kern, & Braff, 2000; Bowie et al., 2008; Bowie et al., 2010). While already present during the first episode, the relationship between cognitive symptoms and functional outcome may increase with time (Verdoux et al. 2002), although cognitive deficits themselves may not worsen over the course of illness (Albus et al., 2006; Mesholam-Gately et al., 2009).

Although negative symptoms may modulate the effect of cognition on clinical outcome (Lin et al., 2013), cognition seems to be an independent, core symptom domain of schizophrenia that separately predicts long-term functional outcome and quality of life (Kane & Lencz, 2008; Keefe & Fenton, 2007; Green, Kern, & Braff, 2000). Despite the clinical and functional importance of cognitive symptoms, there are no currently approved and clearly effective pharmacologic treatments for these deficits (Harvey & Keefe, 2001; Coyle et al., 2010; Menniti et al., 2013; Choi, Wykes, & Kurtz, 2013). The small-to-moderate improvements with antipsychotics may reflect improvements of interfering hallucinations and thought disorganization or even negative symptoms (Harvey & Keefe, 2001). In a meta-analysis of medications targeting cholinergic, glutamatergic, or serotonergic receptors for cognitive impairment in schizophrenia, small-to-moderate effect sizes were found for some cholinergic medications in some aspects of cognition (Choi, Wykes, & Kurtz, 2013). However, these agents also improved negative and general symptoms, confounding the results. Although cognitive remediation has attracted considerable attention, it provides, at best, moderate benefits (Wykes et al., 2011), and patients need to be motivated and adhere to the training schedule. Finally, much of the improvement seen in schizophrenia cognition studies reflect practice effects (Goldberg et al., 2007), and the translation of improvements in isolated cognitive domains to enhanced real-world functioning is unclear.

Antidepressants are safe and used frequently in schizophrenia patients to address depressive and negative symptoms (Rummel et al. 2005; Singh et al. 2010; Hecht and Landy 2011). Theoretically, antidepressants could improve cognition via enhanced serotonergic, adrenergic, and dopaminergic transmission. These benefits may be anticipated to vary by antidepressant class, with, for example, those antidepressants showing marked anticholinergic activity (i.e., tricyclic antidepressants) expected to be less beneficial than other classes. While individual studies that used antidepressants to augment antipsychotics in schizophrenia have measured cognition, no meta-analysis has investigated the pooled efficacy of antidepressants for cognitive symptoms in schizophrenia. Therefore, we conducted a systematic review and meta-analysis to explore the effects of adjunctive antidepressants for cognition in patients with schizophrenia.

2. Methods

2.1. Search Strategy and Data Extraction

PubMed, Ovid (MEDLINE), PsycINFO, and Cochrane Library databases were searched (without time or language restriction) for randomized controlled trials (RCTs) comparing adjunctive antidepressants with placebo in the treatment of schizophrenia. The final search update was performed on 12/27/2013. Keywords included schizophrenia, random*, antidepressant, antidepressants, anti-depressant, anti-depressants, plus a list of all antidepressants ever approved for use in any country. This electronic search was supplemented by a hand search of references in review articles and articles pertinent to this meta- analysis. Article authors were contacted for additional data. Two of four authors (J.A.V., E.G., A.J.S., and M.S.V.) independently extracted study data. Two of three authors (J.A.V., E.G., and A.J.S.) independently entered and checked data entered into Review Manager Version 5.2.7 for Windows (Cochrane Collaboration, http://ims.cochrane.org/revman). Two authors (J.A.V. and C.U.C.) independently entered and checked data entered into Comprehensive Meta-Analysis V2 (Biostat, http://www.meta-analysis.com). Any discrepancies were resolved by consensus.

2.2. Inclusion Criteria

Eligible studies had to compare any antipsychotic plus any adjunctive antidepressant with any antipsychotic plus placebo and had to report on treatment effects on any cognitive domain. Agents with only theoretical antidepressant properties never approved in any country for depression were excluded from this meta-analysis. We also excluded studies whose sole cognition outcome was a scale that did not measure a specific cognitive function or domain, such as the Mini-Mental State Examination or Positive and Negative Syndrome Scale (PANSS)–cognitive scale.

2.3. Outcomes

Primary outcomes were test scores of any cognitive measure pooled on a study level to derive the following nine cognitive domain scores: executive function, attention, processing speed, visuospatial processing, auditory verbal long-term memory, visuospatial long-term memory, auditory verbal working memory, visuospatial working memory, and verbal fluency. Key secondary outcomes included higher-level cognitive domain scores (auditory verbal memory, visuospatial memory, long-term memory, working memory, memory) as well as a composite cognition score comprised of all included tests per study (see details below). Additional, secondary outcomes included all-cause discontinuation; discontinuation due to intolerability, inefficacy, and other reasons; total psychopathology; positive symptoms; negative symptoms; depressive symptoms; Parkinsonism; akathisia; dyskinesia; and other adverse events. For specific information about outcomes measured by each study see Supplementary Table 1.

2.4. Data Synthesis

For a detailed description of the data synthesis, see Supplementary Methods.

2.5. Statistical Analysis

Analyses were performed using Review Manager Version 5.2.7, except for the pooling of effect sizes of individual cognitive tests within a specific domain in order to obtain and pool domain sum scores across studies, which was done using Comprehensive Meta-Analysis V2. Analyses were carried out on outcomes for which data from ≥3 studies were available. We calculated the standardized mean difference (SMD)±95% confidence interval (CI) for continuous outcomes and the risk ratio (RR)±95%CI for categorical outcomes. Cognitive outcomes were standardized so that a positive SMD favors the antidepressant group. For all other continuous outcomes, a negative SMD (i.e., reduction in symptoms) favors the antidepressant group. When both change scores and endpoint scores were available, change scores were used preferentially unless they were significantly skewed (i.e., standard deviation more than double the mean), in which case endpoint scores were utilized, unless they, too, were skewed. Analyses for continuous outcomes were based on intention-to-treat (ITT; i.e., all randomized subjects receiving ≥1 dose of study medication) or modified ITT (i.e., all randomized subjects receiving ≥1 dose of study medication and having ≥1 post-baseline assessments) data, using last-observation-carried-forward or mixed models repeated measures analyses. Analyses for categorical outcomes were based on ITT data. All data were initially analyzed using a fixed effects model. Heterogeneity was studied using the I2 statistic, with I2≥50% indicating significant heterogeneity, as well as the chi square test for heterogeneity. All tests were two-sided, and alpha was set at 0.05.

In case of significant heterogeneity, the outcome was reanalyzed using a DerSirmonian and Laird (1986) random effects model. If the results remained significantly heterogeneous, preplanned subgroup analyses using the random effects model were conducted as follows when ≥3 studies were available for a given subanalysis: 1) not focusing on smoking cessation; 2) cognition as the primary outcome; 3) antipsychotic treatment – second-generation agents; 4) alpha-2 antagonist antidepressant (mirtazapine and mianserin) treatment; 5) mirtazapine treatment; 6) selective serotonin reuptake inhibitor (SSRI) treatment; 7) serotonergic antidepressant (SSRIs and duloxetine) treatment; and 8) noradrenergic antidepressant (duloxetine, reboxetine, and bupropion) treatment. Finally, for significant findings, pre-planned moderator analyses were conducted in studies: 1) not focusing on smoking cessation (as change in smoking status could affect outcomes) and 2) focusing on cognition as the primary outcome. Additionally, if the result for the cognitive composite was found to be significant, a third subanalysis was to be run utilizing only studies that measured ≥2 cognitive domains.

3. Results

3.1. Search

Our electronic search yielded 5,262 hits (Figure 1). After electronic filtering of duplicate records, 1,504 unique articles remained, of which 1,384 articles were excluded based on a review of titles/abstracts. The remaining 120 articles as well as 166 articles found via hand search underwent full-text inspection. Of these 286 articles, 16 were not relevant to the meta-analysis, 1 was not available for review, and—upon contacting the sponsoring agency— it was determined that 1 study had been scheduled but was not performed. Other reasons for exclusion were: no, insufficient, or unclear randomization (studies=92); no cognitive outcomes (studies=72); data based on a duplicate sample (studies=34); study not conducted in antipsychotic + antidepressant vs. antipsychotic + placebo format (studies=33); no meta-analyzable outcome data (studies=21); and discontinuation trial (studies=5). Ultimately, 11 studies were meta-analyzed (Table 1), including previously unpublished data from 8 studies (Acknowledgements).

Figure 1.

Figure 1

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Flow diagram of article search and review process

Table 1.

Study, Patient, and Treatment Characteristics

Study/
Sponsor		 Design Total
N		 Time
(wks)		 Population Mean
Age		 Male
Sex
(%)		 Illness
duration
(years)		 Treatments Mean
Dose
(mg/d)		 Primary
Outcome(s)		 Secondary
Outcomes
Selective Serotonin Reuptake Inhibitor
Dawes 2012/Zisook 2009a/Zisook 2010/Kasckow 2010 NIMH Department of Veterans Affairs DBRPCT 212 8 Schizophrenia (n=117) or schizoaffective D/O (n=81) All subjects had “subsyndromal depression” Outpatients Baseline total PANSS or CGI-S score NR 52.5 (n=198) 78.3 (n=198) NR AP+citalopram
AP+PBO		 AP doses not provided
Citalopram = 28.9		 Cognitive Tests; Psycho-pathology; Suicidality EPS; Quality of Life; Metabolic side effects
Friedman 2005a Forest Laboratories DBRPCT Cross overb 19 12 Chronic schizophrenia (n=17) or schizoaffective D/O (n=2) Stable Inpatients (42.1%) and outpatients (57.9%) Baseline total PANSS score = 78.90±14.46 Baseline CGI-S score = 4.00±0.69 45.0 68.4 25.6 AP+citalopram
SGA+PBO		 AP doses not provided
Citalopram = 40		 Cognitive Tests Psycho-pathology; EPS
Niitsu 2012a No external funding DBRPCT 47 8 Chronic schizophrenia Outpatients Baseline total PANSS score = 74.6 ± 10.7 37.4 61.7 11.5 SGA+fluvoxamine
SGA+PBO		 SGA = 257.9 CPZ equivalents
Fluvoxamine = 150		 Cognitive Tests Psycho-pathology; EPS; Quality of Life
Serotonin-Norepinephrine Reuptake Inhibitor
Mico 2011 Funding source not specified DBRPCT 40 16 Chronic schizophrenia Active positive and negative symptoms Outpatients Baseline total PANSS score = 65.7±12.6 35.0 60.0 6.5 Clozapine+duloxetine
Clozapine+PBO		 Clozapine = 518.3 (1036.6 CPZ equivalents)
Duloxetine = 60		 Total Psycho-pathology Psycho-pathology; Cognitive Tests
Norepinephrine Reuptake Inhibitor
Poyurovsky 2009/Poyurovsky 2007 Stanley Medical Research Institute DBRPCT 33 6 First-episode schizophrenia or schizophreniform D/O Remitted Inpatients Baseline CGI-S score = 4.18±0.64 31.1 63.6 3.6 Olanzapine+reboxetine
Olanzapine+PBO		 Olanzapine = 10 (200 CPZ equivalents)
Reboxetine = 4		 Cognitive Tests Psycho-pathology; EPS
Dopamine-Norepinephrine Reuptake Inhibitor
Bloch 2010a National Alliance for Research on Schizophrenia and Depression Phillip Morris DBRPCT 61 14 Schizophrenia (n=41), Schizoaffective D/O (n=19) or Diagnosis unclear (n=1) Smokers Stable Outpatients Baseline total PANSS = 72.90±21.63 (n=60) 41.67 (n=60) 75.4 NR AP+bupropion SR
AP+PBO		 AP doses not provided
Bupropion = 300		 Smoking Cessation; Genetic Testing Psycho-pathology; Cognitive Tests
Alpha 2 Antagonist
Berk 2009a Organon Australia DBRPCT 38 6 Schizophrenia NR Inpatients (39.5%) or outpatients (39.5%) with unreported data for 21.1% of patients Baseline total PANSS score = 84.76±19.85 Baseline CGI-S score = 4.13±0.89 36.8 84.2 NR SGA+mirtazapine
SGA+PBO		 SGA = 333.6 CPZ equivalents (n=27)
Mirtazapine = 30		 Total Psycho-pathology Psycho-pathology; Cognitive Tests
Caforio 2013a Stanley Medical Research Institute Organon Italy (Schering Plough) DBRPCT 28 8 Schizophrenia Recent exacerbation of psychotic symptoms requiring hospitalization Inpatients Baseline total PANSS score = 67.05±18.40 29.3 (n=20) 75.0 (n=20) 7.1 (n=20) Olanzapine+mirtazapine
Olanzapine+PBO		 Olanzapine = 17.3 (346.0 CPZ equivalents) (n=20)
Mirtazapine = 30 (n=20)		 Negative symptoms; Cognitive Tests Psycho-pathology
Cho 2011/Lee 2011 Funding source not specified DBRPCT 21 8 Schizophrenia Stable Outpatients Baseline total PANSS score = 83.65±13.55 35.7 (n=20) 50.0 (n=20) 6.5 (n=20) Risperidone+mirtazapine
Risperidone+PBO		 Risperidone = 3.5 (175 CPZ equivalents) (n=20)
Mirtazapine = 30 (n=20)		 Negative Symptoms; Cognitive Tests; EPS; Metabolic side effects Cognitive Tests; Psycho-pathology; Adherence
Poyurovsky 2003a Funding source not specified but author states in a personal communication “This trial was not funded by any external sources.” DBRPCT 30 4 Chronic schizophrenia Stable Inpatients Baseline CGI-S score = 3.5±0.6 (n=24) 44.1 (n=24) 70.8 (n=24) 17.2 (n=24) FGA+mianserin
FGA+PBO		 FGA Defined Daily Dosage = 4.0 (n=24)
Mianserin = 15 (n=24)		 Cognitive Tests Psycho-pathology; EPS
Stenberg 2010a/Joffe 2009a/Terevnikov 2011 Stanley Medical Research Institute DBRPCT 39 6 Chronic schizophrenia (n=38) or schizoaffective D/O, depressive type (n=1) Active positive and/or negative symptoms; at least moderate illness severity Inpatients (46.2%) and outpatients (53.8%) Baseline total PANSS score = 102.92±13.77 Baseline CGI-S score = 4.33±0.54 45.7 51.3 22.4 FGA+mirtazapine
FGA+PBO		 FGA = 323.8
CPZ equivalents
Mirtazapine = 30		 Psycho-pathology; Cognitive Tests Psycho-pathology; Patient-rated Improvement
Total (unweighted means)
11 Trials; Industry: N=4 Foundation: N=4 Government: N=1 Not reported/No external funding : N=4 DBR PCT: N=11; Parallel: N=10 Cross-over: N=1 568 8.7±3.7 SCZ:91.3% SZA:7.7% Chronic SCZ: 88.9%; first-episode SCZ or schizophreniform D/O: 5.8%; Outpatients: 60.1% Baseline total PANSS score = 78.5±12.1 (N=8) Baseline CGI-S score = 4.0±0.34 (N=5) 39.5±6.9 67.2±10.9 12.5±8.0 (N=8) Active: mirtazapine=4 mianserin=1 citalopram=2 duloxetine=1 fluvoxamine=1 reboxetine=1 bupropion=1 Comparator: SGA+PBO=6; FGA+PBO=2; CLO+PBO=1; OLA+PBO=2; RIS+PBO=1 Citalopram: 29.7 (weighted mean) Fluvoxamine: 150 Duloxetine: 60 Reboxetine: 4 Bupropion: 300 Mirtazapine: 30 Mianserin: 15
CPZ equivalents = 382.7±285.1 (N=7) 		Cognitive Tests: N=8; Total psycho-pathology: N=2; Psycho-pathology: N=2 Negative symptoms: N=2; Suicidality: N=1 Smoking cessation: N=1 Genetic testing : N=1 EPS:N=1 Metabolic side effects : N=1 Psycho-pathology: N=10; EPS: N=5; Cognitive Tests: N=4; Patient rated improvement: N=1; Metabolic side effects: N=1; Adherence: N=1 Quality of Life = 2
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a

additional, unpublished data were obtained from study author

b

pre-crossover data were obtained from study author

Abbreviations: AD=Antidepressant; AP=Antipsychotic; CGI-S=Clinical Global Impression–Severity Scale; CLO=Clozapine; CPZ=Chlorpromazine; DBRPCT=Double-blind, randomized, placebo-controlled trial; EPS=Extrapyramidal symptoms; FGA=First-generation antipsychotic; NR=Not reported; OLA=Olanzapine; PANSS=Positive and Negative Syndrome Scale; PBO=Placebo; RIS=Risperidone; SGA=Second-generation antipsychotic, SCZ=Schizophrenia; SZA=Schizoaffective disorder

3.2. Study, Patient, and Treatment Characteristics

All 11 studies were published in English and were randomized, double-blinded, and placebo-controlled. 10 studies (91%) were parallel studies; one was a crossover study, and pre-crossover data were obtained. Mean study duration was 8.7±3.7 weeks (range=4-16 weeks). Altogether, 568 subjects were included (sample size: n=19-212, age=39.5±6.9 years, male=67.2±10.9%). Only two studies reported ethnicity. All but one study (Poyurovsky et al., 2009), which included mostly first-episode schizophrenia patients, focused on patients with chronic schizophrenia (88.9% of patients). Mean illness duration was 12.5±8.0 years (range=3.6-25.6 years) (studies=8). Altogether, 60.1% were outpatients. The baseline total Positive and Negative Syndrome Scale (PANSS) score was 78.5±12.1 (studies=8), while the baseline Clinical Global Impression-Severity (CGI-S) score was 4.0±0.34 (studies=5).

6 studies used second-generation antipsychotics (SGAs; 1 using clozapine), 2 used only first-generation antipsychotics (FGAs), and 3 used both SGAs and FGAs. The average antipsychotic dose was 382.7±285.1 mg chlorpromazine (CPZ) equivalents (studies=7).

Add-on antidepressants included: the alpha-2 antagonists (studies=5) mirtazapine (studies=4; n=126; mean dose=30 mg/d) and mianserin (study=1; n=30; mean dose=15 mg/d); the SSRIs (studies=3) citalopram (studies=2; n=231; mean dose=29.7 mg/d) and fluvoxamine (study=1; n=47; mean dose=150 mg/d); the serotonin-norepinephrine reuptake inhibitor (SNRI; study=1) duloxetine (n=40; mean dose=60 mg/d); the norepinephrine reuptake inhibitor (NRI; study=1) reboxetine (n=33; mean dose=4 mg/d); and the dopamine-norepinephrine reuptake inhibitor (DNRI, study=1) bupropion (n=61; mean dose=300 mg/d).

3.3. Cognitive Outcomes

For specific cognitive outcomes that were analyzed per study and domain, see Supplemental Tables 1-3. Statistically significant, but clinically negligible, advantages were found for pooled antidepressants compared to placebo in executive function (Hedges’ g=0.17, 95%CI=0.025-0.31, p=0.02, I2=47%) and the cognitive composite (Hedges’ g=0.095, 95%CI=0.021-0.17, p=0.012, I2=45%) (Table 2). To explore possible moderating factors of significant results, pre-planned subanalyses were run for studies: 1) not focusing on smoking cessation (executive function=7 studies; cognitive composite=10 studies), and 2) using cognition as the primary outcome (executive function=5 studies; cognitive composite=8 studies). In these moderator analyses, results remained statistically significant, but all results became more heterogeneous. Moreover, results remained clinically negligible, except for executive function in studies where cognition was the primary outcome (Hedges’ g=0.25, 95%CI=0.06-0.43, p=0.01, I2=60%). Since this result was significantly heterogeneous, it was further explored using a random effects model, and the result remained heterogeneous but became statistically insignificant (Hedges’ g=0.27, 95%CI= -0.034 to 0.57, p=0.082, I2=60%). As the initial fixed effects analyses for executive function and composite cognition were not significantly heterogeneous, preplanned subgroup analyses based on medication class were not conducted.

Table 2.

Cognitive Test Domain Results

Pooled Antidepressants vs. Placebo
Cognitive Domain N Studies N Participants Hedges’ g 95% CI P I2%
Executive function 8 259 0.17 0.025,0.31 0.02 47
Attention 5 321 0.022 −0.19,0.23 0.84 0
Processing Speed 6 344 0.09 −0.031,−0.21 0.15 16
Visuospatial Processinga 3 94 0.14 −0.73,1.00 0.76 78b
Auditory Verbal Long-Term Memory 4 110 0.058 −0.20,0.31 0.66 41
Visuospatial Long-Term Memorya 4 141 0.07 −0.45,0.59 0.79 66b
Long-Term Memorya 7 214 0.11 −0.18,0.40 0.45 45
Auditory Verbal Working Memory 4 288 0.11 −0.12,0.34 0.34 0
Visuospatial Working Memory 4 123 0.063 −0.18,0.31 0.61 7
Working Memory 8 412 0.074 −0.087,0.24 0.37 0
Auditory Verbal Memory 5 308 0.084 −0.081,0.25 0.32 20
Visuospatial Memorya 5 160 0.065 −0.16,0.29 0.57 0
Memory 9 432 0.077 −0.038,0.19 0.19 46
Verbal Fluency 5 327 0.019 −0.14,0.18 0.81 0
Composite Cognition Score 11 501 0.095 0.021,0.17 0.012 45
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Positive Hedges’ g favors treatment group; fixed effects models, except where noted

Bolded p-values: p < 0.05

a

Random effects

b

< 3 studies available per subgroup so planned subanalyses not run

Antidepressants did not differ from placebo on any other cognitive domain scores for pooled antidepressants (Table 2). Significant heterogeneity (I2≥50%) was found for visuospatial processing, visuospatial long-term memory, long-term memory, and visuospatial memory. Therefore, these domains were re-analyzed using a random effects model. Visuospatial processing and visuospatial long-term memory remained significantly heterogeneous, but too few studies had data to conduct preplanned subgroup analyses.

3.4. Psychopathology Outcomes

Significant heterogeneity was found for total psychopathology, positive symptoms, negative symptoms, and depression. Therefore, these domains were explored using a random effects model. There were no significant differences between pooled antidepressants and placebo for total psychopathology (Hedges’ g=-0.27, 95%CI= -0.60 to 0.07, p=0.12, I2=65%), positive symptoms (Hedges’ g=-0.14, 95%CI= -0.45 to 0.17, p=0.38, I2=60%), or negative symptoms (Hedges’ g=-0.29, 95%CI= -0.62 to 0.05, p=0.09, I2=64%) (Table 3), but results were significantly heterogeneous. Therefore, subanalyses based on medication class were performed for SGAs (studies=6); alpha-2 antagonists (mirtazapine and mianserin, studies=5); mirtazapine (studies=4); serotonergic antidepressants (SSRIs and duloxetine; studies=4); SSRIs (studies=3); and noradrenergic antidepressants (duloxetine, reboxetine, and bupropion; studies=3). No significant differences were found (Table 4). Subanalyses excluding 1) 1 study focusing on smoking cessation and 2) 3 studies that did not use cognition as the primary outcome remained non-significant.

Table 3.

Psychopathology and Adverse Effects Outcomes

Pooled Antidepressants vs. Placebo
Continuous Outcome N Studies N Participants Hedges’ g 95% CI p I2%
Total Psychopathologya 11 491 −0.27 −0.60,0.07 0.12 65
Positive Symptomsa 11 500 −0.14 −0.45,0.17 0.38 60
Negative Symptomsa 11 500 −0.29 −0.62,0.05 0.09 64
Depression (HAM-D-predominant)a 9 455 −0.14 −0.47,0.18 0.39 58
Depression (CDSS-predominant)a 9 455 −0.22 −0.53,0.09 0.17 54
EPS: Any 8 407 −0.13 −0.33,0.06 0.18 13
Parkinsonism 7 360 −0.11 −0.32,0.10 0.30 21
Akathisiaa 4 265 −0.64 −1.71,0.43 0.24 85b
Dyskinesia 3 230 −0.13 −0.39,0.13 0.32 39
Categorical Outcome N n RR 95% CI p I2%
Discontinuation: All-cause 11 568 1.16 0.85,1.59 0.36 0
Discontinuation: Inefficacy 10 540 0.39 0.12,1.33 0.13 0
Discontinuation: Intolerability 10 540 1.79 0.75,4.27 0.19 0
Discontinuation: Other Reasons 10 540 1.33 0.84,2.11 0.22 0
<50% Decrease in PANSS Total Score 7 442 1.00 0.98,1.03 0.71 0
<20% Decrease in Any Negative Symptom Rating Scale 7 236 0.96 0.87,1.06 0.47 0
≥20% Increase in PANSS Total Score 4 163 2.70 0.47,15.32 0.26 0
Study-defined Inefficacy (with HAM-D) 3 272 0.78 0.68,0.91 0.0009 0
Study-defined Inefficacy (with CDSS) 3 272 0.76 0.65,0.90 0.0009 0
Total Neuropsychiatric Adverse Events 4 312 1.11 0.96,1.28 0.16 0
Total Neurological Adverse Events 4 312 1.24 0.83,1.85 0.30 12
Headache 4 312 1.06 0.56,2.00 0.86 16
Total Psychiatric Adverse Events 6 389 1.08 0.85,1.39 0.53 0
Suicidal Ideation 4 213 0.50 0.18,1.39 0.19 N/A
Worsening of Psychosis 5 168 3.08 0.65,14.54 0.16 0
Psychiatric Hospitalization 4 359 1.39 0.43,4.49 0.58 0
Insomnia 4 312 1.45 0.82,2.57 0.21 17
Sedation 4 118 2.91 1.03,8.17 0.04 0
Weakness/Fatigue 3 272 0.71 0.41,1.23 0.22 0
Agitation/Irritability 4 319 1.03 0.44,2.41 0.94 0
Total GI Adverse Events 4 312 1.17 0.99,1.39 0.06 0
Total Metabolic Adverse Eventsa 3 272 2.67 0.52,13.84 0.24 62b
Increase in Appetite 3 272 1.34 0.59,3.05 0.48 0
Weight Gain 4 300 2.08 0.87,4.97 0.10 1
Total Cardiorespiratory Adverse Events 3 272 1.03 0.60,1.77 0.92 0
Total Cardiac Adverse Events 3 272 0.93 0.43,2.00 0.85 0
Total Respiratory Adverse Events 3 272 1.14 0.50,2.61 0.75 0
Total Ophthalmological Adverse Events 3 291 0.36 0.10,1.33 0.13 15
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For continuous outcomes, negative Hedges’ g favors treatment group; for categorical outcomes values < 1 favor treatment group; fixed effects models, except where noted

Bolded p-value: p < 0.05

a

Random effects

b

< 3 studies available per subgroup so planned subanalyses not run

Abbreviations CDSS: Calgary Depression Scale for Schizophrenia; HAM-D: Hamilton Depression Rating Scale

Table 4.

Subanalyses of Psychopathology: Continuous Outcomes

Subanalyses by Medication Class
Total Psychopathology N Studies N Participants Hedges’ g 95% CI P I2%
SGAs 6 196 −0.42 −0.92,0.08 0.10 65
Alpha 2 Antagonists 5 139 −0.37 −0.94,0.20 0.20 62
Mirtazapine 4 115 −0.50 −1.17,0.16 0.14 66
Serotonergic Ads 4 285 −0.40 −1.02,0.23 0.21 79
SSRIs 3 245 −0.08 −0.47,0.31 0.67 38
Noradrenergic ADs 3 107 −0.26 −1.23,0.71 0.59 83
Positive Symptoms N n Hedges’ g 95% CI P I2%
SGAs 6 196 −0.01 −0.44,0.43 0.98 56
Alpha 2 Antagonists 5 139 −0.50 −1.12,0.12 0.12 68
Mirtazapine 4 115 −0.53 −1.33,0.27 0.19 76
Serotonergic ADs 4 285 0.07 −0.30,0.43 0.72 44
SSRIs 3 245 0.09 −0.44,0.61 0.75 62
Noradrenergic ADs 3 107 0.09 −0.30,0.48 0.65 0
Negative Symptoms N n Hedges’ g 95% CI P I2%
SGAs 6 196 −0.28 −0.84,0.27 0.32 72
Alpha 2 Antagonists 5 139 −0.42 −0.96,0.12 0.13 58
Mirtazapine 4 115 −0.55 −1.17,0.07 0.08 61
Serotonergic ADs 4 285 −0.32 −0.96,0.32 0.32 80
SSRIs 3 245 −0.03 −0.55,0.48 0.90 61
Noradrenergic ADs 3 107 −0.39 −1.37,0.58 0.43 83
Depression (HAM-D-predominant) N n Hedges’ g 95% CI P I2%
SGAs 5 178 0.00 −0.60,0.60 1.00 74
Alpha 2 Antagonists 4 118 0.05 −0.46,0.55 0.85 46
Mirtazapine 3 94 0.01 −0.68,0.71 0.97 63
Serotonergic ADs 4 304 −0.39 −0.61,−0.16 0.0009 0
SSRIs 3 264 −0.33 −0.57,−0.08 0.009 0
Depression (CDSS-predominant) N n Hedges’ g 95% CI P I2%
SGAs 5 178 −0.08 −0.62,0.47 0.78 68
Alpha 2 Antagonists 4 118 −0.06 −0.44,0.32 0.76 9
Mirtazapine 3 94 −0.12 −0.62,0.38 0.64 31
Serotonergic ADs 4 304 −0.51 −0.74,−0.28 <0.0001 0
SSRIs 3 264 −0.47 −0.71,−0.22 0.0002 0
Open in a new tab

Negative Hedges’ g favors treatment group; random effects models

Bolded p-values: p < 0.05

Abbreviations: AD=Antidepressants; CDSS: Calgary Depression Scale for Schizophrenia; HAM-D: Hamilton Depression Rating Scale

Antidepressants did not differ from placebo for depression in either the HAM-D-predominant analysis (Hedges’ g=-0.14, 95%CI= -0.47 to 0.18, p=0.39, I2=58%) or the CDSS-predominant analysis (Hedges’ g=-0.22, 95%CI= -0.53 to 0.09, p=0.17, I2=54%) (Table 3). Due to significant heterogeneity, subgroup analyses based on medication class were performed for SGAs (studies=5); alpha-2 antagonists (studies=4); mirtazapine (studies=3); serotonergic antidepressants (studies=4); and SSRIs (studies=3). Depression improved with serotonergic antidepressants compared to placebo for both the HAM-D-predominant analysis (Hedges’ g=-0.39, 95%CI= -0.61 to -0.16, p=0.0009, I2=0%) and CDSS-predominant analysis (Hedges’ g=-0.51, 95%CI= -0.74 to -0.28, p<0.0001, I2=0%) (Table 4). Depression also improved with SSRIs compared to placebo for both the HAM-D-predominant analysis (Hedges’ g=- 0.33, 95%CI= -0.57 to -0.08, p=0.009, I2=0%) and the CDSS-predominant analysis (Hedges’ g=-0.47, 95%CI= -0.71 to -0.22, p=0.0002, I2=0%) (Table 4). Antidepressants outperformed placebo regarding study-defined inefficacy in both the HAM-D-included data condition (RR=0.78, 95%CI=0.68-0.91, p=0.0009, I2=0%) and the CDSS-included data condition (RR=0.76, 95%CI=0.65-0.90, p=0.0009, I2=0%) (Table 3). There were no statistically significant differences for any of the remaining psychopathology outcomes (Table 3).

3.5. Study Discontinuation

Antidepressants did not differ from placebo in all-cause discontinuation (RR=1.16, 95%CI=0.85-1.59, p=0.36, I2=0%) or in discontinuation due to inefficacy (RR=0.39, 95%CI=0.12-1.33, p=0.13, I2=0%), intolerability (RR=1.79, 95%CI=0.75-4.27, p=0.19, I2=0%), or other reasons (RR=1.33, 95%CI=0.84- 2.11, p=0.22, I2=0%) (Table 3).

3.6. Adverse Events

Sedation was more common with pooled antidepressants compared with placebo (RR=2.91, 95%CI=1.03-8.17, p=0.04, I2=0%) (Table 3), but this analysis was based entirely on alpha-2 antagonists. No other significant differences were found for any adverse event (Table 3).

4. Discussion

To our knowledge, this is the first meta-analysis of antidepressant augmentation of antipsychotics for the treatment of cognitive deficits in schizophrenia. Across 11 studies and 568 patients, no clinically meaningful improvement in any cognitive domain or the composite score was found for pooled antidepressants or any class of studied antidepressants compared with placebo. Though disappointing, the enhancement of serotonergic or noradrenergic neurotransmission on top of antipsychotic therapy does not appear to relevantly improve cognition in patients with chronic schizophrenia. The exact mechanism of cognitive dysfunction in schizophrenia is unclear, but glutamatergic, cholinergic, GABAergic, and histaminergic hypotheses have the most support (Abi-Dargham, 2004; Lisman et al., 2012; Nakazawa et al., 2012; Miyamoto et al., 2012; Jones et al., 2012; Foster et al., 2010; Vohora & Bhowmik, 2012). Since none of the studied antidepressants targets these neurotransmitter systems, it is not that surprising that they were ineffective for cognitive impairment in schizophrenia. While it is theoretically plausible that these neurotransmitter systems might be affected by the studied antidepressants via neurotransmitter cross-talk, the strength of such postulated indirect effects may be insufficient to significantly improve cognition.

Antidepressants have been found in some studies to significantly reduce depressive symptoms in schizophrenia patients with comorbid depression (Whitehead et al., 2003). However, in the schizophrenia patients included in this meta-analysis who were unselected for depression, antidepressants did not significantly improve depression. One exception was significant antidepressant efficacy in the 4 and 3 studies with serotonergic agents and SSRIs, respectively. Nevertheless, this non-significant effect on depression reduces the potential bias of a pseudo-specific finding of cognitive improvement secondary to improved depression.

Moreover, at least in chronic patients with schizophrenia unselected for any specific symptomatology or severity, antidepressant augmentation of antipsychotics was not associated with benefits in positive, negative, or general psychopathology symptoms. Likewise, except for a higher incidence of sedation confined to alpha-2 antagonists, antidepressants were not associated with higher drop-out rates or specific adverse effects. The lack of efficacy of antidepressants on schizophrenia psychopathology is in contrast to several meta-analyses that found antidepressant augmentation to significantly reduce negative symptoms (Rummel-Kluge et al., 2006; Sepehry et al., 2007; Singh et al., 2010; Hecht & Landy, 2012). However, these meta-analyses either focused on predominant negative symptom patients (Rummel-Kluge et al., 2006) or included many more studies measuring negative symptoms, whereas we only included studies with cognitive data.

There are several limitations of this study. The number of included studies and subjects was small. Data from five studies utilizing bupropion that tested cognition (Culhane et al., 2008; Evins et al., 2007; Evins et al., 2005a; Evins et al., 2005b; George et al., 2002; George et al., 2008; George et al., 2006; Moss et al., 2009; Weiner et al., 2012) were not meta-analyzable as presented in the published papers and were not obtainable from the authors. Notably, however, all bupropion studies targeted smoking cessation, and cognition was only a secondary outcome. Moreover, since bupropion has been found to significantly reduce smoking in schizophrenia (Tsoi et al., 2013), and since nicotine has pro-cognitive effects (Herman & Sofuoglu, 2010; Barr et al., 2008), results of these studies might have been confounded by change in smoking status.

Statistically significant but likely clinically irrelevant effects on executive function and composite cognition were found for pooled antidepressants. It is possible that subgroups of patients may have a more robust, clinically meaningful response to treatment, and a search for relevant biomarkers to identify such subgroups may prove fruitful. Antidepressant doses were also low- to mid-range; thus, higher doses could possibly produce greater effects, which should be explored in future studies of non-depressed patients with schizophrenia. Additionally, studied antidepressants were heterogeneous, as were the cognitive tests and outcomes. No study contained a complete cognitive battery or a complete subscale of a cognitive battery. Future studies should comprehensively measure a broad range of cognitive domains using complete neurocognitive batteries. Further, baseline antipsychotics and degree of patient stability varied. Studies were also short-term, yet even with these short intervention periods statistically significant effects were found on some aspects of cognition. It is possible longer durations of treatment might lead to clinically relevant effects. Finally, the majority of analyzed studies used chronic patients with a long duration of illness. It may be that earlier intervention with add-on antidepressants has a greater chance of success in the treatment of cognitive symptoms, and future studies should investigate the use of antidepressants in people with first-episode or early-phase schizophrenia. However, the one study in first-episode patients did not find significant effects either, although it was small (n=33).

Despite its limitations, this meta-analysis of adjunctive antidepressant treatment for cognition in schizophrenia provides important suggestive information about lack of efficacy. Additionally, results can guide the design of future studies of adjunctive antidepressants for cognitive impairment in schizophrenia.

Supplementary Material

Supplement
Supplement 1

Acknowledgements

We thank the following authors for providing us with additional, unpublished data: Alessandro Bertolino, MD, PhD, Grazia Caforio, MD, PhD, Seetal Dodd, MD, PhD, Richard P. Ebstein, PhD, Joseph I. Friedman, MD, Shahrokh Golshan, MD, Kenji Hashimoto, PhD, Salomon Israel, PhD, Ilana Kremer, MD, Tomihisa Niitsu, MD, PhD, Michael Poyurovsky, MD, Viatcheslav Terevnikov, MD, and Sidney Zisook, MD

Funding

This work was partially supported by the National Institute of Mental Health Advanced Center for Services and Intervention Research, The Zucker Hillside Hospital (P30MH090590); the National Institutes of Health (NIH) P50 Centers for Intervention Development and Applied Research (P50MH080173); and the Case Western Reserve University/Cleveland Clinic CTSA Grant Number UL1 RR024989 provided by the National Center for Research Resources and the National Center for Advancing Translational Sciences, NIH.

Financial Disclosure:

Drs. Vernon, Grundnikoff, Vemulapalli, Pareek, and Goldberg and Mr. Seidman have nothing to disclose.

Dr. Frazier has received federal funding or research support from, acted as a consultant to, received travel support from, and/or received a speaker's honorarium from the Simons Foundation, Ingalls Foundation, Forest Laboratories, Ecoeos, IntegraGen, Shire Development, Bristol-Myers Squibb, National Institutes of Health, and the Brain and Behavior Research Foundation.

Dr. Kane has been a consultant to Alkermes, Amgen, Astra-Zeneca, Janssen, Pfizer, Eli Lilly, Bristol-Myers Squibb, Dainippon Sumitomo/Sepracor/Sunovion, Johnson & Johnson, Otsuka, Pierre Fabre. Vanda, Proteus, Takeda, Targacept, IntraCellular Therapies, Merck, Lundbeck, Novartis, Roche, Rules Based Medicine, Sunovion and has received honoraria for lectures from Otsuka, Eli Lilly, Esai, Boehringer-Ingelheim, Bristol-Myers Squibb, Merck and Janssen. He is a shareholder of MedAvante.

Dr. Correll has been a consultant and/or advisor to or has received honoraria from: Actelion, Alexza; Bristol-Myers Squibb, Cephalon, Eli Lilly, Genentech, Gerson Lehrman Group, IntraCellular Therapies, Janssen/J&J, Lundbeck, Medavante, Medscape, Merck, Otsuka, Pfizer, ProPhase, Roche, Sunovion, Supernus, Takeda, Teva, and Vanda. He has received grant support from BMS, Janssen/J&J, Novo Nordisk A/S and Otsuka.

Role of the Funding Source

The National Institute of Mental Health and National Institutes of Health had no role in the study design; collection, analysis, or interpretation of data; writing of the report; or decision to submit the paper for publication.

Footnotes

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