Effects of Second-Generation Antidepressants on Cognitive Functions: A Systematic Review and Meta-Analysis

Objectives: Second-generation antidepressants are currently the first-line of treatment for depression and are widely used. The aim of this study was to determine the effects on cognition by second-generation antidepressants through a systematic review and meta-analysis of recent scientific literature.

Methods: Electronic search in Medline, PubMed, PsycINFO, CINAHL, and Embase for English-language abstracts from 1980 through May 2014, supplemented with a manual search from reference lists of relevant review articles was carried out to identify eligible studies. Studies were included if they met the following selection criteria: Population: adults (age≥18) with diagnosis of depression; Intervention: second-generation antidepressants (SGAD) marketed in the United States based on the American Hospital Formulary Service (AHFS) 2014 drug classification; Comparator: placebo or second-generation antidepressants; Outcomes: attention, processing speed, executive function and memory; and Study Design: Randomized Controlled Trials (RCTs) and observational studies. Data management and screening procedures were carried out by using RefWorks (ProQuest) and Microsoft Excel workbook. Data extraction and synthesis was conducted by the primary author using a data extraction form specially designed for this study. Studies were sorted according to type of neurocognitive test used and a minimum of 3 studies per test per study design type was required in order to conduct further systematic review and meta-analysis. The methodological quality of the included studies was assessed by Cochrane risk of bias tool. A random effects model was used to estimate the pooled effects of antidepressant use on cognitive functioning. Heterogeneity was assessed by I2 testing. Egger's regression test and Trim and Fill method were used to examine for the presence of potential publication bias along with analysis of funnel plots. All analyses were performed using Comprehensive Meta-Analysis, v2.2 (Biostat, Englewood, NJ)

Results: A total of 4,274 abstracts were screened; 342 were retrieved for a full-text review. Of the reviewed full text articles, 17 (13 RCTs and 4 Observational) studies involving a total of 2,437 depressed patients) met the inclusion criteria. Studies were of optimum quality as assessed by the Risk of bias tool. Out of the 43 unique neurocognitive test; Mini-Mental State Exam (MMSE), Stroop Color Word test (SCWT), Choice Reaction Time Task (CRT) and Digit Symbol Substitution Test (DSST) were the most common tests used across the studies which fulfilled the selection criteria (minimum of 3 studies per test per study design type) for further systematic review and meta-analysis. Six studies were found eligible for inclusion into the meta-analysis for MMSE and the results were not significant with (SMD=0.126; 95%CI -0.046, 0.298; p > 0.05). There was no heterogeneity (I2=0%, p= 0.975) and publication bias (Egger’s regression intercept (B0= 0.29359; 95%CI -1.04627, 1.63344; p > 0.05). Insufficient and inconsistent reporting of results involving SCWT, CRT and DSST prevented meta-analysis of study findings; hence, a systematic review was performed. Four studies were found eligible for SCWT out of which two studies with positive findings which had a combined sample size of almost 13 times that of the non-significant study, which suggests improvement in executive function with second-generation antidepressants compared to placebo. The systematic review conducted on four studies which had used CRT suggests positive results with one study with sample size 30 times that of the non-significant study showing improvements in attention and processing speed in depressed patients treated with low dose second-generation antidepressants. The systematic review conducted on three studies which had used Digit Symbol Substitution Test suggested mixed evidence with two studies showing significant improvement in attention and processing speed with SMs compared to placebo while one study suggesting otherwise with SNRIs.

Conclusions: Meta-analysis of studies using MMSE suggests that SGADs do not affect global cognition but might affect other specific domains. Systematic reviews on studies involving SCWT, CRT and DSST suggest variable evidence regarding the effects of second-generation antidepressants on specific domains of cognition. However, there were indications of possible improvements in executive function, attention and processing speed with SGADs compared with placebo. Further studies involving reliable and widely used neurocognitive tests reporting necessary statistical detail for computing effect sizes are needed to estimate and quantify the effects of second-generation antidepressants on cognition.