The meta-analysis by Helfer et al also determined that antidepressants are relatively safe for use in patients with schizophrenia. Analysis indicated that there were no significant differences between the treatment and control groups for the majority of AEs studied.  Only four of the 38 individual AEs studied yielded a difference between the groups, which were abdominal pain, constipation, dizziness, and dry mouth. No significant differences were seen between the treatment and control groups when measuring exacerbations of psychosis, premature discontinuation rates, and the number of patients with at least one AE. The safety results are summarized in Table 3. 

The quality of evidence for the primary outcomes in this meta-analysis was rated as high, however several other outcomes measured in this study had a lower quality of evidence. The authors stated that there were several limitations in this analysis. First, many of the studies analyzed were small, potentially leading to an increase in the effect sizes. Second, it was noted that there was an increased risk of statistically significant results calculated by chance due to performing several secondary and subgroup analyses. Third, due to poor reporting of AEs and small sample sizes, the safety data was somewhat difficult to analyze and interpret. Lastly, it was noted that none of the trials analyzed distinguished between primary and secondary negative symptoms. Since there are several sources of secondary negative symptoms (e.g. antipsychotic medications, depression), it is difficult to determine whether adjunctive antidepressants are treating these symptoms versus the psychopathology of the disease.

In this recent meta-analysis, Helfer et al sought to determine the safety and efficacy of adjunctive antidepressants in the treatment of schizophrenia. Results indicated that antidepressants are efficacious at treating many of the symptoms associated with schizophrenia, however the effect size is rather small. Safety data from this analysis indicated that add-on antidepressants are relatively safe for use and do not exacerbate psychosis in patients with schizophrenia.

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1.     Helfer B, Samara MT, Huhn M, et al. Efficacy and Safety of Antidepressants Added to Antipsychotics for Schizophrenia: A Systematic Review and Meta-Analysis. Am. J. Psychiatry. 2016 June 10.

Table 1 – Summary of Pooled and Subgroup Analysis Efficacy Results1

Outcome Number of Participants/Trials Data [95% CI] Number Needed to Treat to Benefit [95% CI]

Depressive Symptoms

Pooled analysis: 1,849
Subgroup analysis: 777

SMD = -0.25 [-0.38, -0.12], p = 0.0001

Subgroup analysis: SMD = -0.34 [-0.58, -0.09], p = 0.007

9 [7, 29]

Negative Symptoms

Pooled analysis: 1,905
Subgroup analysis: 406

SMD = -0.30 [-0.44, -0.16], p < 0.0001

Subgroup analysis: SMD = -0.58 [-0.94, -0.21], p = 0.002

9 [7, 14]

Overall Symptoms


SMD = -0.24 [-0.39, -0.09], p = 0.002

14 [7,29]

Positive Symptoms


SMD = -0.17 [-0.33, -0.01], p = 0.04

14 [7,29]

Quality of Life


SMD = -0.32 [-0.57, -0.06], p = 0.02

9 [5,29]


23 trials

RR = 1.52 [1.29, 1.78], p < 0.0001

5 [4, 7]

Abbreviations: CI = confidence interval, RR = risk ratio, SMD = standardized mean difference