Antidepressants Assessed for Reducing Negative Symptoms of Schizophrenia

Of the antidepressants which have been trialed as adjuncts to antipsychotics in reducing negative symptoms of schizophrenia, mirtazapine and duloxetine appear significantly better than placebo (with mirtazapine superior to several other antidepressants) in a recent systematic review and network meta-analysis.¹

"These findings suggest adjunctive use of mirtazapine and duloxetine can effectively improve the negative symptoms of schizophrenia in patients who are stably receiving antipsychotic treatment," indicated Bo Xiang, MD, Department of Psychiatry, Southwest Medical University, Luzhou, China, and colleagues. "Therefore, incorporating antidepressants into future treatment plans for negative symptoms of schizophrenia is a promising strategy that warrants further exploration."

The investigators combed through over 1400 potentially relevant studies of the effect of adjunct antidepressant treatment on negative symptoms of schizophrenia to identify 15 randomized, placebo-controlled trials, comprising 655 adult patients that met inclusion criteria. These trials assessed change in negative symptoms on either the Scale for the Assessment of Negative Symptoms (SANS) or the Positive and Negative Syndrome Scale (PANSS).

Xiang and colleagues describe their study as "the first network meta-analysis examining the efficacy of adjunctive antidepressant medication in treating negative symptoms."While previous studies have suggested that adjunctive antidepressants can improve negative symptoms, the investigators point out that the patients had received first-generation antipsychotics, and contend that the effect remains to be confirmed in those treated with newer agents.²

The investigators also acknowledge other studies which have not found that antidepressants reduce negative symptoms. They attribute the contradictory findings to such factors as different methodologies, small samples, short trial lengths, a range of concomitant antipsychotic regimens, or not having excluded subjects with depressive symptoms.In contrast, Xiang and colleagues emphasize, "we specifically focused on negative symptoms and made them a key aspect of the inclusion criteria."

The median duration of the reviewed trials was 8 weeks (4 to 48 weeks).Several studies did not specify whether patients or staff were blinded, but Xiang and colleagues did not find a high risk for bias related to insufficient blinding. The 10 antidepressants compared in one or more studies with placebo for effect on negative symptoms were: vortioxetine (n=1), fluvoxamine (n=2), paroxetine (n=1), mirtazapine (n=2), escitalopram (n=1), reboxetine (n=3), citalopram (n=3), fluoxetine (n=2), duloxetine (n=1), and bupropion (n=1).

The investigators report that, in 2 studies, mirtazapine significantly outperformed placebo in reducing negative symptoms (standard mean difference [SMD] -1.73, confidence interval [CI] -2.60, -0.87). Duloxetine was also statistically significantly superior in the one placebo-controlled trial (SMD -1.19, -2.17, -0.21).

In addition to relative effect, Xiang and colleagues estimated efficacy as an area under the curve (AUC) plot of cumulative probabilities against rank. Mirtazapine exhibited the largest AUC, representing greatest efficacy, followed by duloxetine. Bupropion appeared less effective than other antidepressants, with an almost identical AUC to placebo. Further analysis yielded cumulative probability prediction values, with a 93.9% probability of mirtazapine being effective for negative symptoms, followed by duloxetine with 76.2% probability.

Primary, Secondary Negative Symptoms, or Symptoms of Depression?

In considering limitations of this network meta-analysis, the investigators recognize the difficulty in distinguishing between primary negative symptoms of schizophrenia, and some manifestations of, extrapyramidal or sedative drug side effects. Additionally, as most of the reviewed studies involved patients with 10 to 20 years of illness, the investigators were unable to ascertain whether efficacy of antidepressants might be different earlier in the course of illness. The analysis also did not distinguish persistent from transient negative symptoms, nor ascertain whether improvement with antidepressants was sustained.

"Since negative symptoms are a chronic aspect of schizophrenia, clinical trials must be sufficiently long to demonstrate that the observed treatment response is not temporary," Xiang and colleagues argue. "Moreover, certain specific negative symptoms that need to be addressed depend on interactions with the environment, and it may take months to observe measurable and stable improvements."

The investigators also considered, however, that longer studies can also confound the assessment of antidepressant effectiveness for negative symptoms. The loss of clinical stability in longer treatment, for example, can lead to presentations such as social withdrawal that appear similar to negative symptoms. Conversely, emergence of psychotic agitation may appear as reduction in negative symptoms.

Finally, they concede the difficulty in ascertaining whether antidepressants are reducing negative symptoms of schizophrenia, or improving undiagnosed, comorbid depression.

"Although this meta-analysis screened for depressive symptoms and focused on negative symptoms, the final observed effect may reflect improvements in depressive symptoms that were mistakenly attributed to negative symptoms," Xiang and colleagues allow. "This is due to factors such as the inconsistency of assessment scales for depressive and negative symptoms across studies, as well as the variability in evaluation standards among experimenters."

Dr Bender reports on medical innovations and advances in practice and edits presentations for news and professional education publications. He previously taught and mentored pharmacy and medical students, and he provided and managed pharmacy care and drug information services.

References

1. Li Y, Yu M, Yang H, et al. Efficacy of adjunctive antidepressants in treating negative symptoms of schizophrenia: a systematic review and network meta-analysis. Psychol Med. 2025;55:e317.

2. Andreasen NC. Negative symptoms in schizophrenia. Definition and reliability. Arch Gen Psychiatry. 1982;39(7):784-788.