Noninvasive Brain Stimulation for the Treatment of Negative Symptoms in Schizophrenia

Study data published in JAMA Psychiatry compare the relative efficacies of noninvasive brain stimulation (NIBS) interventions for the treatment of negative symptoms in schizophrenia. Compared with sham protocols, excitatory NIBS protocols over the left dorsolateral prefrontal cortex were associated with the greatest symptom improvements.

While NIBS is theorized to reduce negative symptoms in schizophrenia, the relative efficacy and acceptability of different NIBS protocols is unclear. To inform this gap, investigators conducted a systematic review of the ClinicalKey, Cochrane CENTRAL, Embase, ProQuest, PubMed, ScienceDirect,, and Web of Science electronic databases from inception through December 2021 for randomized clinical trials comparing the effects of different NIBS Methods on the negative symptoms of schizophrenia. Data were independently extracted by multiple reviewers for the following outcomes: (1) changes in the severity of negative symptoms; and (2) acceptability, or the proportion of patients dropping out of treatment for any reason. Standardized mean differences (SMDs) were calculated to compare reductions in negative symptoms across treatment methods. Pairwise meta-analyses were conducted using random effects models.

A total of 48 trials were included in the meta-analysis. The pooled study cohort comprised 2211 patients with schizophrenia. Mean age at enrollment was 38.7 years; the proportion of women participating in each trial ranged from 0% to 70%, with an average of 30.6%. The mean study duration was 9 weeks.

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Compared with sham conditions, the greatest symptom improvements were observed with excitatory NIBS strategies over the left dorsolateral prefrontal cortex, with or without other inhibitory stimulation in contralateral regions of the brain. Specifically, the greatest symptom reductions vs. sham were observed with high-definition transcranial random noise stimulation (SMD, -2.19; 95% CI, -3.36 to -1.02); intermittent theta-burst stimulation (-1.32; -1.88 to -0.76); anodal transcranial direct current stimulation (-1.28; -2.55 to -0.02]; high-frequency repetitive transcranial magnetic stimulation (rTMS) (-0.43; -0.68 to -0.18); and extreme high-frequency rTMS (-0.45; -0.79 to -0.12). Of these, only anodal transcranial direct-current stimulation was associated with a substantial reduction in depressive symptoms.

Acceptability did not vary significantly between treatment protocols. Risk for bias was low in most studies.

Results from this trial provide evidence in support of excitatory NIBS protocols for the treatment of negative symptoms in schizophrenia. As study limitations, investigators noted between-study heterogeneity in patient characteristics and treatment methods.

“Our findings might serve as a starting point for future large-scale [randomized controlled trials] with longer follow-up periods and sham control to investigate the association between NIBS and negative symptoms in schizophrenia,” investigators wrote.

Disclosure: Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.


Tseng PT, Zeng BS, Hung CM, et al. Assessment of noninvasive brain stimulation interventions for negative symptoms of schizophrenia: A systematic review and network meta-analysis. JAMA Psychiatry. Published online June 22, 2022. doi:10.1001/jamapsychiatry.2022.1513

This article originally appeared on Psychiatry Advisor

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