Efficacy and Safety of Transcranial Direct Current Stimulation for Treating Negative Symptoms in Schizophrenia: A Randomized Clinical Trial

Abstract

Importance: Negative symptoms represent a substantial burden in schizophrenia. Although preliminary studies have suggested that transcranial direct current stimulation (tDCS) is effective for some clusters of symptoms, the clinical benefits for negative symptoms are unclear.

Objective: To determine the efficacy and safety of tDCS vs sham as an add-on treatment for patients with schizophrenia and predominant negative symptoms.

Design, setting, and participants: The double-blind Schizophrenia Treatment With Electric Transcranial Stimulation (STARTS) randomized clinical trial was conducted from September 2014 to March 2018 in 2 outpatient clinics in the state of São Paulo, Brazil. Patients with schizophrenia with stable negative and positive symptoms and a minimum score of 20 points in the negative symptoms subscale of the Positive and Negative Syndrome Scale (PANSS) were included.

Interventions: Ten sessions of tDCS performed twice a day for 5 days or a sham procedure. The anode and the cathode were positioned over the left prefrontal cortex and the left temporoparietal junction, respectively.

Main outcomes and measures: Change in the PANSS negative symptoms subscale score at week 6 was the primary outcome. Patients were followed-up for an additional 6 weeks.

Results: Of the 100 included patients, 20 (20.0%) were female, and the mean (SD) age was 35.3 (9.3) years. A total of 95 patients (95.0%) finished the trial. In the intention-to-treat analysis, patients receiving active tDCS showed a significantly greater improvement in PANSS score compared with those receiving the sham procedure (difference, 2.65; 95% CI, 1.51-3.79; number needed to treat, 3.18; 95% CI, 2.12-6.99; P < .001). Response rates for negative symptoms (20% improvement or greater) were also higher in the active group (20 of 50 [40%]) vs the sham group (2 of 50 [4%]) (P < .001). These effects persisted at follow-up. Transcranial direct current stimulation was well tolerated, and adverse effects did not differ between groups, except for burning sensation over the scalp in the active group (43.8%) vs the sham group (14.3%) (P = .003).

Conclusions and relevance: Transcranial direct current stimulation was effective and safe in ameliorating negative symptoms in patients with schizophrenia.

Trial registration: ClinicalTrials.gov identifier: NCT02535676.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Valiengo has received grants from the Stanley Medical Research Institute. Dr Gordon has received personal fees from Fundação Faculdade de Medicina and grants from the EXIST Project. Dr Padberg has received grants from the German Federal Ministry of Education and Research, personal fees from Brainsway and MAG & More, and nonfinancial support from MAG & More and neuroCare Group. Dr Lacerda has received grants and personal fees from Janssen Pharmaceutica, Cristália Produtos Químicos Farmacêuticos, and Eli Lilly and Company; grants from Lundbeck, Servier Laboratories, Forum Pharmaceuticals, and National Council for Scientific and Technological Development; and personal fees from Sanofi, Aché Laboratórios, Mantecorp Skincare, Libbs Farmacêutica, Daiichi Sankyo, Eurofarma, Pfizer, and Myralis Pharma. Dr Gattaz has received grants from the São Paulo Research Foundation. Dr Brunoni has received grants from the Stanley Foundation, National Council for Scientific and Technological Development, and Alexander von Humboldt return fellowship; personal fees from neuroCare Group; and is the Chief Medical Advisor of Flow Neuroscience. No other disclosures were reported.

Figures

Figure 1.. Study Flowchart

Analysis was performed in the intention-to-treat sample. PANSS indicates Positive and Negative Syndrome Scale; tDCS, transcranial direct current stimulation.

Figure 2.. Change in Negative Symptoms Subscale Score on the Positive and Negative Syndrome Scale (PANSS)

The mean reduction in the PANSS negative symptoms subscale scores (intention-to-treat analysis) in the active transcranial direct current stimulation (tDCS) and sham tDCS treatment groups from baseline to week 12. Scores on the PANSS negative symptoms subscale range from 7 to 26, with higher scores indicating more severe negative symptoms. Treatment with active tDCS was superior to sham tDCS at week 6 (PANSS score point difference, 2.65; 95% CI, 1.51-3.79; P < .001) and at week 12 (PANSS score point difference, 2.35; 95% CI, 1.02-3.67; P < .001). Error bars represent 1 SE.