Moderating Role of Cigarette Smoking on the Efficacy of tDCS in the Treatment of Negative and Cognitive Symptoms of Schizophrenia: Results from a Randomized Clinical Trial

Background: Transcranial Direct Current Stimulation (tDCS) has shown potential in improving negative symptoms (NS) and Cognitive Impairment Associated with Schizophrenia (CIAS). However, heterogeneity in stimulation protocols and sample characteristics limit definitive conclusions regarding tDCS effectiveness in schizophrenia. Given the detrimental effects of cigarette smoking, particularly on cognition, this study explored the role of cigarette smoking as a modifiable individual factor potentially contributing to methodological heterogeneity by evaluating tDCS effects on NS and CIAS in Smoker (SM) and Non-Smoker (NoSM) patients. Methods: Post hoc analyses of a double-blind RCT were performed on 50 patients, randomized to 2 mA active or sham-tDCS (15 weekday sessions) with bilateral bipolar-nonbalanced prefrontal placement. The sample was divided according to the smoking status, consisting of 28 SM and 22 NoSM. Separate one-way analyses of covariance (ANCOVA) were performed within each subgroup to assess changes over time between treatment conditions. Clinical outcomes included Positive and Negative Symptoms Scale (PANSS), Brief Assessment of Cognition in Schizophrenia (BACS), Clinical Global Impression (CGI) and Calgary Depression Scale for Schizophrenia (CDSS) total scores. Results: SM exhibited baseline lower cognitive scores in verbal memory, motor speed and working memory domains. NS improved in both SM and NoSM with large effect size. Significant improvement in CIAS, specifically in working memory and verbal fluency, were found exclusively in NoSM. Conclusions: Cigarette smoking appeared to limit tDCS effectiveness in improving CIAS but not NS in schizophrenia. We suggested that the neurotoxic milieu linked to chronic exposure to neurotoxins of cigarette smoking could be responsible for these effects, counterbalancing the neuroprotective effects of tDCS. Further studies are warranted to replicate these findings.