Combining HD-tDCS and iTBS in Treating Negative Symptoms of Schizophrenia

The Efficacy of Combined HD-tDCS and iTBS in Treating Negative Symptoms of Schizophrenia

Dysfunction of the dorsolateral prefrontal cortex (DLPFC) is central to the persistence of negative symptoms in schizophrenia. Both HD-tDCS and iTBS targeting the left DLPFC have shown therapeutic benefit. This trial will test the hypothesis that combining HD-tDCS with iTBS yields additive efficacy.

Dysfunction of the left dorsolateral prefrontal cortex (DLPFC) is central to the persistence of negative symptoms in schizophrenia, an area of unmet therapeutic need. High-definition transcranial direct current stimulation (HD-tDCS) and intermittent theta burst stimulation (iTBS), an optimized form of repetitive transcranial magnetic stimulation (rTMS), have each demonstrated efficacy in alleviating negative symptoms when applied to the left DLPFC. However, meta-analyses indicate only moderate effect sizes for these interventions individually. Evidence suggests that combining iTBS with tDCS may enhance cortical plasticity beyond either technique alone, warranting trials to assess additive efficacy. This double-blind, randomized, sham-controlled study will test the hypothesis that combined HD-tDCS and iTBS produce superior therapeutic benefit for negative symptoms in schizophrenia.

Inclusion Criteria:

• Subjects diagnosed with DSM-5 schizophrenia or schizoaffective disorder;
• With a clinical presentation characterized by predominant negative symptoms, as determined by psychiatric assessment and a score of at least 20 on the Negative Symptoms Subscale of the Positive and Negative Syndrome Scale (PANSS);
• Stable positive and negative symptoms for at least 4 weeks, as documented in medical records and confirmed by clinical judgment and psychiatric interview;

Exclusion Criteria:

• Unstable medical conditions;
• Current psychiatric comorbidity or active substance use disorder (except for tobacco use disorders);
• Contraindications for MRI, tDCS or rTMS;
• Pregnancy or breastfeeding at the time of enrollment;
• History of meningitis, encephalitis, seizures, intracranial neoplasms or surgery, severe head injury or cerebrovascular disease, or a family history of seizures;
• rTMS or tDCS treatment within the past 6 months as well as a history of electroconvulsive therapy (ECT);
• Any skin lesion at the stimulation sites;
• Patients receiving medications that significantly change the seizure threshold;
• A history of suicidal behavior within the past 6 months, or symptom worsening and emergence of suicidal ideation during the screening period.