Cognitive Flexibility in Depression and TMS Response

The primary aim of this prospective study is to determine the level of cognitive flexibility in patients with treatment-resistant depression (TRD) before treatment and to explore whether there is a relationship between cognitive flexibility and their response to TMS treatment. TRD represents a subset of major depressive disorder in which patients do not adequately respond to conventional antidepressant treatments. Emerging evidence suggests that TMS, a noninvasive brain stimulation technique, can effectively alleviate symptoms in TRD patients. However, the Stanford Accelerated Intelligent Neuromodulation Therapy study suggests that 20% of the TRD group may not respond to treatment and could represent an endophenotypic subgroup. In this context, patients with better cognitive flexibility may show a better response to TMS, and the addition of behavioral methods to enhance flexibility could be considered as an adjunct to TMS treatment. The study will enroll 49 patients diagnosed with treatment-resistant depression (TRD) based on the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) criteria. Participants will undergo a TMS treatment regimen using the MagVenture™ X100™ device. The treatment protocol will consist of 20 sessions over four weeks, delivering 18,000 pulses in total (using theta burst stimulation). The stimulation will target the left dorsolateral prefrontal cortex, with parameters designed to achieve optimal therapeutic effects while minimizing side effects. Motor threshold measurements will be conducted prior to treatment initiation and adjusted weekly to maintain consistent treatment intensity. A control group consisting of 65 healthy participants will undergo a single evaluation for neuropsychological and psychometric assessments, with no treatment or follow-up. Before starting TMS treatment, all patients will undergo a neuropsychological test battery, including the Wisconsin Card Sorting Test (WCST), Trail Making Test (TMT, Verbal Fluency (VF) Tests to determine their cognitive flexibility levels. The Cognitive Flexibility and Control Scale (CFCS), a self-report measure, will be administered to patients who meet the eligibility criteria. Psychiatric assessments will include the Patient Health Questionnaire (PHQ-9) to evaluate changes in depressive symptoms, while the Clinical Global Impression - Severity (CGI-S) and Clinical Global Impression - Improvement (CGI-I) scales will be administered before and after the 20 sessions of TMS treatment. The primary objective is to assess improvements in symptom severity and the relationship with cognitive flexibility, as measured by the neurocognitive test battery. This will provide valuable insights for clinicians to better understand which patients are most likely to benefit from TMS treatment. The secondary objectives include identifying clinical and neurocognitive features in patients who do not respond to TMS treatment, assessing side effects, and examining whether concurrent medication, such as anti-obsessive medications, influences the efficacy of TMS therapy.This study will offer valuable data for clinicians and researchers, ultimately guiding safer and more effective use of TMS in psychiatric practice.