Abstract <p>Major depressive disorder (MDD) is a common condition that negatively affects individuals’ emotions, thinking, and overall functioning. The primary objective of this study was to investigate the potential utility of <i>DISC1</i> gene expression as a peripheral blood biomarker for the diagnosis and monitoring of treatment response in individuals with MDD. 80 healthy control participants and 80 patients diagnosed with Major Depressive Disorder (MDD) according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria. The MDD patients were randomly assigned to two distinct treatment groups: one group received a standardized dose of fluoxetine (20 mg/day) (<i>n</i> = 40), while the other group underwent a 12-session cognitive-behavioral therapy (CBT) intervention (<i>n</i> = 40). The expression levels of the <i>DISC1</i> gene were quantitatively assessed in both control and patient samples via qPCR before and after treatment in each group. Patients with depression had significantly lower levels of the <i>DISC1</i> gene expression than the healthy control (<i>p</i> = 0.0025). In the fluoxetine therapy group, there was a notable reduction in the expression of the <i>DISC1</i> gene (<i>p</i> = 0.005), while the expression in the psychotherapy group remained relatively unchanged from pre-treatment levels (<i>p</i> = 0.177). The expression of the <i>Disc1</i> gene may serve as a putative blood biomarker for the diagnosis of MDD. Notably, the differential effects of fluoxetine and CBT on <i>DISC1</i> expression highlight distinct therapeutic mechanisms. CBT may be a more effective treatment strategy for compensating the decline in <i>DISC1</i> gene expression observed in patients with MDD.</p>