<p>Major depressive disorder (MDD) shows striking heterogeneity in both symptoms and underlying pathophysiology, and the absence of biologically grounded subtypes often results in a prolonged trial-and-error process when selecting effective treatments. This has motivated efforts to identify biomarkers that may predict individual treatment responses. Although mirtazapine is widely used and its efficacy is well established in clinical settings, neuroscientific studies on its treatment response remain limited relative to other antidepressants. To address this gap, this study examined pre-treatment pathophysiological neural features associated with subsequent response to mirtazapine. Sixty-seven individuals with MDD underwent functional magnetic resonance imaging during a conditioned reward task and then received monotherapy with mirtazapine or one of two comparator antidepressants (agomelatine or a selective serotonin reuptake inhibitor). Mirtazapine responders demonstrated increased pre-treatment activation in core components of the mesolimbic dopaminergic pathway, particularly the ventral tegmental area and ventral striatum, as well as in prefrontal and functionally connected regions implicated in reward evaluation, reward-related behavioral inhibition, and reward-based decision-making. Importantly, many of these response-related activations were specific to the mirtazapine group. These findings suggest that altered engagement of mesolimbic dopaminergic pathways and prefrontal regulatory networks during reward processing may characterize an MDD subtype responsive to mirtazapine, and that such patterns may serve as biomarkers for identifying patients likely to benefit from this treatment.</p>