Neuropathophysiological changes associated with mirtazapine treatment response in major depressive disorder: insights into bottom-up dopaminergic pathways and prefrontal control networks

Due to the heterogeneity in symptoms and underlying biological mechanisms of major depressive disorder (MDD), as well as the lack of biologically validated approaches for subtyping, effective treatment often requires a prolonged trial-and-error process. This heterogeneity underscores the need for objective biomarkers that can predict individual treatment responses and guide antidepressant selection. 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, the present study investigated pathophysiological changes in MDD patients that were associated with subsequent treatment response to mirtazapine, using functional magnetic resonance imaging with a conditioned reward task. Sixty-seven individuals diagnosed with MDD were enrolled and treated with either mirtazapine or one of two comparator antidepressants: agomelatine or a selective serotonin reuptake inhibitor. Participants were classified as responders or non-responders after six weeks of treatment. 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 the observed activation patterns may reflect alterations in the mesolimbic dopaminergic pathway and prefrontal regulatory networks during reward processing, which may characterize the pathophysiological brain features of MDD patients who respond to mirtazapine treatment. Moreover, these activation patterns may serve as promising biomarkers for identifying an MDD subtype more likely to benefit from mirtazapine.