Cariprazine as a candidate for drug repurposing in anorexia nervosa: a mechanistic hypothesis grounded in neuroimaging evidence.

Anorexia nervosa (AN) carries the highest mortality of any psychiatric disorder, yet no pharmacological agent has received regulatory approval for its treatment in adults. Multimodal neuroimaging has now revealed a coherent neurobiological architecture: functional MRI documents blunted ventral striatal and amygdalar responses to food, alongside excessive prefrontal-cingulate engagement; PET corroborates trait-level reductions in 5-HT2A binding, elevations in 5-HT1A binding across cingulate, frontal, parietal, temporal, and dorsal raphe regions, and compensatory upregulation of D2/D3 receptors in the anteroventral striatum; SPECT identifies persistent temporal and cingulate hypoperfusion; and EEG reveals attenuated P300 amplitudes, delayed N2 latencies, and parieto-occipital theta hyperarousal. We propose that cariprazine-a dopamine D3-preferring D3/D2 receptor partial agonist with 5-HT1A partial agonism and 5-HT2A/2B antagonism-confers a uniquely matched pharmacological toolkit for this disorder. Cariprazine's D3 partial agonism is predicted to restore mesolimbic dopamine signaling, thereby reinstating incentive salience to food cues; its 5-HT1A stabilizer property attenuates the trait-amplified corticolimbic inhibitory tone underlying harm avoidance and anxiety; its prefrontal glutamate-modulating action attenuates excessive cognitive control over eating, and chronic administration confers substrate-dependent set-point recalibration of the upregulated mesolimbic D3 receptor pool. Furthermore, cariprazine's favorable metabolic profile (number needed to harm for clinically significant weight gain of 34 versus 6 for olanzapine) renders its safety burden meaningfully lower than that of currently used agents. In summary, the receptor pharmacology of cariprazine maps with notable specificity onto the neuroimaging-defined substrate of AN, providing a mechanistically grounded rationale for prospective clinical investigation of cariprazine as a candidate pharmacotherapy for this otherwise intractable disorder.