Dopamine Release in Antidepressant-Naive Major Depressive Disorder: A Multimodal [¹¹C]-(+)-PHNO Positron Emission Tomography and Functional Magnetic Resonance Imaging Study

Background: Mesolimbic dopamine system dysfunction is believed to contribute to major depressive disorder (MDD), but molecular neuroimaging of striatal dopamine neurotransmission has yielded mixed results, possibly owing to limited sensitivity of antagonist radioligands used with positron emission tomography to assess dopamine release capacity. This study used an agonist radioligand with agonist challenge to assess dopamine release capacity and D₂/D₃ receptor availability in MDD. Methods: Twenty-six treatment-naive adults with MDD and 26 healthy comparison participants underwent functional magnetic resonance imaging during a probabilistic reinforcement task, and positron emission tomography with the D₃-preferring ligand [¹¹C]-(+)-PHNO, before and after oral dextroamphetamine. MDD participants then received pramipexole treatment for 6 weeks. Results: MDD participants had trend-level greater dopamine release capacity in the ventral striatum, as measured by percent change in baseline binding potential relative to nondisplaceable compartment (ΔBP_ND) (−34% vs. −30%; p =.072, d = 0.58) but no difference in D₂/D₃ receptor availability (BP_ND). Striatal and extrastriatal BP_ND and percent change in baseline BP_ND were not significantly associated with blood oxygen level–dependent response to reward prediction error in the ventral striatum, severity of depression and anhedonia, or antidepressant response to pramipexole (response rate = 72.7%). Conclusions: [¹¹C]-(+)-PHNO demonstrated high sensitivity to displacement by amphetamine-induced dopamine release, but dopamine release capacity and D₂/D₃ availability were not associated with ventral striatal activation to reward prediction error or clinical features, in this study powered to detect large effects. While a preponderance of indirect evidence implicates dopaminergic dysfunction in MDD, these findings suggest that presynaptic dopamine dysregulation may not be a feature of MDD or a prerequisite for treatment response to dopamine agonists.