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

Abstract

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 (ΔBPND) (-34% vs. -30%; p = .072, d = 0.58) but no difference in D2/D3 receptor availability (BPND). Striatal and extrastriatal BPND and percent change in baseline BPND 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.

Trial registration: ClinicalTrials.gov NCT02033369.

Keywords: Dopamine; Functional magnetic resonance imaging; Major depressive disorder; Positron emission tomography; Pramipexole; [(11)C]-(+)-PHNO.

Conflict of interest statement

Disclosures: Dr. Schneier has received research support from Forest Laboratories; Dr. Slifstein has received research support from Forest Laboratories, Pierre-Fabre, CHDI, and Otsuka and has provided consultation for Amgen. Dr. Pizzagalli has received consulting fees from Akili Interactive Labs, BlackThorn Therapeutics, Boehringer Ingelheim, Pfizer and Posit Science, for activities unrelated to the current research. Dr. Iosifescu has received consulting fees from Axsome, MyndAnalytics (CNS Response), Jazz, Lundbeck, Otsuka, Sunovion, and has received research support (through his academic institutions) from Alkermes, Astra Zeneca, Brainsway, LiteCure, Neosync, Roche, Shire. Dr. Abi-Dargham has received research support from Takeda and Forest Pharmaceuticals and has served on advisory boards for Roche, Forum, and Otsuka. All other authors report no biomedical financial interests or potential conflicts of interest.

Copyright © 2018 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Figures

Figure 1:

Probabilistic Reinforcement Learning Task

Figure 2:

PET scatterplot of post-amphetamine change in binding potential (ΔBPND) as a measure of dopamine release in the ventral striatum (VST): Healthy Comparison subjects, mean 29.6% (SD = 7.6) vs. Major Depressive Disorder subjects, mean 34.2% (SD = 8.3), t = 1.85, P = .07