Baseline reward processing and ventrostriatal dopamine function are associated with pramipexole response in depression

Abstract

The efficacy of dopamine agonists in treating major depressive disorder has been hypothesized to stem from effects on ventrostriatal dopamine and reward function. However, an important question is whether dopamine agonists are most beneficial for patients with reward-based deficits. This study evaluated whether measures of reward processing and ventrostriatal dopamine function predicted response to the dopamine agonist, pramipexole (ClinicalTrials.gov Identifier: NCT02033369). Individuals with major depressive disorder (n = 26) and healthy controls (n = 26) (mean ± SD age = 26.5 ± 5.9; 50% female) first underwent assessments of reward learning behaviour and ventrostriatal prediction error signalling (measured using functional MRI). 11C-(+)-PHNO PET before and after oral amphetamine was used to assess ventrostriatal dopamine release. The depressed group then received open-label pramipexole treatment for 6 weeks (0.5 mg/day titrated to a maximum daily dose of 2.5 mg). Symptoms were assessed weekly, and reward learning was reassessed post-treatment. At baseline, relative to controls, the depressed group showed lower reward learning (P = 0.02), a trend towards blunted reward-related prediction error signals (P = 0.07), and a trend towards increased amphetamine-induced dopamine release (P = 0.07). Despite symptom improvements following pramipexole (Cohen's d ranging from 0.51 to 2.16 across symptom subscales), reward learning did not change after treatment. At a group level, baseline reward learning (P = 0.001) and prediction error signalling (P = 0.004) were both associated with symptom improvement, albeit in a direction opposite to initial predictions: patients with stronger pretreatment reward learning and reward-related prediction error signalling improved most. Baseline D2/3 receptor availability (P = 0.02) and dopamine release (P = 0.05) also predicted improvements in clinical functioning, with lower D2/3 receptor availability and lower dopamine release predicting greater improvements. Although these findings await replication, they suggest that measures of reward-related mesolimbic dopamine function may hold promise for identifying depressed individuals likely to respond favourably to dopaminergic pharmacotherapy.

Keywords: depression; dopamine; pramipexole; reward learning; striatum.

© The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Figures

Figure 1

Group differences in reward learning and measures of ventrostriatal dopamine function. Middle line shows the median and the top and bottom box lines show the first and third quartiles. Individual data points are overlaid onto each box-and-whisker plot. At baseline, relative to the healthy control group, the major depressive disorder group had blunted overall response bias in the Probabilistic Reward Task (A) (Cohen’s d = 0.73), a trend towards blunted ventral striatal gain prediction error signal (d = 0.54) but equivalent loss prediction error (B) (d = 0.61), equivalent dopamine (DA) D2/3 receptor availability (C) (d = 0.03) and a trend towards greater ventral striatal dopamine release (D) (d = 0.58). Note that dopamine release (ΔBPND) is expressed as a percentage change from baseline BPND with the sign reversed for ease of interpretation; higher values indicate more DA release. n.s. = not statistically significant (P < 0.05) or trend (P < 0.1). HC = healthy control; MDD = major depressive disorder; PE = prediction error; VS = ventral striatal.

Figure 2

Baseline reward learning and reward sensitivity predict post-treatment anhedonia. Partial regression plots showing that (A) better baseline reward learning and (B) greater baseline reward sensitivity (as assessed using computational modelling) on the Probabilistic Reward Task (PRT) predicted lower post-treatment anhedonia (as assessed by the SHAPS) after controlling for baseline SHAPS scores. For visualization purposes, the grey dashed line shows the healthy control group mean and indicates that patients with scores equal to or greater than the control group mean (i.e. those with relatively more normative scores) showed the lowest post-treatment anhedonia.

Figure 3

Predictors of change in global illness severity across the 6 weeks of treatment. Figures show the moderating effect of baseline ventral striatal gain prediction error (A), ventral striatal dopamine D2/3 receptor availability (B) and the trend-level moderating effect of ventral striatal dopamine release (C) on the rate of global clinical improvement on the CGI across the 6 weeks of treatment. For visualization purposes, scores for values at the mean, 1 SD above the mean (‘High’), and 1 SD below the mean (‘Low’) are plotted. Scores for values equal to the healthy control group mean are also shown. Higher baseline gain prediction error signals, lower dopamine D2/3 receptor availability and lower dopamine release, predicted greater global clinical improvement. For the models involving the gain prediction error signal (A) and dopamine release (C) as predictors, patients with scores more similar to the healthy control group mean (i.e. those with relatively more normative scores), were those showing the greatest clinical improvement over the course of treatment. For the model involving ventral striatal dopamine D2/3 receptor availability as the predictor (B), the MDD group mean was equal to and overlapped with the healthy control group mean. DA = dopamine; HC = healthy control; PE = prediction error; VS = ventral striatal.