Primary Outcome

The primary outcome for evaluating “Proof of Mechanism” that engaging the target (kappa opioid antagonism) had the hypothesized effect on reward-related brain function, was the baseline corrected fMRI activation at the end of 8 weeks of double-blind treatment in an a priori bilateral non-thresholded ventral striatal area mask, defined by the Harvard-Oxford Subcortical Atlas, during anticipation of monetary gain in the Monetary Incentive Delay (MID) Task contrasted with neutral (non-gain/non-loss) trials.

Owing to the experimental medicine approach taken, the driving factor leading to the choice of the primary outcome measure was the neurobiological target. Accordingly, based on the compelling preclinical literature available to us when we designed the study indicating that KOR antagonism releases inhibition on DA neurons and increases nucleus accumbens function,^14–21 we chose reward-related activation in the nucleus accumbens as our primary target. Having committed to this mechanism and target, we sought an fMRI paradigm that would reliably engage the nucleus accumbens in response to rewards. Based on the early work of Knutson^41,43–45 and others,^46,47 the use of the monetary incentive delay (MID) task in anticipation of gains was selected. We note that, although lack of replications exist,^42,48 prior studies in both MDD and psychiatrically healthy samples available to us when the study was designed have linked reward-related ventral striatal activation and anhedonic symptoms,⁷⁴ and this relationship has been replicated in more recent studies.^49–50 Further, recent meta-analyses of fMRI data collected among healthy controls have confirmed that the ventral striatum (nucleus accumbens) is reliably recruited during reward anticipation.^51,78

This choice was further supported by the fact that there was data from a prior treatment study (open-label escitalopram administered to 15 MDD patients and 15 controls) where outcome was assessed with fMRI determined ventral striatum activation during anticipation of gains and losses in the MID.⁵⁴ That study provided a set of findings that differed for ventral striatal activation in anticipation of gains and losses but overall suggested the promise of both measures. Findings suggesting the relative utility of ventral striatal activation in anticipation of loss are that the baseline Beck Depression Inventory (BDI) anhedonia item score was significantly related to ventral striatal loss anticipation and not gain and that escitalopram led to a significant change in ventral striatal loss anticipation-related activity not gain. However, a number of findings supported our choice to employ ventral striatal activation in anticipation of gains in our study. These include: (1) depressed subjects had a significantly smaller ventral striatal activation in anticipation of gain than the control group before treatment with escitalopram (p=0.025) but not after treatment; (2) there was a trend for a group*time interaction with treatment with ventral striatal activation in anticipation of gain (p<0.07) in this study with only 15 subjects per group; and (3) there was a trend for the decrease in BDI score over treatment to be correlated with the increase in ventral striatal activation in anticipation of gain (r=0.54, p=0.058).