Neural correlates of change in major depressive disorder anhedonia following open-label ketamine

Abstract

Anhedonia is a cardinal symptom of major depression and is often refractory to standard treatment, yet no approved medication for this specific symptom exists. In this exploratory re-analysis, we assessed whether administration of rapid-acting antidepressant ketamine was associated specifically with reduced anhedonia in medication-free treatment-refractory patients with major depressive disorder in an open-label investigation. Additionally, participants received either oral riluzole or placebo daily beginning 4 hours post-infusion. A subgroup of patients underwent fluorodeoxyglucose positron emission tomography scans at baseline (1-3 days pre-infusion) and 2 hours post-ketamine infusion. Anhedonia rapidly decreased following a single ketamine infusion; this was sustained for up to three days, but was not altered by riluzole. Reduced anhedonia correlated with increased glucose metabolism in the hippocampus and dorsal anterior cingulate cortex (dACC) and decreased metabolism in the inferior frontal gyrus and orbitofrontal cortex (OFC). The tentative relationship between change in anhedonia and glucose metabolism remained significant in dACC and OFC, and at trend level in the hippocampus, a result not anticipated, when controlling for change in total depression score. Results, however, remain tenuous due to the lack of a placebo control for ketamine. In addition to alleviating overall depressive symptoms, ketamine could possess anti-anhedonic potential in major depressive disorder, which speculatively, may be mediated by alterations in metabolic activity in the hippocampus, dACC and OFC.

Keywords: 18FDG-PET; Anti-anhedonic; NMDA; depression; dorsal anterior cingulate cortex; glutamate; hippocampus; orbitofrontal cortex; reward; riluzole; subiculum.

Figure 1

Change in anhedonia levels (SHAPS) across time (minutes = −60 to 230, days = 1 to 28) following open-label ketamine. The values presented here are derived from the estimated marginal means from the linear mixed model using all subjects (placebo and riluzole combined). The baseline value, to which the other values are compared, is represented by a square (time point −60). White and grey circles indicate time points at which statistically significant reductions were detected relative to baseline at p < .001 and p < .005, respectively (corrected for multiple comparisons). Error bars represent 1 SEM.

Figure 2

Increased dorsal anterior cingulate cortex (dACC) metabolism correlated with anti-anhedonic response following ketamine administration. (a) Presented in a sagittal plane, the analysis, which survived small volume correction, entailed a 10 mm radius sphere centered on a peak derived from our previous investigation demonstrating the anti-anhedonic effect of ketamine in bipolar depression (Lally et al., 2014). Colour bar indicates t-values and the image is displayed at an uncorrected threshold of p < .001. (b) Scatter plot depicting increased dACC glucose metabolism at the peak voxel associated with decreased anhedonia levels.

Figure 3

Results of percentage change in SHAPS regressed against FDG-PET difference images. Associations (whole-brain corrected, cluster-level) were identified in (a) the hippocampus (yellow) and (b) both the inferior frontal and orbitofrontal cortex (blue). (c) Increased glucose metabolism in the hippocampus and (d) decreased metabolism in the orbitofrontal cortex (OFC) and inferior frontal gyrus were associated with the greatest anti-anhedonic response. Images are displayed at an uncorrected threshold of p < .001, and at an extent threshold such that only clusters surviving whole-brain correction are presented. Colour bars indicate t-values.