Regulation of neural responses to emotion perception by ketamine in individuals with treatment-resistant major depressive disorder

Abstract

The glutamate N-methyl-D-aspartate receptor antagonist ketamine has demonstrated antidepressant effects in individuals with treatment-resistant major depressive disorder (TRD) within 24 h of a single dose. The current study utilized functional magnetic resonance imaging (fMRI) and two separate emotion perception tasks to examine the neural effects of ketamine in patients with TRD. One task used happy and neutral facial expressions; the other used sad and neutral facial expressions. Twenty patients with TRD free of concomitant antidepressant medication underwent fMRI at baseline and 24 h following administration of a single intravenous dose of ketamine (0.5 mg kg−1). Adequate data were available for 18 patients for each task. Twenty age- and sex-matched healthy volunteers were scanned at one time point for baseline comparison. Whole-brain, voxel-wise analyses were conducted controlling for a family-wise error rate (FWE) of P<0.05. Compared with healthy volunteers, TRD patients showed reduced neural responses to positive faces within the right caudate. Following ketamine, neural responses to positive faces were selectively increased within a similar region of right caudate. Connectivity analyses showed that greater connectivity of the right caudate during positive emotion perception was associated with improvement in depression severity following ketamine. No main effect of group was observed for the sad faces task. Our results indicate that ketamine specifically enhances neural responses to positive emotion within the right caudate in depressed individuals in a pattern that appears to reverse baseline deficits and that connectivity of this region may be important for the antidepressant effects of ketamine.

Cortical abnormalities and association with symptom dimensions across the depressive spectrum

“…In a meta-analysis of fMRI studies examining neural activation correlates of antidepressant treatment response, increased neural activity in the rostral anterior cingulate cortex (rACC) robustly (Cohen’s d: 0.918) predicted an antidepressant response across 23 studies using different treatment interventions (Pizzagalli 2011). In a recently published fMRI study from our group, patients with treatment-resistant depression, in contrast to a healthy comparison group, showed reduced neural responses to positive faces in the right caudate, which appeared to increase in association with an antidepressant response to ketamine within a similar region of the right caudate (Murrough et al 2015). Yet, in the clinical setting, the diagnosis of MDD is based on the coexistence of discrete symptoms taken from the Diagnostic and Statistical Manual of Mental Disorders (ie.…”

Ketamine for treatment-resistant depression: recent developments and clinical applications: Table 1

“…Improvement in anhedonia was correlated with improvement in depression overall,32 so it is unclear whether improvement in anhedonia is pseudo-specific (eg, caused by the antidepressant effect). Given that impairments in the reward system of the brain are associated with depression, suicidality and anhedonia, it is likely that ketamine targets this neural circuit, which includes areas of the dorsal anterior cingulate cortex, orbitofrontal cortex, hippocampus and basal ganglia 15 31 33. It is important for physicians to be aware that clinical presentations including severe depression, anhedonia, SI and/or cognitive deficits have been associated with positive outcomes after IV ketamine.…”

Ketamine Treatment and Global Brain Connectivity in Major Depression

“…Enrollment and treatment procedures have been previously reported (Murrough et al, 2015). Study criteria included negative urine drug screen, no unstable medical illness, and no MR contraindication.…”

“…Within a week of baseline scans, ketamine 0.5 mg/kg infusion over 40 min was administered intravenously to MDD participants as previously described (Murrough et al, 2015). Briefly, patients were admitted to a clinical research unit; an indwelling catheter was placed in the antecubital vein of the non-dominant arm, and pulse, blood pressure, digital pulse oximetry, and ECG monitoring were instituted.…”