The Nucleus Accumbens and Ketamine Treatment in Major Depressive Disorder

Abstract

Animal models of depression repeatedly showed stress-induced nucleus accumbens (NAc) hypertrophy. Recently, ketamine was found to normalize this stress-induced NAc structural growth. Here, we investigated NAc structural abnormalities in major depressive disorder (MDD) in two cohorts. Cohort A included a cross-sectional sample of 34 MDD and 26 healthy control (HC) subjects, with high-resolution magnetic resonance imaging (MRI) to estimate NAc volumes. Proton MR spectroscopy (¹H MRS) was used to divide MDD subjects into two subgroups: glutamate-based depression (GBD) and non-GBD. A separate longitudinal sample (cohort B) included 16 MDD patients who underwent MRI at baseline then 24 h following intravenous infusion of ketamine (0.5 mg/kg). In cohort A, we found larger left NAc volume in MDD compared to controls (Cohen's d=1.05), but no significant enlargement in the right NAc (d=0.44). Follow-up analyses revealed significant subgrouping effects on the left (d⩾1.48) and right NAc (d⩾0.95) with larger bilateral NAc in non-GBD compared to GBD and HC. NAc volumes were not different between GBD and HC. In cohort B, ketamine treatment reduced left NAc, but increased left hippocampal, volumes in patients achieving remission. The cross-sectional data provided the first evidence of enlarged NAc in patients with MDD. These NAc abnormalities were limited to patients with non-GBD. The pilot longitudinal data revealed a pattern of normalization of left NAc and hippocampal volumes particularly in patients who achieved remission following ketamine treatment, an intriguing preliminary finding that awaits replication.

Figure 1

NAc volume in MDD vs HC. Larger left NAc in MDD subjects compared to HC (mean difference±SEM=111±28 mm³). Right NAc was numerically larger in MDD (mean difference±SEM=39±23 mm³). HC, healthy control; MDD, major depressive disorder; NAc, nucleus accumbens.

Figure 2

NAc volume in GBD vs non-GBD vs HC. Significant group effect with post hoc analyses showing larger left and right NAc in non-GBD compared to GBD and HC. *p⩽0.05 compared to HC. ^#p⩽0.05 compared to GBD. GBD=glutamate-based depression; HC, healthy control; NAc, nucleus accumbens.

Figure 3

Ketamine effects on the nucleus accumbens (NAc). In the treatment cohort, a linear mixed model revealed a modest but statistically significant reduction in left NAc volume post ketamine treatment (mean difference±SEM=33±14 mm³). Ketamine had no significant effect on the right NAc volume (a). Further exploring the left NAc changes by adding the remission status to the model revealed a treatment-by-remission interaction trend, such that ketamine reduced left NAc in remitters (mean difference±SEM=54±18 mm³), but not in non-remitters (b).

Figure 4

Ketamine effects on the hippocampus (HPC). In the treatment cohort, a linear mixed model revealed a treatment-by-remission interaction, such that ketamine increased left HPC in remitters.

Figure 5

Ketamine effects on the nucleus accumbens (NAc) volume in major depressive disorder (MDD) subgroups based on hippocampal (HPC) volume. In panel (a and b), patients were stratified based on total HPC volume using median split. This analysis showed significant reduction of right NAc (R-NAc), but not left (L-NAc), in the high HPC subgroup. The were no significant L-NAc or R-NAc changes in the low HPC subgroup. In (c and d), patients were stratified based on left HPC (L-HPC) volume using median split. This analysis showed significant reduction in L-NAc and right NAc (R-NAc) volumes in the high L-HPC subgroup. The were no significant L-NAc or R-NAc changes in the low L-HPC subgroup.