The Nucleus Accumbens and Ketamine Treatment in Major Depressive Disorder

Major depressive disorder (MDD) is prevalent, often chronic, and frequently resistant to standard antidepressants. Preclinical work has repeatedly shown that chronic stress produces contrasting patterns of structural plasticity across brain regions: hippocampal atrophy on the one hand and hypertrophy of the nucleus accumbens (NAc) on the other. Ketamine, a rapid-acting antidepressant, has been shown in animal models to reverse stress-induced NAc hypertrophy. Translating these findings to humans has been limited by a paucity of in vivo data on NAc volumes in MDD. Abdallah and colleagues set out to test two linked hypotheses. First, they asked whether people with MDD have larger NAc volumes than healthy controls. Second, in a separate sample, they examined whether a single intravenous ketamine infusion (0.5 mg/kg) would alter NAc volume 24 hours after treatment, and whether such changes related to clinical remission. A further aim was to explore whether an MDD subgrouping based on medial prefrontal cortical (mPFC) GABA/Glx measures—defined as glutamate-based depression (GBD) versus non-GBD—would differentially show NAc abnormalities, consistent with a proposed dichotomy of amino acid– versus monoamine-based structural pathology.

The study used two independent cohorts. Cohort A was a cross-sectional sample that included 34 MDD patients and 26 healthy controls (HC) with successful high-resolution structural MRI; proton magnetic resonance spectroscopy (1H MRS) of the mPFC was available for 26 MDD and 20 HC. MDD inclusion criteria required current MDD diagnosis, psychotropic-free status for at least 2 weeks, no recent substance/alcohol use disorders, and exclusion of bipolar, psychotic or developmental disorders. Clinical severity scales included the Hamilton Depression Rating Scale (HDRS), Hamilton Anxiety Rating Scale (HAM-A) and Penn State Worry Questionnaire (PSWQ). Using a median split of mPFC GABA, MDD participants were stratified into GBD (low GABA; n = 13) and non-GBD (high GABA; n = 13) subgroups. Cohort B was a longitudinal, open-label sample of 16 treatment-refractory MDD patients who received a single intravenous infusion of ketamine 0.5 mg/kg over 40 minutes. Depression severity was measured with the Montgomery–Åsberg Depression Rating Scale (MADRS), with remission defined as post-treatment MADRS ≤ 10. Structural MRI was acquired within 24 hours before infusion and repeated at 24 hours post-infusion. Some scans in cohort B were unsuccessful due to motion (three pre-treatment and two post-treatment), as noted by the investigators. All structural images were processed using the automated FreeSurfer recon-all pipeline, with longitudinal-specific processing used for cohort B to increase sensitivity to within-subject change. NAc volumes were obtained from subcortical segmentation and quality-checked blind to clinical status. Test–retest reliability for FreeSurfer NAc segmentation reported earlier was high (ICC ≈ 0.98). Statistical analyses combined general linear models (GLM) for cross-sectional comparisons and linear mixed models (LMM) for longitudinal analyses. Cross-sectional GLMs controlled for intracranial volume (ICV) and age, with Bonferroni-corrected pairwise tests for subgroup comparisons. Exploratory Spearman correlations with false discovery rate (FDR) correction examined associations between NAc volumes, clinical measures and mPFC Glx. For cohort B, LMMs tested time effects (pre vs post) on MADRS and NAc/hippocampal volumes, with age as a random factor and post-hoc models including remission as an additional factor. Significance was set at p ≤ 0.05.

Cohort demographics showed no significant age or gender differences between MDD and HC groups in cohort A. In cohort A, MDD patients had moderate symptom severity (HDRS 20 ± 1.1; HAM-A 22 ± 1.5; PSWQ 57 ± 2.5). Cohort B had a mean age of 45.9 ± 2.7 years (7 females). Ketamine produced a large clinical effect in cohort B: MADRS decreased from 34 ± 1.2 pre-treatment to 14 ± 2.2 post-treatment (F(1,14) = 62.6, p < 0.001). Six of 16 patients (38%) met remission criteria, and 10 of 16 (62%) showed >50% improvement. Cross-sectional primary findings (cohort A) showed that left NAc volume was larger in MDD than HC when controlling for age and ICV: MDD 599 ± 18 mm3 versus HC 489 ± 21 mm3 (F(1,56) = 15.7, p = 0.0002; Cohen's d = 1.05). The right NAc did not differ significantly (MDD 479 ± 15 mm3 vs HC 440 ± 17 mm3; F(1,56) = 2.7, p = 0.10; Cohen's d = 0.44). A diagnosis-by-hemisphere interaction was significant (F(1,56) = 6.2, p = 0.02). Exploratory correlations in the MDD group revealed that right NAc volume positively correlated with trait worry (PSWQ; r = 0.48, corrected p = 0.02), whereas NAc volumes did not correlate significantly with HDRS or HAM-A. Subgroup analyses based on mPFC GABA (GBD vs non-GBD) indicated that NAc enlargement was concentrated in the non-GBD subgroup. There was a significant group effect for left (F(2,47) = 16.1, p = 0.000005) and right NAc (F(2,47) = 5.7, p = 0.006). Non-GBD patients had larger bilateral NAc than both GBD and HC: left NAc effect sizes were d = 1.48 (vs GBD) and d = 1.90 (vs HC); right NAc d = 0.95 (vs GBD) and d = 1.12 (vs HC). No significant differences were observed between GBD and HC. mPFC Glx correlated with right NAc (r = 0.44, corrected p = 0.05) but not with left NAc; mediation analysis indicated mPFC Glx did not mediate the NAc–worry relationship (p = 0.52). In cohort B, LMMs detected a modest but significant reduction in left NAc volume 24 hours after ketamine (F(1,11) = 5.4, p = 0.04), with no significant change in the right NAc (p = 0.52). Follow-up analyses suggested the left NAc reduction was driven by remitters: a significant time effect (F(1,11) = 7.2, p = 0.02) and a trend for time*remission interaction (F(1,11) = 5.4, p = 0.098) were reported; remitters showed a significant left NAc decrease (p = 0.01) whereas non-remitters did not (p = 0.53). Exploratory hippocampal analyses found a time*remission interaction for the left hippocampus (F(1,12) = 5.3, p = 0.04), with a trend toward increased left hippocampal volume in remitters; no significant effects emerged for the right hippocampus. Median-split stratification by baseline hippocampal volume suggested that ketamine-induced NAc reductions occurred predominantly in the subgroup with higher baseline left hippocampal volume in cohort B, while no change was seen in the low-hippocampus subgroup. The investigators noted the exploratory nature and small sample size for these longitudinal findings.

Abdallah and colleagues interpret their cross-sectional findings as the first in vivo human evidence of NAc enlargement in MDD, particularly in the left hemisphere. They report that this enlargement appears concentrated in a non-GBD subgroup—patients without the glutamate/GABA cortical abnormalities—which they frame as consistent with a putative dichotomy between amino acid–based (GBD) and monoamine-based (non-GBD) structural pathology in MDD. The positive correlations between right NAc volume and both trait worry and mPFC Glx are presented as additional, though limited, evidence linking NAc structure to specific symptom domains and cortical glutamatergic status. The investigators further link the ketamine-related reductions in left NAc and increases in left hippocampal volume—observed mainly in clinical remitters—to preclinical demonstrations that ketamine rapidly reverses stress-induced synaptic changes. They propose dopaminergic mechanisms as a plausible pathway, noting that stress-induced NAc hypertrophy in animals relates to VTA-to-NAc dopaminergic signalling and BDNF release, that ketamine modulates VTA dopaminergic activity and NAc dopamine levels in rodents, and that dopamine receptor antagonism can block ketamine’s antidepressant-like effects in preclinical models. The authors explicitly caution about the preliminary nature of the longitudinal results. Key limitations they acknowledge include the secondary/ancillary nature of the analyses (parent studies were not designed specifically to assess the NAc), the absence of MRS data in the longitudinal cohort, the use of median splits for subgrouping which may limit generalisability, the small sample size in cohort B and the number of unsuccessful scans, and the fact that Glx reflects total glutamate plus glutamine rather than synaptic neurotransmission specifically. They also note uncertainty about whether MRI volumetric estimates can capture rapid microstructural changes, while citing converging preclinical and some human pharmacological evidence that gross MRI can detect fast volumetric shifts. The investigators recommend future studies designed specifically to probe NAc structure and function in MDD, ideally integrating RDoC-informed measures, multimodal imaging (including functional and diffusion MRI), and replication of the ketamine-related plasticity findings before firm conclusions are drawn.

The study provides in vivo evidence that NAc volume is enlarged in MDD, but that this abnormality is largely absent in patients with prominent glutamate-based cortical abnormalities (GBD). Abdallah and colleagues suggest these results support stratifying patients by underlying pathophysiology—amino acid– versus monoamine-based—to inform targeted treatments. The pilot longitudinal data indicate a pattern of rapid normalisation of left NAc and left hippocampal volumes following ketamine in patients who achieve remission; however, the authors emphasise that these findings are preliminary and require replication before clinical or mechanistic conclusions can be drawn.