This open-label cohort study (n=76) examined the effects of ketamine (35mg/70kg) on gray matter enlargement in relation to glutamate-based and non-glutamate-based abnormalities in patients with depression. They found that patients with non-glutamate-based depression exhibited an enlarged Nucleus Accumbens and that ketamine treatment leads to the rapid reduction in Nucleus Accumbens and an enlargement of the hippocampus only within patients who achieve remission of their depressive symptoms.
Introduction
Animal models of depression repeatedly showed stress-induced nucleus accumbens (NAc) hypertrophy. Recently, ketamine was found to normalize this stress-induced NAc structural growth.
Methods
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).
Results
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.
Discussion
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.
Papers cited by this study that are also in Blossom
Abdallah, C. G., Averill, L. A., Collins, K. A. et al. · Neuropsychopharmacology (2016)
Ari, A., Abdallah, C. G., Sanacora, G. et al. · Annual Review of Medicine (2014)
Papers in Blossom that reference this study
Calder, A. E., Hase, A., Hasler, G. · Molecular Psychiatry (2024)
Agnorelli, C., Spriggs, M. J., Godfrey, K. et al. · Preprints (2024)
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.
Major depressive disorder (MDD) is a common mental illness that is often chronic and disabling, with more than one-third of patients treatment resistant to traditional antidepressants. A major challenge for drug development in MDD is the limited understanding of the pathophysiology of the disorder and the lack of biomarkers of treatment response. The nucleus accumbens (NAc) is a brain region that plays a critical role in reward circuitry and has been extensively studied in preclinical models of chronic stress and depression. In contrast to the hippocampus, where atrophy has been tied to depression, preclinical studies repeatedly demonstrated hypertrophy of the NAc in models of depression. In this study, we investigated whether these preclinical findings of enhanced neuronal remodeling in the NAc would translate into an increase in NAc volume in MDD subjects (cohort A). We then studied, in a separate sample (cohort B), the association between NAc volume and treatment with ketamine, a rapid acting antidepressant with robust effects on neuronal remodeling. The synaptic hypothesis of depression proposes that depression and chronic stress reduce astrocytic glutamate reuptake in the hippocampus and prefrontal cortex leading to increased extracellular glutamate and excitotoxicity, subsequently precipitating neuronal atrophy including reductions of synaptic strength, spine density, and dendritic branching and length. Antidepressants, in particular ketamine, are believed to exert their beneficial effects by reversing the stress-induced prefrontal and hippocampal neuronal atrophy. Consistent with these preclinical models, reduced prefrontal and hippocampal volumes in MDD patients have been demonstrated in meta-analyses, though these findings were not ubiquitous across individual studies. In addition, ketamine treatment of MDD patients was recently found to robustly reverse widespread depression-related prefrontal dysconnectivity, a measure believed to parallel the stress-induced neuronal deficits. These MRI findings could reflect changes in dendritic arborization, water content shift, or other inflammation-related abnormalities. Intriguingly, preclinical models of depression have repeatedly shown almost the exact opposite neuroplasticity effects in the NAc, demonstrating stress-induced increased synaptic strength, spine density, and dendritic branching and length. A recent preclinical study has confirmed that chronic unpredictable stress induces an increase in dendritic length and spine density in the NAc. In addition, the study revealed that ketamine treatment reversed stress-induced neuroplasticity alterations in the NAc. The question is therefore raised whether these preclinical findings in the NAc would translate into tangible evidence in patients suffering from MDD. Thus, we investigated the hypothesis that MDD would be associated with larger NAc volumes and that ketamine would induce a reduction in NAc volume in depressed patients. In cohort A, we previously demonstrated that gammaaminobutyric acid (GABA) levels in medial prefrontal cortex (mPFC) can be used as a robust biomarker to stratify patients into two subgroups, a glutamate-based depression (GBD) and a non-GBD. The GBD patients have abnormally low mPFC Glx and GABA, and large hippocampal volume reduction, compared to healthy control (HC). The non-GBD have normal levels of mPFC GABA and Glx, and no hippocampal volume differences compared to HC (Supplementary Information). Therefore, we also investigated whether the GBD subgroup would show the largest increase in NAc volume. However, we note that the preclinical stress-induced NAc hypertrophy is related to maladaptive dopaminergic transmission in the NAc, which raises the alternative possibility of increased NAc volume in the non-GBD group. The latter hypothesis, if confirmed, would support a working model in which MDD patients are divided into subgroups with amino acid-based (GBD) vs monoamine-based (non-GBD) gray matter abnormalities. In contrast to the glutamate-induced excitotoxicity and hippocampal atrophy, the stress-induced NAc hypertrophy is related to monoamine abnormalities, in particular the dopaminergic neurotransmission in the ventral tegmental area (VTA) to the NAc pathway. Stress and depression are believed to precipitate phasic activation of the VTA-to-NAc pathway, leading to corelease of dopamine and BDNF in the NAc. Subsequently, the stress-induced BDNF release results in NAc hypertrophy and in depressive-like behavior (Wook. Consistent with the amino acid-vs monoamine-based model, the stress-induced monoamine dysregulation is also limited to a subgroup of animals. Among rodents exposed to stress, there is a subgroup of resilient animals that do not develop NAc hypertrophy, BDNF increases, or depressive-like behavior. To test these hypotheses, we conducted a set of analyses in two separate cohorts. In cohort A, we compared NAc volumes in patients with MDD compared to HC. In addition, follow-up analyses compared the NAc volume between the GBD, non-GBD, and HC groups. Exploratory analyses in the MDD group examined the relationship between NAc volumes and clinical severity. In cohort B, we investigated the effects of ketamine on NAc volume in MDD patients, followed by post-hoc analyses exploring whether the effects of ketamine were related to achieving remission.
The details of study cohorts and assessment procedures, and the GABA results were previously reported. The NAc region of interest was not previously studied. All participants completed an informed consent process and an Institutional Review Board approved all study procedures. Cohort A included 26 HC and 34 MDD (Supplementary Table) subjects with successful structural magnetic resonance imaging (MRI). Proton magnetic resonance spectroscopy ( 1 H MRS) data were available on 20 HC and 26 MDD subjects. Study criteria for the Cohort A MDD group included a diagnosis of current MDD, no psychotropic treatment for at least 2 weeks, no substance or alcohol use disorders for at least 6 months, no current eating disorders, no unstable medical condition, and no history of mental retardation, or developmental, bipolar, or psychotic disorders. HC had no DSM-IV Axis I disorders. In cohort A, trait worry was assessed using Penn State Worry Questionnaire (PSWQ), and current depression and anxiety severity were assessed using Hamilton Depression Rating Scale (HDRS) and Hamilton Rating Scale for Anxiety (HAM-A), respectively. Cohort B included 16 MDD subjects (Supplementary Table). Depression severity was assessed using Montgomery-Åsberg Depression Rating Scale (MADRS) as primary outcome, with remission defined as post-treatment MADRSo10. Participants completed MADRS and MRI scans at baseline (within 24 h prior to infusion) and 24 h following treatment with a single infusion of ketamine 0.5 mg/kg administered intravenously over 40 min. Study criteria included current MDD diagnosis, treatment refractory to at least three antidepressants, no psychotropic treatment for at least 1 week (4 weeks for fluoxetine), no substance use disorder for at least 24 months, no unstable medical condition, and no history of bipolar or psychotic disorders. MRI contraindications were exclusionary for cohort A and B.
In cohort A, MRI and MRS acquisition were completed in one session on a 3.0T GE EXCITE magnet, with the following parameter: MRI T1 sequence with TR = 8.7 ms, TE = 1.8 ms, flip angle = 7°, and voxel size = 0.9 × 0.9 ×1.5 mm; 1 H MRS 13 min GABA editing sequence from a single mPFC voxel (2.5 × 2.5 × 3 mm; see Supplementary Fig.) with TR = 1500 ms, TE = 68 ms, a 1024 sample points, 5-KHz spectral width, and 256 interleaved excitations, which provided level of two metabolites: GABA and Glx (gluta-mate+glutamine). For additional details regarding MRS acquisition and processing see;. In cohort B, MRI scans were completed on a 3.0 T Siemens Trio system (TR = 1200 ms, TE = 2.66 ms, flip angle = 12°, voxel size = 1 × 1 × 1 mm) within 24 h prior to treatment then repeated 24 h following ketamine infusion. NAc volumes were estimated using the publically available Freesurfer image analysis suite (). The fully automated recon-all pipeline, followed by routine quality checks, was completed. Briefly, this includes resampling to 1 × 1 × 1 mm images, intensity normalization, skull stripping, and segmentation of the gray/white matter and subcortical structures (including NAc). For cohort B, the longitudinal recon-all pipeline was used to enhance sensitivity in detecting changes overtime. This pipeline includes creation of an unbiased within subject template and resampling each time point scans to this base template to reduce variability. For technical details regarding Freesurfer methods seeand. While blinded to the clinical status of participants, routine quality assurance checks and visual inspection were performed. In cohort B, three pre-treatment and two post-treatment scans were unsuccessful due to high motion artifacts. Freesurfer segmentation of the NAc has been previously shown to be successful in identifying neural correlates of the reward system. Test-retest reliability using Freesurfer segmentation was previously reported at ICC = 0.98 for NAc and ICC = 0.99 for the hippocampus.
The distribution of outcome measures was examined using test statistics and probability plots. Non-parametric tests and transformations were used as necessary. SEM is provided as an estimate of variance. Significance was set at p ⩽ 0.05. In cohort A, we performed ANOVA, t-test and χ 2 to assess age and gender differences between groups. As previously described, the median split cutoff point of the mPFC GABA level was used to divide MDD subjects into two groups: GBD (n = 13; ie, MDD with low GABA) and non-GBD (n = 13; ie, MDD with high GABA). Proportions of gray matter (GM), white matter (WM), and cerebrospinal fluid (CSF) for the mPFC voxel were computed (Supplementary Information). Percent GM, WM, and CSF did not differ between groups (all p-values40.05). In addition, each of these variables were examined as covariates, but did no significantly alter the study findings. General linear model (GLM) analyses were conducted to examine the diagnosis and subgroup effects on the NAc volume, controlling for intracranial volume (ICV) and age, followed by pairwise comparison with Bonferroni correction. These cross-sectional group comparisons were repeated without controlling for ICV or with using amygdala as covariate, which did not affect the study results (see Supplementary Information). Exploratory Spearman correlations in the MDD group, with FDR correction for multiple comparisons, examined the relationship between NAc and clinical severity, as well as the association between NAc and mPFC Glx levels. To examine the effects of ketamine treatment on MADRS scores, and left and right NAc volumes, we constructed linear mixed models (LMM) with time (pre-treatment vs posttreatment) as fixed factor, controlling for age as random factor. Follow-up exploratory analysis added remission status as a fixed factor to examine the effects of time, remission, and time*remission interactions, followed by pairwise comparison with Bonferroni correction. Comparable mixed models were constructed to examine the effect of hippocampal stratification. Results of the GLM and LMM analyses are provided as estimated marginal mean ± SEM.
In cohort A, there were no significant age and gender differences between MDD (41.7 ± 2 years; 11 females) and HC groups (37.4 ± 3 years; 14 females; all p-values40.05). Similarly, age, gender, and tissue composition of the MRS voxel did not differ between subgroups (ie HC vs GBD vs non-GBD; all p values40.1). MDD patients had moderate clinical severity with HDRS = 20 ± 1.1, HAM-A = 22 ± 1.5, and PSWQ = 57 ± 2.5. In cohort B, average age was 45.9 ± 2.7 (7 females). Ketamine had a significant effect on depression severity (pre-treatment MADRS = 34 ± 1.2; post-treatment MADRS = 14 ± 2.2; F (1,14) = 62.6, po0.001) and 6 of 16 (38%) subjects met MADRS remission criteria, while 10 of 16 (62%) showed more than 50% improvement.
Controlling for age and intracranial volume, we found larger left NAc in the MDD (599 ± 18 mm 3 ) compared to HC (489 ± 21 mm 3 ; F (1,56) = 15.7, p = 0.0002; Cohen's d = 1.05; Figure). The right NAc was not statistically different between MDD (479 ± 15 mm 3 ) and HC (440 ± 17 mm 3 ; F (1,56) = 2.7, p = 0.10; Cohen's d = 0.44; Figure). The interaction between diagnosis and hemisphere was statistically significant (F (1,56) = 6.2, p = 0.02). Exploratory correlational analyses revealed a positive correlation between right NAc and PSWQ, which remained significant following correction for multiple comparisons (r = 0.48, df = 33, corrected p = 0.02; Supplementary Figure), but no correlations between left NAc and PSWQ or left or right NAc and HDRS or HAM-A (all p-values40.05). In the follow-up subgroup analysis, we found a significant effect of group on the left (F (2,47) = 16.1, p = 0.000005) and right NAc (F (2,47) = 5.7, p = 0.006), with post hoc pairwise comparisons showing larger left and right NAc in the non-GBD compared to GBD (left: Cohen's d = 1.48; right: Cohen's d = 0.95) and HC (left: Cohen's d = 1.90; right: Cohen's d = 1.12), but no significant differences between GBD and HC (Figure). The interaction between subgroup status and hemisphere was statistically significant (F (2,57) = 6.2, p = 0.05). Examining the relationship between NAc and Glx showed positive correlation between mPFC Glx and right NAc (r = 0.44, df = 25, corrected p = 0.05; Supplementary Fig.), but not left NAc (r = 0.15, corrected p = 0.47). To examine whether mPFC Glx mediated the link between NAc hypertrophy and severity of worry symptoms, we conducted a mediation analysis with bootstrapping (n = 10 000). We found that mPFC Glx did not mediate the relationship NAc volume and PSWQ (p = 0.52).
The LMM revealed a small, but statistically significant, effect of time on the left (F (1,11) = 5.4, p = 0.04), but not on the right NAc (p = 0.52), showing reduction in left NAc volume following treatment (Figure; Supplementary Table). We found no significant hemisphere by time interaction (p = 0.2). Follow-up exploratory analysis, examining whether the left NAc changes were affected by treatment response, found 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), but no remission effects (F (1,15) = 2.2, p = 0.16), with significant reduction in left NAc in remitters (p = 0.01), but not non-remitters (p = 0.53; Figure). Considering preclinical evidence relating the rapid antidepressant effects of ketamine to its reversal of depressionrelated gray matter deficits in the hippocampus, we conducted an exploratory analysis examining the effects of ketamine on left and right hippocampal volumes. The LMM in the left hippocampus revealed a significant time*remission interaction (F (1,12) = 5.3, p = 0.04), with a trend of increased volume in the remitters (Figure). We found no significant time (F (1,12) = 0.7, p = 0.44) or remission effects (F (1,16) = 0.1, p = 0.80). There were no significant effects of time (F (1,11) = 0.05, p = 0.83), remission (F (1,16) = 0.01, p = 0.94), or time*remission interaction (F (1,11) = 0.8, p = 0.40) in the right hippocampus. There was no significant hemisphere by time interaction (p = 0.8). See online Supplementary Information for exploratory analyses related to anhedonia.
The lack of GABA measure in Cohort B hindered our ability to test whether the ketamine effects on the NAc were more profound in a subgroup of non-GBD patients. Therefore, we conducted an exploratory analysis in which MDD patients were stratified based on the median split of baseline total hippocampal volume (ie, 17 vs 17 in Cohort A and 8 vs 8 in Cohort B). For completeness, we have also included the stratification based on the left hippocampal volume, considering that depression and ketamine effects were most evident in the left hemisphere. In Cohort A, we found a significant subgroup effect on left, but not right, NAc volumes using either total or left hippocampus for stratification (for details see Supplementary Fig.). In Cohort B, ketamine reduced left and right NAc volumes in the subgroup with high left hippocampal volumes, but no significant changes were found in the subgroup with low total or left hippocampal volumes (for details see Figure).
Consistent with preclinical findings of depression-related hypertrophy in the NAc, we found increased NAc volumes in the MDD group compared to HC. These NAc volume abnormalities were significant only in the left hemisphere, with a trend for larger right NAc in MDD. The data revealed that the NAc alterations in MDD are primarily limited to the subgroup of MDD patients with no glutamate-based abnormalities. Similarly, mPFC Glx positively correlated with right NAc volume. Together, these data suggest that the preclinical evidence of stress-induced synchronous NAc hypertrophy and hippocampal hypotrophy is not paralleled by synchronous gray matter abnormalities in both structures in depressed humans. In MDD, the study evidence supports the division of patients into subgroups with amino acid-based (ie, GBD) vs monoamine-based (ie, non-GBD) gray matter abnormalities (for additional discussion see Supplementary Information). Within MDD patients, there were no significant correlations between NAc volumes and current severity of depression or anxiety. However, individuals with high trait worry scores exhibited relatively larger right NAc volumes. One possible interpretation of the latter finding is that trait worry may be related to failure in error detection and correction, a function that was recently attributed to NAc in humans. An alternative interpretation could be the hypothesized causal role between worry and anhedonia (Burrows-Kerr, 2015). Comparable to preclinical we found rapid reduction in left NAc, but increase hippocampal, volumes following ketamine treatment, particularly in patients who achieve remission. In line with the GBD model, subgrouping patients based on hippocampal volumes was statistically significant showing a pattern in which the higher NAc volumes were in the subgroup with large hippocampus. However, the GABA stratification effects appeared to be more profound. Interestingly, the preliminary analysis examining the effects of hippocampal stratification suggested that the ketamine-induced reduction in the NAc is mostly restricted to the subgroup with high hippocampal volume. However, the ketamine-related plasticity findings and hippocampal stratification should be interpreted with extreme caution considering the exploratory nature, the relatively small sample and the need for replication. While underscoring the preliminary nature of the ketamine findings, the results add to extensive preclinical evidence, and nascent human studies, directly relating the rapid acting antidepressant effect of ketamine to region specific synaptogenic alterations. Although the longitudinal findings are anticipated by extent preclinical evidence, it is still remarkable-and perhaps dubious-that the MRI estimates of NAc and hippocampal volumes were sufficiently sensitive to detect these rapid changes following treatment. Though we reiterate that the reader should be cautious not to over interpret these results, we here describe related evidence that support these intriguing findings. First, there is the intuitive concept that structural brain changes would require prolonged time to occur, for example aging-and stress-induced neuronal atrophy would require weeks to years. However, accumulating evidence suggest that neuronal plasticity is an often prompt continuous process that could be functionally and micro-structurally evident within minutes to hours, for example neuronal atrophy induced by a 21-day of chronic unpredictable stress was fully reversed within 24 h of ketamine infusion in rodents. Second, there is the question whether these 21-day stressrelated microstructural changes would be evident with gross MRI estimates of volume. Yet, this was already demonstrated in rodents where the MRI estimates of gray matter volumes were able to capture the percent changes in microstructural neuronal atrophy following a 21-stress paradigm. Third, these preclinical findings may not necessarily translate into humans, raising the question whether MRI estimates could be sensitive to detect within hours structural changes. In addition to the current data demonstrating rapid volumetric changes that were specifically related to treatment efficacy, a recent study provides another example of rapid gray matter volumetric changes demonstrated by MRI. The dopamine antagonist haloperidol was found to reduce striatal volume, as estimated by MRI, within 2 h of intravenous administration. These volumetric changes were associated with the drug-induced neuroleptic extrapyramidal effects and were believed to reflect preclinical evidence of microstructural changes. Considering that the stress-induced NAc hypertrophy is related to perturbation in dopaminergic neurons, a putative mechanism for the ketamine-induced NAc reduction could be a direct modulation of dopaminergic neurons by ketamine. Ketamine infusion in rodents increase spontaneous activation of dopaminergic neurons in the VTA and increase extracellular dopamine in the NAc. In addition, dopamine receptors antagonists block the antidepressant-like effects of ketamine in rodents. At the network level, ketamine has been shown in rodents to restore the stressinduced dopaminergic perturbation and synaptic dysfunction. These changes partly involve the hippocampal input to the NAc and blocked by D1 receptor antagonists and Grace, 2014). Limitations of the current study include the secondary nature of the approach. The parent studies, from which the biological and behavioral measures were extracted, were not designed to interrogate the NAc abnormalities in MDD. For example, it would have been more optimal if both the cross sectional (MDD vs HC) and longitudinal study aims (effects of ketamine) were investigated in the same cohort (ie, treatment of the MDD and repeated scans in both MDD and HC). Future studies would also greatly benefit from using a Research Domain Criteria (RDoC) approach to investigate the reward system, while capitalizing on the unique ketamine paradigm of rapid behavioral response, large effect size, and extensive literature of the drug mechanisms which would facilitate the integration of new findings in previously developed working models. Furthermore, while the multimodal MRI/MRS approach is a strength of the cohort A study, the MRS scans were not conducted in cohort B. Moreover, the addition of functional and diffusion MRI in future studies might further unravel the role of NAc in the neurobiology and treatment of MDD. The use of median split is consistent with our previous reports, however, this limit the generalizability of the findings. While cortical GABA in MDD has been relatively consistent finding, a major challenge in the field is to identify a cutoff value that could be used to stratify patients. Another limitation is that the correlation between NAc volume and Glx may not necessarily reflect glutamate neurotransmission as Glx is a total level of glutamate and glutamine, both of which are primarily intracellular rather than intrasynaptic. The sample size of cohort B could be considered a limitation. Among the current study strengths are the use of: well-characterized psychotropic-free cohorts; crosssectional and longitudinal approaches; well validated structural and neuroimaging methods; and the capitalization on the ketamine paradigm, which exerts rapid behavioral and biological effects within 24 h of treatment.
This study provides the first in vivo in-human evidence of enlarged NAc volume in MDD. We also demonstrated that the NAc volumetric abnormalities are absent in patients with prominent glutamate based abnormalities. Together the results supported the notion that patients with and without NAc abnormalities may have differing underlying pathology that could be targeted with differential antidepressant treatment, offering hope for individualized medicine, as well as potentially shedding light on putative causes of the pervasive failure of numerous antidepressant trials. Finally, the longitudinal data revealed a pattern of rapid normalization of NAc and hippocampal volumes limited to patients who achieved remission, an intriguing finding that awaits replication prior to any firm conclusions.
CGA has served as a consultant or on advisory boards for Genentech and Janssen. He also serves as editor for the
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