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.

Abstract

“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.”

Authors: Chadi G. Abdallah, Andrea Jackowski, Ramiro Salas, Swapnil Gupta, João R. Sato, Xiangling Mao, Jeremy D. Coplan, Dikoma C. Shungu & Sanjay J. Mathew

Summary

INTRODUCTION

Major depressive disorder (MDD) is a common mental illness that is often chronic and disabling. Preclinical studies repeatedly demonstrated enhanced neuronal remodeling in the nucleus accumbens in models of depression, which was then studied in a separate sample of patients treated with ketamine.

Depression and chronic stress reduce astrocytic glutamate reuptake in the hippocampus and prefrontal cortex, leading to increased extracellular glutamate and excitotoxicity and neuronal atrophy. Ketamine treatment of MDD patients reverses widespread depression-related prefrontal dysconnectivity.

Preclinical models of depression show increased synaptic strength, spine density, and dendritic branching and length in the NAc, while ketamine treatment reverses these alterations. This raises the question whether these findings would translate into tangible evidence in patients suffering from MDD.

We previously demonstrated that gamma-aminobutyric acid levels in medial prefrontal cortex can be used as a robust biomarker to stratify patients into two subgroups, a glutamate-based depression (GBD) and a non-GBD. The non-GBD group showed no hippocampal volume differences compared to healthy control. Stress induces NAc hypertrophy in a subgroup of animals, whereas glutamate induces excitotoxicity and hippocampal atrophy. The stress-induced NAc hypertrophy is related to monoamine abnormalities, in particular the dopaminergic neurotransmission in the ventral tegmental area to the NAc pathway.

We conducted a set of analyses in two separate cohorts to test the hypotheses that NAc volumes were different in patients with MDD compared to HC, and that ketamine affected NAc volumes in MDD patients.

Participants

The study cohorts, assessment procedures, and GABA results were previously reported. The NAc region of interest was not previously studied. 26 HC and 34 MDD subjects received successful structural magnetic resonance imaging (MRI) and proton magnetic resonance spectroscopy (1H MRS) treatment. The primary outcome was depression severity as measured by the Montgomery-sberg Depression Rating Scale (MADRS) and remission was defined as post-treatment MADRSo10 (Hawley et al., 2002).

Neuroimaging

In cohort A, MRI and MRS were completed in one session on a 3.0T GE EXCITE magnet, and in cohort B, MRI and MRS were completed within 24 h prior to treatment and repeated 24 h following ketamine infusion.

NAc volumes were estimated using the publically available Freesurfer image analysis suite. The longitudinal recon-all pipeline was used to enhance sensitivity in detecting changes overtime, and three pre-treatment and two post-treatment scans were unsuccessful due to high motion artifacts.

Statistical Analyses

We performed ANOVA, t-test and 2 to assess age and gender differences between groups, and computed the proportions of gray matter, white matter, and cerebrospinal fluid in the mPFC voxel. These variables did not significantly alter the study findings.

General linear model analyses were conducted to examine the relationship between NAc volume and clinical severity in patients with MDD, as well as the association between NAc volume and mPFC Glx levels.

To examine the effects of ketamine treatment on MADRS scores and NAc volumes, we constructed linear mixed models with time and remission status as fixed factors, and added exploratory analysis with time*remission interactions.

RESULTS

Ketamine treatment reduced depression severity in patients with moderate clinical severity (HDRS = 20 1.1, HAM-A = 22 1.5, PSWQ = 57 2.5), and 6 of 16 (38%) subjects met MADRS remission criteria.

NAc Volume in MDD

We found a statistically significant difference in left NAc between MDD and HC, and a significant interaction between diagnosis and hemisphere. The right NAc was correlated with PSWQ, but not with HDRS or HAM-A.

In the follow-up subgroup analysis, we found that left and right NAc were larger in non-GBD compared to GBD and HC, but no significant differences between GBD and HC. mPFC Glx did not mediate the relationship between NAc volume and PSWQ.

NAc Volume & Ketamine Treatment

The LMM revealed a small but statistically significant effect of time on the left NAc, but not on the right NAc. The left NAc changes were affected by treatment response, but not by remission.

Ketamine’s antidepressant effects were correlated with its reversal of depression-related gray matter deficits in the hippocampus. Ketamine treatment was associated with increased volume in the remitters, but no significant time or remission effects were found in the non-remitters.

Stratification Based on Hippocampal Volume

We conducted an exploratory analysis in which MDD patients were stratified based on the median split of baseline total hippocampal volume. Ketamine reduced left and right NAc volumes in the subgroup with high left hippocampal volumes, but not in the subgroup with low total or left hippocampal volumes.

DISCUSSION

Consistent with preclinical findings, we found increased NAc volumes in MDD patients compared to HC, but these alterations were limited to the subgroup of MDD patients with no glutamate-based abnormalities. Similarly, mPFC Glx positively correlated with right NAc volume.

Patients with MDD showed no significant correlations between NAc volumes and current severity of depression or anxiety, but individuals with high trait worry scores exhibited relatively larger right NAc volumes. Ketamine treatment was associated with rapid reduction in left NAc, but increase hippocampal, volumes.

The preliminary findings of the ketamine studies add to extensive preclinical evidence and nascent human studies directly relating the rapid acting antidepressant effect of ketamine to region specific synaptogenic alterations.

Results suggest that structural brain changes are often prompt continuous processes that could be functionally and micro-structurally evident within minutes to hours, and that MRI estimates could be sensitive to detect within hours structural changes. A recent study demonstrated that the dopamine antagonist haloperidol reduced striatal volume within 2 h of intravenous administration, which was believed to reflect preclinical evidence of microstructural changes.

Ketamine has been shown to reduce stress-induced NAc hypertrophy by directly modulating dopaminergic neurons in the VTA and NAc. Ketamine also restores stress-induced dopaminergic perturbation and synaptic dysfunction in rodents.

The current study has limitations, such as the secondary nature of the approach and the lack of MRS scans in cohort B. However, future studies could benefit from including functional and diffusion MRI to further unravel the role of NAc in MDD. The median split was used in this study, and the findings are consistent with previous reports. However, the correlation between NAc volume and Glx may not necessarily reflect glutamate neurotransmission.

The current study uses well-characterized psychotropic-free cohorts, cross-sectional and longitudinal approaches, well validated structural and neuroimaging methods, and capitalizes on the ketamine paradigm.

CONCLUSIONS

This study provides the first in vivo in-human evidence of enlarged NAc volume in MDD, and reveals a pattern of rapid normalization of NAc and hippocampal volumes limited to patients who achieved remission.

FUNDING AND DISCLOSURE

CGA, JDC, and SJM declare that they have no conflicts of interest. CGA has received consulting fees from Genentech and Janssen, and SJM has received grant support from Pfizer.

ACKNOWLEDGMENTS

We thank the subjects who participated in this study for their invaluable contribution, and we thank the National Institutes of Health and the Department of Veterans Affairs for supporting our research.