This randomized, placebo-controlled, crossover trial study (n=17) investigates concurrent neurochemical effects of ketamine on glutamate-glutamine and gamma-aminobutyric acid in obsessive-compulsive disorder (OCD). It suggested that models of OCD pathology should examine the role of GABAergic abnormalities in OCD symptomatology.

Abstract

“We previously reported the rapid and robust clinical effects of ketamine versus saline infusions in a proof-of-concept crossover trial in unmedicated adults with obsessive-compulsive disorder (OCD). This study examined the concurrent neurochemical effects of ketamine versus saline infusions using proton magnetic resonance spectroscopy (1H MRS) during the clinical proof-of-concept crossover trial. Levels of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) and the excitatory neurochemicals glutamate+glutamine (Glx) were acquired in the medial prefrontal cortex (MPFC), a region implicated in OCD pathology. Seventeen unmedicated OCD adults received two intravenous infusions at least 1 week apart, one of saline and one of ketamine, while lying supine in a 3.0T GE MR scanner. The order of each infusion pair was randomized. Levels of GABA and Glx were measured in the MPFC before, during, and after each infusion and normalized to water (W). A mixed effects model found that MPFC GABA/W significantly increased over time in the ketamine compared with the saline infusion. In contrast, there were no significant differences in Glx/W between the ketamine and saline infusions. Together with earlier evidence of low cortical GABA in OCD, our findings suggest that models of OCD pathology should consider the role of GABAergic abnormalities in OCD symptomatology.”

Authors: Carolyn I. Rodriguez, Lawrence S. Kegeles, Amanda Levinson, R. Todd Ogden, Xiangling Mao, Matthew S. Milak, Donna Vermes, Shan Xie, Liane Hunter, Pamela Flood, Holly Moore, Dikoma C. Shungu & Helen B. Simpson

Summary

In a clinical proof-of-concept crossover trial, 17 unmedicated adults with OCD received ketamine or saline infusions. The inhibitory neurotransmitter gamma-aminobutyric acid (GABA) and the excitatory neurochemicals glutamate+glutamine (Glx) were measured in the medial prefrontal cortex before, during, and after each infusion.

Introduction

Obsessive-compulsive disorder (OCD) is associated with dysfunction in frontostriatal circuits and is characterized by repetitive thoughts and behaviors. Serotonin reuptake inhibitors (SRIs) are the only evidence-based medication strategy for treating OCD, but are only partially effective.

Converging lines of evidence from in vivo brain-imaging, genetic, and pharmacological studies implicate abnormalities of glutamate and GABA in the pathogenesis of OCD. Ketamine, a glutamatergic N-methyl-D-aspartate receptor antagonist, reduces OCD symptoms in the absence of an SRI.

Proton magnetic resonance spectroscopy (1H MRS) is the only noninvasive neuroimaging technique that allows investigation of glutamatergic and GABAergic abnormalities within brain regions of interest in vivo. Ketamine-induced increases in glutamatergic compounds have been reported in the medial prefrontal cortex in healthy and depressed human subjects.

We used 1H MRS to dynamically monitor the changes in the levels of GABA and Glx in the MPFC of 17 medication-free adults with OCD during administration of ketamine and saline. Ketamine increased Glx levels, and GABA levels decreased with ketamine.

2.1. Participants

Subjects were recruited by clinical referral and advertisements and provided written informed consent before participation. They had to be off all psychotropic medications and have at least moderate symptoms of OCD.

Subjects were excluded if they had comorbid major depression, bipolar, psychotic, eating disorders, substance dependence, substance abuse within the past year, or prominent suicidal ideation, as well as if they had an unstable medical or neurological condition.

Seventeen participants with OCD received two 40-min intravenous infusions of ketamine (0.5 mg/ kg) while lying supine in a General Electric 3.0-T EXCITE MRI scanner. They were monitored continuously during the infusion.

We previously reported in a nearly identical sample examining the clinical effects of ketamine in OCD. The Y-BOCS was used to evaluate obsessive and compulsive symptoms at baseline, during the infusion, and at 90, 110, 230 min post-infusion.

Structural MRI was performed on the patient, and the results were negative for gross structural abnormalities.

In vivo 1H MRS was used to acquire brain spectra containing GABA and Glx resonances. The PRESS J-editing difference method was used to achieve reliable detection of the combined resonances of Glx at 3.7 p.p.m. Spectra were acquired from a 2.5 x 3.0 x 2.5-cm3 (18.8 x 18.8-cm3) MPFC voxel using the J-editing technique with TE/TR 68/1500 ms and 256 interleaved excitations. The achieved static field homogeneity was typically 12-13 Hz, with 20 Hz being the upper limit that was considered acceptable.

The alternative of fitting Glx in the unedited spectrum was considered, but not pursued for two reasons: it would have been difficult to model the baseline and the Glx resonance would have been obstructed by other resonances.

Eight-channel phased-array coil data were combined into a single regular time-domain free-induction decay signal, which was Fourier-transformed to obtain the GABA and Glx spectra. The area under each neurotransmitter peak was obtained using a robust and highly optimized public-domain Levenberg – Marquardt nonlinear least-squares IDL minimization routine.

IDL-fitting was used to estimate MRS parameters and to assess quality of the fits. GABA and Glx peak areas were expressed as ratios relative to the area of unsuppressed voxel tissue water.

2.3. Statistical analyses

We fitted mixed effects linear models to the Glx/W and GABA/W data using fixed effects, random effects, and post hoc analyses to identify potential effects of ketamine at each of the six 13-min acquisitions.

3.1. Sample characteristics

The demographics and clinical characteristics of 16 OCD subjects with viable MRS data are provided, except for one subject who was an extreme outlier. All five OCD symptom dimensions were represented, and no statistically significant differences were found between groups in sex, age, race, or number of earlier SRI trials.

3.2. Effects of ketamine on MPFC Glx and GABA levels in vivo

OCD subjects did not show significant differences in Glx/W between ketamine and saline conditions over time, but did show modest differences in GABA/W over six successive 13-min acquisitions.

3.3. Clinical correlations

GABA/W significantly increased 60-73 min post-infusion in the ketamine condition compared with the saline condition and compared with baseline, and was positively correlated with changes in OCD symptoms.

Discussion

This study found that ketamine did not significantly increase MPFC Glx/W levels in unmedicated adult OCD participants over time, but did significantly increase MPFC GABA/W levels. This effect was due to a single time point, approximately 1 hour post-ketamine infusion.

GABA/W levels in the MPFC were increased in our sample of patients with OCD, which is interesting given recent findings indicating GABA abnormalities in OCD.

A post-hoc analysis of ketamine blood-level findings and clinical OCD symptoms revealed increases in GABA/W at approximately 1 hour post-infusion during the ketamine infusion compared with the saline infusion and compared with baseline. This increase was positively correlated with changes in OCD symptoms.

Future studies should explore the underlying brain basis of GABA and how it relates to obsessions and compulsions across disorders, including OCD-related disorders, tic disorder and OCD symptom dimensions.

The study’s sample size was small, and the J-editing method cannot separate the individual components that form Glx (i.e., glutamate from glutamine). Future studies should aim to derive less ambiguous data by using MRS methods that measure glutamate and glutamine separately.

Although we did not find evidence of a neurochemical carryover effect, we cannot rule out that clinical carryover effects may have non-specific effects on neurochemical events. Finally, future studies of ketamine’s effects in OCD should use a parallel design and incorporate MRS assessments within 1-3 days following the infusion.

In conclusion, ketamine increased GABA/W levels in adults with OCD, but not Glx/W levels. Further research is warranted.

Fig. 1.

Medial prefrontal cortex (MPFC) voxel and sample 1H spectral data were acquired in 13 min from the MPFC voxel using TE/TR 68/1500 ms, and 256 interleaved excitations (total 512). The GABA and Glx concentrations were calculated using the best-fit model.