This randomised, 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.
Papers in Blossom that reference this study
Beaglehole, B., Glue, P., Neehoff, S. et al. · Journal of Psychopharmacology (2024)
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.
Obsessive-compulsive disorder (OCD) involves frontostriatal circuit dysfunction and is commonly treated with serotonin reuptake inhibitors (SRIs), which typically require 2–3 months to produce partial benefit. Earlier research has increasingly implicated glutamatergic abnormalities in OCD pathophysiology, and there is growing evidence for GABAergic disturbances as well. Ketamine, an NMDA receptor antagonist that modulates glutamatergic signalling, has been shown in prior work to reduce OCD symptoms rapidly and robustly; however, the in vivo neurochemical effects of ketamine in people with OCD had not been characterised. Rodriguez and colleagues set out to measure dynamic changes in medial prefrontal cortex (MPFC) glutamate+glutamine (Glx) and gamma-aminobutyric acid (GABA) during intravenous ketamine versus saline infusions in medication-free adults with OCD. The primary hypothesis was that ketamine would increase MPFC Glx relative to saline; exploratory analyses examined whether ketamine would also affect MPFC GABA levels.
This proof-of-concept, randomized crossover study delivered two 40‑minute intravenous infusions (ketamine 0.5 mg/kg and saline) to each participant at least 1 week apart, with infusion order randomised. Seventeen adults with a primary DSM-IV diagnosis of OCD and Yale-Brown Obsessive-Compulsive Scale (YBOCS) ≥16 were enrolled; after excluding one extreme MRS outlier, 16 participants comprised the final MRS sample. Key exclusion criteria included comorbid major depression (HDRS-17 ≥25), bipolar, psychotic or eating disorders, recent substance abuse or dependence, current psychotropic medication use, pregnancy, and MRI contraindications. Diagnoses were confirmed with the SCID-IV and clinical interviews. Magnetic resonance data were acquired on a General Electric 3.0‑T scanner while participants lay supine. A 2.5 × 3.0 × 2.5 cm3 MPFC voxel (approximately 18.8 cm3) was positioned anterior to the genu of the corpus callosum, encompassing portions of Brodmann areas 24, 32 and 10 including the pregenual anterior cingulate cortex. Each scanning session lasted about 90 minutes and included a structural T1 SPGR plus six 13‑minute proton MRS frames (one baseline [0–13 min], three during the infusion, and two post‑infusion), with a 2‑minute gap between frames for automatic shimming. The J‑editing PRESS difference method optimised for GABA detection was used (TE/TR 68/1500 ms; 256 interleaved excitations per edited condition), and metabolite signals were expressed semi‑quantitatively as ratios to the unsuppressed voxel tissue water (Glx/W and GABA/W). Spectral data from the eight‑channel phased‑array coil were quality‑assessed, combined into time‑domain signals, and the editing on/off signals subtracted to yield difference spectra. Metabolite peaks were fitted in the frequency domain using a Levenberg–Marquardt nonlinear least‑squares routine modelling resonances as pseudo‑Voigt functions; goodness of fit metrics and visual inspection were used for quality control. Voxel tissue segmentation and metabolite correction were not performed because the principal focus was within‑subject changes over time. Clinical symptom measures included the OCD‑visual analogue scale (VAS) at multiple intra‑ and post‑infusion time points, baseline YBOCS, and HDRS‑17. Glx/W (primary) and GABA/W (exploratory) were analysed using mixed effects linear models with fixed effects for infusion type, infusion order, MRS data frame, and responder status, and random effects for subject and scan nested within subject. Where overall F‑tests reached p<0.05, post hoc tests examined individual 13‑minute acquisitions; these post hoc tests were treated as exploratory and were not corrected for multiple comparisons. Carryover was assessed with paired t‑tests on baseline Glx/W and GABA/W between first and second infusions, and no evidence of neurochemical carryover was found, permitting collapse across phases.
After excluding one extreme Glx/W outlier, 16 participants contributed viable MRS data. The final sample had substantial OCD severity (mean YBOCS 26, SD 4.2) and an average illness duration of 17.3 years (SD 9.7). Most participants (11/16; 69%) had no other psychiatric comorbidity; two had comorbid depression with baseline HDRS‑17 scores of 13 and 16. No participants were receiving medication or psychotherapy at the time of scanning. In the MPFC voxel, mixed model analyses showed no significant difference between ketamine and saline over time in Glx/W (F=0.65; df=6,141; p=0.689). By contrast, GABA/W showed a modest overall difference across the six successive 13‑minute acquisitions (F=2.16; df=6,146; p=0.048). Analyses restricted to the first treatment phase yielded similar directionality but did not meet the pre‑specified significance threshold for GABA/W (F=1.90; df=6,66; p=0.094). Post hoc tests identified a specific time window driving the GABA/W effect: GABA/W increased significantly at approximately 60–73 minutes post‑infusion in the ketamine condition compared with saline (t(146)=2.38, p=0.02) and compared with baseline (t(72)=2.22, p=0.03). The change in GABA/W from baseline to 60–73 minutes post‑infusion correlated positively with reductions in OCD symptoms as measured by the OCD‑VAS at multiple assessments during and up to 7 days after the infusion, with Pearson r values ranging from 0.46 to 0.63 and p‑values from 0.01 to 0.06. No significant correlations were found between GABA/W changes and dissociative or psychotic symptoms as measured by the Clinician Administered Dissociative Symptoms Scale and the Brief Psychiatric Rating Scale.
Rodriguez and colleagues report that a single subanaesthetic ketamine infusion did not increase MPFC Glx/W over time in unmedicated adults with OCD, contrary to their primary hypothesis and to some prior MRS studies in other populations. Instead, the principal neurochemical effect observed was an increase in MPFC GABA/W, driven predominantly by a single time point about 1 hour after infusion. The authors note that this pattern differs from some studies in healthy volunteers and depressed subjects that documented Glx or glutamate changes, and suggest that Glx changes in OCD may be smaller or less readily detected with the methods used. The increase in GABA/W is discussed in light of emerging evidence for GABAergic abnormalities in OCD, including transcranial magnetic stimulation findings and genetic associations implicating GABBR1. The authors note prior reports of baseline MPFC GABA deficits in unmedicated OCD, and propose that the observed ketamine‑related GABA change could reflect engagement of cortical GABAergic interneurons; this is consistent with animal and human work indicating ketamine can activate subpopulations of GABAergic interneurons and alter cortical oscillatory activity. The positive correlation between GABA/W change and acute and short‑term improvement in OCD symptoms is described as counterintuitive and needing replication; the investigators speculate that larger GABA/W changes during ketamine may index greater underlying GABAergic abnormalities that are engaged by the drug. Several limitations acknowledged by the authors temper the conclusions. The sample size was small, limiting statistical power and the ability to examine potential confounds such as gender. The J‑editing MRS method cannot separate glutamate from glutamine, so changes in one component could be obscured; whole‑tissue MRS may miss transient increases in synaptic glutamate release that do not alter tissue pools. The GABA peak includes contributions from mobile macromolecules, so ketamine‑induced macromolecular changes might influence the observed signal. Large voxel sizes required for reliable GABA quantification introduce variability in tissue composition, which could mask Glx changes. Although no neurochemical carryover was detected, clinical carryover cannot be entirely ruled out, and the psychoactive effects of ketamine make blinding difficult in crossover designs. To address these issues, the authors recommend larger samples, parallel‑group designs with active controls that mimic dissociative effects, and MRS methods capable of distinguishing glutamate and glutamine (for example higher‑field or multi‑dimensional techniques) as well as additional post‑infusion timepoints within 1–3 days. In summary, the study provides preliminary evidence that ketamine increases MPFC GABA/W but does not alter Glx/W in this OCD sample, and that GABA/W changes were associated with short‑term symptom change; the authors call for further research to clarify how glutamatergic and GABAergic abnormalities in fronto‑striatal circuits relate to OCD pathophysiology and treatment response.
Glx/W levels were fitted using mixed effects linear models with infusion type (ketamine/ saline), infusion order, MRS data frame, and responder status as fixed effects, and subject and scan (nested within subject) as random effects. GABA/W levels were explored using similar models. Where the overall F-test was significant (p <0.05, two-tailed), post hoc analyses were conducted to identify potential effects of ketamine at each of the six 13-min acquisitions to give a more detailed picture of which time points are driving the trend; correction for multiple comparisons was not conducted for pos thoc analyses, given their exploratory nature. We first tested for neurochemical carryover effects using a paired t-test between baseline Glx/W and GABA/W levels between the first and second infusions (GABA/W: p=0.383; Glx/W: p = 0.673); finding no evidence of carryover effects, we collapsed the neurochemical data across phases in the final analyses.
This is the first report to examine the time course of neurochemical effects of a single intravenous infusion of ketamine in OCD. Contrary to our hypothesis, in this proof-ofconcept study, ketamine did not significantly increase MPFC Glx/W levels in unmedicated adult OCD participants over time. However, ketamine did significantly increase MPFC GABA/W levels over time. Post hoc analyses showed that a single time point, approximately 1 hour post-ketamine infusion, was driving this effect. Our Glx/W finding is in agreement with a study that found no differences in cortical Glx in healthy volunteers between ketamine and saline groups, and a study that did not detect differences in cortical glutamate+glutamine in healthy volunteers between pre-and post-ketamine infusion (in a region partially overlapping with and slightly dorsal to the voxel in the present study). That GABA/W increased in our sample is interesting given recent findings indicating GABA abnormalities in OCD. Specifically, abnormalities in cortical inhibitory processes in OCD have been reported using transcranial magnetic stimulation paradigms. In addition, a study of the association between markers in the GABA B receptor 1 (GABBR1) gene and OCD found evidence for GABBR1 as a susceptibility factor in OCD. Finally, we previously reported that unmedicated patients with OCD show baseline GABA deficits in MPFC compared with matched healthy controls; low baseline MPFC GABA levels may be part of the brain's attempt to regulate or compensate for OCD symptoms. Exploratory post hoc analyses revealed increases in GABA/W at approximately 1 hour postinfusion during the ketamine compared with the saline infusion and compared with baseline. The change in GABA/W levels was positively correlated with changes in OCD symptoms, but not correlated with (and thus unlikely to be manifestations of) psychotic or dissociative symptoms. This is also consistent with lack of significant correlation between psychotic or dissociative symptoms and ketamine blood-level findings or clinical OCD symptoms, which we previously reported in a nearly identical sample examining the clinical effects of ketamine in OCD. The post-ketamine increase in GABA/W is consistent with recent studies suggesting that ketamine concurrently activates a subpopulation of GABAergic interneurons and projection neurons in the cortex. The finding is interesting given that ketamine also impacts oscillatory activity in a manner consistent with evolving models of cortical microcircuitry, suggesting that rhythmic physiological signals (thought to modulate or "gate" processing of inputs) are mediated by precisely timed activation of GABA interneurons and projection neurons. That change in GABA/W was positively correlated with change in OCD symptoms is counterintuitive and warrants further study in a larger sample: we speculate that greater GABA/W changes during ketamine infusion may reflect greater underlying GABAergic abnormalities in OCD. Understanding the underlying brain basis of GABA and how it relates to obsessions and compulsions across disorders as traditionally defined (i.e., exploring OCD-related disorders, disorders often comorbid with OCD [e.g. tic disorder] and OCD symptom dimensions) in a larger sample in future studies is needed given emerging findings of GABA abnormalities in other disorders. Although participants in the present study did not endorse tics, and dimensions were not correlated with clinical effect, larger samples may prove fruitful for this type of analysis. Our findings need to be tempered in light of several limitations. First, the sample size was small. As a result, we may have insufficient statistical power to rule out type I error (e.g., distinguishing baseline variability from ketamine's effects at specific time points) or addressing important potential confounds like gender. Second, although the J-editing method can separate GABA from Glx, it cannot separate the individual components that form Glx (i.e., glutamate from glutamine). Given that one study has shown glutamine (thought to be a marker of neurotransmitter glutamate release) rather than glutamate increases in healthy volunteers administered ketamine, while another has shown glutamate increases, future studies investigating the response of the glutamatergic system to drug effects should aim to derive less ambiguous data by using MRS methods (e.g. 2D J-resolved at 7 T) that are capable of reliably measuring glutamate and glutamine separately. At the same time, Glx obtained with J-editing is predominantly glutamate and shows excellent test-retest reliability. In addition, MRS measures whole-tissue levels; thus, an increase in glutamate release without an elevation in overall tissue levels might not be detected by MRS. Furthermore, the GABA MRS peak is an admixture of signals from both mobile macromolecules and GABA; thus, if ketamine affects macromolecules, the observed changes in the study may not be exclusively due to changes in GABA. Also, low tissue concentration of GABA necessitates relatively large voxels (e.g., 10-20 cm 3 ) to attain adequate signal-to-noise ratio for reliable quantification in a clinically tolerable scan time. Given Glx levels may be sensitive to voxel white-matter content, it is possible that putative changes in Glx levels are masked by the white matter that is unavoidably present in the large voxels required by GABA J-editing. Nevertheless, these methods have found Glx differences in the same brain region following ketamine in healthy subjectsand in depressed subjects, as well as in schizophrenia compared with controls, indicating that Glx changes in OCD are smaller than in these conditions. Third, although we did not find evidence of a neurochemical carryover effect, we cannot rule out that clinical carryover effectsmay have non-specific effects on neurochemical events. Finally, because of the psychoactive effects of ketamine, blinding patients to the dissociative side effects was difficult. Thus, the design of future studies of ketamine's effects in OCD should use a parallel design (with an active control that can mimic dissociative side effects) and incorporate MRS assessments within 1-3 days following the infusion. In conclusion, we found that a single ketamine infusion increased GABA/W levels in adults with OCD in a MPFC voxel that included the pregenual ACC, but we did not find that ketamine increased Glx/W levels. Further research is warranted to examine how GABA and glutamate abnormalities in the fronto-striatal brain circuits contribute to the pathophysiology of OCD.
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