In vivo effects of ketamine on glutamate-glutamine and gamma-aminobutyric acid in obsessive-compulsive disorder: Proof of concept

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 3.0 T 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.

Ketamine: 50 Years of Modulating the Mind

“…Gonadal hormones, such as estrogen and progesterone, may also potentiate the rapidity and potency of ketamine’s antidepressant effects, as demonstrated in preclinical models (Carrier and Kabbaj, 2013; Franceschelli et al, 2015; Hashimoto, 2016). Lastly, ketamine interaction with GABA receptors has been implicated in various clinical pathologies, including obsessive-compulsive disorder (Rodriguez et al, 2015), depression (Perrine et al, 2014) and learning disabilities following chronic exposure (Tan et al, 2011). …”

Ketamine increases activity of a fronto-striatal projection that regulates compulsive behavior

“…Previous studies suggest that ketamine increases glutamatergic transmission and alters excitatory/inhibitory balance within the mPFC 45,46,47 . However, our baseline photometry recordings ( Figure 1) indicated that KO animals had increased fronto-striatal activity compared to WT animals during grooming, leading us to hypothesize that the therapeutic effect of ketamine might be associated with decreasing activity in this projection to resemble WT activity patterns during grooming.…”

Pediatric Obsessive-Compulsive Disorder: A Psychopharmacology Update

“…Ketamine (Ketalar), a voltage-dependent, non-competitive and non-selective N-methyl-D-aspartate (NMDA) receptor antagonist, acts by inhibiting the fluidity of calcium and sodium cations in the presence of glutamate and glycine (Niciu, Henter, Luckenbaugh, Zarate, Jr., & Charney, 2014). In adults with OCD, ketamine infusions appear to normalize low GABA levels in medial prefrontal cortex (Rodriguez et al, 2015). While ketamine has shown utility in the treatment of refractory depression (Iadarola et al, 2015), only case reports are available for the use of ketamine in OCD.…”