The antidepressant effect of ketamine is not associated with changes in occipital amino acid neurotransmitter content as measured by [1H]-MRS

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Abstract

The NMDA receptor antagonist ketamine can induce a rapid improvement in depressive symptoms that often endures for days after a single intravenous dose. The pharmacodynamic basis for this effect is poorly understood. Using a proton magnetic resonance spectroscopy ([1H]-MRS) method that previously detected a normalization of amino acid neurotransmitter (AANt) content after chronic treatment with conventional antidepressant treatments, we examined whether the acute action of ketamine is associated with alterations in AANt content as well. Ten subjects with major depressive disorder (MDD) received saline, then ketamine in a fixed order, one week apart, under single-blind conditions. Each infusion was associated with three [1H] MRS scans (baseline, 3 h and 48 h post-infusion) that measured glutamate, GABA and glutamine within the occipital cortex. Rating scales were administered before, during and after each infusion. The rapid (1 h) and sustained (at least 7 days) antidepressant effect we observed after ketamine infusion was not associated with either baseline measures of, or changes in, occipital AANt content. Dissociative symptoms were not correlated with changes in depression scores. While our results indicate that changes in occipital AANt content are not a correlate of ketamine's antidepressant action, this may only apply to the regional and temporal windows of our MRS measurements.

Introduction

Innovation in the clinical therapeutics of major depressive disorder (MDD) may be derived from revised pathophysiological models that incorporate the accumulating evidence for a role of dysregulated glutamatergic neurotransmission. Indeed, both preclinical and clinical studies have demonstrated that a variety of glutamatergic compounds have antidepressant effects (Sanacora et al., 2008, Machado-Vieira et al., 2009). In particular, the N-methyl-d-aspartate receptor (NMDAR) antagonist ketamine has emerged as a leading prototype for antidepressant development because it can be both rapidly acting and efficacious in ‘treatment-resistant’ MDD subjects (i.e. those without an adequate clinical response to monoaminergic drugs) (Berman et al., 2000, Zarate et al., 2006, Mathew et al., 2009). Furthermore, the antidepressant effect induced by a single, intravenous administration of ketamine often endures for days, well beyond the transient changes in perception and cognition commonly observed during an infusion of a subanesthetic dose. The identification of how this relatively brief pharmacological blockade of the NMDAR induces a rapid and sustained improvement in depressive symptoms would have important theoretical and practical implications.

Preclinically, NMDAR antagonists induce a variety neurophysiological effects implicated in antidepressant action including the modulation of monoaminergic neurotransmission (Paul et al., 1992, Dall'Olio et al., 1999), the enhancement of both hippocampal neurogenesis (Gould et al., 1997, Nacher et al., 2001, Nacher et al., 2003, Keilhoff et al., 2004) and long-term potentiation (Buck et al., 2006), and increased hippocampal brain-derived neurotrophic factor (BDNF) levels (Garcia et al., 2008). In addition, recent studies suggest that increased alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA)-receptor-mediated synaptic potentiation and subsequent activation of the mTOR signaling pathway initiate the physiological responses that generate ketamine's antidepressant-like actions in rodent models (Maeng et al., 2008, Li et al., 2010). These studies are in line with a previous report showing that ketamine acutely increases glutamatergic neurotransmission in the prefrontal cortex of rodents (Moghaddam et al., 1997), and collectively, these findings suggest that an acute increase in non-NMDA mediated glutamate neurotransmission is a critical step in ketamine's mechanism of antidepressant action.

In humans, subanesthetic doses of ketamine appear to acutely increase glutamatergic activity in the prefrontal cortex (Breier et al., 1997, Rowland et al., 2005), however we are not aware of any studies characterizing changes in glutamatergic activity or AANt levels during the window of symptomatic improvement that opens after the acute effects of ketamine have dissipated. Using proton magnetic resonance spectroscopy (1H-MRS), we sought to determine whether measureable alterations in amino acid neurotransmitter (AANt) content are associated with ketamine's antidepressant activity. Our spectroscopy group has previously identified decreased levels of GABA and increased levels of glutamate in the occipital cortex of adult patients with unipolar depression as compared to levels in healthy controls (Sanacora et al., 2004). In addition, we have found that chronic treatment with either a chemical antidepressant (Sanacora et al., 2002), or electroconvulsive treatment (ECT) (Sanacora et al., 2003), is associated with a normalization of GABA levels. Consequently, changes in AANt levels may represent a neurochemical correlate of antidepressant efficacy that extends to NMDAR antagonists.

The primary aims of this study were to replicate the sustained antidepressant effect in subjects with MDD that has been previously observed after a single ketamine infusion, and to assess for correlations between this clinical response and measures of AANt content in the occipital cortex, the brain region that we have previously shown is associated with abnormal levels in MDD subjects. We predicted that ketamine would reduce scores on depression psychometrics, and that these changes would correlate with an increase in GABA content and alterations in glutamate and glutamine content. Contrary to this prediction, we found that the antidepressant effect of ketamine present at 3 h and 2 days post-infusion was not associated with changes in AANt content.

Section snippets

Study participants

Between November 2004 and October 2006, subjects from the greater New Haven area were recruited through advertisements in local newspapers, on the Internet, and by direct contact with physicians. Men and women (21 to 65 years old) meeting DSM-IV criteria for Major Depressive Disorder, as by determined by the Structured Clinical Interview for DSM-IV (SCID) — Patient Edition (First et al. 2001), who also had a screening Hamilton Depression Rating Scale (HDRS-25, Mazure et al., 1986) score > 25 were

Participant characteristics

Seventy-three subjects were evaluated after phone screening. Eighteen subjects were considered eligible and subsequently consented. Five subjects were deemed screen failures after providing consent (one from a medical issue; two secondary to substance abuse and two due to inability to wash-off medication). Three subjects withdrew (one based on failure to return before the testing period; one from difficulty with head placement in the scanner, and one from elevated blood pressure during the

Discussion

The antidepressant effect of ketamine reported here replicates two important features described in the previous controlled studies that used identical infusion parameters (40-minute infusion of racemic ketamine at 0.5 mg/kg) (Berman et al., 2000, Zarate et al., 2006). First, the improvement in symptoms was rapid, as measured by significant decreases in HDRS and BDI scores 1 h post-infusion. Second, the antidepressant effect persisted for up to one week as measured by a significant decrease in

Acknowledgments

We would like to thank Ms. Yael Levin and Ms. Jessica Howell for their assistance on this project, and Ms. Lisa Roach for her assistance with data management and manuscript preparation. This study was supported by the Yale/Pfizer imaging alliance and from NIH 5K02MH076222-05 (GS). Additional funding was provided by R01 DA021785 (GM) and K02 AA13430 (GM). Dr. Sanacora has received consulting fees form AstraZeneca, Bristol-Myers Squibb, Evotec, Eli Lilly & Co., Johnson & Johnson, Roche, Novartis

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