Glutamate and the Neural Basis of the Subjective Effects of Ketamine: A Pharmaco-Magnetic Resonance Imaging Study

Impaired signalling through N-methyl-D-aspartate (NMDA) glutamate receptors has been implicated in the pathogenesis of schizophrenia because NMDA antagonists such as phencyclidine and ketamine produce psychosislike symptoms in healthy volunteers and exacerbate symptoms in patients. Previous animal and human work indicates that NMDA blockade can both reduce inhibitory GABAergic interneuron activity and provoke secondary increases in cortical glutamate release; this glutamate surge has been linked experimentally to behavioural effects and may act via non-NMDA receptors. Positron emission tomography studies of ketamine in humans have reported frontal and sometimes anterior cingulate effects, but have not reproduced posterior cingulate, retrosplenial or hippocampal findings seen in rodents, possibly because of dose/timing differences and the temporal resolution of PET methods. Deakin and colleagues set out to map the immediate neural correlates of ketamine's subjective effects in healthy volunteers using continuous functional magnetic resonance imaging (fMRI) and to test whether those effects are mediated by increased glutamate release. They performed two double-blind, placebo-controlled, randomized, within-subject crossover experiments: first comparing intravenous ketamine with saline placebo, and second testing whether pretreatment with the glutamate-release inhibitor lamotrigine (300 mg) attenuated ketamine's behavioural and BOLD (blood oxygenation level-dependent) signal effects. The investigators used a minute-by-minute phMRI pseudoblock analysis to capture rapid, regionally specific time courses of drug effects during the early infusion period.

The study comprised two separate experiments with healthy male volunteers, both using double-blind, placebo-controlled, randomized, within-subject crossover designs and a 1-week washout between sessions. Participants were screened for physical and psychiatric health, excluded for recent psychoactive drug use, and provided written informed consent. Thirty-three men were enrolled: 12 completed the ketamine-versus-placebo experiment (mean age 22.2 years) and 19 completed the lamotrigine–ketamine experiment (mean age 21.95 years) after two dropouts in the latter arm. In both experiments the ketamine infusion consisted of a 1-minute intravenous bolus of 0.26 mg/kg followed by a maintenance infusion of 0.25 mg/kg/h. In experiment 1 each participant received ketamine in one session and saline placebo in the other. In experiment 2 all participants received ketamine in both sessions but were pretreated orally with 300 mg lamotrigine or matching placebo 2 hours before the infusion. Imaging began 8 minutes before infusion and continued for 8 minutes during infusion; participants were debriefed and discharged 1 hour after infusion end. T2*-weighted echo-planar images were acquired on a 1.5-T scanner with 40 contiguous axial slices (TR/TE = 5000/40 ms, 3.5 mm slice thickness, 3.5 x 3.5 mm in-plane). A T1 structural image excluded gross abnormalities. Subjective effects were measured before and after phMRI using the Brief Psychiatric Rating Scale (BPRS; total and six subscales) and the Clinician-Administered Dissociative States Scale (CADSS; total and subjective/objective subscales including depersonalisation and derealisation). In the lamotrigine experiment additional pre-lamotrigine ratings were obtained. Behavioural data were analysed with repeated-measures analysis of variance and paired t tests as presented. fMRI data preprocessing and analysis used SPM2: motion realignment, normalisation to MNI space, 10-mm smoothing. A pseudoblock time-series analysis treated each preinfusion minute as baseline and each subsequent minute as an independent epoch (1-minute blocks) to generate voxelwise effect-size maps per epoch per subject; group-level repeated-measures random-effects analyses tested main effects of treatment and time. For experiment 1, a familywise error-corrected threshold of P < .05 was applied. To test lamotrigine effects, small-volume correction was applied in regions identified in experiment 1 using a 20-mm radius sphere centred on peak voxels. Correlation analyses related ketamine-minus-placebo BOLD contrast images to differential behavioural measures (ketamine minus placebo) and masked correlations by the main effect map to highlight overlapping regions.

Behavioural effects: Intravenous ketamine increased total BPRS scores and all BPRS subscales, and it increased CADSS total and subscale scores compared with saline placebo in experiment 1. The BPRS and CADSS changes were only modestly correlated (r = 0.33), indicating partially distinct subjective dimensions. In the lamotrigine–ketamine experiment, lamotrigine alone produced no significant subjective effects before ketamine. After ketamine, lamotrigine pretreatment attenuated most ketamine-evoked increases: BPRS total, thought disorder, activation, and hallucinations subscales were significantly reduced by lamotrigine, whereas withdrawal, anxiety–depression and hostility–suspicion were not. Ratings of euphoria were unchanged by lamotrigine. CADSS total, derealization and depersonalization scores were significantly lower with lamotrigine pretreatment. Imaging — ketamine versus placebo: Ketamine produced regionally specific increases and decreases in BOLD signal with distinct time courses, most peaking 4–5 minutes after infusion start. Increases were observed bilaterally in precuneus (BA7), mid–posterior cingulate (BA23/30/31), motor cortex (BA6), superior frontal gyrus (BA8), inferior temporal gyrus (BA20), superior temporal gyrus (BA22) and hippocampus/parahippocampal regions. Early and sustained decreases occurred bilaterally in medial orbitofrontal cortex (OFC; BA11), temporal pole (BA38) and subgenual cingulate/BA10; OFC deactivation emerged within 2 minutes and persisted longer than other changes. A focal activation of anterior thalamus and mid–posterior cingulate appeared around minute 3. Correlations with subjective measures: Deactivations in OFC/subgenual cingulate and temporal pole correlated strongly with dissociative symptoms (CADSS; r = 0.90), whereas only OFC deactivation correlated with psychosis ratings (BPRS). Left frontal pole (BA10) activation correlated most strongly with psychosis (r = 0.70), with parahippocampal and posterior cingulate activations showing weaker correlations (r ≈ 0.60). Thalamic BOLD changes did not correlate with symptom ratings. Effects of lamotrigine pretreatment: Lamotrigine largely antagonised ketamine-evoked BOLD changes; the placebo-ketamine minus lamotrigine-ketamine contrast resembled the ketamine-minus-placebo map from experiment 1. Regions in which ketamine increased BOLD (mid–posterior cingulate BA23, superior/middle/inferior temporal gyri BA22/21/20, supramarginal gyrus BA40, hippocampus and parahippocampal gyrus) showed reduced responses after lamotrigine pretreatment. Similarly, OFC/subgenual cingulate and temporal pole deactivations seen with ketamine were attenuated by lamotrigine. The behavioural attenuation paralleled these imaging effects, supporting the role of increased glutamate release in many of ketamine's subjective and regional neural responses.

Deakin and colleagues interpret their findings as evidence that many subjective effects of ketamine are mediated by secondary increases in glutamate release. The attenuation by lamotrigine of both BPRS/CADSS ratings and most ketamine-evoked BOLD responses supports a model in which enhanced non-NMDA glutamate neurotransmission contributes to dissociation and psychosislike experiences, whereas ketamine's mood-elevating euphoria may reflect direct NMDA receptor blockade and was not reduced by lamotrigine. The investigators highlight three principal features of the ketamine BOLD response relevant to psychosis: (1) early and prolonged deactivation of ventromedial prefrontal regions including medial OFC and subgenual cingulate together with temporal pole deactivation; (2) focal activation of mid–posterior cingulate/precuneus and anterior thalamus; and (3) activations across temporal and hippocampal regions implicated in perceptual and memory processing. Correlational analyses implicated OFC/subgenual cingulate deactivation and posterior cingulate activation in dissociative and psychosis ratings, and left frontal pole activation correlated with psychosis ratings, suggesting these regions may mediate key subjective phenomena. The paper discusses mechanistic possibilities: ventromedial deactivation might reflect indirect inhibitory influences triggered by ketamine-evoked glutamate release elsewhere, potentially involving serotonin 1A receptor–mediated hyperpolarisation; this could explain both emotional detachment and a pattern of regional change that resembles normalization seen after effective depression treatments and may relate to ketamine's reported rapid antidepressant effects. Mid–posterior cingulate and connected temporal/hippocampal activations are proposed to underlie aberrant perceptual processing and impaired self-related cognition, offering a network-level account for dissociation and psychosislike experiences. Limitations and caveats noted by the authors include the temporal resolution trade-offs inherent in the pseudoblock 1-minute epoch approach (which may miss effects reversed in under 1 minute or very slow small-magnitude effects), and that BOLD signal changes principally reflect metabolic consequences of glutamatergic neurotransmission but could also involve other signalling pathways (for example nitric oxide, noradrenaline, potassium) that were not excluded. They also acknowledge dose and species differences that may account for discrepancies with some animal findings. The investigators report that the observed effects are unlikely to reflect a nonspecific alteration of the haemodynamic response because concurrent cognitive activation studies did not show general modulation by the drugs (to be reported elsewhere). Finally, the correlational nature of fMRI means causal inferences are limited, and the authors present their interpretations as hypotheses linking glutamate-mediated neural changes to ketamine-induced subjective states rather than definitive proof.