The effects of low-dose ketamine on the prefrontal cortex and amygdala in treatment-resistant depression: A randomized controlled study

Ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, produces rapid antidepressant effects at low doses and acts directly on the glutamatergic system. Prior work has suggested that treatment-resistant depression (TRD) is characterised by hypoactivity in the prefrontal cortex (PFC) alongside hyperactivity in limbic regions such as the amygdala, but it is unclear whether ketamine's rapid clinical benefits in TRD involve changes in glutamatergic neurotransmission specifically within these regions. Li and colleagues designed a randomized, double-blind, placebo-controlled study using 18F-fluorodeoxyglucose positron-emission tomography (18F-FDG-PET) to probe rapid changes in brain glucose uptake as a proxy for glutamate-related activity. The primary hypothesis was that low-dose ketamine would rapidly increase PFC activity; the amygdala was also examined as a key limbic node in mood circuitry. Scans and clinical ratings were scheduled to capture effects within the first hour after infusion and to relate imaging changes to fast antidepressant responses.

This was a double-blind, randomized, placebo-controlled trial in 48 adults (aged 21–65) meeting DSM-IV-TR criteria for major depressive disorder who met prespecified criteria for treatment-resistant depression (failure to respond to at least three antidepressants across adequate doses/durations plus at least one failed trial during the current episode). Key medical, neurological and substance-use exclusions applied; informed consent and ethical approval were obtained. Participants continued their background medications (the study was an add-on design). Subjects were randomised 1:1:1 to receive a 40-minute intravenous infusion of ketamine 0.5 mg/kg (Group A), ketamine 0.2 mg/kg (Group B), or normal saline (Group C), with 16 subjects per group. Depressive symptoms were assessed with the 17-item Hamilton Depression Rating Scale (HDRS-17) at baseline and at 40, 80, 120 and 240 minutes post-infusion; responders were defined as ≥50% reduction in HDRS-17. The positive symptoms subscale of the Brief Psychiatric Rating Scale (BPRS) and systematic side-effect monitoring were used to track psychotomimetic and other adverse effects. Neuroimaging comprised two resting 15-minute 18F-FDG-PET acquisitions (pre- and post-infusion) together with structural MRI for normalisation. The protocol involved two FDG injections and timing intended to capture glucose uptake before and after the 40-minute infusion; standardised uptake values (SUVs) were calculated as a semi-quantitative index of glucose metabolism and were interpreted here as a proxy for glutamatergic neurotransmission (FDG uptake is largely driven by astrocytic metabolism in response to neuronal glutamate release). Analysis included region-of-interest (ROI) extraction for the PFC and amygdala using automated anatomical labelling (AAL) templates and normalisation of PFC SUV to global mean SUV, together with voxel-wise whole-brain analyses using SPM8. The primary statistical approaches were two-way repeated-measures ANOVA (time × group) with age and sex as covariates, post hoc t-tests (adjusted for multiple comparisons), Pearson correlations relating SUV changes to HDRS-17 percent change, and linear regression models including age, sex, baseline HDRS-17 and SUV changes to predict antidepressant response. Standard thresholds for significance (P < 0.05, with family-wise error correction applied for voxel-wise maps) were used.

All 48 randomised participants (16 per group) completed the first-stage protocol. Baseline demographics, illness duration, comorbidities and baseline HDRS-17 scores were similar across groups. Clinically, both active ketamine groups showed superior rapid antidepressant responses compared with placebo, with significantly more responders in Groups A and B than Group C at 40 and 80 minutes (P < 0.05). The largest mean HDRS-17 improvement occurred at 40 minutes post-infusion for the active ketamine arms (post hoc: 0.5 mg/kg > placebo; 0.2 mg/kg > placebo). BPRS positive-symptom scores did not differ between groups over follow-up. Adverse events were described as mild and self-limiting. Group A (0.5 mg/kg) reported more floating sensations than Group B (0.2 mg/kg); otherwise side-effect rates were similar and no additional medical treatment was required. The presence of floating sensations did not associate with larger PFC SUV changes. ROI analysis showed a significant group-by-time interaction for the PFC (F = 7.373, P = 0.002): both ketamine doses produced increases in PFC SUV that were not observed in the placebo group. Reported effect sizes for PFC change were Cohen's d = 0.316 for Group A and d = 1.019 for Group B. For the amygdala there was no group or interaction effect, but a strong main effect of time (F = 40.695, P < 0.001), with SUV decreasing after treatment across all three groups. Changes in PFC SUV correlated with clinical improvement (percent HDRS-17 change) (r = −0.433, P = 0.002), whereas amygdala SUV changes did not correlate with symptom change (r = 0.070, P = 0.705). PFC and amygdala SUV differences were negatively correlated in the ketamine groups, consistent with reciprocal regulation of these regions; this correlation was not present in the placebo group. Whole-brain voxel-wise analyses confirmed a significant main effect of group in the PFC and additionally identified group effects in the supplementary motor area, dorsal anterior cingulate cortex (dACC), and bilateral post-central gyrus. Post hoc contrasts indicated greater post-treatment increases in SUV in the PFC, SMA and parts of the post-central gyrus for both ketamine groups versus placebo. The extracted text reports that Group A showed larger SUV increases than Group B in the dACC and bilateral post-central gyrus; the reporting on right PFC differences between doses in the extracted text is inconsistent and not clearly presented. Exploratory paired tests showed bilateral PFC increases and decreases in limbic structures (amygdala, hippocampus, parahippocampus) and cerebellum in the ketamine groups; the placebo group exhibited increases in posterior cortical regions and decreases in limbic and brainstem areas. Linear regression identified the change in PFC SUV as the strongest predictor of antidepressant response at both 40 minutes (b = −0.403, P = 0.031) and 240 minutes (b = −0.549, P = 0.008). Being in a ketamine treatment group also predicted response at 40 minutes (b = 0.305, P = 0.047) but not at 240 minutes. Changes in amygdala SUV, age and sex were not significant predictors in these models.

Li and colleagues interpret their findings as evidence that rapid antidepressant effects of low-dose ketamine in TRD are associated with facilitation of glutamatergic neurotransmission in the PFC. Both ROI and voxel-wise analyses converged on the PFC as a ketamine-sensitive locus, and the magnitude of PFC SUV increase related to clinical improvement within the first day. The observed negative correlation between PFC and amygdala SUV changes in the ketamine groups is taken to support a functional reciprocity in PFC–amygdala circuitry, whereby augmentation of PFC activity may help suppress limbic hyperactivity implicated in depression. The authors position these results within prior imaging and preclinical work showing ketamine-induced PFC changes and downstream synaptic mechanisms; they note consistency with earlier PET and functional studies in healthy volunteers and psychiatric samples. Placebo-associated brain changes differed from ketamine effects, with the placebo group showing posterior cortical activations and amygdala decreases that the authors suggest may reflect expectancy and perceptual processing rather than ketamine-specific glutamatergic modulation. In addressing potential confounds, the investigators argue that psychotomimetic side effects do not account for the PFC findings: side effects were mostly mild, 0.2 mg/kg did not produce more adverse effects than placebo, and PFC changes were similar across ketamine doses and independent of floating sensations. They also cite preclinical timing data (mTOR signalling and synaptic changes) that are temporally compatible with rapid PFC effects. Key limitations acknowledged by the authors include the add-on design (participants remained on their existing medications, so observed effects may reflect interactions with background treatments), the possible suboptimal sensitivity of the HDRS-17 for very short-term symptom change, and the fact that the present report covers only the first-hour stage—whether PFC activation relates to sustained antidepressant effects beyond the acute period remains unresolved and requires further study.

The double-blind, placebo-controlled data reported by Li and colleagues indicate that low doses of ketamine produce rapid antidepressant effects in treatment-resistant depression that are associated with increased glutamate-linked glucose metabolism in the prefrontal cortex. The authors conclude that facilitation of PFC glutamatergic neurotransmission is a key component of ketamine's early antidepressant mechanism.