Prolonged ketamine infusion modulates limbic connectivity and induces sustained remission of treatment-resistant depression

Traditional antidepressants primarily target monoamine systems (serotonin, dopamine, norepinephrine), act slowly, and often fail to produce remission in people with treatment-resistant depression (TRD). Ketamine, an NMDA glutamate receptor antagonist, produces rapid antidepressant effects after brief infusions but these effects commonly wane within about a week. Prolonged ketamine infusions have produced sustained benefit in chronic pain, and a prior feasibility study suggested a 96-h infusion could produce durable improvement in TRD, motivating further investigation of both clinical efficacy and underlying neurocircuit mechanisms. Siegel and colleagues set out to evaluate the safety, tolerability, clinical efficacy, and resting-state functional MRI (rsfMRI) correlates of a single 96-h intravenous ketamine infusion in adults with TRD. The study tested two linked hypotheses: that responders would show response-dependent decreases in subgenual anterior cingulate cortex (sgACC) and default mode network (DMN) connectivity, and that all participants would show treatment-dependent changes within limbic circuitry. The investigators combined clinical ratings (MADRS, CGI-I), assessments of psychotomimetic effects, and pre- and post-treatment rsfMRI to probe these questions.

This was an open-label, proof-of-principle intervention study enrolling adults aged 18–65 with major depressive disorder and a Montgomery-Åsberg Depression Rating Scale (MADRS) score ≥ 22, who had not responded to at least two adequate antidepressant trials in the current episode. Twenty-three eligible participants initiated the infusion; a matched healthy control group (n = 27) was recruited for imaging comparisons. Continued stable use of SSRIs or SNRIs was permitted if doses had been unchanged for ≥ 6 weeks. Institutional review board approval and written informed consent were obtained. Participants were admitted for a 5-day/4-night stay and received a continuous intravenous ketamine infusion for 96 h, started at 0.15 mg/kg/h and titrated twice daily toward a target of 0.6 mg/kg/h as tolerated. Oral clonidine (started ~7 days prior, up-titrated as tolerated) was co-administered to reduce psychotomimetic effects and stopped at infusion completion. Serum ketamine and metabolite concentrations were measured during treatment. Clinical assessments included the MADRS and Clinical Global Impressions-Improvement (CGI-I) at baseline and by phone at 2, 4, 6, and 8 weeks post-infusion; psychotomimetic and other side effects were tracked with the Brief Psychiatric Rating Scale (BPRS) positive symptom subscale and an adverse event checklist. Cognitive measures and other safety monitoring were reported but details are in supplemental methods. Resting-state fMRI was acquired on a 3-T Siemens Trio scanner. Two baseline rsfMRI sessions were obtained 1–14 days apart to estimate baseline FC stability, and a single post-treatment session was acquired at 2 weeks. Two EPI runs of 6 min each were collected per timepoint. After quality control and matching, 19 patients had at least one pre- and post-scan for imaging analyses; 27 matched controls were included for between-group comparisons. Cortical parcellation used a surface-based atlas; subcortical limbic regions were represented by expanded spherical ROIs covering amygdala, anterior/posterior hippocampus, nucleus accumbens and anteromedial thalamus. Region-wise timeseries were averaged and functional connectivity (FC) computed with Fisher z-transformed Pearson correlations. Primary imaging hypotheses focused on (1) DMN within-network FC decrease in clinical responders, (2) decreased sgACC–DMN FC in responders, and (3) change in FC within the limbic network after treatment. The visual network served as a negative control. Participants were classified as responders if they had ≥ 50% MADRS reduction at 2 weeks. FC changes were evaluated with linear mixed-effects models including fixed effects for time and time-by-response interaction and a random participant effect; 21 subjects with 40 observations were entered into these models due to missing post-treatment data in some cases. Clinical outcomes were analysed with repeated-measures ANOVA and post hoc paired t tests; response and remission rates were secondary outcomes. Eight primary outcomes (two clinical, six imaging) were prespecified and a Bonferroni-corrected significance threshold of p < 0.00625 was noted, although raw (uncorrected) p values are presented. Exploratory volumetric analyses correlated normalized pre-treatment limbic volumes with MADRS change using Pearson correlations (uncorrected for multiple comparisons).

Enrollment and tolerability: Of 27 consented, 23 were eligible and initiated the infusion. All but one individual completed the infusion period (the extract reports 22 completed the 96-h infusion); two participants were missing post-treatment imaging data for some analyses. The mean final infusion rate among completers was 0.54 mg/kg/h (SD = 0.13). Clonidine was administered per protocol. Side effects were generally mild, peak psychotomimetic symptoms measured by the BPRS-positive scale occurred around infusion day 3 (mean 6.3 ± 1.58) and tended to decline during days 4–5. Small average increases in blood pressure were observed (systolic +8 mm Hg, diastolic +5 mm Hg at 8 AM on day 5 versus pre-infusion). Reported discharge symptoms included fatigue, inattention and sedation in a minority; adverse effects diminished rapidly after stopping infusion. Side-effect severity did not correlate with serum ketamine or metabolite concentrations. Clinical efficacy: MADRS scores decreased markedly after the infusion and improvements were sustained over 8 weeks. Mean MADRS fell from 29 (SD = 4) at baseline to 9 (SD = 8) one day post-infusion (p < 0.001, Cohen's d = 1.7), 13 (SD = 8) at 2 weeks (p < 0.001, d = 1.6), and 15 (SD = 8) at 8 weeks (p < 0.001, d = 1.5). One day post-infusion, 73% (16/22) met response criteria and 59% (13/22) were in remission (MADRS < 10). At 2 weeks, 52% (11/21) remained responders with 38% (8/21) in remission; the same 52% response rate persisted at 8 weeks, with 33% in remission. CGI-I ratings tracked MADRS changes (73% much/very much improved at day 1; 71% at 2 weeks; 62% at 8 weeks). An inverse correlation between mean BPRS positive scores during infusion and MADRS improvement was observed at 1 day (r = -0.54, p = 0.009) but not at later timepoints. Response at 2 weeks did not correlate significantly with mean serum ketamine or major metabolite concentrations. Imaging — DMN and sgACC: After image quality exclusions, 19 subjects had pre- and post-scans. Within-network DMN FC decreased at 2 weeks post-infusion (p = 0.003, T = -3.2, DF = 37). The time-by-response interaction for DMN connectivity showed a trend (p = 0.051), indicating responders tended toward larger DMN FC decreases. FC between bilateral sgACC and the rest of the DMN decreased after ketamine (p = 0.001, T = -3.5, DF = 37). Responders exhibited a larger sgACC–DMN decrease than non-responders (p = 0.028), but this difference did not survive the Bonferroni-corrected threshold of p < 0.00625. Visualization showed concomitant increases in sgACC FC to frontal areas such as bilateral caudal anterior cingulate and anterior insula. Imaging — limbic system and volumetrics: FC within the anatomically defined limbic network (amygdala, hippocampus, nucleus accumbens, anteromedial thalamus) decreased after ketamine (p = 0.003, T = -3.2, DF = 37). Changes within limbic FC did not differ between responders and non-responders (p = 0.54). The anterior thalamus showed particularly large decreases in connectivity with other limbic structures. When limbic–cortex FC was visualized, increased connectivity to frontal cortical areas, notably components of the cingulo-opercular network, was observed post-treatment, although some of these frontal changes reflected loss of pre-treatment anticorrelation rather than an absolute increase. Comparing patients and matched healthy controls, baseline TRD subjects showed hyperconnectivity in the limbic system, DMN, and sgACC–DMN connections (p < 0.05 uncorrected), whereas post-ketamine patients no longer differed from controls in these systems. In exploratory volumetric analyses, smaller right hippocampal volume (normalized to intracranial volume) correlated with greater MADRS improvement at 2 weeks (Pearson r = 0.52, p = 0.023 uncorrected); no other limbic volumes showed significant associations.

Siegel and colleagues interpret the findings as two primary observations. First, a single prolonged 96-h ketamine infusion produced rapid and sustained antidepressant effects in this open-label cohort, with marked MADRS improvement at one day that remained largely stable through 8 weeks in about half of participants. The authors note that the 52% response rate at 2 and 8 weeks is comparable to response rates reported for repeated intranasal esketamine in ketamine-naive TRD samples, and that these results align with prior feasibility work and with reports from prolonged ketamine infusions for chronic pain. They acknowledge, however, that a placebo-controlled trial is required to determine whether the prolonged infusion per se accounts for the durability of effect. Second, the investigators observed normalization of depression-related hyperconnectivity after treatment. Specifically, ketamine reduced sgACC–DMN connectivity (a change that was larger in clinical responders) and reduced connectivity within limbic circuitry regardless of clinical response. The limbic FC effect — notably involving the anterior thalamus and anterior hippocampus — is presented as novel in human ketamine studies, made possible by methodological steps to improve subcortical signal-to-noise. The authors suggest limbic FC changes may reflect modulation of stress-related limbic circuitry and possibly activation of hippocampal–prefrontal pathways implicated in ketamine's antidepressant mechanisms; however, they caution that some frontal increases represented loss of pre-treatment anticorrelations, complicating interpretation. The observed association between smaller right hippocampal volume and greater antidepressant response is highlighted as potentially useful for patient selection, noting that hippocampal volume has been variously associated with treatment outcomes across interventions. Limitations acknowledged by the study team include the open-label design and absence of an active placebo control, which precludes strong causal inferences about clinical efficacy or attribution of connectivity changes to ketamine rather than nonspecific trial effects. The potential impact of clonidine on antidepressant efficacy was not determined, and logistical barriers (cost, inpatient monitoring) could limit generalisability of a 96-h infusion paradigm in outpatient settings. The authors therefore call for randomized controlled trials to confirm efficacy, investigations varying infusion duration to determine minimal effective exposure, and further work to validate neurobiological predictors (such as hippocampal volume) to optimise patient selection and treatment strategies. Overall, the study presents preliminary evidence that a prolonged ketamine infusion is tolerable, produces sustained clinical improvement in a subset of TRD patients, and is associated with normalisation of depression-related hyperconnectivity in limbic and default-mode circuits.