Investigation of medical effect of multiple ketamine infusions on patients with major depressive disorder

Major depressive disorder (MDD) is a common, chronic and disabling condition for which many patients continue to experience residual symptoms, relapse and treatment resistance despite existing pharmacological and nonpharmacological therapies. Growing interest in glutamatergic mechanisms, particularly dysfunction of the N-methyl-D-aspartate (NMDA) receptor, has led to investigation of NMDA antagonists such as ketamine, which produce rapid but typically transient antidepressant effects when given as a single intravenous (IV) infusion (commonly 0.5 mg/kg over 40 minutes). Previous open-label and small-sample studies of repeated ketamine infusions have reported mixed results and have often enrolled only treatment-resistant samples, been small, or required washout of concomitant medications, limiting generalisability and applicability to real-world clinical settings and to Chinese patients in particular. Zheng and colleagues set out to examine whether a course of six consecutive subanesthetic IV ketamine infusions (0.5 mg/kg over 40 minutes, given Monday–Wednesday–Friday across 12 days) as an augmentation to ongoing antidepressant treatment would increase rates of response and remission compared with the typical single-dose ketamine effect, and to evaluate effects on suicidal ideation, anxiety and safety in Chinese adults with MDD. The investigators hypothesised that repeated infusions would produce higher response and remission rates than a single infusion and sought to describe clinical predictors and tolerability in this population.

This was an open-label clinical study conducted at inpatient and outpatient units of the Affiliated Brain Hospital of Guangzhou Medical University between November 2016 and December 2017. The protocol was approved by the local ethics committee and registered in the Chinese Clinical Trial Registry. Each enrolled participant received six IV infusions of ketamine (0.5 mg/kg diluted in 40 mL saline, administered over 40 minutes via an infusion pump) delivered across 12 days (Monday, Wednesday, Friday). The ketamine dose was calculated from the patient’s measured bodyweight on the morning of the first infusion. Infusions were given after overnight fasting, with at least one psychiatrist present and anaesthesiologists available as needed; vital signs were checked every 10 minutes for one hour starting 10 minutes before infusion and patients remained under observation for 30 minutes after each session. Eligibility criteria required adults aged 18–65 years with DSM-5 diagnosis of MDD confirmed by two psychiatrists and a baseline 17-item Hamilton Rating Scale for Depression (HAMD-17) score ≥17. Participants either had suicidal ideation (SSI-part 1 score ≥2) or met a definition of treatment-resistant depression (TRD: failure to respond to ≥2 adequate antidepressant trials during the current episode). Exclusion criteria included other primary psychiatric diagnoses (comorbid anxiety-spectrum disorders were allowed if not primary in the past year), positive urine toxicology, pregnancy or lactation, major medical or neurologic disease. Concomitant psychotropic medications were permitted and were to be kept at stable dosages for at least four weeks before the first infusion; nonpharmacological interventions (psychotherapy, repeated transcranial magnetic stimulation) were not allowed. Clinical assessments used the 10-item Montgomery–Åsberg Depression Rating Scale (MADRS) as the primary instrument. Coprimary outcomes were response (≥50% reduction from baseline MADRS) and remission (MADRS ≤10) at 24 hours after completion of the sixth infusion. Suicidal ideation was measured with SSI-part 1, anxiety with the 14-item Hamilton Anxiety Scale (HAMA), dissociation with the Clinician Administered Dissociative States Scale (CADSS) and psychotomimetic symptoms with the four-item positive symptom subscale of the Brief Psychiatric Rating Scale (BPRS). Ratings occurred at baseline, four hours and 24 hours after each infusion and at a two-week follow-up. Five experienced raters performed assessments and demonstrated interrater reliability with intraclass correlations >0.9. Statistical analyses were conducted on an intent-to-treat basis using SPSS v.24. Continuous variables were tested for normality with the Kolmogorov–Smirnov test. Comparisons between responders and nonresponders used t-tests or Mann–Whitney U tests for continuous variables and χ2 or Fisher’s exact tests for categorical variables as appropriate. Binary logistic regression examined independent predictors of response at 24 hours after the sixth infusion; a Bonferroni correction adjusted for multiple comparisons. Longitudinal changes in continuous outcomes were analysed with linear mixed models. Paired-samples t-tests compared BPRS and CADSS scores from baseline to four hours after the first infusion. Two-tailed significance was set at p<0.05.

Seventy-seven patients with MDD received ketamine infusions and were included in the analyses; 68 (88.3%) completed all six infusions. The sample had a mean baseline MADRS of 32.6±7.3, and 77.9% (60/77) met criteria for TRD. Comparing baseline characteristics, responders at 24 hours after the sixth infusion were more likely to be employed, have higher income and education, and have no history of psychiatric hospitalisation. At 24 hours after completion of the six-infusion course, 52 of 77 patients met response criteria (67.5%, 95% CI: 56.8–78.2) and 37 of 77 met remission criteria (48.1%, 95% CI: 36.6–59.5). In the TRD subgroup the rates were similar: 66.7% response (95% CI: 54.4–78.9) and 46.7% remission (95% CI: 33.7–59.7). By contrast, 24 hours after the first infusion the response and remission rates were 13.0% (95% CI: 5.3–20.7) and 7.8% (95% CI: 1.7–13.9), respectively; TRD patients showed comparable early rates. Among those who responded at the end of treatment, 15 of 52 relapsed by the two-week follow-up, giving a relapse rate of 28.8% (30.0% in the TRD subgroup). Logistic regression identified no history of psychiatric hospitalisation as an independent predictor of response (odds ratio=3.56, p=0.009), and this association remained significant after Bonferroni correction. No significant difference was found between eventual responders and nonresponders in response status 24 hours after the first infusion. Symptom ratings showed a rapid improvement: at four hours after the first infusion mean MADRS fell by 7.0±7.5 points (from 32.6 to 25.6, p<0.001), SSI-part 1 decreased by 2.0±2.5 (from 3.5 to 1.5, p<0.001) and HAMA decreased by 4.7±6.9 (from 19.7 to 15.0, p<0.001). These reductions were sustained over the subsequent infusions across the whole sample. In the nonresponder subgroup ketamine was associated with sustained reductions in suicidal ideation (SSI-part 1) but not in MADRS or HAMA. Statistically significant differences between responder and nonresponder groups were observed for MADRS improvement from four hours to 26 days (maximum effect size=2.2) and for HAMA (maximum effect size=1.3); fewer time points showed between-group differences for SSI. Regarding acute adverse effects, no significant increases in psychotomimetic (BPRS four-item subscale: 4.3±1.1 vs 4.2±0.7, p=0.17) or dissociative (CADSS: 0.4±1.5 vs 0.8±2.3, p=0.09) symptoms were detected from baseline to four hours after the first infusion. The authors report these effects as generally mild and well tolerated across the infusion series.

Zheng and colleagues interpret their findings as indicating that a six-infusion course of subanesthetic IV ketamine (0.5 mg/kg over 40 minutes) administered as an augmentation to ongoing antidepressant therapy produced substantially higher rates of response and remission at 24 hours after the final infusion than are typically reported after a single ketamine infusion. The study demonstrated a rapid reduction in depressive symptoms and suicidal ideation within hours of the first infusion, with sustained improvement over the course of the six infusions; suicidal ideation declined even among participants who did not meet formal response criteria. Psychotomimetic and dissociative symptoms were described as generally mild and tolerable. The authors place these results in the context of prior reports: single-dose ketamine trials commonly show rapid onset with effects lasting several days, whereas repeated-infusion open-label studies have reported mixed but sometimes large cumulative benefits. This study’s end-of-treatment response (67.5%) and remission (48.1%) compare favourably with earlier single-dose reports (around 50% response and 29.4% remission) and with other repeated-dose series. The relapse rate observed at two weeks (28.8%) was lower than relapse rates reported after single-dose protocols in prior studies. The investigators discuss putative mechanisms for ketamine’s antidepressant action, including NMDA antagonism, AMPA receptor activation, downstream neuroplasticity pathways such as BDNF and mTOR signalling, and synaptogenesis; they also note that cytochrome P450 polymorphisms (CYP2B6, CYP3A4) can influence ketamine exposure. Several limitations acknowledged by the authors temper interpretation. The open-label design without a placebo control limits causal inference about efficacy, although the stated intent was to compare cumulative six-infusion outcomes with typical single-infusion effects reported in the literature. Heterogeneity of concomitant antidepressant regimens is a potential confounder, though medications were stabilised before infusion to reduce acute pharmacological confounding. The authors note an unexplained temporary increase in mean HAMA scores at 24 hours after the last infusion that requires confirmation. Other limitations include ketamine dosing by actual bodyweight rather than adjusted methods and a relatively brief follow-up period of two weeks, which precluded formal estimation of time to relapse. The discussion concludes that controlled studies are needed to confirm and extend these open-label findings.

In this open-label study of Chinese patients with MDD, six IV infusions of ketamine (0.5 mg/kg over 40 minutes) given across 12 days as augmentation to ongoing antidepressant treatment produced higher rates of response (67.5%) and remission (48.1%) at 24 hours after the final infusion than typically reported after a single infusion, with rapid reductions in suicidal ideation and generally mild dissociative and psychotomimetic effects. The authors recommend future controlled trials to confirm and expand on these findings.