Ketamine, an anesthetic with antidepressant properties, has shown promise in treating TRD. Single subanesthetic doses provide rapid mood improvement, but the effect is short-lived. While repeated ketamine infusions have been suggested to enhance and prolong antidepressant effects in open-label studies and those using saline placebo, robust evidence from rigorous controlled trials has been lacking to support this approach, leading to a lack of consensus in guidelines regarding frequent ketamine administration. This study aimed to address this gap by comparing the efficacy and safety of a regimen of six repeated ketamine infusions to a single ketamine infusion given after five midazolam infusions (used as an active placebo) in patients with TRD. The study's importance lies in its potential to provide evidence-based guidance for ketamine treatment optimization in this patient population, improving treatment outcomes and potentially reducing the duration of suffering.

Existing literature demonstrated that single subanesthetic doses of ketamine (0.5 mg/kg for 40 min) can improve mood within hours in some TRD patients, with peak effects observed at 24 hours post-infusion and a gradual decline in therapeutic benefit within 5–8 days. Open-label studies and studies using saline as a control suggested that repeated ketamine infusions could increase antidepressant response and prolong its duration. However, these studies suffered from limitations, such as the absence of a proper placebo control or the use of saline which doesn't fully address the effects of the infusion process itself. The lack of robust evidence from well-designed, placebo-controlled trials to support frequent ketamine administration prompted the need for this study.

This randomized, double-blind, active placebo-controlled study was conducted at the Minneapolis Veterans Affairs Medical Center. 178 individuals were screened, with 54 completing the study. Participants were outpatients aged 18–75 years with TRD (defined as failure to respond to at least two adequate antidepressant trials). Exclusion criteria included PTSD, significant traumatic brain injury, psychotic disorders, bipolar disorder, or other Axis I disorders, as well as recent substance use or suicidal/homicidal ideation. Participants were randomized (permuted blocks of 4 and 1) to receive either six ketamine infusions (0.25 mg/kg) or five midazolam infusions (0.045 mg/kg) followed by one ketamine infusion. Infusions were administered over 12 days (Monday-Wednesday-Friday schedule). The last infusion was ketamine in both groups (blinded to participants and raters). Assessments included the MADRS, CGI, BAI, CEQ, PRISE, BPRS, CADSS, and YMRS at various time points, including baseline, during the infusion phase, and at regular intervals for six months post-treatment. Vital signs were monitored during infusions, and safety guidelines were implemented. The primary outcome measure was the change in MADRS score at 24 hours after the last infusion. Statistical analysis included repeated measures ANOVA and multi-level models.

Fifty-four participants completed the study (25 in the six-ketamine group and 29 in the five-midazolam-plus-single-ketamine group). Baseline characteristics were comparable between the groups. There was no significant difference between groups in the change in MADRS scores at 24 hours post-last infusion (primary outcome). However, remission and response rates favored the six-ketamine group after infusions 4 and 5 compared to the midazolam group before the single ketamine infusion. Time-to-relapse was nominally longer in the six-ketamine group (6 weeks vs. 2 weeks), but this difference was not statistically significant. The mean MADRS score was significantly lower in the six-ketamine group compared to the midazolam group before infusion 5, at 24 hours after infusion 5, and before infusion 6, though the difference before infusion 6 only approached significance (p=0.050). Response and remission rates at the end of the six infusions were not significantly different between groups. The most common side effects in the ketamine group were general malaise, decreased energy, increased blood pressure, headache, fatigue, nausea/vomiting, anxiety, and poor concentration. For the midazolam group the most common side effects were anxiety, decreased energy, increased blood pressure, fatigue, and headache.

This study found no significant difference in the primary outcome (change in MADRS at 24 hours post-last infusion) between repeated and single ketamine infusions for TRD. However, secondary outcomes suggested that repeated ketamine may offer advantages, particularly in terms of response and remission rates after multiple infusions compared to the active placebo before the final ketamine infusion. The longer time-to-relapse observed in the repeated ketamine group, although not statistically significant, hints at a potential durability benefit. These findings suggest that the benefit of repeated ketamine may be evident only after several infusions, necessitating a longer treatment course than currently considered standard practice. The use of midazolam as an active placebo aimed to control for the effects of the infusion procedure itself, providing more robust evidence compared to studies using saline as a control. Further research is needed to establish the optimal dosing regimen and duration of treatment with repeated ketamine.

This study provides valuable insights into the efficacy and safety of repeated versus single subanesthetic ketamine for TRD. While the primary outcome did not reach significance, secondary outcome measures suggested potential benefits of repeated ketamine infusions, especially regarding response and remission rates after multiple infusions and potential durability. The use of midazolam as an active placebo strengthens the study's design. Further research is warranted to investigate the optimal dosing and duration of repeated ketamine treatment, considering the potential benefits observed in this study and increasing our understanding of ketamine's mechanisms of action.

The sample size, while sufficient for the primary outcome, might have limited the power to detect smaller differences in secondary outcomes. The six-month follow-up period may not be sufficient to capture the long-term durability of response, and the study focused on short term efficacy of the ketamine. The relatively short duration of the study and lack of long-term follow-up limited the ability to fully assess the durability of response. Future studies with larger samples and longer follow-up periods are needed to confirm these findings and to better understand the long-term effects of repeated ketamine infusions.