Real-world effectiveness of repeated ketamine infusions for treatment resistant depression during the COVID-19 pandemic

Since March 2020, public health measures to limit SARS-CoV-2 transmission—including closure of non-essential services, prolonged social isolation and quarantines—have been widely implemented and are associated with increased risk of adverse mental health outcomes, particularly among people with pre-existing mood disorders. Social support is identified as a key determinant of resilience and positive outcomes in mood disorders, and pandemic-related stressors such as loneliness and circadian disruption might plausibly attenuate the effectiveness of antidepressant treatments. Intravenous (IV) ketamine is a rapid-acting treatment option for adults with treatment-resistant depression (TRD) and has been shown to reduce suicidal ideation quickly, but its outcomes in the context of pandemic restrictions had not been assessed. Rosenblat and colleagues set out to compare real-world antidepressant effectiveness of a standard course of repeated IV ketamine infusions delivered in an outpatient clinic before versus during the COVID-19 pandemic in Ontario, Canada. The study aimed to determine whether public health restrictions and related changes in social interaction altered clinical response to ketamine in adults with TRD who received four infusions over approximately two weeks.

The investigators performed a retrospective case series analysis of adults with TRD who received four IV ketamine infusions (dose range 0.5–0.75 mg/kg) over roughly two weeks at a single outpatient clinic in Ontario. Two cohorts were compared: patients treated during the COVID-19 period (March 2020–February 2021) and a historical control cohort treated in the year prior to the pandemic (March 2019–February 2020). The extracted text does not specify additional inclusion or exclusion criteria beyond a clinical diagnosis of TRD and attendance for the four-infusion course; the authors note that the full treatment protocol has been described elsewhere. Clinic procedures were adapted to public health guidance during the pandemic: initial and follow-up psychiatric assessments were conducted virtually; arrival screening, hand hygiene and individual room completion of forms replaced waiting-room activity; personal protective equipment (PPE) was required for staff and patients; and capacity and scheduling were adjusted between March and May 2020 (including a temporary suspension of new out-of-province patients and increased booking times). The clinic returned to pre-COVID capacity in May 2020 when PPE supply allowed. Primary and secondary outcomes were clinical symptom measures collected at baseline and after infusions. Depressive symptoms were measured with the Quick Inventory for Depressive Symptomatology—Self Report 16 (QIDS-SR16), suicidal ideation (SI) using the QIDS-SR16 SI item, anxiety with the Generalized Anxiety Disorder-7 (GAD-7) scale, and functional disability with the Sheehan Disability Scale (SDS). Depressive symptoms and SI were analysed from pre-treatment to post-infusion 4 with symptom ratings collected after each infusion; anxiety and function were analysed from pre-treatment to post-infusion 3 and post-infusion 4. Statistical analysis used mixed-effects models with an autoregressive covariance structure to account for repeated measures, adjusting for age, sex, number of past antidepressant trials and baseline symptom severity. Bonferroni corrections were applied for multiple post-hoc comparisons. Analyses were conducted in SPSS v26.0. Ethics approval for the analysis was provided by a community research ethics board.

A total of 267 patients met inclusion for analysis: 107 received ketamine during the COVID-19 period (mean age 44.5 years, SD 13.3; 52.0% female) and 160 served as pre-pandemic comparators (mean age 46.2 years, SD 15.2; 56.3% female). Both groups had comparable levels of treatment resistance, with a mean of 8 prior antidepressant trials (SD 5) in each cohort. Mixed model analyses showed significant overall improvements with repeated ketamine infusions across outcomes. Specifically, depressive symptoms decreased significantly (F(4, 630) = 48.73, p < .001), suicidal ideation declined (F(4, 627) = 17.34, p < .001), anxiety scores fell (F(2, 344) = 52.84, p < .001) and functional disability improved (F(2, 318) = 36.17, p < .001) from baseline to the assessed post-infusion time points. When comparing the COVID-19 cohort to the pre-pandemic controls, the mixed models did not show statistically significant differences in overall response to IV ketamine; in other words, effectiveness was comparable between the two periods. One exception was a significant group-by-infusion interaction on GAD-7 scores: pairwise comparisons indicated a greater reduction in anxiety from baseline to post-infusion 3 in the pre-pandemic control group (p = .044). However, by post-infusion 4 there was no statistically significant between-group difference in anxiety reduction (p = .078). The extracted text references figures but these were not included in the provided extraction. Adverse events, response or remission rates, and longer-term outcomes are not reported in the extracted Results section.

Rosenblat and colleagues conclude that adults with TRD who received a standard four‑infusion course of IV ketamine during COVID-19 experienced symptomatic improvements that were commensurate with those observed in patients treated before the pandemic. The authors note that this appears to be the first study to examine whether pandemic-related restrictions on in-person social interactions attenuate the antidepressant effectiveness of a treatment that must be administered face-to-face. They emphasise the clinical trade-off inherent to in-person ketamine delivery during a pandemic: potential increased exposure risk to COVID-19 weighed against a rapid-acting, potentially life-saving intervention for severe depression and suicidal ideation. The authors suggest that, given the comparable effectiveness observed, patients and clinicians need not expect an attenuated response to IV ketamine solely because of pandemic-era social restrictions. The discussion also highlights broader considerations: people with serious mental illness, including TRD, may be at elevated risk of contracting COVID-19 and experiencing worse outcomes if hospitalised, and treating these conditions could hypothetically reduce adverse COVID-related outcomes in this population, although the underlying mechanisms were not evaluated in this study. The authors acknowledge limits to generalisability, stating that it remains to be determined whether these findings extend to other psychiatric disorders or treatment modalities. The extracted text does not present a detailed list of study limitations such as potential confounding in a non-randomised design, missing data, or longer-term follow-up, beyond the general caution about generalisability.