Frequency analysis of symptomatic worsening following ketamine infusions for treatment resistant depression in a real-world sample: Results from the canadian rapid treatment center of excellence

Depressive symptoms sometimes worsen after starting antidepressant treatments, with earlier research estimating that roughly 5-10% of patients experience increased symptom severity after treatment initiation. This phenomenon has been reported across drug classes (SSRIs, TCAs, atypical antidepressants), in placebo arms of randomised trials, and even with non-pharmacological interventions such as cognitive behavioural therapy. The authors note that symptomatic worsening may reflect illness-related fluctuations, treatment-related effects, expectancy/nocebo phenomena, or a combination of factors, and that identifying the frequency of such events for a given intervention is important for clinical monitoring and treatment selection. Vincenzo and colleagues set out to establish how commonly patients with treatment resistant depression (TRD) report clinically significant worsening of depressive symptoms during an acute, real-world course of intravenous (IV) ketamine. Because ketamine acts on glutamatergic pathways rather than monoamines, the investigators aimed to describe the rate and pattern of symptom worsening following repeated sub‑anesthetic infusions, while acknowledging that a retrospective, uncontrolled design cannot determine causality. The question is framed as a pragmatic assessment of frequency to inform monitoring and decision-making in clinical practice.

The study is a retrospective analysis of outpatients treated at the Canadian Rapid Treatment Centre of Excellence (CRTCE). Inclusion criteria for the clinical service were treatment resistant depression, operationalised here as non-response to at least two adequate antidepressant trials in the current major depressive episode. The analytic sample included 164 patients with complete data; primary diagnoses were major depressive disorder (n = 142) or bipolar disorder (n = 22). Patients received an acute course of four IV ketamine infusions administered over two weeks. Dosing began at 0.5 mg/kg (actual body weight) infused over 40 minutes for the first two sessions. Patients who achieved ≤20% reduction in QIDS-SR16 score after the initial doses were eligible for a dose increase to 0.75 mg/kg for infusions three and four. Depressive symptoms were measured with the Quick Inventory of Depressive Symptomatology—Self-Report 16 (QIDS-SR16) at baseline (before infusion 1) and again 2–4 days after each infusion. The primary outcome was the proportion of patients experiencing clinically significant worsening at each post-infusion assessment, defined a priori as a ≥20% increase in QIDS-SR16 score from baseline. The authors chose the 20% threshold to maximise sensitivity, noting that the minimal clinically important difference (MCID) for QIDS-SR16 is not well established and that some prior work suggests an MCID closer to >28%. Secondary descriptive analyses stratified worsening by simple point increases on the QIDS-SR16 (no change, +1, +2, +3 points) and calculated mean increases among those whose scores rose. The data were also stratified by primary diagnosis. Planned exploratory analyses to identify predictors of worsening (age, sex, baseline severity, number of failed trials) were not pursued because the subgroup of worsened patients was very small at each time point.

The analysis included 164 participants (142 with major depressive disorder, 22 with bipolar disorder). Across the treatment course, nine participants (9/164, 5.5%) experienced clinically significant worsening (≥20% increase from baseline on the QIDS-SR16) at one or more post-infusion assessments. When examined at each time point, the frequency of clinically significant worsening varied between 1.83% and 5.49%, and 3.66% of participants met the worsening criterion at the end of the four‑infusion acute course. Eight of the nine participants who showed clinically significant worsening after one or two infusions received a dose escalation to 0.75 mg/kg for infusions three and four; the remaining patient continued on 0.5 mg/kg. Of the eight who had their dose increased, three reported improvement relative to baseline after the higher doses, while five did not improve and three of those five reported further deterioration following the increase. The bipolar subgroup (n = 22) had no reports of clinically significant worsening at any assessment. Supplementary data stratifying outcomes by simple QIDS-SR16 point increases indicated that, when scores rose, the magnitude of worsening was generally small, typically ≤3 points. Because the worsened subgroup at any given time point ranged from only 3 to 9 patients, the investigators did not perform statistical analyses to identify predictors of worsening. The extracted text does not report additional inferential statistics, confidence intervals, or formal hypothesis tests for these frequencies.

Vincenzo and colleagues interpret their findings as indicating that clinically significant worsening of depressive symptoms during an acute, community‑based course of IV ketamine for TRD is uncommon. The observed point prevalences across assessments (approximately 2–6%) and a 3.66% rate at treatment end are presented as broadly comparable to rates reported for other antidepressant treatments in the literature. Because the study lacked a placebo or active comparator, the authors emphasise that causality cannot be established; natural symptom fluctuation, extrinsic life factors, comorbidity, concomitant medications, and nocebo effects are cited as plausible contributors to observed worsening. The authors highlight several nuances that may affect interpretation. Their ≥20% threshold for clinically significant worsening was conservative and may yield lower estimates than studies using any deterioration as a criterion; conversely, other stringent criteria in some trials have produced comparable rates of worsening. The absence of worsening in the small bipolar subgroup is noted as an intriguing preliminary observation but one limited by sample size. The community, private‑clinic setting may also influence outcomes and generalisability—potentially reducing nocebo-related deterioration compared with placebo‑controlled RCTs while enhancing external validity for real‑world, treatment‑seeking TRD populations. Key limitations acknowledged by the authors include the single‑centre, retrospective, open‑label design, reliance on self‑reported symptoms (QIDS‑SR16), and the absence of a control group. These design features permit subject‑expectancy bias and preclude differentiation of treatment effects from the natural course of illness. The small number of patients who worsened prevented meaningful subgroup or predictor analyses. Clinically, the investigators suggest routine measurement‑based care to detect worsening early; their data also hint that worsening after the first infusion may predict persistent deterioration, but they state that larger studies are required to confirm this and to identify predictors. Finally, the authors call for longitudinal research in larger and more diverse cohorts to better understand mechanisms and risk factors for symptomatic worsening after ketamine and other antidepressant treatments.