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

This retrospective analysis (n=164) assessed the rates of symptomatic worsening in patients with unipolar and bipolar treatment-resistant depression (TRD) following a two-week course of IV ketamine. Using the QIDS-SR16 to assess symptoms, it was found that clinically significant worsening for those with unipolar TRD fluctuated between 1.83% to 5.49%, while no participants with bipolar TRD reported symptomatic worsening. Rates of symptomatic worsening were similar to conventional antidepressants.


“Antidepressants are associated with symptomatic worsening in a subgroup of patients. Replicated evidence has demonstrated rapid and robust antidepressant effects with intravenous (IV) ketamine in treatment resistant depression (TRD); however, the risk of ketamine worsening depressive symptoms in a subgroup of patients remains unknown. Herein we report a retrospective analysis on the rates of symptomatic worsening during an acute course of IV ketamine in individuals with unipolar (n = 142) and bipolar (n = 22) TRD. Adults (N = 164; mean age = 45.97) with TRD underwent four sub-anesthetic infusions (0.5-0.75 mg/kg over 40 min) of IV ketamine over two weeks, and were assessed with the Quick Inventory for Depression Symptomatology-Self Report-16 (QIDS-SR16) at baseline and after each infusion. The primary outcome was the proportion of patients experiencing clinically significant worsening of depressive symptoms (≥20% increase on the QIDS-SR16) at each time point relative to baseline. Secondary analyses explored trends in the results. The frequency of clinically significant worsening fluctuated between 1.83% to 5.49%, with no identifiable trend across time. Zero individuals with bipolar TRD reported symptomatic worsening. Limitations include the single-centered, uncontrolled, retrospective nature of this study. Rates of symptomatic worsening associated with IV ketamine therapy for TRD appear to be very low and similar to conventional antidepressants.”

Authors: Joshua Di Vincenzo, Orly Lipsitz, Nelson B. Rodrigues, Brett D. M. Jones, Hartej Gill, Yena Lee, Leanna M. W. Lui, Kayla M. Teopiz, Roger Ho, Kangguang Lin, Flora Nasri, Roger S. McIntyre & Joshua D. Rosenblat


A retrospective analysis of 164 patients with treatment resistant depression (TRD) who received four sub-anesthetic infusions of IV ketamine over two weeks found that 1.83% to 5.49% experienced clinically significant worsening of depressive symptoms, with no identifiable trend across time.

  1. Introduction

While many patients with depression significantly benefit from pharmacological treatments, approximately 5 – 10% of patients experience increased severity of depressive symptoms compared to baseline after taking antidepressants. This worsening of symptoms has been observed across treatment modalities and across various depression rating scales.

Identifying patients with worsening symptoms while receiving a specific treatment does not establish a causal relationship, but is important for patient monitoring and defining treatment goals. Various clinical variables, including early negative response and high anxiety, may predict worsening symptoms with antidepressants, whereas early positive response may predict a sustained response with continued treatment.

Ketamine has been demonstrated to have rapid and robust acute antidepressant effects and to reduce suicidal thoughts in individuals with treatment resistant depression. However, some individuals experience worsening of depressive symptoms following repeated ketamine infusions, which may be different as compared to conventional monoaminergic antidepressants.

  1. Methods

Effectiveness, safety, and tolerability results for IV ketamine administration at CRTCE have been previously reported. Outpatients with TRD received four IV ketamine infusions over two weeks and were assessed using the QIDS-SR16 at baseline, prior to each infusion, and after the four infusions.

We assessed patients who reported clinically significant worsening on the QIDS-SR16 from their baseline score at each infusion, and calculated mean QIDS-SR16 increase among those whose QIDS-SR16 score did increase.

The authors planned to analyze the subgroup of patients with worsening depressive symptoms, but due to the small sample size, this analysis could not be completed.

  1. Results

Nine out of 164 participants reported clinically significant worsening from baseline on the QIDS-SR16 after one or more infusions. Eight out of nine participants who received a dose increase reported improvements in depressive symptoms, relative to baseline, after infusions 3 and 4, while one patient remained on the 0.5 mg/kg dose.

  1. Discussion

Herein we report that 3.66% of patients with treatment-resistant depression experienced clinically significant depressive symptom worsening during an acute course of IV ketamine treatment.

Our results suggest that a small proportion of patients receiving IV ketamine for TRD will reliably report worsening of depressive symptoms following antidepressant treatment, and that this proportion is similar across different modalities of antidepressant treatment. Many factors could contribute to a worsening of depressive symptoms following treatment with antidepressant drugs like ketamine, including fluctuations in mood, life events, menstrual/hormonal cycles, comorbidities, and concomitant medications. The nocebo effect may also have contributed to the worsening of depressive symptoms.

Moreover, worsening of depressive symptoms does not appear to be a significant cause for discontinuation of ketamine therapy. However, worsening after infusion 1 may indicate persistent worsening, and clinicians may be able to determine early on whether to continue, increase dose, or discontinue altogether.

In our current study, 2 – 6% of patients reported clinically significant worsening, which is marginally lower than what has been reported in previous studies. This may be explained by methodological and population factors.

In our sample of 22 patients with bipolar TRD, zero experienced symptomatic worsening at any time point. This preliminary finding is encouraging and merits further investigation.

Our community-based study may possess greater external validity (generalizability) than an RCT to the real-world, treatment-seeking, complex TRD population, as compared to conventional antidepressant studies that were primarily conducted in patients whose depression is not treatment resistant.

The study herein has several limitations, including a lack of active or placebo control, subject-expectancy bias, and the potential influence of comorbidity on treatment outcomes.

Ketamine, a novel antidepressant, has provided much hope and optimism for patients and clinicians, but a very small proportion of patients report worsening depression scores after initiating treatment. Clinicians must remain vigilant for signs of worsening among their patients.

CRediT authorship contribution statement

Joshua D. Di Vincenzo, Orly Lipsitz, Nelson B. Rodrigues, Brett D.M. Jones, Yena Lee, Leanna M.W. Lui, Kayla M. Teopiz, Roger Ho, Kangguang Lin, Flora Nasri, Roger S. McIntyre, Joshua D. Rosenblat contributed to this work.

Declaration of Competing Interest

JDR has received grant support from CIHR, the Canadian Cancer Society, the Canadian Psychiatric Association, the American Psychiatric Association, the American Society of Psychopharmacology, and the University of Toronto.


Institutes associated with this publication

University of Toronto
The University of Toronto has established the Psychedelic Studies Research Program.