Low-dose ketamine for treatment resistant depression in an academic clinical practice setting

This open-label retrospective study (n=41) evaluated the efficacy and safety of intravenous ketamine (35mg/70kg) infusion in a sample of patients who had treatment-resistant depression (TRD) and were being treated in a ‘naturalistic’ clinical context. Low-dose ketamine was efficacious and generally well-tolerated in the sample population, as participants reported improvements in depressive symptoms with a 53.7% response rate 24 hours post-infusion.


Background: Recent studies demonstrating a rapid, robust improvement in treatment resistant depression (TRD) following a single sub-anesthetic infusion of ketamine have generated much excitement. However, these studies are limited in their generalizability to the broader TRD population due to their subject exclusion criteria which typically limit psychiatric comorbidity, concurrent medication, and level of suicide risk. This paper describes the safety and efficacy of sub-anesthetic ketamine infusions in a naturalistic TRD patient sample participating in a real-world TRD treatment program within a major university health system.

Methods: The effects of a sub-anesthetic dose (0.5 mg/kg) of ketamine infused IV over forty minutes on TRD patients participating in a treatment program at the University of California, San Diego was investigated by retrospectively analyzing the medical charts of 41 adult TRD patients with a diagnosis of Major Depressive Disorder (MDD) or Bipolar Disorder (BD).

Results: Subjects were aged 48.6, 78% white, 36.6% female, and 82.9% had MDD. Significant psychiatric comorbidity existed in 73%. Average pre-infusion BDI score was 32.6 ± 8.4 (S.D) and dropped to 16.8 ± 3.1 at 24-h post-infusion (p < 0.001). The 24-h response (≥ 50% reduction from pre-infusion) and remission (BDI <13) rates were 53.7% and 41.5%, respectively. Three quarters of responders maintained responder status at 7-days. Ketamine infusions were well tolerated with occasional nausea or anxiety and mild hemodynamic effects during the infusion.

Limitations: Retrospective nature of this study, lack of control group and use of self-report depression ratings scales.

Conclusions: This is the first published study of sub-anesthetic ketamine infusions in a real-world TRD population. The results suggest that this treatment is effective and well tolerated in this population”

Authors: David Feifel, Benjamin Malcolm, Danielle Boggie & Kelly Lee



Clinical depression is a prevalent debilitating psychiatric illness involving physical, mood, and cognitive symptoms. Treatment resistant depression (TRD) is defined as failure of at least two trials of first line antidepressants of both adequate duration and dose, and is treated with electroconvulsive therapy or repetitive transcranial magnetic stimulation.

Several recent studies have demonstrated that a single infusion of low-dose ketamine significantly reduces symptoms of depression within 24-h in TRD patients with Major Depressive Disorder (MDD) or Bipolar Affective Disorder (BD).

Ketamine has an unprecedented average response rate and speed of efficacy for a depression treatment, let alone a treatment for TRD. However, most studies have excluded patients with suicidal behavior or comorbid psychiatric conditions other than anxiety.

It has been shown that subjects recruited for clinical trials in depression are poorly representative of outpatients who seek treatment for depression.

Ketamine’s safety and efficacy in reducing suicidal ideation have been demonstrated in many studies, but the inclusion and exclusion criteria for these studies are not representative of patient selection criteria in real-world clinical practice.

Ketamine has shown promising results in clinical trials, but at least three open label studies have investigated its efficacy and safety in TRD patients without excluding suicidal ideation or concomitant medication. These studies reported lower response rates and higher rates of adverse events.

Based on the published studies suggesting robust and rapid efficacy of sub-anesthetic ketamine, an outpatient ketamine treatment program was developed at University of California at San Diego.

2.1. Patient selection for ketamine treatment

Patients receiving ketamine infusions for treatment of TRD were self-referred or referred by their treating psychiatrist. The prescribing psychiatrist determined whether ketamine was a favorable risk vs benefit treatment for the patient, and this was less formal and less restrictive than the inclusion and exclusion criteria used in prospective research studies.

Candidates for treatment with ketamine were generally experiencing severe depression that significantly reduced their quality of life or placed them at significant risk of suicide. They had failed several trials of medications and/or ECT.

Patients deemed appropriate for ketamine treatment were provided with relevant information about the treatment, including potential risks and limitations, and were given an opportunity to ask questions.

2.2. Ketamine infusions

Ketamine infusions were conducted in a UCSD same-day outpatient procedure center. Patients were monitored for mental status changes, orthostatic hypotension or unsteadiness, and any other significant adverse effects, and were deemed appropriate for discharge home under the care of a present caregiver.

Patients completed a Beck Depression Inventory (BDI) scale prior to their infusion, and again just before leaving the infusion center. They were instructed to complete another BDI 24 h post-infusion.

2.3. Retrospective analysis

A retrospective chart review was conducted of the first 50 patients who received low-dose ketamine infusion in this clinical program. The charts were abstracted using an electronic abstraction sheet.

The dose of ketamine administered was verified by reviewing the patient’s weight at the time of infusion and nursing documentation of the milligrams administered. Efficacy and safety data were extracted from the BDI scores pre-infusion, 1-h, 24-h, and 7-days post-infusion.

2.4. Clinical outcomes and statistical analysis

The primary outcome of the study was the percentage of patients classified as responders at 24-h after infusion, and other outcome measures included response at 1-h and 7-days, remission rate, and mean change in BDI scores from baseline to 1-h, 24-h, and 7-days.

3.1. Sample demographics

41 patients met inclusion criteria for this analysis, 8 were excluded due to missing baseline or 24-h BDI scores, and 1 was excluded due to being 18 years of age. No serious adverse events were identified.

3.2. Psychiatric and cardiovascular history

Thirty-four patients had a primary diagnosis of MDD, 7 had BD, and 10 had hypertension.

3.4. Efficacy

Fifty-four percent of patients met the criterion for response 24 h after ketamine infusion, and 41.5% achieved remission. The mean baseline BDI score improved to 16.8 12.1 (49.5% reduction) and 16.0 11.4 (51% reduction), respectively.

3.5. Hemodynamic effects

Ketamine increased blood pressure and heart rate in 17.1% of patients and 29.3% of patients had a rise in blood pressure or heart rate greater than 25 BPM.

3.6. Adverse effects

Three patients required an antiemetic due to post-infusion nausea, one patient experienced vomiting, and one patient required oral lorazepam due to significant pre-existing anxiety. All patients met the criteria for remission at 24 h.

3.7. Subjective effects and patient experience

Patients reported experiencing a psychedelic phenomenon, including perceptual disorders, a sense of detachment from their bodies (dissociation), enhancement of insight into reality, and a sense of relaxation or well-being. All but one reported that the experience was pleasant.

  1. Discussion

In this retrospective study, we evaluated the efficacy and safety of a single infusion of low-dose ketamine in a sample of patients with TRD treated in an outpatient academic clinical practice.

The response rate in this sample at 24-h after the index infusion was 53.7%, which is slightly lower than the average response rate of 61% reported in prospective studies evaluating ketamine in TRD patients. However, the presence of concomitant medication(s) in these patients makes interpretation of ketamine’s efficacy somewhat more complicated.

The Diamond et al. study, which utilized the BDI self-rating as the primary measure, found a lower response rate (11%) and worse tolerability within the first 24-h after ketamine infusion compared to the UCSD ketamine treatment program, which administered ketamine in an outpatient procedure center.

Ketamine may augment or diminish the response to utilization of ketamine in TRD, but post-hoc exploratory analyses using contingency tables did not reveal apparent differences in response or remission rates by gender, comorbid anxiety, or medication use.

Although the study is more generalizable to patients with TRD than clinical trials due to less restrictive exclusion criteria, there are several limitations to the study including the retrospective nature of the study design, lack of a control group, and a more financially secure sample population.

Study details

Compounds studied

Topics studied
Depression Treatment-Resistant Depression

Study characteristics


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