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
Papers cited by this study that are also in Blossom
Berman, R. M., Cappiello, A., Anand, A. et al. · Biological Psychiatry (2000)
Coyle, C. M., Laws, K. R. · Human Psychopharmacology (2015)
Kraus, C., Rabl, U., Vanicek, T. et al. · International Journal of Psychiatry in Clinical Practice (2017)
Sos, P., Klirova, M., Novák, T. et al. · Neuropsychiatric Disease And Treatment (2013)
Clinical depression is common and disabling, and a substantial minority of patients fail to respond to multiple standard antidepressant trials. Earlier research shows that a single sub‑anesthetic intravenous infusion of ketamine can produce rapid antidepressant effects in treatment‑resistant depression (TRD), with aggregated response rates around 61% in published randomised and open‑label studies. However, most of those prospective trials applied strict inclusion and exclusion criteria that limited psychiatric comorbidity, concurrent medications and suicide risk, raising concerns about the generalisability of their findings to routine clinical populations. This paper reports a retrospective analysis of outcomes following a single 0.5 mg/kg, 40‑minute intravenous ketamine infusion delivered in an outpatient academic clinical programme at the University of California, San Diego. Feifel and colleagues set out to examine the safety and efficacy of that initial infusion in a ‘‘naturalistic’’ TRD sample that included prevalent comorbidities and concurrent psychotropic medications, using self‑reported Beck Depression Inventory (BDI) scores at baseline, 1‑hour, 24‑hours and, when available, 7‑days post‑infusion as the primary outcome measures. The study aims to assess real‑world response and tolerability outside the constraints of typical clinical trials.
Patients were referred to the UCSD ketamine programme by themselves or by treating psychiatrists and were interviewed by the prescribing psychiatrist to determine whether the clinical risk–benefit balance favoured a trial of ketamine. Unlike prospective trials, there were no fixed a priori inclusion/exclusion criteria; candidacy was based on clinical judgement. Typical reasons supporting treatment were severe, functionally impairing depression or suicide risk after failure of multiple antidepressant trials (generally at least four), and some patients had previously received ECT or rTMS. Relative contraindications that did not automatically preclude treatment included a history of psychosis, uncontrolled hypertension, prior adverse reaction to ketamine, active medical conditions, substance use, pregnancy or breastfeeding. Patients provided written informed consent detailing risks and the non‑FDA‑approved status of the treatment. Infusions were delivered in a same‑day outpatient procedure centre. Ketamine was administered at 0.5 mg/kg based on actual body weight, infused intravenously over 40 minutes. Patients were allowed to continue concurrent psychotropic medications; morning benzodiazepines or opiates were held on the day of infusion. Monitoring included periodic vital signs, oxygen saturation and mental status during the infusion and for at least 30 minutes afterwards. Nurses and the attending psychiatrist assessed patients for ongoing mental status changes, orthostatic instability or other adverse effects prior to discharge. Patients completed the BDI prior to infusion, immediately before leaving the centre (≈1 hour post‑infusion), and were given a BDI to complete at 24 hours; a follow‑up visit typically occurred 24–72 hours after infusion. An additional 7‑day BDI was solicited from patients who reported substantial benefit at 24 hours. Feifel and colleagues conducted a retrospective chart review of the first 50 patients treated in the programme; charts were included if patients were ≥18 years old, had a primary diagnosis of Major Depressive Disorder (MDD) or Bipolar Disorder (BD), and had recorded pre‑infusion, 1‑hour and 24‑hour BDI scores. The institutional review board approved the review. One author abstracted de‑identified data using a predefined electronic abstraction sheet agreed by the study team. Extracted variables included demographics, psychiatric and medical history, prior treatments, concurrent medications, ketamine dose verification, BDI scores at the specified timepoints, nursing and physician notes, and safety data (blood pressure, heart rate, oxygenation). The primary outcome was response at 24 hours, defined as ≥50% reduction in BDI from baseline; remission was defined as BDI < 13. Changes in mean BDI were analysed with paired Student’s t‑tests (α < 0.05). Predefined hemodynamic thresholds (SBP increase >20 mmHg, DBP increase >10 mmHg, HR increase >25 bpm) were summarised with frequencies, and adverse events were identified from nursing documentation and medication administration records.
Of the first 50 charts reviewed, 41 met inclusion criteria; eight were excluded for missing baseline or 24‑hour BDI and one for age <18. No serious adverse events were identified in excluded charts. The analysed sample had a mean age of 48.6 ± 12.7 years. Thirty‑four patients (82.9%) had a primary diagnosis of MDD and seven (17.1%) had BD. Anxiety disorders were the most common psychiatric comorbidity (24 patients, 58.5%). Hypertension was the most common cardiovascular comorbidity (10 patients, 24.4%). Concurrent psychotropic medication use was common: patients were taking an average of 2.4 psychotropic agents at infusion and seven patients (17.1%) were taking no psychotropic medications at the time of ketamine. Efficacy outcomes showed rapid and substantial reductions in self‑reported depressive symptoms. The mean baseline BDI was 32.6 ± 8.4. At 1 hour post‑infusion the mean BDI fell to 16.8 ± 12.1 (49.5% reduction; p < 0.001) and at 24 hours to 16.0 ± 11.4 (51% reduction; p < 0.001). Twenty‑four hours after infusion, 22 of 41 patients (53.7%) met the predefined response criterion (≥50% reduction) and 17 (41.5%) met remission (BDI < 13). One‑hour response and remission rates were 51% and 44%, respectively. Patients with BD and MDD showed comparable mean percentage reductions at 24 hours (49% and 51%). Among the 22 responders at 24 hours, 16 had a recorded 7‑day BDI and 12 of those 16 (75%) remained responders at 7 days; when excluding charts missing 7‑day scores, the authors report a 7‑day response rate of 46% (16/35), comparable with prior prospective studies. Hemodynamic effects were generally modest and transient. Seven patients (17.1%) experienced an increase in systolic blood pressure >20 mmHg, 12 patients (29.3%) had an increase in diastolic blood pressure >10 mmHg, and one patient had a heart‑rate increase >25 bpm. No patient required antihypertensive intervention and no oxygen desaturation events (SaO2 < 93%) occurred. Adverse events recorded in the immediate peri‑infusion period included nausea requiring antiemetic in three patients (7.3%) and one episode of vomiting. One patient with significant baseline anxiety required stopping the infusion at 10 minutes and received 1 mg oral lorazepam; the infusion was restarted after symptom control and the patient met remission at 24 hours. Five patients had small (<20%) increases in BDI at 24 hours that were not considered clinically significant by patients or clinicians. Subjective experiences during infusion were described in all charts as a ‘‘psychedelic’’ phenomenon varying in intensity and content (perceptual changes, dissociation, emotional insight, relaxation or wellbeing). Among 18 charts that included detailed emotional descriptions, all but one characterised the experience as pleasant. Select short patient comments documented included: "It was like I was in a biological membrane…very pleasurable" and "it melted my armour (of depression)."
Feifel and colleagues interpret their findings as supporting a rapid antidepressant effect of a single low‑dose ketamine infusion in a real‑world outpatient TRD population, with generally favourable tolerability. The 24‑hour response rate of 53.7% is somewhat lower than the pooled 61% reported in prior prospective studies, but the authors note methodological differences that complicate direct comparison: this study used the self‑rated BDI rather than clinician‑administered scales (MADRS, HAM‑D), allowed concurrent medications, and was delivered in a naturalistic clinical setting rather than a tightly controlled trial. Those factors might reduce or modulate measured efficacy, and expectancy or selection biases could also influence open‑label or retrospective results. The discussion contrasts these findings with other open‑label series that enrolled less selected populations and reported lower response and greater immediate adverse effects; setting may be important, as the investigators observed poorer outcomes when ketamine was administered in noisy, chaotic ECT or PACU environments versus a dedicated outpatient procedure centre. Exploratory post‑hoc analyses in this cohort did not reveal clear differences in response or remission by gender, comorbid anxiety or medication use, but the authors emphasise the study was not powered for subgroup comparisons. Hemodynamic increases were common but transient and did not necessitate intervention. Limitations are acknowledged in detail: the retrospective design raises risks of selection and information bias and limits adverse‑event ascertainment to what was documented in charts; missing data (notably missing BDI scores) may bias estimates; lack of a control group prevents definitive attribution of effects to ketamine versus placebo or regression to the mean, although large effects in randomised trials elsewhere mitigate this concern; and the sample may be unrepresentative because patients self‑paid for treatment and the cohort was drawn from a single academic site with all patients assessed by a single prescribing psychiatrist. Taken together, the authors conclude that, within these constraints, a single 0.5 mg/kg ketamine infusion produced rapid antidepressant effects and was generally well tolerated in this naturalistic outpatient TRD sample, but they underline the need to interpret findings in light of the study's methodological limitations.
Clinical depression is a prevalent debilitating psychiatric illness involving physical, mood, and cognitive symptoms. It has been reported that approximately 7.6% of the United States (US) population over the age of 12 experience depression over any given two week periodand despite the increasing number of antidepressant medication prescriptions, suicides in the United States increased by 24% between 1999 to 2014, making it the 10th leading cause of death overall in the United States. Approximately one-third of patients with major depression fail to adequately respond to serial trials of currently approved antidepressants, which all share the primary effect of modulating monoamine neurotransmission. While the definition of Treatment Resistant Depression (TRD) is variable, literature has commonly defined the condition as failure of at least two trials of first line antidepressants of both adequate duration and dose. There are limited treatment options for TRD. Electroconvulsive Therapy (ECT) is currently considered the gold standard for TRD, however is limited by cognitive side effects as well as need for anesthesia and seizure induction. Repetitive transcranial magnetic stimulation (rTMS) is a more recent option for TRD which is better tolerated than ECT but may take longer to exhibit efficacy. 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). A review of studies investigating low-dose ketamine found that aggregated response rates (≥ 50% reduction from the baseline score on a validated depression rating scale) in randomized controlled trials as well as open label studies were 61%. These findings represent an unprecedented average response rate and speed of efficacy for a depression treatment, let alone a treatment for TRD and they have, understandably, led to great interest in the possibility that ketamine, or another drug designed to mimic ketamine's mechanism of antidepressant action, may represent an effective and rapid treatment for TRD. However, the aforementioned prospective published studies generally selected subjects who met a priori determined inclusion and exclusion criteria. For example, most of these studies either only included patients who were willing and able to discontinue their psychotropic medicationsor severely limited allowed medications. A history of suicidal behavior, active suicidal ideation, and comorbid psychiatric conditions other than anxiety were typically exclusionary in the earlier studies of ketamine for TRD. It has been shown that subjects recruited for clinical trials in depression are poorly representative of outpatients who seek treatment for depression. Indeed, it has been estimated that 86% of outpatients with clinical depression would not qualify for a typical clinical trial in depression due to exclusion criteria and that candidates who would be excluded are more chronically ill and have greater psychosocial impairment. As evidence accrued demonstrating ketamine's safety and its efficacy in reducing suicidal ideation, the inclusion and exclusion criteria of clinical studies investigating ketamine's antidepressant effects have become less stringent. Nevertheless, even these recent studies have subject eligibility criteria that are not representative of patient selection criteria in real -world clinical practice.. In some recent studies, suicidal ideation is an inclusion requirement rather than an exclusion criteria as it was in earlier studies.. Given the strong interest in ketamine's potential as a treatment for TRD based on the highly positive results obtained in published clinical trials, it is important to investigate its efficacy and safety in patients who are more representative of the TRD population. In this regard, it is notable that at least three open label studies investigated the effects of IV low-dose ketamine in a TRD sample that did not exclude suicidal ideation or concomitant medication. The reported response rates in these studies were 11-25% after a single infusion, a rate much lower than reported in studies that had more restrictive eligibility criteria, and at least one of these reported a significantly higher rate of adverse events as well. These findings raise questions about the generalizability of the prospective controlled and open-label studies which showed robust efficacy and tolerability of ketamine in carefully selected TRD subjects. Based on the published studies suggesting robust and rapid efficacy along with established safety of sub-anesthetic ketamine, an outpatient ketamine treatment program for patients with TRD was developed by one of the authors (DF) at University of California at San Diego (UCSD). In this paper, we report the results of a retrospective analysis of the safety and efficacy of the initial ketamine infusion administered to a cohort of patients in this program.
Patients who received ketamine infusions were generally self-referred or referred by their treating psychiatrist for consideration to receive ketamine treatment for TRD. Candidates were interviewed by the prescribing psychiatrist (author DF) to assess the severity of their depression as well as the extent and outcome of previous treatment trials. As is typical for a clinical practice, the criteria for accepting any patient for ketamine treatment in this clinical program was the determination of a favorable risk vs benefit calculus for that particular patient as determined by the treating clinician. This is a process which is considerably less formal and less restrictive than the a priori inclusion and exclusion criteria utilized in prospective research studies because in those studies patient characteristics determined to be unfavorable for a treatment are predetermined for all prospective subjects and applied immutably as exclusionary criteria. However, in real-world clinical treatment, patient characteristics rendering a treatment such as ketamine an unfavorable option may be sufficiently counterbalanced, in the judgement of the treating clinician, by other patient characteristic or circumstances. For example, a clinician may decide to treat a patient with uncontrolled hypertension with ketamine infusions if he has severe debilitating depression associated with concerning loss of appetite and weight loss and suicidal impulses that has not responded to all other reasonable treatments including ECT. However, in a clinical study in which uncontrolled hypertension is an exclusion criteria, this same patient would not be enrolled. While there were no formal criteria for treatment with ketamine in the clinical practice we are reporting on, candidates were generally deemed to be appropriate if they were experiencing severe depression that significantly reduced their quality of life or placed them at significant risk of suicide and they had failed to respond to several trials of medications in the current episode despite an adequate dose and duration (at least four weeks) or due to intolerance of the medication. Some patients had also failed a course of ECT and/or rTMS. In contrast, factors that significantly reduced, but did not necessarily preclude a patient's candidacy included a history of a psychotic disorder, uncontrolled hypertension, a previous adverse reaction to ketamine, significant active medical conditions, active substance use, pregnancy or breastfeeding. Patients deemed appropriate for a trial of ketamine treatment were provided with relevant information about the treatment, including the fact that the treatment is not currently FDA approved and not reimbursed by insurance. Patients were provided with a written informed consent document for treatment which described potential risks and limitations in detail as well as reasonable expectations of ketamine treatment for depression. Patients were given an opportunity to ask questions which were addressed by the prescribing physician.
Ketamine infusions were conducted in a UCSD same-day outpatient procedure center. Patients were permitted to continue their current medication regimen unchanged, but if that regimen included a morning benzodiazepine or opiate, they were asked to hold it on the morning of their ketamine infusion. Ketamine was dosed at 0.5 mg/kg based on the patient's actual body weight on the day of infusion and infused over 40 min, which is consistent with most previous studies of ketamine for TRD. The ketamine was prescribed by the treating psychiatrist (DF) and prepared by the procedure center pharmacy staff. The infusion was administered by a nurse on staff at the infusion facility who also conducted the monitoring. Safety monitoring included periodic assessment of vital signs, oxygen saturation, and mental status during the infusion, and for at least 30-min post-infusion. Beginning 30 min post-infusion, patients were assessed by the nurse and the attending psychiatrist (DF) for the persistence of significant mental status changes, orthostatic hypotension or unsteadiness and any other significant adverse effect (e.g. nausea) that required ongoing monitoring. In the absence of any of these, patients were deemed appropriate for discharge home from the center 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 (approximately 1 h post-infusion). Patients were provided with a BDI and instructed to complete it 24 h post-infusion and to document in narrative fashion any changes in their mental state since the infusion. The BDI and narrative were reviewed during a follow-up visit which typically occurred 24-72 h after the infusion. An additional BDI survey was solicited from patients who reported having a significant positive response on their BDI at 24 h post-infusion.
A retrospective chart review of the first 50 patients who received low-dose ketamine infusion in this clinical program was conducted. This retrospective study was approved by UCSD Human Research Protection Program. Charts were included in the analysis if the patient's primary diagnosis was MDD or BD, they were ≥18 years old, and there was a record of the pre-infusion, 1-h and 24-h post-infusion BDI score. The charts were abstracted by one of the authors (BM) using an electronic abstraction sheet. The abstraction sheet was developed before chart reviews began by identifying informational elements from the chart that would be relevant to the analysis. The informational elements were determined by consensus of the authors. The information entered into the abstraction sheet was de-identified. 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. Extracted demographic variables included age, weight, sex, ethnicity, psychiatric history (e.g. psychiatric diagnoses, past medication trials during current episode, history of ECT, past ketamine), medical history, past treatments and concurrent psychiatric medications at the time of infusion. Extracted efficacy data included BDI scores pre-infusion, 1-h, 24-h, and, when available, 7-days post-infusion as well as relevant documented comments by attending psychiatrist and nurses. Safety variables extracted included blood pressure, heart rate, and oxygenation status. Adverse effects were assessed by review of the nursing documentation and medication administration record (MAR) records for the administration of medications with antiemetic, anxiolytic, analgesic, or cardiovascular indications during or in the immediate post-infusion period. Any documented verbal reports by patients during or immediately after infusions regarding their subjective experience were also extracted.
For most outcome variables, descriptive statistics such as means and standard deviation are reported. Demographic and safety variables, adverse effects, and subjective experience reports were described with mean ± standard deviation for continuous variables and frequencies for categorical variables. The study's primary outcome was percentage of patients classified as responders at 24-h after infusion, with response defined as ≥ 50% reduction in their BDI score from baseline. This was the same primary outcome used in almost all the published randomized and open-label prospective studies of ketamine for depression, although we used a self-reported rather than clinician administered scale. Other outcome measures included response at 1-h and 7-days, remission rate defined as (BDI < 13)at 24-h and 7-days, and mean change in BDI scores from baseline to 1-h, 24-h, and 7-days analyzed using a paired student t-test with α < 0.05 considered significant. Significant changes in hemodynamic parameters, delineated a priori as an increase greater than 20 mmHg in systolic blood pressure (SBP) or 10 mmHg in diastolic blood pressure (DBP) as well as 25 beats per minute (BPM) for heart rate (HR) were described using frequencies.
Of the first 50 patient charts examined, 41 met inclusion criteria for this analysis. Eight patients were excluded due to missing either a baseline or 24-h BDI score and one patient was excluded due to being < 18 years of age. Excluded charts were reviewed for serious adverse events of which none were identified. Subjects mean age was 48.6 ± 12.73 years. Demographic variables including gender and ethnicity are displayed in Table. All patients had failed therapy with at least four antidepressant medications previously; 11 (26.8%) had received past ECT, 10 (24.4%) had past rTMS, and 5 (12.2%) had taken ketamine recreationally at least once by intranasal (n = 1) or oral (n = 4) routes in the remote past.
Thirty-four (82.9%) patients had a primary diagnosis of MDD while 7 (17.1%) patients had BD. Anxiety was the most common psychiatric comorbidity and was present in 24 (58.5%) patients, while hypertension was the most common pre-existing cardiovascular comorbidity occurring in 10 (24.4%) patients. Other comorbid psychiatric conditions are displayed in Table.
Tablesummarizes the concurrent medication(s) of the patient included in this analysis. Patients were taking an average of 2.4 psychotropic medications concurrently when they received ketamine therapy (Table). There were 7 patients (17.1%) who were not taking any psychotropic medication at the time of ketamine therapy.
Fifty-four percent of the sample (n = 22) met the criterion for response 24 h after ketamine and 41.5% (n = 17) achieved remission. Response and remission rates for 1-h post infusion assessments were 51% and 44%, respectively. The mean baseline BDI score was 32.6 ± 8.43 (SD) which improved to 16.8 ± 12.1 (49.5% reduction; p < 0.001) and 16.0 ± 11.4 (51% reduction; p < 0.001), 1-h and 24-h post-infusion, respectively (Fig.). Patients with BD and MDD had comparable reductions in BDI at 24-h (49% and 51%). Sixteen of the 22 patients who were responders at 24-h had record of a 7-day post-infusion BDI. Among that subset of patients, 12 (75%) continued to meet the responder criterion. The mean BDI scores for this subset of patients across the 7 days is illustrated in Fig..
Effects on heart rate and blood pressure differed from patient to patient although ketamine tended to produce a modest and transient increase in blood pressure and heart rate. Seven patients (17.1%) experienced a rise in SBP > 20 mmHg and 12 (29.3%) had a rise in DBP > 10 mmHg, while one patient had a rise in HR > 25 BPM. No patient's blood pressure required intervention with antihypertensive medication and no oxygen desaturation (SaO2 < 93%) events occurred.
Three patients required the use of an antiemetic (7.3%) due to postinfusion nausea while they were still in the infusion center, and one patient experienced vomiting. One patient with significant pre-existing anxiety at baseline required stopping the infusion within 10 min and the administration of 1 mg of oral lorazepam. After approximately 15 min of receiving the lorazepam, the patient requested the infusion be re-started and was able to finish the infusion without further problems or excessive anxiety. Notably this patient met the criteria for remission at 24 h. Five of the patients had a mild (< 20%) increase in their BDI from baseline to 24 h. However, the score increases were small and not identified as clinically significant by patients or treating psychiatrist.
Every patient reported experiencing a 'psychedelic' phenomenon although the quality and intensity varied. The subjective phenomenon they reported including one or more of the following: perceptual disorders, a sense of detachment from their bodies (dissociation), enhancement of insight into reality, a sense of relaxation or well-being. Among the charts that included patient descriptions of the emotional quality of the psychedelic experience (n = 18), all but one reported that it was pleasant. Comments made by patients right after the infusion included: "It was like I was in a biological membrane…very pleasurable"; "it was like it melted my armor (of depression)"; "Ketamine filled in my missing piece. I feel whole for the first time since the accident 33 years ago." Select comments from patients that felt a therapeutic benefit at 24-h included: "the world was brighter"; "a Christmas miracle"; and "I was finally standing up straight and experiencing the world".
In this retrospective study, we evaluated the efficacy and safety of an initial 0.5 mg/kg, 40-min intravenous ketamine infusion in a sample of TRD patients treated as part of an outpatient academic clinical practice. We believe this to be the first report of ketamine infusion treatment for TRD patients participating in a clinical practice (rather than prospective research), although a retrospective report of oral ketamine treatment in a depressed hospice population has been reported. Our results generally show that a single infusion of low-dose ketamine is efficacious and generally well tolerated in the sample population treated in a 'naturalistic' clinical context. The response rate in this sample at 24-h after the index infusion (53.7% responders) is slightly lower than the average response rate of 61% reported at 24-h post infusion in prospective studies evaluating ketamine in TRD patients, although those studies tended to use an interviewer-based rating scale (MADRS, HAM-D) as the primary measure rather than BDI. Excluding the 6 patients whose charts were missing 7- day BDI scores, the 7-day response rate was 46% (16/35). This is comparable to the 7-day response rates from prospective studies (35-52%). Of note, the presence of concomitant medication(s) in these patients makes interpretation of ketamine's efficacy somewhat more complicated. A previous meta-analysis found ketamine to have a larger effect size in open-label trials compared to randomized trials, which the authors attributed to an expectancy bias. This may suggest that ketamine was slightly less efficacious in our sample given patients were aware they were receiving ketamine. However, the authors also remark on the disparity of response rates in published literature and call for larger sample sizes to ensure more precise estimates of response rates. The prospective study in the extant literature that most closely resembles the naturalistic features of the clinical practice we analyzed was the open-label case series bywhich also utilized the BDI self-rating as the primary measure. In that study, concomitant medications were not required to be discontinued and suicidal ideation did not exclude patients. Surprisingly, that study found a much lower response rate (11%) and much worse tolerability within the first 24-h after ketamine infusion. The administration of ketamine in an ECT suite in the Diamond et al. study may have contributed to the lower tolerability and efficacy of those treatments. In fact, despite patients in this study rating the ECT suite as 'suitable' for ketamine administration, many patients complained it was too noisy, chaotic, or distressing. Notably, prior to relocating to the current outpatient setting, the UCSD ketamine treatment program administered ketamine in a Post-Anesthesia Care Unit (PACU) which is similar to an ECT setting. Three TRD patients received ketamine in that location and none of them experienced any notable benefit, prompting a location change to the outpatient procedure center. Differences in patient populations, methodological differences between the prospective openlabel design used in their study versus retrospective evaluation in ours, or small sample size may also explain differing results between our sample and that reported by Diamond et al. The use of various psychotropic medications, baseline demographics, and comorbid conditions may play a role in augmenting or diminishing the response to utilization of ketamine in TRD. However, post-hoc exploratory analyses using contingency tables in our study did not reveal apparent differences in response or remission rates by gender, comorbid anxiety, or medication use, although this study was not powered to show differences in these areas. Ketamine is known to transiently increase hemodynamic parameters, and about 50% of our sample population experienced a transient increase in blood pressure and/or heart rate, but none of them required medication treatment or infusion interruption for these changes. There are several limitations to our study. First, the retrospective nature of the studies design may introduce various forms of bias including selection or information bias. Charts that were excluded due to missing data which if included may have resulting in different efficacy rates. In addition, the ability to fully capture adverse effects may be limited when reviewing paper chart or electronic medical record data as analysis relies heavily on nursing and/or physician documentation. Second, lack of a control group may introduce a placebo effect, although large effect size and available randomized data published elsewhere may help to alleviate concerns that results found are due to a placebo effect alone. Third, ketamine for TRD is not covered by private or public sector insurance plans, which required patients pay for their treatment out of pocket. Additionally, some patients in our sample traveled from out of state to receive ketamine therapy, both of which suggest a more financially secure sample population than the average patient with TRD. Lastly, the sample described is from a single academic site and all patients were interviewed by a single psychiatrist (DF) who also prescribed the ketamine treatments. Therefore, although our sample is more generalizable to patients with TRD than those enrolled in clinical trials due to less restrictive exclusion criteria it may not be truly representative of all patients with TRD in the United States. In conclusion, ketamine appears to produce a rapid antidepressant effect and is well tolerated in a naturalistic outpatient community TRD sample with prevalent comorbidities and concurrent psychiatric medications.
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Zarate, C. A., Brutsche, N. E., Ibrahim, L. et al. · Biological Psychiatry (2012)
Papers in Blossom that reference this study
Basso, L., Bönke, L., Aust, S. et al. · Journal of Psychiatric Research (2020)
Ho, J. T., Preller, K. H., Lenggenhager, B. · Neuroscience and Biobehavioral Reviews (2020)