This meta-analysis (2015) of open-label studies (n=97) examined the safety, tolerability, and acceptability of intravenous ketamine (35mg/70kg) infusion for patients with depression. They found that it was safe and well-tolerated with little to no psychotomimetic effects, adverse medical effects, or any increase in long-term substance abuse.
Objective
Ketamine has demonstrated rapid antidepressant effects in patients with treatment-resistant depression (TRD); however, the safety and tolerability of ketamine in this population have not been fully described. Herein we report the largest study to date of the safety, tolerability, and acceptability of ketamine in TRD.
Method
Data from 205 intravenous (IV) ketamine infusions (0.5 mg/kg over 40 minutes) in 97 participants with DSM-IV-defined major depressive disorder (MDD) were pooled from 3 clinical trials conducted between 2006 and 2012 at 2 academic medical centers. Safety and tolerability measures included attrition, adverse events (AEs), hemodynamic changes, and assessments of psychosis and dissociation.
Results
The overall antidepressant response rate, defined as a ≥ 50% improvement in Montgomery-Asberg Depression Rating Scale score, was 67% (65 of 97 participants). Four of 205 infusions (1.95%) were discontinued due to AEs. The overall attrition rate was 3.1% (3 of 97). In the first 4 hours after the infusion, the most common general AEs were drowsiness, dizziness, poor coordination, blurred vision, and feeling strange or unreal. Approximately one third of individuals experienced protocol-defined hemodynamic changes. Ketamine resulted in small but significant increases in psychotomimetic and dissociative symptoms (all P < .05). There were no cases of persistent psychotomimetic effects, adverse medical effects, or increased substance use in a subgroup of patients with available long-term follow-up information.
Conclusions
In this relatively large group of patients with TRD, ketamine was safe and well tolerated. Further research investigating the safety of ketamine in severe and refractory depression is warranted.
Papers cited by this study that are also in Blossom
Murrough, J. W., Perez, A. M., Pillemer, S. et al. · Biological Psychiatry (2012)
Murrough, J. W., Iosifescu, D. V., Chang, L. C. et al. · American Journal of Psychiatry (2013)
Diazgranados, N., Ibrahim, L., Brutsche, N. E. et al. · JAMA Psychiatry (2010)
Zarate, C. A., Brutsche, N. E., Ibrahim, L. et al. · Biological Psychiatry (2012)
Murrough and colleagues pooled patient-level data from three clinical trials conducted between 2006 and 2012 at two academic centres to evaluate the safety, tolerability, and acceptability of low-dose intravenous ketamine in treatment-resistant depression. The pooled dataset comprised 205 infusions of racemic ketamine (0.5 mg/kg administered over 40 minutes) given to 97 enrolled participants meeting DSM-IV criteria for major depressive disorder; because some individuals took part in more than one trial, 84 unique subjects are presented in certain analyses. Eligibility required failure to respond to at least two or three FDA-approved antidepressants per the Antidepressant Treatment History Form. Exclusion criteria included recent substance abuse or dependence, lifetime psychosis or any psychotic disorder, bipolar disorder, developmental disorder, recreational ketamine or phencyclidine use, uncontrolled hypertension, arrhythmia or other significant cardiac disease, and unstable medical illness. Subjects were washed off psychotropic medications 2–4 weeks prior to randomisation; physical exam, vital signs, ECG, blood tests, urinalysis, and urine toxicology were used to confirm medical stability and absence of illicit substances. Each infusion was administered under the supervision of an anaesthesiologist with standard telemetry (pulse oximetry, heart rate, blood pressure, end-tidal CO2). Behavioural and safety measures were collected before infusion, at 40 minutes (immediately post-infusion), and at 240 minutes; a subset had 24-hour assessments. Antidepressant response was defined as a ≥ 50% improvement on the Montgomery–Åsberg Depression Rating Scale (MADRS) at 24 hours. Psychotomimetic symptoms were measured with the 4-item positive symptom subscale of the Brief Psychiatric Rating Scale (BPRS+), dissociation with the Clinician-Administered Dissociative States Scale (CADSS), and general side effects with the SAFTEE-SI or PRISE instruments. A protocol allowed the anaesthesiologist to treat sustained blood pressure elevations (> 180/100 mm Hg) or heart rate > 110 bpm and to discontinue the infusion if three consecutive measurements remained above limits despite intervention. Longer-term follow-up was attempted by telephone at varying intervals (range 8 months to 6 years) to assess persistent adverse effects and acceptability; 46 of 84 unique subjects completed this interview. Statistical analyses were performed in SPSS v20 using repeated-measures ANOVA for within-subject changes, paired t tests to localise differences, Mann–Whitney U or independent t tests for between-group comparisons, χ2 tests for categorical associations, and Pearson correlations for relationships among continuous change scores.
Across the pooled sample, the 24-hour antidepressant response rate was 67% (65 of 97 participants), with a mean MADRS reduction of 19.0 ± 11.7 points from baseline. Responders were older on average than nonresponders (mean age 50.4 ± 11.7 years versus 43.2 ± 12.4 years; P = .01); other demographic and clinical characteristics did not differ significantly between groups in univariate analyses. Retention was high: overall attrition was 3.1% (3 of 97 subjects). Of 205 infusions, four (1.95% of infusions; affecting 4.1% of subjects) were discontinued because of adverse events. Two discontinuations were for antihypertensive-resistant blood pressure elevations (maxima 180/115 mm Hg and 187/91 mm Hg) that normalised after stopping the infusion. A third subject requested discontinuation for increased anxiety; a fourth experienced transient hypotension and bradycardia during blood draw and was hospitalised for overnight cardiac monitoring. That single serious adverse event (SAE) represented 0.49% of infusions. Adverse effects peaked within 120 minutes after infusion and largely resolved by 240 minutes and 24 hours. Mean peak systolic blood pressure during infusion was 141.9 ± 21.2 mm Hg, a mean increase of 19.6 ± 12.8 mm Hg (P < .001); mean peak diastolic pressure was 86.4 ± 12.7 mm Hg, a mean increase of 13.4 ± 9.8 mm Hg (P < .001). Transient tachycardia was also observed; there was no change in blood oxygen saturation (P = .3). Protocol-defined increases in blood pressure or pulse occurred in 29.8% of participants (25/84), and 14.3% (12/84) received medication intervention, typically a short-acting antihypertensive, for a mean duration of 14.4 ± 12.6 minutes. Hemodynamic changes were associated with body mass index ≥ 30 (P = .03) and with a higher absolute ketamine dose (mean 45.8 ± 9.3 mg versus 41.5 ± 11.1 mg; P = .03). Hemodynamic change, comorbid medical conditions, and mean ketamine dose did not differ between responders and nonresponders. Psychotomimetic symptoms measured by the BPRS+ increased slightly from 4.2 ± 1.3 at baseline to 4.5 ± 1.3 at 40 minutes (P = .001), a change the authors characterise as very mild on the scale range of 4–28. Dissociative symptoms measured by the CADSS increased from 0.7 ± 2.9 at baseline to 9.8 ± 13.9 at 40 minutes (P < .001); the mean peak CADSS sits in a range the authors describe as mild. For a subset of 72 infusions with 24-hour data, delayed effects did not differ significantly from baseline. Changes in CADSS and BPRS+ did not differ between responders and nonresponders (P = .2 for both), and Pearson correlations showed no association between change in MADRS score and change in CADSS or BPRS scores. Longer-term follow-up interviews were completed by 46 of 84 unique subjects at a mean interval of 2.9 ± 1.9 years (range 8 months to 6 years) from first exposure. Most participants did not report persistent physical, emotional, or psychological symptoms; one individual reported increased anxiety and dysphoria lasting just over 1 month. No participants reported increased craving for ketamine or increased illicit substance use. On a 5-point acceptability scale, mean acceptability was 3.7 ± 1.5 (median 4), with primary reasons for rating ketamine as "not at all acceptable" including lack of antidepressant benefit, increased anxiety, or dissociative effects.
Murrough and colleagues interpret these pooled data as indicating that subanaesthetic, low-dose intravenous ketamine (0.5 mg/kg over 40 minutes) is safe and generally well tolerated in patients with treatment-resistant unipolar depression when administered in a controlled medical research setting. The authors highlight a 67% 24-hour response rate and note that most general side effects and acute behavioural changes resolved within four hours of administration. A single SAE requiring overnight cardiac monitoring was reported; otherwise adverse effects tended to be transient. The investigators emphasise the relatively high prevalence of transient hemodynamic changes: nearly 30% of participants experienced protocol-defined increases in blood pressure or pulse and 14.3% required pharmacological intervention. These elevations were associated with obesity (BMI ≥ 30) and with larger absolute ketamine dose, prompting the suggestion that doses below 0.5 mg/kg may be appropriate for some patients and that optimal dosing requires further study. Small but statistically significant increases in psychotomimetic and dissociative symptoms were observed during infusion; the magnitude of psychotomimetic change was characterised as very mild while dissociative responses were mild on average but pronounced in a minority. Longer-term follow-up showed no evidence of persistent dissociative or psychotomimetic effects, nor of increased substance use among the participants who could be re-contacted. The authors acknowledge several important limitations. Combining patient-level data from studies with different designs, including both controlled and uncontrolled trials, limits confidence in pooled summary estimates. Adverse event rates were derived from two different assessment instruments, which may bias reporting toward shared items. The dataset reflects short-term administration and excludes patients with current substance use, lifetime psychotic or manic symptoms, unstable medical illness, or concomitant psychotropic treatment, limiting generalisability to broader clinical populations. The investigators also note the paucity of data on longer-term or repeated ketamine exposure, and on interactions with concurrent antidepressant medications. They call for additional research to characterise safety and efficacy over longer durations, to examine repeated-infusion effects on hemodynamics, and to determine optimal dosing strategies for individual patients. In conclusion, the study team presents these data as the first systematic analysis of acute and some longer-term neuropsychiatric and physical adverse effects of ketamine in treatment-resistant depression, concluding that, within a controlled research environment, subanaesthetic ketamine carries a low and acceptable short-term risk profile but requires adequate monitoring and further study to define long-term safety.
interview with a study psychiatrist. Depending on the study, participants had to have failed to respond to at least 2 or 3 US Food and Drug Administration (FDA)-approved antidepressant medications according to the Antidepressant Treatment History Form.Exclusion criteria included recent substance abuse or dependence, lifetime history of psychosis or any psychotic disorder, bipolar disorder, developmental disorder, or recreational use or abuse of ketamine or phencyclidine. Physical examination, vital signs, electrocardiogram, standard blood tests, urinalysis, and urine toxicology confirmed the absence of unstable medical illnesses and illicit substance use. Subjects in all studies were washed off psychotropic medications 2-4 weeks prior to randomization. Treatment response was defined as a ≥ 50% improvement in the Montgomery-Asberg Depression Rating Scale (MADRS) score. See the primary references for further details.For each infusion, an anesthesiologist administered racemic ketamine (0.5 mg/kg) over 40 minutes by IV infusion pump with standard telemetry monitoring (eg, pulse oximetry, heart rate, blood pressure, end-tidal CO 2 ). Dissociative and psychotomimetic effects of ketamine were assessed before the start of each infusion, immediately upon completion of each infusion (40 minutes), and after 240 minutes. Behavior and adverse events measures at 24 hours were available for a subset of infusions.See the study by Murrough et alfor a detailed description of the ketamine administration protocol. Psychotomimetic effects were measured with the 4-item positive symptom subscale of the Brief Psychiatric Rating Scale (BPRS+; scale range, 4-28); dissociative effects were measured with the Clinician-Administered Dissociative States Scale (CADSS; scale range, 0-92).General side effects were measured with the Systematic Assessment For Treatment Emergent Effects Self-Report Inventory (SAFTEE-SI)or the Patient-Rated Inventory of Side Effects (PRISE).General side effects according to the SAFTEE-SI or the PRISE were defined as moderate to severe increases in symptoms in the period from baseline to 120 minutes, and persistence of side effects was noted at the 240-minute and 24-hour time points. The same or similar SAFTEE-SI and PRISE items were combined as single composite items. Per protocol, a study anesthesiologist, present throughout the infusion, had the option to treat increases in blood pressure to levels exceeding 180/100 mm Hg or heart rate greater than 110 bpm (for example, with the short-acting β-blocker labetalol). If these elevations resolved spontaneously within a short time period, they were generally not treated. The study infusion was discontinued in the event that 3 consecutive measurements remained above protocoldefined limits despite anesthesiology intervention. Longer-term follow-up assessments were conducted including all available subjects to determine whether there were any long-term adverse effects of ketamine exposure and to assess the overall acceptability of ketamine as a treatment for depression. Subjects were contacted by telephone at varying intervals depending on the study (range, 8 months to 6 years). The study was approved by the institutional review boards at each institution, and all subjects gave verbal consent before participating. The interviews were conducted by a trained clinician or study coordinator. See eAppendix 1 at Psychiatrist.com for the questionnaire, which was adapted from Perry et aland included an assessment of how acceptable treatment with ketamine would be in the future if ketamine were to gain FDA approval for this indication. We attempted to re-contact all study participants by telephone and e-mail when available. Telephone contact was attempted at least 3 times prior to determining that the subject was not available for follow-up assessment. All statistical analyses were performed with IBM SPSS Statistics software (version 20; IBM Corporation, Armonk, New York). Repeated-measures analysis of variance (ANOVA) was used to assess within-subject differences in continuous measures across time. Two-tailed, paired t tests were conducted to localize significant differences. Mann-Whitney U tests or t tests were used to compare means across 2 independent groups. The relationship between hemodynamic change and comorbid medical conditions was assessed using χ 2 tests. Univariate tests were also used to assess relationships between ketamine response at 24 hours and demographic and clinical characteristics, comorbid medical conditions, hemodynamic change, ketamine dose, change in CADSS score, and change in BPRS score. Follow-up Pearson correlation analyses were used to assess the relationship between change in MADRS score and change in CADSS and BPRS scores.
The study included 205 intravenous ketamine infusions (0.5 mg/kg over 40 minutes) in 97 enrolled participants across 3 clinical trials at 2 centers (Table). Demographic and clinical features for 84 unique subjects are presented in Table(13 individuals participated in more than 1 trial). The 24-hour response rate among all participants was 67%, with a mean MADRS decrease of 19 ± 11.7 points compared to baseline. The mean age of ketamine responders was significantly higher (50.4 ± 11.7 years) than nonresponders (43.2 ± 12.4 years; P = .01). Other demographic and clinical characteristics did not differ between ketamine responders and nonresponders (P > .05 for all univariate analyses).
■ Ketamine is a promising treatment option for refractory depression that carries acceptable short-term risk in the context of a medical research setting. ■ Important risks associated with ketamine include transient changes in hemodynamic parameters and dissociation. ■ The use of adequate vital signs and behavioral monitoring and the availability of medical support during infusions are important to optimize safety. ■ The longer-term safety and effectiveness of ketamine in psychiatric populations are largely unknown, dissuading widespread clinical use pending future studies. The overall attrition rate due to any cause was 3.1% (3 of 97 subjects). Of the 205 infusions, 4 were discontinued due to AEs (1.95% of infusions; 4.1% of subjects). Of these 4 discontinuations, 2 subjects experienced elevated blood pressure during the infusion that did not respond satisfactorily to 3 separate administrations of antihypertensive medication (maximum blood pressure: 180/115 mm Hg and 187/91 mm Hg, respectively). In both cases, vital signs normalized shortly after ketamine discontinuation. A third subject experienced an increase in anxiety and requested that the infusion be stopped. A fourth subject, while undergoing venipuncture for a blood draw, experienced transient hypotension and bradycardia and was placed on cardiac monitoring for 24 hours. The event was considered a serious adverse event (SAE) due to prolongation of existing hospitalization. The single SAE represented 0.49% of infusions. Other nonserious adverse events are presented in Table. Side effects peaked within the 120-minute period after infusion and largely resolved by the 240-minute and 24-hour time points. As expected, transient increases in mean blood pressure were observed during the ketamine infusion (Figure). The mean peak systolic blood pressure was 141.9 ± 21.2 mm Hg (mean increase of 19.6 ± 12.8 mm Hg, P < .001) and peak diastolic blood pressure was 86.4 ± 12.7 mm Hg (mean increase of 13.4 ± 9.8 mmHg, P < .001). Transient increases in pulse were also observed during the ketamine infusion. There was no change in blood oxygen level (P = .3). A protocol-defined increase in blood pressure or pulse was experienced by 29.8% of participants (25/84). A total of 14.3% of participants (12/84) received medication intervention for these changes, which lasted a mean of 14.4 ± 12.6 minutes. The occurrence of hemodynamic changes was associated with a body mass index (BMI) of 30 or greater (P = .03) and with a higher ketamine dose (45.8 ± 9.3 mg compared to 41.5 ± 11.1 mg, P = .03). Hemodynamic change, comorbid medical conditions, and mean ketamine dose did not differ between ketamine responders and nonresponders (P > .05 for all analyses). BPRS+ and CADSS scores are presented in Figure. Ketamine was associated with a small but significant increase in psychotic symptoms as measured by the BPRS+ (increase from a mean baseline of 4.2 ± 1.3 to 4.5 ± 1.3 at the 40-minute time point, P = .001). Ketamine resulted in a mild, significant increase in dissociative symptoms as measured by the CADSS (increase from a mean baseline of 0.7 ± 2.9 to 9.8 ± 13.9 at the 40-minute time point, P < .001). For a subset of infusions (no. = 72), delayed effects were measured after 24 hours and did not differ significantly from baseline. Changes in CADSS score did not differ significantly between ketamine responders (12.4 ± 14.1) and nonresponders (8.6 ± 10.2, P = .2). The mean increase in BPRS+ score was also not significantly different (P = .2). Pearson correlation analysis showed no association between change in MADRS score and change in CADSS score or change in BPRS score (See Supplementary eFigure 1). Of 84 unique subjects who participated in the ketamine studies included in this analysis, 46 could be reached and consented to a phone interview to assess longer-term or persistent adverse effects of ketamine (Supplementary eTable 1). The mean length of time from the first ketamine administration was 2.9 ± 1.9 years, with a range of 8 months to 6 years. In general, subjects did not report persistent physical, emotional, or psychological symptoms. One subject did endorse increased levels of anxiety and dysphoria after ketamine administration, persisting for slightly over 1 month. There were no reports of increased cravings or use of ketamine or other illicit substances. The mean score for acceptability was 3.7 ± 1.5 ("somewhat acceptable" to "very acceptable") out of 5, with a median of 4 (Supplementary eFigure 2). Of those subjects who rated ketamine "not at all acceptable, " 5 cited lack of improvement in depressive symptoms, 1 cited increased anxiety, and 1 cited dissociative effects. There was no reason given for 1 subject.
The findings from this study show that low-dose ketamine is safe and well tolerated in depressed patients in the context of a well-controlled medical research setting. The overall antidepressant response rate across 3 studies and 97 enrolled participants was 67%. General side effects and acute behavioral changes associated with ketamine in depressed subjects resolved by 4 hours after ketamine administration. Across all study participants, a single SAE consisted of an overnight hospitalization for cardiac monitoring. In our longer-term follow-up data, we found no evidence of ketamine abuse, increased drug cravings, or substance abuse following study participation. We found that older age was associated with better response to ketamine. No other demographic or clinical variable was associated, and there was no association between antidepressant response and dissociation or other side effects. Protocol-defined changes in vital signs-by and large, elevations in blood pressure-were experienced by 29.8% of subjects receiving ketamine and 14.3% of subjects received a medication intervention for these changes (typically a short-acting antihypertensive agent). In all but 2 cases, the elevated blood pressure responded rapidly to the intervention. In the other 2 cases, the infusion was discontinued, at which time the blood pressure returned to normal. These findings underscore the need for adequate hemodynamic monitoring during ketamine infusions. These changes were associated with both obesity and total ketamine dose, suggesting that ketamine doses below 0.5 mg/kg may be appropriate in some patients. More research investigating the safety and efficacy of doses other than 0.5 mg/kg is required in order to determine the optimal dosing strategy for individual patients. We found small but statistically significant increases in psychotomimetic and dissociative effects during ketamine administration. The 4-item positive symptom subscale of the BPRS-measuring conceptual disorganization, hallucinations, suspiciousness, and unusual thought content-was used as an index of psychosis based on previous reports.The average observed peak score of 4.5 in this sample is consistent with symptom severity described as "very mild" (scale range, 4-28).In our studies, we excluded patients with a history of psychosis due to concerns regarding the potential for ketamine to exacerbate or trigger psychotic symptoms. Therefore, while we found that ketamine was associated with minimal psychotic symptoms in our samples, caution is warranted in extrapolating our findings to larger patient groups with more diverse symptom histories. Dissociative symptoms associated with ketamine were pronounced in a minority of patients in our sample. The average observed peak score of 9.8 (scale range, 0-92) 30 falls within a range defining mild symptomatology in the context of what has been reported in disorders characterized by dissociation. In a validation study, roughly half the average baseline score of a cohort of subjects with PTSD fell in this range.Our findings suggest that psychotomimetic effects associated with ketamine are uncommon in this patient group, while dissociative effects are relatively more common. In some reports, healthy subjects seem to have more severe psychotic reactions than those we observed in our sample of depressed patients; however, a quantitative comparison is difficult in this context. Our longer-term follow up data were noteworthy for the absence of persistent dissociative or psychotomimetic effects. There were no cases of persistent physical symptoms or increased substance use. Case reports of depressed patients receiving repeated ketamine infusions have generally reported favorable long-term outcomes. For example, Correll and Futter 34 described 2 subjects with TRD; the first received continuous low-dose IV ketamine (up to 0.27 mg/kg/h) for 5 days, and the second received 3 ketamine infusions (up to 0.3 mg/kg/h for 5 days) over 6 months. Both subjects demonstrated marked functional improvement after 12 months without reported adverse consequences. Another case report described a subject who received 6 ketamine infusions (0.5 mg/kg) over 2 weeks and did not report long-term adverse consequences after 12 months.On the other hand, 2 cases of delayed-onset suicidal ideation and dysphoria following ketamine administration in patients with obsessive-compulsive disorder were recently reported.An isolated case of mania following ketamine treatment has also been reported.Clearly, substantially more data on longer-term safety and efficacy of ketamine in these populations are required. This study has several limitations. The efficacy and side-effect profile of ketamine reported herein result from combining patient-level data from studies utilizing different clinical trial designs, including controlled and uncontrolled designs, thereby limiting the confidence in the pooled summary statistics. Rates of adverse events were derived from 2 different assessment instruments, potentially biasing results toward shared items. The study is limited to short-term administration of ketamine. If ketamine were to be used as a treatment for refractory depression, patients may be exposed to ketamine over longer periods of time. There are currently very few data regarding the safety and efficacy of longer-term use of ketamine to treat TRD, and much more research is required to more fully understand the risks and benefits of this approach. In particular, future studies should assess the persistence of hemodynamic changes in repeated-infusion studies. The generalizability of this study is limited by the exclusion of subjects with concurrent psychotropic treatment, current substance use, lifetime psychotic or manic symptoms, and unstable medical illnesses. Particularly important given our observations of increased blood pressure with ketamine, we excluded uncontrolled hypertension and history of arrhythmia or other cardiac disease. Since participants were not taking concomitant medication treatment for depression, we are unable to assess potential interactions. Future studies will be needed to more fully document the longer-term safety profile of ketamine in depression. In conclusion, this study is the first systematic analysis of the acute and longer-term neuropsychiatric and physical adverse effects of ketamine in subjects with TRD. The data suggest that subanesthetic doses of ketamine administered to unipolar depressed patients in a controlled research setting present a low and acceptable level of risk. Notably, almost 30% of patients experienced transient but significantly elevated blood pressure or other hemodynamic changes, compelling the use of adequate monitoring and medical support during infusions. -Using a 5-point scale, where "1" is not at all acceptable, "3" is somewhat acceptable, and "5" is very acceptable, how acceptable would ketamine be to you for the treatment of your depression if ketamine were to become an approved treatment option in the future? In deciding on the acceptability of the treatment, please consider factors including perceived benefit compared to risk, convenience, and potential stigma of the treatment.
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