This randomised, double-blind, placebo-controlled study (n=26) investigated the efficacy of ketamine (35mg/70kg) treatment for patients with severe depression and found that, in contrast to other studies, ketamine did not outperform placebo in terms of short- or long-term antidepressant or antisuicidal efficacy.
Background
Several studies indicate that ketamine has rapid antidepressant effects in patients with treatment-resistant depression (TRD). The extent to which repeated doses of ketamine (versus placebo) reduce depression in the short and long term among outpatients with TRD and chronic, current suicidal ideation remains unknown.
Methods
Twenty-six medicated outpatients with severe major depressive disorder with current, chronic suicidal ideation were randomized in a double-blind fashion to six ketamine infusions (0.5 mg/kg over 45 minutes) or saline placebo over three weeks. Depression and suicidal ideation were assessed at baseline, 240 min post-infusion, and during a three-month follow-up phase.
Results
During the infusion phase, there was no differences in depression severity or suicidal ideation between placebo and ketamine (p = 0.47 and p = 0.32, respectively). At the end of the infusion phase, two patients in the ketamine group and one in the placebo group met criteria for remission of depression. At three-month follow-up, two patients in each group met criteria for remission from depression.
Limitations
Limitations include the small sample size, uncontrolled outpatient medication regimens, and restriction to outpatients, which may have resulted in lower levels of suicidal ideation than would be seen in emergency or inpatient settings.
Conclusions
Repeated, non-escalating doses of ketamine did not outperform placebo in this double-blind, placebo controlled study of patients with severe TRD and current, chronic suicidal ideation. This result may support our previously published open-label data that, in this severely and chronically ill outpatient population, the commonly used dose of 0.5 mg/kg is not sufficient.
Major depressive disorder (MDD) is highly prevalent and a substantial minority of patients remain symptomatic despite multiple adequate treatments; approximately 30% of patients meet criteria for treatment-resistant depression (TRD). Chronic suicidal ideation (SI) is common among people with TRD and these individuals are more likely to engage in suicidal behaviour than treatment responders. Most clinical trials have excluded patients with high suicide risk, leaving a gap in evidence for interventions that might benefit this high-risk outpatient population. Ketamine, an NMDA–receptor antagonist originally developed as an anaesthetic, has attracted interest because of its rapid antidepressant and putative antisuicidal effects that appear mechanistically distinct from monoaminergic antidepressants, but evidence on repeated-dose efficacy in TRD patients with chronic, current SI is limited and mixed. Ionescu and colleagues designed a double-blind, randomized, placebo-controlled trial to test whether repeated, non-escalating intravenous ketamine (0.5 mg/kg over 45 minutes) would produce superior short-term and longer-term reductions in depressive symptoms and suicidal ideation compared with saline in medicated outpatients with severe TRD and documented chronic SI (≥ 3 months). The primary aim was to assess antidepressant efficacy using the Hamilton Depression Rating Scale (HDRS); a secondary aim was to assess antisuicidal effects using the Columbia-Suicide Severity Rating Scale (C-SSRS). The investigators hypothesised that ketamine would show rapid and sustained superiority over placebo.
This study was a double-blind, placebo-controlled, randomised trial conducted at Massachusetts General Hospital between January 2013 and November 2015. After an initial screening visit, participants were seen twice more during a pre-infusion phase to confirm ongoing eligibility and symptom stability; the third pre-infusion visit served as baseline. Eligible outpatients were randomised by a computer algorithm to receive six 45-minute intravenous infusions of ketamine (0.5 mg/kg) or saline placebo, administered twice weekly over three weeks. All clinicians, patients, and raters were blinded to allocation; a senior anaesthesiologist held the randomisation list. During infusions a physician remained present, vital signs were monitored every five minutes, and adverse events could prompt immediate discontinuation. Inclusion and exclusion criteria were detailed and intended to target severely ill, chronically suicidal outpatients. Key inclusion criteria included: age 18–65; current primary diagnosis of MDD by SCID; HDRS-28 score ≥ 20; history of ≥ 3 failed antidepressant trials in the current episode; SI for ≥ 3 months with C-SSRS SI score ≥ 1 and HDRS suicide item ≥ 2 at screening or pre-infusion visits; and a stable antidepressant regimen for ≥ 4 weeks prior to infusions. Major exclusions included pregnancy, unstable medical illness, bipolar or psychotic disorders, substance-use disorder within the past year, positive urine toxicology, ketamine abuse history, or SI requiring immediate hospitalisation. Concomitant antidepressant medication was maintained for ethical reasons; some medications with interaction risk were exclusionary. Primary and secondary outcome measures were prespecified. The primary outcome was HDRS total score (clinician-rated, 28 items); response was defined as ≥ 50% improvement. Suicidal ideation was assessed with the C-SSRS (presence/absence and an intensity rating 0–25). Dissociative effects were measured with the Clinician Administered Dissociative States Scale (CADSS) at multiple time points during infusions. Depression and SI scales were administered approximately 240 minutes (4 hours) after each infusion. After the infusion phase participants entered a naturalistic follow-up with visits every other week for three months; medication adjustments were allowed and recorded. Analyses used an intent-to-treat (ITT) approach including all randomised patients, modelled with mixed-effects models with repeated measures (MMRM) to test group-by-time interactions for HDRS and C-SSRS outcomes, controlling for baseline scores (the third pre-infusion visit). Demographic comparisons employed chi-square tests and t-tests. Statistical significance was set at p < 0.05 (two-sided) and analyses were conducted in STATA SE v12. The extracted text does not report a formal sample size calculation or target power, though the investigators anticipated large effect sizes based on prior studies.
Thirty-seven outpatients were screened, 26 met criteria and were randomised (13 to ketamine, 13 to placebo). Demographic and clinical characteristics did not differ significantly between groups on reported variables (all p > 0.05). During the infusion phase, 9/13 (69%) ketamine and 9/13 placebo participants completed all six infusions; overall 24/26 randomised patients completed at least one set of post-infusion ratings. Dropouts occurred for a variety of reasons including side effects (two ketamine patients withdrew before the second infusion and one stopped an infusion due to hallucinatory side effects), belief of receiving placebo (three placebo participants withdrew after the first infusion), and one inpatient hospitalisation in the placebo arm. Depression outcomes during the infusion phase showed a significant overall decrease in HDRS total scores across time for the whole sample (p < 0.01), but there was no significant group-by-time interaction indicating superiority of ketamine over placebo (p = 0.47). Mean HDRS scores in both groups remained above 20 at the end of the infusion series, consistent with at least moderate depression. After the final infusion, antidepressant response rates were 3/12 (25%) in the ketamine group and 4/12 (33%) in the placebo group; remission rates were 2/12 (17%) and 1/12 (8%), respectively. Differences in proportions of responders or remitters between groups were not statistically significant. Suicidal ideation measured pre-infusion (C-SSRS) decreased significantly across the first three pre-infusion visits for the whole sample (F(23.806) = 14.679, p < 0.001), suggesting an improvement during the pre-randomisation phase. There was no significant group-by-time interaction for C-SSRS SI score (p = 0.32) or SI intensity rating (p = 0.23) during the infusion phase. After the final infusion, absence of SI (C-SSRS = 0) occurred in 5/12 (42%) ketamine patients and 3/12 (25%) placebo patients, a non-significant difference. Dissociative symptoms were greater in the ketamine group: mean CADSS total scores during infusion visits were significantly higher with ketamine than placebo (F(396) = 34.514, p < 0.001), with the largest difference at 30 minutes post infusion start (p < 0.01). In the three-month naturalistic follow-up phase, two participants in each group were lost to follow-up and 14/26 (54%) completed all visits (7 per group). At three months after the final infusion, among remaining participants 2/9 (22%) ketamine patients met criteria for both antidepressant response and remission, compared with 3/11 (27%) response and 2/11 (18%) remission in the placebo group; group differences were not significant. Of the five ketamine-treated patients who achieved absence of SI at the last infusion, four maintained absence at the beginning of follow-up but only one of the nine remaining ketamine patients (11%) continued to meet absence of SI criteria at the end of follow-up. The extracted text indicates that all three placebo patients who had absence of SI at the last infusion “continued” but the sentence is incomplete in the extraction and it is not clearly reported whether they maintained absence of SI through the end of follow-up. Overall, the trial found no statistically significant advantage of repeated 0.5 mg/kg ketamine infusions over saline for depression or suicidal ideation in this sample.
Ionescu and colleagues interpret their negative findings—no superiority of repeated 0.5 mg/kg ketamine over placebo for antidepressant or antisuicidal outcomes—as potentially attributable to several factors. They emphasise the high degree of chronicity and treatment resistance in the sample: many participants had failed more than five adequate antidepressant trials in the current episode, nearly 50% had previously not responded to electroconvulsive therapy (ECT), and the mean length of the current depressive episode was 115 months (about 9.6 years). Such severe, chronic TRD may be less responsive to the commonly used ketamine dose of 0.5 mg/kg. The investigators contrast these results with their prior open-label study of escalating doses (0.5 mg/kg for three infusions then 0.75 mg/kg for three), in which significant antidepressant and antisuicidal effects emerged only after dose escalation to 0.75 mg/kg (p < 0.01; Cohen’s d = 1.01). They therefore propose that higher or escalating doses may be required for similarly ill outpatient populations. Other possible explanations raised by the authors include limited statistical power due to the small sample, and an imbalance in sex distribution between groups that, while not statistically substantiated as an effect modifier, could have influenced outcomes. Acknowledged limitations are several. Recruitment and retention difficulties produced a small sample and attrition (only 14/26 completed the entire protocol), which may have left the study underpowered. Maintaining participants on stable outpatient medication regimens throughout the infusion phase precludes ruling out interactions between ketamine and concomitant treatments. By design, the study excluded patients requiring immediate hospitalisation, so the sample reflects outpatients with chronic rather than acute SI and may not generalise to emergency or inpatient populations; this may have produced a floor effect for change in SI. Timing of assessments was another constraint: symptom ratings were obtained at 4 hours post-infusion only, with no same-day baseline or daily assessments in the week immediately after the final infusion, limiting the ability to capture acute or short-term durability of effects. The authors note strengths as well: targeting a severely ill TRD outpatient group with chronic SI, using a double-blind placebo-controlled design, and including a three-month follow-up period. They also highlight that the pre-infusion lag and multiple baseline visits revealed a significant decline in C-SSRS SI scores before infusions began, suggesting the act of study participation or baseline assessment may produce treatment-independent improvements in SI even when depressive symptoms do not change. Finally, they recommend continued investigation of ketamine’s antidepressant and antisuicidal potential, including dose-finding studies, examination of patient subtypes (for example, treatment-resistant anxious depression or SI with insomnia), and further work to identify who is most likely to benefit from ketamine-based interventions.
A N U S C R I P T 1 Highlights Controlled studies of ketamine for treatment-resistant depression (TRD) are needed. We enrolled 26 outpatients with TRD and current, chronic suicidal ideation (SI). Ketamine did not produce significantly better effects on depression than placebo. Ketamine did not produce significantly better effects on SI than placebo. Severely ill, chronically depressed patients may need higher doses of ketamine.
Major depressive disorder (MDD) is a very common psychiatric disorder, impacting between 7.0 and 12% of men and between 20.0 and 25.0% of women in the general population.Though numerous well-established treatments for MDD exist (e.g., antidepressants, psychotherapy, somatic interventions), approximately 30% of MDD patients remain symptomatic, even after multiple adequate medication trials.Risk of hospitalization among such patients with -treatment-resistant depression‖ (TRD) is at least twice as high, and TRD patients incur significantly higher costs than their non-treatment-resistant, depressed.Chronic suicidal ideation (SI) is also common among individuals with TRD, who are more likely to engage in suicidal behavior than treatment responders.Patients with TRD and SI are an especially difficult-to-treat group, as patients with SI also tend to respond less well to antidepressants in the short term.Unfortunately, given the severity of their illness, high number of failed treatment trials, and elevated suicide risk, individuals with TRD and current, significant SI are often excluded from clinical trials, which has impeded the much-needed development of novel interventions for this high-risk population. In recent years, increasing attention has been paid to an agent that may provide a gateway to the discovery of new antidepressant (and possibly anti-suicidal) treatments, ketamine. As opposed to currently-approved FDA approved antidepressants-which primarily are thought to modulate monoaminergic neurotransmitters-ketamine's glutamatergic modulation properties may be important for its effects on depression. Originally approved by the FDA as an anesthetic in 1970, ketamine is at the center of much psychiatric research for its rapid, robust, and relatively sustained (up to a week or more) antidepressant properties.Among TRD patients specifically, multiple randomized and open-label trials have shown
A N U S C R I P T 5 ketamine infusions to produce acute reductions in depressive symptoms compared to placebo conditions.One recent double-blind, randomized, placebo-controlled trial also showed both twice-weekly and thrice-weekly dosing regimens of ketamine (0.5mg/kg) to maintain antidepressant efficacy across a 15-day assessment periods among TRD outpatients.Additionally, findings indicate that ketamine may also have rapid antisuicidal properties with minimal side effects.However, with recent notable exceptionsmost previous studies of ketamine for TRD (and SI in the context of depression) are limited by the fact that patients with high suicide risk have often been excluded from participation.In addition, results from studies designed to assess the extent to which ketamine's antidepressant effects are sustained over longer periods of time (e.g., two weeks post-administration), are mixed.Finally, studies specifically examining the antisuicidal properties of ketamine among TRD populations have largely used very short follow-up periods or open-label or case study designswith several notable (and very recent) exceptions of randomized, double-blind, placebocontrolled studies of ketamine for patients at imminent risk of suicide.. Though growing recent evidence in this area is promising, the extent to which repeated doses of ketamine (versus placebo) reduce depressive symptoms, including thoughts of suicide, in the short term and long term among TRD outpatients with current and chronic SI remains understudied and not well understood.
To explore this issue, our primary aim was to examine the short-term and long-term antidepressant efficacy of repeated-dose (0.5mg/kg) ketamine augmentation compared to placebo in medicated, TRD outpatients with chronic SI. Given the outpatient setting in which this research was conducted, we excluded patients in need of immediate hospitalization for suicide risk; however, as our aim was to examine a population with the highest level of suicidality typically seen in outpatient settings, we required that participants report distressing levels of SI for at least 3 months. Our secondary aim was to examine ketamine's antisuicidal effects compared to placebo. We hypothesized that ketamine would have rapid and superior antidepressant and antisuicidal efficacy compared to placebo. We also hypothesized that ketamine's antidepressant and antisuicidal efficacy would persist for a period of time after the final infusion in a small group of patients, based on the results of our previously published openlabel study.
This study was approved at the Massachusetts General Hospital (MGH) by the Partners Human Research Committee (Institutional Review Board; IRB) and was conducted in accordance with the ethical principles of the Declaration of Helsinki. Prior to study entrance, all patients provided written, informed consent. This study is registered on the ClinicalTrials.gov Registry with (; NCT01582945). All procedures were conducted at the MGH. Outpatients were recruited primarily through referrals. Inclusion criteria were: 1) 18-65 years old; 2) Primary diagnosis of current major depressive disorder (MDD), based on the Structured Clinical Interview for DSM-IV Diagnoses (SCID);3) Hamilton Depression Rating Scale, 28-Item (HDRS)score ≥ 20 at screening; 4) History of ≥ 3 failed antidepressant treatment trials of adequate dose and duration during the current episode (including the current regimen), as measured by the MGH Antidepressant Treatment History Questionnaire (ATHQ);5) SI for ≥ 3 months (as measured by ≥ 1 on the Columbia-Suicide Severity Rating Scale (C-SSRS) SI scorewithout the requirement for immediate hospitalization, and have a HDRS suicide item score ≥ 2 (current SI, thoughts of own death) at screening or one of the other two pre-infusion phase visits; 6) Ability to remain on an adequate, stable antidepressant regimen (on-and off-label treatments) for ≥ 4 weeks prior to infusions; 7) Ability to secure a reliable adult chaperone after ketamine infusion days; and 8) Maintain a treating psychiatrist in agreement with study participation, and who was aware of the safety plan in the protocol. Exclusionary criteria were as follows: 1) pregnancy; 2) unstable medical illness; 3) bipolar disorder; 4) past multiple adverse drug reactions; 4) psychotic illness; 5) substance use disorder within the past year; 6) positive urine toxicology; 7) past history of ketamine abuse; 8) SI requiring immediate hospitalization or indicating immediate risk. In addition, although patients were maintained on their stable outpatient medication regimens prior to the start of the study and during infusions, certain medications were exclusionary due to risk of interactions: St. John's wort, theophylline, tramadol, and any use of illicit narcotics or barbiturates within the previous six months. All patients were physically healthy as determined by physical exam, blood laboratory testing, electrocardiogram, and medical history obtained by a board-certified physician. Because participants were outpatients with current and clinically significant SI, ethical concerns prevented the tapering of current on-and-off label antidepressant regimens; the risks versus benefits of tapering patients off medications for research were deemed too great by the IRB. Therefore, patients were required to maintain their current antidepressant medication regimen stable for at least four weeks prior to the start of the study and for the duration of the ketamine Patients on a stable regimen of benzodiazepines for sleep or anxiety were instructed take their last dose no closer to infusion than the prior evening.
This double-blind, placebo controlled study was conducted between January 2013 and November 2015. During the -pre-infusion‖ phase patients were screened by a trained study clinician. After the initial screening visit, patients were evaluated in the clinic twice more within two weeks, as we have observed in prior studies that a percentage of patients report a noticeable improvement in mood after being enrolled in a ketamine treatment study but prior to procedures being performed. The purpose of these first three visits was to 1) verify that patients continued to meet inclusion criteria for the study, 2) examine the stability of SI from screening through the pre-infusion phase, and 3) verify that patients remained on a stable medication regimen for at least four weeks prior to receiving the ketamine infusions. The third pre-infusion phase visit (i.e., the last visit before the active phase) was considered the -baseline.‖ If participants continued to meet entry criteria after this pre-infusion phase, they were admitted as outpatients to the Clinical Research Center (CRC) at MGH for the infusions (-infusion phase‖). Infusions were generally scheduled to start at the same time of day (i.e., morning), and on the same two days each week, in an attempt to keep the administrations as consistent as possible. Patients were randomized (immediately following the pre-infusion phase) to receive six 45-minute intravenous infusions of either ketamine (0.5mg/kg) or saline placebo, over three weeks (two infusions per week). Group allocation was completed by a computer-generated randomization algorithm. The randomization list was maintained in a locked cabinet by a senior anesthesiologist. All clinicians, patients, and raters were blind to the randomization assignments. During the infusion, a board-certified anesthesiologist or psychiatrist programmed the infusion pump, and a physician remained present for the entire infusion. During the infusion, a nurse recorded vital signs (heart rate, blood pressure, respirations, pulse oximetry) and clinical status every five minutes. Any concerning or intolerable treatment-emergent side effects (e.g., hemodynamic instability, severe dissociation, worsening depression, or anxiety) prompted discontinuation of the infusion. Side effects were monitored 30 minutes prior to the infusion (for a baseline evaluation), every five minutes during the infusion, and for two hours post-infusion. At the end of each infusion, patients were clinically monitored for at least an additional two hours by the nursing staff in the CRC. Afterwards, a study doctor administered assessments of depression and SI (see Outcome Measures) at the four-hour post-infusion timepoint. At the completion of the visit, patients were discharged home with a responsible adult. After the completion of the six infusions, follow-up visits occurred every other week for 3-months (-follow-up phase‖). Visits were conducted in person or via telephone. During this naturalistic follow-up, necessary medication adjustments were allowed (per clinical judgment of the treating psychiatrist and were recorded by a study clinician). Throughout the entire study-pre-infusion, infusion, and follow-up phases-patients were evaluated a total of 15 times. The full trial protocol is available from the Principal Investigator by request.
The primary outcome measure for assessing ketamine's antisuicidal efficacy compared to placebo was HDRS total score. The HDRS is a clinician-administered, 28-item rating scale that assesses symptoms of depression experienced over the past week. Response was defined as a ≥ 50% improvement on the HDRS;C-SSRS SI score captures the presence of suicidal thoughts, as rated on a 5-point ordinal scale. Absence of SI was defined as C-SSRS SI score = 0. C-SSRS SI intensity rating refers to the intensity of SI, as rated on a 5-point ordinal scale for five items: frequency, duration, controllability, deterrents, and reason for ideation. Total C-SSRS SI intensity ratings range from 0 to 25, with 25 indicating the most severe SI. The Clinician Administered Dissociative States Scale (CADSS)was also administered immediately prior to and after the start of the ketamine infusion at 30, 60, and 120 minutes to assess dissociative effects. During the infusion phase, depression and SI rating scales were administered approximately 240 minutes (4 hours) after the start of each infusion. At all visits, patients were asked to rate their overall symptoms based on the period since the last visit/infusion.
Demographic variables were compared using frequencies and chi-square analyses for categorical variables and t-tests for continuous variables. For the analysis of depression (primary outcome; HDRS total score) and SI (secondary outcome; C-SSRS SI score and C-SSRS SI intensity rating), the intent-to-treat (ITT) model was utilized to include all patients. A mixed effect model with repeated measures (MMRM) approach was used to model the interaction effect of group x time for all efficacy analyses. Following the screening, an additional two evaluations were conducted to ensure that patients continued to meet eligibility criteria for the study throughout the pre-infusion phase; the third pre-infusion phase visit was used as the baseline for analysis, since this was the visit closest to the start of the infusions. Baseline scores were controlled for in all MMRM models. For visual purposes, all pre-infusion visit values are included in Figure.
All tests were conducted with a significance level of p < 0.05 (2-sided), using STATA SE Version 12 statistical software (StataCorp LP, College Station, TX). Based on prior studies reporting moderate-to-large effect sizes in similar samples,we also expected to observe large effect sizes.
The study was supported by the American Foundation for Suicide Prevention (AFSP), the Clinical Research Center at Massachusetts General Hospital, and the Department of Psychiatry at Massachusetts General Hospital. The project was also funded by grant number 8UL1TR000170-05, Harvard Clinical and Translational Science Center, from the National Center for Advancing Translational Science. The funding agencies did not have a direct role in the conduct or publication of this study.
There were no differences between the ketamine vs. placebo group with regard to age, sex, race, history of self-harm, history of trauma/abuse, family history of suicide, history of failed ECT, age of first depressive episode, number of past suicide attempts, number of failed medication trials in the current episode, length of current depressive episode, number of lifetime depressive episodes, or drug dose (based on weight); all p's > 0.05. See Table 1a/1b for other specific demographic information.
A total of 37 outpatients signed informed consent and were screened for study inclusion/exclusion criteria. Of these patients, 26 met all study criteria and were randomized to During the infusion phase of the study, 9 of the 13 (69%) patients randomized to ketamine and 9 of the 13 patients randomized to placebo completed all six infusions. One patient randomized to placebo missed the fourth infusion due to inpatient hospitalization for SI, but otherwise completed the other visits. One patient randomized to ketamine stopped the infusion due to hallucinatory side effects and was discontinued from the study; no post-infusion depression or SI data were collected for this participant. Two patients in the ketamine group withdrew before receiving their second infusion due to side effects, and one patient withdrew after three infusions because he did not believe the treatment was helping. In the placebo group, three patients withdrew after the first infusion due to belief of receiving placebo; no post-infusion depression or SI data were collected for one of these three participants. Overall, 24/26 randomized patients completed at least one set of post-infusion ratings.
There was no significant change of HDRS total scores between the screening and baseline visit prior to randomization (Figure; F(23.084) = 0.695, p = 0.51), indicating that there was not a significant effect of simply being enrolled in the study on depression severity. There were no differences between ketamine vs. placebo groups on HDRS total score at any pre-infusion phase visit (Table; p > 0.05).
In the sample as a whole, depression decreased significantly across infusions (i.e., over time) (Table; p < .01). However, there were no statistically significant differences in HDRS total scores between the ketamine and placebo groups across infusions (i.e., group x time interaction) (Table; p = 0.47). Mean HDRS total scores for both the ketamine and placebo groups remained above 20 at the end of the infusions, suggesting that both groups remained at least moderately depressed. After the final infusion, 3/12 (25%) subjects met criteria for antidepressant response in the ketamine group; 4/12 (33%) met criteria the placebo group. Two of 12 (17%) in the ketamine group and 1/12 (8%) in the placebo group met antidepressant remission criteria. There was no significant difference between the proportion of responders or remitters in the two groups (Table; all p's > 0.05).
There was a significant effect of time on pre-infusion C-SSRS SI score, regardless of eventual randomization to ketamine or placebo (F(23.806) = 14.679, p < 0.001); specifically, the average C-SSRS SI score significantly decreased across the first three pre-infusion visits for the whole sample. There was not a significant effect of time on pre-infusion C-SSRS SI intensity ratings (p > 0.05). There were no group differences between ketamine vs. placebo on C-SSRS SI score or SI intensity rating at screening or baseline (Table; all p's > 0.05). There was no significant group x time interaction between ketamine vs. placebo groups for the C-SSRS SI score (Table; p = 0.32) or C-SSRS SI intensity rating (Table; p = 0.23).
After the final infusion, 5/12 (42%) patients met criteria for absence of SI (i.e., C-SSRS SI score = 0) in the ketamine group, compared to 3/12 (25%) in the placebo group. Differences in absence of SI between groups were statistically insignificant (Table; p > 0.05).
There was a significant difference between ketamine vs. placebo groups on mean CADSS total scores during the infusion visits, with patients in the ketamine group reporting higher dissociative symptoms (Figure; F(396) = 34.514, p < 0.001). The largest difference between groups was at 30 minutes after the start of the infusion (F(16.6) = 13.075; p < 0.01).
In the three-month naturalistic follow up phase, 2 patients in the ketamine group and 2 in the placebo group were lost to follow-up. Overall, 14/26 total patients (54%) completed all visits (7 in the ketamine group and 7 in the placebo group). Follow-up data were analyzed for depression efficacy at three months after the final infusion. At the end of follow-up, 2 (22%) of the remaining 9 patients in the ketamine group met criteria for both antidepressant response and antidepressant remission. In the placebo group, 3 (27%) of the remaining 11 patients met criteria for antidepressant response and 2/11 (18%) met criteria for antidepressant remission at the end of the three-month follow-up period. There was no significant difference between the proportion of responders or remitters in the two groups. Of the 5 patients in the ketamine group who achieved absence of SI at the last infusion, 4 continued to meet absence of SI criteria at the beginning of the follow-up phase. Only 1 (11%) of the 9 remaining ketamine patients continued to have absence of SI at the end of the follow-up period. All 3 patients in the placebo group who had absence of SI at the last infusion continued
In numerous published studies to date, ketamine has been shown to outperform control conditions in antidepressant efficacy among TRD individuals.Results from recent studies also suggest the promising antisuicidal effects of ketamine.In contrast to earlier trials, in this double-blind, placebo controlled study of patients with severe TRD and current, chronic SI, ketamine did not outperform placebo in terms of short-or longterm antidepressant or antisuicidal efficacy. Specifically, there was no significant advantage of ketamine over placebo for improvements in depression, as measured by HDRS total scores. Ketamine treatment also did not have a significant advantage in terms of reducing SI, as measured with the C-SSRS. There are several possible reasons why we did not observe a significant advantage of ketamine over placebo. First, the level of chronicity and treatment-resistance in this sample was higher than in most prior studies. Specifically, most patients had failed more than 5 adequate antidepressant trials in the current episode. Furthermore, nearly 50% of participants had prior failure to respond to ECT, and the average length of current major depressive episode was 115 months (9.6 years). Thus, it is possible that, among severely treatment-resistant patients, the traditional dose of ketamine (0.5mg/kg over 40 minutes) used in this study was not sufficient to produce an improvement.
Of note, results from our previous open-label trial of escalating repeated doses of ketamine (0.5mg/kg for the first three infusions to 0.75mg/kg for the last three infusions) supported ketamine's antidepressant and antisuicidal properties in a sample of patients with similar baseline levels of depression and SI.Importantly, in that open-label study, we began to see statistically significant antidepressant effects with a large effect size only when we increased the dose to 0.75mg/kg (p < 0.01; Cohen's d = 1.01).Thus, for outpatients with treatment-resistant depression and chronic SI on concomitant medications, the increase of doses beyond the traditional 0.5mg/kg over 40 minutes may be critical to achieve clinically significant effects. Toward this end, a single-infusion dose finding study was recently completed (ClinicalTrials.gov unique identifier: NCT01920555) to examine the antidepressant efficacy of ketamine at doses of 0.1mg/kg, 0.2mg/kg, 0.5mg/kg, and 1.0mg/kg versus to the active comparator midazolam. Another possibility why we did not observe an advantage to ketamine is that the small sample rendered us vulnerable to Type II error (i.e., incorrect rejection of the null hypothesis). Last, though not statistically significant, the difference in percentage of females in the two conditions (54% versus 23% for ketamine versus placebo, respectively) may have impacted our results; however, there is not currently strong evidence to support sex differences in ketamine response.. This study had a number of limitations. First, our sample was small primarily due to challenges with recruitment and retention. Of our 26 randomized patients, only 14 completed the entire study; this was due to multiple reasons, including the challenge for severely depressed patients to participate in such a time-intensive research study and lack of study resources to provide compensation. This may have left us underpowered to detect a true difference between the treatment groups. Second, all patients were maintained on their outpatient medication regimens throughout the infusion phase. Therefore, we cannot rule out the impact that concomitant medications may have on ketamine's effects. Third, we examined outpatients with clinically significant and chronic SI; by definition, the suicide risk of these individuals was not imminent enough to warrant immediate hospitalization. Thus, we missed a large group of patients with more acute SI (e.g., in ER settings). Given that patients reporting chronic passive suicidal ideation still met our inclusion criteria, there may not have been significant room for change in SI. Because self-reported levels of SI were relatively low during the pre-infusion phase, we may have faced a -floor effect‖ that made it difficult to detect significant change in SI across the infusions. Fourth, all ratings were obtained at the 4-hour mark post-infusion; due to scheduling limitations, we did not assess same-day baselines. Perhaps other evaluation time points (e.g., 24 hours, 48 hours) would more acutely capture ketamine's effects. Last, we did not conduct symptom assessments during the week immediately following the final ketamine infusion, which did not allow us to assess the persistence of response over this one-week time frame. Despite these limitations, this study also had notable strengths. First, our selection of TRD patients specifically for current and chronic suicidal ideation is a strength. Second, the use of a double-blind, placebo controlled trial is an important design advantage over our previous openlabel study in a similar population.Third, whereas many previous studies of ketamine examined only the short-term efficacy of this drug, we used a three-month follow-up period. Fourth, the purposeful inclusion of a lag time between enrollment and beginning the infusions allowed us to observe a significant decrease in C-SSRS SI scores during the pre-infusion phase. This suggests that even when recruitment is targeted at TRD patients with current, chronic SI, the effects of joining a time-intensive research study utilizing a drug like ketamine may yield treatment-independent improvements. In contrast, there was no significant pre-infusion decrease in depression scores. Patients with TRD are generally considered less likely to experience placebo response to treatment;however, these results suggest that separate processes may be involved in the improvement of SI vs. depressive symptoms. Though the results of this small study were not significant, the investigation into ketamine's potential as a rapid antidepressant and antisuicidal agent merits continuation. In addition to studying ketamine in heterogeneous patient populations, future trials should focus on elucidating the specific subtypes of patients for whom ketamine is most effective in reducing chronic depression and perhaps, decreases suicidal thinking. For example, there are preliminary results to indicate that ketamine may have superior antidepressant properties among treatment-resistant patients with anxious depression as opposed to nonanxious depression.Further, recent research suggests that ketamine's antisuicidal effects may be correlated with its ability to improve sleep between the hours of 12AM and 5AM, perhaps elucidating a certain subtype of patients with SI and insomnia.Certainly, further exploration of ketamine's antidepressant and antisuicidal properties, particularly among treatment-resistant individuals, have the potential to lead to improved, targeted treatments for TRD and SI.
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Randomised, quadruple-blind, parallel Phase II trial (n=99) comparing single IV ketamine infusions (0.1, 0.2, 0.5, 1.0 mg/kg) versus active placebo midazolam (0.045 mg/kg) in patients with treatment-resistant depression on stable antidepressant therapy.
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