Effects of Low-Dose and Very Low-Dose Ketamine Among Patients with Major Depression

International Journal of Neuropsychopharmacology Advance Access published December 17, 2015

International Journal of Neuropsychopharmacology, 2015, 1–15

doi:10.1093/ijnp/pyv124 Advance Access Publication: November 17, 2015 Review

review Effects of Low-Dose and Very Low-Dose Ketamine among Patients with Major Depression: a Systematic Review and Meta-Analysis Downloaded from Ying Xu, Maree Hackett, Gregory Carter, Colleen Loo, Verònica Gálvez, Nick Glozier, Paul Glue, Kyle Lapidus, Alexander McGirr, Andrew A. Somogyi, Philip B. Mitchell, Anthony Rodgers http://ijnp.oxfordjournals.org/ The George Institute for Global Health, The University of Sydney, Sydney, Australia (Drs Xu, Hackett, and Rodgers); Centre for Translational Neuroscience and Mental Health, University of Newcastle, Australia (Dr Carter); School of Psychiatry, University of New South Wales & Black Dog Institute, Sydney, Australia (Drs Loo, Gálvez, and Mitchell); Brain and Mind Research Institute, University of Sydney, Australia (Dr Glozier); Department of Psychiatry, University of Otago, New Zealand (Dr Glue); Departments of Psychiatry and Neurobiology, Stony Brook University, Stony Brook, NY (Dr Lapidus); Department of Psychiatry, University of British Colombia, Canada (Dr McGirr); Discipline of Pharmacology, Faculty of Health Sciences, The University of Adelaide, Adelaide, Australia (Dr Somogyi). by Karin Lavoie on April 20, 2016 Correspondence: Colleen Loo, MD, School of Psychiatry, University of New South Wales & Black Dog Institute, Sydney, Australia ([email protected]).

Abstract Background: Several recent trials indicate low-dose ketamine produces rapid antidepressant effects. However, uncertainty remains in several areas: dose response, consistency across patient groups, effects on suicidality, and possible biases arising from crossover trials. Methods: A systematic search was conducted for relevant randomized trials in Medline, Embase, and PsycINFO databases up to August 2014. The primary endpoints were change in depression scale scores at days 1, 3 and 7, remission, response, suicidality, safety, and tolerability. Data were independently abstracted by 2 reviewers. Where possible, unpublished data were obtained on treatment effects in the first period of crossover trials. Results: Nine trials were identified, including 201 patients (52% female, mean age 46 years). Six trials assessed low-dose ketamine (0.5 mg/kg i.v.) and 3 tested very low-dose ketamine (one trial assessed 50 mg intra-nasal spray, another assessed 0.1–0.4 mg/kg i.v., and another assessed 0.1–0.5 mg/kg i.v., intramuscular, or s.c.). At day 3, the reduction in depression severity score was less marked in the very low-dose trials (P homogeneity <.05) and among bipolar patients. In analyses excluding the second period of crossover trials, response rates at day 7 were increased with ketamine (relative risk 3.4, 95% CI 1.6–7.1, P = .001), as were remission rates (relative risk 2.6, CI 1.2–5.7, P = .02). The absolute benefits were large, with day 7 remission rates of 24% vs 6% (P = .02). Seven trials provided unpublished data on suicidality item scores, which were reduced on days 1 and 3 (both P < .01) but not day 7. Conclusion: Low-dose ketamine appears more effective than very low dose. There is substantial heterogeneity in clinical response, with remission among one-fifth of patients at 1 week but most others having benefits that are less durable. Larger, longer term parallel group trials are needed to determine if efficacy can be extended and to further assess safety.

Keywords: Ketamine, major depression, meta-analysis

Received: September 2, 2015; Revised: November 5, 2015; Accepted: November 11, 2015 © The Author 2015. Published by Oxford University Press on behalf of CINP. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons. org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is 1 properly cited. 2 | International Journal of Neuropsychopharmacology, 2015

Introduction Aside from electro-convulsive therapy (ECT), there are no 7. Other outcomes were: clinical remission (defined as HAM-D widely used treatments that provide large or rapid benefits <7 or MADRS <10); clinical response (defined as ≥50% reduction for patients suffering from severe depression (Martinowich in depression severity score); suicidality measures, including et al., 2013). This presents a major clinical challenge, espe- the suicidality item of HAM-D or MADRS; safety and tolerability cially for patients who have not responded fully to existing as assessed by reported adverse events and dropouts. therapy or if symptoms include suicidality. In 2000 a small crossover trial suggested that a single subanaesthetic dose of Search Methods for Identification of Trials ketamine could provide a large antidepressant benefit, start- ing within a few hours and lasting for at least several days Reports were restricted to English language publications. (Berman et al., 2000). Ketamine appeared to improve specific Publications for this review were identified by searching depressive symptoms such as sadness, suicidality, and help- Medline, Embase, and PsycINFO databases before August 2014 lessness, rather than induce a nonspecific mood-elevating using the following search terms as free text or subject head- effect. Since then, several more trials have been published ings as appropriate for each database: (“ketamine” OR “NMDA (Zarate et al., 2006; Diazgranados et al., 2010a; Zarate et al., receptor antagonist”) AND (“depression” OR “major depressive 2012; Murrough et al., 2013; Sos et al., 2013), but existing disorder” OR “bipolar depression” OR “depressive disorder” OR reports and reviews (aan het Rot et al., 2010; Aan Het Rot “dysthymic disorder” OR “treatment resistant depression”) AND et al., 2012; Katalinic et al., 2013; Brittner et al., 2014; Caddy (“ randomized controlled trial” OR “controlled clinical trial” OR Downloaded from et al., 2014; McGirr et al., 2014) do not easily allow a direct “randomized” OR “placebo”) (full details available in supplemen- comparison of how treatment effects persist in the days fol- tary Table 1 in the online data supplement). If additional studies lowing treatment, given differences in graphical and tabular cited in these articles met with these criteria, then they were reporting methods and outcome scales. Three very recently also included. reported trials (Lai et al., 2014; Lapidus et al., 2014) (C. K. Loo, V. Galvez, E. O’Keefe, unpublished data) evaluated lower doses Selection of Studies http://ijnp.oxfordjournals.org/ of ketamine than previously tested, providing an opportu- nity to compare treatment efficacy and tolerability of differ- Two authors (A.R. and Y.X.) reviewed the search strategy and ent doses. One other key issue is the extent of bias resulting selected studies for inclusion in the review. In case of disagree- from the use of a crossover design in all but one previous trial. ment, M.H. arbitrated. Potential biases from crossover designs, such as carryover of treatment effect into the second treatment period, can be Data Extraction and Analysis addressed by restricting analyses to the first treatment period When relevant publications were selected, 2 authors (A.R. and but often requires unpublished data. We therefore conducted Y.X.) independently extracted information on year of publica- a systematic review of trials of ketamine in patients with tion, geographic location, sample size, loss to follow-up, mean by Karin Lavoie on April 20, 2016 treatment-resistant depression to evaluate antidepressant age, study design, major inclusion and exclusion criteria, con- efficacy, suicidality, safety, and tolerability. comitant treatments, and outcome measures as well as safety and tolerability. Methods Potential sources of bias were identified for each trial using criteria recommended in the Cochrane Handbook Types of Trials (Higgins and Green, 2009). For random sequence generation, we categorized trials as “low risk” if random-number charts or We considered all relevant randomized trials (either crossover or coin tossing was used, as “unclear” if there were no details of parallel) in which ketamine was used specifically for the treat- sequence generation, and as “high risk” if sequence was gen- ment of a Major Depressive Episode (DSM-IV diagnosis) and was erated by odd/even date of birth. For allocation concealment, compared with placebo, including active placebo. Eligible trials we categorized trials as low risk if opaque or sealed envelopes included participants with either unipolar or bipolar affective were used, as unclear if there was no detailed information disorder. We excluded trials conducted in the context of ECT and and as high risk if assignments could possibly be foreseen. surgery, but there were no restrictions on concomitant pharma- For blinding, we categorized studies as low risk if blinding was cological or psychological treatments. ensured and unlikely to be broken, as unclear if an inactive placebo was used, and as high risk if outcome measurement Types of Interventions was likely to be influenced by lack of blinding. For incomplete outcome data, we categorized trials as low risk if missing We included any trial that attempted to evaluate a comparison outcome data balanced in numbers and with similar reasons between single administration of ketamine and placebo for the across intervention groups, as unclear if reports of dropouts treatment of major depressive disorder. There was no restriction were insufficient, and as high risk if there were imbalances on ketamine regimen used (eg, dose or route). in numbers or reasons for missing data across intervention groups. For selective reporting, we categorized trials as low Types of Outcome Measures risk if there was a published protocol and the outcome measures listed in the protocol were reported, as unclear if proto- The primary endpoint was change in depression severity scores col could not be found and as high risk if a described outcome from baseline on depression scales such as the Hamilton measure in the protocol or methods was not reported in Depression Rating Scale (HAM-D; Hamilton, 1960) and/or the results. Assessment of period and carryover effects were Montgomery Åsberg Depression Rating Scale [MADRS]) at the listed under “other sources of bias.” We categorized crossover following times: day 1 (24 hours after first dose), day 3, and day trials as high risk and parallel trials as low risk. Xu et al. | 3

Depression severity score (HAM-D and/or MADRS) at each of trial results, and subgroup heterogeneity was tested using follow-up time point was calculated for each trial, for ketamine a chi-squared statistic (Higgins and Green, 2009). Data were or placebo groups, and a placebo-corrected value for each time available only on day 4 for one trial (Sos et al., 2013), and this point was calculated. If not available in tabular form, HAM-D was included in the day 3 category. Data were sought from the and/or MADRS results at different time points were estimated crossover trials for each treatment period separately. independently from Figureures in the articles by 2 authors. Placebo-corrected HAM-D scores were plotted separately for Results each trial with that outcome measure, and placebo-corrected MADRS scores for all trials with that outcome measure. In Search Results addition, we plotted a percentage reduction in depression severity score for all trials based on MADRS score where avail- The search results and study selection process are summarized able and HAM-D for other trials. We conducted a meta-analysis in a PRISMA flowchart (Figure 1) showing the number of unique of mean MADRS score at day 1, 3, and 7, with day of administra- references identified by the search, the number of records tion defined as day 0. These analyses were conducted initially excluded, and the number of full-text records retrieved. One to include the data from the single parallel trial and the first placebo-controlled trial was not included because the sequence period of all crossover trials. We also compared the relative risk was not randomized (Valentine et al., 2011) and one randomized (RR) during the first period against the second period in crosso- trial was not included because ketamine was compared with ver trials in order to examine the direction and magnitude of ECT (Ghasemi et al., 2014). One unpublished trial of the effects of

carryover effects. Meta-analysis of continuous outcomes was intra-operative ketamine on depression was identified, but data Downloaded from conducted using Stata13 (www.stata.com), Windows 7. Meta- were not available (M. Bastos, personal communication). analyses of response rates and clinical remission at days 1, 3, and 7 were conducted using Review Manager Version 5.3. Baseline Characteristics software (RevMan, 2014) to estimate RR and number needed to treat (NNT). All meta-analyses were done using a random Nine randomized, placebo-controlled trials were identified, effects model. The I2 statistic was used to assess heterogeneity and a total of 201 patients (105 females and 96 males) were http://ijnp.oxfordjournals.org/ by Karin Lavoie on April 20, 2016

Figure 1. Flow diagram for systematic review. 4 | International Journal of Neuropsychopharmacology, 2015

included (Table 1) (Berman et al., 2000; Zarate et al., 2006, 2012; effect largely dissipated by days 4 to 7 (Diazgranados et al., Diazgranados et al., 2010a; Murrough et al., 2013; Sos et al., 2010a; Zarate et al., 2012). A smaller treatment effect in BD 2013; Lai et al., 2014; Lapidus et al., 2014) (C. K. Loo, V. Galvez, patients compared with unipolar patients on the HAM-D was E. O’Keefe, unpublished data). Eight studies (Berman et al., 2000; evident by 24 hours. There was no evidence of greater benefit Zarate et al., 2006, 2012; Diazgranados et al., 2010a; Sos et al., in trials that aimed to attain high peak concentrations, either 2013; Lai et al., 2014; Lapidus et al., 2014) (C. K. Loo, V. Galvez, with an i.v. push during a few minutes (Lai et al., 2014) or an E. O’Keefe, unpublished data) were crossover trials with a 1- initial loading dose of 0.27 mg/kg during the first 10 minutes to 2-week washout period between treatments, and one was a (Sos et al., 2013). parallel group design with 1 week of follow-up (Murrough et al., 2013). Two trials (Diazgranados et al., 2010a; Zarate et al., 2012) Effects on Response and Remission Rates over Time included only patients with bipolar disorder (BD), and 7 trials (Berman et al., 2000; Zarate et al., 2006; Murrough et al., 2013; Analyses of treatment effects on response and remission, Sos et al., 2013; Lai et al., 2014; Lapidus et al., 2014) (C. K. Loo, including only the single parallel group trial and the first treat- V. Galvez, E. O’Keefe, unpublished data) included patients ment period of crossover trials, are summarized in Figure 5. At with only unipolar depression (although one trial [Berman day 1, there was a large treatment effect, with 50% of those in et al., 2000] included one patient with BD). All patients were the ketamine group compared with 13% in the placebo group treatment resistant, variously defined (Table 1). Patients with meeting criteria for response (RR 2.6, 95% CI 1.6 to 4.4, P = .0003; history of psychosis or recent substance use disorders were NNT 2.9, 1.9–7.1). There was a similarly large effect on remis-

generally excluded. Patients in the 2 BD trials (Diazgranados sion of symptoms at day 1 (RR 5.2, 95% CI 2.1–12.9, P = .0003; NNT Downloaded from et al., 2010a; Zarate et al., 2012) were drug free except for lith- 4.5, 3.1–8.3) among those receiving ketamine. At day 7, response ium or valproate. In the other 7 trials, patients were drug free rates were substantially increased in the ketamine group and to in 2 (Berman et al., 2000; Zarate et al., 2006), allowed to take a larger degree (RR 3.4, 95% CI 1.6 to 7.1, P = .001; NNT 6.3, 3.4–25). only a nonbenzodiazepine hypnotic in one (Murrough et al., Remission rates were still substantially increased in the keta- 2013), and taking stable doses of other psychotropic medica- mine group, although to a lesser degree (RR 2.6, 95% CI 1.2–5.7, tions in 4 trials (Sos et al., 2013; Lai et al., 2014; Lapidus et al., P = .02; NNT 9.1, 5–50). While the pooled results of 3 trials of very http://ijnp.oxfordjournals.org/ 2014) (C. K. Loo, V. Galvez, E. O’Keefe, unpublished data). Six tri- low-dose ketamine showed no significant effect on response or als (Berman et al., 2000; Zarate et al., 2006, 2012; Diazgranados remission on days 1, 3, or 7 and the treatment effect appeared et al., 2010a; Murrough et al., 2013; Sos et al., 2013) assessed a smaller compared to low-dose ketamine, formal subgroup het- single 40-minute infusion of i.v. ketamine at a subanaesthetic erogeneity tests were not significant (P = .09 for response and low dose of 0.5 mg/kg (defined here as low dose). Three tri- P = .12 for remission on day 3). als tested lower doses (defined here as very low-dose trials): One of the major potential biases in crossover trials is drop- 50 mg intranasally (as 10 mg every 5 minutes), estimated to out after the first treatment, and this occurred in 12/46 patients achieve plasma concentrations equivalent to about 0.3 mg/kg who received ketamine initially compared with 5/55 who

i.v. (Lapidus et al., 2014); 0.1 to 0.4 mg/kg i.v. (Lai et al., 2014), or received placebo initially in 5 trials (Zarate et al., 2006, 2012; by Karin Lavoie on April 20, 2016 0.1 to 0.5 mg/kg i.v., intramuscular, or s.c. in an ascending dose Diazgranados et al., 2010a; Sos et al., 2013; Lapidus et al., 2014). design (with placebo randomly inserted) (C. K. Loo, V. Galvez, Dropout was for improved mood for 4 patients in the ketamine E. O’Keefe, unpublished data). Seven trials (Berman et al., 2000; group and 2 in the placebo group. In terms of treatment effects Zarate et al., 2006, 2012; Diazgranados et al., 2010a; Sos et al., in the second period of the crossover trials, overall 0/34 patients 2013; Lai et al., 2014; Lapidus et al., 2014) used 0.9% saline responded at day 1 who received placebo as their second treat- as placebo and 2 used 0.045 mg/kg (Murrough et al., 2013) or ment compared with 22/50 patients responding at day 1 after 0.01 mg/kg (C. K. Loo, V. Galvez, E. O’Keefe, unpublished data) receiving ketamine as their second treatment. Remission was midazolam as an active placebo. Potential sources of bias are achieved in 0/34 patients at day 1 who received placebo as their summarized in Figure 2. second treatment compared with 8/50 patients after receiving ketamine as their second treatment. Thus, it did appear that carryover effects were not marked, although this cannot be Effects on Depression Severity Scores over Time assessed reliably since fewer patients in the ketamine groups Effects on depression severity over time are presented in proceeded to the second period. Figure 3, with data redrawn from original trials and placed on a uniform linear scale, and shown in Figure 4 with data from Effects on Suicidality the single parallel trial and from the first period of crossover trials. A large reduction in depression severity was evident Measures of suicidality were published in 4 trials (Berman within 4 hours in all but one small trial of very low-dose keta- et al., 2000; Zarate et al., 2006, 2012; Murrough et al., 2013) and mine, and treatment effects were largest at day 1. In the tri- these are summarized in Table 2. Each trial reported a signifi- als of very low-dose ketamine (Lai et al., 2014; Lapidus et al., cant reduction in suicidality assessed using different measures. 2014) (C. K. Loo, V. Galvez, E. O’Keefe, unpublished data), the Seven trials provided unpublished data on the suicide item com- reduction in overall severity appeared smaller and shorter ponent of a depression scale, 1 for HAM-D (Zarate et al., 2006), lived. A test for heterogeneity indicated a significant differ- and 6 for MADRS (Diazgranados et al., 2010a; Zarate et al., 2012; ence in treatment effects at day 3 for low-dose compared with Sos et al., 2013; Lai et al., 2014; Lapidus et al., 2014) (C. K. Loo, very low-dose trials (P = .02). In the 4 trials conducted with V. Galvez, E. O’Keefe, unpublished data). Overall, reported suici- ketamine 0.5 mg/kg i.v. for patients with unipolar depression dality scores were low at baseline, with an average of 1.6 on the (Berman et al., 2000; Zarate et al., 2006; Murrough et al., 2013; MADRS suicidality item (which ranges from 0 to 6) for trials that Sos et al., 2013), the large reduction in average mood score at reported this outcome, as shown in Table 3. Nonetheless, a sig- 24 hours remained evident, though moderately attenuated, up nificant reduction in suicidality severity score was observed for to day 7. In the 2 trials among patients with BD, the treatment the ketamine group at days 1 and 3, as seen in Figure 6. Xu et al. | 5 , a , , a a a BDI, (BPRS), (YMRS), VAS-depression HAM-D-17, BDI, VAS-depression, VAS-anxiety, HAM-A, (BPRS), (YMRS) QIDS-SR, CGI, (CADSS), (BPRS), (YMRS); HAM-D-17, BDI, VAS-depression, VAS-anxiety, HAM-A, (BPRS), (CADSS), (YMRS) Outcome Measures† MADRS MADRS MADRS HAM-D-25, BDI, (VAS-high), (BPRS) HAM-D-21 (2 ketamine, 1 placebo), 1 placebo), (2 ketamine, didn`t finish follow-ups. didn`t finish ketamine), follow-ups. (3 ketamine, 1 placebo), 1 placebo), (3 ketamine, didn`t finish follow-ups. (1 placebo, 1 ketamine), 1 ketamine), (1 placebo, attended all previous follow-ups. (placebo), attended all (placebo), follow-ups; previous didn`t attend (placebo), 2. after Day follow-up Loss to Follow-Up 3 after first treatment 3 after first treatment (both 2 after last treatment 4 after first treatment 4 after first treatment 2 from ketamine arm: 2 from both after 24-hour evaluation; arm: placebo 3 from all after 24-hour evaluation 2 before last treatment last treatment 2 before 4 before last treatment last treatment 4 before 1 after first treatment Downloaded from y prn valproate valproate no other drugs during trial nor in prior 2 weeks (5 for no fluoxetine); psychotherapy valproate no valproate other drugs during trial nor in (5 prior 2 weeks for fluoxetine); no psychotherapy epine epine hypnotic; 1 drug free before week for (4 weeks no fluoxetine); psychotherapy drug free 2 drug free prior weeks drug free 2 drug free prior weeks Concomitant Treatments Lithium/ Lithium/ nonbenzodiaz- Onl Nil and Nil and

mg/

bo i.v. bo i.v. bo i.v. bo i.v. 25)

= place place kg place place

. . 0.045 http://ijnp.oxfordjournals.org/ Saline Saline (N Midazolam i.v Saline Saline mg/kg mg/kg mg/kg

47)

mg/kg mg/kg

Intervention Control Ketamine i.v. 0.5 Ketamine i.v. 0.5 (N Ketamine i.v. 0.5 Ketamine i.v. 0.5 Ketamine i.v. 0.5 buse; by Karin Lavoie on April 20, 2016 substance abuse substance abuse or dependence in last 3 months; medical unstable condition; serious risk of suicide; previous with treatment ketamine unstable medical unstable condition; substance abuse or dependence in last 3 months; previous with treatment ketamine bipolar disorder; bipolar disorder; alcohol/substance in the abuse 2 years; previous medical unstable illness; serious and imminent suicidal or homicidal risk; <27 on MMSE disorders substance a bipolar disorder; bipolar disorder; of history antidepressant- or substance- induced Major Exclusion Criteria Psychotic features; features; Psychotic Psychotic features; features; Psychotic Psychotic illness or Psychotic any other Axis I other any Recent alcohol or Psychotic features; features; Psychotic hypomania/mania 1)

der (N 8);

depression, depression, failed DSM-IV, antidepressant trial and mood stabilizer; MADRS ≥ 20; major current depressive ≥4 episode weeks depression, depression, failed DSM-IV, antidepressant trial and mood stabilizer; MADRS ≥ 20; major current depressive ≥4 weeks episode disorder, DSM-IV; DSM-IV; disorder, failed ≥3 antidepressant trials; ≥1 previous major depressive or lasting episode ≥32 ≥2 years; IDS-C disor unipolar major depression (N disorder, disorder, DSM-IV; failed ≥2 antidepressant trials; HAMD- 21 ≥ 18 Major Inclusion Criteria Bipolar I or II Bipolar I or II Bipolar Recurrent Recurrent Major depression Major depression week) (washout 2 weeks) (washout 2 weeks) (washout ≥1 (washout (washout 1 week) Male (N) Design 35 Parallel Major depressive Mean (y) Age (SD), Ketamine 43 (12) Midazolam evious Trials of One-Off Ketamine in Patients with Severe Mood Disorder with Severe in Patients of One-Off Ketamine Trials evious

b Sample Sample Size (N) 18 48 (13) 6 Crossover 15 47 (10) 7 Crossover 72 47 (13) 9 37 (10) 4 Crossover 18 47 (11) 6 Crossover

Maryland Texas Texas and York New City Maryland Region, Region, Country Bethesda, Bethesda, Bethesda, Maryland Houston, Houston, Connecticut Bethesda, Bethesda,

Characteristics of Pr Characteristics

et al., et al., 2010a et al., et al., 2012 et al., et al., 2013 et al., et al., 2000 et al., et al., 2006 Table 1. Trial Diazgranados Zarate Zarate Murrough Murrough Berman Zarate Zarate 6 | International Journal of Neuropsychopharmacology, 2015 , , a a a QIDS-SR, HAM-A, (BPRS), (CADSS), (YMRS), (SAFTEE) CGI, QIDS-SR, (BPRS), (YMRS), (CADSS), (SAFTEE). (BPRS) MADRS Outcome Measures† MADRS MADRS mg/kg

mg/kg

evious evious evious (ketamine), attended all (ketamine), follow-ups. previous didn`t finish (ketamine), follow-ups. 2 placebo), ketamine, didn`t finish follow-ups. 0.1, and 0.2 0.1, (attended all pr follow-ups); 0.2 and 0.1, 0.3 follow-ups). (attended all pr treatment treatment 1 placebo). (1 ketamine, 1 before last treatment last treatment 1 before 2 after first treatment (3 5 after last treatment Loss to Follow-Up 1 after placebo, 1 after placebo, 1 after placebo, 2 before first 2 before Downloaded from medications and dosages maintained throughout the duration of the study stable doses stable of psychotropic medications; in no changes medication dosage and no ECT 4 weeks prior to trial entry psychotropic psychotropic medication, including antidepressant treatment Remained on antidepressant Concomitant Treatments Remain on Stable doses of Stable bo bo place http://ijnp.oxfordjournals.org/ i.v. Saline place Saline i.v. Saline placebo intranasal mg/kg mg/kg

mg/Kg

intranasal intranasal 50 mg Ketamine i.v. Ketamine Loading: 0.27 Maintenance: 0.27 Intervention Control Ketamine i.v. 0.1, 0.2, 0.3, 0.4 Ketamine Ketamine

nd /2

st by Karin Lavoie on April 20, 2016 degree relatives; relatives; degree electroconvulsive within therapy 3 months I or II disorders I or II disorders one (aside from subject with phobic disorder); I disorders; I disorders; suicide risk; substance abuse or dependence in last 6 months; disorder; psychotic bipolar disorder; developmental previous disorder; abuse/ on dependence ketamine other Axis I or II other unstable disorders; medical illness or neurological psychotic disorder; symptom/ in 1 disorder Major Exclusion Criteria Comorbid Axis Any Any other Axis Suicide risk, any any Suicide risk, sive episode ≥4 episode sive DSM-IV; weeks, MADRS ≥ 20; failed ≥ 1 trial of antidepressant during current episode disorder, DSM-IV; DSM-IV; disorder, failed ≥1 trial of adequate dose of and duration antidepressant; IDS-C ≥ 30 disorder, DSM- disorder, of ≥20 score IV; on MADRS at baseline Major Inclusion Criteria Major depres- Major depressive Major depressive Major depressive Major depressive week) ketamine week) week) (washout 1 (washout 4 dosages of (washout ≥1 (washout (washout 1 (washout Male (N) Design 15 Crossover first Mean (y) Age (SD), Ketamine Ketamine 45 (11) first placebo

b Sample Sample Size (N) 4 51 (17) 2 Crossover 20 48 (13) 10 Crossover 30 42 (15)

Australia City, USA City, Czech Czech Republic Region, Region, Country Sydney, Sydney, New York York New Prague, Prague, Continued

et al., 2014 et al., et al., et al., 2014 et al., et al., 2013 Table 1. Trial Lai Lapidus Sos Xu et al. | 7 , (BPRS), (BPRS), , a (YMRS - item (CADSS), 1), (SAFTEE) Outcome Measures† MADRS mg/kg

, 0.1, 0.2, 0.2, 0.1, , bo SC; , 0.1 and , mg/kg IM; 1 after mg/kg IM; 1 after

bo, 0.1, and 0.2 0.1, bo, 0.3 0.2, 0.1, bo, mg/kg i.v.; 1 after mg/kg i.v.; mg/kg SC; 1

place IM; 1 after placebo and 0.3 place placebo 0.2 after place 0.2 and 0.4 Loss to Follow-Up 40 1 after placebo, 0.1, and 0.1, 1 after placebo, ble doses ble Downloaded from concomitant medications; um/valproate; nonbenzodiaz- hypnotic; epine psychotropic medications sta of psychotropic of psychotropic medications; no changes in medication dosage and no ECT 4 weeks prior to trial entry Concomitant Treatments 27 (13%) no 33 (16%) on Lithi- 72 (36%) only 69 (34%) on other Remain on mg/kg

i.v.; intranasal; 5 (3%) i.v.; intramuscular; 6 (4%) s.c. 0.01 ., SC or IM ., http://ijnp.oxfordjournals.org/ Saline: 94 (61%) 20 (13%) Midazolam: 29 (19%) Midazolam i.v mg/kg

20 (11%) intranasal; 5 (3%) intramuscular; 6 (3%) s.c. IM or SC; 0.4, 0.3, 0.5 Intervention Control Ketamine: 145 (82%) i.v.; Ketamine i.v., i.v., Ketamine 0.2, 0.1, by Karin Lavoie on April 20, 2016 rapid cycling cycling rapid bipolar disorder current or any psychotic symptoms Major Exclusion Criteria Schizophrenia, Schizophrenia, pressive pressive Disorder, Disorder, depression of episode ≥ 4 duration DSM IV; weeks, MADRS ≥ 20; failed to ≥1 trial of antidepressant during current episode Major Inclusion Criteria Major De 6) 5);

= =

4);

= N

N patients in patients in crossover (IM, (SC, week) ketamine 129 (64%) (washout 1 (washout 5 dosages of (i.v., N Male (N) Design 96 (48%) Mean (y) Age (SD),

b Sample Sample Size (N) 201 46 15 49 (11) 11 Crossover Australia Region, Region, Country Sydney Sydney Continued

V. Galvez, V. Galvez, O’Keefe, E. unpublished data Primary outcome measures. Primary did One patient in the ketamine group after allocation. and 72 remained 73 patients at the time of randomization were There 2013 . et al., for Murrough exception with an randomization, identified at the time of Sample size was not receive intervention. Characteristics (eg, age and sex) were reported based on the 72 patients. reported were age and sex) (eg, Characteristics intervention. not receive Abbreviations: MMSE: Mini-Mental State Examination; IDS-C, the Inventory of Depressive Symptomatology—Clinician Rated. †HAM-D, Hamilton Depression Rating Scale scores; BDI, Beck Depression Inventory; VAS(-high), Visual Visual VAS(-high), Inventory; Depression Beck BDI, Rating Scale scores; Hamilton Depression †HAM-D, Rated. Symptomatology—Clinician of Depressive the Inventory MMSE: Mini-Mental State Examination; IDS-C, Abbreviations: Clinician Anxiety Rating Scale; CADSS, Hamilton Rating Scale; HAM-A, Depression Montgomery-Åsberg Mania Rating Scale; MADRS, Young Rating Scale;YMRS, Brief Psychiatric “high”); BPRS, (for intoxication Scales score Analog in paren- Effects.Measures Emergent Treatment Assessment for Systematic SAFTEE, Clinical Global Impression; CGI, Report; Symptomatology-Self of Depressive Inventory States Scale; QIDS-SR,Quick Dissociative Administered measures. theses indicate the safety and tolerability a b Table 1. Trial Total/ average C. K. Loo, K. Loo, C. 8 | International Journal of Neuropsychopharmacology, 2015 Downloaded from

Figure 2. Potential sources of bias in included trials. See Methods for explanation of potential biases. http://ijnp.oxfordjournals.org/

Tolerability and Side Effects no lasting effects. Thus, it could be summarized that 3 major psychiatric events (suicide attempt before treatment, transient Measures of tolerability and side effects were summarized manic symptoms, and affective switch) were reported in the in Table 4. Low-dose ketamine at 0.5 mg/kg, infused over 40 studies, of which only one was potentially attributable to keta- minutes, was generally well tolerated, with transient, mild- mine (transient manic symptoms). No major medical events to-moderate dissociative symptoms and blood pressure and/ occurred in the trials. or heart rate increases in a minority of patients. For example, Diverse measures were used to test possible psychotomi- in the largest trial, 17% of patients had significant dissociative metic, dissociative, or mood elevation symptoms, including by Karin Lavoie on April 20, 2016 symptoms immediately after ketamine infusion, but these all Visual Analogue Scale score for intoxication “high” (Aitken, resolved within 2 hours and no severe psychotic symptoms 1969), Brief Psychiatric Rating Scale (Overall and Gorham, 1962), (paranoia, hallucinations, or delusions) occurred in either arm Young Mania Rating Scale (Young et al., 1978), and Clinician (Murrough et al., 2013). The characteristic symptomatic side Administered Dissociative States Scale (Bremner et al., 1998). effects (eg, confusion, blurred vision) and the increases in heart The results showed that Visual Analogue Scale score for intoxi- rate and blood pressure resolved within 4 hours of adminis- cation “high” scores returned to baseline within 110 minutes tration in all trials. These side effects were less marked with of the infusion (Berman et al., 2000). In no case did euphoria, very low-dose ketamine delivered intranasally for 20 minutes derealization, or depersonalization persist beyond 110 minutes (Lapidus et al., 2014) but were more marked with very low- (Zarate et al., 2006). dose ketamine given as an i.v. push for a few minutes (Lai Continuation into the second phase of the crossover trial et al., 2014). Among trials that reported a full listing of adverse was also assessed as a proxy of tolerability, and most dropouts events in both groups, there was no excess in the ketamine were reported as being due to changes in mood rather than vs placebo after administration day (Murrough et al., 2013; Lai adverse events. In 5 crossover trials with first-phase data avail- et al., 2014; Lapidus et al., 2014) (C. K. Loo, V. Galvez, E. O’Keefe, able (Zarate et al., 2006, 2012; Diazgranados et al., 2010a; Sos unpublished data). et al., 2013; Lapidus et al., 2014), 12 of 46 patients did not pro- Eleven events were reported as serious adverse events in ceed to placebo treatment after receiving ketamine first. For 4 the ketamine group: hypotension and bradycardia occurred patients, this was due to improved mood (Zarate et al., 2006), for in 1 person, which resolved in <1 minute and was considered 4 it was due to worsening mood (Diazgranados et al., 2010a; Sos to be due to a vaso-vagal episode (Murrough et al., 2013); sui- et al., 2013), and other reasons were involved for an additional 4 cide attempt occurred in 1 patient while tapering off of psy- (Zarate et al., 2012; Lapidus et al., 2014). chotropic medication (Murrough et al., 2013); tachycardia (>150 bpm) occurred in 2 patients (Lai et al., 2014); and mean arterial Discussion pressure elevations >20% from baseline in 5 patients (Lai et al., 2014) (C. K. Loo, V. Galvez, E. O’Keefe, unpublished data). Also, Summary of Findings while not reported as serious adverse events, one ketamine- treated patient developed manic symptoms that resolved This systematic review of trials of single-dose ketamine com- within 80 minutes, and an affective switch occurred for one pared with placebo for treatment-resistant patients in a major patient in the placebo group (Diazgranados et al., 2010a). All depressive episode confirms a large reduction in depression the hemodynamic side effects resolved within a few hours with severity and suicidality that is apparent within 4 hours after Xu et al. | 9 Downloaded from http://ijnp.oxfordjournals.org/ by Karin Lavoie on April 20, 2016

Figure 3. Reductions in depression severity scores following single-dose ketamine in patients with major depression. (A) Placebo-corrected changes in Hamilton Depression Rating Sclae Scores (HAM-D). (B) Placebo-corrected changes in Montgomery-Åsberg Depression Rating Scale (MADRS). (C) Placebo-corrected percentage changes in HAM-D/MADRS. Data are placebo-corrected, and axes redrawn on a linear scale to avoid a visual misrepresentation of how the treatment effect evolves over time. Lines with circular markers represent trials among patients with bipolar disorder depression. Other trials were among patients with unipolar depression. Lines with square markers represent patients remained on pretrial antidepressant treatment. Solid lines represent low dose (i.v. ketamine 0.5 mg/kg). Dashed lines represent very low dose (intranasal ketamine 50 mg or i.v. 0.3 mg/kg; Lai et al. and Loo et al. used an ascending dose design and the data for 0.3 mg/kg are shown). ketamine administration. The data suggest benefits are smaller when assessing a fully reversible treatment, with outcomes and shorter lived with very low-dose ketamine. There is also a that return to baseline levels after a suitable washout period suggestion of short-lived effects in patients with BD. There is (ie, short-lived interventions that do not affect the natural his- substantial heterogeneity in clinical response, with benefits tory of a stable illness). For treatments that do not have these lasting <1 week for most patients, but approximately one-fifth criteria, one can observe period effects (ie, the treatment effect of patients remaining in remission at 1 week. in the first period is systematically different from that in the second period) and/or carryover effects (ie, the treatment effect Limitations in the first period is still operating during the second period). Statistical tests to detect period and carryover effects are rela- This systematic review has a number of methodological limi- tively insensitive, and analytic approaches to overcome these tations. Most important is the small sample size (average of issues are generally unsatisfactory (Senn, 2002). However, these only 23 patients per trial) and 201 patients in total. The use of a issues can be addressed with a separate analysis of first period crossover design in all but one trial is a potential issue. While a data, which was possible in this meta-analysis. Finally, all tri- crossover design improves study power to partly mitigate prob- als involved one-off treatments and varying measures of side lems associated with small sample size, it can have limitations effects and had relatively short follow-up; hence, the safety and for mood disorder trials. Crossover designs are most reliable efficacy of long-term treatment remain uncertain. 10 | International Journal of Neuropsychopharmacology, 2015

Figure 4. Difference in standardized mean mood score on days 1, 3, and 7 for crossover trials, first period only. Data are shown only for the first period in crossover trials. Hamilton Depression Rating Sclae Scores (HAM-D) was reported by Zarate et al., 2006 with the remainder reporting Montgomery-Åsberg Depression Rating Scale (MADRS). 95% CIs of treatment effects are represented by horizontal lines for individual trials, by grey diamonds for trial subgroups, and by black diamonds for all Downloaded from trials. A vertical dashed line goes through the overall pooled result for all trials, with a result to the left of the vertical line indicating a reduction in mood score in the ketamine group.

Strengths of this review include the reporting of additional potential of repeated dosing is a critical issue for future trials. unpublished data from numerous trials and analyses of only While some reassurance can be taken from the much more the first treatment period, increasing the reliability. It is also extensive use of i.v., oral, and sublingual ketamine in chronic http://ijnp.oxfordjournals.org/ the first review to compare results of low-dose and very low- pain control (Chong et al., 2009), future longer term trials must dose ketamine, suggesting larger benefits with the former. The assess safety in this patient population. Trials should assess consistency of the findings described in this review suggest the likelihood of abuse potiential in subjects with major a true treatment effect in improving depressive symptoms, depression, while incorporating strategies to mitigate this. albeit temporarily for most. Several additional strands of evi- Second, trials should adopt parallel designs rather than dence indicate that the benefit observed in these trials is a crossover designs, since benefits remain for more than 1 week result of depression treatment, rather than nonspecific mood in a significant proportion of patients; hence, this situation elevation or a ‘high’ following ketamine administration: there does not meet the fundamental criterion for crossover trials is improvement in core depressive symptoms such as sad- to have a stable disease baseline and short-lived treatment by Karin Lavoie on April 20, 2016 ness, suicidality, and helplessness; the time course of ben- effect in all patients. Third, trials should recruit many times efits is in the following days and sometimes weeks, whereas more patients, so that the effects in different subgroups can mood elevation with drugs of abuse is generally limited to be assessed reliably given the considerable heterogeneity in the time of intoxication; the response pathway can be inter- response. Fourth, trial designs should reflect the possibility rupted in animal models of depression treatment (Autry et al., of different effects among patients with bipolar and unipolar 2011); and postoperative mood improvement occurs among disorder. Fifth, there is no evidence concerning first-line treat- patients given ketamine intra-operatively, who would have ment of major depressive disorder: ketamine may have a role been unaware of immediate subjective effects (Kudoh et al., to play in patients with severe presenting symptoms, includ- 2002; Argiriadou et al., 2004). Recent trials have also suggested ing suicidality, and could conceivably cover the lag phase possible benefits among patients with posttraumatic stress before SSRI efficacy onset (and reduction of suicidal ideation disorder (Whiteford et al., 2015) and in obsessive compulsive may be particularly important in young adults). Further evi- disorder (Rodriguez et al., 2013), and there is encouraging ini- dence of reduction in suicidality was recently provided by an tial evidence comparing ketamine with ECT (Ghasemi et al., additional trial published after our search cut-off date, con- 2014). ducted among 27 patients with mood and anxiety spectrum disorders who presented with clinically significant suicidal Relevance for Clinical Practice and Research ideation.(Murrough et al., 2015) Ketamine may also augment the response from standard treatments. For example, while Most clinicians, drug regulators, and health funders will require ECT is indicated in severe depression with acute suicidality further research evidence before low-dose ketamine is adopted it may take a week or longer to alleviate symptoms and keta- in clinical practice. The results of this review have several impli- mine may play an important role by acting more quickly in cations for future research. this setting. Finally, further data on safety and efficacy of use First, research is urgently required on efficacy and safety in ‘real world’ clinical settings is clearly required, given that of longer treatment regimens. A key issue is whether the many of the trials were conducted in highly medically con- ketamine response can be maintained or even enhanced by trolled environments. While i.v. infusions may be practical in repeated dosing, such as the 2 to 3 times weekly schedule that service settings used for ECT, other formulations and delivery has been assessed in some case series with promising find- routes, such as intranasal spray, s.c., intramuscular, or oral, ings (Price et al., 2009; aan het Rot et al., 2010; DiazGranados are likely to be more broadly applicable to clinical practice. et al., 2010b; Larkin and Beautrais, 2011; Rasmussen et al., Minimizing dissociative and hemodynamic side effects is 2013; Shiroma et al., 2014). Safety, tolerability, and abuse important for widespread applicability, and this is likely to Xu et al. | 11 Downloaded from http://ijnp.oxfordjournals.org/ by Karin Lavoie on April 20, 2016

Figure 5. Effects of single-dose ketamine on response and remission rates at days 1, 3, and 7. Data included from the parallel trial (Murrough et al.) and from the first period of crossover trials. 95% CIs of treatment effects are represented by horizontal lines for individual trials and by diamonds for subgroups or all trials. Results on the right side of the vertical line indicated benifit in the ketamine group.

involve avoiding high peak plasma levels (Lai et al., 2014). and heemodynamic effects occurred. There were no major However, very low doses are associated with lower efficacy, medical events. Collectively, these data suggest ketamine suggesting multiple low doses delivered gradually or sequen- has considerable promise for the acute treatment of major tially may be optimal. Future trials could also assess ketamine depression and provide the rationale for a large, parallel enantiomers (Paul et al., 2009), metabolites (Zarate Jr et al., group, randomized, placebo-controlled trial to assess safety 2012), or other glutamatergic agents. and efficacy of a longer course of ketamine in patients with severe mood disorders. Conclusions Acknowledgments This systematic review confirmed a large, rapid benefit in response and remission following a single dose of ketamine Unpublished data were provided by Veronica Galvez, Kyle in patients with treatment resistant depression. There was Lapidus, Colleen Loo, David A. Luckenbaugh, Alexander McGirr, also a reduction in suicidality. Transient psychotomimetic Peter Sos, and Carlos A. Zarate. 12 | International Journal of Neuropsychopharmacology, 2015

Table 2. Published Measures of Suicidality

Trial Measure Used Outcome Reported in Publication

Berman et al., 2000 HAM-D suicidality item While undergoing active treatment, significant decreases were observed for suicidality (P < .02). Control treatment was not associated with significant improvement in any of the HAM-D items. Zarate et al., 2006 HAM-D suicidality item Significant main effect for drug Zarate et al., 2012 Changes in suicide item scores on the Within 40 min, suicidal ideation significantly MADRS, HAM-D, and BDI improved in subjects receiving ketamine compared with placebo (Cohen’s d 0.98, 95% CI 0.64 –1.33); this improvement remained significant through day 3. Reductions in suicide item scores for each of the MADRS, HAM-D, and BDI using linear mixed models (each P < .001) Murrough et al., 2013 Composite index of explicit suicidal Fifty-three percent of ketamine-treated patients ideation (Beck Scale for Suicidal scored 0 on all 3 explicit suicide measures at Ideation, MADRS suicide item, Quick 24 h compared with 24% of the midazolam group Inventory of Depressive Symptoms (χ = 4.6; P = .03) Downloaded from suicide item)

Abbreviations: BDI, Beck Depression Inventory; HAM-D, Hamilton Depression Rating Scale; MADRS, Montgomery Åsberg Rating Scale.

Table 3. Unpublished Data on Suicidality Scores at Baseline http://ijnp.oxfordjournals.org/

Ketamine Placebo

Trial Suicidality Item Subscale Used Mean SD Mean SD

Zarate et al., 2006 HAM-D, item 4* 1.9 1.1 1.2 1.1 Diazgranados et al., 2010a MADRS, item 10** 2.0 1.9 2.4 1.9 Zarate et al., 2012 MADRS, item 10** 2.3 1.6 2.5 1.5 Sos et al., 2013 MADRS, item 10** 0.4 0.7 0.4 0.7 Lapidus et al., 2014 MADRS, item 10** 1.7 1.4 1.7 1.7 Lai et al., 2014 MADRS, item 10** 1.8 1.0 1.8 1.0 by Karin Lavoie on April 20, 2016 Loo et al., unpublished MADRS, item 10** 1.9 1.2 2.3 1.0

Abbreviations: MADRS, Montgomery Åsberg Rating Scale. *Ranges from 0 to 4; **ranges from 0 to 6.

Figure 6. Standardized mean differences in suicide item scores at days 1, 3, and 7. Suicide item score from Hamilton Depression Rating Sclae Scores (HAM-D) provided by Zarate et al., 2006, and from Montgomery-Åsberg Depression Rating Scale (MADRS) for other trials. 95% CIls of treatment effects are represented by horizontal lines for individual trials and by diamonds for all trials. A vertical dashed line goes through the overall pooled result for all trials, with a result to the left of the vertical line indicating a reduction in mood suicide item score in the ketamine group.

National Heart Foundation Future Leader Fellowship to K.L. National Health and Medical Research Council (grant number 100034) (Level 2) to M.H. National Institutes of (NHMRC) Centre for Research Excellence (grant number Health (grant number K23 MH104465), the Brain and Behavior 1061043), Janssen, and Lundbeck to N.G. National Health and Research Foundation, APIRE/Janssen, and the Le Foundation Medical Research Council (NHMRC) (grant number 1037196) to Xu et al. | 13

Table 4. Measures of Safety and Tolerability in Included Trials

Trial VAS-High BPRS CADSS YMRS SAEs

Berman Ketamine produced Ketamine produced Not mentioned Not mentioned Not mentioned et al., 2000 markedly greater significantly greater scores. Scores scores, especially the are significantly positive symptoms. different between Scores are significantly two groups till different between 2 40 min and return groups until 40 min to baseline by and return to baseline 110 min. by 120 min. Zerate Not mentioned The positive symptoms Not mentioned Worse for participants Nil et al., 2006 subscale scores were receiving ketamine worse for participants than placebo at 40 receiving ketamine minutes, but they than those receiving were significantly placebo only at 40 min. better from days 1 to 2. Diazgranados Not mentioned Ketamine and placebo A ketamine/placebo Patients receiving One patient developed Downloaded from et al., 2010a differed only at difference was ketamine had higher manic symptoms in 40 min, and this seen at 40 min only scores at 40 min but the ketamine group difference was due to (large increase on significantly lower that resolved within a small, nonsignificant ketamine). scores at days 2 and 80 min and an affective decrease with 14. Compared with switch occurred for placebo and an even baseline, there was one patient in the http://ijnp.oxfordjournals.org/ smaller increase with no significant change placebo group. ketamine. in manic symptoms in patients receiving placebo. Zarate Not mentioned No significant drug Higher values in No significant drug Nil et al., 2012 effect or interaction. patients receiving effect or interaction. ketamine only at 40 min.

Murrough Not mentioned The positive symptoms At 40 min, the average The first item of the Patient 1: BP = 73/40 by Karin Lavoie on April 20, 2016 et al., 2013 subscale scores for score for the ketamine YMRS at 40 min was (1 min) HR <30 bpm ketamine patients group was 14.7 (10.6– 0.6 for ketamine and (30 sec), spontaneous beyond the 40 min 18.8), and 2.28 (0.0–4.8) 0.12 for midazolam recovery; Patient ranged from 4.02 to for the midazolam group. 2: Suicide attempt 4.04. group. Average scores while tapering off for the ketamine of psychotropic group beyond 40 min medication, patient ranged between 0.065 was hospitalized. and 0.533. Lapidus et al., Not mentioned No relationship between No relationship Measured, but not Nil 2014 ketamine associated between ketamine reported changes in dissociative associated changes or psychotomimetic in dissociative or symptoms and antide- psychotomimetic pressant response was symptoms and anti- found depressant response was found Lai et al., 2014 Not mentioned Clear dose–response Clear dose–response Not mentioned During 0.4 mg/kg dosage relationship for relationship for Two patients: psychotomimetic psychotomimetic tachycardia (150 bpm); symptoms occurring symptoms occurring One patient: BP increase within 40 min. Scores within 40 min. Scores (140/80 to 195/105). returned to pre- returned to pre-treat- Spontaneous recovery treatment levels within ment levels within 4h within 15 min 4h for all subjects. for all subjects. 14 | International Journal of Neuropsychopharmacology, 2015

Table 4. Continued

Trial VAS-High BPRS CADSS YMRS SAEs

C. K. Loo, Not mentioned No evidence of treatment Dose-response No evidence of Across groups, MAP V. Galvez, emergent mania, at relationship between treatment emergent elevations did not E. O’Keefe, any time point, across psychotomimetic mania, at any time exceed >20% from unpublished routes of effects and ketamine point, across routes baseline, except for 4 data administration and treatment for all of administration patientsa (i.v., N = 2; IM, doses routes, with higher and doses N = 2). These effects peak scores in the resolved by 30 min i.v. group. Scores without intervention. resolved without Increases in heart rate intervention by 40 did not exceed 120% of minutes post- baseline, except in injection for all three participants routes. (N = 1, i.v.; N = 1 intramuscular; N = 1, S.C.). Downloaded from Abbreviations: AE, adverse event; BPRS, Brief Psychiatric Rating Scale; CADSS, Clinician Administered Dissociative States Scale; CGI, Clinical Global Impression; MAP, mean arterial pressure; QIDS-SR, Quick Inventory of Depressive Symptomatology-Self Report; SAE, serious adverse event; SAFTEE, Systematic Assessment for Treat- ment Emergent Effects; VAS-high, Visual Analog Scales score for intoxication “high”; YMRS, Young Mania Rating Scale. aIn the i.v. group, 1 participant experienced a 25% increase 1 hour posttreatment (0.1 mg/kg) and a 24% MAP increase 5 min posttreatment (0.2–0.5 mg/kg). A second participant experienced a 44% MAP increase 10 min posttreatment (0.1 mg/kg). In the IM group, 1 participant experienced a 30% MAP increase 10 min posttreatment (0.4 mg/kg) and a second experienced a 39% MAP increase 5 min posttreatment (0.3 mg/kg). http://ijnp.oxfordjournals.org/

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