This review (2015, n=118) found that ketamine showed reliable anti-depressive effects in patients diagnosed with either MDD or bipolar disorder (BD). The duration of effects, however, requires further research.
Introduction
Ketamine’s efficacy in depressive disorders has been established in several controlled trials. The aim of the present study was to determine whether or not ketamine administration significantly improves depressive symptomatology in depression and more specifically in major depressive disorder (MDD), bipolar depression, resistant depression (non-ECT studies), and as an anesthetic agent in electroconvulsive therapy (ECT) for resistant depression (ECT studies). Secondary outcomes were the duration of ketamine’s effect, the efficacy on suicidal ideations, the existence of a dose effect, and the safety/tolerance of the treatment.
Methods
Studies were included if they met the following criteria (without any language or date restriction): design: randomized controlled trials, intervention: ketamine administration, participants: diagnosis of depression, and evaluation of severity based on a validated scale. We calculated standardized mean differences (SMDs) with 95 % confidence intervals (CIs) for each study. We used fixed and random effects models. Heterogeneity was assessed using the I2 statistic.
Results
We included nine non-ECT studies in our quantitative analysis (192 patients with major depressive disorder and 34 patients with bipolar depression). Overall, depression scores were significantly decreased in the ketamine groups compared to those in the control groups (SMD = −0.99; 95 % CI −1.23, −0.75; p < 0.01). Ketamine’s efficacy was confirmed in MDD (resistant to previous pharmacological treatments or not) (SMD = −0.91; 95 % CI −1.19,−0.64; p < 0.01), in bipolar depression (SMD = −1.34; 95 % CI −1.94, −0.75), and in drug-free patients as well as patients under medication. Four ECT trials (118 patients) were included in our quantitative analysis. One hundred and three patients were diagnosed with major depressive disorder and 15 with bipolar depression. Overall, depression scores were significantly improved in the 58 patients receiving ketamine in ECT anesthesia induction compared to the 60 patients (SMD = −0.56; 95 % CI −1.10, −0.02; p = 0.04; I2 = 52.4 %). The duration of ketamine’s effects was assessed in only two non-ECT studies and seemed to persist for 2-3 days; this result needs to be confirmed. Three of four studies found significant decrease of suicidal thoughts and one found no difference between groups, but suicidal ideations were only studied by the suicide item of the depressive scales. It was not possible to determine a dose effect; 0.5 mg/kg was used in the majority of the studies. Some cardiovascular events were described (mostly transient blood pressure elevation that may require treatment), and ketamine’s use should remain cautious in patients with a cardiovascular history.
Conclusion
The present meta-analysis confirms ketamine’s efficacy in depressive disorders in non-ECT studies, as well as in ECT studies. The results of this first meta-analysis are encouraging, and further studies are warranted to detail efficacy in bipolar disorders and other specific depressed populations. Middle- and long-term efficacy and safety have yet to be explored. Extrapolation should be cautious: Patients included had no history of psychotic episodes and no history of alcohol or substance use disorders, which is not representative of all the depressed patients that may benefit from this therapy.
Papers cited by this study that are also in Blossom
Berman, R. M., Cappiello, A., Anand, A. et al. · Biological Psychiatry (2000)
Diazgranados, N., Ibrahim, L., Brutsche, N. E. et al. · JAMA Psychiatry (2010)
Murrough, J. W., Iosifescu, D. V., Chang, L. C. et al. · American Journal of Psychiatry (2013)
Sos, P., Klirova, M., Novák, T. et al. · Neuropsychiatric Disease And Treatment (2013)
Major depressive disorder (MDD) and bipolar disorders are major contributors to global disability and carry large social costs. Despite available treatments, a substantial proportion of patients do not respond to conventional medication, motivating investigation of novel therapies. Ketamine, an anaesthetic with N-methyl-D-aspartate receptor (NMDAR) antagonist properties, has been reported to have rapid antidepressant effects in clinical studies, but results across trials have been inconsistent and clinical questions remain regarding indications, dose, duration of effect, impact on suicidal ideation, and safety. Fond and colleagues therefore undertook a systematic review and meta-analysis of randomised controlled trials to assess whether ketamine administration reduces depressive symptomatology. The primary focus was on efficacy in MDD, bipolar depression, treatment-resistant depression (non-ECT trials), and when ketamine is used as the anaesthetic agent during electroconvulsive therapy (ECT). Secondary aims included characterising duration of effect, effects on suicidal ideation, possible dose–response relationships, and safety/tolerability.
The investigators performed a PRISMA-based systematic search across multiple databases (PubMed/MEDLINE from 1966 to September 2013, Embase from 1980, PsycINFO from 1806, BIOSIS from 1926, Science Direct from 2006, and ProQuest Dissertations) using terms for ketamine, depression-related disorders and controlled clinical trials. There were no language or date restrictions. Eligible studies were randomised controlled trials comparing ketamine administration (single or repeated doses, alone or with other anaesthetic agents) against control conditions in participants diagnosed with a depressive disorder, with outcomes assessed on validated depression rating scales. Trials without a comparator or those where a standardised mean difference (SMD) could not be calculated were excluded. Study selection and data extraction were conducted by multiple reviewers with disagreements resolved by consensus. Extracted items included authorship, publication year, design, sample size, diagnostic composition (MDD versus bipolar), rating scales used (HDRS or MADRS), whether patients were drug-free at baseline, co-administration with ECT or other anaesthetics, and ketamine dose. Methodological quality was assessed using Cochrane risk-of-bias markers (sequence generation, allocation concealment, blinding, incomplete outcome data) and trials were further classified by a four-tiered evidence scheme (class I–IV). For quantitative synthesis the researchers calculated standardised mean differences (SMDs) and 95% confidence intervals based on between-group pre–post change scores, and they pooled estimates using fixed- and random-effects models. Heterogeneity was quantified with I2, with I2>50% considered large. Publication-bias assessments included funnel plots, Rosenthal’s fail-safe N and Egger’s regression intercept. Prespecified subgroup and sensitivity analyses examined effects by diagnosis (unipolar vs bipolar), resistance status, drug-free versus medicated status, co-administration with other anaesthetics, and placebo-controlled versus non-placebo-controlled designs. Analyses used Comprehensive Meta-Analysis software (version 2.0). In total, 13 RCTs met inclusion criteria: nine non-ECT trials (including some crossover designs) and four ECT trials.
Thirteen randomised trials were included: nine non-ECT studies (conducted 2000–2013) and four ECT studies (2012–2013). Across non-ECT trials the pooled sample comprised 192 patients with MDD and 34 with bipolar depression; some crossover studies contributed within-subject data. Ketamine hydrochloride was used in all trials (no S-ketamine in the included studies) at doses of 0.4, 0.5, 0.8 or 1 mg/kg, with 0.5 mg/kg the most common regimen. Depression severity was assessed with HDRS in five trials and MADRS in four trials. Several studies enrolled patients who were drug-free for at least 2 weeks, while others enrolled medicated patients and some specifically included pharmacologically treatment-resistant cases. Primary efficacy in non-ECT trials: pooled analysis showed a large and statistically significant reduction in depressive symptoms for ketamine versus control (SMD = -0.99; 95% CI -1.23 to -0.75; p<0.001), with low heterogeneity (I2 = 2.9%). Sensitivity analysis excluding two studies at high risk of bias yielded a similar result (SMD = -1.10; 95% CI -1.39 to -0.81; p<0.01). Tests for small-study/publication bias showed a reasonably symmetrical funnel plot, Egger’s intercept p = 0.76, and a Rosenthal fail-safe N of 138. Subgroup findings: ketamine was effective in MDD (127 cases versus 112 controls; SMD = -0.91; 95% CI -1.19 to -0.64; p<0.01; I2 = 4.4%) and in bipolar depression (27 cases versus 27 controls; SMD = -1.34; 95% CI -1.94 to -0.75; p<0.01; I2 = 24.1%), though bipolar data derived from a small number of participants and two studies from the same centre. Ketamine showed benefit in both drug-free studies (SMD = -1.15; 95% CI -1.52 to -0.79; I2 = 0.0%) and studies where participants remained on antidepressant or mood-stabilising treatment (SMD = -0.87; 95% CI -1.19 to -0.55; I2 = 27.1%). Trials that enrolled pharmacological non-responders also demonstrated efficacy. ECT trials: four studies totalling 118 patients (58 cases, 60 controls) were pooled. Ketamine used in ECT anaesthesia (various regimens including combinations with thiopental or propofol) was associated with a modest but statistically significant improvement in depression scores compared with other anaesthetics (SMD = -0.56; 95% CI -1.10 to -0.02; p = 0.04), but heterogeneity was moderate to high (I2 = 52.4%) and study designs and timing of outcome assessment varied. Time course and suicidal ideation: in non-ECT trials symptom reduction was rapid, with differences detectable as early as 40 minutes post-infusion and effects persisting in reported studies for about 2–3 days; only two trials provided such duration data. Suicidal ideation was evaluated in five RCTs, typically via the suicide item on depression scales. Three trials reported significant reductions in suicidal thoughts after ketamine versus control; one trial reported no effect on suicidal ideation despite improvement in other depressive symptoms. One study reported reduced suicidal ideation from 40 minutes up to day 10. The authors note that assessments were heterogeneous and were not adjusted for overall depression change. Safety and adverse events: common acute side-effects included transient dissociation, dry mouth, dizziness, blurred vision, headache, nausea, tachycardia and blood-pressure elevation. More pronounced cardiovascular events (tachycardia or hypertension requiring treatment) were reported with higher doses (0.8–1 mg/kg), and some ECT studies reported severe hypertension with 0.8 mg/kg. Eight of 47 ketamine recipients (17%) in one comparison experienced notable dissociative symptoms that resolved within 2 hours. Two infusions were halted for haemodynamic changes in one trial (one hypertensive episode, one transient hypotension with bradycardia). Manic or hypomanic switches were uncommon but were observed in isolated cases in bipolar samples. Overall tolerability was described as acceptable within the trial settings, but the authors caution about cardiovascular risks.
Fond and colleagues interpret their meta-analysis as supporting ketamine’s rapid antidepressant efficacy across a range of depressive disorders. They highlight consistently large pooled effect sizes in non-ECT randomised trials and a smaller but statistically significant benefit when ketamine is used for ECT anaesthesia, while noting heterogeneity among the ECT studies. The investigators consider the evidence positive for MDD and suggestive for bipolar depression, although the bipolar dataset was small and derived mainly from two low-risk-of-bias studies from a single centre. The authors emphasise the rapid onset of effect—observable within 40 minutes—and short-term duration of benefit reported (about 2–3 days in the limited trials that measured this), underscoring the need for research into maintenance strategies such as repeated dosing. They describe preliminary and promising findings for reduction in suicidal ideation, but caution that suicidal outcomes were measured heterogeneously (usually via single suicide-items on depression scales) and were not adjusted for overall changes in depressive symptoms, so a specific anti-suicidal effect remains unproven. Key limitations acknowledged by the study team include the small number of RCTs (13) and the limited diversity of ketamine doses studied (0.4–1 mg/kg), which precluded dose–response analysis. The participant populations were generally middle-aged with longstanding mood disorders; most trials excluded people with substance dependence and those with psychotic histories, limiting generalisability. The bipolar evidence base was small and the ECT literature was heterogeneous in anaesthetic regimens and timing of outcome assessment. Safety concerns were highlighted, particularly transient dissociative effects and the potential for clinically significant cardiovascular events at higher doses; the authors therefore advise caution when considering ketamine for patients with cardiovascular disease. Finally, they note uncertainty about whether an anaesthesiologist is required for ketamine administration in psychiatric settings. The investigators recommend further randomised trials focusing on bipolar depression, systematic study of repeated or maintenance dosing schedules to assess longer-term efficacy and safety, exploration of alternative administration routes (for example intramuscular), and more rigorous assessment of suicidal outcomes and cardiovascular risk management.
The meta-analysis concluded that ketamine administration produces significant short-term reductions in depressive symptoms in both non-ECT and ECT settings, though ECT-study designs were heterogeneous. Promising preliminary evidence was observed for reductions in suicidal ideation, but it remains unclear whether this effect is independent of overall antidepressant response. The authors advise cautious use of ketamine in patients with cardiovascular disease and state that middle- and long-term efficacy and safety remain unknown, warranting additional trials in bipolar depression, ECT settings, and studies of repeated/maintenance dosing.
Major psychiatric disorders such as major depressive disorder (MDD) and bipolar disorders are among the four most disabling mental, neurological, and substance-use related illnesses worldwide with a global social cost of respectively 66.5 and 16.8 million disability-adjusted life years (DALYs). While forecasts predict an increase in the prevalence of mental disorders in the general population worldwide, a nonnegligible proportion of patients do not respond to medication. They therefore represent a major and rising public health concern and there is an urgent need to develop more effective therapies to treat and delay the onset of these disorders or their deleterious phases by exploring new therapeutic approaches such as ketamine administration. The antidepressant properties of ketamine, an anesthetic agent with N-methyl-D-aspartic acid receptor (NMDAR) antagonist properties, were first described just over a decade ago. Since then, ketamine administration has been assessed in MDD, resistant depression, and bipolar depression and in electroconvulsive therapy (ECT) induction ( Ab d a l la h e t a l . 2012;. However, results are inconsistent and the qualities of some studies are questionable. Moreover, there is some reluctance to use ketamine in clinical practice (at least in France) due to the potential misuse of this drug, and clinical questions remain unclearly answered to date, such as indications, possible adverse events, recommended doses, duration of efficacy, and effect on suicidal ideations. A metaanalysis seemed warranted to draw the state of knowledge of ketamine use in depressive disorders. The aim of this study was to perform a systematic review and meta-analysis of controlled trials to investigate the efficacy of the ketamine's administration on depressive symptomatology and more specifically in MDD, resistant depression, and bipolar depression and as an anesthetic agent in ECT for resistant depression. Secondary outcomes were the duration of ketamine's effect on depressive symptomatology, the efficacy on suicidal ideations, the existence of a dose effect, and the safety/tolerability of the treatment.
This meta-analysis was based on the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) criteria. A specific search strategy was developed for the interface PubMed (MEDLINE database), based on a combination of MeSH terms "ketamine," as well as indexed terms related to depression ("Depression" OR "Depressive Disorders" OR "Mood Disorders" OR "Affective Disorders," OR "Anxiety") and study design ("controlled clinical trial"), and was used in different computerized databases: PubMed (from 1966 to September 2013), Embase (from 1980 to September 2013), PsycINFO (from 1806 to September 2013), BIOSIS (from 1926 to September 2013), Science Direct (from 2006 to September 2013),. Furthermore, we searched ProQuest Dissertations and Theses full-text database to identify unpublished dissertations. The references of included studies were examined to search for further trials.
Studies were included if they met the following criteria: -Design: randomized controlled trials -Intervention: ketamine administration (one administration or more, alone or with other anesthetic agent) -Participants: participants with a diagnosis of depression (major depression or bipolar depression, resistant or not) -Evaluation of depression severity based on a validated scale There was no language or date restriction. The manuscripts with the following criteria were excluded: (1) absence of comparison between patients with ketamine administration and controls and (2) a standardized mean difference that could not be calculated.
One author (M.B.) screened titles and abstracts of database records and retrieved full texts for eligibility assessment. Two authors independently checked the full-text records for eligibility (G.F. and L.B.). Disagreements were resolved by consensus discussion. The manuscripts of the studies were then independently reviewed by two of the authors (G.F. and L.B.). Data was independently extracted into a standard electronic form: first author name, date of publication, design, country, sample size, number of MDD included subjects, depression assessment scales, delay to depression assessment, diagnoses of resistant depression in inclusion criteria, co-administration of ECT sessions, previous withdrawal of antidepressant medications ("drug-free studies"), administered treatment of the cases and the control groups, and ketamine administered dose. Any discrepancies were resolved by consensus with a third reviewer (A.L.).
The methodological quality of included studies was assessed independently by two of the authors (G.F. and L.B.). Any discrepancies were resolved by consensus with a third reviewer (A.L.). First, we used markers of internal validity from the Cochrane risk of bias tool. The risk of selection bias was assessed at study level (sequence generation, allocation sequence concealment), the risk of performance bias at comparison level (blinding of medical personnel), and the risk of detection bias as well as attrition bias was assessed at outcome level (blinding of outcome assessors, handling incomplete outcome data). Studies' risk of bias could then be qualified as low, unclear, or high. Second, we further classified studies according to their level of evidence using the classification scheme requirements for therapeutic questions. The level of evidence was classified using a four-tiered system (class I through class IV), with class I indicating the strongest evidence and class IV the weakest.
We calculated standardized mean difference (SMD) with 95 % confidence intervals (CIs) for each study, defined as the difference in pre-post treatment mean changes between the two groups (depressed patients with ketamine administration vs those without) divided by the pooled standard deviation of the measurements. We used fixed effectsand random effects modelswhich account for between-study heterogeneity by weighting studies similarly. Heterogeneity was assessed using the I2 statistic, which represents the percentage of variance due to between-study factors rather than sampling error. We considered values of I2>50 % as indicative of large heterogeneity. We used funnel plots, Rosenthal fail-safe N (i.e., which estimates the number of missing studies needed to change the results of the meta-analysis) and the Egger's regression intercept (i.e., which assesses the degree of funnel plot asymmetry by the intercept from regression of standard normal deviates against precision) to estimate risk of bias. Forest plots were generated to show SMD with corresponding CIs for each study and the overall estimate of pooled random effects. We conducted several subgroups and sensitivity analyses to determine the impact of various factors (i.e., unipolar or bipolar depression, resistant depression, co-administration with thiopental, in drug-free/non-drug-free trials and placebocontrolled/non-placebo-controlled trials) on effect size estimates for ketamine effectiveness and also in order to explore potential reasons for heterogeneity or inconsistency. Analyses were performed with comprehensive meta-analysis software (version 2.0, National Institute of Health).
Fifty-four abstracts were initially identified through database searches. We excluded 42 articles because they did not meet the inclusion criteria. The selection process is summarized in Fig.. Nine non-ECT studies (conducted between 2000 and 2013) and four ECT studies (conducted in 2012 and 2013) were included in our quantitative analysis.
Overall, 192 patients (cases +controls) with MDD and 34 (cases+controls) patients with bipolar depression were included (Tablesand). Some patients were their own controls in four crossover studies. One hundred and sixty-three cases received ketamine hydrochloride. One hundred and forty eight controls received respectively placebo (N=79) or midazolam, ECT (with thiopental as anesthetic agent for ECT induction), or propofol-fentanyl combination as anesthetic agents before surgery (that was also administered to cases). The Ghasemi et al. study was classified as "non-ECT study" because only controls received ECT. Diagnoses were made by Diagnostic and Statistical Manual (DSM)-IV-based structured interviews in all studies. The DSM diagnosis was completed by validated scales for inclusion criteria to evaluate baseline severity (four used a Montgomery-Asberg Depression Rating Scale (MADRS) score ≥20, and one a mini-mental status examination (MMSE) score ≥27). Depression scores before and after treatment administration were assessed by the Hamilton Depression Rating Scale (HDRS) in five studiesand MADRS in four studies. Six studies were conducted in the USA, one in Iran, one in Czech Republic, and one in Japan. All patients received ketamine hydrochloride; Sketamine was not used in the included studies. Tablecontains further information on methodological quality indicators.
Overall, the depression score was significantly improved in patients receiving ketamine compared to controls (SMD= -0.99; 95 % CI -1.23, -0.75; p<0.001; I2=2.9 %) (Fig.). The efficacy of ketamine remained significant (SMD=-1.10; 95 % CI -1.39, -0.81; p<0.01; I2=6.3 %) after excluding the two studies with high risk of bias (as defined in Table 3). The associated funnel plot was reasonably symmetrical, although the limited number of studies does not allow the exclusion of publication bias (Appendix). The p value of the Egger's regression intercept was 0.76, and the asymmetry is considered to be statistically non-significant. The Rosenthal's fail-safe N value was 138. Given that we identified nine studies that looked at ketamine and depression, it is highly unlikely that nearly 140 studies were missed.
Six studies included patients with only MDD, two included patients with only bipolar depression, and the remaining study included patients with either MDD (eight) or bipolar depression (one)(Fig.). Overall, depression scores were significantly improved in the 127 MDD cases compared to the 112 MDD controls (SMD=-0.91; 95 % CI -1.19, -0.64; p<0.01; I2=4.4 %). Depression scores were also significantly improved in the 27 bipolar cases compared to those in the 27 bipolar controls (SMD=-1.34; 95 % CI -1.94, -0.75; p<0.01, I2=24.1 %).
Study design: drug-free patients versus patients under antidepressant or mood-stabilizing treatment Only four studies included in their protocol at least 2-week withdrawal of any antidepressant or mood-stabilizing treatment (Fig.). Ketamine was effective in both drug-free and non-drug-free studies (SMD=-1.15; 95 % CI -1.52, -0.79; p<0.01; I2=0.0 % vs SMD=-0.87; 95 % CI -1.19, -0.55; p<0.01; I2=27.1 %). Effect of ketamine in studies including pharmacological resistance to antidepressants or mood stabilizers in inclusion criteria Overall, five studies included pharmacologicalresistant patientsand the other four studies included patients with depression, independently of the resistance to a previous treatment (Fig.). Resistance was not always defined as an inclusion criterion, but some studies included patients that were under medication with persistent depressive symptomatology, who may therefore be defined as resistant to pharmacological treatment. For example, resistance was defined by a MADRS score ≥20 after 3 weeks of stable
Overall, 118 patients (58 cases and 60 controls) were included in four ECT studies; Jarventausta et al.and). One and three patients were diagnosed with MDD and 15 with bipolar depression. Thirty-two cases received a combination of ketamine hydrochloride 0.5 mg/kg and thiopental, 12 received ketamine hydrochloride 0.8 mg/kg alone, and 16 cases received S-ketamine 0.4 mg/kg in combination with propofol. Thirty-two controls received thiopental) and 28 propofol). All patients were on pharmaceutical antidepressant or mood-stabilizing treatment during the whole protocol. Delays between ketamine administration (before the first ECT session) and first mood evaluation were highly heterogeneous 24 h, 24 to 72 h, after three ECT sessions (Jarventausta et al. 2013), and 1 week.
Overall, depression scores were significantly improved in the 58 patients with major depression receiving ketamine in ECT anesthesia induction compared to those in the 60 patients receiving thiopental or propofol (SMD=-0.56; 95 % CI -1.10, -0.02; p=0.04, I2=52.4 %) (Fig.).
To date, the quantity and quality of the available literature on ketamine for reducing suicidal ideations and suicide risk is relatively low. Suicidality or suicidal ideations were assessed in five randomized controlled trials (RCTs) included in our quantitative analysis. The effect of ketamine administration on suicidal thoughts was mostly measured by the suicide item of the depression scales in the non-ECT studies. In the study by Murrough et al., patients at serious and imminent suicidal risk were excluded, but those only presenting suicidal ideations were not. The presence of suicidal ideations or suicidal risk was not exclusion criteria in the other studies. Three studies reported significant decrease of suicidal thoughts in depressed patients after ketamine administration compared to controls). In the study by, repeated assessments showed that patients who received ketamine had lower suicidal ideation scores from the 40th minute to day 2 and at day 10. However, one other study in bipolar depression found no significant effect of ketamine on this item contrary to other depressive symptoms.
Repeated ratings of depression scores over time in non-ECT studies showed that depressive symptoms were significantly improved compared to controls as early as 40 min after injection. This difference could be maintained during 2 to 3 days. As a 0.5 mg/kg dose was used in most studies, the calculation of a dose effect was not possible.
In non-ECT studies, common side effects of ketamine administration included dry mouth, tachycardia, increased blood pressure, and dissociation. These adverse events were transient and benign. More severe cardiovascular events (mostly tachycardia/hypertension requiring treatment) associated with higher doses of ketamine (0.8-1 mg/kg) during anesthesia were also described (Table). In ECT studies, cardiovascular events (severe hypertension, diastole blood pressure >100 mmHg) were described only when 0.8 mg/kg ketamine hydrochloride was administered. Studies using lower doses (0.4 or 0.5 mg/kg) described transient disorientation and restlessness. One drug-induced agitation was described with a combination of 0.4 mg/kg ketamine hydrochloride and propofol. Of the nine bipolar participants included in Loo et al. study, one became hypomanic and one developed rapid cycling manic symptoms).
Overall, depression scores were significantly improved in ketamine groups compared to those in controls. The results remained significant in all our subgroups and sensitivity analyses. Ketamine was found to be effective in MDD as well as in bipolar depression (Figs.and). However, only two studies, conducted by the same research center but classified as "low risk of bias", were carried out in bipolar depression. Significant positive effects of ketamine were reported in both studies. Overall, both bipolar I (N=8+9) and bipolar II (N=10+6) patients were included, but it was not possible to determine if ketamine was more effective in a specific type of bipolar disorder. While rapid cycling (>4 mood episodes within 12 months, based on DSM-IV criteria) was not an exclusion criterion, no rapid cyclers were included, and hence, results cannot be extrapolated to this subgroup. In the study by, four patients receiving ketamine dropped out of Both ketamine treatment and ECT were well tolerated in all patients. Overall, there was no significant change in hemodynamic parameters including heart rate and blood pressure in both groups. There was only increase in systolic blood pressure as well as heart rate in three patients after the second and the third doses of ketamine which was temporary, and this rise was not clinically significantKetamine hydrochloride, 0.5 mg/kg, once
The most common adverse events in the ketamine group for up to 4 h after infusion were dizziness, blurred vision, headache, nausea or vomiting, dry mouth, poor coordination, poor concentration, and restlessness. Within this same time period, the most common adverse events in the midazolam group were general malaise, dizziness, headache, restlessness, nausea or vomiting, dry mouth, decreased energy, and poor coordination. Eight of the 47 patients receiving ketamine (17 %) had significant dissociative symptoms (i.e., feeling outside of one's body or perceiving that time is moving more slowly or more quickly than normal) immediately after the ketamine infusion; these symptoms resolved by 2 h postinfusion. No severe psychotic symptoms (paranoia, hallucinations, delusions, or thought disorder) occurred in any patient. On average, mild transient changes in blood pressure were observed on the infusion day. The infusion was discontinued for two patients in the ketamine group because of hemodynamic changes. In one case, a blood pressure elevation (peak, 187/91 mm Hg) unresponsive to beta-blocker therapy resulted in infusion termination after 30 min. The blood pressure normalized within 10 min of infusion cessation. In the other case, there was transient but pronounced hypotension and bradycardia that resolved without sequelae and was followed by overnight observation in the hospitalKetamine hydrochloride, 0.5 mg/kg, once Placebo Ketamine was well tolerated and no serious adverse or side effects (other than the expected acute psychotomimetic effect) occurred during the study. Typical effects occurring at subanesthetic doses of ketamine were dissociation/perceptual disturbances, confusion, mild increases the study due to anxiety. No manic or hypomanic switches were reported. Further studies are warranted to confirm ketamine's efficacy in bipolar depression. Ketamine was effective in drug-free studies, as well as in studies in which patients were under active treatment (antidepressants or mood-stabilizing agents). As it does not seem reasonable to recommend a complete withdrawal of antidepressant or mood-stabilizing treatment for 2 weeks in clinical practice and as ketamine remained significantly effective in patients who were administered an active treatment, ketamine seems recommended as adjunctive treatment in patients treated by antidepressants or mood-stabilizing agents with partial/ incomplete response or with the need of a faster response. Ketamine was also effective when resistance to previous pharmacological treatment figured in inclusion criteria (Fig.). Nevertheless, all patients received at least one antidepressant or mood-stabilizing treatment before inclusion in the protocol and may therefore all be considered as resistant to pharmacological treatment. This suggests that ketamine may be recommended in patients that did not respond to previous ECT electroconvulsive therapy conventional treatments. However, while standardized criteria to establish resistance are available for MDD, the is not true for bipolar depression, given the lack of effective treatments in this condition. Promising results were found for suicidal ideation, but they should be confirmed in future studies because of the high degree of heterogeneity of current protocols and assessments of suicidal ideations. Moreover, suicidal ideation improvement was not adjusted by global depression improvement; it is therefore not possible to conclude to a specific effect of ketamine on suicidal ideations.
Ketamine has been used in ECT anesthesia for decades, with preliminary evidence suggesting that ketamine anesthesia in ECT may improve seizure duration relative to other anesthetic agents that are commonly used and minimize side effects, particularly cognitive impairment. Only four studies were included in our quantitative analysis (Table). Overall, ketamine administration was found to significantly improve depressive symptomatology (p =0.04) (Fig.). However, this result should be considered with caution due to the high heterogeneity of studies' designs: (1) depression score was assessed after 24 h in(2) Two of the three studies that found non-significant results administered thiopental (a barbiturate anesthetic) with a 0.5 mg/kg dose of ketamine hydrochloride, while the other one used a 0.4 mg/kg dose with propofol. On the other hand, Wang et al. administered a 0.8 mg/kg dose alone). The negative results may therefore be explained by a lower dose of ketamine in
The cardiovascular events described in the studies (requiring higher antihypentensive agent dosages) should be considered as a warning that caution is always required in patients with cardiovascular disease (e.g., patients with ischemic heart disease or hypertension). This may be due to a systemic release of catecholamines and an inhibition of norepinephrine re-uptake at peripheral nerves and nonneuronal tissues such as the myocardium induced by ketamine administration. Besides cardiovascular side effects, dissociative symptoms can appear even with doses between 0.5 and 1 mg/kg. All patients should have a physical examination, routine hematologic and biochemical tests, urine toxicology measurements, and an electrocardiogram (ECG) to detect unstable medical illness or substance use before ketamine administration. In regard of the data presented in this work, it does not seem possible to determine if the presence of an anesthesiologist is necessary during ketamine administration in a psychiatric ward.
Despite a comprehensive review of the literature, the use of stringent inclusion criteria, and the examination of potential publication bias, only 13 RCTs were included in this meta-analysis. However, 10 of 13 studies were classified as low risk of bias. As only four doses were used (0.4, 0.5, 0.8, and 1 mg/kg), it was not possible to carry out a correlation to highlight a dose effect. Included patients were overall middle-aged (group mean ages between 37.6±15 and 65±15 years) with a long history of mood disorders for most of them, even in studies that had no criteria of resistance at inclusion. Thus, these results cannot be extrapolated to date to early onset bipolar disorders, for example, or to mood disorders in the elderly for whom the cardiovascular risk of ketamine administration may overweigh the benefit. Studies in these specific populations should be carried out, as treatments for bipolar depression and MDD in the elderly remain unsatisfactory at times. As in other trials assessing new innovative treatments, patients with alcohol dependence and substance abuse were excluded in most of the studies, as well as those with a history of psychotic episode. These results can therefore not be extrapolated to patients with psychotic features, especially in regard to the risk of dissociation and derealization that is described in the transient side effects of ketamine. In the study by, ketamine was administered as an anesthetic agent for orthopedic surgery in depressed patients, and haloperidol 5 mg was administrated for treatment of the postoperative confusion, which may have masked psychotic symptomatology due to ketamine administration. It is thus unclear to date if ketamine may the onset of persistent psychotic symptomatology vulnerable patients.
Further studies should focus on ketamine's efficacy in bipolar depression and on the long-term efficacy of repeated doses (perhaps every 2-3 days) to assess whether or not ketamine maintains its effect over time and if no undesirable long-term adverse effects appear. Another form of administration (intramuscular administration) has recently been used and may improve the treatment feasibility in daily practice.
The present meta-analysis confirmed ketamine's efficacy in depressive disorders in both the nine non-ECT studies and the four ECT studies, but designs in ECT studies were highly heterogeneous. Further non-ECT studies in bipolar depression and ECT studies are warranted. Promising preliminary results were found for suicidal ideations, but it is unclear whether ketamine improves suicidal ideations independently of global depression improvement or not. The use of ketamine should remain cautious for patients with cardiovascular history. Middle-and long-term efficacy and side effects are still not known to date.
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Zarate, C. A., Brutsche, N. E., Ibrahim, L. et al. · Biological Psychiatry (2012)
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