This review (2021; s=6; n=135) found that ketamine (35mg/70kg; 1-6 doses) achieved a response (>50% reduction) on a score of depression for 61% of those suffering from bipolar depression (BD), compared to 5% for placebo.
Background
Ketamine appears to have a therapeutic role in certain mental disorders, most notably unipolar major depressive disorder. However, the efficacy in bipolar depression is less clear.
Objectives
This study aimed to assess the efficacy and tolerability of ketamine for bipolar depression.
Methods
We conducted a systematic review of experimental studies using ketamine for the treatment of bipolar depression. We searched PubMed, MEDLINE, Embase, PsycINFO, and the Cochrane Central Register for relevant studies published since database inception. We synthesized evidence regarding efficacy (improvement in depression rating scores) and tolerability (adverse events, dissociation, dropouts) across studies.
Findings
We identified six studies, with 135 participants (53% female, 44.7 years, SD 11.7 years). All studies used 0.5 mg/kg of add-on intravenous racemic ketamine, with the number of doses ranging from one to six; all participants continued a mood-stabilizing agent. The overall proportion achieving a response (defined as those having a reduction in their baseline depression severity of at least 50%) was 61% for those receiving ketamine and 5% for those receiving a placebo. The overall response rates varied from 52% to 80% across studies. Ketamine was reasonably well-tolerated; however, two participants (one receiving ketamine and one receiving placebo) developed manic symptoms. Some participants developed significant dissociative symptoms at the 40-minute mark following ketamine infusion in two trials.
Conclusions
There is some preliminary evidence for intravenous racemic ketamine to treat adults with bipolar depression. There is a need for additional studies exploring longer-term outcomes and alterative formulations of ketamine.
Papers cited by this study that are also in Blossom
Alberich, S., Martínez-Cengotitabengoa, M., López, P. et al. · Revista de Psiquiatría y Salud Mental (2017)
Bahji, A., Vazquez, G. H., Zarate, C. A. · Journal of Affective Disorders (2021)
Berman, R. M., Cappiello, A., Anand, A. et al. · Biological Psychiatry (2000)
Bobo, W. V., Vande Voort, J. L., Croarkin, P. E. et al. · Depression and Anxiety (2016)
Bipolar depression is a major contributor to global disability and treatment-resistant bipolar depression (TRBD) is common yet undertreated, with few well-established therapeutic options beyond electroconvulsive therapy and repetitive transcranial magnetic stimulation. Earlier research has shown rapid antidepressant effects of single sub‑anaesthetic intravenous racemic ketamine in unipolar major depression, including short‑term reductions in suicidal ideation, but the evidence base for ketamine in bipolar depression has been smaller and less clear. Attempts to prolong ketamine's acute effects with other glutamatergic agents have produced inconsistent results, and questions remain about optimal dosing, formulation, and long‑term outcomes in bipolar disorder. Bahji and colleagues set out to update prior reviews by systematically synthesising experimental studies that examined the efficacy and tolerability of ketamine for bipolar depression. The authors focused on controlled and nonrandomised experimental studies in adults and aimed to summarise outcomes related to depressive symptom change, response rates, and adverse events, while assessing study quality and gaps that warrant further research.
This work was conducted as a systematic review registered on the Open Science Framework and followed PRISMA reporting guidance. The investigators searched MEDLINE, Embase, PsycINFO, CENTRAL and the Cochrane Database via Ovid from database inception to 13 December 2019, and also searched clinical trial registries (ClinicalTrials.gov, EU Clinical Trials Register, Australian and New Zealand Clinical Trials Registry) and reference lists to identify published, ongoing or unpublished trials. Eligibility criteria included randomised controlled trials and nonrandomised experimental studies of ketamine in adults (≥18 years) with bipolar depression; observational designs, reviews, secondary analyses, commentaries and studies that did not separate bipolar from unipolar depression were excluded. Any ketamine formulation and combination with psychotropic medications or psychotherapies were eligible in principle. Two authors independently screened records using Covidence, retrieved full texts, and resolved disagreements by consensus. Data extraction used a piloted Excel form completed by two co‑authors, prioritising conservative analyses (preference for intention‑to‑treat where available); the reviewers collected information on population characteristics, intervention details (dose, route, number of doses), comparators, outcomes, withdrawals and adverse events, and contacted authors when data were missing. Risk of bias for randomised trials was assessed with the Cochrane Risk of Bias tool examining selection, performance, detection, attrition and reporting biases, with assessments conducted independently by two authors. Although a meta‑analysis had been planned, only six eligible studies were identified (three randomised controlled trials and three open‑label single‑arm studies), so the authors presented a narrative synthesis and tabulated study characteristics and outcomes. The search initially yielded 2,494 records; after deduplication and screening, 361 full texts were assessed and six studies met inclusion criteria.
Six experimental studies met inclusion criteria, comprising 135 participants (53% female; mean age 44.7 years, SD 11.7). Three studies were double‑blind randomised controlled trials and three were open‑label, single‑arm studies. By country, half of the trials were conducted in the United States (k = 3) and two were from Poland. Five studies used DSM‑IV or DSM‑5 criteria for bipolar disorder; one study did not report diagnostic criteria. All included trials administered adjunctive intravenous racemic ketamine at 0.5 mg/kg while participants continued a primary mood stabiliser. Dosing regimens varied: three studies delivered a single dose, two studies used a two‑test‑dose design (one ketamine and one placebo two weeks apart), and one study administered six doses across two weeks. Most trials recruited participants with TRBD; common exclusions were serious medical comorbidity, pregnancy or breastfeeding, psychosis and substance use disorder. Across the six studies, 61% of participants who received ketamine at some point achieved a response, defined as ≥50% reduction in baseline depression severity (77/126 as reported). Study‑level response rates ranged from 52% to 80%. In the three controlled trials, the pooled response among control participants was 5% (2/42). Depression rating scores improved over time in all studies, although in a trial that used midazolam as an active control in a non‑TRBD sample the between‑group difference was not statistically significant. Single‑dose ketamine effects generally did not extend beyond two weeks, whereas the study that delivered six doses over two weeks suggested more durable benefit. Tolerability was generally acceptable across studies. Two participants developed manic symptoms (one participant receiving ketamine and one receiving placebo). Significant dissociative symptoms were reported in two trials, typically peaking around 40 minutes after infusion; the other four trials did not report substantial dissociation or mania. Regarding study quality, the three randomised, double‑blind trials with concealed allocation were judged at very low risk of bias, while the three open‑label single‑arm studies lacked control groups and were more susceptible to participation and other biases.
Bahji and colleagues interpret the assembled evidence as preliminary but supportive of a role for adjunctive intravenous racemic ketamine (0.5 mg/kg) in producing rapid antidepressant effects in adults with bipolar depression, including TRBD. The pattern of rapid onset observed in these bipolar samples mirrors findings from unipolar depression studies, but the evidence for bipolar disorder is based only on racemic intravenous ketamine and derives from a small number of trials with short follow‑up. The authors highlight that there are no published studies of intranasal esketamine specifically in bipolar depression, creating uncertainty about whether findings for racemic ketamine generalise to other formulations or routes. They recommend head‑to‑head comparisons between racemic ketamine and esketamine and suggest measuring blood levels of ketamine and norketamine to explore pharmacokinetic differences. Concerning safety, dissociation and affective switching to mania or hypomania are identified as the principal concerns; however, most trials did not observe these adverse events and the limited data do not establish a clear risk of manic switching after single sub‑anaesthetic doses. The authors note that trials to date are typically short and small, which limits the ability to detect less common adverse outcomes such as treatment‑emergent mania. Key limitations acknowledged by the reviewers include the inability to perform a quantitative meta‑analysis due to the small number of trials, potential publication bias, very limited data beyond two weeks of follow‑up, restrictive trial eligibility that limits generalisability to real‑world bipolar populations, and heterogeneity across studies in participant treatment resistance status, treatment setting, and dosing schedules. The authors therefore call for larger, longer randomised controlled trials that examine different ketamine formulations, compare routes of administration, assess longer‑term outcomes and monitor safety signals comprehensively.
Ketamine is described as an innovative, rapidly acting experimental treatment for bipolar depression with preliminary evidence supporting short‑term efficacy for intravenous racemic ketamine as an adjunct to mood stabilisers. No studies to date have tested other formulations such as intranasal esketamine in bipolar depression; the intravenous route also presents practical limitations. Long‑term benefits remain insufficiently explored and the overall level of proof is judged to be low. The authors conclude that further randomised controlled trials are needed to clarify efficacy, compare formulations and routes, and establish safety and longer‑term outcomes in bipolar disorder.
Bipolar depression is a leading cause of disability globally, affecting nearly 1% of individuals worldwide. As in unipolar depression, treatment-resistant bipolar depression (TRBD) is widespread but remains understudied. One definition of TRBD involves the failure to reach sustained symptomatic remission for 8 consecutive weeks after 2 different treatment trials, at adequate therapeutic doses, with at least 2 recommended monotherapy treatments or at least 1 monotherapy treatment and another combination treatment. Despite the importance of TRBD, only a small number of recognized treatment options are available. A few trials have indicated a role for electroconvulsive therapy and repetitive transcranial magnetic stimulation. While recent network meta-analyses have shown consistent evidence for use of multiple pharmacotherapies in non-TRBD, there is more limited evidence for use of medication-based treatments in TRBD. Fortunately, there appears to be an emerging role for ketamine in managing unipolar depression. Early ketamine studies demonstrated rapid, potent reductions in depressive symptoms following administration of a single sub-anesthetic dose of intravenous racemic ketamine. While these initial results were promising, effective means of maintaining the acute effects were actively sought. To date, the use of other glutamatergic agents to prolong the acute antidepressant effects of ketamine has been mostly inconsistent, with some successful case reports and small open-label studies. While repeat doses of intravenous racemic ketamine appear to sustain short-term antidepressant effects for individuals with unipolar depression, it is unclear whether this holds for bipolar depression. Racemic ketamine can also rapidly reduce suicidal thoughts within 1 day and for up to 1 week in depressed patients with suicidal ideation. While these findings are mostly limited to unipolar depression, some emerging studies point to the efficacy of ketamine for bipolar significant depression. Racemic ketamine has also led to many preclinical and biomarker discoveries, leading to new possibilities and safer alternatives for mitigating dissociation and reducing the propensity for misuse and diversion of ketamine. Although clinical studies of ketamine for TRBD are now underway, the level of proof of efficacy remains low, and more RCTs are needed to explore efficacy and safety issues of ketamine. While previous reviews have explored ketamine's utility in the treatment of TRBD, there is a need to update previous reviews given the recent increase in ketamine studies.
We aimed to provide an updated synthesis of findings from studies examining the efficacy and safety of ketamine for bipolar depression.
We registered this study with the Open Science Framework (). We followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses.
We included randomized controlled trials and nonrandomized studies examining the use of ketamine in adults (aged 18 years or older) to treat bipolar depression. We considered studies examining any formulation of ketamine (e.g., intravenous racemic ketamine, intranasal enantiomeric S-ketamine [esketamine]) as a standalone treatment or in combination with psychotropic medications or psychotherapies. We excluded observational designs (i.e., surveys, cohort studies, case series, and case-control studies), reviews, post hoc and secondary analyses, commentaries, and clinical overviews. We also excluded studies pairing ketamine with a neurostimulation-based treatment. We only included studies reporting at least 1 outcome related to the efficacy or safety of ketamine, such as the response to treatment or adverse events. Finally, we excluded studies that did not separate participants with bipolar depression from those with unipolar depression.
We searched MEDLINE, Embase, PsycINFO, the Cochrane Central Register of Controlled Clinical Trials (CENTRAL), and the Cochrane Database of Systematic Reviews via Ovid for studies published from inception to December 13, 2019. To identify ongoing or unpublished studies, we also searched ClinicalTrials. gov, the EU Clinical Trials Register, and the Australian and New Zealand Clinical Trials Registry using the keywords "ketamine" and "bipolar depression." We also hand-searched reference lists of included studies and topical reviews for potentially relevant articles.
Two researchers (AB, GHV) independently examined titles and abstracts using the web-based systematic review program Covidence (Veritas Health Innovation, 2019). Relevant articles were obtained in full and assessed for inclusion independently by the 2 coauthors. Any disagreement between them was resolved via discussion to reach a consensus.
Two co-authors (AB, GHV) extracted data via a pre-piloted, standardized data extraction tool in Microsoft Excel 2016. We pulled data on details of the populations, interventions, comparisons, outcomes of significance to the mental disorder, study methods, ketamine dose and route of administration, study withdrawals, and study withdrawals due to adverse events. Where data were missing, we contacted the authors for additional information. When authors reported multiple analyses (e.g., intention-to-treat or per-protocol analyses), we extracted the more conservative analysis, with a preference for intentionto-treat analyses.
We assessed the risk of bias within individual trials using the Cochrane risk of bias tool for randomized controlled trials. Specifically, the bias tool assesses indicators of selection bias, performance bias, detection bias, attrition bias, and reporting bias. The risk of bias assessments were completed independently by 2 authors (AB or GHV). Interresearcher disagreements were resolved via discussion to reach a consensus.
While we intended to conduct a meta-analysis, we only identified a total of 6 studies, of which only 3 were randomized controlled trials. Instead, we present the results in tables and discuss the findings comprehensively in the text.
The search strategy identified a total of 2494 records (Figure). After removing duplicates, we screened the remaining 1972 unique articles by title and abstract. We then excluded 1611 irrelevant records, leaving 361 documents for a full-text review. After a full-text review, only 6 studies met the final inclusion criteria.
Tableprovides an overview of the study characteristics. Three studies were randomized controlled trials, while the other 3 were open-label, single-arm studies. By country, most studies were from the United States (50%; k = 3) or Poland (33%; k = 2). There were 135 participants (53% female; 44.7 years; standard deviation, 11.7 years). Except for 1 study not reporting the diagnostic criteria for bipolar depression (BD; Permoda-Osip et al., 2014), the remaining 5 used Diagnostic and Statistical Manual of Mental Disorders fourth or fifth edition criteria. All 6 studies used add-on racemic ketamine at a dose of 0.5 mg/kg delivered intravenously; hence, all participants continued treatment with a primary mood-stabilizing agent throughout ketamine treatment. However, the number of doses varied across studies, with 3 single-dose studies, 2 studies with 2 test doses (1 ketamine and 1 placebo) 2 weeks apart, and 1 study with 6 doses across 2 weeks. Except for 1 study, the remaining 5 involved TRBD, defined as an insufficient response to at least 1or 2previous antidepressant trials. Two trials also required that participants have an inadequate response to prospective trials of lithium or valproate. Notably, most excluded those who had cooccurring general medical conditions, were pregnant or breastfeeding, or had comorbid psychosis or addiction.
Across all 6 studies, the proportion achieving a response (defined as those having a reduction in their baseline depression severity of at least 50%) was 61% for those receiving ketamine at some point during the trial (77/126). The overall response rate across studies varied from 52%to 80%. For the 3 studies that involved control groups, the overall pooled response rate was only 5% (2/42). There were improvements in depression rating scores over time in all studies; however, in the 1 trial using a midazolam control in non-TRBD subjects, the difference was not statistically significant. The efficacy of single-dose ketamine did not extend beyond the 2-week mark; however, the study that used 6 doses of ketamine over 2 weeks appeared to show longer-lasting efficacy.
Across most of the included studies, participants tolerated ketamine treatment reasonably well. However, there were some significant adverse events. For example, 2 participants (1 receiving ketamine and 1 receiving placebo) developed manic symptoms. In 2 trials, participants developed significant dissociative symptoms, primarily at the 40-minute mark following ketamine infusion. However, the remaining 4 trials did not note substantial dissociation or mania symptoms at any point during the study.
Three studies were double-blind, randomized, controlled trials with concealed allocation. These studies were at very low risk of bias as per the Cochrane Risk of Bias Tool. The remaining 3 were all nonrandomized, open-label, single-arm studies, which lacked a control group and were more susceptible to participation bias.
To our knowledge, this is the most recent systematic review that has explored the effectiveness and tolerability of ketamine for the treatment of BD. Overall, our findings-derived from 6 studies-indicate that ketamine appears to be an effective and relatively safe treatment for BD and TRBD. All 6 studies in our review involved intravenous racemic ketamine at a dose of 0.5 mg/kg as an add-on treatment to primary mood-stabilizing medications. To that end, the rapid antidepressant effects of ketamine seen in individuals with TRBD appears to be predictive of a sustained outcome. In a previous meta-analysis, there was no significant difference in the clinical response to intravenous ketamine between patients with unipolar major depression and bipolar depression. However, there are no available studies on intranasal esketamine for bipolar depression; hence, there are still unclear aspects concerning the role of ketamine in bipolar disorder. In contrast, several prior studies indicate a role for intravenous ketamine in treating bipolar depression. For very short-term use, the available data demonstrates a clear and consistent antidepressive effect of ketamine versus esketamine treatment in unipolar major depression, relative to various control conditions, beginning within hours of administration and lasting up to 7 days after a single dose. However, we do not know whether this pattern is also present in cases of bipolar disorder, where we only have data for racemic ketamine. Hence, there is a need for head-to-head studies comparing ketamine to esketamine in bipolar disorder. Future studies could also measure blood levels of ketamine and norketamine with intravenous racemic ketamine and esketamine and determine whether the differences remain significant after controlling. Regarding the side effect profiles, most studies indicate that ketamine is reasonably well tolerated for bipolar depression treatment. Two significant concerns involve the risk of dissociation and induction of mania or hypomania. However, in our review, most trials and most participants did not experience either of these adverse events. However, in 2 trials, participants developed significant dissociative symptoms, primarily at the 40-minute mark following ketamine infusion. However, the remaining 4 trials did not note substantial dissociation or mania symptoms at any point during the study. A related concern for ketamine in bipolar disorder involves the risk of switching to a manic or hypomanic episode. In 1 trial, 2 participants (1 receiving ketamine and 1 receiving placebo) developed manic symptoms. While standard antidepressants can induce rapid cycling, it is unclear whether this can occur with ketamine, as trials are typically short. Still, mania switches with single-ketamine infusions or pulsed treatment (where repeated doses are spaced over several days or weeks) have had small sample sizes, which may be insufficiently powered to identify manic switching. However, there was insufficient evidence to support mania induction with a single subanesthetic dose of ketamine in 98 major depressed patients. Nonetheless, there is a real necessity in our therapeutic armamentarium to discover and add more effective and safer treatments for patients with TRBD. Part of the challenge in elucidating the comparative performance of different formulations of ketamine may lie in the lack of a clear consensus on the mechanisms underlying ketamine's therapeutic effects. With the isolation of esketamine, there was also an option of providing much lower doses of ketamine and the opportunity to reduce the dose-dependent dissociative properties of ketamine. As esketamine was also available through an intranasal delivery system, it presented a substantially more practical option than intravenous racemic ketamine. Ultimately, intranasal esketamine was approved by the US Food and Drug Administration on March 5, 2019, for use in TRBD; on December 19, 2019, Europe followed suit with approval of esketamine for the same indication.
Although this review has several strengths, a few fundamental limitations deserve some expansion here. First, we were unable to conduct a meta-analysis given the low study yield. Despite this, we were still able to present the results across studies in a meaningful way. Second, there is always the possibility of publication bias, such that our review may not have identified negative studies (where ketamine did not improve depression scores). Third, while our review attempted to cover as much follow-up time as possible after ketamine treatment administration, there remains minimal information regarding longer-term follow-up beyond the 2-week mark. Hence, the results of our study are also limited to this treatment window. Fourth, participants in the presented trials are relatively unrepresentative of the real-world population with BD, given the studies' strict exclusion criteria. Thus, the results of the trials may not represent the real-world efficacy of ketamine. Fifth, the high heterogeneity within the selected studies could have impacted our findings. For example, there are differences between patients with TRBD versus non-TRBD, between those who receive treatment as an inpatient versus at community clinics, and between studies where participants received single or multiple ketamine doses.
Ketamine represents an innovative, rapidly acting, experimental treatment for bipolar depression. This review found that preliminary evidence supports the use of intravenous racemic ketamine for the treatment of individuals with bipolar depression. At present, there are no studies that have used other formulations of ketamine, such as intranasal esketamine. To that end, the intravenous administration route presents a practical limitation. Future studies should explore the use of an intranasal formulation of esketamine for individuals with bipolar depression. While racemic ketamine has demonstrated significant short-term benefits in several clinical studies highlighted in this review, the long-term benefits remain insufficiently explored, which may contribute to the current lack of Food and Drug Administration approval for use in individuals with bipolar disorder. At present, the level of proof of efficacy remains low. More randomized controlled trials are needed to explore efficacy and safety issues for administering all forms of ketamine in the treatment of bipolar depression.
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Papers in Blossom that reference this study
Shamabadi, A., Ahmadzade, A., Hasanzadeh, A. · British Journal of Clinical Pharmacology (2022)