Progress in treatment‐resistant bipolar depression using repeated ketamine infusions

In 2017, major depressive disorder and bipolar disorder affected approximately 163 and 45 million people, respectively. Bipolar disorder (BD) is a mental disorder with high morbidity and the highest lifetime risk of suicide. Most patients with BD suffer from depression during an important part of their lifespan. Another feature of BD is its high rate of treatment resistance, which is higher than that of major depressive disorder, urging the need for new BD treatment strategies. Ketamine is a promising drug in the treatment of bipolar disorder considering its rapid antidepressive and antisuicidal effects. However, the potential therapeutic value of ketamine in the treatment of bipolar or unipolar depression was and still is not established. Fancy et al.1 correctly mention that there were already two small (n = 15–­18)­ randomized­ crossover­ studies­ and­ one­ relative­ large­ (n = 53)­open-­label­ study­with­a­ single­ketamine­ infusion,­but­ they­ fail to mention that there were also already three small (n = 13–­38)­ multiple infusion (6– 9 infusions) openlabel studies in patients with treatmentresistant bipolar depression (TRBD) with most studies showing a rapid and robust reduction of depressive symptoms especially after multiple infusions.2 In addition, there was already a small (n = 16)­ parallel­ RCT­ comparing­ ketamine­with­midazolam­ in­ suicidal patients with bipolar depression showing a substantial, but not significant, reduction in suicidal ideations after a single ketamine infusion. The authors correctly conclude that the evidence and the clinical relevance of these studies is limited because the studies were generally (very) small and all studies were performed in research settings with selected groups of BD patients with little or no psychiatric comorbidity, but the authors are not correct in stating that all studies used a single dose of ketamine. The authors wanted to perform the first adequately powered study to establish the realworld effectiveness of four intravenous ketamine infusions across 8–­14 days­in­TRBD­patients­form­a­community­clinic­setting,­that­is,­ in a nonselected group of TRBD patients. Indeed, with n = 66­BD­patients­ in­this­single-­arm­study,­ this­ is­ the largest ketamine study in TRBD patients until now and patients were recruited from a standard community clinic with only few exclusion criteria. However, patients with an active psychosis or a current substance use disorder were excluded. This is problematic since active psychoses are present in more than half of the patients with type I BD (BDI) and in more than 10% of patients with type II BD (BDII), whereas current alcohol and drug use disorders are present in about 60% of BDI and in half of all BDII patients. Moreover, there are strong indications that shortterm ketamine treatments are effective and safe in mood disorder patients with a history of psychosis and current psychotic symptoms,3 whereas ketamine seems to have a beneficial effect in patients with an alcohol, cocaine, or cannabis use disorder. Moreover, this article fails to mention how many patients refused participation in the trial and whether these patients were clinically different from the ones that participated. It is, therefore, questionable whether patients with (a history of) psychosis and/ or a substance use disorder had to be excluded from the study and whether­ the­ results­of­ this­study­can­be­generalized­ to­ real-­world­ (TR)BD patients; one of the main objectives of this study. The results of the intervention are very similar to previous uncontrolled studies and crossover RCTs with about 35% responders (≥50­reduction­in­depressive­symptoms),­20%­patients­in­full­remission, and a substantial reduction in suicidal ideation at the posttreatment­assessment­1 week­after­the­last­ketamine­infusion.­However,­

In 2017, major depressive disorder and bipolar disorder affected approximately 163 and 45 million people, respectively.Bipolar disorder (BD) is a mental disorder with high morbidity and the highest lifetime risk of suicide.Most patients with BD suffer from depression during an important part of their lifespan.Another feature of BD is its high rate of treatment resistance, which is higher than that of major depressive disorder, urging the need for new BD treatment strategies.Ketamine is a promising drug in the treatment of bipolar disorder considering its rapid antidepressive and antisuicidal effects.
However, the potential therapeutic value of ketamine in the treatment of bipolar or unipolar depression was and still is not established.Fancy et al. 1 correctly mention that there were already two small (n = 15-18) randomized crossover studies and one relative large (n = 53) open-label study with a single ketamine infusion, but they fail to mention that there were also already three small (n = 13-38) multiple infusion (6-9 infusions) open-label studies in patients with treatment-resistant bipolar depression (TRBD) with most studies showing a rapid and robust reduction of depressive symptoms especially after multiple infusions. 2In addition, there was already a small (n = 16) parallel RCT comparing ketamine with midazolam in suicidal patients with bipolar depression showing a substantial, but not significant, reduction in suicidal ideations after a single ketamine infusion.
The authors correctly conclude that the evidence and the clinical relevance of these studies is limited because the studies were generally (very) small and all studies were performed in research settings with selected groups of BD patients with little or no psychiatric comorbidity, but the authors are not correct in stating that all studies used a single dose of ketamine.The authors wanted to perform the first adequately powered study to establish the realworld effectiveness of four intravenous ketamine infusions across 8-14 daysinTRBDpatientsformacommunityclinicsetting,thatis, in a nonselected group of TRBD patients.Indeed, with n = 66 BD patients in this single-arm study, this is the largest ketamine study in TRBD patients until now and patients were recruited from a standard community clinic with only few exclusion criteria.However, patients with an active psychosis or a current substance use disorder were excluded.This is problematic since active psychoses are present in more than half of the patients with type I BD (BDI) and in more than 10% of patients with type II BD (BDII), whereas current alcohol and drug use disorders are present in about 60% of BDI and in half of all BDII patients.Moreover, there are strong indications that short-term ketamine treatments are effective and safe in mood disorder patients with a history of psychosis and current psychotic symptoms, 3 whereas ketamine seems to have a beneficial effect in patients with an alcohol, cocaine, or cannabis use disorder.Moreover, this article fails to mention how many patients refused participation in the trial and whether these patients were clinically different from the ones that participated.It is, therefore, questionable whether patients with (a history of) psychosis and/ or a substance use disorder had to be excluded from the study and whether the results of this study can be generalized to real-world (TR)BD patients; one of the main objectives of this study.this also means that many patients were still seriously symptomatic and that additional treatment options or changes in the ketamine treatment should be considered, such as a combination of ketamine with psychotherapeutic sessions before and after the ketamine sessions which seem to maximize and prolong the reductions in pain, anxiety, and depression. 4 interesting finding is the increasing effect of ketamine on depressive symptoms over time with a parallel decrease of dissociation severity over time and with increasing ketamine doses (0.5 mg/kg for the first and second infusions with a potential in-creaseupto0.75mg/kgforthethirdandfourthinfusionsifthere no minimal response, i.e., ≤20% symptoms reduction).Previous studies have shown that treatments response is (partly) mediated by dissociative and mystical experiences 5 and, therefore, one would expect a positive correlation, something that did not occur in this study.
Finally, it is important that the study by Fancy et al. 1 not only found positive effects of ketamine on depressive and anxiety symptoms in TRBD patients but also improvements in social and family functioning, but not in work functioning.This is important because these outcomes are more objective than self-reported symptoms which is especially relevant in open-label studies because they are less sensitive to expectancy bias.
Overall, this is an important study suggesting that ketamine is a promising drug in the treatment of patients with TRBD, but additionalrandomizeddouble-blindcontrolledtrialswithobjective outcomes are needed before it can become a standard treatment.

CO N FLI C T O F I NTER E S T S TATEM ENT
WvdB has been a consultant to Janssen and is consultant for Clearmind Pharmaceuticals.JvA has no conflict of interest in connection with this article.

R E FE R E N C E S
The results of the intervention are very similar to previous uncontrolled studies and crossover RCTs with about 35% responders (≥50reductionindepressivesymptoms),20%patientsinfullremission, and a substantial reduction in suicidal ideation at the posttreat-mentassessment1 weekafterthelastketamineinfusion.However, This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.© 2023 The Authors.Bipolar Disorders published by John Wiley & Sons Ltd.