Can ketamine be a safe option for treatment-resistant bipolar depression?

KEYWORDS:

• Ketamine
• bipolar disorders
• treatment-resistant bipolar depression

1. Introduction

Bipolar disorder (BD) is a recurrent condition with fluctuating mood swings from energetic mania/hypomania to severe depression, leading to significant disability and a high risk of mortality. Patients with BD spend most of their time in depressive episodes compared with manic or hypomanic episodes. Despite advances in psychopharmacology, only five FDA-approved treatment options for bipolar depression are available, four of which are atypical antipsychotics (quetiapine, lurasidone, cariprazine, and lumateperone), and the fifth is a combination atypical antipsychotic (olanzapine) and antidepressant (fluoxetine). These medications often work slowly and carry a significant side-effect burden, including the risk of irreversible tardive dyskinesia. Despite adequate trials, a significant proportion of patients remain treatment-resistant. There is a lack of faster-acting antidepressants, causing significant distress and poor quality of life for patients with treatment-resistant bipolar depression (TRBD). Thus, identifying novel molecules that have a rapid onset of antidepressant effects is a major priority.

Ketamine, a glutamatergic anesthetic agent, ‘repurposed’ as a rapid-acting antidepressant for treatment-resistant depression at subanesthetic doses (usually 0.5 mg/kg body weight), is touted as a miracle drug [1]. Intravenous (IV) racemic ketamine was initially investigated for bipolar depression in three, small, single-infusion, randomized controlled trials (RCTs) (n = 49) and found to be safe and well tolerated [2–4]. The rapid effectiveness of ketamine was apparent within 24 hours, but the effect only lasted for approximately 3 days [5]. Despite the relatively temporary benefit, results suggest that ketamine may play a role in treating TRBD. However, the evidence base of ketamine for TRBD remains limited, highlighting the need for more data.

In this issue of ‘Expert Opinion On Drug Safety’ we reviewed if ketamine can be a safe treatment option for TRBD

1.1. Key findings and weaknesses in the research done in this field so far

Preclinical studies have shown that ketamine is an N-methyl-D-aspartate (NMDA) receptor antagonist, however, the antidepressant effect of ketamine is not entirely explained by the antagonizing effect on the NMDA receptor alone [5]. Recent studies have shown direct and indirect actions on the mu opioid receptors, attenuating GABA deficits to reduce neuronal excitability, mammalian target of rapamycin (mTOR) activation leading to dendritic remodeling and synaptogenesis as mechanism of actions [3–7]. There is a need for further basic research in understanding the mechanism of ketamine.

Three RCTs and two open-label trials enrolling a total of 110 patients with bipolar depression demonstrated significant, albeit temporary, improvement in depressive symptoms after a single IV infusion of ketamine [5]. A major weakness in the current literature regarding ketamine for bipolar depression is the dearth of evidence for serial infusions in this population. Clinically, if ketamine is to be used for TRBD, serial infusions will be needed to maintain a sustained response. Two small open-label naturalistic studies used 6–8 serial ketamine infusions and reported extension of benefit were maintained across the subsequent infusions [8,9]. The response rates in both the studies were higher than single infusion studies but the depression scores started to increase 1 week after treatment. This is consistent with another open-label study by Zhuo et al [10]. Unfortunately, given the lack of data for this approach, the safety of continuation and maintenance phase infusions remains largely unknown. Table 1 highlights summary of the single and multiple ketamine infusion studies in bipolar depression.

Table 1. Summary of the single and serial/multiple intravenous ketamine studies for bipolar depression.

Study (First author et al)	Type of Study	Number of infusions	Total Patients, (Females %)	Main findings
Single infusion studies
Diazgranados et al.	RCT, Crossover (ketamine-Saline placebo)	One	18, (66.7%)	Single ketamine infusion resulted in a robust and rapid antidepressant effect at day 1, which remained significant through day 3.
Zarate et al.	RCT, Crossover (ketamine-Saline placebo)	One	15, (53.3%)	Single ketamine infusion resulted in a robust and rapid antidepressant effect and improvement in suicidal ideation, which remained significant through day 3.
Kantrowitz et al.	Open label	One	8, (62.5%)	25% or more improvement in HAM-D in 7 patients after ketamine infusion.
Grunebaum et al.	RCT, parallel group, (ketamine vs midazolam)	One	16, (62.5%)	There was a non-statistically significant reduction in the depression scores and a trend level of significant reduction in suicidal thoughts with ketamine compared to midazolam.
Rybakowski et al.	Open label	One	53, (75.5%)	Rapid antidepressant effect after single intravenous dose of ketamine infusion and a reduction of ≥50% on HAM-D in 24.5% patients at 24hrs and in 51% patients on the 7^th day after infusion.
Multiple /serial infusion studies
Zheng et al	Open-label	Six	19, (31.6%)	Repeated ketamine infusions at subanesthetic doses for patients with TRBD is feasible. Response and remission rates after the 6^th infusion were 73.7% and 63.2%, respectively.
Wilkowska et al	Open-label Naturalistic observational	Eight	13, (76.9%)	Response and remission rates after the 7^th infusion were 61.5% and 46.2%, respectively. IV ketamine was feasible, safe, and well-tolerated,
Zhuo et al	Open-label	Nine	38, (42.1%)	Average depression scores decreased by 49.8% after starting ketamine augmentation, however, these effects were maintained for only one week. Depressive symptoms started to relapse within two weeks post-ketamine initiation, raising concerns regarding ketamine’s longitudinal efficacy in TRBD.

In the treatment of bipolar depression, the risk of switch to mania is an important safety concern. Two RCTs [2,3] which utilized a single-infusion paradigm required patients to be on a mood stabilizer (lithium or valproate). In the first study, one patient had manic symptoms, but while in the placebo arm [2]. In three RCTs of single infusions, there was no mood switch in the ketamine group [2–4]. In the two open-label single infusion studies, there was only one mood switch in a patient two weeks after stopping the antipsychotic [11,12]. In three open-label multiple infusions studies, there was no reported mood switch [8–10]. Of course, there are case reports of mood switching, such as in a young patient with bipolar-II disorder treated with multiple large doses of ketamine [13]. The small numbers of patients with bipolar depression being treated with ketamine, along with the heterogeneity of the illness and associated variables such as comorbidities, will make it difficult to estimate the risk of mood switches. There is a need to further investigate the mechanism and risk for mood switching in TRBD.

1.2. What potential does this research hold?

Ketamine holds great potential as a rapid-acting antidepressant and antisuicidal medication for TRBD. For example, ketamine can be life-saving, with a systematic review showing a single ketamine infusion can reduce suicidal ideation within 1 day [14]. Long-term efficacy and safety data, especially with regards to mood switching and addiction, will be needed to develop its usefulness as a treatment for TRBD.

1.3. What research or knowledge is needed to achieve this goal and what is the biggest challenge in this goal being achieved?

There are several factors leading to the sparse literature of ketamine for bipolar depression. One major challenge is recruitment and funding. In the studies by Diazgranados et al [2] and Zarate et el [3], recruitment consisted of 18 and 15 subjects, respectively, over the course of 2.5 and 2 years, respectively. Industry-funded phase-III esketamine trials did not enroll bipolar depressed participants and thus, there is no established efficacy. These numbers reflect the long duration of time that is often needed to find enough patients with bipolar depression who meet a pre-defined set of inclusion criteria for a given research study, and this limitation can also have implications on funding. To compound the problem of recruitment, ketamine is available off-label for bipolar depression, so patients who have the financial means to pay out-of-pocket may simply go to a clinic instead of enrolling in a clinical trial. Unfortunately, this avenue for treatment does not often add to the literature as many clinical practices are busy and not designed to gather data and publish outcomes.

1.4. Concerns regarding ketamine use in TRBD and potential pitfalls? Need for more collaboration

Given the challenges with recruiting and enrolling sufficient numbers of patients with TRBD in a timely manner for RCTs, it is likely that the field will need to rely on clinical data from real-world practices. There are several pitfalls to this approach: (a) The majority of patients would likely be from private practices (not necessarily with psychiatric expertise), where data would be retrospective and formal rating scales for depression and mania are not collected; (b) If institutions collaborate and compile datasets to increase sample size, there may be limitations due to lack of standardized methods; and (c) Since there is no FDA approval for the use of ketamine for TRBD, and thus no insurance coverage, the results would be applicable to a more affluent patient population which can afford ketamine and not generalizable. However, this approach may provide the data which helps researchers and clinicians understand long-term efficacy, safety, tolerability, and risk of switching from depressive to manic states.

Another safety concern with ketamine is that of addiction, and the field needs to have a better understanding of this risk factor. Worldwide, ketamine is a popular drug of abuse, although the amounts and frequency used are much higher than the subtherapeutic doses for mood disorders. Nevertheless, ketamine has effects on the opioid receptor, and blocking the opioid receptor before ketamine treatment has been shown to decrease its antidepressant efficacy [6]. Anecdotally, patients regularly comment that they look forward to ketamine treatments because it provides several hours where they can be free of their ruminative thoughts and worries. There are also case reports of addictive behaviors with ketamine for depression. While our current knowledgebase downplays addiction with subtherapeutic ketamine for depression, the field must continue to be vigilant about these concerns, especially with ketamine’s wider and longer-term use. In a recent preclinical model study investigating the abuse liability of (S)- and (R)-ketamine enantiomers, Bonaventura et al [15] conducted thorough systematic assessments at multiple levels (pharmacological screening and behavioral modeling) and demonstrated divergence in the ‘pharmacological, functional, and behavioral effects of ketamine enantiomers,’ with (S)-ketamine showing a higher affinity at mu-opioid receptor, and potential for abuse liability compared to (R)-ketamine. This further highlights the need for further preclinical studies regarding ketamine use as a repurposed rapid-acting antidepressant investigating its mechanism of action and abuse liability.

2. Expert opinion

The evidence to support the safety of ketamine in bipolar depression is small but encouraging. Despite concerns regarding mood switch and possible iatrogenic dependency, we believe ketamine could be safely used in certain cases. Consistent with the cautions of antidepressants in BD, ketamine could be used in bipolar disorder type II, and not in type I unless robust mood stabilizers are concurrently prescribed. We also believe that ketamine should not be used long-term. What duration constitutes long-term is not known. Mood cycling is a feature of BD, and the longer one uses ketamine, it may coincide with a mood elevation, in which the conventional clinical approach is to stop any antidepressants. Thus, ketamine could be limited to a duration of 6–12 months to minimize the risk of inducing a mood switch and iatrogenic dependency. Like antidepressants, ketamine tachyphylaxis is a reality, probably underreported. To provide more data to answer questions such as the optimal duration of ketamine use, we need more data. Encouraging collaborations, including with private practices, to aggregate knowledge and create a registry to report mood switches and addiction with ketamine treatments would be ideal. However, the registry would work only if the providers of the treatment recognize that a mood switch or addiction had occurred and are willing to report, as they might be concerned about reporting adverse effects in the context of using a novel treatment off-label. Filling these gaps in our knowledgebase would provide us more confidence in saying that ketamine is safe for use in bipolar disorder.

Author’s contributions

B Singh, JL Vande Voort, and S Kung designed the paper. All authors participated in drafting and reviewing. All authors read and approved the final version of the manuscript.

Declaration of interests

B Singh reports grant support from Mayo Clinic. JL Vande Voort is a co-primary investigator on an investigator-initiated study that has a grant-in-kind for supplies and genotyping only through Assurex Health. MA Frye has received Grant Support from Assurex Health, and Mayo Foundation. He also has financial interests in Chymia LLC. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

A peer reviewer on this manuscript has received manuscript or speaker’s fees from Astellas, Dainippon Sumitomo Pharma, Eisai, Eli Lilly, Elsevier Japan, Janssen Pharmaceuticals, Kyowa Yakuhin, Lundbeck, Meiji Seika Pharma, Mitsubishi Tanabe Pharma, MSD, Nihon Medi-Physics, Novartis, Otsuka Pharmaceutical, Shionogi, Shire, Takeda Pharmaceutical, Tsumura, Wiley Japan, and Yoshitomi Yakuhin, and research grants from Dainippon Sumitomo Pharma, Eisai, Mochida Pharmaceutical, Meiji Seika Pharma and Shionogi. All other peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Data availability statement

Data sharing not applicable to this article as no datasets were generated or analyzed during the current study.

Additional information

Funding

This paper was not funded.