Is esketamine (generic name: esketamine) recommended as a treatment for resistant bipolar depression?

From the Guidelines

Esketamine is not currently recommended as a standard treatment for resistant bipolar depression. While esketamine (brand name Spravato) has received FDA approval for treatment-resistant unipolar depression and for depressive symptoms with suicidal ideation, it has not been specifically approved for bipolar depression. The distinction between unipolar and bipolar depression is important because treatments effective for one may not be appropriate for the other, and some antidepressant approaches can potentially trigger manic episodes in bipolar patients. For patients with treatment-resistant bipolar depression, established approaches typically include optimizing mood stabilizers (lithium, lamotrigine, valproate), adding second-generation antipsychotics (quetiapine, lurasidone, cariprazine), or considering electroconvulsive therapy. If esketamine were to be considered, it would be as an off-label use and should only be done under close psychiatric supervision with careful monitoring for mood switching, as suggested by the 2022 U.S. Department of Veterans Affairs and U.S. Department of Defense clinical practice guideline 1. The glutamatergic mechanism of esketamine differs from traditional antidepressants, which theoretically might reduce switch risk, but sufficient evidence from controlled trials in bipolar populations is currently lacking to support its routine use in bipolar depression.

Some key points to consider in the management of resistant bipolar depression include:

• Optimizing mood stabilizers and adding second-generation antipsychotics are established approaches for treatment-resistant bipolar depression.
• Electroconvulsive therapy is also a consideration for patients who have not responded to other treatments.
• Esketamine, while approved for treatment-resistant unipolar depression, lacks specific approval and sufficient evidence for routine use in bipolar depression.
• Any consideration of esketamine in bipolar depression should be done with caution and under close psychiatric supervision, given the potential risks and the lack of specific evidence supporting its use in this population, as noted in the guideline 1.

Given the current state of evidence, the use of esketamine in resistant bipolar depression should be approached with caution and considered on a case-by-case basis, prioritizing the patient's safety and the potential benefits and risks of the treatment, as emphasized by the need for careful consideration of treatment options in clinical practice guidelines 1.

From the FDA Drug Label

14.1 Treatment-Resistant Depression Short-Term Study SPRAVATO was evaluated in a randomized, placebo-controlled, double-blind, multicenter, short-term (4-week), Phase 3 study (Study 1; NCT02418585) in adult patients 18 to <65 years old with treatment-resistant depression (TRD)

The FDA drug label does mention treatment-resistant depression, but it does not explicitly state that esketamine is recommended for resistant bipolar depression.

• Key point: The study mentioned in the label is for treatment-resistant depression, not specifically resistant bipolar depression.
• Conclusion: The information provided does not directly support the use of esketamine for resistant bipolar depression 2.

From the Research

Esketamine for Resistant Bipolar Depression

• Esketamine has been studied as a potential treatment for resistant bipolar depression, with some studies suggesting its effectiveness in reducing depressive symptoms 3, 4.
• A study published in 2023 found that esketamine was effective in reducing depressive symptoms in patients with treatment-resistant bipolar depression, with no significant differences in response or remission rates compared to patients with unipolar treatment-resistant depression 3.
• Another study published in 2024 found that ketamine/esketamine treatment was associated with a significant reduction in depression severity in patients with bipolar depression, with 39% of patients achieving clinical response and 13.2% achieving remission 4.
• However, the same study also found that 28.9% of patients experienced symptoms consistent with a hypomanic or manic episode at some point during the maintenance phase of treatment, highlighting the need for further research on the safety of esketamine in bipolar depression 4.
• Overall, the available evidence suggests that esketamine may be a useful treatment option for resistant bipolar depression, but more research is needed to fully understand its efficacy and safety in this population 3, 4, 5.

Key Findings

• Esketamine has been shown to be effective in reducing depressive symptoms in patients with resistant bipolar depression 3, 4.
• The treatment is generally well-tolerated, but may be associated with a risk of hypomanic or manic episodes in some patients 4.
• Further research is needed to fully understand the efficacy and safety of esketamine in resistant bipolar depression, particularly in terms of its long-term effects and potential interactions with other medications 5.

Treatment Considerations

• Esketamine may be considered as a treatment option for patients with resistant bipolar depression who have not responded to other treatments 3, 4.
• Patients should be closely monitored for signs of hypomanic or manic episodes, particularly during the maintenance phase of treatment 4.
• The treatment should be used in conjunction with other antidepressant medications, and patients should be carefully selected and monitored to minimize the risk of adverse effects 6, 7.