The recent report by Fancy and colleagues 1 on their experience with R,S-ketamine infusions for treatment-resistant depression in bipolar disorder (BD) patients is timely and encouraging in addressing treatment for BD II (BD2) and BD1 patients. Their findings add to emerging evidence that ketamine is effective in depression, including otherwise treatment-resistant depression in BD and major depressive disorder (MDD) (Table 1).2 The study's limitations include being uncontrolled and unblinded, with only brief self-assessments of a small sample and inclusion of other uncontrolled treatments. Nevertheless, it adds to urgently needed research support for effective treatments for BP-depression and particularly for BD2 and BD1 patients.3 Ketamine may also reduce suicidal ideation (behavior remaining untested) in depressed patients.1, 2 Indeed, optimal treatment for depression in BD1 and especially in BD2 remains especially important in view of the strong association of BD depression with morbidity, co-occurring anxiety and substance-use disorders, disability, and excess medical mortality as well as extraordinarily high suicide rates, which are among the highest of all psychiatric disorders and approximately 20 times greater than in the general population.4 Depressive/dysthymic phases of BD are by far the dominant morbidity, particularly in BD2.5 Indeed, mood disorder patients treated clinically by community standards averaged 45% time-ill during long-term follow-up; depression accounted for approximately three-quarters of time-ill in BD, and somewhat more with BD2 (81%) than BD1 (70%).5 Treatment of bipolar depression and associated efforts at suicide-prevention are complicated by ongoing emotional and behavioral instability, mixed manic-depressive features, and psychosis, even in BD2 depression, as well as very high risk of suicidal behavior.3, 4 Remarkably, few treatments have demonstrated high effectiveness in acute episodes of bipolar depression, and there is even less evidence supporting long-term prevention of recurrences. Whether antidepressants are effective and safe for treating bipolar depression—particularly in BD1 with its potentially dangerous elevations of mood and risky behavior associated with mood-elevating treatments—remains controversial owing to limited and inconsistent evidence, which contrasts markedly to their prevalent use for that purpose.3 Indeed, bipolar depression remains a leading challenge for modern psychiatric therapeutics. The state of development of an evidence-base treatment for bipolar depression contrasts markedly to that for MDD—in many ways a markedly dissimilar disorder which has provided few clues to appropriate treatment of bipolar depression.3 Lithium, though underutilized to treat BD despite its established long-term benefits for mania more than depression and growing evidence of ability to limit suicidal risks, remains extraordinarily little-studied in acute bipolar depression.3 Some anticonvulsants are used to treat bipolar depression despite still-limited research support. Lamotrigine has limited efficacy in off-label use for acute bipolar depression and is challenged to use for that purpose in slowly increasing doses to avoid toxic dermatological-mucosal reactions.3 It has regulatory approval only for long-term prophylaxis of bipolar depression, for which it is partially effective and much less so versus mania.3 Carbamazepine is approved only for short-term treatment of mania and mixed-states; sodium valproate is also approved only for acute mania though it may have some benefits in bipolar depression that require further study.3 Rapidly emerging for treatment of BD and psychotic disorders are several “second-generation” antipsychotics (SGAs) including cariprazine, lumateperone, lurasidone, olanzapine-fluoxetine, and quetiapine. They are the only specifically FDA-approved medicines for short-term treatment of acute depressive episodes in BD, though their efficacy for that indication is modest and possible long-term protective effects and safety of most SGAs require further study.3 Adverse effects of SGAs include weight gain, metabolic syndrome, oversedation and akathisia, as well as some risk of tardive dyskinesia; too, the theoretical basis of their effects in depression remain uncertain.3 Electroconvulsive treatment (ECT) has long had a place in the treatment of severe and psychotic forms of depression in BD and MDD, though its access and use are quite limited in many areas. Additional pharmacological and nonpharmacological treatments, including repeated transcranial magnetic stimulation (rTMS), intense light therapy, sleep-deprivation, vagal stimulation, and use of psychedelic agents, as well as group and individual psychotherapies, all require further critical evaluation.3 Finally, even though evidence for short-term efficacy of ketamine for acute bipolar depression is growing (Table 1),1, 2 its optimal use and risks with more than a few weeks of treatment remains unresolved for both bipolar depression and for MDD. In conclusion, we welcome the new research evidence of effectiveness of R,S-ketamine for bipolar depression, including for BD2 and MDD, even with treatment-resistance (Table 1) 1 but must emphasize that the therapeutics of bipolar depression generally remain far from adequately developed and well-supported by multiple, scientifically rigorous therapeutic trials. It also is increasingly clear that the bipolar depression syndrome is markedly dissimilar to MDD in many ways and that progress in the treatment of MDD does not always lead to improvements in the treatment of bipolar depression as appears to have happened with ketamine. Supported in part by a grant from the Bruce J. Anderson Foundation and by the McLean Private Donors Psychiatric Research Fund (to RJB). Neither author nor immediate family members have financial relationships with any commercial organization that might appear to represent a potential conflict of interest with the material presented.
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May 1, 2024
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