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Background: Bipolar depression accounts for most of the disease duration in type I and type II bipolar disorder (BD), with few treatment options, often poorly tolerated. Many individuals do not respond to first‐line therapeutic options, resulting in treatment‐resistant bipolar depression (B‐TRD). Esketamine, the S‐enantiomer of ketamine, has recently been approved for treatment‐resistant depression (TRD), but no data are available on its use in B‐TRD. Objectives: To compare the efficacy of esketamine in two samples of unipolar and bipolar TRD, providing preliminary indications of its effectiveness in B‐TRD. Secondary outcomes included the evaluation of the safety and tolerability of esketamine in B‐TRD, focusing on the average risk of an affective switch. Methods: Thirty‐five B‐TRD subjects treated with esketamine nasal spray were enrolled and compared with 35 TRD patients. Anamnestic data and psychometric assessments (Montgomery‐Asberg Depression Rating Scale/MADRS, Hamilton‐depression scale/HAM‐D, Hamilton‐anxiety scale/HAM‐A) were collected at baseline (T0), at one month (T1), and three months (T2) follow up. Results: A significant reduction in depressive symptoms was found at T1 and T2 compared to T0, with no significant differences in response or remission rates between subjects with B‐TRD and TRD. Esketamine showed a greater anxiolytic action in subjects with B‐TRD than in those with TRD. Improvement in depressive symptoms was not associated with treatment‐emergent affective switch. Conclusions: Our results supported the effectiveness and tolerability of esketamine in a real‐world population of subjects with B‐TRD. The low risk of manic switch in B‐TRD patients confirmed the safety of this treatment. [ABSTRACT FROM AUTHOR]

Protease inhibitors are all metabolized in the liver by the cytochrome P450 (CYP) enzyme system, especially the CYP3A4 isoenzyme.3 The CYP system is also the major hepatic enzyme complex involved in the metabolism of many other drugs, including most of the psychotropic drugs used in clinical practice. Within only about 7 months from its appearance, COVID-19 has rapidly spread across the globe, infecting (at the time of writing) more than 62 million worldwide and causing the death of more than 1 455 030 persons.1 Several extant antivirals have been investigated as potential treatment options for COVID-19, including a combination of protease inhibitors lopinavir/ritonavir.2 Front-line COVID-19 physicians should be well aware that the use of these drugs requires particular attention due to their possible adverse effects on the central nervous system, especially in the treatment of psychiatric patients and the vulnerable elderly population, characterized by many comorbidities and co-treatments. Ritonavir is the best alternative to ketoconazole as an index inhibitor of cytochrome P450-3A in drug-drug interaction studies. [Extracted from the article]