Esketamine-Nasal Spray Safe and Effective for Treatment-Resistant Bipolar Depression

Treatment-resistant bipolar depression was effectively treated with esketamine-nasal spray.

Esketamine-nasal spray (ESK-NS) was found to be effective and tolerable for treatment-resistant bipolar depression (B-TRD) in a real-world setting. These findings were published in Bipolar Disorders.

The REAL-ESK study was an observational, retrospective, multicenter study conducted in Italy. Patients (n=35) with B-TRD who had received early access to ESK-NS through national mental health centers were retrospectively compared for outcomes at 3 months with a matched group of patients with treatment-resistant depression (TRD; n=35) who had also received ESK-NS.

The B-TRD and TRD cohorts comprised patients with mean ages 52.77±10.9 and 52.77±10.9 years, the male:female ratios were 17:18 and 15:20, their depression onset at 33.31±11.65 and 34.35±14.2 years of age, the duration of their depressive episode was 15.94±11.81 and 13.68±11.12 months, and 11 and 4 patients had previously attempted suicide, respectively.

The B-TRD and TRD cohorts were receiving selective serotonin reuptake inhibitors (45.71% vs 45.71%), serotonin-norepinephrine reuptake inhibitors (20% vs 42.8%), and other antidepressants (51.43% vs 54.28%), respectively. In addition, the B-TRD cohort had a higher rate of taking mood stabilizers (100% vs 57.14%) and antipsychotics (68.57% vs 45.7%) compared with the TRD cohort, respectively.

The prolonged effectiveness to three months and the possible action on mixed features in patients with bipolar disorder represent intriguing results.

Esketamine was dosed at 84 mg for 28.6% of the B-TRD and 60% for the TRD recipients, 56 mg for 57.1% and 34.3%, and 28 mg for 14.3% and 5.7%, respectively.

At baseline, average Montgomery–Åsberg Depression Rating Scale (MADRS) scores were 37.07 points among the B-TRD group. After 1 month of treatment, MADRS scores decreased to 24.04 points and to 12.78 points after 3 months of treatment. The MADRS scores for the TRD group were comparable at baseline (mean, 34 points) and after 1      (mean, 21.79 points) and 3 (mean, 14.97 points) months of EST-NS treatment, respectively.

The proportion of responders after 1 month of treatment were 25.7% and 25.7% and after 3 months were 68.57% and 57.14% in the B-TRD and TRD groups, respectively. However, 48.57% of the B-TRD group were MADRS remitters in month 3 compared with 28.57% in the TRD group.

For Hamilton Anxiety Rating Scale (HAM-A) scores, similar decreases in scores were observed among the B-TRD and TRD groups from baseline (mean, 29.88 vs 30.9 points) to 3 months of treatment (mean, 11.2 vs 16.2 points), respectively. As with symptoms of depression, more of the B-TRD group remitted in month 3 compared with TRD (35% vs 2.86%; P =.002), respectively.

Fewer of the B-TRD cohort reported any side effect (57.14%) compared with the TRD group (77.14%). Among the B-TRD group, the most common side effects were dissociation (31.4%) and sedation (28.57%). The rate of affective switch or maniacal symptom development was rare (2.86%) in both groups.

The major limitation of this study was the small sample size.

Study authors concluded, “Our findings support the effectiveness and tolerability of ESK-NS in a real-world population of subjects affected by B-TRD. The prolonged effectiveness to 3 months and the possible action on mixed features in patients with bipolar disorder represent intriguing results. Furthermore, the low risk of manic switch in patients with B-TRD, superimposed on the TRD group, confirms the safety of this treatment.”

Disclosure: Multiple authors declared affiliations with industry. Please refer to the original article for a full list of disclosures.


Martinotti G, Dell’Osso B, Lorenzo GD, et al. Treating bipolar depression with esketamine: safety and effectiveness data from a naturalistic multicentric study on esketamine in bipolar versus unipolar treatment-resistant depression. Bipolar Disord. Published online January 13, 2023. doi:10.1111/bdi.13296