Esketamine Safe for Treatment-Resistant Depression

In contrast with ketamine, esketamine showed no evidence of abuse, misuse, withdrawal, and no long-term cognitive, urogenital or hepatic toxicity.

Esketamine is effective for treatment-resistant depression (TRD) in a real-world setting, according to study findings published in Journal of Affective Disorders.

Researchers conducted an observational, retrospective, multicenter study on esketamine nasal spray outcomes among 116 patients (mean age, 50 [SD, 12.45] years, 52.6% women) with TRD who were being treated at 22 mental health facilities in Italy. Changes in Montgomery-Åsberg Depression Rating Scale (MADRS) and 21-item Hamilton Depression Scale (HAMD-21) scores were evaluated from baseline to month 3. Remission was defined as a MADRS score of less than 10 or HAMD-21 score of less than 7 and response as an at least 50% reduction in MADRS or HAMD-21 from baseline.

The patients were each experiencing a current major depressive episode had lasted 16.5 (SD, 6.4) months and had had an overall mean depression duration of 19 (SD, 11.05) years. Among the participants, the mean MADRS score was 35 (SD, 8.53) points and the mean HAMD-21 score was 27.7 (SD, 8.48) points.

At the 1-month follow-up, 7.5% of participants were receiving an esketamine dose of 28 mg, 66% were receiving a dose of 56 mg, and 26.5% were receiving a dose of 84 mg. At month 3, 8.8% were receiving a dose of 28 mg, 52.7% were receiving a dose of 56 mg, and 38.5% were receiving a dose of 84 mg.

There were no evidence of abuse, misuse, withdrawal, gateway activity, and no long term cognitive or urogenital or hepatic toxicity, as previously documented for ketamine.

Compared with baseline, MADRS scores decreased at months 1 (mean, 22.27 points; P <.0001) and 3 (mean, 14.69 points; P <.0001).

No socioeconomic differences were observed between the 68 responders and 23 nonresponders at month 3.

Stratified by concomitant medication use, 50% of patients without augmentation strategies and 35% with augmentation (ie, mood stabilizers or antipsychotics) responded at month 1, and 100% and 70% responded at 3 months, respectively.

The total dropout rate was 12.93%, in which 1.72% dropped out at month 1 due to side effects and 6.03% and 4.31% dropped out at months 1 and 3, respectively, due to low effect. The most common side effects included dissociative symptoms (39.7%), sedation (28.4%), and transitory hypertension (10.3%). A single case of severe psychomotor agitation occurred.

The major limitation of the study is the lack of a comparator group.

Study authors concluded, “Our observational data support the safety and tolerability of esketamine in a real-world sample of adults with TRD. Our data also indicate clinical effectiveness of esketamine in this population.”

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


Martinotti G, Vita A, Fagiolini A, et al. Real-world experience of esketamine use to manage treatment-resistant depression: a multicentric study on safety and efficacy (REAL-ESK study). J Affect Disord. 2022;319:646-654. doi:10.1016/j.jad.2022.09.043