Comparison of intranasal esketamine versus other pharmacological strategies in treatment-resistant depression with high suicide risk

Introduction

Treatment-resistant depression (TRD) represents a major clinical challenge, particularly when accompanied by suicidal behaviour [1],[2]. Intranasal esketamine has demonstrated rapid antidepressant effects in TRD; however, comparative evidence in real-world settings remains limited. The aim of this study was to compare, in routine clinical practice, the evolution of suicidal ideation and depressive symptoms in patients with TRD at high risk of suicide undergoing fourth-line treatment. Patients treated with intranasal esketamine were compared with those receiving alternative pharmacological strategies. In addition, changes in overall functioning were explored.

Methods

This observational study was conducted among psychiatric outpatients in two Spanish mental health centres. The sample comprised patients diagnosed with TRD who had just initiated a new psychopharmacological strategy. To be included, patients had to have previously received at least three different therapeutic strategies. Patients were followed for six months. The choice of treatment was entirely at the discretion of the attending psychiatrists, with no influence from the investigators. We compared patients initiated on intranasal esketamine with those prescribed a different pharmacological approach. All participants provided informed consent. Assessments were conducted at baseline, and at 1, 3, and 6 months. Depressive symptoms were measured using the Hamilton Depression Rating Scale, suicidal ideation using the Columbia–Suicide Severity Rating Scale, and functioning using the Functioning Assessment Short Test. A repeated-measures ANOVA was performed to compare both groups, an independent-samples Student’s t-test was used to assess differences in percentage clinical improvement and reduction in suicide risk, and the number needed to treat (NNT) was calculated.

Results

A total of 62 patients were recruited: 30 received intranasal esketamine and 32 initiated other pharmacological strategies. The sample had a mean age of 43.5 years and included a higher proportion of men (53.2%). Overall, the groups were comparable in most baseline sociodemographic and clinical characteristics, except for gender distribution. Both groups showed significant improvement during follow-up; however, patients treated with esketamine exhibited a faster and greater reduction in suicidal ideation and depressive symptoms. After one month of treatment, the mean suicide risk score decreased by 71% in the esketamine group compared with 42.3% in the other group. The NNT to prevent one case of high suicide risk was 1.35. Functional improvement was comparable between groups.

Conclusions

Treatment with intranasal esketamine was associated with clinically relevant improvements in depressive symptoms and suicidal behaviour compared with other pharmacological strategies. These findings suggest that esketamine may represent a rapid and effective fourth-line therapeutic option for this particularly severe population in routine clinical practice. However, given the observational design, the limited sample size and the duration of follow-up, these results should be interpreted with caution, and further prospective, controlled and longer-term studies are needed to confirm these findings and to better understand the long-term effectiveness and safety of esketamine in patients with TRD and a high risk of suicide.

References

Tondo, L., Isacsson, G., & Baldessarini, R. J. (2003). Suicidal behaviour in mood disorders: Risk and prevention. CNS Drugs, 17(7), 491–511.
Fu, D. J., Ionescu, D. F., Li, X., Lane, R., Lim, P., Sanacora, G., Hough, D., Manji, H., Drevets, W. C., & Canuso, C. M. (2020). Esketamine nasal spray for rapid reduction of depressive symptoms in major depressive disorder with acute suicidal ideation or behavior: Pooled analysis of ASPIRE I and II. Journal of Clinical Psychiatry, 81(3), Article 19m13191. https://doi.org/10.4088/JCP.19m13191