Personalizing ketamine therapy: Real-world predictors of response to IV ketamine and intranasal esketamine in treatment-resistant depression.
Ahmed Z Elmaadawi, Imane Naha, Shruti Prabhudesai, Mohamed Eltohami
Psychiatry Research December 1, 2025 DOI: 10.1016/j.psychres.2025.116821 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Retrospective chart review Peer reviewed |
|---|---|
| Sample size | 200 |
| Population | Adults with treatment-resistant depression treated at a specialized clinic |
| Intervention | Intranasal esketamine |
| Duration | Acute treatment (median 6 infusions for IV ketamine, median 8 sessions for intranasal esketamine) |
| Topics | Depression Esketamine Ketamine |
| Keywords | Retrospective Trd |
| Citations | 2 |
| Key findings | IV ketamine produced a greater reduction in depressive symptoms than intranasal esketamine, especially in highly treatment-resistant patients, but comorbid borderline personality disorder attenuated the benefits of both treatments. |
Abstract
Treatment-resistant depression (TRD) poses significant clinical challenges, often necessitating alternative treatments such as intravenous (IV) ketamine or intranasal esketamine. This study compared the effectiveness of these modalities and examined predictors of treatment response, including comorbidity profile, prior antidepressant failures, age, and gender. A retrospective chart review was conducted on 200 adults with TRD treated with IV ketamine (median 6 infusions) or intranasal esketamine (median 8 sessions) at a specialized clinic. Depression severity was assessed using the Montgomery-Åsberg Depression Rating Scale (MADRS) and the Patient Health Questionnaire-9 (PHQ-9) at baseline and after acute treatment. Multivariable analyses evaluated the impact of treatment type, psychiatric comorbidities (none, anxiety, PTSD, borderline personality disorder [BPD], multiple), number of failed medications, age, and gender on treatment outcomes. Both treatments significantly reduced depressive symptoms (MADRS mean change: -8.9; PHQ-9: -4, p < 0.0001). IV ketamine produced a greater MADRS reduction than esketamine (mean difference ∼5 points, p = 0.03), especially in highly treatment-resistant patients. Comorbidity profile was a strong moderator: patients without comorbidities experienced the greatest improvement (MADRS -22.0), while those with BPD showed minimal response (MADRS -3.7). Sex had some influence over MADRS outcomes, with males improving more than females (p = 0.03), although no sex difference was evident on the patient-rated PHQ-9 (p = 0.45). Patients age had no effect. IV ketamine may offer superior antidepressant effects compared to esketamine, particularly in patients with severe treatment resistance. However, comorbid psychiatric conditions, especially BPD, attenuate the benefits of both ketamine and esketamine. Personalized approaches considering comorbidity profiles are critical to optimizing outcomes in TRD.
Comparable studies
Other observational and cohort studies on esketamine for depression, most cited first.
Citations in the library
Cites 31
- A Randomized Trial of an N-methyl-D-aspartate Antagonist in Treatment-Resistant Major Depression Archives of General Psychiatry August 1, 2006
- Mechanisms of Ketamine Action as an Antidepressant Molecular Psychiatry March 13, 2018
- Efficacy and Safety of Flexibly Dosed Esketamine Nasal Spray Combined With a Newly Initiated Oral Antidepressant in Treatment-Resistant Depression: A Randomized Double-Blind Active-Controlled Study American Journal of Psychiatry May 21, 2019
- Efficacy and Safety of Intranasal Esketamine Adjunctive to Oral Antidepressant Therapy in Treatment-Resistant Depression JAMA Psychiatry December 27, 2017
- Comparative efficacy of racemic ketamine and esketamine for depression: a systematic review and meta-analysis Journal of Affective Disorders September 23, 2020
and 26 more in the library