Personalizing ketamine therapy: Real-world predictors of response to IV ketamine and intranasal esketamine in treatment-resistant depression

🎖️ Top 10% JournalNov 12, 2025Psychiatry research

Factors that predict how people with hard-to-treat depression respond to IV ketamine and nasal esketamine treatments

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Abstract

IV ketamine may reduce depressive symptoms more effectively than intranasal esketamine, especially in patients with severe treatment resistance.

Both IV ketamine and intranasal esketamine significantly lowered depression scores, with a mean change of -8.9 on the MADRS and -4 on the PHQ-9.
IV ketamine led to a greater reduction in MADRS scores compared to esketamine, with an approximate difference of 5 points.
Patients without psychiatric comorbidities experienced the most significant improvement, showing a MADRS change of -22.0.
Those with borderline personality disorder (BPD) had minimal improvement, with a MADRS change of only -3.7.
Males showed more improvement than females on the MADRS, although no difference was found on the PHQ-9 ratings.
Age did not appear to influence treatment outcomes in these patients.

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BACKGROUND: 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.

METHODS: 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.

RESULTS: 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.

CONCLUSIONS: 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.

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