Using Esketamine to Manage Treatment-Resistant Depression
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Reviewed by Dat Tien Nguyen, B.A, ScM.
Translated by Nhi Phuong Quynh Le, B.A |
Posted on December 17th, 2025
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Although many treatments are approved for major depressive disorder, about 35 percent of patients fail to respond to at least two antidepressants. These individuals are classified as having treatment-resistant depression, a condition associated with greater illness burden and a markedly increased risk of suicide. To explore alternative therapies, Janssen funded a study evaluating esketamine for this difficult-to-treat population.
The phase 4 trial enrolled 378 adults with an average age of 45.4 years. All participants had experienced either a single episode or recurrent major depressive disorder without psychotic features within the previous two years. About 60 percent had failed to respond to two antidepressants, and the remainder had not improved despite trying three or more treatments. Their average score on the Montgomery-Åsberg Depression Rating Scale (MADRS) was 37.3 out of 60, indicating severe depression.
Participants were randomly assigned to receive intranasal placebo or esketamine at doses of 56 mg or 84 mg, administered twice weekly. After 28 days, esketamine produced a significantly greater reduction in depressive symptoms, with an average drop of about 13 points on the MADRS compared with a 7-point reduction in the placebo group. Notably, some improvement was observed as early as the day after the first esketamine dose. However, treatment with esketamine was associated with higher rates of side effects, including nausea, dizziness, headache, and feelings of dissociation. While the results highlight esketamine as a promising option for treatment-resistant depression, its use requires careful consideration of these potential adverse effects.
The phase 4 trial enrolled 378 adults with an average age of 45.4 years. All participants had experienced either a single episode or recurrent major depressive disorder without psychotic features within the previous two years. About 60 percent had failed to respond to two antidepressants, and the remainder had not improved despite trying three or more treatments. Their average score on the Montgomery-Åsberg Depression Rating Scale (MADRS) was 37.3 out of 60, indicating severe depression.
Participants were randomly assigned to receive intranasal placebo or esketamine at doses of 56 mg or 84 mg, administered twice weekly. After 28 days, esketamine produced a significantly greater reduction in depressive symptoms, with an average drop of about 13 points on the MADRS compared with a 7-point reduction in the placebo group. Notably, some improvement was observed as early as the day after the first esketamine dose. However, treatment with esketamine was associated with higher rates of side effects, including nausea, dizziness, headache, and feelings of dissociation. While the results highlight esketamine as a promising option for treatment-resistant depression, its use requires careful consideration of these potential adverse effects.