Paradoxical Depressive Response to Intranasal Esketamine in Treatment-Resistant Depression: A Case Series

BACKGROUND Esketamine is the only pharmacological agent with glutamatergic neuromodulator properties approved by the US Food and Drug Administration and European Medicines Agency to enhance the effects of serotonin selective or serotonin and norepinephrine reuptake inhibitors. Treatment-resistant depression (TRD) is a challenging and prevalent condition in the psychiatric field, in which patients often experience persistent and severe depressive symptoms, as well as a higher risk of suicidal thoughts and attempts. Esketamine has demonstrated its safety and effectiveness as a pharmacological therapy for TRD. Our report aims to present 2 cases of depressive symptom deterioration and suicide ideation in patients treated with esketamine. CASE REPORT We present 2 cases of TRD that initially responded well to intranasal esketamine but later deteriorated rapidly, with a worsening of depressive symptoms and suicidal ideation. Upon discontinuing esketamine, both patients clinically improved and showed a reduction in suicide ideation. The evaluation of affective symptoms' response to esketamine and evolution was assessed using the Montgomery-Asberg Scale and Clinical Global Impression Severity and Improvement scales. CONCLUSIONS The underlying cause for the paradoxical antidepressant reaction is not entirely clear, but we observed this phenomenon in 2 patients with TRD who were treated with esketamine. Identifications of paradoxical reactions could be difficult in TRD, with highly resistant responses to treatment and suicidal ideation. However, it is relevant to know the prevalence of this phenomenon and for clinicians to be aware of the complications of esketamine treatment.