Spravato for Treatment-Resistant Depression: Efficacy and Sexual Side Effect Profile.

Intranasal esketamine (Spravato) rapidly relieves depression symptoms—often within hours—and improves remission and response rates in treatment-resistant depression (TRD) and severe major depressive disorder. Unlike conventional antidepressants, it works by blocking NMDA receptors to promote synaptogenesis and neuroplasticity. Its use is associated with a very low incidence of treatment-emergent sexual dysfunction (less than 1% of patients), a common side effect of SSRIs and SNRIs. However, esketamine can cause dissociative symptoms and blood pressure changes, and its administration requires in-clinic monitoring under a REMS program. Despite these limitations, it offers a valuable option for patients who do not respond to standard therapies.

Study at a glance

Abstract

Major Depressive Disorder (MDD) and Treatment-Resistant Depression (TRD) are debilitating psychiatric conditions associated with significant psychosocial and economic burdens. Conventional antidepressants, particularly SSRIs and SNRIs, often produce inadequate responses and cause sexual dysfunction, contributing to poor adherence and diminished quality of life. This review aims to evaluate the clinical efficacy, safety, and sexual side effect profile of intranasal esketamine (Spravato) in the treatment of MDD and TRD, highlighting its potential advantages over traditional antidepressants. A narrative literature review was conducted using PubMed, ScienceDirect, Cochrane Library, and Google Scholar. Clinical trials, meta-analyses, and systematic reviews published between 2000 and 2025 were included. Keywords used included "Spravato", "esketamine", "treatment-resistant depression", and "sexual dysfunction.". Clinical trials such as TRANSFORM-2, SUSTAIN-1, and ASPIRE I/II demonstrate that esketamine provides rapid antidepressant effects-often within hours-and improves remission and response rates in TRD. Its NMDA receptor antagonism promotes synaptogenesis and neuroplasticity, distinguishing it mechanistically from monoaminergic antidepressants. Compared to SSRIs/SNRIs, Spravato exhibits a significantly lower incidence of treatment-emergent sexual dysfunction (TESD), with less than 1% of patients reporting such side effects. However, the drug's use is constrained by dissociative symptoms, blood pressure changes, and its mandatory in-clinic administration due to REMS (Risk Evaluation and Mitigation Strategy) requirements. Spravato (esketamine) is an innovative and effective treatment option for TRD and severe MDD, offering rapid symptom relief and a favorable sexual side effect profile. Despite logistical and financial limitations, it represents a critical advancement in personalized psychiatry, especially for patients unresponsive to conventional therapy.