Intranasal esketamine for treatment resistant depression has emerged as one of the most important new tools for people who have not responded to traditional antidepressants. This treatment, known commercially as Spravato, works differently from standard medications and is given in a supervised clinic setting. Recent research highlights both its benefits and its limitations, offering clarity for clinicians and patients navigating treatment resistant depression.
How Intranasal Esketamine Works
Traditional antidepressants target serotonin and other monoamines, which can take weeks to deliver results. In contrast, intranasal esketamine works through the glutamate system, specifically the NMDA receptor. By briefly blocking this receptor, esketamine triggers a cascade of brain changes that may help restore healthier communication between brain cells. Some researchers also believe there may be additional opioid related effects, although this remains an area of scientific debate.
Unlike intravenous ketamine, intranasal esketamine is delivered through a nasal spray and is always paired with an oral antidepressant. Patients self administer the spray under direct clinical observation and are monitored afterward for safety and symptom changes.
What the Research Shows About Effectiveness
Clinical trials have compared intranasal esketamine plus an antidepressant with a placebo nasal spray plus an antidepressant. After four weeks, the esketamine group achieved a significantly higher remission rate, with about a 37 percent improvement compared to placebo. For many individuals who have cycled through multiple medications without relief, this quicker improvement can be meaningful.
Studies also show that benefits tend to continue with ongoing treatment. When patients who achieved stable remission stayed on intranasal esketamine, their risk of relapse was about 25 percent over six months. When esketamine was stopped, relapse rose to 45 percent. This suggests that maintenance treatment may be important for sustained benefit.
However, not everyone responds equally. People with many prior antidepressant failures often show a lower likelihood of improvement. This highlights the need for careful patient selection and realistic expectations when using intranasal esketamine for treatment resistant depression.
Safety, Side Effects, and Monitoring
Most patients tolerate intranasal esketamine well, but side effects are common. These include dizziness, nausea, headache, sedation, and temporary feelings of dissociation. Importantly, clinical trials have not shown cases of psychosis related to treatment.
Blood pressure increases can occur, with about 13 percent of patients experiencing temporary hypertension. Older adults are particularly vulnerable, which makes pre treatment screening and on site monitoring especially important.
Because the medication is given only in certified clinics, the risk of misuse is minimized. To date, no abuse cases have been reported in the trials reviewed.
Treatment Schedule and Practical Considerations
Intranasal esketamine is typically given twice per week for the first month. After that, treatments usually decrease to once weekly or once every two weeks depending on symptom stability. Many patients stay on long term treatment to prevent relapse.
Cost remains a significant barrier in many regions. Without insurance support, the medication and required clinic time may be financially out of reach for some patients. Clinicians should discuss cost early so patients can plan realistically.
What Clinicians Should Take Away
Intranasal esketamine for treatment resistant depression offers moderate but meaningful benefits for individuals who have not found relief elsewhere. It provides faster symptom improvement for some patients and reduces relapse when used long term. At the same time, clinicians must consider side effects, blood pressure risks, long term treatment needs, and the financial limitations that may affect access.
As research continues, intranasal esketamine will likely become part of a broader toolkit that includes other interventional approaches such as TMS, neurofeedback, and emerging psychedelic therapies. For now, it represents a promising option for a group of patients who urgently need more effective solutions.