Spravato Treatment or Antidepressants: Which Is Right for You?
Comparing conventional oral medications with FDA-approved esketamine nasal spray for patients battling treatment-resistant depression in the Chicago suburbs.
Key Clinical Takeaways
- Traditional oral antidepressants (SSRIs, SNRIs) target serotonin and norepinephrine, often requiring 4 to 8 weeks to demonstrate clinical benefits.
- Spravato® (esketamine) is an NMDA receptor antagonist that acts on the brain’s glutamate system; the exact way it relieves depression is not known.
- Spravato® is FDA-approved for adults with Treatment-Resistant Depression (TRD), as monotherapy or with an oral antidepressant, and for depressive symptoms in adults with MDD with acute suicidal ideation or behavior, together with an oral antidepressant.
- Self-administered only in REMS-certified healthcare settings under direct observation, with blood pressure checks before and after the dose and at least 2 hours of monitoring.
- Driving restriction: patients should not drive until the next day after a restful sleep and will need someone to drive them home after each session.
When Standard Antidepressants Fall Short
For many individuals, oral antidepressants are effective and life-changing. However, in the NIMH-funded STAR*D study, roughly one-third of participants who stayed in the study had not reached remission after up to four treatment steps.
When two or more antidepressants of adequate dose and duration have not brought enough relief, the condition is commonly described as Treatment-Resistant Depression (TRD). In STAR*D, remission rates were generally lower at later treatment steps. This is where treatments like Spravato® (esketamine) may be worth discussing with your provider.
Key Differences: Spravato® vs. Oral Antidepressants
| Feature | Oral Antidepressants (SSRIs/SNRIs) | Spravato® (Esketamine Spray) |
|---|---|---|
| Neurotransmitter Target | Serotonin, norepinephrine, or dopamine | Glutamate (NMDA receptor antagonism) |
| Clinical Mechanism | Monoamine reuptake inhibition; full effect usually takes 4 to 8 weeks | NMDA receptor antagonist; exact antidepressant mechanism unknown |
| Administration | Daily oral pill at home | In-office nasal spray, twice weekly for the first 4 weeks. TRD: alone or with an oral antidepressant. MDD with acute suicidal ideation or behavior: with an oral antidepressant |
| Safety & Monitoring | Outpatient prescription with regular follow-up visits | REMS-certified healthcare setting; blood pressure checks and at least 2 hours of observation |
| Post-Dose Driving | No routine post-dose restriction; use caution until you know how the medication affects you | Not until the next day after a restful sleep; someone must drive you home |
| Common Side Effects | Weight changes, sexual side effects, insomnia, nausea | Dissociation, dizziness, nausea, sedation, vertigo, increased blood pressure (monitored after each dose) |
The Science of Glutamate and Neuroplasticity
Research has linked chronic depression with changes in synaptic connections in brain areas involved in mood and decision-making. Traditional antidepressants increase the availability of monoamines, and their full effect usually takes several weeks.
In contrast, esketamine blocks NMDA glutamate receptors. Researchers think this may lead to the release of Brain-Derived Neurotrophic Factor (BDNF) and the formation of new synaptic connections (synaptogenesis), but the FDA-approved label states that the mechanism of its antidepressant effect is unknown. In clinical studies, much of the difference from placebo appeared within about 24 hours of the first dose; results vary from person to person.
The In-Office Treatment Experience
Spravato® is never dispensed for home use. It is given only in REMS-certified healthcare settings. Spravato® is offered at our Orland Park and Willowbrook offices. Ask our office about eligibility and next steps.
What to Expect During Your Session:
You will self-administer the nasal spray under the direct observation of a healthcare provider. You will then be monitored for at least two hours, including your breathing (with pulse oximetry), your blood pressure (before the dose, about 40 minutes after it, and afterward as needed) and your overall stability, until you are assessed as ready to leave. Because sedation or dissociation can occur, you will need someone to drive you home after each session.
Authoritative Clinical Sources
- • SPRAVATO® (esketamine) nasal spray FDA-approved Prescribing Information, including Boxed Warning (Janssen Pharmaceuticals, revised March 2026).
- • Rush AJ, et al. Acute and Longer-Term Outcomes in Depressed Outpatients Requiring One or Several Treatment Steps: A STAR*D Report. Am J Psychiatry. 2006;163(11):1905-1917.
- • National Institute of Mental Health (NIMH): Questions and Answers about the NIMH STAR*D Study, All Medication Levels (2006).