Does Spravato Cause Anxiety When Discontinued?
Anxiety is listed as an adverse reaction during Spravato treatment (occurring in 13% of patients), and withdrawal symptoms including anxiety have been reported after discontinuation of ketamine when used frequently at high doses, though no withdrawal symptoms were captured up to 4 weeks after cessation in esketamine clinical trials. 1
Key Evidence from FDA Labeling
The FDA label for Spravato provides critical information about anxiety in two distinct contexts:
During Active Treatment
- Anxiety occurred in 13% of patients receiving Spravato plus oral antidepressant versus 6% receiving placebo plus oral antidepressant 1
- Anxiety was the most common reason for treatment discontinuation (1.2% of all patients across Phase 3 studies) 1
- This represents anxiety as a treatment-emergent adverse effect, not necessarily a withdrawal phenomenon
Upon Discontinuation
The FDA label explicitly states: "There were no withdrawal symptoms captured up to 4 weeks after cessation of esketamine treatment" in clinical trials 1. However, there is an important caveat:
- Withdrawal symptoms have been reported with ketamine (the racemic mixture) after discontinuation of frequently used large doses over long periods 1
- Reported ketamine withdrawal symptoms include: craving, fatigue, poor appetite, and anxiety 1
- The label notes: "Such withdrawal symptoms are likely to occur if esketamine were similarly abused" 1
Clinical Context and Interpretation
The distinction between therapeutic use and abuse patterns is critical here:
At therapeutic doses with proper monitoring: Clinical trial data showed no withdrawal symptoms including anxiety up to 4 weeks post-discontinuation 1
With frequent high-dose or prolonged use: The potential for withdrawal-related anxiety exists based on ketamine data, though this scenario is unlikely in properly supervised clinical settings 1
Relapse vs. Withdrawal: Research suggests that after terminating maintenance treatment, anxiety symptoms may re-emerge 2. This likely represents return of underlying symptoms (relapse) rather than true withdrawal, as esketamine reduces anxiety during treatment 2
Practical Monitoring Recommendations
Monitor patients for:
- Return of baseline depressive and anxiety symptoms (relapse) rather than new-onset withdrawal anxiety
- The FDA requires monitoring for "symptoms and signs of physical dependence upon discontinuation" 1
- Any patient using Spravato more frequently than prescribed or at higher doses requires heightened surveillance
Important Caveats
- Anxiety during treatment is more common than anxiety from discontinuation in clinical practice 1
- The evidence for withdrawal-related anxiety specifically comes from ketamine abuse patterns, not therapeutic esketamine use 1
- Research indicates anxiety symptoms treated by esketamine may return after stopping, but this represents disease recurrence, not withdrawal 2
Bottom line: In patients using Spravato as prescribed under proper medical supervision, clinically significant withdrawal-related anxiety has not been demonstrated in trials. Any anxiety emerging after discontinuation is more likely to represent relapse of underlying symptoms rather than a withdrawal syndrome.