In a patient with a history of substance‑use disorder who is receiving Spravato (esketamine) and has improved depression but new‑onset anxiety, how should the management be approached?

Management of New-Onset Anxiety in Spravato Patient with History of SUD

Continue Spravato under enhanced monitoring while addressing the new-onset anxiety as a known adverse effect of esketamine, recognizing that anxiety is explicitly listed as a potential side effect in the FDA label and that the drug has demonstrated efficacy in patients with comorbid anxiety symptoms.

Understanding the Clinical Context

The FDA label for Spravato explicitly warns that the medication "may cause...anxiety" as a direct adverse effect 1. This is critical information—your patient's new anxiety may be treatment-emergent rather than a separate psychiatric condition. However, the presence of a history of substance use disorder adds complexity, as the FDA label specifically states that "individuals with a history of drug abuse or dependence may be at greater risk for abuse and misuse of SPRAVATO" and that "careful consideration is advised prior to use of individuals with a history of substance use disorder" 1.

Key Decision Points

1. Assess Whether Anxiety is Esketamine-Related or Independent

Look specifically for:

• Temporal relationship: Does anxiety occur primarily within 2 hours post-dose (suggesting acute dissociative/anxiogenic effects)?
• Pattern: Is it persistent throughout the week or dose-related?
• Characteristics: Dissociative symptoms ("feeling disconnected from yourself, your thoughts, feelings, space and time"), disorientation, or feelings of being "spaced out" suggest drug-related anxiety 1

2. Monitor for Abuse/Misuse Red Flags

Given the SUD history, actively screen for:

• Drug-seeking behaviors
• Requests for dose escalation beyond clinical indication
• Symptoms that Spravato "may produce" including "anxiety, dysphoria, disorientation, insomnia, flashback, hallucinations" 1
• The FDA mandates "monitoring for signs of abuse and misuse is recommended" 1

Management Algorithm

If Anxiety Appears Esketamine-Related (Acute, Dose-Dependent):

1. Optimize dosing: Consider dose reduction if patient is on higher doses (84 mg). The FDA label notes that 112 mg doses were associated with significantly higher scores for dissociative symptoms compared to 84 mg 1

2. Extend monitoring: The standard 2-hour post-dose observation may need extension in this patient given both the anxiety and SUD history 1

3. Continue treatment: Research demonstrates that esketamine maintains efficacy in patients with comorbid anxiety. A post-hoc analysis of TRANSFORM-2 showed that 72% of patients had baseline comorbid anxiety, and esketamine demonstrated significant MADRS reductions regardless of anxiety presence (mean change -21.0 in those with anxiety) 2

If Anxiety Appears Independent (Persistent, Not Dose-Related):

1. Add evidence-based adjunctive therapy: Per recent systematic review evidence, combined CBT and pharmacotherapy is superior to usual care plus pharmacotherapy for patients with comorbid conditions 3. Specifically, initiate CBT or another evidence-based psychotherapy alongside continuing Spravato and the oral antidepressant.

2. Consider anxiolytic augmentation: Recent evidence suggests that atypical antipsychotics (aripiprazole, brexpiprazole, quetiapine XR) have demonstrated improvement in both depression and anxiety symptoms in MDD patients with anxiety 4. However, avoid benzodiazepines given the SUD history.

3. Do not discontinue Spravato prematurely: Multiple studies show esketamine reduces anxiety symptoms over time with continued treatment. A 2026 systematic review found that "es/ketamine is associated with a reduction of anxiety...these effects are sustained, especially with repeated doses and maintenance treatment" 5

Critical Safety Considerations

Enhanced monitoring is mandatory given the SUD history. Recent real-world data from 30,670 esketamine users showed that those with comorbid SUD had significantly elevated risks for adverse outcomes including self-harm (HR 2.99), suicide attempt (HR 2.13), emergency visits (HR 1.78), and hospitalization (HR 1.70) 6. This doesn't mean discontinuation is required, but rather that:

• Maintain enrollment in the SPRAVATO REMS Program (required by FDA) 1
• Ensure 2-hour minimum post-dose monitoring at each visit
• Schedule more frequent follow-up visits between Spravato sessions
• Actively assess for suicidal ideation at each contact, as "antidepressant medicines may increase suicidal thoughts and actions" 1

Encouraging Evidence for Continuation

The presence of SUD history should not automatically disqualify continued Spravato use. A 2025 case report documented a patient with MDD and polysubstance use (daily opioids, intermittent methamphetamine) who achieved complete abstinence and return to work after 6 months of esketamine treatment, with PHQ-9 scores dropping from 24 to 4 7. A 2026 narrative review concluded that "esketamine holds potential as a dual-action therapeutic in patients with TRD and comorbid addiction" by potentially reducing drug-seeking behavior and attenuating cravings 8.

Common Pitfalls to Avoid

• Don't discontinue Spravato solely due to anxiety emergence without first determining if it's dose-related and transient
• Don't prescribe benzodiazepines for the anxiety given the SUD history and potential for CNS depression interaction 1
• Don't reduce monitoring frequency despite depression improvement—the SUD history mandates sustained vigilance 6
• Don't ignore the possibility of relapse to substance use, as anxiety may be an early warning sign

1, 2, 5, 6