A patient with cannabis-induced psychosis is taking brexpiprazole (Rexulti) 2 mg, which has improved paranoia and psychosis but still has significant anxiety; what non‑benzodiazepine anxiolytic can be added?

Add an SSRI or Buspirone for Residual Anxiety in Cannabis-Induced Psychosis

For residual anxiety in a patient with cannabis-induced psychosis stabilized on brexpiprazole 2 mg, add an SSRI (such as sertraline or escitalopram) as first-line, or buspirone as an alternative non-benzodiazepine anxiolytic.

Rationale and Clinical Approach

Why Not Optimize the Antipsychotic First?

Before adding another medication, consider whether the brexpiprazole dose is optimized. The current 2 mg dose is within the therapeutic range for psychosis 1, and since paranoia and psychosis have improved, the antipsychotic is working for its primary indication. However, brexpiprazole's pharmacological profile—with partial D2 agonism and 5-HT1A partial agonism—theoretically should help with anxiety 2, 3. If anxiety persists despite adequate antipsychotic response, augmentation is appropriate rather than dose escalation, which could increase side effects without targeting the anxiety specifically.

First-Line: SSRIs for Anxiety

SSRIs are the most evidence-based non-benzodiazepine option for anxiety disorders and are commonly used in clinical practice for anxiety symptoms in psychotic disorders. While the provided guidelines 4, 5 don't specifically address anxiety management in substance-induced psychosis, standard psychiatric practice supports SSRIs as first-line anxiolytics with favorable safety profiles:

• Start with sertraline 25-50 mg daily or escitalopram 5-10 mg daily, titrating based on response
• SSRIs have no abuse potential, unlike benzodiazepines
• They don't worsen psychosis and may have modest benefits for negative symptoms
• Allow 4-6 weeks for full anxiolytic effect

Alternative: Buspirone

Buspirone (5-HT1A partial agonist) is a reasonable alternative if SSRIs are contraindicated or not tolerated:

• Start 7.5 mg twice daily, can titrate to 15-30 mg twice daily
• No sedation, no abuse potential, no withdrawal syndrome
• Takes 2-4 weeks for effect
• May theoretically complement brexpiprazole's 5-HT1A activity

What About Other Antipsychotics?

The evidence shows brexpiprazole has a relatively low incidence of akathisia, insomnia, and agitation compared to aripiprazole 3, making it a good choice for this patient. Real-world data confirms reasonable tolerability 6. Switching antipsychotics solely for anxiety—when psychosis is controlled—risks destabilization. The guidelines emphasize maintaining the same antipsychotic once symptoms improve 5.

Cannabis-Specific Considerations

For cannabis-induced psychosis specifically, antipsychotics remain the mainstay 7, 8. Recent data suggests optimal dosing for relapse prevention is typically 0.6-1.4 DDDs/day for most agents 9. Your patient's brexpiprazole 2 mg (approximately 0.5-1.0 DDD depending on indication) is reasonable. The key is ensuring complete cannabis cessation, as continued use dramatically increases relapse risk 10, 9.

Medications to Avoid

• Benzodiazepines: You've already ruled these out appropriately—high abuse potential, especially problematic in substance use populations
• Hydroxyzine/antihistamines: Sedating, anticholinergic, less effective for persistent anxiety
• Gabapentin/pregabalin: While gabapentin showed some promise for cannabis withdrawal 7, these have abuse potential and are not first-line for anxiety in psychosis
• Beta-blockers: Limited to somatic anxiety symptoms, not comprehensive anxiolysis

Common Pitfalls

• Don't add multiple medications simultaneously—start one anxiolytic and assess response over 4-6 weeks
• Screen for akathisia—this can masquerade as anxiety and is treated differently (propranolol, dose reduction) 5
• Verify cannabis abstinence—ongoing use will undermine all pharmacological interventions 9
• Monitor for activation syndrome with SSRIs in the first 2 weeks, though this is less common in patients already on antipsychotics

Implementation Algorithm

1. Confirm brexpiprazole adherence and cannabis abstinence
2. Rule out akathisia (restlessness worse with movement vs. anxiety improved with activity)
3. Start SSRI (sertraline 25-50 mg or escitalopram 5-10 mg daily)
4. Reassess at 2 weeks for tolerability, 6 weeks for efficacy
5. If inadequate response, titrate SSRI dose before considering alternatives
6. If SSRI not tolerated, switch to buspirone 7.5 mg BID