Can Trazodone Be Given with Zyprexa (Olanzapine) and Depakote (Valproate)?
Yes, trazodone can be safely combined with olanzapine and valproate, as this is an established clinical practice supported by guidelines for managing psychiatric conditions, particularly when treating agitation, insomnia, or mood disorders in patients requiring multiple medications. 1
Guideline Support for This Combination
The combination of these three medications is explicitly recognized in clinical practice:
Trazodone with mood stabilizers like valproate (Depakote) is documented as a therapeutic approach for managing agitation and behavioral symptoms, with trazodone dosed at 25 mg initially up to 200-400 mg daily in divided doses 1
Olanzapine with valproate is a well-established combination for bipolar disorder and psychotic conditions, with olanzapine typically started at 2.5 mg daily up to 10 mg daily 1
Valproate serves as a mood stabilizer that can be combined with antipsychotics like olanzapine, with dosing starting at 125 mg twice daily and titrated to therapeutic blood levels (40-90 mcg/mL) 1
Clinical Monitoring Requirements
When using this three-drug combination, specific monitoring is essential:
Monitor liver enzyme levels regularly due to valproate's hepatotoxicity risk 1
Check platelet counts, PT, and PTT as indicated with valproate therapy 1
Watch for excessive sedation since all three medications have CNS depressant effects 2
Monitor for cardiovascular effects, particularly QTc prolongation with olanzapine, especially if other QT-prolonging medications are present 1
Assess for orthostatic hypotension which can occur with both trazodone and olanzapine 1
Pharmacokinetic Considerations
Important drug-drug interactions exist within this combination:
Valproate may increase olanzapine levels through pharmacokinetic interactions, potentially requiring dose adjustments 3
Trazodone does not significantly affect valproate levels and may actually increase valproate brain concentrations, which could be therapeutically beneficial 4
Start with lower doses when combining these medications to minimize additive side effects 2
Specific Precautions
Critical safety considerations for this combination include:
Use caution in patients with premature ventricular contractions when prescribing trazodone 1
Avoid in patients with compromised respiratory function (asthma, COPD, sleep apnea) due to additive CNS depression 2
Exercise special caution in elderly patients who require downward dose adjustments for all three medications 2
Warn patients about avoiding alcohol due to additive psychomotor impairment 2
Allow adequate time for sleep (7-8 hours) when taking this combination at bedtime 2
Documented Clinical Experience
Real-world evidence supports the safety profile:
A case report documented a patient with schizophrenia maintained on olanzapine 20 mg/day and trazodone 50 mg/day, though heat stroke occurred during a heat wave (not directly attributed to the drug combination itself) 5
The combination of valproate with atypical antipsychotics like olanzapine provides synergistic mood-stabilizing effects in bipolar and schizoaffective disorders 3
Dosing Strategy
Recommended approach for initiating this combination:
- Start trazodone at 25-50 mg at bedtime when combined with other CNS depressants 2
- Begin olanzapine at 2.5 mg daily, increasing gradually as tolerated 1
- Initiate valproate at 125 mg twice daily, titrating to therapeutic levels 1
- Titrate each medication separately based on clinical response and tolerability
- Monitor for additive sedation and adjust timing of doses if daytime impairment occurs 2