Is Mirtazapine Safe to Combine with Aripiprazole?
Yes, combining mirtazapine with aripiprazole is safe and well-tolerated, with evidence suggesting this combination may accelerate antidepressant response in treatment-resistant depression while potentially mitigating certain side effects of each medication. 1
Evidence for Safety and Efficacy
Direct Evidence from Combination Studies
A 4-week open-label study specifically evaluated mirtazapine (45 mg/day) combined with aripiprazole (15 mg/day) in 40 depressed inpatients without psychotic features 1. Key findings include:
- No serious safety concerns emerged from the combination therapy 1
- No extrapyramidal side effects were observed in the combination group 1
- The combination accelerated the onset of antidepressant action compared to mirtazapine monotherapy, particularly in treatment-resistant depression 1
- Aripiprazole addition reduced mirtazapine-induced weight gain (decreased body mass index increase) 1
- Mirtazapine had favorable effects on aripiprazole-induced akathisia 1
Mechanistic Compatibility
The pharmacological profiles of these medications are complementary rather than conflicting:
- Mirtazapine enhances noradrenergic and serotonergic neurotransmission via α2-adrenergic receptor blockade, while also blocking 5-HT2 and 5-HT3 receptors 2, 3
- Aripiprazole acts as a partial agonist at D2 and 5-HT1A receptors and antagonist at 5-HT2A receptors 1
- These mechanisms do not create overlapping risks for serotonin syndrome or other serious drug interactions 1
Guideline Context for Polypharmacy
While guidelines emphasize avoiding unnecessary polypharmacy in bipolar disorder 4, they acknowledge that multiple agents are often required 4. Aripiprazole is FDA-approved for acute mania in adults 4, and antidepressants may be useful adjuncts for depression when combined with mood stabilizers 4.
Recent evidence on antipsychotic polypharmacy in schizophrenia demonstrates that certain combinations can reduce psychiatric hospitalization and mortality risks 4. Specifically, aripiprazole combinations showed favorable outcomes in large-scale studies 4.
Important Clinical Considerations
Serotonin Syndrome Risk is Minimal
While mirtazapine can contribute to serotonin syndrome when combined with multiple serotonergic agents (particularly SSRIs, SNRIs, or tramadol) 5, 6, aripiprazole does not significantly increase serotonin activity in a manner that would precipitate this syndrome 1. The documented cases of serotonin syndrome with mirtazapine involved combinations with venlafaxine, tramadol, or other potent serotonin reuptake inhibitors 5, 6—not atypical antipsychotics.
Bipolar Depression Caution
In patients with bipolar disorder, antidepressants should only be used with concurrent mood stabilizers to prevent mood destabilization or manic episodes 4. Since aripiprazole is approved for acute mania 4, it provides mood stabilization in this combination.
Monitoring Parameters
- Weight and metabolic parameters: Both medications can affect weight, though aripiprazole may mitigate mirtazapine's weight gain 1
- Akathisia: Monitor for restlessness, though mirtazapine may reduce this aripiprazole side effect 1
- Sedation: Mirtazapine causes sedation, particularly at lower doses; evening dosing is recommended 3
- Blood pressure and heart rate: Routine monitoring as with any psychotropic combination 2
Dosing Considerations
The studied and effective combination used mirtazapine 45 mg/day with aripiprazole 15 mg/day 1. Mirtazapine should be started at 15 mg/day for 4 days, then increased to 30 mg/day, with further titration to 45 mg/day if needed 2.
Clinical Bottom Line
This combination is particularly valuable for treatment-resistant depression, where it may provide faster symptom relief than monotherapy while maintaining a favorable safety profile 1. The mutual mitigation of side effects (aripiprazole reducing weight gain, mirtazapine reducing akathisia) makes this a rational polypharmacy approach 1.