Can Mirtazapine (Remeron) Be Taken with Clozapine?
Yes, mirtazapine can be safely taken with clozapine, and this combination may provide therapeutic benefits for negative symptoms and cognitive dysfunction in schizophrenia. The FDA drug label for Remeron does not list clozapine as a contraindicated or cautioned combination, and multiple clinical studies demonstrate both safety and potential efficacy of this augmentation strategy 1.
Safety Profile of the Combination
The pharmacokinetic interaction between mirtazapine and clozapine is negligible. A study of 24 patients with chronic schizophrenia found that adding mirtazapine 30 mg daily to clozapine (200-650 mg/day) produced only minimal and statistically insignificant changes in clozapine plasma concentrations 2. This means mirtazapine does not meaningfully alter clozapine levels, eliminating concerns about toxicity or loss of efficacy due to drug-drug interactions.
The combination was well-tolerated across multiple studies, with no serious adverse events reported specifically attributable to the drug interaction 2, 3, 4.
Potential Clinical Benefits
Mirtazapine augmentation of clozapine may improve negative symptoms and cognitive function in patients with schizophrenia:
Negative symptoms: A double-blind, placebo-controlled trial demonstrated significant reduction in Scale for Assessment of Negative Symptoms (SANS) total scores (p<0.01), with particular improvement in avolition/apathy and anhedonia/asociality subscales 4
Cognitive enhancement: An 8-week open-label trial showed significant improvement in cognitive performance measured by RBANS total score and immediate/delayed memory subscales (p<0.01) 3. Importantly, these cognitive improvements appeared to be direct effects rather than secondary to mood improvement.
Treatment-resistant cases: A systematic review and network meta-analysis ranked mirtazapine as one of the top three augmentation strategies for clozapine-resistant schizophrenia, alongside ECT and memantine 5
Practical Prescribing Considerations
When combining these medications, monitor for:
Additive sedation: Both drugs cause sedation; mirtazapine is particularly sedating 6, 7. Dose at bedtime and counsel patients about daytime drowsiness.
Weight gain: Both clozapine and mirtazapine are associated with significant weight gain 8. Mirtazapine causes approximately 1.5 kg weight gain on average 8. Consider prophylactic metformin with clozapine 9.
QTc prolongation: The FDA label cautions about using mirtazapine with other QTc-prolonging drugs 1. While clozapine can prolong QTc, this is not an absolute contraindication—use clinical judgment and consider baseline ECG monitoring.
Constipation: Clozapine causes severe constipation and gastrointestinal hypomotility 10. Mirtazapine's anticholinergic effects may worsen this. Implement prophylactic laxative regimens (docusate, senna, macrogols) 10.
Dosing Recommendations
Standard mirtazapine dosing when added to clozapine is 30 mg daily at bedtime 2, 4, 11. This dose was used in most efficacy trials. Start at 7.5-15 mg in elderly or frail patients 6.
Continue clozapine at its established therapeutic dose. No dose adjustment of clozapine is needed when adding mirtazapine 2.
Important Caveats
The evidence base consists primarily of small studies with short durations (6-8 weeks) 11, 12. Larger, longer-term trials are needed.
Most benefit appears in negative symptoms and cognition rather than positive symptoms 3, 4, 11.
This is an augmentation strategy for patients already stabilized on clozapine, not a first-line approach 12.
Avoid combining mirtazapine with MAOIs (contraindicated) and use caution with other serotonergic drugs due to serotonin syndrome risk 1.