Major
Fluoxetine × Mirtazapine
Selective serotonin reuptake inhibitors×Other antidepressants (NaSSA)
Mechanism
Additive serotonergic effect. Mirtazapine blocks 5-HT2/3 but activates 5-HT1A. Combined with a potent SSRI, serotonin syndrome has been reported, especially at high doses.
Symptoms
Serotonin syndrome: agitation, confusion, tremor, myoclonus, hyperreflexia. Autonomic features: sweating, tachycardia, fever.
Management
The combination is used for augmentation in resistant depression ('California rocket fuel'). Keep doses low: fluoxetine 20 mg, mirtazapine 30 mg/day. Monitor mental status in the early weeks.
Check the full regimen, not just this pair
Opens the checker with these two drugs prefilled. Add the rest of the regimen and recompute additive risks.