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.