Is Mirtazapine an SSRI and Serotonin Syndrome Risk
No, mirtazapine is not an SSRI—it is classified as a noradrenergic and specific serotonergic antidepressant (NaSSA)—and while you should be aware of serotonin syndrome risk, the evidence suggests mirtazapine has minimal serotonergic effects in humans and is significantly less likely to cause serotonin syndrome compared to true SSRIs. 1, 2
Drug Classification
Mirtazapine is NOT an SSRI. It belongs to a different class of antidepressants with a distinct mechanism of action from selective serotonin reuptake inhibitors like fluoxetine, paroxetine, or sertraline. 1
The FDA labels mirtazapine as having serotonergic properties and warns about serotonin syndrome risk, particularly when combined with other serotonergic drugs including SSRIs, SNRIs, triptans, tramadol, fentanyl, lithium, buspirone, amphetamines, and St. John's Wort. 2
Evidence on Serotonin Syndrome Risk
Contradictory Evidence Exists
There is a significant discrepancy between FDA labeling and clinical research evidence:
FDA Position: The official drug label warns that mirtazapine can precipitate serotonin syndrome, especially when combined with other serotonergic agents, and lists it among drugs that increase serotonin. 2
Clinical Research Evidence: A systematic review found that mirtazapine exhibits no demonstrable serotonergic effects in humans, does not precipitate serotonin toxicity in overdose by itself, and does not cause serotonin syndrome when combined with MAOIs—which would be expected if it truly raised intrasynaptic serotonin levels. 3, 4
The research indicates mirtazapine is unable to precipitate serotonin toxicity in overdose or when mixed with monoamine oxidase inhibitors, suggesting it may not elevate serotonin in the manner initially assumed from animal studies. 3
Case Reports Show Rare Risk
Despite the systematic review findings, isolated case reports document serotonin syndrome when mirtazapine was combined with:
- Venlafaxine and tramadol (triple combination) 5
- Olanzapine (complicated by rhabdomyolysis and acute renal failure) 6
- Fluvoxamine (possibly due to pharmacokinetic interaction where fluvoxamine inhibited mirtazapine metabolism) 7
Practical Clinical Guidance
When to Be Cautious
You should monitor for serotonin syndrome when mirtazapine is combined with:
- MAOIs: Contraindicated; do not use within 14 days of each other. 2
- Multiple serotonergic agents: The risk increases substantially when combining three or more serotonergic drugs (e.g., mirtazapine + SSRI + tramadol). 5
- Strong CYP inhibitors with other serotonergic drugs: Fluvoxamine can increase mirtazapine levels, potentially increasing risk when combined with additional serotonergic agents. 7
Signs and Symptoms to Monitor
Watch for the classic triad within 24-48 hours of starting or dose changes: 1, 2
- Mental status changes: Agitation, confusion, delirium, hallucinations
- Autonomic instability: Tachycardia, labile blood pressure, hyperthermia, diaphoresis, flushing, dizziness
- Neuromuscular abnormalities: Tremor, rigidity, myoclonus, hyperreflexia, clonus, incoordination
Management if Serotonin Syndrome Occurs
Immediately discontinue all serotonergic agents and provide supportive care: 2
- Stop mirtazapine and any concomitant serotonergic drugs
- Provide hospital-based supportive care with continuous cardiac monitoring and IV fluids
- Administer benzodiazepines for agitation and muscle rigidity
- In severe cases, use cyproheptadine (serotonin antagonist) and consider ICU admission
- Provide external cooling for hyperthermia
Common Pitfalls
Assuming mirtazapine is an SSRI: This leads to incorrect assumptions about its mechanism and side effect profile. Mirtazapine does not cause the typical SSRI side effects like sexual dysfunction or GI disturbances at the same rate. 1
Over-estimating serotonin syndrome risk with mirtazapine monotherapy: The systematic review evidence suggests mirtazapine alone poses minimal risk, though the FDA label maintains caution. 3, 4
Ignoring drug interactions that increase mirtazapine levels: Fluvoxamine and other strong CYP inhibitors can increase mirtazapine concentrations, potentially increasing risk when other serotonergic drugs are present. 7
Forgetting non-psychiatric serotonergic drugs: Tramadol, fentanyl, dextromethorphan (in cough medicines), and triptans (for migraines) all increase serotonin syndrome risk. 2, 5
Bottom Line for Clinical Practice
While the FDA requires warnings about serotonin syndrome with mirtazapine, the actual clinical risk appears lower than with true SSRIs based on overdose data and systematic reviews. However, exercise appropriate caution when combining mirtazapine with multiple other serotonergic agents, avoid MAOIs entirely, and monitor patients closely during the first 24-48 hours after initiation or dose changes. 2, 3, 4