Can the regimen of fluoxetine 10 mg daily, buspirone 15 mg twice daily, glycopyrrolate, serdexmethyl‑/dexmethyl‑phenidate (Azstarys), tizanidine, and alprazolam cause serotonin syndrome?

Risk of Serotonin Syndrome with This Medication Combination

This medication regimen carries a moderate risk of serotonin syndrome due to the combination of fluoxetine (an SSRI) with buspirone (a serotonergic anxiolytic), and this risk warrants close monitoring, particularly in the first 24-48 hours after any dose changes. 1

Primary Serotonergic Agents in This Regimen

The two medications that contribute serotonergic activity are:

• Fluoxetine 10 mg daily: This SSRI increases serotonin availability at the synaptic cleft and is specifically identified as a potentially serious contributor to serotonin syndrome 2
• Buspirone 15 mg twice daily: This medication has variable effects on 5-HT1A receptors and can cause serotonin syndrome when combined with other serotonergic drugs, despite having lower risk as monotherapy 3

The specific combination of fluoxetine and buspirone has been documented to cause serotonin syndrome, with a case report describing a 37-year-old patient who developed confusion, diaphoresis, incoordination, diarrhea, and myoclonus after buspirone was added to fluoxetine 3.

Medications That Do NOT Significantly Contribute

The other medications in this regimen have minimal to no serotonergic activity:

• Azstarys (serdexmethylphenidate/dexmethylphenidate): While stimulants may theoretically increase serotonin syndrome risk when combined with SSRIs, the evidence is limited and this is not a primary concern 1
• Tizanidine: This alpha-2 agonist muscle relaxant does not have serotonergic properties
• Alprazolam (Xanax): Benzodiazepines do not contribute to serotonin syndrome and are actually used therapeutically to manage agitation in serotonin syndrome 1
• Glycopyrrolate: This anticholinergic has no serotonergic activity

Risk Assessment and Monitoring

Symptoms to Monitor For

Educate the patient to immediately report these symptoms, which typically emerge within 24-48 hours after combining medications or dose increases 4, 1:

• Neuromuscular findings: Myoclonus (muscle twitching, occurs in 57% of cases), clonus (especially in ankles), hyperreflexia, tremor, or muscle rigidity 4, 1
• Autonomic instability: Tachycardia, hypertension, fever, profuse sweating, or hot flashes 1, 5
• Mental status changes: Confusion, agitation, restlessness, or altered consciousness 1, 5

Severity Considerations

• Mild cases may present with only tachycardia and hypertension without fever, making diagnosis challenging 1
• Severe cases can progress to seizures, arrhythmias, rhabdomyolysis, renal failure, and death, with approximately 25% requiring ICU admission and an 11% mortality rate 4, 1

Risk Mitigation Strategies

Since this patient is already on both fluoxetine and buspirone:

1. Do not increase doses of either medication without careful consideration and enhanced monitoring 1
2. Avoid adding additional serotonergic agents, particularly:
   • Other antidepressants (SSRIs, SNRIs, tricyclics, MAOIs) 2, 6
   • High-risk opioids (tramadol, meperidine, methadone, fentanyl) 4, 6
   • Over-the-counter medications (dextromethorphan, St. John's Wort, L-tryptophan supplements) 4, 1
3. Monitor closely during the highest-risk period: The first 24-48 hours after any medication changes 4, 1

Common Pitfalls to Avoid

• Misinterpreting early symptoms: Early manifestations of serotonin syndrome (restlessness, anxiety, insomnia) can be mistaken for worsening of the underlying psychiatric condition, leading to inappropriate dose increases that worsen the syndrome 7
• Underestimating over-the-counter medications: Failure to consider dextromethorphan (in cough medicines), St. John's Wort, or other supplements as contributors is a common error 1
• Delayed recognition: The combination of fluoxetine's long half-life (particularly its active metabolite) means serotonin syndrome can develop gradually over several weeks rather than acutely 2, 3

Management if Serotonin Syndrome Occurs

Immediately discontinue all serotonergic agents (fluoxetine and buspirone) if serotonin syndrome is suspected, as the risk of death from untreated serotonin syndrome far outweighs any discomfort from withdrawal symptoms 1:

• Provide supportive care with benzodiazepines for agitation and muscle rigidity 1
• Consider cyproheptadine (12 mg initially, then 2 mg every 2 hours for continuing symptoms) in moderate to severe cases 1
• Arrange immediate hospital evaluation for fever >101°F, severe muscle rigidity, confusion, or rapid heart rate 1