What are the most common medications involved in serotonin syndrome, including Selective Serotonin Reuptake Inhibitors (SSRIs), Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs), Monoamine Oxidase Inhibitors (MAOIs), and triptans?

Most Common Medications Involved in Serotonin Syndrome

Monoamine oxidase inhibitors (MAOIs) play a role in most cases of serotonin syndrome and pose the highest risk, especially when combined with other serotonergic medications. 1

Primary Drug Classes Associated with Serotonin Syndrome

Highest Risk Medications

1. MAOIs

   • Highest reporting odds ratio (ROR 45.99) among all drug classes 2
   • Examples: phenelzine, isocarboxazid, moclobemide, tranylcypromine, linezolid (antibiotic with MAOI properties)
   • MAOIs should never be combined with any other serotonergic drug 1, 3

2. Selective Serotonin Reuptake Inhibitors (SSRIs)

   • Second highest reporting odds ratio (ROR 32.66) 2
   • Examples: fluoxetine (Prozac), paroxetine (Paxil), sertraline (Zoloft), citalopram (Celexa), escitalopram (Lexapro), fluvoxamine (Luvox)
   • Most frequently reported class in adverse event databases 2

3. Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs)

   • Examples: venlafaxine, desvenlafaxine, duloxetine
   • Similar risk profile to SSRIs 1

Other Significant Contributors

1. Opioid Analgesics (particularly certain types)

   • Phenylpiperidine series: pethidine (meperidine), tramadol, methadone
   • Dextromethorphan (cough suppressant)
   • These act as weak serotonin reuptake inhibitors 4
   • Note: Morphine, codeine, oxycodone, and buprenorphine do NOT precipitate serotonin syndrome with MAOIs 4

2. Triptans

   • Examples: sumatriptan, eletriptan
   • FDA warning exists for combination with SSRIs/SNRIs, though evidence is limited 5, 6

3. Other Medications and Substances

   • Tricyclic antidepressants
   • Tryptophan supplements (high ROR of 44.19) 2
   • St. John's Wort
   • Certain stimulants (amphetamines, methylphenidate)
   • Certain antihistamines (chlorpheniramine)
   • Illicit drugs (ecstasy, methamphetamine, cocaine, LSD) 1

High-Risk Drug Combinations

The most dangerous combinations that frequently trigger serotonin syndrome are:

1. MAOIs + SSRIs - highest risk combination 7
2. MAOIs + SNRIs
3. MAOIs + Tricyclic antidepressants
4. MAOIs + Tryptophan
5. MAOIs + Pethidine (meperidine) 7
6. Two or more non-MAOI serotonergic drugs in combination 1

Clinical Presentation and Diagnosis

Serotonin syndrome typically presents within 24-48 hours after starting or combining serotonergic medications with:

• Mental status changes: confusion, agitation, anxiety
• Neuromuscular abnormalities: tremors, clonus (most common sign, present in 57% of cases), hyperreflexia, muscle rigidity 1
• Autonomic hyperactivity: hypertension, tachycardia, arrhythmias, tachypnea, diaphoresis, shivering, vomiting, diarrhea 1

Severe cases can progress to:

• Fever (temperature >41.1°C)
• Seizures
• Arrhythmias
• Unconsciousness
• Death 1

Risk Factors

• Age: Higher reporting odds ratio in adults over 65 years 2
• Sex: Higher reporting in males 2
• Polypharmacy: Taking multiple serotonergic medications
• Dosage increases of serotonergic medications
• Recent addition of a new serotonergic agent

Prevention and Management

1. Avoid high-risk combinations - particularly MAOIs with any other serotonergic agent
2. Observe medication-free intervals when switching between serotonergic drugs:
   • At least 2 weeks after stopping an MAOI before starting another serotonergic drug
   • At least 5 weeks after stopping fluoxetine before starting an MAOI (due to its long half-life) 3
3. Treatment:
   • Discontinue all serotonergic agents
   • Provide supportive care with continuous cardiac monitoring
   • For severe cases: external cooling, sedation, possibly neuromuscular paralysis and intubation
   • Consider cyproheptadine (a serotonin 2A antagonist) for severe cases 1, 7

Clinicians should maintain high vigilance when prescribing any combination of serotonergic medications and report suspected cases to pharmacovigilance systems.