Lamotrigine and Zonisamide Do Not Typically Cause Serotonin Syndrome as Monotherapy, But Lamotrigine Has Been Implicated in Rare Cases When Combined with Other Serotonergic Agents
Neither lamotrigine (Lamictal) nor zonisamide (Zonegran) are classic serotonergic medications and do not independently cause serotonin syndrome under normal circumstances. However, lamotrigine has been reported in rare case reports to contribute to serotonin syndrome when combined with other serotonergic drugs, while zonisamide has no documented association with this condition 1, 2.
Lamotrigine and Serotonin Syndrome Risk
Evidence of Rare Association
Lamotrigine has been implicated in serotonin toxicity only in case reports involving overdose or combination with other serotonergic agents, not as a standalone cause 1, 2.
A documented case involved a 17-year-old who developed serotonin toxicity after suicidal ingestion of 1000 mg lamotrigine combined with 400 mg citalopram (an SSRI), presenting with agitation, diaphoresis, tremor, hyperreflexia, myoclonus, and tachycardia 1.
Another case report described serotonin syndrome occurring with higher-than-prescribed doses of lamotrigine combined with aripiprazole and cocaine use, suggesting pharmacokinetic and pharmacodynamic interactions leading to increased CNS serotonergic activity 2.
Clinical Context
The mechanism by which lamotrigine might contribute to serotonin syndrome remains unclear, as it is primarily a sodium channel blocker and does not have direct serotonergic activity 1, 2.
These cases suggest lamotrigine should be considered a potential contributor to serotonin toxicity when combined with known serotonergic drugs, particularly SSRIs, SNRIs, MAOIs, or illicit substances like cocaine 1, 2.
Zonisamide and Serotonin Syndrome Risk
There is no documented evidence linking zonisamide to serotonin syndrome in the available literature.
Zonisamide is a sulfonamide anticonvulsant that works through multiple mechanisms including sodium and calcium channel blockade, but does not have recognized serotonergic properties.
Classic Serotonergic Medications That DO Cause Serotonin Syndrome
For context, the medications with well-established risk of serotonin syndrome include:
MAOIs combined with SSRIs, SNRIs, tricyclic antidepressants, or tryptophan represent the highest-risk combinations 3, 4.
Opioids (particularly tramadol, meperidine, methadone, fentanyl) when combined with antidepressants 5, 6, 7.
Triptans combined with SSRIs or SNRIs, though the risk is considered low and these are sometimes co-prescribed 5.
Ergotamine with opioids poses risk of serotonin syndrome in the perioperative setting 5.
Over-the-counter medications including dextromethorphan, St. John's Wort, and L-tryptophan supplements when combined with prescription serotonergic agents 6, 7.
Clinical Recommendations
Monitoring Considerations
If prescribing lamotrigine alongside SSRIs, SNRIs, MAOIs, or other serotonergic medications, educate patients about serotonin syndrome symptoms: confusion/agitation, muscle twitching/rigidity, fever, rapid heart rate, and profuse sweating 6, 7.
Symptoms typically emerge within 24-48 hours after combining medications or dose increases, making this the highest-risk monitoring period 6, 8, 7.
Myoclonus (muscle twitching) occurs in 57% of serotonin syndrome cases and is the most common finding, while clonus and hyperreflexia are highly diagnostic 8, 7.
Management if Serotonin Syndrome Develops
Immediately discontinue all serotonergic agents including lamotrigine if suspected to be contributing 6, 8, 7.
Provide supportive care with benzodiazepines for agitation, IV fluids, external cooling for hyperthermia, and continuous cardiac monitoring 6, 8, 7.
Consider cyproheptadine (a serotonin antagonist) in severe cases, as approximately 25% of patients require ICU admission with mechanical ventilation 8, 3.
The mortality rate for severe serotonin syndrome is approximately 11%, with complications including rhabdomyolysis, renal failure, seizures, and disseminated intravascular coagulopathy 8, 7.
Key Clinical Pitfall
The most important pitfall is failing to recognize that lamotrigine, while not a classic serotonergic medication, has been implicated in rare cases of serotonin toxicity when combined with other serotonergic drugs 1, 2. This is particularly relevant in overdose situations or when multiple psychotropic medications are prescribed concurrently. Zonisamide does not share this risk based on available evidence.