Case Presentation: A 24 year old female with a history of bipolar disorder was admitted for nausea, dizziness and jitteriness that started after intentional ingestion of 4 gm of lamotrigine and 80 mg of aripiprazole, in addition to cocaine abuse. Physical examination revealed diaphoresis, tachycardia, bilateral horizontal nystagmus, and bilateral lower extremity hyperreflexia with inducible patellar and ankle clonus. Laboratory studies were remarkable for mildly elevated liver enzymes that normalized within 24 hours. Urine was positive for codeine, cocaine and lamotrigine. Blood levels of lamotrigine and aripiprazole drawn on the date of admission were within normal limits. She was diagnosed with Serotonin syndrome (SS) with severity classified as mild. Lamotrigine and Aripiprazole were discontinued, and Lorazepam was given for symptomatic management. During the hospital stay, her tachycardia, nystagmus, clonus and hyperreflexia resolved within 48 hours. Her symptoms of nausea, dizziness, jitteriness and diaphoresis also resolved. This was followed by initiation of Divalproex and Risperidone for her psychiatric condition. On follow up, she continued to abuse cocaine, but did not develop similar clinical features.
Discussion: SS is a potentially life-threatening condition associated with increased serotonergic activity in the central nervous system (CNS). It is characterized by mental status changes, autonomic hyperactivity and neuromuscular abnormalities along a spectrum ranging from mild to severe. Using the Hunter criteria, diagnosis is established if the patient has taken a serotonergic agent and meets any one of the following criteria: spontaneous clonus; inducible clonus plus agitation or diaphoresis; ocular clonus plus agitation or diaphoresis; tremor plus hyperreflexia; hypertonia plus temperature above 38ºC plus ocular clonus or inducible clonus. Differential diagnoses include anticholinergic poisoning, malignant hyperthermia, neuroleptic malignant syndrome and sympathomimetic toxicity. SSRIs are perhaps the most commonly implicated medications associated with this syndrome. Our patient developed features of SS after the ingestion of higher than prescribed doses of Lamotrigine and Aripiprazole, in addition to cocaine abuse. None of these agents have strong serotonergic activity by themselves, and the blood levels of lamotrigine and aripiprazole in our patient were within normal limits. However, these agents do have some effect on serotonin neurotransmission. Lamotrigine has a weak inhibitory effect on 5-HT3 receptor, Aripiprazole is a partial agonist at 5-HT1A receptor and an antagonist at serotonin reuptake transporter, and Cocaine increases the release and inhibits the reuptake of serotonin at the synaptic cleft. An extensive literature search on PubMed did not yield any case description of SS induced by these agents alone or in combination. Also, Micromedex and Epocrates do not list this syndrome as an adverse effect for any of these agents.
Conclusions: The pharmacokinetic and pharmacodynamic interactions between Lamotrigine, Aripiprazole and Cocaine can lead to increased CNS serotonergic activity. Hence, SS should be considered in a patient who takes these medications and demonstrates even subtle features of neuromuscular hyperactivity. Management includes discontinuation of the offending agents, supportive care and benzodiazepines for symptom control, with serotonin antagonists being a last resort.