To the Editor:
The serotonin syndrome is a life-threatening constellation of signs and symptoms as a result of serotoninergic agents. Clozapine is an atypical antipsychotic agent with antagonistic effect on serotonin receptor subtype 2A (5HT2A).Citation1,Citation2 Withdrawal of clozapine with concomitant serotoninergic agents use may increase risk for the serotonin syndrome. We report a case of serotonin syndrome precipitated by abrupt clozapine withdrawal in conjunction with sertraline use.
A 62-year-old man with known obsessive–compulsive disorder (OCD) was admitted to a psychiatric unit in a tertiary care hospital for treatment of acute psychosis. He was prescribed clozapine 12.5 mg/day and clonazepam 0.5 mg/day. The dose of clozapine was gradually increased, reaching 50 mg/day by hospital day 20. For OCD, he received sertraline 50 mg/day which was gradually increased to 150 mg/day by hospital day 14. After successful psychosis resolution for two weeks, clozapine was abruptly discontinued on hospital day 35.
On hospital day 38, he developed fever, agitation, diaphoresis and tremor in his hands and feet. His vital signs were temperature, 39.1°C; heart rate, 90 beats per minute; blood pressure, 130/70 mmHg; and respiratory rate, 16 times per minute. On physical examination, he was alert but agitated, restless, and responded only to simple commands. His pupils were 4 mm and reactive to light bilaterally. Physical examination revealed increased muscle tone, fine tremor in both hands and feet, hyperreflexia in all extremities, and bilateral clonus at the ankles. He had no neck stiffness, a negative Babinski sign, and no other localizing signs. The remainder of the physical examination was unremarkable.
Investigations included complete blood count, urinalysis, chest x-rays, hemoculture, thyroid function test, MRI brain, and cerebrospinal fluid study and culture. All the investigation results were unremarkable.
Without evidence of bacterial infection, antibiotics were not administered. He received clonazepam 2 mg/day and quetiapine 50 mg/day for restlessness as well as intravenous fluids for supportive treatment. On hospital day 44, serotonin syndrome was suspected. Sertraline was discontinued and a loading dose of oral cyproheptadine 8 mg was administered. Three hours after administration of cyproheptadine, he was alert and cooperative. His fever, tremor, clonus, agitation, restlessness, and muscle spasticity resolved. Cyproheptadine 4 mg every 8 h was administered for maintenance. Thirty hours after the loading dose, mild tremor and low-grade fever (37.9°C) returned. The cyproheptadine dose was increased to 8 mg every 8 h, and the symptoms resolved. Cyproheptadine was continued with the plan to avoid serotoninergic agents for 1 week. He was alert, oriented, clinically well, and subsequently discharged from the hospital.
Onset of serotonin syndrome is usually within 24 h after started or increased dose of serotoninergic agents.Citation3 This case developed serotonin syndrome after continuing the same dose of sertraline for 24 days, and after clozapine was stopped for 3 days. Knowing that clozapine has 5HT2A antagonistic effectCitation2, the abrupt discontinuation of clozapine with the concomitant use of sertraline likely lead to excessive serotonin activity. Serotonin syndrome from combination of serotoninergic agents and clozapine withdrawal had been rarely reported.Citation4,Citation5 The delayed onset in this case can be explained by the effect of persistent clozapine and its active metabolite norclozapine; elimination half-lives are 12 hCitation1 and 13–16 hCitation6, respectively. Clinicians should be aware of the potential risk of serotonin syndrome in rapid clozapine discontinuation especially when simultaneously prescribing high-dose serotoninergic agents.
Serotonin syndrome is usually resolved within 24 h after treatment and discontinuation of serotoninergic agents.Citation3 This case needed antiserotoninergic agent (cyproheptadine) to control symptoms and even sertraline was stopped for more than 24 h. This can be explained by slow clearance of sertraline (half-life, 22–32 hCitation7). Although there is no consensus cyproheptadine regimen for serotonin syndrome, we continued cyproheptadine and avoided serotoninergic agents for 1 week (5 times of sertraline half-life) to ensure sertraline clearance.
Declaration of interest
The authors report no declarations of interest. The authors alone are responsible for the content and writing of the paper.
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