Selected Topics: ToxicologyTreatment of the serotonin syndrome with cyproheptadine☆
Introduction
With the increasing use of the serotonin re-uptake inhibitors (SSRIs) and the reversible, monoamine oxidase-A inhibitor moclobemide in the treatment of depression, there have been numerous reports of adverse drug interactions occurring when these medications have been ingested alone or in combination with other serotonin enhancing agents 1, 2, 3, 4. Excessive stimulation of serotonin-5-hydroxytryptamine (5HT)-1a or 5HT-2 receptors in the central nervous system is thought to mediate these reactions, which may be mild to severe (3). This syndrome has been labeled “the serotonin syndrome.” It is manifested clinically by the presence of alterations in mental status, autonomic instability, and neuromuscular abnormalities such as tremor, hyperreflexia, myoclonus, and agitation (4). We report five cases of the serotonin syndrome, treated with cyproheptadine, a histamine-1 receptor blocking agent with additional non-specific serotonin receptor blockade effects.
In this descriptive case series, five non-consecutive female patients (age range 17 to 69 years) presented with signs and symptoms consistent with the serotonin syndrome. Drugs ingested and patient clinical signs are presented in Table 1. All patients were treated with cyproheptadine. The clinical course of each patient is described in detail.
The patient was a 42-year-old female with a history of depression treated with moclobemide and sertraline. She presented to the emergency department (ED) 2 h following the ingestion of 1050 mg moclobemide, 750 mg sertraline, and 54 mg diazepam. On initial examination, the patient was afebrile and drowsy but easily rousable with a Glasgow coma scale (GCS) of 14. Vital signs were: blood pressure 119/60 torr, pulse 110 beats/min, and respirations 18 breaths/min. Three hours post-ingestion the patient complained of nausea, vomiting, and that her “jaw was stiff.” She was noted to be diaphoretic, restless, agitated, and confused. The limbs were generally rigid and she exhibited recurrent flexed posturing of the arms and legs. Eight milligrams of cyproheptadine were administered via a nasogastric tube. Over the next 2 h the patient’s rigidity and abnormal posturing ceased. She remained drowsy, but was fully oriented for the remainder of her admission. The patient remained well and discharged herself from hospital 36 h post-ingestion.
A 69-year-old female with a background of depression presented to the ED with a 2 h history of nausea, vomiting, diarrhea, and colicky abdominal pain. This was associated with generalized flushing, sweating, and uncontrollable restlessness. The patient had commenced moclobemide 75 mg tid 3 weeks earlier for depressive symptoms. She was prescribed paroxetine 20 mg daily by a second medical practitioner 2 days prior to presentation, having ingested 20 mg one h prior to the onset of symptoms. On examination, the patient was afebrile, alert and oriented. Vital signs were: blood pressure 181/80 torr, pulse 112 beats/min, and respirations 20 breaths/min. She was generally flushed and diaphoretic, restless, and vomiting. Pupils were 4 mm in diameter and reactive. The patient exhibited generalized hyperreflexia. There was no myoclonus. Abdominal examination revealed mild epigastric tenderness without rebound or guarding. Cyproheptadine (8 mg) was administered orally. Within 2 h the patient was no longer restless, flushed, or diaphoretic. Gastrointestinal symptoms completely resolved. Subsequent abdominal ultrasound examination was unremarkable. The patient was admitted for observation overnight with no recurrence of symptoms.
A 43-year-old female with a history of depression maintained on moclobemide 150 mg tid was commenced on paroxetine 40 mg daily on the day prior to presentation. She ingested moclobemide 150 mg and paroxetine 40 mg on the morning of presentation. Within 2 h she developed nausea, diarrhea, blurred vision, sweating, tremor, and muscular jerking. On arrival to the ED, the patient was restless and anxious. She was afebrile, alert and oriented, with 7 mm dilated pupils. Vital signs were: blood pressure 140/80 torr, pulse 80 beats/min, and respirations 24 breaths/min. Diaphoresis, flushing, generalized tremor and hyperreflexia were apparent. Trismus developed in the ED. Intravenous diazepam, 10 mg, did not relieve the symptoms. Cyproheptadine, 8 mg, was subsequently administered orally with resolution of symptoms over the next 2 h. The patient was observed for 24 h with no recurrence of symptoms.
A 17-year-old female presented to the ED with a history of ingestion of 7 × 20 mg paroxetine 6 h prior to arrival. On examination, vital signs were blood pressure 140/100 torr, pulse 110 beats/min, respirations 30 breaths/min, and temperature 37.1°C. She was conscious, vomiting, but unable to talk, and had unreactive dilated pupils. Neurologic examination revealed generalized hypertonia with myoclonic jerking of the lower limbs and ankle clonus. Cyproheptadine 4 mg was administered orally with resolution of symptoms, except mild hypertonia, in 1 h. The hypertonia resolved following two further 4 mg doses of cyproheptadine at 8 h intervals.
A 43-year-old female with a history of depression was brought to the ED by her husband following ingestion of 1875 mg of venlafaxine 20 h earlier. She was noted to have a brief episode of generalized jerking movements 14 h post-ingestion at home. Three hours later, sweating, restlessness, and confusion were apparent. On arrival at the ED, the patient was flushed, diaphoretic, agitated, and mute. Vital signs were: blood pressure 130/70 torr, pulse 163 beats/min, respiration 30 breaths/min, and tympanic temperature 37.9°C. The patient had roving eye movements with 7 mm non-reactive pupils. Hyperreflexia, hypertonia, and lower limb myoclonus were apparent. Five milligrams of diazepam was administered i.v. without effect. Cyproheptadine 8 mg orally was subsequently administered. Over the next 2 h agitation, hyperreflexia, myoclonus, and mutism resolved. The patient was alert and cooperative, but still had a fine resting tremor and shivering with a temperature of 38°C. A further 4 mg of cyproheptadine was administered with complete resolution of symptoms and signs over the next 6 h. A further three doses of cyproheptadine were administered over the next 24 h with the patient remaining asymptomatic during this period.
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Discussion
The serotonin syndrome, initially described experimentally in rats given monoamine oxidase inhibitors and l-tryptophan, results from overstimulation of 5HT-1a and possibly 5HT-2 receptors in the central nervous system 3, 5. Human reports consistent with this syndrome, but unrecognized as such, are present in the medical literature as early as the 1950s (6). The serotonin syndrome in humans is characterized by the presence of a mixture of clinical features, falling into three broad groups:
Summary
Cyproheptadine is a 5-HT receptor antagonist that may have utility in the management of patients with mild to moderate cases of the serotonin syndrome. Although all the cases in this report appeared to improve rapidly following administration of this agent, its efficacy is as yet unreported in more severe forms of this syndrome. Early, aggressive supportive care remains the mainstay of therapy in patients exhibiting severe serotonergic manifestations. It is currently unknown whether the use of
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Toxicology is coordinated by Kenneth Kulig, md, of Toxicology Associates, Denver, Colorado