Serotonin Syndrome With Paroxetine Overdose: A Case Report

Sir: Serotonin syndrome can be a serious complication of treatment with selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants, monoamine oxidase inhibitors (MAOIs), and other serotonergic medications. The syndrome is characterized by the sudden onset of cognitive/behavioral changes (e.g., confusion, agitation, lethargy, coma), autonomic instability (e.g., hyperthermia, tachycardia, diaphoresis, nausea, vomiting, diarrhea, dilated pupils), and neuro-muscular changes (e.g., myoclonus, hyperreflexia, rigidity, trismus). The syndrome usually occurs when 2 or more serotonergic drugs are inadvertently administered or through overdose; it rarely occurs at therapeutic doses of a single drug.^1,2 We report a case of an 18-year-old woman who developed serotonin syndrome resulting from overdose of paroxetine.

Case report

Ms. A, an 18-year-old female patient, was admitted in 2007 for altered mental status and agitation. Her psychiatric history was notable for major depressive disorder (DSM-IV criteria), for which she had begun treatment with paroxetine (20 mg/day) 1 week before admission. Ten hours before admission, she had taken 9 tablets of paroxetine (180 mg) after an argument with her boyfriend. She was found at home by her parents, was noted to be very agitated, and was brought immediately to the emergency department. Twelve pills remained in the prescription box (it had included 28 pills when the prescription was filled). It was stated that she had not taken any other medications or other substances for 3 weeks.

On admission, the patient was confused, disoriented, and agitated. After gastric lavage did not result in recovery of pill fragments, charcoal was administered. Her physical examination was significant for tachycardia (110 beats/minute), hypertension (150/80 mm Hg), tachypnea (22 breaths/minute), elevated body temperature (38.1°C), and generalized anxiousness. Neurologic examination was positive for hyperreflexia, particularly of the lower extremities, and her laboratory results revealed no abnormalities. Computerized tomography of the head showed normal results.

Serotonin syndrome was considered after ruling out infection and cerebrovascular factors as possible etiologies. Paroxetine was stopped, and the patient was aggressively hydrated with intravenous fluids. She was administered 1 dose of alprazolam (2 mg p.o.) and was started on 18 mg/day of cyproheptadine in 3 divided doses. Within 24 hours, the patient's mental status had improved. Treatment was continued with cyproheptadine and intravenous fluids. By the second day on this treatment regimen, the patient's function returned to baseline, and she was discharged from the hospital with psychiatric follow-up.

This case presents a rare incidence of serotonin syndrome occurring after overdose of paroxetine. As such, it highlights the importance for physicians to have a lowered threshold to make the diagnosis when presented with an agitated or confused patient known to be on serotonin-modifying drugs.

Paroxetine³ is an SSRI with anxiolytic properties, and it is one of the most frequently prescribed antidepressants. It is approved for the treatment of generalized anxiety disorder, depression, panic disorder, and social anxiety disorder. Therapeutic doses range from 10 mg/day to a maximum of 60 mg/day; our patient was on 20 mg/day. Common side effects with paroxetine use are nausea, constipation, diarrhea, yawning, and impotence. An adverse effect of paroxetine, as with other SSRIs, is the serotonin syndrome. The symptoms are protean and can easily be missed.¹ Serotonin syndrome is thought to occur as a result of excess stimulation of the serotonin-1A (5-HT_1A) and possibly the 5-HT₂ receptor.⁴

The diagnosis of serotonin syndrome is made on a clinical basis. There are no specific laboratory findings, and blood 5-HT levels are not useful because it is the local concentration at nerve terminals that is responsible for the physiologic effects.^5,6 A strong clinical suspicion, known exposure to serotonergic agents, demonstration of specific signs and symptoms, and exclusion of other medical and psychiatric conditions are required for the diagnosis. The clinical presentation is usually marked by the triad of cognitive/behavioral changes (e.g., confusion, agitation, lethargy, coma), autonomic instability (e.g., hyperthermia, tachycardia, diaphoresis, nausea, vomiting, diarrhea, dilated pupils), and neuromuscular changes (e.g., myoclonus, hyperreflexia, rigidity, trismus).

Key differential diagnoses to the serotonin syndrome are the other potentially fatal hyperthermic syndromes: neuroleptic malignant syndrome (NMS) and malignant hyperthermia.¹ However, important points in history and physical examination facilitate the distinction between the three. NMS is an idiosyncratic reaction to several antipsychotic drugs, e.g., phenothiazines such as chlorpromazine and butyrophenones such as haloperidol.⁷ It is thought to be due to dopamine receptor blockade or removal of exogenous dopaminergic agonists. It usually starts with muscular rigidity followed by hyperthermia and altered consciousness. Unlike the serotonin syndrome, NMS is exclusively caused by dopaminergic drugs and symptoms develop over days and resolve over days to weeks.^1,7 In the serotonin syndrome, the onset and resolution of symptoms occur within hours. Most patients present within 6 hours of increasing dosage, starting a new drug, or taking an overdose.¹ A history of neuroleptic usage combined with the presence of bradykinesia or “lead pipe” rigidity on examination distinguish the syndrome from that caused by serotonin excess.⁷

Malignant hyperthermia is a life-threatening condition that results from a genetic susceptibility to volatile anesthetics such as halothane and neuromuscular-blocking drugs such as succinylcholine. It is due to an abnormally increased release of calcium from the sarcoplasmic reticulum, which is often caused by an inherited mutation in the RYR1 gene.⁶ The syndrome occurs within minutes of exposure to the anesthetic agents, unlike serotonin syndrome, and presents with muscular rigidity, a hypermetabolic state reflecting increased oxygen consumption and increased carbon dioxide production, metabolic acidosis, and hyperthermia.⁸ The onset of symptoms, history of exposure to anesthetic agents, family history, and physical examination positive for skin mottling and hyporeflexia may distinguish malignant hyperthermia from serotonin syndrome.

No specific antidote exists for serotonergic toxicity. Successful management relies upon prevention, early recognition, and supportive care. Prevention is based on knowledge of pharmacology and avoidance of potential drug interactions between 2 serotonergic medications. Specifically, pharmacology and clinical experience have taught us that combinations of serotonergic medications should be avoided and that at least 2 to 4 weeks should pass between discontinuation of an MAOI and initiation of another serotonergic agent.^5,9,10 Early recognition involves a high index of suspicion for the diagnosis in any patient taking serotonergic medication who presents with the constellation of signs and symptoms described above. Acute management is based on 2 simple principles: discontinuation of all serotonergic medications and provision of necessary supportive care. Severe forms of the syndrome may require aggressive measures, including neuromuscular-blocking agents, mechanical ventilation, benzodiazepines (for sedation), and external cooling.¹¹

In addition to supportive care and discontinuation of offending medications, there also may be a role for pharmacologic therapy in the acute management of serotonin syndrome. Specific agents have included benzodiazepines and nonspecific serotonin receptor blockers such as cyproheptadine, chlorpromazine, methysergide, and propranolol. Each of these agents has been credited with shortening the syndrome's duration.¹² Benzodiazepines are not recommended as first-line therapy but might have protective effects via inhibition of serotonergic neurotransmission.¹³ As a first-generation antihistamine, cyproheptadine also has antagonist properties at 5-HT_1A and 5-HT₂ receptors. While no randomized controlled trials have been conducted to evaluate fully the efficacy of cyproheptadine, its use in the treatment of serotonin syndrome has been documented.^10,14

Paroxetine by itself has rarely been shown to cause the serotonin syndrome. It is indispensable that physicians are familiar with the signs and symptoms of serotonin syndrome and should suspect it in anyone with altered mental status who is taking serotonin-modifying drugs. Owing to its variable manifestations, the illness can easily be missed while the patient is subjected to a battery of unnecessary tests. In addition, the offending agent would continue to be administered, leading to an exacerbation of the syndrome with hazardous consequences.