Life-Threatening Serotonin Syndrome in a Patient With Chronic Heart Failure and CYP2D6*1/*5

Abstract

We report a case of serotonin syndrome that occurred in a patient with chronic heart failure associated with a panic disorder. The 39-year-old Japanese man had been treated with paroxetine at 20 mg/d for 1 1/2 years. He presented with rhabdomyolysis, renal failure, fulminant liver failure, cardiac conduction disturbance, and disseminated intravascular coagulation, as well as conventional symptoms of serotonin syndrome including alterations in cognition (disorientation, confusion) and behavior (restlessness), autonomic nervous system dysfunction (fever, shivering), and abnormal neuromuscular activity (ataxia, hyperreflexia, myoclonus). All medications prescribed before hospital admission were discontinued. After 24 hours of continuous venovenous hemofiltration, diuresis resumed and renal and liver function improved rapidly. Disorientation, restlessness, hyperreflexia, and myoclonus abated slowly over the next 72 hours. The patient's anxiety subsided more slowly, and he recovered completely 1 week later. The plasma concentration of paroxetine was elevated far above the upper limit of the therapeutic range. The patient had cytochrome P-450 (CYP) 2D6*1/*5, a heterozygosity of an inactivated allele of CYP2D6, which metabolizes paroxetine. The patient was determined to be an intermediate metabolizer who was potentially vulnerable to paroxetine, a major inhibitor of CYP2D6. Heart failure is often accompanied by psychiatric disorders. A wide range of drugs commonly prescribed for these conditions, including beta-blockers, antiarrhythmics, and antidepressants, are metabolized by CYP2D6. Genetic screening for CYP2D6 in patients with these conditions may prevent life-threatening drug intoxication.

Rhabdomyolysis after Prolonged Suspension in a Cave

“…11,12 Shivering has been implicated, but shiveringassociated muscle damage has been more commonly seen in hyperthermic syndromes such as malignant hyperthermia, neuroleptic malignant syndrome, and serotonin syndrome. 11,13 We believe that this person's rhabdomyolysis was likely caused by deoxygenated blood in the lower limbs secondary to being passively suspended in a harness for a prolonged time. Rhabdomyolysis has been described in other victims immobilized on rope.…”

“…11,12 Shivering has been implicated, but shivering-associated muscle damage has been more commonly seen in hyperthermic syndromes such as malignant hyperthermia, neuroleptic malignant syndrome, and serotonin syndrome. 11,13…”

Ticlopidine-Induced Cholestatic Inflammatory Hepatitis: New Insights into Pathogenetic Mechanisms of Drug-Related Hepatotoxicity

“…The previous studies suggest a key role of the immune system in the development of ticlopidineinduced liver damage (18)(19)(20)(21)(22)(23)(24)(25)(26)(27). Few results from [11][12][13][14] N/A N/A N/A past research suspected the contribution of cytochrome P450 enzyme system variability to drug-induced hepatotoxicity (28)(29). The genetic polymorphism of certain cytochrome P450 enzymes lead to differences in actual drug metabolism.…”

“…The genetic polymorphism of certain cytochrome P450 enzymes lead to differences in actual drug metabolism. The evidence from published studies showed that "slow metabolizers" have increased susceptibility to drug-induced toxicity (11,(28)(29). We aimed to investigate the role of cytochrome CYP2C 19 genetic polymorphism in the development of ticlopidineinduced cholestatic hepatitis and relate it to the specific immune reactivity and the inducement of necrosis and apoptosis as possible mechanisms of liver damage.…”

Pharmacokinetic Pharmacogenetic Prescribing Guidelines for Antidepressants: A Template for Psychiatric Precision Medicine

“…As reported previously by Alderman et al, 42 a single-point pharmacokinetic study by Nichols et al 43 found that when treated with paroxetine, healthy controls had a 419% increase in the CYP2D6 substrate desipramine AUC and a 90% increase in peak plasma concentration in comparison to desipramine substrate alone. Sato et al 44 described a case of serotonin syndrome treated with paroxetine at 20 mg/d. The plasma concentration of paroxetine was substantially elevated (70 ng/mL; reference range, <23 ng/ mL), which was attributed in part to the patient's CYP2D6 genotype of intermediate metabolizer.…”