Did Internet-Purchased Diet Pills Cause Serotonin Syndrome?
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Did Internet-purchased diet pills cause serotonin syndrome? Phentermine also may have increased patient’s neuroleptic malignant syndrome risk s. G, age 28, presents to a tertiary® careDowden hospital Health Media with altered mental status. Six weeks ago she Mstarted taking phentermine, 37.5 mg/d, to lose weight. Her body mass indexCopyright is 24 kg/mFor2 (normal personal range), use only and she obtained the stimulant agent via the Internet. Her family reports Ms. G was very busy in the past week, staying up until 2 AM cleaning. They say she also was irritable with her 5-year-old son. Two days ago, Ms. G complained of fatigue and nausea without emesis. She went to bed early and did not awaken the next morning. Her sister found her in bed, minimally re- DIONISI sponsive to verbal stimuli, and brought her to the hospital. Patients have used phentermine as a weight-reducing IMAGES/SANDRA GETTY agent since the FDA approved this amphetamine-like © compound in 1960.1 Phentermine’s mechanism of ac- tion is thought to involve dopaminergic, noradrenergic, Kyoung Bin Im, MD and serotonergic effects.2 Stimulation of norepineph- Chief resident Internal medicine and psychiatry combined residency program rine (NE) release is its most potent effect, followed Departments of internal medicine and psychiatry by NE reuptake inhibition, stimulation of dopamine Jess G. Fiedorowicz, MD (DA) release, DA reuptake inhibition, stimulation of Associate in psychiatry serotonin (5-HT) release, and 5-HT reuptake inhibition Department of psychiatry (weak).3 Roy J. and Lucille A. Carver College of Medicine Because phentermine could in theory cause serotonin 4 University of Iowa syndrome, its use is contraindicated with monoamine Iowa City oxidase inhibitors (MAOIs) and not recommended with selective serotonin reuptake inhibitors (SSRIs).5 One case report describes an interaction between fl uox- etine and phentermine that appears consistent with se- rotonin syndrome.6 We are aware of no case reports of Current Psychiatry serotonin syndrome caused by phentermine alone. Vol. 7, No. 7 67 continued For mass reproduction, content licensing and permissions contact Dowden Health Media. 067_CPSY0708 067 6/16/08 3:51:11 PM Box 1 between the serotonergic and dopaminer- Serotonin syndrome: gic systems, which have reciprocal rela- tionships in the CNS.19 Excessive serotonin activity Differentiating between serotonin syn- ternbach7 fi rst summarized serotonin drome and NMS is further complicated Ssyndrome’s clinical presentation in when both antipsychotics and serotonergic a review of 38 cases. The most frequent agents may be implicated.20 Clinical trials Serotonin clinical features include changes in are not feasible because NMS and serotonin syndrome mental status, restlessness, myoclonus, syndrome rarely occur. hyperrefl exia, diaphoresis, shivering, and tremor (Table 1). CASE CONTINUED The clinical syndrome varies in scope Fever follows haloperidol and intensity. Animal models suggest the pathophysiologic mechanism involves Initial workup. Ms. G has no signifi cant medi- brainstem and spinal cord inundation with cal or psychiatric history. She has no history of serotonin, acting on 5-HT1A and 5-HT2A seizures, head trauma, changes in mental sta- receptors. Recent evidence supports a tus, recent travel, tick bites, or mosquito bites. Clinical Point greater role for 5-HT2A receptors.8 Family history is relevant only for a maternal We hypothesize Primary treatment calls for discontinuing aunt with a history of 1 seizure. Ms. G is em- the suspected serotonergic agent ployed and lives with her husband and son. that phentermine and instituting supportive measures. She is not taking other medications, herbal Case reports also suggest using use may increase supplements, or vitamins and does not use to- serotonin receptor antagonists—such bacco, alcohol, caff eine, or illicit drugs. NMS risk through as cyproheptadine, methysergide, adverse drug events chlorpromazine, or propranolol—to clinically On admission, she is somnolent and arous- manage serotonin syndrome, although able only to painful stimuli. Temperature is empiric support is limited.9 36.7°C, blood pressure 89/58 mm Hg, heart The syndrome often improves within rate 73 bpm, and respirations 21/minute. She 24 hours of primary treatment, although does not talk but is cooperative to physical ex- confusion sometimes last for days and amination, which is otherwise unremarkable. 10 death has been reported. Neurologic exam also is unremarkable, with no evidence of meningeal irritation, abnor- This article reports the case of Ms. G, mal refl exes, or muscle tone. Serum ammonia who presented with probable serotonin (51 μmol/L; normal range 7 to 42 μmol/L) is syndrome associated with phentermine slightly elevated. Liver function tests, electro- use and subsequently developed a rapid- lytes, blood urea nitrogen, creatinine, com- onset, superimposed neuroleptic malig- plete blood counts, urinalysis, urine culture, nant syndrome (NMS). We hypothesize and blood cultures are unremarkable. Etha- that phentermine use may increase NMS nol, salicylate, and acetaminophen levels are risk through adverse drug events and dis- negative. Evaluation reveals a positive urine cuss potential pathophysiologic mecha- drug screen only for amphetamines, attribut- nisms and treatment implications. ed to use of phentermine. Chest radiography and head CT are unremarkable. Electroencephalography (EEG) 17 hours Serotonin syndrome vs NMS after admission reveals left anterior temporal Serotonin syndrome is an infrequent and spikes suggestive of seizure activity lasting potentially life-threatening adverse drug 50 seconds. The patient is described as stu- reaction that presumably results from ex- porous but arousable during EEG, and diff use cess serotonin activity (Box 1).7-10 NMS also delta slow waves are superimposed on an is an infrequent and potentially life-threat- alpha rhythm with intermittent diff use delta ening neurologic emergency (Box 2, page bursts. Brain MRI is unremarkable. 70).11-18 Similarities between disorders of Despite no clinical evidence of seizure, Ms. increased serotonergic activity and disor- G is transferred to the cardiac telemetry ward ders of low dopaminergic activity (Table 1) to monitor for potential side eff ects from IV Current Psychiatry 68 July 2008 suggest both may result from an imbalance phenytoin loading, at which time (24 hours 068_CPSY0708 068 6/16/08 3:51:17 PM Table 1 Signs and symptoms of NMS vs serotonin syndrome NMS Serotonin syndrome Onset Insidious, days to weeks Acute (minutes to hours) Resolution Slow, often >1 week Improvement or resolution often within 24 hours Autonomic Fever, tachycardia, diaphoresis, elevated Diaphoresis, shivering, fever, or labile blood pressure, sialorrhea, tachycardia, hypertension, mydriasis tachypnea, incontinence Gastrointestinal Dysphagia, elevated transaminases Diarrhea, nausea, vomiting, elevated ammonia and transaminases Neuromuscular Rigidity, bradykinesia, dysarthria, Clonus, myoclonus, hyperrefl exia, dyskinesias, coarse tremor, ataxia, ataxia, incoordination, rigidity, tremor opisthotonos, oculogyric crisis, rhabdomyolysis Clinical Point Psychiatric Altered mental status, stupor, Altered mental status, agitation, somnolence, mutism hypomania, hyperactivity, restlessness, Diff erentiating somnolence (less common) between serotonin Other Leukocytosis, elevated creatine kinase Leukocytosis (rarely >20K cells/mm3), syndrome and NMS (signifi cant), elevated serum creatinine, elevated creatine kinase (less common), proteinuria, renal failure, disseminated disseminated intravascular coagulation, is diffi cult when both intravascular coagulation metabolic acidosis antipsychotics and NMS: neuroleptic malignant syndrome serotonergic agents Note: Classically reported symptoms are italicized may be implicated after admission) she is found to have inter- Ms. G receives empiric vancomycin, ceftri- mittent sinus tachycardia ≤140 bpm. axone, ampicillin, and acyclovir for possible Antipsychotic therapy. Thirty hours after infectious encephalitis, and lumbar puncture admission—after phenytoin loading and nor- is done emergently. Further laboratory tests malized EEG—Ms. G shows periodic episodes reveal creatine kinase (CK) elevation (17,282 of sudden startling, with repetitive leg shak- U/L, from 270 on admission), leukocytosis ing. Continuous ankle clonus is present bilat- (white blood cell count 16.1K/mm3, from 7.2K erally. She complains of severe paresthesias in on admission), and elevated transaminases her legs and is unable to urinate on her own. (AST 199 U/L, up from 21 on admission; ALT 84 Because of her altered mental status and U/L, up from 19 on admission). prominent lower extremity neurologic signs, MRI of the spine and lumbar puncture are or- dered to rule out epidural abscess, meningitis, and/or encephalitis. Results are normal. Be- Promising New Investigator cause her agitation interfered with these exam- Kyoung Bin Im, MD inations, she was given IV haloperidol, a total 12 mg this day. This paper was among those entered in NMS signs emerge. Forty-eight hours after the 2007 Promising New Investigators admission, Ms. G becomes febrile (38.3°C) competition sponsored by the Neuroleptic and shows tachycardia, with heart rate con- Malignant Syndrome Information Service (NMSIS). The theme of this sistently >130 bpm. Her vital signs did not year’s competition was “New insights on normalize before the fever developed. She psychotropic drug safety and side effects.” remains somnolent