Did Internet-Purchased Diet Pills Cause Serotonin Syndrome?

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 Because phentermine could in theory cause serotonin Roy J. and Lucille A. Carver College of Medicine 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 uoxetine and phentermine that appears consistent with serotonin syndrome.6 We are aware of no case reports of Current Psychiatry serotonin syndrome caused by phentermine alone. Vol. 7, No. 7 67 continued

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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 and continues to have CURRENT PSYCHIATRY is honored to publish spastic lower leg and ankle clonus. She shows this peer-reviewed, evidence-based article no seizure activity on video EEG monitoring on a clinically important topic for practicing during later episodes of repetitive leg shak- psychiatrists. Current Psychiatry ing, approximately 60 hours after admission. Vol. 7, No. 7 69 continued

069_CPSY0708 069 6/16/08 3:51:22 PM Box 2 EEG, with no evidence of seizure activity before diazepam was added or after it is tapered oﬀ by NMS: Disorder of low day 23. dopaminergic activity Discharge. Ms. G is extubated on hospital day

euroleptic malignant syndrome (NMS)— 18. On day 23 she can follow commands but Ncharacterized by fever, extrapyramidal is not fully oriented, and levodopa, phenytoin, rigidity, and disturbances of autonomic bromocriptine, and dantrolene are tapered Serotonin function and consciousness—was fi rst off . She is discharged to a rehabilitation facil- syndrome described with the use of haloperidol.11 ity, where she again requires phenytoin for a Risk factors include catatonia, disorganized witnessed seizure, attributed to anticonvul- presentation, and dehydration.12 NMS sant withdrawal. is thought to result from defi cient On follow-up phone interviews 4 and 18 compensatory mechanisms following months after hospitalization, Ms. G says she blockade of dopaminergic regulation of remains seizure-free without taking anticon- muscle tone and autonomic function.13 Although possibly idiosyncratic, the vulsants. She reports a subjective, interval reaction has been associated with: improvement in cognitive function, which has Clinical Point • intramuscular, higher total dose, or since returned to baseline. Phentermine abruptly increasing doses of antipsychotics14 increases serotonin • withdrawal of dopaminergic agents, Evidence for serotonin syndrome effl ux in the rat such as those used to treat Parkinson’s This case involves a young woman with a disease.15 hypothalamus several-week history of phentermine use Akin to serotonin syndrome, managing for weight reduction who presented with to a greater degree NMS focuses on removing the offending than fl uoxetine agent(s) and providing supportive care. confusion, sedation, mutism, and nausea. Severe cases require intensive monitoring, She was initially found to have an abnormal aggressive IV hydration, and respiratory EEG, for which she was loaded with the support. Dopaminergics such as anticonvulsant phenytoin. However, she bromocriptine16 and skeletal muscle continued to exhibit altered mental status, relaxants such as dantrolene17 also have myoclonus, and hyperrefl exia along with been used to manage NMS. autonomic dysregulation—such as urinary Unlike serotonin syndrome, NMS often retention and tachycardia—despite a nega- resolves slowly (typically >1 week). NMS’ tive EEG on continuous monitoring. mortality rate of 11% to 38% appears to be declining in recent years, perhaps On retrospective review, we believe she because it is being recognized more rapidly.18 likely was experiencing serotonin toxicity from phentermine. She later developed NMS within several hours of receiving the She is transferred to the ICU with a prelimi- antipsychotic haloperidol. nary diagnosis of NMS. Again, continuous EEG Seizure has been reported with Fen- monitoring does not show seizure activity. Phen (fenfl uramine and phentermine),21 CSF specimen is negative for infection (nega- but not to date with phentermine mono- tive cultures, negative herpes simplex virus therapy. On the other hand, seizure—often PCR, protein 31 mg/dl, glucose 75 mg/dl). She generalized, tonic-clonic in nature—has is started on dantrolene, bromocriptine, and been reported with serotonin syndrome.22 levodopa but shows no initial improvement. Partial seizures might explain Ms. G’s ini- Intubation. On hospital day 8, the patient is tial confusion. However, neuromuscular intubated to protect her airway and placed in abnormalities persisted after a normalized a pentobarbital coma for 2 days, with no im- EEG, further supporting the diagnosis of provement. On hospital day 9, cyproheptadine, serotonin syndrome. 24 mg/d, is added for possible serotonin syn- Even though phentermine is thought to drome, and continued for 9 days. have a relatively weak serotonergic effect,3 On day 11, the addition of IV diazepam, 10 it has been shown to markedly increase se- mg per hour, is followed by gradual improve- rotonin effl ux in the rat hypothalamus (to Current Psychiatry 70 July 2008 ment in rigidity. Ms. G remains on continuous a greater degree than the SSRI fl uoxetine).23 continued on page 77

070_CPSY0708 070 6/16/08 3:51:33 PM continued from page 70 Although Ms. G did not report having con- Table 2 sumed foods or supplements that could Serotonin syndrome or NMS? have interfered with phentermine’s metab- When in doubt, follow olism, such use could have contributed to 4 management principles or prolonged a serotonin syndrome.20 Phen-

termine misuse also cannot be ruled out. Avoid serotonin agonists and dopamine antagonists when a patient presents with Excess phentermine or concomitant use features of serotonin syndrome or neuroleptic of other serotonergic agents may have malignant syndrome (NMS) and the diagnosis precipitated serotonin syndrome. Ms. G’s is unclear20 hyperactivity a few days before she com- Provide supportive care with monitoring, plained of fatigue and somnolence may cooling blankets as needed, and hydration represent: Avoid using antipsychotics for agitation, when • a sign of phentermine intoxication or possible; benzodiazepines may be preferable, overuse although their use in NMS is controversial25 • a harbinger of serotonin syndrome, Avoid using bromocriptine, given its because these symptoms were followed contraindication in serotonin syndrome, but Clinical Point by overt serotonin syndrome signs such as consider cyproheptadine for the serotonin Sympathetic confusion, disorientation, myoclonus, and syndrome component and dantrolene for 20 hyperactivity from autonomic dysfunction. skeletal muscle rigidity Features such as slow progression to the phentermine or full-blown signs and unclear medication Although phentermine-induced sym- serotonin syndrome history may obscure the clinical picture at pathetic hyperactivity also could have may increase the risk 24 31 presentation in this and similar cases. predisposed Ms. G to NMS, we think of developing NMS this is unlikely because phentermine was discontinued 3 to 4 days before she devel- Evidence for NMS oped NMS. Nonetheless, sympathetic hy- Ms. G received haloperidol because her ag- peractivity secondary to phentermine or itation obstructed urgent evaluation. After serotonin syndrome may increase the risk several doses, she rapidly developed signs of developing NMS. and symptoms highly consistent with NMS. Onset was rapid compared with the typically described, more insidious NMS Treatment strategy evolution of 24 to 72 hours, however.25 Because serotonin syndrome and NMS Rapid NMS onset may have been precipi- share many clinical fi ndings, differentiating tated in 2 ways: between the 2 syndromes may be diffi cult, • dopaminergic (phentermine) with- especially when the patient’s medication drawal combined with dopamine an- history does not implicate a specifi c agent. tagonist challenge (haloperidol)25,26 A detailed history and physical may help • background serotonin syndrome caused distinguish the syndromes. Clonus may by amphetamine (phentermine) predis- be particularly specifi c and is important posing the patient to develop NMS.27 in the diagnosis of serotonin syndrome.32 For the fi rst possibility, 1 case report has If you are unable to differentiate between described a narcolepsy patient developing serotonin syndrome and NMS in a pa- NMS after discontinuing dextroamphet- tient with this acute neurotoxic abnormal amine, which he had been taking for 16 behavior syndrome,33 consider a common years.28 NMS also has been observed dur- treatment strategy (Table 2).19,25 ing withdrawal of dopaminergic medica- In Ms. G’s case, she probably should not tions used in Parkinson’s disease.29 For the have received bromocriptine for NMS,20 second possibility, Kline et al30 reported a given the potential role of serotonin syn- similar case of a 45-year-old woman with drome in precipitating her symptoms. probable serotonin syndrome who devel- Case reports support our hypotheses Current Psychiatry oped NMS after a single neuroleptic dose. of an increased predilection for NMS with Vol. 7, No. 7 77

077_CPSY0708 077 6/16/08 3:51:37 PM dopaminergic withdrawal or serotonin syndrome. Growing evidence supports Related Resources the use of chlorpromazine for serotonin • Carbone JR. The neuroleptic malignant and serotonin syndromes. Emerg Med Clin North Am 2000;18:317-25. syndrome,34 but consider its use contrain- • Gillman PK. The serotonin syndrome and its treatment. dicated in patients with NMS. J Psychopharmacol 1999;13:100-9. • Neuroleptic Malignant Syndrome Information Service References (NMSIS). www.nmsis.org. NMS hotline for medical 1. Mosby’s Drug Consult, 16th ed. St. Louis, MO: Mosby; 2006. professionals (toll-free 888-667-8367) handles calls on NMS, Serotonin 2. McEvoy G. AHFS drug information. Bethesda, MD: American serotonin syndrome, heat stroke, malignant catatonia, and Society of Health-System Pharmacists; 2006. other drug-induced heat-related disorders. syndrome 3. Rothman RB, Baumann MH, Dersch CM, et al. Amphetamine- type central nervous system stimulants release norepinephrine Drug Brand Names more potently than they release dopamine and serotonin. Synapse 2001;39:32-41. Acyclovir • Zovirax Fluoxetine • Prozac 4. Ener RA, Meglathery SB, Van Decker WA, Gallagher RM. Ampicillin • various Haloperidol • Haldol Serotonin syndrome and other serotonergic disorders. Pain Bromocriptine • Parlodel Levodopa • various Med 2003;4:63-74. Ceftriaxone • Rocephin Methysergide • Sansert 5. Phentermine hydrochloride. Physicians’ Desk Reference. 53rd Chlorpromazine • Thorazine Pentobarbital • Nembutal ed. Montvale, NJ: Medical Economics; 1999:3055-6. Cyproheptadine • Periactin Phentermine • various 6. Bostwick JM, Brown TM. A toxic reaction from combining fl uoxetine and phentermine. J Clin Psychopharmacol Dantrolene • Dantrium Phenytoin • Dilantin 1996;16:189-90. Diazepam • Valium Propranolol • Inderal Clinical Point 7. Sternbach H. The serotonin syndrome. Am J Psychiatry Dextroamphetamine • Vancomycin • various 1991;148(6):705-13. Dexedrine 8. Nisijima K, Yoshino T, Yui K, Katoh S. Potent serotonin Consider a common (5-HT)(2A) receptor antagonists completely prevent the Disclosure development of hyperthermia in an animal model of the 5-HT treatment strategy syndrome. Brain Res 2001;890:23-31. The authors report no fi nancial relationship with any 9. Mason PJ, Morris VA, Balcezak TJ. Serotonin syndrome. company whose products are mentioned in this article or if you are unable Presentation of 2 cases and review of the literature. Medicine with manufacturers of competing products. (Baltimore) 2000;79:201-9. to diff erentiate 10. Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med 2005;352:1112-20. 23. Tao R, Fray A, Aspley S, et al. Effects on serotonin in rat between serotonin 11. Delay J, Pichot P, Lemperiere T, et al. 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Treatment of neuroleptic or—dopaminergic malignant syndrome—due to levodopa malignant syndrome with dantrolene sodium: a case report. therapy withdrawal. Clinical features in 11 patients. Am J Psychiatry 1982;139:944-5. Parkinsonism Relat Disord 2003;9:175-8. 18. Spivak B, Maline DI, Kozyrev VN, et al. Frequency of 30. Kline SS, Mauro LS, Scala-Barnett DM, Zick D. Serotonin neuroleptic malignant syndrome in a large psychiatric syndrome versus neuroleptic malignant syndrome as a cause hospital in Moscow. Eur Psychiatry 2000;15:330-3. of death. Clin Pharm 1989;8(7):510-14. 19. Gerber PE, Lynd LD. Selective serotonin-reuptake inhibitor- 31. Gurrera RJ. Sympathoadrenal hyperactivity and the induced movement disorders. Ann Pharmacother 1998;32:692-8. etiology of neuroleptic malignant syndrome. Am J Psychiatry 20. Kaufman KR, Levitt MJ, Schiltz JF, Sunderram J. Neuroleptic 1999;156:169-80. malignant syndrome and serotonin syndrome in the critical 32. Dunkley EJ, Isbister GK, Sibbritt D, et al. The Hunter Serotonin care setting: case analysis. Ann Clin Psychiatry 2006;18:201-4. Toxicity Criteria: simple and accurate diagnostic decision rules 21. Spencer DC, Hwang J, Morrell MJ. Fenfl uramine-phentermine for serotonin toxicity. QJM 2003;96:635-42. (Fen-Phen) and seizures: evidence for an association. Epilepsy 33. Fink M. Toxic serotonin syndrome or neuroleptic malignant Behav 2000;1(6):448-52. syndrome? Pharmacopsychiatry 1996;29:159-61. 22. Mills KC. Serotonin syndrome. A clinical update. Crit Care Clin 34. Gillman PK. Serotonin syndrome treated with chlorpromazine. 1997;13(4):763-83. J Clin Psychopharmacol 1997;17:128-9. Bottom Line Diagnosis of serotonin syndrome or neuroleptic malignant syndrome (NMS) is clinical because confi rmatory tests do not exist. We cannot be certain this patient had serotonin syndrome followed by NMS, but this case suggests the possibility of increased NMS risk in patients with serotonin syndrome, perhaps mediated by Current Psychiatry 78 July 2008 sympathetic hyperactivity.

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