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Home , Cyproheptadine, Hyperforin, Selegiline

Serotonin syndrome How to avoid, identify, &

As the list of agents grows, recognizing hyperthermic states and potentially dangerous drug combinations is critical to our patients’ safety.

14 Current VOL. 2, NO. 5 / MAY 2003 p SYCHIATRY Current p SYCHIATRY treat dangerous drug interactions

Harvey Sternbach, MD Clinical professor of psychiatry UCLA Neuropsychiatric Institute Los Angeles, CA

romptly identifying syn- drome and acting decisively can keep side effects at the mild end of the spec- Ptrum. Symptoms of this potentially dangerous syndrome range from minimal in patients starting selective serotonin reuptake inhibitors (SSRIs) to fatal in those combining monoamine oxidase inhibitors (MAOIs) with serotonergic agents. This article presents the latest evidence on how to: • reduce the risk of • recognize its symptoms • and treat patients with mild to life- threatening symptoms.

WHAT IS SEROTONIN SYNDROME? Serotonin syndrome is characterized by changes in autonomic, neuromotor, and cognitive-behav- ioral function (Table 1) triggered by increased serotonergic stimulation. It typically results from pharmacodynamic and/or pharmacokinetic in- teractions between drugs that increase serotonin activity.1,2 continued

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Table 1 activity or reduced ability to How to recognize serotonin syndrome secrete endothelium-derived nitric oxide may diminish the System Clinical signs and symptoms ability to metabolize serotonin.2 Autonomic Diaphoresis, hyperthermia, , tachycardia, pupillary dilatation, , POTENTIALLY DANGEROUS , shivering COMBINATIONS Neuromotor Hyperreflexia, myoclonus, restlessness, MAOIs. Serotonin syndrome tremor, incoordination, rigidity, clonus, has been reported as a result of teeth chattering, trismus, seizures interactions between MAOIs— Cognitive-behavioral , agitation, anxiety, hypomania, including and , , headache reversible MAO-A inhibitors (RIMAs)—and various sero- tonergic compounds. These The syndrome was first identified in animal reports have included fatalities,4 some of which studies, followed by case reports in humans. The were preceded by severe hyperthermia with com- first review—with suggested diagnostic criteria— plications such as disseminated intravascular was published in 1991.1 coagulation, rhabdomyolysis, and renal failure. Since then, case reports have described sero- Some cases resulted from overdoses, but others tonin syndrome with many drug combinations, did not. including nonpsychotropics and illicit drugs. Most disturbingly, some cases occurred after Using an irreversible MAOI with a serotonergic patients had undergone agent is the most toxic reported the traditional 2-week combination, but any drug or com- washout from the MAOI and then bination that increases serotonin Some fatal MAOI- took a serotonergic agent.5-7 In one can, in theory, cause serotonin syn- serotonergic instance,8 a patient who had discon- drome (Table 2). A clinical scale3 is interactions occur tinued for 6 weeks devel- being developed to define and iden- after the usual oped serotonin syndrome after starting tify this potentially dangerous state, 2-week washout . These cases remind but no consensus has emerged on us to be vigilant when switching diagnostic criteria. patients from irreversible MAOIs to Pathophysiology. Serotonin syndrome’s symptoms serotonergic or vice and signs appear to result from stimulation of versa—even when recommended wash-out times specific central and peripheral serotonin recep- are observed—and not to combine these agents tors, especially 5HT1a and 5HT2. Others—such acutely. as 5HT3 and 5HT4—may also be involved in Selegiline is a relatively selective MAO-B inhibitor causing GI symptoms and may affect dopaminer- when used at 5 to 10 mg/d to treat Parkinson’s dis- gic transmission. ease, though it loses MAO-B selectivity when Damaged vascular or pulmonary endotheli- used at higher dosages to treat . In a um, atherosclerosis, hypertension, or hypercho- study9 of 4,568 patients with Parkinson’s disease lesterolemia may increase the risk for serotonin who received selegiline (in dosages selective for syndrome. In patients with these common med- MAO-B) plus an : ical conditions, reduced endothelial MAO-A • 11 (0.24%) experienced symptoms “possi- continued on page 19

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continued from page 16

bly” consistent with Table 2 serotonin syndrome Serotonergic agents and their actions • 2 others (0.04%) expe- rienced serious Actions Agents serotonin syndrome Inhibit serotonin Fluoxetine, , , symptoms.9 reuptake , , , Serotonin syndrome has , , , been reported when MAO- , , B-selective doses of selegiline antidepressants, , , were combined with meperi- , meperidine, St. John’s wort dine10 and .11 Increases serotonin This underscores the need synthesis for caution when combining Inhibit serotonin , tranylcypromine, , these agents, especially if selegiline (deprenyl), , selegiline— Increase serotonin MDMA (“Ecstasy”), amphetamine, cocaine, which would not be MAO- release B-selective—becomes avail- Increase serotonin , ECT able for treating depression. activity Moclobemide is a RIMA used Serotonin , and other “” in treating depression and agonists used for anxiety, with a purported reduced risk of drug and food interactions compared with other MAOIs. Moclobemide is not approved in inhibition. Cases of potential serotonin syndrome the United States, but some patients obtain it have been reported with linezolid plus paroxe- elsewhere. tine17 or sertraline.18 Patients in each case were Joffe and Bakish reported on safely combin- medically ill and taking several other medica- ing moclobemide with SSRIs,12 and a review of tions, which complicates interpretation of these MAOIs—including RIMAs—indicated that reports. Nonetheless, physicians should be aware moclobemide was involved in only 9 of 226 cases of the potential risk of serotonin syndrome if this of adverse effects and 3 of 105 cases of defined antibiotic is combined with serotonergic agents. serotonin syndrome.13 Most moclobemide-SSRI Atypical . Original diagnostic crite- interactions—including fatalities—involved ria for serotonin syndrome excluded the addition overdoses in attempts, although toxic of, or increase in, an prior to the symptoms have been reported with clomipramine syndrome’s onset.1 However, serotonin syndrome or meperidine taken at normal dosages.14,15 has been reported with combinations of risperi- In one study,16 18 healthy controls received done with paroxetine,19 with mirtaza- fluoxetine, 20 to 40 mg/d, for 23 days, then were pine and tramadol,20 and olanzapine with lithium given moclobemide, up to 600 mg/d, or placebo and citalopram.21 The 5HT2 antagonist effect of and observed for adverse effects. No indication of these atypical antipsychotics may have led indi- serotonin syndrome was observed. rectly to overactivation of 5HT1a receptors and Linezolid is an oxazolidinone antibiotic with rela- serotonin syndrome. In each case, neuroleptic tively weak, nonspecific, but reversible MAO malignant syndrome was ruled out.

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Table 3 Signs and symptoms that differentiate 5 hyperthermic states

Hyperthermic state Symptoms/signs Lab findings Cause Serotonin Typically rapid onset with Nonspecific Increased syndrome hyperreflexia, tremors, serotonergic tone myoclonus, diaphoresis, confusion, agitation, or shivering; muscular rigidity not invariably present Neuroleptic Variable rapidity of onset; Elevated CPK, Blockade of malignant severe muscular rigidity, leukocytosis receptors or abrupt syndrome diaphoresis, delirium, withdrawal of a fluctuating blood pressure, tachycardia, extrapyramidal symptoms Lethal catatonia Muscular rigidity, Nonspecific Evidence of pre-existing diaphoresis, delirium, psychosis (bipolar alternating extreme disorder, ) excitement and stupor, tremors, hypertension Hot, dry skin, pupillary Nonspecific Agents that block central toxicity dilatation, tachycardia, and peripheral constipation, urinary muscarinic retention, confusion, receptors hallucinations, muscular relaxation Malignant Rapid onset, severe Elevated CPK, Inherited disorder hyperthermia muscular rigidity, potassium, with onset after exposure ischemia, hypotension ; to anesthetic agents DIC; acidosis; that block the rhabdomyolysis neuromuscular junction CPK: creatine phosphokinase DIC: disseminated intravascular coagulation

Tramadol is an analgesic with and sero- nists used in treating migraine. Gardner and tonin-reuptake inhibiting properties that is Lynd24 concluded that most patients tolerate metabolized by the cytochrome P (CYP)-450 iso- sumatriptan with SSRIs or lithium. They felt 2D6. Serotonin syndrome has been they could not ensure the safety of sumatriptan reported from interactions between tramadol and with MAOIs, however, because sumatriptan sertraline22 and fluoxetine.23 Possible causes elimination depends on hepatic MAO activity. include SSRI inhibition of CYP 2D6 metabolism Among the 5HT1D agonists, using suma- of tramadol, tramadol abuse,23 and multiple co- , , , or administered medications.22 with an MAOI or within 2 weeks of discontinu- Sumatriptan is one of the selective 5HT1D ago- ing an MAOI is contraindicated. and

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appear less likely to interact with MISCELLANEOUS COMBINATIONS MAOIs, based on FDA-approved labeling. Antiretroviral therapy. Five cases of serotonin syn- MDMA. 3,4-methylenedioxymethamphetamine drome were reported in HIV-infected patients (MDMA, “Ecstasy”) is widely used as a recre- taking fluoxetine with antiretroviral therapy.31 ational drug, especially at crowded dances In particular, the use or addition of — (“raves”) and with other drugs.25 This illicit a potent CYP 2D6 amphetamine derivative stimu- inhibitor—was implicated, lates the release of serotonin and though saquinavir, , or inhibits its reuptake. Cases of purported grapefruit juice (all primarily CYP Kaskey reported the rapid serotonin syndrome 3A4 inhibitors) were also used, sug- onset of serotonin syndrome have been gesting that pharmacokinetic interac- when a patient taking lithium tions increased serotonergic stimulation. associated with and phenelzine ingested All five patients were taking multiple St. John’s wort MDMA.26 Signs and symptoms additional medications and had complex of serotonin syndrome also may medical and/or psychiatric histories. develop when MDMA is used alone, Reducing SSRI dosages by one-half facilitated by the high ambient temperatures on when used with ritonavir has been crowded dance floors and the dancers’ relative recommended to minimize adverse effects from dehydration. a pharmacokinetic interaction. Fatalities have been blamed on complications was reported to induce serotonin including disseminated intravascular coagulation, syndrome in a 12-year-old boy when added to rhabdomyolysis, and acute hepatic, renal, or car- ongoing treatment with sertraline, an effect diac failure.25 Cases are difficult to interpret believed to be secondary to CYP 3A4 inhibition because of uncertainty about whether the victim of sertraline metabolism.32 ingested MDMA or another agent or combination. was reported to induce serotonin syn- St. John’s wort ( perforatum) contains drome in an elderly man 8 days after it was added numerous constituents, including and to a regimen he had been taking for several years , which have been found to inhibit the to treat chronic obstructive pulmonary disease.33 synaptic uptake of monoamines, including sero- Serotonin syndrome also developed in a 12-year- tonin.27 Which constituents are responsible for its old boy with Ewing’s sarcoma when the 5HT3 clinical effect is unclear. Adverse effects from antagonist was added to mirtazap- monotherapy include GI symptoms, confusion, ine and morphine34 and in an 11-year-old girl dry mouth, dizziness, headache, fatigue, allergic with acute lymphoblastic leukemia when skin reactions, photosensitivity, and urinary fre- ondansetron was added to . Interestingly, quency.27 another report35 suggested using mirtazapine to Several cases of purported serotonin syn- treat serotonin syndrome caused by serotonergic drome have been associated with St. John’s wort antagonist effects. alone28 or in combination with SSRIs, nefazodone, Reports have associated the following combi- or fenfluramine.29,30 GI symptoms and anxiety nations with serotonin syndrome, perhaps as the were the primary complaints and resolved with- result of pharmacodynamic and/or pharmacoki- out complications (adjunctive cyproheptadine netic interactions: was prescribed in two cases, though it is not clear • paroxetine plus dextromethorphan and that this agent contributed to resolution).

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Table 4 HOW TO RECOGNIZE Clinical signs that distinguish hyperthermic states SEROTONIN SYNDROME Signs and symptoms of sero- Signs Possible diagnosis tonin syndrome can overlap Prominent muscular rigidity Neuroleptic malignant syndrome, with those seen in neuroleptic malignant hyperthermia, catatonia malignant syndrome, lethal Myoclonus/hyperreflexia Serotonin syndrome catatonia, malignant hyper- thermia, and anticholinergic Diaphoresis Serotonin syndrome, neuroleptic 1,36,37 malignant syndrome, catatonia toxicity (Table 3), particu- larly with fever or hyperther- Hot dry skin Anticholinergic toxicity mia (>40.5 °C, 105 °F). Fink37 Elevated creatine Neuroleptic malignant syndrome, has opined that acute neuro- phosphokinase malignant hyperthermia toxic syndromes such as sero- Family history of Malignant hyperthermia tonin syndrome and neurolep- anesthetic-induced tic malignant syndrome also hyperthermia meet criteria for catatonia and are therefore subtypes of cata- tonia. The types of drugs • paroxetine plus nefazodone involved and clinical findings can help distinguish • fluoxetine plus clomipramine and the various hyperthermic states (Table 4). buspirone As mentioned above, original diagnostic cri- • fluvoxamine plus buspirone teria for serotonin syndrome excluded the addi- • fluoxetine plus buspirone tion of, or increase in, an antipsychotic agent. • plus meperidine and This exclusion was intended to avoid confusion venlafaxine between serotonin syndrome and neuroleptic • venlafaxine and malignant syndrome. Co-administering antipsy- • fluoxetine plus clomipramine. chotic and serotonergic agents requires height- ened awareness for both neurotoxic syndromes.

TREATING MILD TO SEVERE CASES If a patient develops serotonin syndrome, imme- diately discontinue the suspected agent(s) and Any drug or combination that observe carefully. In most cases, serotonin increases serotonin can, in theory, syndrome will resolve within 24 hours. cause serotonin syndrome. In mild cases, , 1 to 2 mg slow IV Avoiding potentially dangerous drug push every 30 minutes until excessive sedation combinations, monitoring patients develops, may help. In moderate to severe cases, carefully, and identifying and treating agents that block serotonin’s action are recom- serotonin syndrome early can mended,2 including: minimize its morbidity and mortality. • cyproheptadine (4 mg po every 4 hours as needed, up to 20 mg in 24 hours) • (1 to 3 mg IV every 5 min-

Bottom Line utes, up to 0.1 mg/kg).

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Case reports attest to these agents’ potential benefit. Other clinicians have reported using mir- Related resources 35 38 1 Di Rosa AE, Morgante L, Spina E et al. Epidemiology and tazapine, nitroglycerin, and . pathoetiology of neurological syndromes with hyperthermia. Serotonin syndrome symptoms resolved Funct Neurol 1995;10:111-19. within minutes when IV nitroglycerin was used Radomski, JW, Dursun SM, Reveley MA, et al. An exploratory approach to the serotonin syndrome: an update of clinical in a patient with serotonin syndrome and cardiac phenomenology and revised diagnostic criteria. Med Hypothesis ischemia. The authors hypothesized that nitro- 2000;55: 218-24. glycerin, via nitric acid, provided an “off ” signal Lane R, Baldwin D. Selective serotonin -induced for serotonin, though they did not advocate this serotonin syndrome: review. J Clin Psychopharmacol 1997;17:208-21. as a routine treatment.38 The rationale for using chlorpromazine is its DRUG BRAND NAMES potential to block serotonin receptors. I would Almotriptan • Axert Nortriptyline • Pamelor Amitriptyline • Elavil Naratriptan, • Amerge avoid the routine use of any antipsychotic agent Buspirone • Buspar Nefazodone • Serzone in this setting, however, to minimize the risk of Chlorpromazine • Thorazine Olanzapine • Zyprexa Citalopram • Celexa Ondansetron • Zofran neuroleptic malignant syndrome. Clomipramine • Anafranil Paroxetine • Paxil Severe cases. Intensive care observation and Cyproheptadine • Periactin Phenelzine • Nardil Dextroamphetamine • Dexedrine Propranolol • Inderal treatment is required for patients with severe Dextromethorphan • Delsym • Risperdal serotonin syndrome, including evidence of Efavirenz • Sustiva Ritonavir • Norvir Escitalopram • Lexapro Rizatriptan • Maxalt hyperthermia, DIC, rhabdomyolysis, renal fail- Fenfluramine • Pondimin Saquinavir • Invirase ure, or aspiration. In cases of hyperthermia, sup- Fentanyl • Sublimaze Selegiline • Eldepryl Fluoxetine • Prozac Sertraline • Zoloft portive measures and standard treatments Fluvoxamine • Luvox Sumatriptan • Imitrex include muscle relaxants, cooling, and endotra- Frovatriptan • Frova Tramadol • Ultram Isocarboxazid • Marplan Tranylcypromine • Parnate cheal intubation. Linezolid • Zyvox Trazodone • Desyrel Severe complications are most likely with Meperidine • Demerol Venlafaxine • Effexor Mirtazapine • Remeron Zolmitriptan • Zomig interactions between MAOIs and serotonergic Moclobemide • Aurorix agents, especially in overdose. Therefore, using such combinations requires close observation. DISCLOSURE Dr. Sternbach receives research grants from Otsuka America Pharmaceuticals References and Eli Lilly and Co. and owns stock in Merck & Co., Pfizer Inc., and Johnson & Johnson. 1. Sternbach H. The serotonin syndrome. Am J Psychiatry 1991;148:705-13. 2. Brown TM, Skop BP, Mareth TR. Pathophysiology and manage- ment of the serotonin syndrome. Ann Pharmacother 1996;30:527-33. 9. Richard IH, Kurlan R, Tanner C, et al. Serotonin syndrome and the 3. Hegerl U, Bottlender R, Gallinat J, et al. The serotonin syndrome combined use of deprenyl and an antidepressant in Parkinson’s dis- scale: first results on validity. Eur Arch Psychiatry Clin Neurosci ease. Neurology 1997;48:1070-7. 1998;248:96-103. 10. Zornberg GL, Bodkin JA, Cohen BM. Severe adverse interaction 4. Beasley CM Jr., Masica DN, Heiligenstein JH, et al. Possible between and selegiline. Lancet 1991;337:246. monoamine-oxidase inhibitor-serotonin uptake inhibitor interac- 11. Hinds NP, Hillier CE, Wiles CM. Possible serotonin syndrome aris- tion: fluoxetine clinical data and pre-clinical findings. J Clin ing from an interaction between nortriptyline and selegiline in a Psychopharmacol 1993;13:312-20. lady with . J Neurol 2000;247:811. 5. Ruiz F. Fluoxetine and the serotonin syndrome. Ann Emerg Med 12. Joffe RT, Bakish D. Combined SSRI-moclobemide treatment of 1994;34:983-5. psychiatric illness. J Clin Psychiatry 1994;55:24-5. 6. Gitlin MJ. Venlafaxine, monoamine oxidase inhibitors and the sero- 13. Hilton SE, Maradit H, Moller HJ. Serotonin syndrome and drug tonin syndrome. J Clin Psychopharmacol 1997;17:66-7. combinations: focus on MAOI and RIMA. Eur Arch Psychiatry Clin 7. Kolecki P. Venlafaxine induced serotonin syndrome occurring after Neurosci 1997;247:113-19. abstinence from phenelzine for more than two weeks. Clin Toxicol 14. Dardennes RM, Even C, Ballon N, et al. Serotonin syndrome 1997;35:211-12. caused by a clomipramine-moclobemide interaction. J Clin 8. Coplan JD, Gorman JM. Detectable levels of fluoxetine metabolites Psychiatry 1998;59:382-3. after discontinuation: an unexpected serotonin syndrome. Am J 15. Gillman PK. Possible serotonin syndrome with moclobemide and Psychiatry 1993;15:837. pethidine. Med J Aust 1995;162:554. continued

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s a practicing psychiatrist 16. Dingemanse J, Wallnofer A, Gieschke R, et al. Pharmacokinetic and pharmacodynamic interaction between fluoxetine and moclobemide A in clinical care, you are in the investigation of development of the “serotonin syndrome.” eligible for a complimentary Clin Pharmacol Ther 1998;63:403-13. 17. Wigen CL, Goetz MB. Serotonin syndrome and linezolid. Clin subscription.* Send us your Infect Dis 2002;34:1651-2. request today to guarantee 18. Lavery S, Ravi H, McDaniel WW, et al. Linezolid and serotonin syndrome. Psychosomatics 2001;42:432-4. uninterrupted service. 19. Hamilton S, Malone K. Serotonin syndrome during treatment with paroxetine and risperidone. J Clin Psychopharmacol 2000;20:103-5. Your practice will continue to benefit from 20. Duggal HS, Fetchko J. Serotonin syndrome and atypical antipsy- chotics. Am J Psychiatry 2002;159:672-3. review articles written by the specialty's leading 21. Haslett CD, Kumar S. Can olanzapine be implicated in causing experts, plus Primary Care Updates, Cases that Test serotonin syndrome? Psychiatry Clin Neurosci 2002;56:533-6. 22. Mason BJ, Blackburn KH. Possible serotonin syndrome associated your Skills, Out of the Pipeline, and Pearls. You will with tramadol and sertraline coadministration. Ann Pharmacother enjoy the confidence that comes with being armed with 1997;31:175-7. 23. Lange-Asschenfeldt C, Weigmann H, Hiemke C, et al. Serotonin practical, evidence-based information. syndrome as a result of fluoxetine in a patient with tramadol abuse: plasma level-correlated symptomatology. J Clin Psychopharmacol Don’t wait! 2002;22:440-1. 24. Gardner DM, Lynd LD. Sumatriptan contraindications and the serotonin syndrome. Ann Pharmacother 1998;32:33-8. Fax: 201-782-5319 Please print your name and address ▼ 25. Parrott AC. Recreational Ecstasy/MDMA, the serotonin syndrome exactly as they appear on your mailing label. OR and serotonergic neurotoxicity. Pharmacol Biochem Behav 2002; 71:837-44. Call: 201-505-5886 OR 26. Kaskey GB. Possible interaction between an MAOI and “Ecstasy.” ▼ Am J Psychiatry 1992;149:411-12. E-mail: [email protected] 27. De Smet PA. Herbal remedies. N Engl J Med 2002;347:2046-56. ▼ 28. Parker V, Wong AH, Boon HS, et al. Adverse reactions to St. John’s * Your specialty must be registered as psychiatry with the American wort. Can J Psychiatry 2001;46:77-9. Medical Association to qualify for a free subscription to CURRENT 29. Lantz MS, Buchalter E, Giambanco V. St. John’s wort and antide- PSYCHIATRY. Offer limited to psychiatrists in direct patient care, plus pressant drug interactions in the elderly. J Geriatr Psychiatry Neurol residents and faculty. If you are not receiving CURRENT PSYCHIATRY but 1999;12:7-10. meet the qualifications, please contact the AMA at 800-262-3211 to 30. Beckman SE, Sommi RW, Switzer J. Consumer use of St. John’s update your data. wort: a survey of effectiveness, safety, and tolerability. Pharmacotherapy 2000;20:568-74. 31. De Silva KE, Le Flore DB, Marston BJ et al. Serotonin syndrome ■ Yes! Please continue my FREE subscription to in HIV-infected individuals receiving antiretroviral therapy and flu- oxetine. AIDS 2001;15:1281-5. CURRENT PSYCHIATRY. 32. Lee DO, Lee CD. Serotonin syndrome in a child associated with ■ No, thanks erythromycin and sertraline. Pharmacotherapy 1999;19:894-6. 33. Hernandez JL, Ramos FJ, Infante J, et al. Severe serotonin syn- Name drome induced by mirtazapine monotherapy. Ann Pharmacother 2002;36:641-3. Address 34. Turkel SB, Nadala JGB, Wincor MZ. Possible serotonin syndrome in association with 5HT3 antagonist agents. Psychosomatics 2001; City 42:258-60. 35. Hoes MJ, Zeijpveld JH. Mirtazapine as treatment for serotonin syn- State ZIP drome. Pharmacopsychiatry 1996;29:81. Specialty 36. Theoharides TC, Harris RS, Weckstein D. Neuroleptic malignant- like syndrome due to ? J Clin Psychopharmacol Type of Practice 1995;15:79-81. 37. Fink M. Toxic serotonin syndrome or neuroleptic malignant syn- Signature drome? Pharmacopsychiatry 1996;29:159-61. (required) 38. Brown TM, Skop BP. Nitroglycerin in the treatment of the sero- Date tonin syndrome. Ann Pharmacother 1996;30:191-2. (required) E- mail

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