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Acute psychosis after amantadine overdose
CASE REPORT amantadine,'overdose
Acute Psychosis After Amantadine Overdose Amantadine is an antiviral agent that is also used in the treatment of parkinsonism and neuroleptic-induced extrapyramidal symptoms. Toxic effects of amantadine relate primarily to the central nervous system and range from mild symptoms to disorientation and hallucinations. Anticholinergic agents may exacerbate these effects. We report a case of unsuspected amantadine overdose in a previously healthy 35-year-old woman who presented with acute psychosis manifested by delirium and visual hallucinations. Concomitant use of diphenhydramine contributed to the clinical presentation. Amantadine toxicity should be considered in the differential diagnosis of altered mental status in patients known to be taking the drug or with conditions commonly treated with amantadine. /Snoey ER, Bessen HA: Acute psychosis after amantadine overdose. A n n Emerg Med June 1990;I9:668-670.] INTRODUCTION Amantadine is a synthetic tricyclic amine with antiviral activity. 1-3 It is used for the prophylaxis and treatment of infections caused by various strains of influenza A virus. 4 In 1969, Schwab et al described the remission of parkinsonism in a 58-year-old woman who was receiving amantadine for influenza prophylaxis, s This serendipitous observation led to further trials confirming its efficacy.5, 6 Amantadine has also proven helpful in the treatment of neuroleptic-induced extrapyramidal symptoms. 7,s Side effects of amantadine relate primarily to the central nervous system (CNS) and may occur even in normal subjects given therapeutic doses. 9 Severe amantadine-induced CNS symptoms such as disorientation and hallucinations have been reported in patients on chronic amantadine therapy, S,10-~2 especially those also taking anticholinergic agents.S,~°,~2, ~,3 Coma, 14 seizures, 1s cardiovascular toxicity, 14,1s and death 14-t 7 have been reported in patients with acute overdoses. Psychosis due to acute overdosage has rarely been reported.~7, ~8 We report a case of acute psychosis after an accidental overdose with 1.2 g amantadine hydrochloride exacerbated by the concomitant use of diphenhydramine.
Eric R Snoey, MD Howard A Bessen, MD, FACEP Torrance, California From the Department of Emergency Medicine, Harbor-UCLA Medical Center, Torrance, California; and the UCLA School of Medicine, Los Angeles. Received for publication November 9, 1989. Accepted for publication December 1, 1989. Address for reprints: Howard A Bessen, MD, FACER Department of Emergency Medicine, Harbor-UCLA Medical Center, 1000 West Carson Street, Torrance, California 90509.
CASE REPORT
A 35-year-old woman was brought to the emergency department by police because of bizarre behavior. She had been found agitated and disoriented, running through the neighborhood in a nightgown. Screaming and inconsolable, che patient was unable to provide a coherent history and was placed on a psychiatric "hold" pending evaluation. On arrival, the patient was delirious and highly agitated, visualizing nonexistent people who were "watching and trying to hurt me." Her vital signs were blood pressure of 106/70 m m Hg; temperature, 37.1 C; pulse, 96i and respirations, 22. The skin was normal, and mucous membranes were moist. There was no evidence of trauma. Pupils were midpoint and reactive, and there was no nystagmus. Examination of the neck, chest, heart, abdomen, and extremities was unremarkable. With the exception of the patient's mental status, a detailed neurological examination was entirely normal. Laboratory evaluation included a CBC, electrolytes, liver and renal panels, urinalysis, and an ECG, all within normal limits. A tox-
19:6 June 1990
Annals of Emergency Medicine
666/83
AMANTADINE OVERDOSE Snoey & Bessen
i c o l o g y s c r e e n was n e g a t i v e for acetaminophen, amphetamines, antid e p r e s s a n t s , b a r b i t u r a t e s , cannabinoids, cocaine, ethanol, opiates, phencyclidine, phenothiazines, and propoxyphene. Because of worsening agitation, the patient was given loxapine and benztropine by the consulting psychiatrist. She was sedated successfully, but she remained disoriented and uncooperative. The course was punctuated by transient episodes in which she became more lucid, followed by a return to her previous delirium. Approximately 12 hours after presentation, the patient's family arrived and provided more information. The patient had no significant medical or psychiatric history but had recently developed an upper respiratory infection for which her physician had prescribed amantadine. Family members stated that the patient had mistakenly taken one tablet (100 mg) every two hours rather than every 12 hours as prescribed, resulting in an ingestion of 1.2 g during a 24-hour period. This was confirmed by counting the number of pills missing from the prescription bottle. The patient had also taken diphenhydramine 25 mg four times daily as prescribed for symptomatic relief. The patient's vital signs remained stable throughout her ED stay, and cardiac monitoring showed no dysrhythmias. She was admitted for observation, monitoring, and IV hydration. The patient's symptoms abated gradually during the next 48 hours, and she was discharged with a completely normal mental status. DISCUSSION Amantadine is considered the drug of choice in the treatment or chemoprophylaxis of influenza. 4 It inhibits the replication of influenza A viruses by a m e c h a n i s m that is not completely understood.4,19 Parkinson's disease involves a deficiency in dopamine activity in the basal ganglia, and amantadine acts to partially reverse this deficiency. Its efficacy in controlling extrapyramidal syndromes is also explained by increased dopamine availability. Specifically, amantadine is believed to increase dopamine activity by blocking the reuptake of dopamine into presynaptic neurons2O, 21 and by releasing dopamine from neuronal storage sites. 2o-22 Amantadine may also 84/669
enhance norepinephrine activity by similar m e c h a n i s m s . 13,23 These effects on neurotransmitters probably explain the prominent CNS toxicity caused by amantadine. Amantadine is well absorbed from the intestine and is not metabolized. In h e a l t h y volunteers, p e a k blood levels are reached within one to four hours after a single oral dose, and an average of 86% of the drug is recovered unchanged in the urine during the next four days. 24 The half-life of elimination is nine to 15 hours. 24,25 Longer half-lives (18 to 45 hours) have been reported in elderly patients, 26 and drug e l i m i n a t i o n is markedly slowed in patients with renal insufficiency, with a half-life of approximately eight days in hemodialysis patients. 25 The half-life in overdose has not been well defined. The recommended dose of amantadine both as an antiviral agent and in central movement disorders is 100 mg twice daily.4,~9, 21 Even at this therapeutic dose, a m a n t a d i n e m a y have significant side effects, primarily CNS. From 5% to 10% of healthy young adults develop side effects such as dizziness, insomnia, and impaired concentration. 4 Flaherty and Bellur reported a 14.6% incidence of side effects in a normal hospital employee population taking amantadine for influenza prophylaxis. Symptoms included mood elevation, insomnia, hypersomnia, m e m o r y disturbances, nightmares, paranoia, and delusions. 9 More dramatic side effects such as hallucinations have been reported, especially in p a t i e n t s who are elderly, ll, 12 t a k i n g m o r e t h a n 200 mg daily, lO,ll or taking anticholinergic drugs in a d d i t i o n to a m a n t a dine 5Ao,12,13 In our patient, the s i m u l t a n e o u s use of diphenhydramine probably exacerbated the overdose symptomatology. The combination of amantadine and an a n t i c h o l i n e r g i c agent (frequently used in the treatment of park i n s o n i s m and influenza) is m u c h more likely to induce CNS toxicity t h a n t r e a t m e n t w i t h e i t h e r drug alone.S,l°,12,13 In patients chronically taking therapeutic doses of amantadine, serious CNS side effects such as confusion and hallucinations almost always result from combined treatment with anticholinergic drugs.S,1°,12,13 Acute overdosage of amantadine presenting primarily with psychosis Annals of Emergency Medicine
has rarely been described. Fahn et al reported an acute psychosis in a 61year-old man after an intentional ingestion of 2.8 g a m a n t a d i n e . The patient was acutely delirious, with disorientation, confusion, and visual hallucinations. His m e n t a l status gradually returned to baseline over several days. 18 S i m p s o n et al described a 34-year-old man who took approximately 2.0 g amantadine and developed disorientation, hallucinations, and v i o l e n t b e h a v i o r ; the patient died suddenly 36 hours after admission.1 z Unlike our patient, neither of these patients had a neurologically normal baseline; the first had p a r k i n s o n i s m and severe depression, 18 and the second had a history of paranoid schizophrenia, lz Our patient had no dysrhythmias or other cardiovascular side effects. Cardiovascular toxicity from amantadine is unusual, but ventricular dysrhythmias can be produced in animals poisoned with amantadine, ~3 and case reports have documented the o c c u r r e n c e of life-threatening rhythm disturbances in patients with significant overdoses. Sartori et a114 and Brown et al is each described one case of malignant ventricular ectopy developing after large overdoses of amantadine; one of these patients had torsade de pointe in addition to v e n t r i c u l a r fibrillation and m o n o morphic ventricular tachycardia.14 Both patients had Q-T prolongation and episodes of bradycardia. The t r e a t m e n t of m o s t p a t i e n t s with amantadine toxicity is expectant and supportive. Observation and sometimes sedation are typically all that are required. Because a high percentage of amantadine is excreted unchanged in the urine, 24 maintaining an adequate urine output is probably important. In the setting of an acute overdose, standard measures such as gastric emptying and the administration of activated charcoal are recommended. 2z Physostigmine has been reported to reverse amantadineinduced delirium in an adult 2s and to reverse dystonic posturing and agitation in an amantadine-intoxicated child, 29 a l t h o u g h its effectiveness and the incidence of serious side effects 30 have not been studied in this setting. Very little drug is removed by hemodialysis.aS,,31, ~ The t r e a t m e n t of amantadine-induced d y s r h y t h m i a s has not been studied, although Sartori et al's pa19:6 June 1990
tient responded to cardioversion and lidocaine, whereas dopamine and isoproterenol were considered to exacerbate the rhythm disturbances: 4 The chemical structure and m e c h a n i s m of action of amantadine are similar to t h o s e of t r i c y c l i c a n t i d e p r e s sants,14, 33 but the ECG manifestations of a m a n t a d i n e i n t o x i c a t i o n have not been well characterized, and alkalinization therapy has not been studied in the setting of amantadineinduced dysrhythmias. The exact incidence of acute psychosis as a manifestation of amantadine toxicity cannot be readily determined from the literature. Overdosage is clearly an important cause of t h i s c o m p l i c a t i o n . D e c r e a s e d r e n a l c l e a r a n c e {a n o r m a l o c c u r r e n c e w i t h aging) and the concomitant use of anticholinergic drugs play a comp l i c a t i n g role. To lessen the risk of
toxicity, a lower-than-usual dose of amantadine is recommended for patients 65 or more years old or those with impaired renal function. 4 For influenza prophylaxis, a recent s t u d y has s h o w n t h a t l o w - d o s e amantadine (100 mg daily) is highly efficacious against experimental challenge with influenza virus and causes few side effects. 34 This dose has not yet been evaluated with clinical trials but may prove to be safe and effective.
SUMMARY A previously healthy 35-year-old woman developed an acute psychosis after ingesting 1.2 g amantadine in 24 hours. Diphenhydramine contributed to the toxic effects, which gradually resolved during a 48-hour time period. A m a n t a d i n e is c o m m o n l y prescribed for patients with parkinsonism and extrapyramidal syndromes, and in otherwise healthy individuals for influenza prophylaxis or therapy. Amantadine toxicity should be considered in the differential diagnosis of any acute psychiatric presentation in patients known to be taking the drug or with conditions c o m m o n l y treated with amantadine. Most patients with amantadine toxicity have benign clinical courses, although se-
19:6 June 1990
rious complications such as coma, seizures, cardiovascular toxicity, and death may occur.
REFERENCES 1. Davies WL, Gnmert RR, Haft RF, et al: Antiviral activity of one-adamantanarnine {amantadine). Science 1964;144:862-863. 2. Wendel HA, Snyder MT, Pell S: Trial of amantadine in epidemic influenza. Clin Pharmacol Ther 1966;7:38-43. 3. Togo Y, Hornick RB, Dawkins AT: Studies o n i n d u c e d i n f l u e n z a in m a n . J A M A 1968;203:1089-1094. 4. Centers for Disease Control: Prevention and control of influenza. Ann Intern Med 1987;107: 521-525. 5. Schwab RS, England AC, Poskanzer DC, et al: Arnantadine in the treatment of Parkinson's disease. JAMA 1969;208:1168-1170. 6. Parkes JD, Zilkha KJ, Calver DM, et al: Controlled trial of amantadine hydrochloride in Parkinson's disease. Lancet 1970;1:259-262. 7. Ananth J, Sangani H, Noonan JPA: Amantadine in drug-induced extrapyramidal signs: A comparative study. Int J Clin Pharmacol 1975; 11:323-326. 8. DiMascio A, Bernardo DL, Greenblatt DJ, et al: A controlled trial of amantadine in druginduced extrapyrarnidal disorders. Arch Gen Psychiatr 1976;33:599-602. 9. Flaherty JA, Bellur SN: Mental side effects of amantadine therapy: Its spectrum and characteristics in a normal population. J Clin Psychiatr 1981;42:344-345. 10. Parkes JD, Marsden P, Zilkha KJ, et al: Amantadine dosage in treatment of Parkinson's disease. Lancet 1970;1:1130-1133. 11. Postma JU, Van Tilburg W: Visual hallucinations and delirium during treatment with amantadine (Symrnetrel). l A m Geriatr Soc 1975;23:212-215.
psychosis from suicidal overdosage of amantadine. Arch Neurol 1971;25:45-48. 19. Sande MA, Mandell GL: Antimicrobial agents (continued): Antifungal and antiviral agents, in Gilman AG, Goodman LS, Rall TW, et al (eds}: The Pharmacological Basis of Therapeutics, ed 7. New York, Macmillan Publishing, 1985, chap 54, p 1219-1239. 20. Heimans RLH, Rand MJ, Fermessy MR: Effects of amantadine on uptake and release of doparnine by a particulate fraction of rat basal ganglia. J Pharm Pharmacol 1972;24:875-879. 21. Bianchine JR: Drugs for Parkinson's disease, spasticity, and acute muscle spasms, in Gilman AG, Goodman LS, Rail TW, et al (eds): The Pharmacological Basis of Therapeutics. ed 7. New York, Macmillan Publishing, 1985, chap 21, p 473-490. 22. Grelak RP, Clark R, Stump JM, et al: Amantadine-doparnine interaction: Possible mode of action in P a r k i n s o n i s m . Science 1970;169: 203-204. 23. Vernier VG, Harmon JB, Stump JM, et al: The toxicologic and pharmacologic properties of amantadine hydrochloride. Toxicol Appl Pharmacol 1969;15:642-665. 24. Bleidner WE, Harmon JB, Hewes WE, et al: Absorption, distribution and excretion of amantadine hydrochloride. J Pharmacol Exp Ther 1965;150:484-490. 25. Horadarn VW, Sharp JG, Smilack JD, et al: Pharmacokinetics of amantadine hydrochloride in subjects with normal and impaired renal function. Ann Intern Med 1981;94:454-458. 26. Aoki FY, Sitar DS: Amantadine kinetics in healthy elderly men: Implications for influenza prevention. Clin Pharrnacol Ther 1985;37: 137-144. 27. Spoerke DG, Rumack BH, Wallace D, et al: Amantadine, in Poisindex. Denver, Micromedex Inc, 1989. 28. Casey DE: Amantadine intoxication reversed by physostigmine (letter). N Engl J Med 1978;298:516.
12. Harper RW, Knothe BUC: Colored lilliputian hallucinations with amantadine. Med J Aust 1973;1:444-445.
29. Berkowitz CD: Treatment of acute amantadine toxicity with physostigmine. J Pediatr 1979; 95:144-145.
13. Parkes D: Amantadine. Adv Drug Res 1974; 8:11-81.
30. Pentel P, Peterson CD: Asystole complicating physostigmine treatment of tricyclic antidepressant overdose. Ann Emerg Med 1980;9: 588-590. 31. Armbruster KB, Rahn AC, Ing TS, et al: Amantadine toxicity in a patient with renal insufficiency. Nephron 1974;13:183-186.
14. Sartori M, Pratt CM, Young JB: Torsade de pointe: Malignant cardiac arrhythrnia induced by arnantadine poisoning. A m J Med 1984~77: 388-391. 15. Brown CR, Hernandez S, Kelly MT: Hypertherrnia and death from amantadine overdose {abstract). Vet Hum Toxicol 1987;29:463. 16. Cook PE, Derrner SW, McGurk T: Fatal overdose with amantadine. Can J Psychiatry 1986;31:757-758. 17. Simpson DM, Ramos F, Ramirez LF: Death of a psychiatric patient from amantadine pois o n i n g (letter). A m J Psychiatr 1988;145: 267-268. 18. Fahn S, Craddock G, Kumin G: Acute toxic
Annals of Emergency Medicine
32. Soung LS, Ing TS, Daugirdas JT, et al: Amantadine hydrochloride kinetics in hernodialysis patients. Ann Intern Med 1980;93: 46-49. 33. Hollister LE: Tricyclic antidepressants. N Engl J Med 1978;299:1106-1109. 34. Sears SD, Clements ML: Protective efficacy of low-dose amantadine in adults challenged with wild-type influenza A virus. Antimicrob Agents Chernother 1987;31:1470-1473.
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Acute Psychosis After Amantadine Overdose Amantadine is an antiviral agent that is also used in the treatment of parkinsonism and neuroleptic-induced extrapyramidal symptoms. Toxic effects of amantadine relate primarily to the central nervous system and range from mild symptoms to disorientation and hallucinations. Anticholinergic agents may exacerbate these effects. We report a case of unsuspected amantadine overdose in a previously healthy 35-year-old woman who presented with acute psychosis manifested by delirium and visual hallucinations. Concomitant use of diphenhydramine contributed to the clinical presentation. Amantadine toxicity should be considered in the differential diagnosis of altered mental status in patients known to be taking the drug or with conditions commonly treated with amantadine. /Snoey ER, Bessen HA: Acute psychosis after amantadine overdose. A n n Emerg Med June 1990;I9:668-670.] INTRODUCTION Amantadine is a synthetic tricyclic amine with antiviral activity. 1-3 It is used for the prophylaxis and treatment of infections caused by various strains of influenza A virus. 4 In 1969, Schwab et al described the remission of parkinsonism in a 58-year-old woman who was receiving amantadine for influenza prophylaxis, s This serendipitous observation led to further trials confirming its efficacy.5, 6 Amantadine has also proven helpful in the treatment of neuroleptic-induced extrapyramidal symptoms. 7,s Side effects of amantadine relate primarily to the central nervous system (CNS) and may occur even in normal subjects given therapeutic doses. 9 Severe amantadine-induced CNS symptoms such as disorientation and hallucinations have been reported in patients on chronic amantadine therapy, S,10-~2 especially those also taking anticholinergic agents.S,~°,~2, ~,3 Coma, 14 seizures, 1s cardiovascular toxicity, 14,1s and death 14-t 7 have been reported in patients with acute overdoses. Psychosis due to acute overdosage has rarely been reported.~7, ~8 We report a case of acute psychosis after an accidental overdose with 1.2 g amantadine hydrochloride exacerbated by the concomitant use of diphenhydramine.
Eric R Snoey, MD Howard A Bessen, MD, FACEP Torrance, California From the Department of Emergency Medicine, Harbor-UCLA Medical Center, Torrance, California; and the UCLA School of Medicine, Los Angeles. Received for publication November 9, 1989. Accepted for publication December 1, 1989. Address for reprints: Howard A Bessen, MD, FACER Department of Emergency Medicine, Harbor-UCLA Medical Center, 1000 West Carson Street, Torrance, California 90509.
CASE REPORT
A 35-year-old woman was brought to the emergency department by police because of bizarre behavior. She had been found agitated and disoriented, running through the neighborhood in a nightgown. Screaming and inconsolable, che patient was unable to provide a coherent history and was placed on a psychiatric "hold" pending evaluation. On arrival, the patient was delirious and highly agitated, visualizing nonexistent people who were "watching and trying to hurt me." Her vital signs were blood pressure of 106/70 m m Hg; temperature, 37.1 C; pulse, 96i and respirations, 22. The skin was normal, and mucous membranes were moist. There was no evidence of trauma. Pupils were midpoint and reactive, and there was no nystagmus. Examination of the neck, chest, heart, abdomen, and extremities was unremarkable. With the exception of the patient's mental status, a detailed neurological examination was entirely normal. Laboratory evaluation included a CBC, electrolytes, liver and renal panels, urinalysis, and an ECG, all within normal limits. A tox-
19:6 June 1990
Annals of Emergency Medicine
666/83
AMANTADINE OVERDOSE Snoey & Bessen
i c o l o g y s c r e e n was n e g a t i v e for acetaminophen, amphetamines, antid e p r e s s a n t s , b a r b i t u r a t e s , cannabinoids, cocaine, ethanol, opiates, phencyclidine, phenothiazines, and propoxyphene. Because of worsening agitation, the patient was given loxapine and benztropine by the consulting psychiatrist. She was sedated successfully, but she remained disoriented and uncooperative. The course was punctuated by transient episodes in which she became more lucid, followed by a return to her previous delirium. Approximately 12 hours after presentation, the patient's family arrived and provided more information. The patient had no significant medical or psychiatric history but had recently developed an upper respiratory infection for which her physician had prescribed amantadine. Family members stated that the patient had mistakenly taken one tablet (100 mg) every two hours rather than every 12 hours as prescribed, resulting in an ingestion of 1.2 g during a 24-hour period. This was confirmed by counting the number of pills missing from the prescription bottle. The patient had also taken diphenhydramine 25 mg four times daily as prescribed for symptomatic relief. The patient's vital signs remained stable throughout her ED stay, and cardiac monitoring showed no dysrhythmias. She was admitted for observation, monitoring, and IV hydration. The patient's symptoms abated gradually during the next 48 hours, and she was discharged with a completely normal mental status. DISCUSSION Amantadine is considered the drug of choice in the treatment or chemoprophylaxis of influenza. 4 It inhibits the replication of influenza A viruses by a m e c h a n i s m that is not completely understood.4,19 Parkinson's disease involves a deficiency in dopamine activity in the basal ganglia, and amantadine acts to partially reverse this deficiency. Its efficacy in controlling extrapyramidal syndromes is also explained by increased dopamine availability. Specifically, amantadine is believed to increase dopamine activity by blocking the reuptake of dopamine into presynaptic neurons2O, 21 and by releasing dopamine from neuronal storage sites. 2o-22 Amantadine may also 84/669
enhance norepinephrine activity by similar m e c h a n i s m s . 13,23 These effects on neurotransmitters probably explain the prominent CNS toxicity caused by amantadine. Amantadine is well absorbed from the intestine and is not metabolized. In h e a l t h y volunteers, p e a k blood levels are reached within one to four hours after a single oral dose, and an average of 86% of the drug is recovered unchanged in the urine during the next four days. 24 The half-life of elimination is nine to 15 hours. 24,25 Longer half-lives (18 to 45 hours) have been reported in elderly patients, 26 and drug e l i m i n a t i o n is markedly slowed in patients with renal insufficiency, with a half-life of approximately eight days in hemodialysis patients. 25 The half-life in overdose has not been well defined. The recommended dose of amantadine both as an antiviral agent and in central movement disorders is 100 mg twice daily.4,~9, 21 Even at this therapeutic dose, a m a n t a d i n e m a y have significant side effects, primarily CNS. From 5% to 10% of healthy young adults develop side effects such as dizziness, insomnia, and impaired concentration. 4 Flaherty and Bellur reported a 14.6% incidence of side effects in a normal hospital employee population taking amantadine for influenza prophylaxis. Symptoms included mood elevation, insomnia, hypersomnia, m e m o r y disturbances, nightmares, paranoia, and delusions. 9 More dramatic side effects such as hallucinations have been reported, especially in p a t i e n t s who are elderly, ll, 12 t a k i n g m o r e t h a n 200 mg daily, lO,ll or taking anticholinergic drugs in a d d i t i o n to a m a n t a dine 5Ao,12,13 In our patient, the s i m u l t a n e o u s use of diphenhydramine probably exacerbated the overdose symptomatology. The combination of amantadine and an a n t i c h o l i n e r g i c agent (frequently used in the treatment of park i n s o n i s m and influenza) is m u c h more likely to induce CNS toxicity t h a n t r e a t m e n t w i t h e i t h e r drug alone.S,l°,12,13 In patients chronically taking therapeutic doses of amantadine, serious CNS side effects such as confusion and hallucinations almost always result from combined treatment with anticholinergic drugs.S,1°,12,13 Acute overdosage of amantadine presenting primarily with psychosis Annals of Emergency Medicine
has rarely been described. Fahn et al reported an acute psychosis in a 61year-old man after an intentional ingestion of 2.8 g a m a n t a d i n e . The patient was acutely delirious, with disorientation, confusion, and visual hallucinations. His m e n t a l status gradually returned to baseline over several days. 18 S i m p s o n et al described a 34-year-old man who took approximately 2.0 g amantadine and developed disorientation, hallucinations, and v i o l e n t b e h a v i o r ; the patient died suddenly 36 hours after admission.1 z Unlike our patient, neither of these patients had a neurologically normal baseline; the first had p a r k i n s o n i s m and severe depression, 18 and the second had a history of paranoid schizophrenia, lz Our patient had no dysrhythmias or other cardiovascular side effects. Cardiovascular toxicity from amantadine is unusual, but ventricular dysrhythmias can be produced in animals poisoned with amantadine, ~3 and case reports have documented the o c c u r r e n c e of life-threatening rhythm disturbances in patients with significant overdoses. Sartori et a114 and Brown et al is each described one case of malignant ventricular ectopy developing after large overdoses of amantadine; one of these patients had torsade de pointe in addition to v e n t r i c u l a r fibrillation and m o n o morphic ventricular tachycardia.14 Both patients had Q-T prolongation and episodes of bradycardia. The t r e a t m e n t of m o s t p a t i e n t s with amantadine toxicity is expectant and supportive. Observation and sometimes sedation are typically all that are required. Because a high percentage of amantadine is excreted unchanged in the urine, 24 maintaining an adequate urine output is probably important. In the setting of an acute overdose, standard measures such as gastric emptying and the administration of activated charcoal are recommended. 2z Physostigmine has been reported to reverse amantadineinduced delirium in an adult 2s and to reverse dystonic posturing and agitation in an amantadine-intoxicated child, 29 a l t h o u g h its effectiveness and the incidence of serious side effects 30 have not been studied in this setting. Very little drug is removed by hemodialysis.aS,,31, ~ The t r e a t m e n t of amantadine-induced d y s r h y t h m i a s has not been studied, although Sartori et al's pa19:6 June 1990
tient responded to cardioversion and lidocaine, whereas dopamine and isoproterenol were considered to exacerbate the rhythm disturbances: 4 The chemical structure and m e c h a n i s m of action of amantadine are similar to t h o s e of t r i c y c l i c a n t i d e p r e s sants,14, 33 but the ECG manifestations of a m a n t a d i n e i n t o x i c a t i o n have not been well characterized, and alkalinization therapy has not been studied in the setting of amantadineinduced dysrhythmias. The exact incidence of acute psychosis as a manifestation of amantadine toxicity cannot be readily determined from the literature. Overdosage is clearly an important cause of t h i s c o m p l i c a t i o n . D e c r e a s e d r e n a l c l e a r a n c e {a n o r m a l o c c u r r e n c e w i t h aging) and the concomitant use of anticholinergic drugs play a comp l i c a t i n g role. To lessen the risk of
toxicity, a lower-than-usual dose of amantadine is recommended for patients 65 or more years old or those with impaired renal function. 4 For influenza prophylaxis, a recent s t u d y has s h o w n t h a t l o w - d o s e amantadine (100 mg daily) is highly efficacious against experimental challenge with influenza virus and causes few side effects. 34 This dose has not yet been evaluated with clinical trials but may prove to be safe and effective.
SUMMARY A previously healthy 35-year-old woman developed an acute psychosis after ingesting 1.2 g amantadine in 24 hours. Diphenhydramine contributed to the toxic effects, which gradually resolved during a 48-hour time period. A m a n t a d i n e is c o m m o n l y prescribed for patients with parkinsonism and extrapyramidal syndromes, and in otherwise healthy individuals for influenza prophylaxis or therapy. Amantadine toxicity should be considered in the differential diagnosis of any acute psychiatric presentation in patients known to be taking the drug or with conditions c o m m o n l y treated with amantadine. Most patients with amantadine toxicity have benign clinical courses, although se-
19:6 June 1990
rious complications such as coma, seizures, cardiovascular toxicity, and death may occur.
REFERENCES 1. Davies WL, Gnmert RR, Haft RF, et al: Antiviral activity of one-adamantanarnine {amantadine). Science 1964;144:862-863. 2. Wendel HA, Snyder MT, Pell S: Trial of amantadine in epidemic influenza. Clin Pharmacol Ther 1966;7:38-43. 3. Togo Y, Hornick RB, Dawkins AT: Studies o n i n d u c e d i n f l u e n z a in m a n . J A M A 1968;203:1089-1094. 4. Centers for Disease Control: Prevention and control of influenza. Ann Intern Med 1987;107: 521-525. 5. Schwab RS, England AC, Poskanzer DC, et al: Arnantadine in the treatment of Parkinson's disease. JAMA 1969;208:1168-1170. 6. Parkes JD, Zilkha KJ, Calver DM, et al: Controlled trial of amantadine hydrochloride in Parkinson's disease. Lancet 1970;1:259-262. 7. Ananth J, Sangani H, Noonan JPA: Amantadine in drug-induced extrapyramidal signs: A comparative study. Int J Clin Pharmacol 1975; 11:323-326. 8. DiMascio A, Bernardo DL, Greenblatt DJ, et al: A controlled trial of amantadine in druginduced extrapyrarnidal disorders. Arch Gen Psychiatr 1976;33:599-602. 9. Flaherty JA, Bellur SN: Mental side effects of amantadine therapy: Its spectrum and characteristics in a normal population. J Clin Psychiatr 1981;42:344-345. 10. Parkes JD, Marsden P, Zilkha KJ, et al: Amantadine dosage in treatment of Parkinson's disease. Lancet 1970;1:1130-1133. 11. Postma JU, Van Tilburg W: Visual hallucinations and delirium during treatment with amantadine (Symrnetrel). l A m Geriatr Soc 1975;23:212-215.
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