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Delirium with manic and psychotic features associated with amantadine
General Hospital Psychiatry xxx (2013) xxx–xxx
Contents lists available at SciVerse ScienceDirect
General Hospital Psychiatry journal homepage: http://www.ghpjournal.com
Case report
Delirium with manic and psychotic features associated with amantadine Adriana D. Neagoe, M.D. ⁎ Harvard Medical School, Boston MA 02302, USA
a r t i c l e
i n f o
Article history: Received 28 January 2013 Revised 26 March 2013 Accepted 27 March 2013 Available online xxxx Keywords: Amantadine Delirium Psychosis Mania
a b s t r a c t While clinicians are familiar with psychosis as a complication in the long-term treatment with amantadine, rapid psychiatric complications are of much less concern. In the case presented, severe decompensation in mental status occurred within 48 h of initiation of standard doses of amantadine hydrochloride. Clinicians should be alert not only for delayed complications but also for early-onset mental decompensation in elderly patients with influenza A treated with amantadine. © 2013 Elsevier Inc. All rights reserved.
Amantadine reduces the severity and the duration of systemic symptoms in individuals with influenza A, but it should be employed cautiously in elderly patients due to its mild dopaminergic and anticholinergic qualities [1]. Psychosis and acute confusional states are often reported when amantadine is used for long-term treatment of parkinsonian symptoms. However, there is typically a “silent interval’ of up to several months between initiation of amantadine and the emergence of above side effects [2]. In patients with influenza A, this interval ordinarily permits a complete course of treatment before the mental status changes. In contrast, we present a case in which severe decompensation in mental status occurred within 48 h of initiation of standard doses of amantadine hydrochloride. Ms. A, an 89-year-old woman with mild cognitive deficits, was admitted to the hospital after a syncopal attack. Prior to this, she had been living fairly independently. She had been in excellent health up to 1 week prior to admission and had no significant medical, psychiatric or substance abuse history. Her vital signs on admission showed blood pressure of 112/51, pulse of 90 and a fever of 103.7°F. Physical exam was unremarkable, except for rhinorrhea and some evidence of dehydration. Laboratory studies revealed complete blood count, coagulation panel, electrolytes, glucose, urea and creatinine within normal limits. However, B12 level was low at 117. A brain computed tomography without contrast was normal. Based on physical exam, electrocardiogram and history, cardiology consultation concluded that her syncope was probably due to dehydration. One week prior to the admission, she had visited the Emergency Service for swollen lower extremities. This was attributed to an “allergic reaction” and she was given methylprednisolone 125 mg intravenously. She was discharged home on a regimen of prednisone ⁎ Tel.: +1 508 897 2000. E-mail address: [email protected].
20 mg twice daily for 5 days with a tapering off schedule and diphenhydramine 25 mg at bedtime. She did not present flu symptoms at that time. Upon admission to our facility, prednisone and diphenhydramine were discontinued. Ms. A had a nasopharyngeal swab positive for influenza A, and she was started on amantadine hydrochloride 100 mg twice daily. Two days later, she became increasingly disoriented for time, place and persons and agitated. On the third day, when the psychiatry service was consulted, she was in a Posey vest restraint, talking to herself. She showed loud, pressured speech; loosening of associations; and inappropriately elevated affect. Delusions with paranoid quality were accompanied by visual and auditory hallucinations of nonexistent neighbors and doctors penetrating the walls of her room. Collateral information from her family and family physician had not revealed any prior psychotic or confusional symptoms. Her Global Assessment of Function score prior to this admission was retrospectively estimated to be 70, whereas on the day we met her, it was 25. The patient’s regimen was changed from amantadine to oseltamivir 75 mg daily for 2 more days. Forty-eight hours later, her mental status improved considerably: paranoid delusion; hallucinations; agitation; and loud, pressured speech were no longer present. Residual disorientation abated within the next few days. This patient experienced a bout of agitated delirium with psychosis associated with use of a weak dopamine agonist, amantadine. In contrast with other numerous reports in the literature where amantadine was prescribed for long-term anti-parkinsonian effect, our patient did not show the typical “lag phase” between the initiation of amantadine and the onset of mental side effects. Indeed, a PubMed search using the key terms amantadine, delirium and psychosis revealed only three other case reports studies with rapid psychiatric complications: one presenting an acute psychosis secondary to an amantadine overdose [3], another an acute psychosis induced by a
0163-8343/$ – see front matter © 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.genhosppsych.2013.03.023
Please cite this article as: Neagoe AD, Delirium with manic and psychotic features associated with amantadine, Gen Hosp Psychiatry (2013), http://dx.doi.org/10.1016/j.genhosppsych.2013.03.023
e2
A.D. Neagoe / General Hospital Psychiatry xxx (2013) xxx–xxx
combination of amantadine with phenylpropanolamine [4] and a third one study showing two cases of psychosis out of 295 subjects of an antiviral trial of amantadine [5]. However, none of them involved treatment with a standard dose of amantadine in the absence of other concomitant medications in an elderly patient. Some authors have suggested that amantadine’s psychotic side effects generally occur in the context of high plasma concentration (1.0–5.0 μg/ml) [1]. Although we did not obtain a plasma amantadine level, there is some evidence that the dose prescribed to our patient may have been excessive given her age. Indeed, 20%–40% of elderly patients experience neuropsychiatric side effects even at doses of 100 mg/day [1]; however, at this dose, the minimum length of time for such side effects to emerge is unknown. Of note, 5 days on 100 mg/day of amantadine would be sufficient for the treatment of influenza A [1]. Although we believe that amantadine was the primary cause of the patient’s decompensation, we cannot exclude other factors. Evidence of premorbid cognitive dysfunction and B12 deficiency suggests that this patient’s brain may have been particularly vulnerable to druginduced toxicity. Influenza A infection and dehydration may have increased this vulnerability. In theory, sudden discontinuation of antihistamines with anticholinergic properties as diphenhydramine might provoke a central “cholinergic rebound,” which may have contributed to the altered mental state of this patient. Neuropsychiatric complications have long been associated with both the use and sudden discontinuation of prednisone. However, discontinuation of corticosteroids more typically provokes a depressive syndrome, whereas the present case showed manic features. Moreover, the dose and the duration of treatment with prednisone were minimal.
Despite these possible confounding factors, we believe that the time course of the patient’s symptoms and their resolution are most consistent with amantadine neurotoxicity. We therefore urge caution with the use of amantadine in elderly patients with underlying risk factors for neuropsychiatric complications. Alternative antiviral agents such as oseltamivir should be considered. A careful assessment of recent medication for their possible withdrawal effects should also be carried out. Clinicians should be alert for both early-onset and delayed complications of amantadine. If it must be used in high-risk patients, dosing should be conservative since lower doses of 100 mg/ day of amantadine are protective for influenza A and better tolerated according to the current Disease Control and Prevention guidelines [6]. Finally, clinicians should be alert for early-onset neuropsychiatric complications. References [1] Hayden FG. Antimicrobial agents. Chapter 50. In: Hardman JG, Limbird LE, editors. Goodman & Gillman’s the pharmacological basis of therapeutics. 10th ed. New York: McGraw-Hill; 2001. p. 1328–30. [2] Harper RW, Knothe UC. Colored Lilliputian hallucinations with amantadine. Med J Aust 1973;1:444–5. [3] Snoey ER, Bessen HA. Acute psychosis after amantadine overdose. Ann Emerg Med 1990;19(6):668–70. [4] Stroe AE, Hall J, Amin F. Psychotic episode related to phenylpropanolamine and amantadine in a healthy female. Gen Hosp Psychiatry 1995;17(6):457–8. [5] Flaherty JA, Bellur SN. Mental side effects of amantadine therapy: its spectrum and characteristics in a normal population. J Clin Psychiatry 1981;42(9):344–5. [6] Centers for Disease Control and Prevention. National Center for Immunization and Respiratory Diseases (NCIRD). Seasonal influenza (flu)-antiviral dosage. Accessed March 18, 2013 http://www.cdc.gov/flu/professionals/antivirals/antiviral-dosage. htm; 2013.
Please cite this article as: Neagoe AD, Delirium with manic and psychotic features associated with amantadine, Gen Hosp Psychiatry (2013), http://dx.doi.org/10.1016/j.genhosppsych.2013.03.023
Contents lists available at SciVerse ScienceDirect
General Hospital Psychiatry journal homepage: http://www.ghpjournal.com
Case report
Delirium with manic and psychotic features associated with amantadine Adriana D. Neagoe, M.D. ⁎ Harvard Medical School, Boston MA 02302, USA
a r t i c l e
i n f o
Article history: Received 28 January 2013 Revised 26 March 2013 Accepted 27 March 2013 Available online xxxx Keywords: Amantadine Delirium Psychosis Mania
a b s t r a c t While clinicians are familiar with psychosis as a complication in the long-term treatment with amantadine, rapid psychiatric complications are of much less concern. In the case presented, severe decompensation in mental status occurred within 48 h of initiation of standard doses of amantadine hydrochloride. Clinicians should be alert not only for delayed complications but also for early-onset mental decompensation in elderly patients with influenza A treated with amantadine. © 2013 Elsevier Inc. All rights reserved.
Amantadine reduces the severity and the duration of systemic symptoms in individuals with influenza A, but it should be employed cautiously in elderly patients due to its mild dopaminergic and anticholinergic qualities [1]. Psychosis and acute confusional states are often reported when amantadine is used for long-term treatment of parkinsonian symptoms. However, there is typically a “silent interval’ of up to several months between initiation of amantadine and the emergence of above side effects [2]. In patients with influenza A, this interval ordinarily permits a complete course of treatment before the mental status changes. In contrast, we present a case in which severe decompensation in mental status occurred within 48 h of initiation of standard doses of amantadine hydrochloride. Ms. A, an 89-year-old woman with mild cognitive deficits, was admitted to the hospital after a syncopal attack. Prior to this, she had been living fairly independently. She had been in excellent health up to 1 week prior to admission and had no significant medical, psychiatric or substance abuse history. Her vital signs on admission showed blood pressure of 112/51, pulse of 90 and a fever of 103.7°F. Physical exam was unremarkable, except for rhinorrhea and some evidence of dehydration. Laboratory studies revealed complete blood count, coagulation panel, electrolytes, glucose, urea and creatinine within normal limits. However, B12 level was low at 117. A brain computed tomography without contrast was normal. Based on physical exam, electrocardiogram and history, cardiology consultation concluded that her syncope was probably due to dehydration. One week prior to the admission, she had visited the Emergency Service for swollen lower extremities. This was attributed to an “allergic reaction” and she was given methylprednisolone 125 mg intravenously. She was discharged home on a regimen of prednisone ⁎ Tel.: +1 508 897 2000. E-mail address: [email protected].
20 mg twice daily for 5 days with a tapering off schedule and diphenhydramine 25 mg at bedtime. She did not present flu symptoms at that time. Upon admission to our facility, prednisone and diphenhydramine were discontinued. Ms. A had a nasopharyngeal swab positive for influenza A, and she was started on amantadine hydrochloride 100 mg twice daily. Two days later, she became increasingly disoriented for time, place and persons and agitated. On the third day, when the psychiatry service was consulted, she was in a Posey vest restraint, talking to herself. She showed loud, pressured speech; loosening of associations; and inappropriately elevated affect. Delusions with paranoid quality were accompanied by visual and auditory hallucinations of nonexistent neighbors and doctors penetrating the walls of her room. Collateral information from her family and family physician had not revealed any prior psychotic or confusional symptoms. Her Global Assessment of Function score prior to this admission was retrospectively estimated to be 70, whereas on the day we met her, it was 25. The patient’s regimen was changed from amantadine to oseltamivir 75 mg daily for 2 more days. Forty-eight hours later, her mental status improved considerably: paranoid delusion; hallucinations; agitation; and loud, pressured speech were no longer present. Residual disorientation abated within the next few days. This patient experienced a bout of agitated delirium with psychosis associated with use of a weak dopamine agonist, amantadine. In contrast with other numerous reports in the literature where amantadine was prescribed for long-term anti-parkinsonian effect, our patient did not show the typical “lag phase” between the initiation of amantadine and the onset of mental side effects. Indeed, a PubMed search using the key terms amantadine, delirium and psychosis revealed only three other case reports studies with rapid psychiatric complications: one presenting an acute psychosis secondary to an amantadine overdose [3], another an acute psychosis induced by a
0163-8343/$ – see front matter © 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.genhosppsych.2013.03.023
Please cite this article as: Neagoe AD, Delirium with manic and psychotic features associated with amantadine, Gen Hosp Psychiatry (2013), http://dx.doi.org/10.1016/j.genhosppsych.2013.03.023
e2
A.D. Neagoe / General Hospital Psychiatry xxx (2013) xxx–xxx
combination of amantadine with phenylpropanolamine [4] and a third one study showing two cases of psychosis out of 295 subjects of an antiviral trial of amantadine [5]. However, none of them involved treatment with a standard dose of amantadine in the absence of other concomitant medications in an elderly patient. Some authors have suggested that amantadine’s psychotic side effects generally occur in the context of high plasma concentration (1.0–5.0 μg/ml) [1]. Although we did not obtain a plasma amantadine level, there is some evidence that the dose prescribed to our patient may have been excessive given her age. Indeed, 20%–40% of elderly patients experience neuropsychiatric side effects even at doses of 100 mg/day [1]; however, at this dose, the minimum length of time for such side effects to emerge is unknown. Of note, 5 days on 100 mg/day of amantadine would be sufficient for the treatment of influenza A [1]. Although we believe that amantadine was the primary cause of the patient’s decompensation, we cannot exclude other factors. Evidence of premorbid cognitive dysfunction and B12 deficiency suggests that this patient’s brain may have been particularly vulnerable to druginduced toxicity. Influenza A infection and dehydration may have increased this vulnerability. In theory, sudden discontinuation of antihistamines with anticholinergic properties as diphenhydramine might provoke a central “cholinergic rebound,” which may have contributed to the altered mental state of this patient. Neuropsychiatric complications have long been associated with both the use and sudden discontinuation of prednisone. However, discontinuation of corticosteroids more typically provokes a depressive syndrome, whereas the present case showed manic features. Moreover, the dose and the duration of treatment with prednisone were minimal.
Despite these possible confounding factors, we believe that the time course of the patient’s symptoms and their resolution are most consistent with amantadine neurotoxicity. We therefore urge caution with the use of amantadine in elderly patients with underlying risk factors for neuropsychiatric complications. Alternative antiviral agents such as oseltamivir should be considered. A careful assessment of recent medication for their possible withdrawal effects should also be carried out. Clinicians should be alert for both early-onset and delayed complications of amantadine. If it must be used in high-risk patients, dosing should be conservative since lower doses of 100 mg/ day of amantadine are protective for influenza A and better tolerated according to the current Disease Control and Prevention guidelines [6]. Finally, clinicians should be alert for early-onset neuropsychiatric complications. References [1] Hayden FG. Antimicrobial agents. Chapter 50. In: Hardman JG, Limbird LE, editors. Goodman & Gillman’s the pharmacological basis of therapeutics. 10th ed. New York: McGraw-Hill; 2001. p. 1328–30. [2] Harper RW, Knothe UC. Colored Lilliputian hallucinations with amantadine. Med J Aust 1973;1:444–5. [3] Snoey ER, Bessen HA. Acute psychosis after amantadine overdose. Ann Emerg Med 1990;19(6):668–70. [4] Stroe AE, Hall J, Amin F. Psychotic episode related to phenylpropanolamine and amantadine in a healthy female. Gen Hosp Psychiatry 1995;17(6):457–8. [5] Flaherty JA, Bellur SN. Mental side effects of amantadine therapy: its spectrum and characteristics in a normal population. J Clin Psychiatry 1981;42(9):344–5. [6] Centers for Disease Control and Prevention. National Center for Immunization and Respiratory Diseases (NCIRD). Seasonal influenza (flu)-antiviral dosage. Accessed March 18, 2013 http://www.cdc.gov/flu/professionals/antivirals/antiviral-dosage. htm; 2013.
Please cite this article as: Neagoe AD, Delirium with manic and psychotic features associated with amantadine, Gen Hosp Psychiatry (2013), http://dx.doi.org/10.1016/j.genhosppsych.2013.03.023