The Role of Amantadine Withdrawal in 3 Cases of Treatment-Refractory Altered Mental Status

Abstract

Amantadine, which was originally developed as an antiviral medication, functions as a dopamine agonist in the central nervous system and consequently is utilized in the treatment of Parkinson disease, drug-induced extrapyramidal reactions, and neuroleptic malignant syndrome. For reasons that are not entirely understood, abrupt changes in amantadine dosage can produce a severe withdrawal syndrome. Existing medical literature describes case reports of amantadine withdrawal leading to delirium, which at times has progressed to neuroleptic malignant syndrome. Amantadine withdrawal may be under-recognized by mental health clinicians, which has the potential to lead to protracted hospital courses and suboptimal outcomes. The goal of this case series is to highlight the role of amantadine withdrawal in the cases of 3 medically complex patients with altered mental status. In the first case, the cognitive side effects of electroconvulsive therapy masked acute amantadine withdrawal in a 64-year-old man with Parkinson disease. In the second case, a 75-year-old depressed patient developed a catatonic delirium when amantadine was discontinued. Finally, a refractory case of neuroleptic malignant syndrome in a 57-year-old patient with schizoaffective disorder rapidly resolved with the reintroduction of outpatient amantadine. These cases highlight several learning objectives regarding amantadine withdrawal syndrome: First, it may be concealed by co-occurring causes of delirium in medically complex patients. Second, its symptoms are likely to be related to a cortical and limbic dopamine shortage, which may be reversed with electroconvulsive therapy or reintroduction of amantadine. Third, its clinical presentation may occur on a spectrum and may include features suggestive of delirium, catatonia, or neuroleptic malignant syndrome.

Implications of dopaminergic medication withdrawal in Parkinson’s disease

“…No alternative explanation for the delirium was evident and other therapies (such as clozapine or intravenous hydration) failed to achieve any improvement. There are a few similar case studies, reporting that amantadine withdrawal contributed to a malignant neuroleptic syndrome (Brantley et al 2009 ; Fryml et al 2017 ).…”

Neuroleptic malignant-like syndrome causing thrombocytopaenia: a rare association

“…Dopamine receptor blockage in hypothalamus causes hyperthermia and autonomic dysfunction; while that in nigrostriatal pathways causes rigidity and tremors 11. Similar disease can also occur in a patient with Parkinson’s disease due to sudden withdrawal of anti-Parkinson dopaminergic drugs and is called NM-like syndrome 1–3. It is believed to have better prognosis than NMS 3.…”

“…Neuroleptic malignant-like syndrome or parkinsonism hyperpyrexia syndrome is a rare but potentially fatal complication of sudden withdrawal of anti-Parkinson medication 1–3. Clinical features are similar to neuroleptic malignant syndrome (NMS) like hyperthermia, autonomic dysfunction, altered sensorium, muscle rigidity and increased serum creatine phosphokinase (CPK) levels 4 5.…”

Drug management in older Parkinson’s disease patients

“…Withdrawal of the drug may lead to delirium, neuroleptic malignant syndrome, and motor deterioration. 29,30 Hence, it is not commonly used in older patients with PD, particularly those with cognitive impairment. Nonetheless, amantadine can reduce levodopa-induced dyskinesia and may have a role in selected PD patients with such condition.…”