Drug‐induced parkinsonism: A review of 17 years' experience in a regional pharmacovigilance center in France

Abstract

Besides antipsychotics, several drugs can induce parkinsonism. We review spontaneous notifications of drug-induced or -worsened parkinsonism to a French regional pharmacovigilance center between 1993 and 2009. During these 17 years, 20,855 adverse drug reactions have been reported, including 155 (0.7%) cases of drug-induced or -worsened parkinsonism. Most of the notifications have involved aged patients (48% between 60 and 79 years) and females (60%). "Seriousness" was found in 43.9% of cases. Worsening of parkinsonism occurred in 28 patients suffering from idiopathic Parkinson's disease. Sixty-nine percent of drug-induced or -worsened parkinsonism cases were observed during the first 3 months after introduction of the "suspect" drug (involving mainly central dopaminergic antagonists). A second peak (20%) was found 12 months after drug introduction (mainly caused by calcium channel blockers). The most frequently reported parkinsonian symptom was rigidity (78.7%). The three cardinal symptoms were found in 37.4% of notifications. Evolution was favorable (after partial or complete withdrawal of suspect drug[s]) in 88.7% of cases. Among the 261 suspect drugs, most involved central dopaminergic antagonists (49%), followed by antidepressants (8%), calcium channel blockers (5%), peripheral dopaminergic antagonists (5%), and H1 antihistamines (5%). Cases with lithium, valproic acid, amiodarone, anticholinesterases, or trimetazidine were also found. Three notifications were the result of pharmacokinetic interactions. We found that drug-induced or -worsened parkinsonism is an often "serious," but reversible, adverse drug reaction. It occurred more frequently between 60 and 79 years. Rigidity was the most frequently reported symptom. Approximately 50% of drug-induced or -worsened parkinsonism cases spontaneously reported were related to drugs other than antipsychotics. Drug-induced or -worsened parkinsonism can also be explained by pharmacokinetic drug interactions.

Drug-induced parkinsonism: diagnosis and management

“…According to the DSM criteria, DIP must become apparent within a few weeks of a change in antipsychotic drug treatment, but there are exceptions. With central dopamine antagonists, most DIP cases develop within 3 months, 15,16 but drug exposure up to 12 months may be necessary in the case of calcium channel blockers, 16 even longer in valproate users. 17 There is no consensus regarding the duration of the recovery period to allow motor signs to fully remit and confirm the diagnosis of DIP following removal of the causative agent, but a drug-free interval of at least 6 months is generally recommended.…”

“…13,24 A preponderance of women is often reported, attributed to drug dosing or interaction issues or hormonal influences. 15,16,18,[25][26][27][28] In addition to old age and female sex, commonly accepted patient-related risk factors for DIP ( In a group of 67 patients with intellectual disability, DIP did not correlate with overt brain damage. 37 Dopamine receptor gene variations seem uninvolved.…”

“…16 Typical, first-generation antipsychotics with high affinity for dopamine D2 receptors constitute a distinct class, including phenothiazines (eg, chlorpromazine, levomepromazine, thioridazine, perphenazine, fluphenazine), thioxanthenes (eg, flupentixol, thiothixene, zuclopenthixol), diphenylbutylpiperidines (eg, pimozide), dibenzoxazepines (eg, loxapine or its metabolite amoxapine), and butyrophenones (eg, haloperidol). Their risk is likely influenced by their antimuscarinic properties.…”

“…1 Many cases are serious enough to be spontaneously reported to sanitary agencies. 7 The condition is not reversible in at least 10% of cases and carries a risk of morbidity and mortality particularly in the elderly, 8 especially if neuroleptic malignant syndrome (NMS) develops. Clinicians must remain wary of its development and manage it diligently.…”

“…17 The underlying molecular mechanisms remain elusive, possibly involving mitochondrial dysfunction and impaired oxidative phosphorylation. 49 Serotonergic (5-HT) antidepressants have long been associated with an intermediate risk of DIP (8%), 16 either in monotherapy or with concomitant medications (antipsychotics in particular). Reported cases have involved all classes.…”