Past exposure to neuroleptic drugs and risk of Parkinson disease in an elderly cohort

Foubert‐Samier, Alexandra; Helmer, Catherine; Pérez, Fabienne; Goff, Mélanie Le; Auriacombe, Sophie; Elbaz, Alexis; Dartigues, Jean‐François; Tison, François

doi:10.1212/wnl.0b013e31826e25ce

Cited by 46 publications

(34 citation statements)

References 37 publications

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“…Interestingly, a recent 15-year prospective population-based study has shown that long-term risk of incident PD was increased by 3.2-fold after past exposure to neuroleptics, with only 30% of the cases developing probable PD during the exposure. 18 This supports the hypothesis that neuroleptic exposure represents in itself a risk factor for subsequent development of degenerative PD and suggests new questions on such a relationship, which we aim to address. First, are patients who develop DIP during neuroleptic exposure those at increased risk of subsequent PD (suggesting common predisposing factors)?…”

supporting

confidence: 76%

“…Prevalence estimates of umPD according to such studies are unexpectedly high (Table ) and would suggest a causal relationship between neuroleptic exposure and degenerative parkinsonism. Interestingly, a recent 15‐year prospective population‐based study has shown that long‐term risk of incident PD was increased by 3.2‐fold after past exposure to neuroleptics, with only 30% of the cases developing probable PD during the exposure …”

Section: Summary Of the Imaging Studies Detailing Prevalence Estimatementioning

confidence: 99%

“…Compelling imaging evidence shows that a number of subjects exposed to neuroleptics develop degenerative parkinsonism, arguably PD (even if the drug is withdrawn). The only prospective study available so far has shown that long‐term neuroleptic exposure is in itself a risk factor for developing subsequent PD . This suggests other underlying mechanisms beyond the functional impairment of dopaminergic neurotransmission.…”

Section: The “Double‐hit” Hypothesismentioning

confidence: 99%

“…The only prospective study available so far has shown that long-term neuroleptic exposure is in itself a risk factor for developing subsequent PD. 18 This suggests other underlying mechanisms beyond the functional impairment of dopaminergic neurotransmission.…”

Section: The "Double-hit" Hypothesismentioning

confidence: 99%

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Parkinsonism following neuroleptic exposure: A double‐hit hypothesis?

2015

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Drug-induced parkinsonism is caused by an offending drug and should resolve after the causative agent has been withdrawn. However, in a number of patients, symptoms persist or may even worsen over time, suggesting the development of concomitant Parkinson's disease. The prevalence estimates of Parkinson's disease after neuroleptic exposure are unexpectedly high, suggesting a causal relationship. We critically review available literature in this regard, and some pathophysiological hypotheses that might explain such a relationship are suggested. Some patients may have an undetermined genetic susceptibility to parkinsonism. We speculate that the possible neurotoxic effect of neuroleptics exerted on a susceptible dopaminergic system would lead over the long-term to a self-fostering, progressive process. Knowledge gaps and future perspectives are discussed.

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supporting

confidence: 76%

Section: Summary Of the Imaging Studies Detailing Prevalence Estimatementioning

confidence: 99%

Section: The “Double‐hit” Hypothesismentioning

confidence: 99%

Section: The "Double-hit" Hypothesismentioning

confidence: 99%

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Parkinsonism following neuroleptic exposure: A double‐hit hypothesis?

2015

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“…[67][68][69] In a French elderly cohort of 2,991 noninstitutionalized individuals, neuroleptic exposure increased 3.2-fold the risk to develop probable PD. 70 The risk was significant for benzamides and the calcium channel blockers flunarizine and cinnarizine. The estimated population-attributable fraction of PD associated with drug exposure suggested that avoidance of drug exposure would yield a 21.7% reduction in the number of new cases of PD.…”

Section: Other Clinical Issues Persistent Parkinsonism Following Neurmentioning

confidence: 99%

Drug-induced parkinsonism: diagnosis and management

Blanchet

Kivenko²

2016

JPRLS

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Drug-induced parkinsonism (DIP) has been known for >60 years. It is the second leading cause of parkinsonism, but still underdiagnosis is likely to influence reported incidence figures. Since DIP is clinically undistinguishable from Lewy-body Parkinson’s disease, any new case of parkinsonism should prompt the search for an offending antipsychotic, hidden neuroleptic, or nonneuroleptic agent that may produce DIP. DIP is reversible upon drug withdrawal in most cases. There is no consensus regarding the duration of the recovery period to allow motor signs to fully remit in order to confirm the diagnosis of DIP following removal of the causative agent, but a drug-free interval of at least 6 months is generally recommended. Interestingly, up to 30% of DIP cases may show persisting or worsening motor signs beyond 6 months following drug withdrawal or adjustment, due to complex postsynaptic and presynaptic factors that may variably interact to negatively influence nigrostriatal dopamine transmission in a so-called “double-hit” hypothesis. The condition significantly impacts on quality of life and increases the risks of morbidity and mortality. Management is challenging in psychiatric patients and requires a team approach to achieve the best outcome

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Association Between Early-Onset Parkinson Disease and 22q11.2 Deletion Syndrome

Butcher¹,

Kiehl²,

Hazrati³

et al. 2013

JAMA Neurol

133

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IMPORTANCE Clinical case reports of parkinsonism co-occurring with hemizygous 22q11.2 deletions and the associated multisystem syndrome, 22q11.2 deletion syndrome (22q11.2DS), suggest that 22q11.2 deletions may lead to increased risk of early-onset Parkinson disease (PD). The frequency of PD and its neuropathological presentation remain unknown in this common genetic condition. OBJECTIVE To evaluate a possible association between 22q11.2 deletions and PD. DESIGN, SETTING, AND PARTICIPANTS An observational study of the occurrence of PD in the world's largest cohort of well-characterized adults with a molecularly confirmed diagnosis of 22q11.2DS (n = 159 [6 with postmortem tissue]; age range, 18.1-68.6 years) was conducted in Toronto, Ontario, Canada. Rare postmortem brain tissue from individuals with 22q11.2DS and a clinical history of PD was investigated for neurodegenerative changes and compared with that from individuals with no history of a movement disorder. MAIN OUTCOMES AND MEASURES A clinical diagnosis of PD made by a neurologist and neuropathological features of PD. RESULTS Adults with 22q11.2DS had a significantly elevated occurrence of PD compared with standard population estimates (standardized morbidity ratio = 69.7; 95% CI, 19.0-178.5). All cases showed early onset and typical PD symptom pattern, treatment response, and course. All were negative for family history of PD and known pathogenic PD-related mutations. The common use of antipsychotics in patients with 22q11.2DS to manage associated psychiatric symptoms delayed diagnosis of PD by up to 10 years. Postmortem brain tissue revealed classic loss of midbrain dopaminergic neurons in all 3 postmortem 22q11.2DS-PD cases. Typical α-synuclein-positive Lewy bodies were present in the expected distribution in 2 cases but absent in another. CONCLUSIONS AND RELEVANCE These findings suggest that 22q11.2 deletions represent a novel genetic risk factor for early-onset PD with variable neuropathological presentation reminiscent of LRRK2-associated PD neuropathology. Individuals with early-onset PD and classic features of 22q11.2DS should be considered for genetic testing, and those with a known 22q11.2 deletion should be monitored for the development of parkinsonian symptoms. Molecular studies of the implicated genes, including DGCR8, may help shed light on the underlying pathophysiology of PD in 22q11.2DS and idiopathic PD.

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Past exposure to neuroleptic drugs and risk of Parkinson disease in an elderly cohort

Abstract: In a French elderly cohort, the risk of probable PD was increased by 3.2-fold after exposure to neuroleptics. This finding suggests the necessity of limiting the use of such drugs in elderly people.

Cited by 46 publications

References 37 publications

Parkinsonism following neuroleptic exposure: A double‐hit hypothesis?

Parkinsonism following neuroleptic exposure: A double‐hit hypothesis?

Drug-induced parkinsonism: diagnosis and management

Association Between Early-Onset Parkinson Disease and 22q11.2 Deletion Syndrome

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