Use of antipsychotics and long-term risk of parkinsonism

Randhawa J., Mehanna R.

We report 2 cases of drug induced Parkinsonism followed longitudinally that remained symptomatic 22 and 27 months after stopping causative agents with normal dopamine ioflupane iodine-123 (DaT) single-photon emission computed tomography (SPECT) scans at 8 and 16 months.

Factor S.A., Burkhard P.R., Caroff S., Friedman J.H., Marras C., Tinazzi M., Comella C.L.

A large and ever-growing number of medications can induce various movement disorders. Drug-induced movement disorders are disabling but are often under-recognised and inappropriately managed. In particular, second generation antipsychotics, like first generation agents, are associated with potentially debilitating side-effects, most notably tardive syndromes and parkinsonism, as well as potentially fatal acute syndromes. Appropriate, evidence-based management is essential as these drugs are being prescribed to a growing population vulnerable to these side-effects, including children and elderly people. Prevention of the development of drug-induced movement disorders is an important consideration when prescribing medications that can induce movement disorders. Recent developments in diagnosis, such as the use of dopamine transporter imaging for drug-induced parkinsonism, and treatment, with the approval of valbenazine and deutetrabenazine, the first drugs indicated for tardive syndromes, have improved outcomes for many patients with drug-induced movement disorders. Future research should focus on development of safer antipsychotics and specific therapies for the different tardive syndromes and the treatment of drug-induced parkinsonism.

Kim S., Cheon S., Suh H.S.

Background: Although drug-induced parkinsonism is reversible in most cases, some patients can suffer from persistent/recurrent symptoms. Therefore, prevention is the most efficient way to manage drug-induced parkinsonism. However, there is a paucity of studies exploring the relationship between parkinsonism and drug exposure. Objective: To examine the association between drug exposure and the risk of parkinsonism using Korean population-based data. Methods: We conducted a matched case-control study using the National Health Insurance Service—National Sample Cohort database. Cases and controls were defined as individuals with and without parkinsonism, respectively, between 2007 and 2013. Cases and controls were matched for sex, age group, income, type of insurance, and Charlson comorbidity index. Drug exposures, including propulsives, antipsychotics, and flunarizine, were identified at 1 year before the first date of parkinsonism and stratified by recency and cumulative dose. Conditional logistic regression was used to estimate odds ratios (ORs) and 95% CIs. Results: We identified 5496 cases and 5496 controls. ORs for current use group of propulsives, antipsychotics, and flunarizine compared with those of the never use group were 2.812 (95% CI = 2.466-3.206), 3.009 (95% CI = 1.667-5.431), and 4.950 (95% CI = 2.711-9.037), respectively. ORs were greater in those more recently exposed and those exposed to higher cumulative doses. Conclusion and Relevance: At the population level, use of propulsives, antipsychotics, and flunarizine had a significant association with the increased risk of parkinsonism, depending on recency and cumulative dose. Drugs associated with parkinsonism should be used with careful monitoring to prevent drug-induced parkinsonism.

Fleury V., Brindel P., Nicastro N., Burkhard P.R.

A large descriptive cross-sectional population-based prevalence study as well as a retrospective incidence study were undertaken to ascertain the frequency of Parkinson's Disease (PD) and other types of degenerative and non-degenerative parkinsonism in the Canton of Geneva, Switzerland.An extensive case-finding approach including records from public hospitals, private neurologists and nursing homes was utilized. All patients with a diagnosis of parkinsonism established between 2003 and 2012 were included. Diagnosis of parkinsonism was ascertained by a movement disorders specialist, based on published and validated consensus diagnostic criteria.A total of 1235 living patients with parkinsonism were identified, from which 80% presented with a degenerative form and 20% with a non-degenerative form of parkinsonism. Among the former, PD was the most frequent diagnosis (81%, age-adjusted prevalence: 183/105 inhabitants, age-adjusted average annual incidence: 20/105/year) followed by dementia with Lewy bodies (9%), progressive supranuclear palsy (3.9%), multisystem atrophy (1.9%) and corticobasal syndrome (1.4%). Among non-degenerative parkinsonism, drug-induced parkinsonism was the most frequent diagnosis (43.4%), followed by vascular parkinsonism (37%), normal pressure hydrocephalus (5.1%) and parkinsonism in the context of a psychiatric disorder or functional parkinsonism (3.8%). Crude, age-, sex-specific and age-adjusted prevalence and incidence of all types of parkinsonism are detailed for each diagnosis.This is the first Swiss population-based epidemiological study of PD and parkinsonism. It provides an extensive overview of the prevalence and incidence of degenerative and non-degenerative forms of parkinsonism. These data may assist clinicians with their clinical workup.

ffytche D.H., Aarsland D.

Although illusions, hallucinations and delusions did not play a prominent role in James Parkinson's original clinical descriptions, the longitudinal view of disease progression he advocated has important lessons for the study of such symptoms today. A focus on longitudinal progression rather than individual symptoms led to the concept of PD psychosis-a spectrum of positive symptoms in Parkinson's disease. The publication of criteria for PD psychosis in 2007 helped unify the disparate set of symptoms, raising their profile and resulting in a rapid expansion of literature focussing on clinical aspects, mechanisms, and treatment. Here we review this literature and the evolving view of PD psychosis. Adding to previous evidence of a prospective risk for dementia and the move to supervised care, key recent developments include: recognition of prevalence increase with disease duration; a broadening of symptoms included in PD psychosis; better characterization of higher visual and cognitive dysfunction risk factors; structural, functional, and neurotransmitter imaging biomarker evidence; and approval of pimavanserin in the United States for the treatment of PD psychosis. The accumulating evidence raises novel questions and directions for future research that promise a better understanding of the clinical management of PD psychosis and its role as a biomarker for PD stage and progression.

Gunnarsson L., Bodin L.

Ascherio A., Schwarzschild M.A.

Since 2006, several longitudinal studies have assessed environmental or behavioural factors that seem to modify the risk of developing Parkinson's disease. Increased risk of Parkinson's disease has been associated with exposure to pesticides, consumption of dairy products, history of melanoma, and traumatic brain injury, whereas a reduced risk has been reported in association with smoking, caffeine consumption, higher serum urate concentrations, physical activity, and use of ibuprofen and other common medications. Randomised trials are investigating the possibility that some of the negative risk factors might be neuroprotective and thus beneficial in individuals with early Parkinson's disease, particularly with respect to smoking (nicotine), caffeine, and urate. In the future, it might be possible to identify Parkinson's disease in its prodromal phase and to promote neuroprotective interventions before the onset of motor symptoms. At this time, however, the only intervention that seems justifiable for the primary prevention of Parkinson's disease is the promotion of physical activity, which is likely to be beneficial for the prevention of several chronic diseases.

Savica R., Grossardt B.R., Bower J.H., Ahlskog J.E., Mielke M.M., Rocca W.A.

Epidemiological studies of drug-induced parkinsonism remain limited.To investigate the incidence and time trends of drug-induced parkinsonism over 30 years in a geographically defined American population.We used the medical records-linkage system of the Rochester Epidemiology Project to identify all persons in Olmsted County, Minnesota, who received a screening diagnostic code for parkinsonism from 1976 through 2005. A movement disorders specialist reviewed the complete medical records of each person to confirm the presence of drug-induced parkinsonism associated with dopamine-blocking or dopamine-depleting medications.Among 906 incident cases of parkinsonism from 1976 to 2005, 108 persons had drug-induced parkinsonism (11.9%). The average annual incidence rate of drug-induced parkinsonism was 3.3 per 100,000 person-years, was higher in women, and increased with older age. Drug-induced parkinsonism was the fifth-most common type of parkinsonism overall; however, it was the most common type among persons younger than age 40 years. Typical antipsychotic drugs were the most common class of drugs associated with parkinsonism, whereas atypical antipsychotic drugs were rarely involved. The incidence rate of drug-induced parkinsonism decreased 32.0% per decade (relative risk = 0.68; 95% confidence interval: 0.49-0.94) and 68.6% over the 30 years of the study. The decrease was similar in men (65.2%) and women (69.4%); however, the trend was significant only in women.The incidence of drug-induced parkinsonism increased with older age and was higher in women at all ages. Typical antipsychotic drugs were the most common cause. The incidence of drug-induced parkinsonism decreased over the 30 years of the study because of changes in drug use. © 2016 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Marras C., Herrmann N., Fischer H.D., Fung K., Gruneir A., Rochon P.A., Rej S., Vigod S., Seitz D., Shulman K.I.

To test the hypothesis of an increased incidence of antiparkinson drug prescribing or Parkinson disease (PD) diagnostic codes after chronic lithium treatment compared with chronic valproic acid or antidepressant treatment among older adults.A retrospective cohort study using healthcare administrative databases in Ontario, Canada included 1,749 lithium users, 1,787 valproic acid users, and 285,154 other antidepressant users ≥ 66 years old having used the drug continuously in monotherapy for at least 1 year. Outcome measures were start of (1) a dopaminergic medication (levodopa or a dopamine agonist), (2) any antiparkinson drug (levodopa, dopamine agonists, anticholinergic medication, amantadine, monoamine oxidase B inhibitors), (3) any antiparkinson drug or a diagnostic code for PD, and (4) any antiparkinson drug in the absence of a diagnostic code for PD.For patients with no previous antipsychotic use, lithium monotherapy was associated with an increased incidence of dopaminergic drug use (adjusted HR: 1.87; 95% CI: 1.06-3.30) and an increased incidence of antiparkinson drug use or a PD diagnosis (adjusted HR: 1. 68; 95% CI: 1.13-2.48) compared with antidepressant monotherapy.Chronic lithium use is associated with an increased incidence of dopaminergic drug use compared with antidepressants, identifying a prescribing cascade related to lithium use in the elderly. Whether this reflects inappropriate treatment of action tremor or treatment of drug-induced parkinsonism should be addressed by a close examination of prescribing practices.

Shuaib U.A., Rajput A.H., Robinson C.A., Rajput A.

Drug-induced parkinsonism is a well-known complication of several different drugs--the most common being neuroleptic-induced parkinsonism. However, very few autopsies have been reported in such cases.Patients assessed at Movement Disorders Clinic Saskatchewan are offered brain autopsy. Detailed clinical records are kept.Brains were obtained from 7 drug-induced parkinsonism patients with parkinsonian symptom onset coinciding with use of drugs known to produce parkinsonism. Six were on antipsychotics and 1 was on metoclopramide. Three cases were treated with levodopa for parkinsonism. In two cases, parkinsonian features reversed after stopping the offending agent. Both had autopsy evidence of preclinical PD. In 4 of the remaining 5, dopamine-blocking drugs were continued until death. In 4 of those 5, brain histology revealed no cause for the parkinsonism, but 1 had mild SN neuronal loss without Lewy bodies.This study shows that reversal of parkinsonism after discontinuing offending drugs does not indicate absence of underlying pathology. Neuroleptics can unmask preclinical PD in patients with insufficient SN damage for the disease to manifest clinically. Though the mechanism of sustained parkinsonian features after discontinuing neuroleptics remains to be established, it is unlikely that dopamine receptor block leads to retrograde SN neuronal degeneration. Furthermore, L-dopa does not appear to be toxic to SN.

Wei W., Teixeira P.L., Mo H., Cronin R.M., Warner J.L., Denny J.C.

Abstract Objective To evaluate the phenotyping performance of three major electronic health record (EHR) components: International Classification of Disease (ICD) diagnosis codes, primary notes, and specific medications. Materials and Methods We conducted the evaluation using de-identified Vanderbilt EHR data. We preselected ten diseases: atrial fibrillation, Alzheimer’s disease, breast cancer, gout, human immunodeficiency virus infection, multiple sclerosis, Parkinson’s disease, rheumatoid arthritis, and types 1 and 2 diabetes mellitus. For each disease, patients were classified into seven categories based on the presence of evidence in diagnosis codes, primary notes, and specific medications. Twenty-five patients per disease category (a total number of 175 patients for each disease, 1750 patients for all ten diseases) were randomly selected for manual chart review. Review results were used to estimate the positive predictive value (PPV), sensitivity, and F -score for each EHR component alone and in combination. Results The PPVs of single components were inconsistent and inadequate for accurately phenotyping (0.06–0.71). Using two or more ICD codes improved the average PPV to 0.84. We observed a more stable and higher accuracy when using at least two components (mean ± standard deviation: 0.91 ± 0.08). Primary notes offered the best sensitivity (0.77). The sensitivity of ICD codes was 0.67. Again, two or more components provided a reasonably high and stable sensitivity (0.59 ± 0.16). Overall, the best performance ( F score: 0.70 ± 0.12) was achieved by using two or more components. Although the overall performance of using ICD codes (0.67 ± 0.14) was only slightly lower than using two or more components, its PPV (0.71 ± 0.13) is substantially worse (0.91 ± 0.08). Conclusion Multiple EHR components provide a more consistent and higher performance than a single one for the selected phenotypes. We suggest considering multiple EHR components for future phenotyping design in order to obtain an ideal result.

Erro R., Bhatia K.P., Tinazzi M.

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.

Brigo F., Erro R., Marangi A., Bhatia K., Tinazzi M.

Drug-induced parkinsonism is the second most common cause of parkinsonism after Parkinson's disease and their distinction has crucial implications in terms of management and prognosis. However, differentiating between these conditions can be challenging on a clinical ground, especially in the early stages. We therefore performed a review to ascertain whether assessment of non-motor symptoms, or use of ancillary investigations, namely dopamine transporter imaging, transcranial sonography of the substantia nigra, and scintigraphy for myocardial sympathetic innervation, can be recommended to distinguish between these conditions. Among non-motor symptoms, there is evidence that hyposmia can differentiate between patients with "pure" drug-induced parkinsonism and those with degenerative parkinsonism unmasked by an anti-dopaminergic drug. However, several issues, including smoking history and cognitive functions, can influence smell function assessment. Higher diagnostic accuracy has been demonstrated for dopamine transporter imaging. Finally, preliminary evidence exists for sympathetic cardiac scintigraphy to predict dopaminergic pathway abnormalities and to differentiate between drug-induced parkinsonism and Parkinson's disease. Imaging of the dopaminergic pathway seems to be the only, reasonably available, technique to aid the differential diagnosis between drug-induced parkinsonism and Parkinson's disease.

Burkhard P.R.

Many pharmacological agents may induce a variety of movement disorders, including dystonia, tremor, parkinsonism, myoclonus and dyskinesia, with an acute, subacute or more chronic time course. Motor symptoms may be isolated or part of a more extensive cerebral or systemic condition, such as the neuroleptic malignant syndrome or the serotonin syndrome. Drug-induced movement disorders share a number of features that should make them easy to identify, including a clear temporal relationship between medication initiation and symptom onset, a dose-effect, and, with the exception of tardive syndromes, complete resolution after discontinuation of the offending agent. Diagnosis relies on a thorough medication history. Medications commonly involved include dopamine receptor blockers, antidepressants and anti-epileptics, among many others. Mechanisms underlying drug-induced movement disorders involve blockade, facilitation or imbalance of dopamine, serotonin, noradrenaline and cholinergic neurotransmission in the basal ganglia. The present review focuses on drug-induced movement disorders that typically develop as an acute (hours to days) or subacute (days to weeks) event, including acute dystonic reactions, akathisia, drug-induced parkinsonism, neuroleptic malignant syndrome, serotonin syndrome, parkinsonism-hyperpyrexia syndrome, drug-induced tremor, drug-induced hyperkinesias and movement disorders associated with the use of recreational drugs.

Foubert-Samier A., Helmer C., Perez F., Le Goff M., Auriacombe S., Elbaz A., Dartigues J.-., Tison F.

Neuroleptics and neuroleptic-like drugs are known to induce parkinsonism, which may reveal underlying Parkinson disease (PD) in some cases. We assessed the long-term risk of developing PD after past exposure to these drugs, in a 15-year prospective population-based elderly cohort study.We used the Cox proportional hazards model to assess the relation between past exposure to neuroleptics and the risk of developing incident PD. All incident cases of parkinsonism were identified by standardized procedure and validated by a committee of experts.Of 2,991 subjects followed, 117 developed parkinsonism and 43 developed probable PD during follow-up, of whom 22.2% and 32.6%, respectively, had been exposed to neuroleptics, compared to 16.6% for subjects without parkinsonism. About a third of subjects presented transient parkinsonism during drug exposure. After adjustment for gender and past occupation, past exposure to neuroleptics was associated with incident PD (relative risk, 3.16; 95% confidence interval [CI], 1.65-6.04). The relative risk was 3.65 (95% CI, 1.41-9.45) for benzamides and 2.59 (95% CI, 1.23-5.43) for phenothiazines. The population-attributable fraction of the risk for developing PD was 8.2% for benzamides and 12.2% for phenothiazines.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.

d’Errico A., Strippoli E., Goldman S.M., Blanc P.D.

Abstract Background Case reports implicate disulfiram treatment in causing parkinsonism, but these observations lack epidemiological confirmation. Aim of the present study was to estimate the risk of incident parkinsonism associated with disulfiram dispensing in a large Italian population. Methods In this observational cohort study, administrative data were used, linking records at the individual level from civic registries, population census, mortality registers, hospital admissions, archives of drug prescriptions, and direct ambulatory drug distribution. Participants included all residents in the Piedmont region of Italy aged ≥ 40 years participating in 2011 census, still resident and alive at the beginning of 2013, followed-up from 2013 to 2019. The outcome was incident parkinsonism identified through multiple prescriptions of levodopa or a hospital admission for Parkinson’s disease or atypical parkinsonism. Exposure to disulfiram and to neuroleptics was assessed through regional drug prescription archives. The association between disulfiram and parkinsonism onset was assessed using Cox proportional hazards models, adjusted for gender, age and neuroleptic use. Results The study population included 2,498,491 individuals (mean age: 62 years). During follow-up, 19,072 parkinsonism cases were identified, 8 of whom had been prescribed disulfiram. Exposure to disulfiram was associated with a three-fold increased risk of parkinsonism (HR = 3.10, 95% CI = 1.55–6.21) that remained significant when adjusted for neuroleptic use (HR = 2.04, 95% CI = 1.01–4.10). The association was stronger among persons unexposed to neuroleptics and among those with more than four disulfiram prescriptions. Conclusions These results support the hypothesis that disulfiram may cause parkinsonism. Clinicians and drug regulatory agencies should consider parkinsonism when assessing the risks and benefits of disulfiram use.

von Scheibler E.N., Swillen A., Repetto G.M., Reyes N.G., Lang A.E., Marras C., Kuijf M.L., Rouhl R.P., van Eeghen A.M., Juri C., Vogels A., van Amelsvoort T.A., Bassett A.S., Boot E.

AbstractBackground22q11.2 deletion syndrome (22q11.2DS) has been associated with increased risk of early‐onset Parkinson's disease (PD).ObjectiveTo determine the prevalence and predictors of PD in a large international 22q11.2DS sample.MethodsThe sample comprised 856 adults (median age 28 (range 16–76) years; 53.0% female). PD was defined as clinical diagnosis by a neurologist (including bradykinesia, rest tremor and/or rigidity). Age‐specific risk and predictors of PD were analyzed using Kaplan–Meier curve and Cox regression.ResultsPD was present in 1.8% (95% CI: 0.9–2.6%) of the sample, 3.4% (95% CI: 2.2–4.6%) when including uncertain PD (clinical diagnosis or suspicion, but not meeting all criteria), and 14.0% (95% CI: 6.9–21.0%) of those aged ≥50 years. Median age at motor onset was 45 (range 20–66) years. None of the factors considered were associated with PD.ConclusionsGiven high PD prevalence and young onset, we propose periodic motor evaluations from age 40 years in 22q11.2DS.

Conn H., Jankovic J.

Calzetti S., Negrotti A.

Parkinsonism induced by dopamine receptor antagonists, traditionally considered completely reversible following offending drug withdrawal, may unmask a degenerative parkinsonism in the patients with an underlying subclinical disease. In elderly patients, parkinsonism induced by the calcium channel blockers such as piperazine derivates cinnarizine and flunarizine may persist following drug discontinuation resulting in a permanent nonprogressive syndrome fulfilling the criteria for tardive parkinsonism. Whether this outcome occurs also following exposure to dopamine receptor antagonists such as neuroleptics and benzamide derivates or represents a class effect of the voltage-gated L-type calcium channel blockers, such as cinnarizine and flunarizine, due to their complex pharmacodynamic properties remains to be established.

Ivan I., Irincu L., Diaconu Ş., Opriţoiu B., Murăşan I., Falup-Pecurariu C.

Movement disorder emergency can be caused by several factors. This term defines a bradykinetic-rigid syndrome that develops over days or weeks. The most common etiologies are infectious and through immune mechanisms (viral, autoimmune, paraneoplastic), drug-induced, toxic-induced, and psychiatric causes. Cerebrospinal fluid analysis, toxicology, normal blood tests and imaging play a significantly important role in the evaluation and diagnostic of acute parkinsonism. Acute parkinsonism should always be treated as a medical emergency, as some forms of these diseases can be cured, depending on the underlying etiology.

Robison R., Singh M., Jiang L., Riester M., Duprey M., McGeary J.E., Goyal P., Wu W.C., Erqou S., Zullo A., Rudolph J.L., Rogus-Pulia N.

Objective Examine whether new antipsychotic (AP) exposure is associated with dysphagia in hospitalized patients with heart failure (HF). Design Retrospective cohort. Settings and Participants AP-naïve Veterans hospitalized with HF and subsequently discharged to a skilled nursing facility (SNF) between October 1, 2010, and November 30, 2019. Methods We linked Veterans Health Administration (VHA) electronic medical records with Centers for Medicare & Medicaid (CMS) Minimum Data Set (MDS) version 3.0 assessments and CMS claims. The exposure variable was administration of ≥1 dose of a typical or atypical AP during hospitalization. Our main outcome measure was dysphagia presence defined by (1) inpatient dysphagia diagnosis codes and (2) the SNF admission MDS 3.0 swallowing-related items to examine post-acute care dysphagia status. Inverse probability of treatment weighting was used for risk adjustment. Results The analytic cohort consisted of 29,591 Veterans (mean age 78.5 ± 10.0 years; female 2.9%; n = 865). Acute APs were administered to 9.9% (n = 2941). Those receiving APs had differences in prior dementia [37.1%, n = 1091, vs 22.3%, n = 5942; standardized mean difference (SMD) = 0.33] and hospital delirium diagnoses (7.7%, n = 227 vs 2.8%, n = 754; SMD = 0.22). Acute AP exposure was associated with nearly double the risk for hospital dysphagia diagnosis codes [adjusted (adj.) relative risk (RR) 1.9, 95% CI 1.8, 2.1]. At the SNF admission MDS assessment, acute AP administration during hospitalization was associated with an increased dysphagia risk (adj. RR 1.2, 95% CI 1.0, 1.5) both in the oral (adj. RR 1.7, 95% CI 1.2, 2.0) and pharyngeal phases (adj. RR 1.3, 95% CI 1.0, 1.7). Conclusions and Implications In this retrospective study, AP medication exposure was associated with increased dysphagia coding and MDS assessment. Considering other adverse effects, acute AP should be cautiously administered during hospitalization, particularly in those with dementia. Swallowing function is critical to hydration, nutrition, and medical management of HF; therefore, when acute APs are initiated, a swallow evaluation should be considered.

Kostoff R.