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Secondary parkinsonism induced by exposure to dopamine (DA) receptor antagonists as first and second generation antipsychotics, DA storage depleters, calcium channel blockers, benzamides substituted and other classes of drugs is traditionally believed to be completely reversible in most of patients following withdrawal of the offending drug even though after a variable time delay. The lack of recovery or initial full recovery with subsequent development of progressive parkinsonism has been regarded to result from an underlying subclinical degenerative process like PD unmasked by the inducing drug. These well-recognized clinical outcomes of drug-induced parkinsonism (DIP) have disregarded the existence of another outcome, characterized by permanent non-progressive parkinsonism. This syndrome may fullfil the criteria of tardive parkinsonism, a controversial entity currently referred to as a persistent condition without indication of its long-term course and clinical features. On reviewing the published literature on DIP, we have identified two prospective long-term follow-up of elderly patients in which parkinsonism induced by the calcium channel antagonists cinnarizine and flunarizine became permanent and non-progressive following drug discontinuation in a non-negligible proportion of patients, consistent with the clinical concept of a true tardive syndrome, according to currently accepted criteria. The authors hypothesize that the development of tardive parkinsonism might be due to a neurotoxic effect of the pharmacodynamic proprieties of the calcium channel blockers and their metabolites, exerted on post-synaptic striatal neurons and/or a neurotoxic damage on presynaptic DA neurons in patients without an underlying subclinical degenerative parkinsonism, so accounting for the stable and non-progressive course over time., Competing Interests: Declaration of Competing Interest The Authors report no conflict of interest related to the content of this article., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Whether there are differences in the time to onset of drug-induced parkinsonism (DIP) depending on the type of drugs causing DIP remains uncertain, so that question was investigated here using a large real-world database. Fourteen DIP-related drug categories were defined to perform a disproportionality analysis using a large Japanese pharmacovigilance database containing more than 600,000 self-reported adverse events (AEs) recorded between April 2004 and September 2021 to identify AEs indicating "parkinsonism" in association with the defined drug categories. The time from drug administration to the onset of DIP was comparatively analyzed. Results indicated that the median time to onset was shorter than 1 month in more than half of the cases of DIP; it was shortest with peripheral dopamine antagonists (median: 0.1 weeks), followed by benzodiazepine (median: 0.5 weeks), butyrophenone (median: 0.7 weeks), novel antidepressants (median: 2.5 weeks), atypical antipsychotics (median: 3.3 weeks), other antidepressants (e.g., lithium, median: 3.7 weeks), and benzamide (median: 4.5 weeks). In contrast, anti-dementia drugs, tricyclic antidepressants, and antiepileptic drugs resulted in a relatively longer time to onset (median: 9.9, 17.2, and 28.4 weeks, respectively). In addition, a maximum delay of even longer than 2 years was reported for benzamide (846 weeks), anti-Parkinsonism drugs (382 weeks), phenothiazine (232 weeks), atypical antipsychotics (167 weeks), anti-dementia drugs (161 weeks), and benzodiazepines (120 weeks). The current results suggested that the characteristics of the time to onset of DIP may substantially differ depending on the type of drug causing that DIP. This finding may help when diagnosing patients with parkinsonism.

Introduction: Few epidemiological studies have assessed the risk of parkinsonisms after prolonged use of neuroleptics. We aimed to examine the long-term risk of degenerative parkinsonisms (DP) associated with previous use of neuroleptics., Methods: All residents in Piedmont, Northern-west Italy, older than 39 years (2,526,319 subjects), were retrospectively followed up from 2013 to 2017. Exposure to neuroleptics was assessed through the regional archive of drug prescriptions. The development of DP was assessed using the regional archives of both drug prescriptions and hospital admissions. We excluded prevalent DP cases at baseline as well as those occurred in the first 18 months (short-term risk). The risk of DP associated with previous use of neuroleptics was examined through Cox regression, using a matched cohort design., Results: The risk of DP was compared between 63,356 exposed and 316,779 unexposed subjects. A more than threefold higher risk of DP was observed among subjects exposed to antipsychotics, compared to those unexposed (HR = 3.27, 95% CI 3.00-3.57), and was higher for exposure to atypical than typical antipsychotics. The risk decreased after 2 years from therapy cessation but remained significantly elevated (HR = 2.38, 95% CI 1.76-3.21)., Conclusions: These results indicate a high risk of developing DP long time from the start of use and from the cessation for both typical and atypical neuroleptics, suggesting the need of monitoring treated patients even after long-term use and cessation., (© 2021. The Author(s).)

Background: Both drug-induced Parkinsonism (DIP) and tardive dyskinesia (TD) have been shown to be associated with lower health-related quality of life (HRQOL) in schizophrenia, but few studies have examined their relative impact., Aims: This study aimed to examine and compare the association of DIP and TD with HRQOL in schizophrenia., Methods: In total, 903 patients with schizophrenia were assessed on the Positive and Negative Syndrome Scale (PANSS), Simpson-Angus Scale (SAS), and Abnormal Involuntary Movement Scale (AIMS). EuroQoL five-dimensional (EQ-5D-5L) utility scores were derived from PANSS scores via a previously validated algorithm and used as a measure of HRQOL., Results: In total, 160 (17.7%) participants had only DIP, 119 (13.2%) had only TD, and 123 (13.6%) had both DIP and TD. HRQOL was lowest for participants with both DIP and TD, followed by only DIP group, only TD group, and highest in the group with neither condition. HRQOL scores differed significantly between the four groups, F (3, 892) = 13.724, p  < 0.001, η p 2  = 0.044). HRQOL of participants having only DIP or both DIP and TD was significantly lower than those having neither condition. There was no significant interaction between the presence of DIP and TD on the association with HRQOL., Conclusions: DIP was the main antipsychotic-induced movement disorder associated with a poorer HRQOL in patients with schizophrenia. Therefore, clinicians should focus on prevention, detection, and effective management of DIP to optimize HRQOL in patients with schizophrenia.

An association between trimetazidine (TMZ), an anti-anginal drug, and parkinsonism has been reported in a number of studies. However, evidence from studies with long-term follow-up and better validity is lacking. We investigated the risk of TMZ-associated parkinsonism, specifically the incidence rate, cumulative dose-response relationship, and combined effects with other parkinsonism-inducing medications. This propensity score-matched retrospective cohort study was conducted using 14-year health insurance claims data in South Korea. The risk of parkinsonism was evaluated using multivariate Cox proportional hazard regression analysis, adjusted for comorbidities and concurrent medications. A total of 9712 TMZ users and 29,116 matched non-TMZ users were included. TMZ users had a significantly higher incidence rate of parkinsonism than non-TMZ users (9.34 vs. 6.71 per 1000 person-years; p < 0.0001). TMZ use significantly increased the risk of parkinsonism (adjusted hazard ratio = 1.38; 95% confidence interval = 1.26-1.51). Increased risks were observed with accumulated doses of TMZ, as well as concurrent use of other parkinsonism-inducing medications. The findings indicate that TMZ use significantly increases the risk of parkinsonism in the South Korean population. Closer monitoring should be considered for TMZ users, especially for those who are older, using TMZ at high cumulative doses and other parkinsonism-inducing medications.

Background: The prevalence of drug-induced parkinsonism (DIP) has been reported with the use of trimetazidine (TMZ), an antianginal medication available in Asian and European countries. Very few studies have evaluated the association between DIP and TMZ use, and studies using population-based data from national databases are lacking., Objectives: To investigate the association between DIP and use of TMZ in patients with angina using data from a national healthcare claims database and to determine the predictive factors of DIP in TMZ use., Methods: A cross-sectional study was conducted on patients aged 40 years or more diagnosed with angina, using the Korean National Healthcare claims 2014 database. The association between TMZ use and DIP was evaluated using multivariate logistic regression analysis, adjusting for confounders, including age; sex; insurance type; comorbidities; and concurrent medications known to be commonly associated with DIP, such as typical and atypical antipsychotics., Results: Of the patients included in the study, 19% were prescribed TMZ. In addition, 2.5% of TMZ users had preexisting extrapyramidal and movement disorders. TMZ use was found to be a significant predictor of a new diagnosis of parkinsonism (adjusted OR [aOR] 1.39; 95% CI 1.06-1.81; p = 0.016). Age ≥65 years (aOR 2.07; 95% CI 1.13- 3.74; p = 0.017) and stroke as comorbid disease (aOR 3.23; 95% CI 1.87-5.61; p < 0.001) were also significantly associated with a new diagnosis of parkinsonism in TMZ users., Conclusions: Treatment with TMZ was a statistically significant predictor of a new diagnosis of parkinsonism. Efforts should focus on close monitoring of, and education on, TMZ use in relation to DIP in all patients who are prescribed TMZ, including those with preexisting extrapyramidal and movement disorders., (© 2019 S. Karger AG, Basel.)

Aim: Drug-induced parkinsonism (DIP) is the most common form of parkinsonism after Parkinson's disease (PD) itself. It has been widely believed that DIP is characterised by symmetry of symptoms. Studies of patients with DIP in whom PD had been ruled out by SPECT-DaTSCAN have shown that symptom asymmetry is a common element of DIP clinical presentation. The aim of our study was to determine whether the asymmetry of symptoms in DIP is related to any abnormality within the presynaptic part of the nigrostriatal dopaminergic system., Materials and Methods: Eleven patients with the diagnosis of DIP and asymmetric symptoms were studied. Their individual SPECT-DaTSCANs were normal. Indices calculated for the whole group of radiotracer uptake in the whole striatum, putamen and caudate contralateral to more severe DIP symptoms were compared to values obtained in the opposite hemisphere., Results: We did not find significant differences in radiotracer uptake in structures contralateral to more severe clinical symptoms when compared to the homolateral hemisphere., Conclusions: Our results have not confirmed the presence of a presynaptic nigrostriatal deficit which could be related to asymmetry of DIP. The factors responsible for the asymmetry of DIP symptoms should be sought in the postsynaptic part of the nigrostriatal dopaminergic system.

Adverse drug reaction (ADR) is a form of unwanted reaction and is the crucial reason for illness and death. Tramadol-induced parkinsonism is a kind of ADR that occurs after the repeated intake of tramadol. Long-term exposure to tramadol has been known to induce tremor and alter the functioning of dopamine. This case report introduces a 75-year-old woman diagnosed with tramadol-induced parkinsonism due to the administration of tramadol for the treatment of post-operated (breast cancer) acute onset of severe pain on the left side of the chest. The assessment of the offending drug was carried out via Naranjo probability scale. A score of 6 was reported for this patient, defining tramadol as a probable cause of this reaction. For the management of the drug-induced parkinsonism, levodopa/carbidopa was prescribed and the symptoms related to parkinsonism resolved within a week. The age of the patient and the female gender is considered to be the main risk factor for the occurrence of such reaction. This case report is an attempt to spread awareness about the negative consequences of long-term use of tramadol in old patients. Thus, the medical practitioners must be very careful while administering tramadol to the old aged population.

Objectives: The onset of parkinsonism in patients with drug-induced parkinsonism (DIP) exhibits extensive individual variability following exposure to offending drugs. We investigated whether the individual variations in the onset time of parkinsonism reflected the underlying subtle dopaminergic dysfunction in DIP., Methods: We enrolled 71 patients with DIP who had visually normal striatal dopamine transporter (DAT) availability in 18 F-FP-CIT positron emission tomography scans. According to their exposure durations to the offending drugs prior to onset of the parkinsonism, the patients were divided into the early-onset group (duration ≤6 months; n=35) and delayed-onset group (duration >6 months; n=36). We performed the quantitative analysis of the DAT availability in each striatal subregion between the groups., Results: No patients with DIP had DAT availability that was more than 2 SD below the normal mean of DAT availability. Compared with the delayed-onset group, the early-onset DIP group had decreased DAT availability in the striatal subregions including the posterior putamen (p=0.018), anterior putamen (p=0.011), caudate (p=0.035) and ventral striatum (p=0.027). After adjusting for age, sex and cross-cultural smell identification test scores, a multivariate analysis revealed that the DAT availability in the striatal subregions of the patients with DIP was significantly and positively associated with the natural logarithm of the duration of drug exposure., Conclusions: These results suggest that a short exposure to the offending drugs before the development of parkinsonism would be associated with subtle nigrostriatal dopaminergic dysfunction in patients with DIP., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Background: Drug-induced parkinsonism (DIP) has a high prevalence and is associated with poorer quality of life. To find a practical clinical tool to assess DIP in patients with severe mental illness (SMI), the association between blink rate and drug-induced parkinsonism (DIP) was assessed., Methods: In a cohort of 204 SMI patients receiving care from the only mental health service of the previous Dutch Antilles, blink rate per minute during conversation was assessed by an additional trained movement disorder specialist. DIP was rated on the Unified Parkinson's Disease Rating Scale (UPDRS) in 878 assessments over a period of 18 years. Diagnostic values of blink rate were calculated., Results: DIP prevalence was 36%, average blink rate was 14 (standard deviation (SD) 11) for patients with DIP, and 19 (SD 14) for patients without. There was a significant association between blink rate and DIP (p < 0.001). With a blink rate cut-off of 20 blinks per minute, sensitivity was 77% and specificity was 38%. A 10% percentile cut-off model resulted in an area under the ROC curve of 0.61. A logistic prediction model between dichotomous DIP and continuous blink rate per minute an area under the ROC curve of 0.70., Conclusions: There is a significant association between blink rate and DIP as diagnosed on the UPDRS. However, blink rate sensitivity and specificity with regard to DIP are too low to replace clinical rating scales in routine psychiatric practice., Trial Registration: The study was started over 20 years ago in 1992, at the time registering a trial was not common practice, therefore the study was never registered.

Introduction: We have recently demonstrated evidence of nigro-striatal denervation, disease progression and response to levodopa in a subgroup of patients with schizophrenia who developed parkinsonism., Objective: In the present study, we investigated whether axial parkinsonian signs might be an early manifestation of parkinsonism in schizophrenia not necessarily related to chronic administration of antipsychotic drugs (AP) drugs., Methods: From a baseline cohort of 299 schizophrenic patients who did not satisfy the diagnostic criteria for parkinsonism (presence of at least two of the following appendicular signs: bradykinesia, tremor, rigidity), we identified a group of patients who manifested two out of three axial parkinsonian signs (abnormality of trunk posture, hypomimia and short-step gait). Accordingly, we obtained two sub-groups of patients with schizophrenia, with (Schiz-Axial, N = 26), and without parkinsonian axial signs (Schiz-NO-Axial, N = 273). Clinical and demographical variables were compared between groups. The motor section of the Unified Parkinson's disease rating scale (UPDRS) was employed to measure motor disability., Results: Schiz-Axial patients were significantly older (p = 0.007) and had longer disease duration (p = 0.04) compared to Schiz-NO-Axial. The two groups did not differ for variables related to AP treatment. Total UPDRS motor score (p < 0.0001) as well as limb (p < 0.0001) and axial (p < 0.0001) UPDRS sub-scores were increased in Schiz-Axial patients compared to Schiz-NO-Axial., Conclusions: Our findings provide evidence that axial parkinsonian signs might be an early manifestation of parkinsonism in schizophrenia associated to older age and longer disease duration., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Purpose: This retrospective cohort study used a population-based dataset to test the risk for parkinsonism in patients receiving flunarizine and cinnarizine, compared with matched controls., Methods: Data were obtained from the National Health Insurance Research Dataset of Taiwan. Patients receiving flunarizine or cinnarizine for more than 1 month between 2000 and 2005 were enrolled. Exclusion criteria included receiving flunarizine, cinnarizine, or antipsychotics for more than 1 month during 1997-1999, a history of neurodegenerative diseases, and an age of less than 30 years. One matched control for each patient was selected. Each participant was followed for diagnosis of parkinsonism within a 3-year observation period. Stroke, diabetes mellitus, total prescription days, and doses of flunarizine or cinnarizine were recorded., Results: The study and control groups consisted of 9830 subjects. In the study group, 280 patients (2.9 %) were diagnosed with parkinsonism with a median observation period of 1.2 years, and 49 participants (0.5 %) were diagnosed in the control group with a median observation period of 1.9 years. The adjusted hazard ratio for parkinsonism among patients receiving flunarizine and cinnarizine was 5.117 (95 % CI = 3.758-6.967). Age, stroke, and diabetes mellitus were significant risk factors, but female sex and total doses of the study drugs were not., Conclusions: This study demonstrates that flunarizine and cinnarizine significantly increase the risk for parkinsonism. The treatment benefits of these two agents should be balanced with this adverse effect. Physicians must look carefully for early signs of parkinsonism in patients treated with flunarizine and cinnarizine.

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., (Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Similarly to subjects with degenerative parkinsonism, (123)I-FP-CIT SPECT has been reported either normal or abnormal in patients with drug-induced parkinsonism (DIP), challenging the notion that parkinsonism might be entirely due to post-synaptic D2-receptors blockade by antipsychotic drugs. In a previous multicenter cross-sectional study conducted on a large sample of patients with schizophrenia, we identified 97 patients who developed parkinsonism with a similar bi-modal distribution of DAT-SPECT. In this longitudinal study, we reported clinical and imaging features associated with progression of motor disability over 2-year follow-up in 60 out of those 97 patients with schizophrenia and parkinsonism who underwent (123)I-FP-CIT SPECT at baseline evaluation (normal SPECT=33; abnormal SPECT=27). As second end-point, chronic response to levodopa over a 3-month period was tested in a subgroup of subjects. Motor Unified Parkinson's Disease Rating Scale (UPDRS) at follow-up significantly increased in patients with abnormal SPECT. Specifically, a 6-point worsening was demonstrated in 18.5% of the subjects with abnormal SPECT and in none of the subjects with normal SPECT. Levodopa treatment improved motor UPDRS only in the group with abnormal SPECT. After adjustment for possible confounders, linear regression analysis demonstrated that abnormal SPECT findings at baseline were the only predictor of motor disability progression and of better outcome of levodopa treatment. Our results support the notion that a degenerative disease might underlie parkinsonism in a minority of schizophrenic patients chronically exposed to antipsychotics. Functional imaging of the dopamine transporter can be helpful to select this patient sub-group that might benefit from levodopa therapy., (Copyright © 2013 Elsevier B.V. All rights reserved.)

We performed a clinical report based, descriptive and retrospective study, aimed at comparing Flunarizine/Cinnarizine-induced parkinsonism (FCIP) patients and Parkinson's disease (PD) patients. The FCIP group (n = 30) presented a lower frequency of rigidity and unilateral tremor than the PD group (n = 70). All FCIP patients improved, 13 after dopaminergic treatment. FCIP patients who improved spontaneously presented lower frequency of rigidity, compared with the other FCIP subgroup and PD group. FCIP patients who did not improve spontaneously showed a clinical pattern similar to PD patients.

Background: The side effect of Parkinsonism due to chlorpromazine emerged three years after its approval for public use, leading to the understanding that conventional anti-psychotics could induce various Extrapyramidal Symptoms (EPS). Drug-Induced Parkinsonism (DIP) generally surfaces within days to weeks, but rare instances present delayed onset. Case Presentation: We present a case involving a 28-year-old male exhibiting drug-induced Parkinsonism triggered by a chlorpromazine-based regimen, three months following its initiation. Subsequent symptom relief was observed post-discontinuation. [ABSTRACT FROM AUTHOR]

Introduction and purpose: The parkinsonian syndrome is a component of Parkinson's disease. A thorough neurological examination can detect symptoms belonging to the parkinsonian syndrome. Diagnosis using the Queen Square Brain Bank criteria is based on the presence of bradykinesia along with one additional symptom in the patient. These include muscle rigidity or resting tremors at a frequency of 4-6 Hz, or postural disturbances that cannot be explained by visual, vestibular, cerebellar, or deep sensory disorders. The parkinsonian syndrome can occur in idiopathic Parkinson's disease, hereditary disorders, secondary parkinsonism, or be part of an atypical parkinsonian syndrome. The aim of the study was to discuss the diagnostic features and differences in the occurrence of the parkinsonian syndrome as a component of Parkinson's disease, both within the context of other neurological disorders. Materials and method: The foundation of the research was medical articles gathered from the Google Scholar database. The studies were conducted by analyzing keywords such as "parkinsonism," "druginduced parkinsonism," and "vascular parkinsonism". Results: Secondary parkinsonism, or secondary parkinsonism syndrome, can be indicated by clinical features such as: disease onset below the age of 40, abrupt onset, rapid disease progression, symptoms related to medication use, and symptoms associated with the underlying condition. In addition to clinical evaluation, imaging studies are also employed. Conclusions: Various conditions can lead to the development of secondary parkinsonism, including hydrocephalus, brain tumors, encephalitis, cerebral atherosclerosis, traumatic brain injuries, medications, and poisoning. The aforementioned conditions exert different mechanisms of influence on the central nervous system. [ABSTRACT FROM AUTHOR]

In the first half of the 20th century, well before the antipsychotic era, paratonia, Gegenhalten and psychomotor hypertonia were described as new forms of hypertonia intrinsic to particular psychoses and catatonic disorders. A series of astute clinical observations and experiments supported their independence from rigidity seen in Parkinson's disease. After World War II, motor disorders went out of fashion in psychiatry, with drug-induced parkinsonism becoming the prevailing explanation for all involuntary resistance to passive motion. With the 'forgetting' of paratonia and Gegenhalten , parkinsonism became the prevailing reading grid, such that the rediscovery of hypertonia in antipsychotic-naive patients at the turn of the 21st century is currently referred to as "spontaneous parkinsonism", implicitly suggesting intrinsic and drug-induced forms to be the same. Classical descriptive psychopathology gives a more nuanced view in suggesting two non-parkinsonian hypertonias: (i) locomotor hypertonia corresponds to Ernest Dupré's paratonia and Karl Kleist's reactive Gegenhalten ; it is a dys-relaxation phenomenon that often needs to be activated. (ii) Psychomotor hypertonia is experienced as an admixture of assistance and resistance that partially overlaps with Kleist's spontaneous Gegenhalten , but was convincingly isolated by Henri Claude and Henri Baruk thanks to electromyogram recordings; psychomotor hypertonia is underpinned by "anticipatory contractions" of cortical origin, occurrence of which in phase or antiphase with the movement accounted for facilitation or opposition to passive motions. This century-old knowledge is not only of historical interest. Some results have recently been replicated in dementia and as now known to involve specific premotor systems. [ABSTRACT FROM AUTHOR]

This retrospective cohort study assessed treatment changes and prognoses after incident drug-induced parkinsonism (DIP). We used the National Health Insurance Service's National Sample Cohort database in South Korea. We selected patients diagnosed with incident DIP and given prescriptions to take offending drugs (antipsychotics, gastrointestinal (GI) motility drugs, or flunarizine) for a period of time that overlapped with the time of DIP diagnosis during 2004–2013. The proportion of patients experiencing each type of treatment change and prognosis was assessed for 2 years after DIP diagnosis. We identified 272 patients with incident DIP (51.9% of patients were aged ≥ 60 years and 62.5% of them were women). Switching (38.4%) and reinitiation (28.8%) were the most common modifications in GI motility drug users, whereas dose adjustment (39.8%) and switching (23.0%) were common in antipsychotic users. The proportion of persistent users was higher among antipsychotic users (7.1%) than that among GI motility drug users (2.1%). Regarding prognosis, 26.9% of patients experienced DIP recurrence or persistence, the rate being the highest in persistent users and the lowest in patients who discontinued the drug. Among patients with incident DIP diagnoses, the patterns of treatment change and prognosis differed across the types of offending drugs. Over 25% of patients experienced DIP recurrence or persistence, highlighting the need for an effective strategy to prevent DIP. [ABSTRACT FROM AUTHOR]

Parkinsonism refers to the clinical combination of bradykinesia, rigidity, tremor, and postural instability. Parkinsonism is often neurodegenerative, but it can be secondary or iatrogenic, as in drug-induced parkinsonism (DIP), which is the topic of this review. We review the pathophysiology of DIP, differentiate DIP and idiopathic Parkinson's disease (PD), list culprit medications in the development of DIP, discuss the diagnosis of DIP as well as the motor and nonmotor signs and symptoms that can help with differentiation of DIP and PD, and detail the management of DIP. [ABSTRACT FROM AUTHOR]

Among neurological adverse reactions in patients with schizophrenia treated with antipsychotics (APs), drug-induced parkinsonism (DIP) is the most common motility disorder caused by drugs affecting dopamine receptors. One of the causes of DIP is the disruption of neurotransmitter interactions that regulate the signaling pathways of the dopaminergic, cholinergic, GABAergic, adenosinergic, endocannabinoid, and other neurotransmitter systems. Presently, the development mechanisms remain poorly understood despite the presence of the considered theories of DIP pathogenesis. [ABSTRACT FROM AUTHOR]

Drug-induced parkinsonism has been commonly studied and discussed regarding antipsychotic agents, but lithium-induced parkinsonism should also be considered when patients present with parkinsonian symptoms and chronic lithium use. There are several reports of parkinsonism arising during lithium administration and regressing following its reduction or discontinuation. Our case is, to date, the first case in the literature in which vocal cord paralysis occurred as the first symptom of lithium-induced parkinsonism, contributing to confuse doctors and patients and to delay diagnosis and treatment. In our clinical case prompt withdrawal of lithium and its reintroduction at lower doses led to complete resolution of this disabling clinical presentation. This report emphasizes the importance of careful monitoring of lithium levels, especially in elderly subjects, and the need to consider lithium-induced parkinsonism even when unusual motor symptoms appear in chronic lithium users. [ABSTRACT FROM AUTHOR]

Whether there are differences in the time to onset of drug-induced parkinsonism (DIP) depending on the type of drugs causing DIP remains uncertain, so that question was investigated here using a large real-world database. Fourteen DIP-related drug categories were defined to perform a disproportionality analysis using a large Japanese pharmacovigilance database containing more than 600,000 self-reported adverse events (AEs) recorded between April 2004 and September 2021 to identify AEs indicating "parkinsonism" in association with the defined drug categories. The time from drug administration to the onset of DIP was comparatively analyzed. Results indicated that the median time to onset was shorter than 1 month in more than half of the cases of DIP; it was shortest with peripheral dopamine antagonists (median: 0.1 weeks), followed by benzodiazepine (median: 0.5 weeks), butyrophenone (median: 0.7 weeks), novel antidepressants (median: 2.5 weeks), atypical antipsychotics (median: 3.3 weeks), other antidepressants (e.g., lithium, median: 3.7 weeks), and benzamide (median: 4.5 weeks). In contrast, anti-dementia drugs, tricyclic antidepressants, and antiepileptic drugs resulted in a relatively longer time to onset (median: 9.9, 17.2, and 28.4 weeks, respectively). In addition, a maximum delay of even longer than 2 years was reported for benzamide (846 weeks), anti-Parkinsonism drugs (382 weeks), phenothiazine (232 weeks), atypical antipsychotics (167 weeks), anti-dementia drugs (161 weeks), and benzodiazepines (120 weeks). The current results suggested that the characteristics of the time to onset of DIP may substantially differ depending on the type of drug causing that DIP. This finding may help when diagnosing patients with parkinsonism. [ABSTRACT FROM AUTHOR]

Background: The last decade has seen development of numerous novel antipsychotic drugs with unique mechanisms including long-acting formulations for clinical use. A comparative assessment of these new drugs with each other and previous antipsychotics have not been performed with regards to risk for drug-induced movement disorders (DIMD). Methods: Medline was searched from January 2010 to February 2022 for primary research articles and review articles in English using the search terms "extrapyramidal" and "tardive" with individual drug names of novel antipsychotics. Results: We identified articles describing the risk of DIMD with 6 novel antipsychotics, 4 novel formulations, and 3 experimental antipsychotics. Both short- and long-term data generally showed comparable to lower risk of DIMD with novel antipsychotics and recent long-acting formulations compared to previously marketed antipsychotics. Discussion: Several novel antipsychotics, particularly lumateperone and pimavanserin, show promise in being able to treat psychosis while reducing the risk of DIMD. Long-acting paliperidone may reduce risk of DIMD while other long-acting injectable formulations of SGA have similar risk of DIMD compared to oral formulations. New drug targets for treating psychosis without dopamine blockade also show promise. [ABSTRACT FROM AUTHOR]

This case report presents the challenging clinical scenario of a middle-aged male patient with a decade-long history of psychiatric illness on chronic neuroleptic therapy. The patient's symptoms initially manifested as tremors a year ago, subsequently progressing to resting tremors, head titubation, and impaired mobility. Typically, Drug-Induced Parkinsonism (DIP) occurs within three months of initiating neuroleptic treatment, this case presents a unique and prolonged timeline, raising questions about the underlying aetiology complexed with patients' imaging studies revealing age related atrophy. The bilateral and symmetrical motor signs observed align with DIP characteristics, although studies report asymmetrical signs, introducing diagnostic complexities. This case emphasizes the need for further research on understanding the effect of chronic neuroleptic use, age-related structural alterations, and the potential unmasking of underlying Parkinsonism for improving diagnostic accuracy and tailoring effective management strategies for patients with similar challenging presentations. [ABSTRACT FROM AUTHOR]

Brainstem auditory evoked response (BAER) is a non-invasive modality that can be used to investigate brainstem neuronal function in movement disorders. The differentiation between drug-induced parkinsonism (DIP) and Parkinson's disease (PD) can be very challenging. Although PD and DIP to some extent display similar clinical symptoms, the underlying pathophysiologic mechanisms are entirely different. Given these differences in pathogenesis, and the diagnostic utility of BAER for detecting brainstem function, BAER may help to distinguish between PD and DIP. This study aimed to assess the accuracy and predictive values of BAER parameters in differentiating DIP from PD. We prospectively studied143 participants classified within three groups, including 50 controls, 57 PD, and 36 DIP. BAER was performed on all patients in the study. Patients in the DIP group were followed up for at least one year after discontinuation of the causative drug and examined for final diagnosis. We compared BAER latencies of the three groups and measured sensitivity, specificity, predictive values, likelihood ratios, and accuracy of BAER in diagnosing DIP. Waves V, I-V, and III-V latencies were significantly prolonged among the PD patients compared to the DIP and the control group; however, there were no significant differences in BAER latencies between the DIP and the control group. Waves V and I-V latencies revealed the highest accuracy (86% and 79%, respectively) in distinguishing DIP from PD with high negative predictive value(89% and 83%, respectively) as well as a high negative likelihood ratio (0.2and 0.3, respectively). This study showed that waves V and I-V latencies are significantly prolonged in PD patients compared to those with DIP, consistent with the proposed mechanisms of neurodegeneration in PD, particularly in the midbrain and pons. Consequently, BAER could be used as a useful diagnostic tool for differentiating DIP from PD. [ABSTRACT FROM AUTHOR]

Drug-induced parkinsonism is the main cause of secondary parkinsonism in the world. Antipsychotics, antidepressants, and mood stabilizers are the most common drugs implicated in the parkinsonism. This is why psychiatrists and neurologists must have deep knowledge of the diverse aspects of these disorders, to take the best diagnostic and therapeutic approaches. [ABSTRACT FROM AUTHOR]

Background: Patients with older age and female sex are known to have increased risk of developing drug‐induced parkinsonism (DIP). Aim: Basic prescription patterns of drugs associated with a risk of causing DIP remain unclear, which we assessed in this study. Methods: Using the publicly distributed data "NDB Open Data Japan," the summary statistics of Japanese nationwide health claims, we calculated the disproportionality in prescriptions among men and women of different age groups to whom tablets/capsules were prescribed at the outpatient clinic from 2014 to 2017. Based on the 2‐by‐2 contingency table, we derived the odds ratio (OR) to identify which drug is more frequently prescribed to elderly (≥65 y/o) women than to men. Results: Among the calculated ORs of 18 generic DIP‐related drugs we investigated, sulpiride had the highest OR (3.85), followed by tiapride (OR = 2.47), olanzapine (OR = 2.43), and risperidone (OR = 2.27). Among all the drug products included in the database, sulpiride again showed a significantly high OR, which was higher than the 95th percentile of ORs of all 3604 products examined. Conclusion: Our results showed that the distribution of sulpiride prescriptions is biased toward older females, who are more susceptible to develop DIP than males. Assuming the limited indication of sulpiride as the primary treatment option for depression or schizophrenia, a future study on why and how sulpiride is prescribed to the elderly female patients might aid in changing the prescription strategy of sulpiride, thereby possibly reducing the overall incidence of DIP in Japan. [ABSTRACT FROM AUTHOR]

Objective: The objective of this study is to examine the effectiveness of an accelerometer-based compact system in detecting and quantifying drug-induced parkinsonism (DIP) in patients with schizophrenia.Method: A pilot study controlled clinical trial comprising 6 people with schizophrenia and 11 control subjects was conducted at Alfred Health, Melbourne. Participants had their movements assessed using Barnes Akathisia Rating Scale (BARS), Simpson Angus Scale (SAS) and Movement Disorder Society Unified Parkinson's Disease Rating Scale Part III (MDS-UPDRS III) followed by an assessment of gait using three triaxial accelerometers.Results: Median BARS, SAS, MDS-UPDRS III and accelerometer scores were significantly higher for patients with schizophrenia than controls. Accelerometers detected three times more rest tremor than clinical rating scales. Patients with schizophrenia had 70% of their dynamic acceleration at frequencies between 4 and 10 Hz, which is almost twice that observed in the control population (38%). Accelerometer scores were significantly correlated with BARS scores.Conclusion: Accelerometers were able to accurately detect patients with DIP better than some clinical rating scale including the SAS. Further larger-scale studies must be conducted to further demonstrate the accuracy of accelerometers in detecting DIP. [ABSTRACT FROM AUTHOR]

Background: Sulpiride is a highly selective dopamine D2 receptor antagonist and is commonly used in psychiatric disorders, Tourette syndrome, peptic ulcer disease (PUD), and gastroesophageal reflux disease (GERD). However, sulpiride has been recognized as a potential cause of drug-induced parkinsonism (DIP) for a long time. In this study, we aimed to focus on analysis of sulpiride-induced parkinsonism (SIP) in PUD and GERD patients based on a nationwide population. Methods: Data were obtained from the Taiwan's National Health Insurance Research Database. The study enrolled 5,275 PUD or GERD patients, of whom were divided into two groups, based on their exposure (1,055 cases) or non-exposure (4,220 cases) to sulpiride. Results: During the study period (2000–2012), the incidence rate of parkinsonism was 261.5 and 762.2 per 100,000 person-years in the control and sulpiride-treated groups, respectively. For patients with at least 14 days of prescription for sulpiride, the adjusted hazard ratio (aHR) was 2.89, 95% confidence interval (CI): 2.04-4.11. Patients with age more than 65 years (aHR = 4.99, 95% CI = 2.58-9.65), hypertension (aHR = 2.39, 95% CI = 1.49-3.82), depression (aHR = 2.00, 95% CI = 1.38-2.91), and anxiety (aHR = 1.45, 95% CI = 1.01-2.09) had significant higher risk of developing parkinsonism. An average annual cumulative sulpiride dose > 1,103 mg was accompanied by the greatest risk of SIP; sulpiride use for ≥ 9 days is a cut-off point for predicting future SIP. Conclusion: At the population level, sulpiride may be frequently prescribed and apparently effective for PUD and GERD. SIP is associated with older age, hypertension, depression or anxiety comorbidities. Physicians should be aware of the neurogenic adverse effects, even when the drug is only used in low-dose or a short duration. [ABSTRACT FROM AUTHOR]

Introduction: Drug-Induced Parkinsonism (DIP) is the second most common cause of parkinsonism after idiopathic Parkinson's disease. Little is known about DIP epidemiology. Using VigiBase®, the objective of this study was to assess the main characteristics of DIP reporting around the world.Methods: We described reports recorded in the WHO pharmacovigilance database, Vigibase® and classified as "Parkinsonism" between 2000 and 2017. Differences of reporting between geographical locations and characteristics of reports were investigated using disproportionality analysis with calculation of Reporting Odds Ratios (ROR) and its 95% confidence interval.Results: Among the 9,009,107 reports recorded in VigiBase®, 4565 (0.05%) were DIP. Co reported terms were mainly "tremor" (n = 408, 8.9%), "gait disturbance" (n = 209, 4.6%) and "extrapyramidal disorders" (n = 180, 3.9%). DIP reports were significantly more frequent in men (ROR = 1.4; 95% CI 1.3-1.5) and in patients aged 75 and over (ROR = 2.12; 95% CI 1.98-2.26). Compared to all other continents, risk of reporting drug-induced parkinsonism was higher in Europe (ROR = 2.89; 95% CI 2.73-3.07), Africa (ROR = 1.81; 95% CI 1.46-2.25) and Oceania (ROR = 1.50; 95% CI 1.27-1.77). The risk was lower in Asia (ROR = 0.55; 95% CI 0.51-0.59) and America (ROR = 0.55 95% CI 0.51-0.59). The highest risk of DIP reporting was found with sulpiride and haloperidol followed by risperidone, aripiprazole, paliperidone, metoclopramide, olanzapine, quetiapine and clozapine.Conclusion: Risk of DIP reports was higher in men, in people aged 75 and over and in Europe. Main drugs involved are antipsychotics not only drugs from the first generation but also those from the second one. [ABSTRACT FROM AUTHOR]

Background: Flunarizine (Fz) is a first-line prophylactic medication that is widely used in migraine. However, Fz has been recognized as a potential cause of drug-induced parkinsonism for a long time. However, to our knowledge, there has been no population-based subgroup analyses for Fz-induced parkinsonism (FIP) in migraine patients. Methods: Data were obtained from the Taiwan's National Health Insurance Research Database. The study comprised 6,470 migraine patients who were divided into two groups, based on their exposure or non-exposure to Fz. Results: During the study period (2000–2012), the incidence rate of parkinsonism was 1.92 and 8.72 per 1,000 person-years in the control and Fz -treated groups, respectively. In the study population, the adjusted hazard ratio was 4.07 (95% confidence interval CI: 2.84–5.85). In 45–64-year old subjects and ≥ 65-year old subjects, the risk of FIP was 3.18 times (95% CI = 1.63–6.20) and 4.89 times (95% CI = 3.09–7.72) more than that in the controls. The Fz-treated subjects with comorbidities also had a higher risk (4.54, 95% CI: 3.14-6.57). An average annual cumulative Fz dose > 445 mg was accompanied by the greatest risk of FIP; Fz use for >60 days is a cut-off point for predicting future FIP. Conclusion: At the population level, this study showed a complete picture of FIP in migraine patients. FIP is associated with older age, history of comorbidities, exposure to high-dose of Fz, and longer duration of exposure to Fz. [ABSTRACT FROM AUTHOR]

Adverse drug reaction (ADR) is a form of unwanted reaction and is the crucial reason for illness and death. Tramadol-induced parkinsonism is a kind of ADR that occurs after the repeated intake of tramadol. Long-term exposure to tramadol has been known to induce tremor and alter the functioning of dopamine. This case report introduces a 75-year-old woman diagnosed with tramadol-induced parkinsonism due to the administration of tramadol for the treatment of post-operated (breast cancer) acute onset of severe pain on the left side of the chest. The assessment of the offending drug was carried out via Naranjo probability scale. A score of 6 was reported for this patient, defining tramadol as a probable cause of this reaction. For the management of the drug-induced parkinsonism, levodopa/carbidopa was prescribed and the symptoms related to parkinsonism resolved within a week. The age of the patient and the female gender is considered to be the main risk factor for the occurrence of such reaction. This case report is an attempt to spread awareness about the negative consequences of long-term use of tramadol in old patients. Thus, the medical practitioners must be very careful while administering tramadol to the old aged population. [ABSTRACT FROM AUTHOR]

Aims: We conducted a cohort study utilizing a nationwide health insurance database to assess the European Medicines Agency's restrictions on using metoclopramide and its association with the risk of parkinsonism. Methods: New oral metoclopramide users aged ≥20 years, and age‐ and gender‐matched non‐users were recruited between 2001 and 2011. Users were divided into high‐exposure (dose >30 mg day–1 and/or duration >5 days) and standard‐exposure (dose ≤30 mg day–1 and duration ≤5 days) groups. The adjusted hazard ratio (aHR) with 95% confidence interval (CI) estimated the risk of parkinsonism. Results: During a 1‐year period, 122 of 218 931 (0.06%) users of metoclopramide vs. 56 of 218 931 (0.03%) non‐users developed parkinsonism (P < 0.001). Among the 122 cases of parkinsonism in users, 64 (0.04%) were from 168 566 standard‐exposure users and 58 (0.12%) from 50 365 high‐exposure users. Compared with non‐users, the risk of parkinsonism was higher in users (aHR 2.16; 95% CI 1.54, 3.02), including standard‐exposure (aHR 1.73; 95% CI 1.11, 2.70), and high‐exposure (aHR 3.15; 95% CI 1.78, 5.57) users. High‐exposure users had a higher risk of parkinsonism than standard‐exposure users (aHR 1.83; 95% CI 1.28, 2.63). Within the high‐exposure group, 45 233 of 50 365 (89.81%) users and 55 of 58 (94.83%) parkinsonism were from long‐duration exposure; 5 132 of 50 365 (10.19%) users and 3 of 58 (5.17%) parkinsonism were from high‐dose exposure and long‐duration + high‐dose exposure. Conclusions: The risk of parkinsonism in metoclopramide users, although extremely low (0.06%), is 2.16‐fold greater than in non‐users. High‐exposure users have a 1.83‐fold higher risk than standard‐exposure users. As users in high‐exposure group had a higher risk of parkinsonism than in standard‐exposure group, and the majority of users and parkinsonism in high‐exposure group were from long‐duration exposure; thus, physician are advised to avoid prescribing metoclopramide for >5 days, even if the daily dose is ≤30 mg. [ABSTRACT FROM AUTHOR]

Objective: Compare clinical characteristics and outcomes in cases where DAT-SPECT imaging is used to distinguish Parkinson's disease from Drug-Induced Parkinsonsim.Background: Clinical uncertainty in diagnosing Parkinson's disease is common when patients are on dopamine-blocking medications. DAT-SPECT imaging can improve diagnostic certainty but little data are available on clinical characteristics and outcomes associated with normal and abnormal scan results.Methods: Retrospective chart review of patients seen at a movement disorders center between 2011 and 2017 where DAT-SPECT was ordered to distinguish Parkinson's disease from Drug-induced Parkinsonism. Descriptive statistics were calculated for variables of interest and compared by scan result. Chi-squared analyses was carried out for categorical variables and students' t-tests for continuous values.Results: 51 patients met inclusion criteria with 36 normal scans and 15 abnormal scans. Those with greater than 2 cardinal manifestations (tremor, rigidity, akinesia, postural instability) were more likely to have an abnormal scan (63.89% vs 93.33%, p = 0.04). No other clinical characteristics assessed were associated with scan results. Atypical antipsychotics (aripiprazole 39.21%, olanzapine 31.37%) and mood stabilizers (valproic acid 33.33%, lithium 17.65%) were most commonly associated with suspected Drug-induced Parkinsonism cases. A post-scan change in management occurred in 41.18% of patients. 55.56% of patients with normal scans responded to changes in the offending medication, with 16.66% taking over 3 months to show improvement.Conclusions: Many DAT-SPECT scans at our institution are ordered to distinguish Parkinson's disease from Drug-induced Parkinsonism because clinical characteristics alone are unreliable. DAT-SPECT results lead to changes in management and the outcomes of these changes are consistent with scan results. [ABSTRACT FROM AUTHOR]

Drug-induced parkinsonism (DIP) is classically described as acute/subacute, bilateral symmetric syndrome in which tremor is infrequent compared to Parkinson's disease. Most DIP cases are caused by classic (CN) and second-generation neuroleptics (SN), and calcium channel blockers (CCB). We evaluated potentially distinctive demographic and clinical features in DIP among different drug classes. This was a prospective study of reversible DIP related to single selected drugs on each class. Baseline assessment included demographic, clinical data, and scales for staging, severity of motor signs of parkinsonism, tremor, and other involuntary movements. Six months after medication withdrawal, patients were reassessed. Those with no parkinsonian signs were included in the final sample. 157 cases were included after strict criteria were applied. Most common agents were haloperidol, levomepromazine, and chlorpromazine for the CN-DIP group, flunarizine and cinnarizine for the CCB-DIP group, and risperidone and olanzapine for the SN-DIP group. Drug exposure was shorter for CN-DIP cases; duration of parkinsonism was longer in the CCB-DIP group. CN-DIP had worse bradykinesia, rigidity, axial, total motor, and disease stage scores, with higher frequency of rigid-akinetic parkinsonism. Tremor scores were worse for CCB-DIP cases. SN-DIP presented as a less severe but similar form of CN-DIP. Tardive-type involuntary movements were less common in the SN-DIP group. DIP profile differs significantly depending on drug class involved, not only in terms of severity, but also regarding the differential combination of signs. These findings may help guiding clinicians in screening and diagnosing DIP in patients exposed to these drugs. [ABSTRACT FROM AUTHOR]

Introduction Response to drug withdrawal in patients with suspected drug-induced parkinsonism ( DIP) is of prognostic and therapeutic importance, but cannot be predicted solely on clinical information. The aim of this study was to validate SN hyperechogenicity ( SN+) assessed by transcranial sonography as a predictor of response to drug withdrawal in this group of patients. Methods Patients were diagnosed according to previously published criteria and prospectively included in the study. All patients were followed until complete recovery of parkinsonian symptoms or at least for 6 months after discontinuation of the offending drug and then diagnosed as DIP or parkinsonism following neuroleptic exposure ( PFNE). Transcranial sonography ( TCS) findings were compared with the clinical diagnosis. Results Sixty patients comprised the group for the final analysis. Sixteen patients were classified as PFNE and 44 as DIP. The area of SN echogenicity was significantly increased in the PFNE group (0.23 cm2; standard deviation [ SD]: 0.04), compared to the DIP group (0.14 cm2; SD, 0.05; one-way analysis of variance; P < 0.001). Normal SN was significantly associated with complete recovery after withdrawal of the parkinsonism-inducing drug ( P < 0.0005). Accuracy of SN+ to distinguish PFNE from DIP was: sensitivity 81.2%; specificity 84.1%; positive predictive value 47.4%; and negative predictive value 96.2%. Conclusions We believe that SN+ assessed with TCS is a valid prognostic marker in the setting of suspected DIP. It is a nonexpensive, feasible technique that can be implemented for proper counseling and guidance of treatment decisions. [ABSTRACT FROM AUTHOR]

Background and purpose Drug-induced parkinsonism usually resolves after discontinuation of the causative agent. However, it persists in some patients, who actually have subclinical neurodegenerative parkinsonism. Identification of this condition is important because these patients could benefit from therapeutic measures. The objective of this study was to prove whether transcranial sonography, a technique used in the diagnosis of neurodegenerative parkinsonism, can be used for the said identification. Methods In this prospective study, patients with drug-induced parkinsonism were followed for at least 6 months after discontinuation of the causative drug and performance of blinded transcranial sonography. Patients were categorized as having iatrogenic parkinsonism if the clinical presentation had resolved or subclinical drug-exacerbated parkinsonism if it persisted. Once the patient was classified into one of the two groups, an expert assessed the transcranial sonography findings and their agreement with the clinical diagnosis. Results Twenty patients composed the group for analysis of results. Assessing hyperechogenicity in the substantia nigra >20 mm2 and/or hyperechogenic lentiform nucleus, differences were detected between the iatrogenic parkinsonism and the subclinical drug-exacerbated parkinsonism groups, although they did not reach statistical significance (Fisher's exact test 0.09). Joint assessment of sonographic alterations in both structures had a negative predictive value of 85.7% for diagnosis of drug-induced parkinsonism, with a negative likelihood ratio of 0.3. Conclusions Although in our study statistically significant differences were not found between the transcranial sonography characteristics of subclinical drug-exacerbated parkinsonism and iatrogenic parkinsonism patients, we believe that transcranial sonography is a valid technique for diagnosis of drug-induced parkinsonism. [ABSTRACT FROM AUTHOR]

Abstract: Adenosine A2A and dopamine D2 receptors interact to regulate diverse aspects of ventral and dorsal striatal functions related to motivational and motor processes, and it has been suggested that adenosine A2A antagonists could be useful for the treatment of depression, parkinsonism and other disorders. The present experiments were performed to characterize the effects of MSX-4, which is an amino acid ester prodrug of the potent and selective adenosine A2A receptor antagonist MSX-2, by assessing its ability to reverse pharmacologically induced motivational and motor impairments. In the first group of studies, MSX-4 reversed the effects of the D2 antagonist eticlopride on a concurrent lever pressing/chow feeding task that is used as a measure of effort-related choice behavior. MSX-4 was less potent after intraperitoneal administration than the comparison compound, MSX-3, though both were equally efficacious. With this task, MSX-4 was orally active in the same dose range as MSX-3. MSX-4 also reversed the locomotor suppression induced by eticlopride in the open field, but did not induce anxiogenic effects as measured by the relative amount of interior activity. Behaviorally active doses of MSX-4 also attenuated the increase in c-Fos and pDARPP-32(Thr34) expression in nucleus accumbens core that was induced by injections of eticlopride. In addition, MSX-4 suppressed the oral tremor induced by the anticholinesterase galantamine, which is consistent with an antiparkinsonian profile. These actions of MSX-4 indicate that this compound could have potential utility as a treatment for parkinsonism, as well as some of the motivational symptoms of depression and other disorders. [Copyright &y& Elsevier]

Abstract: Background: Drug-induced parkinsonism (DIP) is seen in one third of patients exposed to antipsychotic drugs and may lead to complications related to dysphagia and falls. Aside from skilled neurological examination, no tool has been validated to facilitate detection and follow-up. Objective: In this pilot study, three validated screening instruments were tested in an age-biased cohort of schizophrenia patients, including four items of the Liverpool University Neuroleptic Side-Effects Rating Scale (LUNSERS) and two brief questionnaires designed for community survey of parkinsonism. Method: Fifty-six subjects living with chronic schizophrenia between 50 and 75years of age underwent a motor evaluation along the original Unified Parkinson''s Disease Rating Scale-section III and answered questions along the selected screening instruments, and results compared to those of 16 patients with Parkinson''s disease (PD) and 15 neurologically unimpaired volunteers. Odds ratios, sensitivity, specificity, and their 95% confidence intervals, were calculated. Results: All three screening instruments correctly identified the PD state and distinguished PD from healthy participants. Eighteen (32%) schizophrenic patients displayed objective motor signs of parkinsonism. A single item of the LUNSERS (shakiness) significantly distinguished DIP from DIP-free patients, with a sensitivity of 61.1% and a specificity of 83.3%. The positive predictive value was 63.5% and the negative predictive value was 81.9%. The two other screening methods showed insufficient predictive value. Conclusion: Apart from a single query on shakiness, none of the tools examined were adequate to screen for DIP in patients treated for schizophrenia. A different instrument is necessary to monitor this important adverse effect in schizophrenia. [Copyright &y& Elsevier]

Abstract: Dopamine D2 and adenosine A2A receptors interact to regulate aspects of motor and motivational function, and it has been suggested that adenosine A2A antagonists could be useful for the treatment of parkinsonism and depression. The present experiments were performed to characterize the effects of Lu AA47070, which is a phosphonooxymethylene prodrug of a potent and selective adenosine A2A receptor antagonist, for its ability to reverse the motor and motivational effects of D2 antagonism. In the first group of studies, Lu AA47070 (3.75–30mg/kg IP) was assessed for its ability to reverse the effects of the D2 receptor antagonist pimozide (1.0mg/kg IP) using several measures of motor impairment, including catalepsy, locomotion, and tremulous jaw movements, which is a rodent model of parkinsonian tremor. Lu AA47070 produced a significant reversal of the effects of pimozide on all three measures of parkinsonian motor impairment. In addition, Lu AA47070 was able to reverse the effects of a low dose of the D2 antagonist haloperidol on a concurrent lever pressing/chow feeding task that is used as a measure of effort-related choice behavior. The ability of Lu AA47070 to reverse the effects of D2 receptor blockade suggests that this compound could have potential utility as a treatment for parkinsonism, and for some of the motivational symptoms of depression. [Copyright &y& Elsevier]

This report describes a case of likely drug-induced Parkinsonism (DIP) identified by the pharmacist. A 54-year-old female patient was referred by a physician to the pharmacist in a rural, integrated care team for a comprehensive medication review (CMR) to address the patient's concerns of possible Parkinson's disease (PD). While PD may occur over the progression of age, medications that affect dopamine transport can also cause DIP, a secondary form of Parkinson's disease. Although PD and DIP may be clinically indistinguishable, differentiation may be possible by reviewing a patient's medication history for any potential causative drugs correlating to the timeline of the onset of symptoms. In this case, the pharmacist reviewed the medication profile and identified medications that could be responsible for causing DIP, specifically bupropion. The pharmacist suggested discontinuing bupropion and identifying another option for treating depression. The patient appreciated the suggestion and education, but ultimately preferred continuing her bupropion therapy instead of discontinuing therapy or changing to an alternative agent. At a follow-up meeting with the pharmacist, not only was the patient still experiencing tremors despite taking carbidopa/levodopa, but additional medications known to be potential inducers of tremors were added to her regimen. Although the pharmacist repeatedly discussed DIP with the patient and believed stopping bupropion would determine whether her Parkinsonism was PD or DIP, ultimately the patient continued taking bupropion because of concerns related to depression severity and the impact on her well-being. The patient's wishes were respected. [ABSTRACT FROM AUTHOR]