Review Article Open Access J Neurol Neurosurg Volume 3 Issue 4 - May 2017 Copyright © All rights are reserved by Sujith Ovallath DOI: 10.19080/OAJNN.2017.03.555620 Drug Induced Parkinsonism: An Overview Bahiya Sulthana and Sujith Ovallath* James Parkinson’s Research Centre, Kannur Medical College, India Submission: March 22, 2017; Published: May 05, 2017 *Corresponding author: Sujith Ovallath, James Parkinson’s Research Centre, Kannur Medical College, India, Email: Abstract Ever since 1950s from reserpine rat model to [18F] FP-CIT PET scan, our knowledge of drug induced Parkinsonism has been constantly evolving. Trend of suspected agents changed from typical antipsychotic to more commonly used drugs like Metoclopramide and more recently to newer prokinetics like levosulpiride. Even though DIP is mostly reversible, unmasking of subclinical PD and irreversible damage by the drug leads to persistent DIP. Demonstrated risk is higher with elderly and women. Symptoms can appear from 3 months (69%) to 12 months (20%) of the drug intake. Most of causative agents act by blocking the dopaminergic transmission in niagrostriatal pathway. The clinical syndrome is likely to present with subacute onset with symmetrical involvement. Presence of non-motor symptoms especially hyposmia and asymmetrical involvement is suggestive of degenerative Parkinsonism. DaT scan/SPECT are the investigation available to differentiate pure DIP from other forms. Management of this condition comprises of recognition of symptoms early identifying the offending agents and prompt discontinuation of the causal agent . This result in marked improvement in about 90% patients. Medical therapy is indicated only if the symptoms persist or are problematic. Symptomatic treatment includes anti-cholinergic drugs like benztropine and trihexifenidyl, amantidine and ECT for refractory cases. Levodopa and dopminergic agonist do not offer symptomatic improvement unless there is presence of degenerative component. In this era of polypharmacy and traditional medicine, the offender is rarely found and in clinical scenario DIP is rarely suspected leading to unnecessary use of dopaminergic agonist for a prolonged period. Whatever the trends may be, unrecognized DIP is burdensome particularly for the elderly in terms of morbidity, prolonged hospital stay, unnecessary drug intake along with its side effect and devastating economic consequences. Keywords: Parkinsonism; Drug induced; Rigidity; Freezing Introduction For more than half a century, drug induced Parkinsonism (DIP) has captured the attention of the physicians and recognition by the treating physician or over confidence in safety can help prevent unnecessary long term use of dopaminergic researchers alike. More and more drugs underwent extensive profile of certain agents. Although challenging, diagnosing DIP agents and its detrimental side effects. scrutiny and causal agents were penned down from notorious antipsychotics [1] to more innocent anti-arrhythmic agents This review highlights the recent trends, more on the largely [2]. Earlier studies kept DIP as commonest cause of secondary overlooked drugs that can cause DIP and need for awareness Parkinsonism and the second commonest cause of parkinsonism among treating physicians to rethink about their prescriptions. second to idiopathic Parkinson’s disease [3-5]. A recent study showed not only reduction of 68.6% in the incidence of DIP over History a 30-year period from 1976 to 2005 but also a relatively rare Use of chlorpromazine for psychosis and reserpine for high type of parkinsonism compared with other neurodegenerative blood pressure triggered recognition of DIPs in early 1950s [9]. attributed to substitution of typical antipsychotics by newer and types in persons aged 40 years or older [6]. This finding was The reserpine-treated rodent model was instrumental in first safer atypical antipsychotics in psychiatric practice [6]. But due and his collegues in 1957 [10], which still remains the gold demonstrating the therapeutic efficacy of levodopa by carlsson standard till to date. Reversal of reserpine induced akinesia has been overlooked from suspicion of causing DIP [7]. Common by levodopa also demonstrated parkinsonism was related to to reported safety profile, widely used atypical antipsychotics drugs such as levosulpiride used in combination with proton dopamine rather than serotonin [11]. Reserpine induces an pump inhibitors for dyspepsia causing DIP is on the rise [8]. akinetic state and bradykinesia by depleting brain monoamines, Falling incidence can as well be true or it can be due to under which led to understanding links between monoamine depletion Open Access J Neurol Neurosurg 3(4): OAJNN.MS.ID.555620 (2017) 001 Open Access Journal of Neurology & Neurosurgery and parkinsonian symptoms [12]. Basement of treatment for The incidence of DIP increased with older age, and was Parkinsonism was laid when it was recognized that reserpine use higher in women than men at all ages; although incidence of produces parkinsonian features in human similar to idiopathic parkinsonism is more in men [6]. The age-related decline in Parkinson’s disease [13]. This effect was soon recapitulated in number and integrity of dopaminergic neurons [33], a higher humans by Degkwitz and collegues in 1960 [14]. use of dopamine-blocking or dopamine-depleting drugs in older subjects [34,35] for mood disorders and palliative care in the All the agents used to manage parkinsonism symptoms elderly can be contributing reasons for the increased incidence including apomorphine, pramipexole, ropinirole, pergolide, [36]. It is proven that older individual using neuroleptics bromocriptine and cabergoline [15-20] along with muscarinic antagonists such as benztropine and trihexyphenidyl [15], to be started on anti-parkinsons medication than a non-user MAO-B or COMT inhibitors such as selegiline, rasagiline or presenting with parkinsonian symptoms is five times more likely [37]. Increased incidence in women can be explained by the anti- tolcapone [17,21] and amantadine [15,17] has proved their dopaminergic action of estrogen in extrapyramidal system [38] and also secondary factors like higher consumption of drugs Later haloperidol-treated rats and models such as the classical efficacy either alone or in combination in reserpine-treated rats. with better compliance [2]. In a study by Esper and Stewart; 6-hydroxydopamine (6-OHDA) rat and 1-methyl-4-phenyl- out of 354 parkinsonism 24 were cases DIP and 19 out of which 1,2,3,6-tetrahydropyridine (MPTP) mouse models later were were misdiagnosed and started on dopaminergic drug while on used to extensively to study pathogenesis and various drugs inciting drugs [7]. [22]. DIP paved the path to understanding the pathogenesis of Parkinsonism and discovery of levodopa and other drugs useful Causal agents in the treatment of Parkinsonism. In a 17 years surveillance conducted in regional Definition pharmacovigilance center in France; suspected drugs involved were dopaminergic antagonist (49%), followed by antidepressants (8%), calcium channel blockers (5%), peripheral syndrome in patients treated with drugs which impair dopamine DIP can be defined as reversible development of parkinsonian dopaminergic antagonists (5%), and H1 antihistamines (5%) function [23]. Parkinsonian syndromes includes symptom along with some cases with lithium, valproic acid, amiodarone, complexes such as tremor, rigidity and bradykinesia in addition anticholinesterases, or trimetazidine [2]. from DIP may vary from days to years after offensive drugs A 30 year population based study, it was found that typical to loss of postural reflexes and freezing [24]. Time for recovery antipsychotic medications were the drugs most frequently of individuals even after withdrawing the causal agents the associated with DIP. Among study group, 59.3% were treated are withdrawn [25]. Though reversible, in significant amount symptoms persisted [26-29]. This may indicate ongoing toxicity, for schizophrenia and psychosis, 16.7%for severe mood disorders, 12.0% for severe dementia with agitation, 7.4% for syndrome [23,25,30-31]. Symptoms after suspected drug intake chronic nausea, and 4.6% for other indications developed DIP irreversible deficit or unmasking of underlying parkinsonism appears bimodal with 69% showing symptoms after 3 months [6]. Another study done in 2015, suspected drugs were mainly and 20% after 12 months [2]. Nevertheless, it’s clear that un- antipsychotics. levosulpiride, flunarizine and olanzapine compared to typical treatment non-compliance and disability. recognized DIP ultimately results in significant morbidity, In early 1950s neuroleptic agents was extensively used in Epidemiology treatment of schizophrenia, led to discovery of extrapyramidal side effects which included Parkinsonism, akathisia, acute According the record based study done in Minnesota between dystonia and tardive dyskinesia and in one quarter of the patients 1985-2005, the average annual incidence rate of DIP over 30 DIP was observed [39]. Typical antipsychotics which frequently years was 3.3 per 100,000 person-years overall (108 patients), associated with DIP are chlorpromazine, prochlorperazine, 2.1 in men (33 patients), and 4.3 in women (75 patients). In the youngest age group (0-39 years), DIP was the most common pimozide and sulpiride [40]. These agents inhibit dopaminergic type of Parkinsonism, accounting for 11 of 15 cases (73.3%) perphenazine, fluphenazine, promethazine, haloperidol, transmission by blocking D2