Jose Luis Lopez-Sendon, 1,2 Mar a Angeles Mena 2,3 and Justo Garc a de Yebenes 1,2 1 Department of Neurology, Hospital Ramo n y Cajal, Madrid, Spain 2 CIBERNED (Centro de Investigacion Biomedica en Red. Enfermedades Neurodegenerativas), Madrid, Spain 3 Department of Neurobiology, Hospital Ramo n y Cajal, Madrid, Spain Contents Abstract. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106 2. Definition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107 3. Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107 4. Risk Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108 5. Clinical Features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109 6. Causal Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111 7. Pathogenic Mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112 8. Prevention and Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114 9. Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114 Abstract Drug-induced parkinsonism (DIP) has been claimed to be the most pre- valent cause of secondary parkinsonism in clinical practice in the Western world. Since the first descriptions in the early 1950s the prevalence of DIP seems to be increasing and approaching that of idiopathic Parkinsons disease (iPD) due to the aging of the population and the rising of polypharmaco- therapy. Despite the wide interest this subject has raised in the past, it seems to be frequently overlooked by the medical community. It is particularly burdensome for the elderly and its management includes recognition of symptoms and identification of risk factors and offending agents. Prompt discontinuation of the causative agent leads to a marked improvement, although the condition might persist or remit slowly in up to 10%of the patients. Risk factors for developing DIP include older age; female sex; cognitive im- pairment; potency, dose and length of treatment; pre-existing extrapyramidal signs; and, very likely, a background of inherited predisposition. The main causative agents are dopamine receptor antagonists but the list of drugs without such a well known and straightforward mechanism of action is large. All anti- psychotics, including atypicals (except clozapine) may produce parkinsonism. Although many drugs cause parkinsonism in a dose-related manner, there is an enormous variation in individual susceptibility. The clinical syndrome is less likely to produce tremor than iPD, and is more likely to be symmetrical, but the two syndromes might not be distinguished in any individual patient. Functional neuroimaging tests, which use ligands that bind to the dopamine transporter, are REVIEWARTICLE Drugs Aging 2012; 29 (2): 105-118 1170-229X/12/0002-0105/$49.95/0 2012 Adis Data Information BV. All rights reserved. useful for distinguishing iPD from DIP in doubtful cases in patients treated with antipsychotics. The estimated presynaptic dopamine secreting neurons should be diminished in iPD but normal in DIP produced by dopamine receptor blockers, as assessed by molecular imaging techniques evaluating striatal dop- amine transporters (DATs). Prompt recognition and discontinuation of the culprit are the keys to the management of DIP. In persistent cases, specific therapies including anticholinergics and amantadine may provide symptomatic relief. Levodopa and dopamine receptor agonists might be an option in selected cases in which dopamine nerve terminal defects are present. The weight and scope of DIP varies with the age and underlying health of the patient, imposing a significant burden on the elderly who, in many cases, experience significant functional deterioration that leads to hospitalization and has vast economic consequences. This article reviews the epidemiology, pathogenic mechanisms, implicated drugs, clinical features and management of DIP and highlights the need for increased awareness of this iatrogenic condition. 1. Introduction Drug-induced parkinsonism (DIP) was recog- nized in the early 1950s, with the use of chlor- promazine for the treatment of psychosis and reserpine for high blood pressure. [1] Animal studies demonstrated that reserpine induces an akinetic state as well as bradykinesia by depleting brain monoamines. [2] In fact, it was the reversal of reserpine-induced akinesia by levodopa, but not by 5-hydroxytryptophan (5-HTP), in the animal model used by Carlsson and colleagues that demonstrated that parkinsonism was related to dopamine but not to serotonin depletion. [3] That finding provided a tremendous impetus for the treatment of idiopathic Parkinsons disease (iPD) since it was soon recognized that reserpine caused a parkinsonian state in humans undis- tinguishable from iPD. [4] This observation, cou- pled with the known histopathology, led to the discovery that dopamine and its metabolites are severely reduced in iPD [5] and to its effective treatment with dopamine precursors and dopa- mine receptor agonists. A large number of drugs have been identified as potential culprits responsible for DIP and today it is widely accepted that virtually all dop- amine receptor antagonists as well as many other drugs that interfere with dopamine synthesis or release have the potential to cause DIP in predis- posed individuals. Furthermore, other widely used compounds outside the treatment of psychiatric illnesses and with diverse pharmacological mech- anisms of action are known to either induce or exacerbate parkinsonism. DIP has been considered the second leading cause of parkinsonism in the elderly after iPD. [6] Neuroimaging studies per- formed in iPD patients have shown that younger onset iPD patients progress more slowly and seem to endure substantially more damage to the ni- grostriatal dopamine system before the first motor symptoms appear. [7] This suggests that younger patients have more efficient pre- and post-synaptic compensatory mechanisms aimed at maintaining normal dopamine neurotransmission. [7] There is an age-related diminution in the number of nigral dopaminergic neurons and increased Lewy body- like neuronal inclusions, which may suggest presymptomatic iPD in the elderly. [8] Also, this particular group is more frequently subject to polypharmacotherapy and treatment with antipsy- chotics for behaviour-related disorders. Further- more, the prognostic implications of recognizing DIP in this age group are fundamental since the disorder might be particularly burdensome and imply a higher mortality. [9] Therefore, special care should be taken in the use of potential DIP-inducing agents in this population. Several 106 Lopez-Sendon et al. 2012 Adis Data Information BV. All rights reserved. Drugs Aging 2012; 29 (2) factors that might indicate a high risk for devel- oping DIP, other than age, have been suggested and include female sex, exposure time and type of offending drug, and multiple drug therapy. [10] Nevertheless, all the studies have demonstrated a remarkable individual variation in the suscepti- bility to develop DIP. [11] It is essential to bear in mind that the presence of DIP is frequently overlooked, not only by general practitioners and psychiatrists, [12,13] but also by neurologists. [14] Recovery following withdrawal of offending agents may take from weeks to months or even years. In some cases, the persistence of clinical deficits might suggest that, in some patients, the of- fending drugs either unmask pre-existing subclinical parkinsonism or produce irreversible progressive deficits in the nigrostriatal dopamine pathway. This last possibility has been supported by some radio- nuclide studies performed in patients with DIP, which revealed a reduced striatal uptake suggestive of lesions of the presynaptic dopamine terminals indicating that the DIP might be multifactorial. [15] It has also been found that some of the drugs that cause DIP may also cause direct neurotoxic damage to the nigrostriatal dopamine neurons, [16,17] causing an irreversible toxic parkinsonism. The main steps for the management of DIP are prevention, early recognition, withdrawal or re- placement of offending drugs and, in certain cases, pharmacological therapy. A literature search was performed using the terms drug-induced and parkinsonism to iden- tify articles published from 1960 to 2011 on the epidemiology of and agents causing DIP. Studies were identified through electronic MEDLINE and PubMed databases. Manual review of biblio- graphies allowed for the detection of additional articles. This article reviews the drugs that cause DIP; the epidemiology, clinical features, patho- genic mechanisms and management of DIP; and the special role of aging in this syndrome. 2. Definition DIP is defined as an akinetic-rigid syndrome induced by pharmacological agents. [16] The term parkinsonism refers to a clinical syndrome char- acterized by the presence of tremor, rigidity and bradykinesia in addition to loss of postural re- flexes and freezing. DIP falls into the category of secondary parkinsonisms. [18] This definition im- plies a difference between primary or neurode- generative parkinsonisms such as iPD and other secondary parkinsonisms caused by environ- mental agents such as cerebrovascular disease, infections, tumours and toxic agents. DIP is usually considered reversible, at least partially, when the offending drug is withdrawn. However, this is not always the case and long-term studies indicate that up to 20% of patients develop persistent and progressive deficits despite drug discontinuation. [19] 3. Epidemiology The estimates for the prevalence and incidence of DIP are greatly variable depending on the type of study, the clinical scenario and the drugs in- volved in the analysis. Its epidemiology clearly reflects the characteristics of the population being treated (e.g. an elderly population of institutiona- lized patients or a psychiatric ward). Neverthe- less, it seems clear that DIP represents one of the most frequent causes of secondary parkinsonism among certain populations. Approximately 15% of patients on long-term antipsychotic therapy develop DIP, [20] but the prevalence might reach as much as 60%depending on the potency and dose of the drug or the sharp eye of the examining neurologists. A study performed in the setting of a geriatric clinic prospectively reviewed all new cases of parkinson- ism. [21] It was noted that up to 51% of a total of 95 newly diagnosed parkinsonisms were considered re- lated to prescribed drugs. The most common of- fending agent was prochlorperazine, an antiemetic, which the investigators thought was not indicated in any case. Many epidemiological investigations have addressed the prevalence of DIP in the gen- eral population. The figures reported are rather heterogeneous and reflect the different contexts in which the studies were conducted. A study of a population of 208 000 in a district located in the English Midlands showed a PD prevalence of 108.4 per 100000, [22] which is comparable to fig- ures from Rochester (MN), USA [23] and south- west Finland. [22] In this population, DIP was very Drug-Induced Parkinsonism in the Elderly 107 2012 Adis Data Information BV. All rights reserved. Drugs Aging 2012; 29 (2) uncommon. Different findings have been reported in Japan, where DIP represents the second leading cause of parkinsonism after iPD. [24] In a pop- ulation-based survey performed in eight Italian municipalities, DIP represented only 10%of all the cases of parkinsonism. [25] A door-to-door, two- phase-approach study of parkinsonism prevalence in three elderly (age >65 years) population groups of central Spain showed that of 118 subjects with parkinsonism, 26 were considered to have DIP crite- ria (22%). [26] In a community-based survey in Brazil involving an aged population (aged 65 years), the prevalence of parkinsonism (all types) was 7.2%. DIP was the second most common cause (2.7%) after Parkinsons disease (3.3%). [27] A recent pub- lication reviewed the spontaneous notifications of DIP in a French regional pharmacovigilance centre (French Midi-Pyre ne es area of approxi- mately 2 900 000 inhabitants) between 1993 and 2009. [28] During this time, 155 cases of drug in- duced or worsened parkinsonism were reported. In a door-to-door survey in Spain in 2004 to determine the prevalence of parkinsonism in an island community, the rate of DIP matched that of presumed iPD. [29] Other large prospective epide- miological studies have estimated the overall in- cidence of DIP after the initiation of antipsychotics (both typical and atypical) at about 4%. [30] Inter- estingly, some studies have observed a change in the prevalence and type of compounds implicated in certain populations, highlighting perhaps the importance of prescribing tendencies and an im- proved knowledge of the side effect profiles of these drugs. [31] However, it is clear that much par- kinsonism is underdiagnosed, even in a healthcare setting. [32] Another source of data for understand- ing the epidemiology of DIP are drug trials, which tend to use the Simpson-Angus Scale clearly weighted toward rigidity and other scales that are neither ideal nor fully validated. [33] As a result, it is possible that the true prevalence of DIP is even greater than reported in these studies. 4. Risk Factors Many epidemiological studies have addressed the identification of risk factors for the develop- ment of DIP. While some of these risk factors have been confirmed, contradictory reports are not un- common. Only one fact remains unambiguous: all studies have demonstrated a remarkable individual variation in the susceptibility to extrapyramidal side effects with dopamine receptor antagonist drugs. Clearly, older patients are more susceptible to DIP, presumably reflecting the known decline in nigral neurons and striatal dopamine that occurs with normal aging. [34] Among a group of elderly patients, those with associated dementia are at greater risk for development of DIP than patients without dementia. [35] Patients with iPD and de- mentia with Lewy bodies are particularly sensitive to the effects of dopamine receptor antagonist drugs. It is proven that younger psychotic patients, who usually require more drugs than older patients, are less likely to develop DIP. [36] There may also be different sensitivities to antipsychotic motor side effects with different psychiatric disorders as well as with age of onset of the psychiatric disorder. [37] Most but not all studies have shown a higher incidence of DIP in women, [38,39] but the reason for this is not understood given the predominance of iPD among males. The influence of a hereditary predisposition has also been studied as a risk fac- tor for developing DIP. Genetic differences in the functional polymorphisms of the genes coding for dopamine receptors and other proteins in- volved in dopamine neurotransmission are a hy- pothetical explanation for the variability of the interindividual susceptibility to DIP. [40,41] Wide genome analysis and genotype studies have iden- tified several polymorphisms associated with DIP severity in patients with schizophrenia taking an- tipsychotics. Some of these found associations of DIP with dopamine and serotonin receptor and transporter polymorphisms. [42] Also, isolated re- ports have suggested that there may be a familial susceptibility to DIP [43] based on the identification of affected family members. Other studies that performed HLA typing in schizophrenic White men taking antipsychotics found that a single an- tigen was significantly more common in the group with DIP than in the group without it. [44] In sup- port of the hypothesis of a familial predisposition is the observation that single heterozygous muta- tions of the park-2 gene or polymorphisms of par- kin have been found in some cases of DIP. [45] DIP 108 Lopez-Sendon et al. 2012 Adis Data Information BV. All rights reserved. Drugs Aging 2012; 29 (2) can be considered a multifactorial process in which potential neurotoxicity of drugs acts upon a back- groundof inheritedpredisposition. [46] AIDSpatients are more prone to develop DIP when exposed to compounds liable to induce parkinsonism [47] and HIVshould always be considered in young patients with secondary parkinsonism. Histopathological examinations of the pars compacta of the sub- stantia nigra of autopsied AIDS cases found that the total number of neuronal cell bodies was 25% lower in AIDS patients than in age-matched controls, which could possibly explain the higher susceptibility of some of these patients to DIP. [48] Cigarette smoking has been considered to have a protective effect against iPD. [49] Similarly, schizophrenic patients who smoke have signifi- cantly less cognitive impairment and a lower pre- valence of DIP compared with non-smokers, suggesting that cigarettes might play a protective role against the development of dementia and DIP in schizophrenia. [50] 5. Clinical Features The clinical features of DIP are variable, but by definition, all patients must present with a rigid- akinetic syndrome induced by pharmacological agents. This variability can be attributed to both individual factors such as age, sex and individual susceptibility to a certain type of drug and also to drug factors such as potency, dose and length of exposure. Although the clinical characteristics might overlap with those of iPD and other pri- mary and secondary parkinsonisms, making the syndromes undistinguishable in a particular sub- ject, subtle clinical signs might provide help in the differential diagnosis of DIP (table I). Patients tend to be unaware of their parkinsonism when mild except for tremor. [51] Since DIP is a drug- induced syndrome, it is usually considered to be symmetrical (on both sides of the body), but some studies have observed asymmetry in up to half of the patients. [52,53] Not all the cardinal features of iPD are necessarily present, and they are variably severe in an idiosyncratic manner. The complete triad of tremor, rigidity and bradykinesia is seen only in a limited number of cases. Akinesia with loss of arm swing can be the earliest feature. Bradykinesia can also be an early common symp- tom, causing lack of expression in the face, slow initiation of movement and speech difficulties. It is less likely to be associated with tremor, which is uncommon with drugs that selectively involve dopamine neurotransmission, such as dopamine D 2 receptor antagonists, and much more frequent with other compounds that act through a less Table I. Clinical features of DIP and iPD Main features DIP iPD Age at onset More often in the elderly Sixth decade Symptoms at onset Typically symmetrical Typically asymmetrical Onset Acute or subacute Chronic Course with treatment Reversible Progressive Response to causative drug withdrawal Variable Poor Response to levodopa Poor Marked Other features Orofacial dyskinesia, akathisia Rest tremor Uncommon Common Sex More common in females More common in males Freezing Uncommon Common DaTscan Normal Abnormal PET/SPECT imaging Normal uptake of presynaptic markers, reduced uptake of dopamine receptor ligands Reduced uptake of presynaptic markers, normal uptake of dopamine receptor ligands DaTscan=ioflupane 123 I; DIP=drug-induced parkinsonism; iPD= idiopathic Parkinsons disease; PET=positron emission tomography; SPECT= single proton emission computerized tomography. Drug-Induced Parkinsonism in the Elderly 109 2012 Adis Data Information BV. All rights reserved. Drugs Aging 2012; 29 (2) selective mechanism, such as calcium channel an- tagonists or amiodarone. [54] The presence of other drug-induced movement disorders, such as akathisia and buccal-lingual-masticatory syndromes, might accompany the clinical picture, indicating previous exposure to dopamine receptor antagonists. The nature of these associated movement disorders might be acute, such as acute dystonic reactions and akathisia, or tardive disorders that appear after long-term treatment with the causative drug. Gait abnormalities are common in DIP [55] but appear only after many years of progression in Parkinsons disease. Interestingly, freezing is frequently observed in secondary parkinsonisms such as normal-pressure hydrocephalus and vascular parkinsonism, and generally in patients with neurodegenerative par- kinsonism such as supranuclear gait palsy, multiple system atrophy and corticobasal degeneration. [56] Nonmotor features of iPD have not been well studied in DIP. Olfactory tests are reported to be normal in DIP, [57] but other studies have reported conflicting results. [58] Cognitive impairment re- versible with the withdrawal of the offending drug and associated with the severity of the motor symptoms of DIP has been observed in a recent study. [59] The course of DIP is also variable. It usually develops within the 3 months after the patient is exposed to the drug. [16] Most patients maintained on antipsychotics without antiparkinson drugs improve over time, but what percentage or to what degree is unclear. Most patients reach a plateau on a stable dose of antipsychotics and maintain this level or improve. After the causa- tive drug is withdrawn, parkinsonian signs usu- ally begin to improve in several weeks and patients are relieved from their symptoms within several months, [24] although complete resolution may take over a year. [60] The explanation for the persistence of parkinsonism could be that iPD was unmasked by blockade of dopamine recep- tors or by drugs that interfere with dopamine neurotransmission by other mechanisms. In sup- port of this is the clinical observation that in some patients DIP may recover, only to be followed months later by the appearance of iPD. [61] In some cases it could be that the offending agent has not only a reversible functional property but also an irreversible toxic potential that persists after the withdrawal. For instance, dopamine receptor antagonists increase the firing of dop- amine neurons and the synthesis and metabolism of catecholamines. [62] In addition, some dop- amine receptor antagonists, such as haloperidol, have direct toxic effects on neurons due to their inhibition of mitochondrial function and could contribute to the death of nigrostriatal dopamine cells. [63] Other pharmaceutical compounds, in- cluding atypical antipsychotics, may share both mechanisms, that is, pharmacological inhibition and neurotoxic effects on dopamine neurons. On rare occasions an unexplained form of DIP can be caused by antipsychotic withdrawal, known as withdrawal emergent parkinsonism. [64,65] No adequate explanation for this phenomenon has been provided but it clearly contradicts the sim- plistic theory that antipsychotics act primarily by blocking dopamine receptors and suggests a more complex mechanism of action for these compounds. Although the diagnosis is chiefly clinical and history based, several ancillary tests may aid in the differential diagnosis of DIP. It should be empha- sized that the diagnosis of iPD should not be made in patients who have received dopamine receptor antagonists within the past year or longer unless the parkinsonism has slowly worsened while off the drug. The assumption that the parkinsonism was produced by a certain drug would be straightfor- ward in the case of drugs blocking dopamine re- ceptors or those that deplete dopamine stores or when the symptoms disappear after discontinua- tion of the putative responsible agent. There are, however, many cases attributed to certain com- pounds in which the mechanisms of interaction with the dopamine system are unknown and the suspicion of causality is based on the observation that the symptoms appear during the treatment and disappear after its suppression. In this situa- tion, the possible drug effect can only be taken into account once the parkinsonism has developed. When the awareness of the clinician about the harmful effects of the offending drug is insufficient to lead to a correct diagnosis, functional neuroimag- ing might provide information with high sensitivity about the integrity of the nigrostriatal pathway. 110 Lopez-Sendon et al. 2012 Adis Data Information BV. All rights reserved. Drugs Aging 2012; 29 (2) Normal dopamine transporter-single proton emis- sion computerized tomography (DAT-SPECT) findings are helpful in supporting a diagnosis of DIP by excluding underlying true nigrostriatal dysfunc- tion. [66] Antidopaminergic drugs may unmaskactual Parkinsons disease [15] and underlying Parkinsons disease can be detected throughDATimaging. Also, cardiac scintigraphy is normal in patients with DIP, but abnormal in Parkinsons disease, implying intact sympathetic function in DIP. [67] Transcranial ultra- sound studies showed that patients with a pattern of elevated echogenicity of the substantia nigra might be more susceptible to DIP. [66] This might not aid in the differential diagnosis but shows the importance of individual susceptibility to DIP. 6. Causal Agents The drugs that most frequently cause DIP are primarily drugs that block dopamine receptors, particularly D 2 receptors. These are most often antipsychotic drugs, such as first-generation anti- psychotics (haloperidol, chlorpromazine and tri- fluoperazine) and newer atypical antipsychotics such as risperidone or olanzapine (table II). It should be noted that these drugs have different degrees of parkinsonismassociated with them, that is, none for clozapine and probably quetiapine, and progressively more for olanzapine and risper- idone. [68-70] However, several double-blind, placebo- controlled studies carried out by movement disorder experts showed no significant motor worsening compared with placebo with the use of quetiapine in iPD patients. [71-73] The propensity for these agents to cause DIP relates to their degree of D 2 receptor occupancy. [74,75] Despite this, the devel- opment of DIP remains highly unpredictable and it is not uncommon to see patients receiving high doses of antidopaminergics but without parkin- sonism. Other compounds that interfere with Table II. Potential causes of DIP Potential risk of DIP Pharmacological group/mechanism of action Drug High Dopamine D 2 receptor blockers Typical antipsychotics (haloperidol, prochlorperazine, thioxantenes, amisulpride, flupentixol, fluphenazine, levomepromazine, pimozide promazine, sulpiride, thioridazine, zuclopenthixol) Atypical antipsychotics (at higher doses) [risperidone, olanzapine, aripiprazole] Dopamine depleters Tetrabenazine, reserpine Dopamine synthesis blockers a-Methyldopa Calcium channel antagonists (P-channel) Flunarizine, cinnarizine Intermediate Atypical antipsychotics Ziprasidone Calcium channel antagonists (L-channel) Diltiazem, verapamil Antiepileptics Valproate, phenytoin, levetiracetam Antiemetic and gastric motility agents Prochlorperazine, metoclopramide, substituted benzamides Mood stabilizers Lithium Lower Antiarrhythmics Amiodarone, procaine Immunosuppressants Ciclosporin, tacrolimus Antidepressants SSRIs: fluoxetine, sertraline Tricyclic: phenelzine MAOIs: moclobemide, phenelzine Antibacterials Cotrimoxazole Antivirals Aciclovir, vidarabine, anti-HIV Statins Lovastatin Antifungals Amphotericin B Hormones Levothyroxine sodium, medroxyprogesterone, epinephrine (adrenaline) DIP=drug-induced parkinsonism; MAOIs = monoamine oxidase inhibitors; SSRI =selective serotonin reuptake inhibitors. Drug-Induced Parkinsonism in the Elderly 111 2012 Adis Data Information BV. All rights reserved. Drugs Aging 2012; 29 (2) dopamine are the antiemetics prochlorperazine and droperidol, and agents used for gastrointes- tinal complaints such as metoclopramide, clebo- pride and similar substances. Of this group of peripheral receptor blockers the only one that poses no risk of DIP is domperidone, a con- sequence of the fact that its high polarity does not allow its penetration across the blood brain bar- rier (BBB). [76] Domperidone, however, could be equally toxic in subjects with BBB lesions, such as those with recent cerebral infarcts or intracere- bral surgery. In addition, medications that block the synthesis of dopamine such as a-methyldopa or the dopamine depleters reserpine and tetra- benazine are also frequently associated with DIP through a well known mechanism of action re- lated to their ability to interfere with normal nigrostriatal dopamine function. [16] Some calcium channel antagonists available in Europe and South America (flunarizine and cinnarizine), which are piperazine derivates, are thought to cause DIP by blocking dopamine re- ceptors. [77,78] Other calcium channel antagonists (diltiazem and verapamil) [79] have been consid- ered responsible for DIP with a less straightforward mechanism of action. Reports of parkinsonism induced by other compounds such as lithium [80,81] and amiodarone [82] are rare but appear con- sistently over time. In some cases, DIP appears in patients treated with very commonly used drugs that rarely produce this complication and whose interaction with the dopamine system is not well understood. In these cases, the relation- ship with the drug can be discerned only once the parkinsonism has developed. These include some antiepileptics, particularly valproic acid, [83] and antidepressants including serotonin reuptake in- hibitors (fluoxetine, sertraline, paroxetine). [84-86] Cholinesterase inhibitors, widely used to treat dementia, may have increased tremor but did not worsen motor function as measured by the Uni- fied Parkinsons Disease Rating Scale in several clinical trials. [71,87] A recent study reviewed the spontaneous notifications of DIP and worsening of parkinsonism over a period of 17 years in a region that included 2 900 000 inhabitants. [28] Among the suspected drugs most involved were central dopaminergic antagonists (49%), antide- pressants (8%), calcium channel antagonists (5%), peripheral dopaminergic antagonists (5%) and histamine H 1 receptor antagonists (5%). Cases involving lithium, valproic acid, amiodarone and trimetazidine were also found. [28] The distribu- tion of potential culprits might vary over time depending on the prescription tendencies of each region. Indeed, other studies have observed that flunarizine and cinnarizine were amongst the most common causes of DIP in countries in which they were available in the past decades, [88] but their role in DIP has decreased in more recent years probably because of prescribers improved knowledge of the side effect profiles of these drugs. [31] However, new potential culprits might appear in the future. 7. Pathogenic Mechanisms The mechanisms associated with the appearance of DIP have a common final result: diminished D 2 receptor stimulation in the striatum. This occurs primarily with the blockade of D 2 receptors by antipsychotics and related drugs, but also occurs with decreased dopamine release produced by compounds that deplete dopamine storage vesicles such as tetrabenazine, with medications that block the synthesis of dopamine or block the dopamine entry into the vesicles that are released into the sy- napse or with compounds that have a reversible or irreversible neurotoxic effect on dopamine neurons. Several positron emission tomography (PET) studies have shown that the pharmacological ef- fect of antipsychotics is achieved with a blockade of 6070% of dopamine receptors and that anti- psychotic-induced parkinsonism appears when the blockade of dopamine receptors is >75%. [89] Numerous mechanisms have been proposed to explain the age-related increase in prevalence of DIP in the elderly. [90] Some of these include ab- normal pharmacokinetics associated with aging as well as age-related reduction in the numbers of dopamine neurons. [91] Supporting that is the fact that the prevalence of iPD is lower in Asian Indians who do not have age-related drop-out of nigrostriatal dopamine neurons than in other races. [92] 112 Lopez-Sendon et al. 2012 Adis Data Information BV. All rights reserved. Drugs Aging 2012; 29 (2) Recent studies from our laboratory have pro- vided data about the molecular mechanisms im- plicated in age-related increased prevalence of iPD and DIP. Parkin null mice have normal KCl- dependent release of dopamine but abnormal release of the cytoplasmic pool of this neurotransmitter mediated by stress and amphetamine. [93] As a result of this abnormality these animals have an increased intracellular, monoamine oxidase-mediated metab- olism of dopamine and an increased production of H 2 O 2 and other free radicals. These molecular ab- normalities are compensated for by an enhanced production of glutathione (GSH) and the animals do not show a significant drop-out of nigrostriatal dopamine neurons during the first year of age. Par- kin null mice are, however, more susceptible to dopamine neurotoxic drugs, such as cinnarizine, than wild-type animals. Cinnarizine, which blocks dopamine receptors and increases the vesicular re- lease of dopamine, further increased dopamine me- tabolism. Parkin null mice further increased GSH levels as a compensatory mechanism against free radicals. Neuronal markers, such as b-tubulin, slightly increased in parkin null mice and more so with cinnarizine. Astroglial markers decreased in parkin null mice, and this effect was potentiated by cinnarizine. Microglia were hyperactivated in parkin null midbrain, suggesting inflammation in these animals. Proapoptotic proteins were increased by cinnarizine. [94] However, these compensatory mech- anisms disappear with aging. Parkin null mice aged >18 months do not have compensatory increased GSH levels and the compensatory effects of astro- glia disappear. As a result, the number of nigros- triatal dopamine neurons drop out. [95,96] Therefore, the increased susceptibility of elderly people to par- kinsonizing drugs could be related to multiple mechanisms including alterations in pharmacokine- tics, age-related drop-out of dopamine neurons, lack of compensatory mechanisms in the production of free radical chelating agents and lack of neuropro- tective effects of glia. Antipsychotics can be categorized by potency. In general, the more potent drugs have greater affinity for the D 2 receptor, fewer anticholinergic effects, and both greater antipsychotic effects and more parkinsonian effects at lower doses. [97] The severity of the DIP reflects the combined effects of the patients sensitivity, presumably reflecting the untreated state of the striatum, the D 2 -receptor blocking effects of the drug, counterbalanced by the drugs effects on other neurotransmitter systems, which usually include some degree of anticholin- ergic, antihistaminergic activity as well as effects on neuropeptides and other systems. Atypical anti- psychotics also block D 2 receptors; however, there is no apparent correlation between the degree of this blockade and the risk of inducing parkinson- ism. One current hypothesis is the fast off theory, which postulates that the duration of D 2 receptor blockade, rather than the percentage of receptors blocked, determines the likelihood of parkinson- ism. [75] Another theory is that the ratio of serotonin 5-HT 2A receptor blockade versus the D 2 receptor blockade is critical because of the interplay between the serotonin and dopamine systems in the brain. Also, the rapidity of dose escalation, the target dose and the patients intrinsic vulnerability play a key role in the pathogenesis of DIP. Several studies have shown that compounds responsible for DIP may produce not only phar- macological impairment of dopamine neurotrans- mission, but also neurotoxic effects on dopamine neurons. Short-term blockade of D 2 receptors inhibits the production of neurotrophic sub- stances for dopamine neurons, such as brain- derived neurotrophic factor [98] and increases the firing of dopamine neurons, which is associated with a rise in the metabolism of dopamine and enhanced production of neurotoxic free radi- cals. [99] The direct toxic effects on dopamine neurons have been investigated in the case of haloperidol. DIP by haloperidol has been related to the levels of the haloperidol piridinium ion, a metabolite of haloperidol toxic to dopamine neurons. [100,101] The clinical course of DIP, reaching a plateau and then remitting, is thought to be due to two factors known to occur in animals. Initially the dopamine neurons release increased amounts of dopamine in response to receptor blockade; over time, upregulation of D 2 receptors occurs, thus bypassing some of the blockade effects. [102] It is also likely that changes develop inother neurotransmitter systems as well as in the neurophysiology of basal ganglia neuronal populations. Drug-Induced Parkinsonism in the Elderly 113 2012 Adis Data Information BV. All rights reserved. Drugs Aging 2012; 29 (2) 8. Prevention and Treatment The best treatment of DIP is prevention, in- cluding the avoidance of prescription of causative drugs whenever this is not strictly necessary or when these could be substituted with compounds with a safer profile. Other important considera- tions are to preclude prescribing drugs with no evidence of their usefulness [103] and to avoid maintenance of drugs for longer than they remain valuable. The risk of developing DIP should be weighed in each patient and special monitoring is warranted in individuals with higher risk, such as elderly and demented patients, those with extra- pyramidal signs such as tremor, patients with a family history of parkinsonismand those who are being treated with multiple drugs. Therefore, the medical staff should be vigilant in advance of the appearance of parkinsonian signs upon initiation of certain medications. After the identification of a DIP, the first step would be to ponder the degree of the problem in each patient. DIP is a problem only if it is troublesome for the patient, either socially or functionally. By itself, it might not necessarily need to be treated since it has no implications for the treatment of underlying psychosis and is not ne- cessarily a forerunner of a worse movement dis- order. For a time, it was theorized that proper control of psychosis could only be achieved once DIP occurred, but this has been clearly disproved, leaving DIP as an undesirable adverse effect of some antipsychotic drugs. The first treatment strat- egy would be to substitute the suspected com- pounds with a related drug with a more favourable side effect profile. Since DIP is related to potency and dosage, the severity of DIP can be prevented or reduced by using low-potency drugs at the lowest effective dose of whatever drug is chosen. If it is possible to discontinue the offending agent, recovery usually occurs over several weeks. DIP may improve with the use of anticholinergics, [104] and there seems to be no difference between the efficacy of the two most popular anticholinergics benztropine and trihexyphenidyl. The controversy centres on whether the side effects of these drugs, including dry mouth, constipation, urinary reten- tion, blurred vision and memory impairment, are offset by the benefit. They might be of some symptomatic value when underlying psychiatric illness precludes antipsychotic discontinuation, but they must be used with great caution in the elderly because of the risk of delirium and amnesia. It is, therefore, good practice to continue these drugs only if their use provides clear improvement. Amantadine is an alternative to anticholinergic drugs, being equally effective as trihexifenidyl for the treatment of DIPbut associated with fewer and less severe side effects. [105] Medical therapy should be indicated when withdrawal of the offending substance does not result in improvement or if the patient requires therapy with the offending drug. Levodopa or dopamine receptor agonists are usu- ally ineffective due to striatal D 2 receptor blockade and have been implicated in exacerbating psy- chosis. [53] However, patients with a DIP secondary to a loss of dopamine nerve terminals in the context of a progressive degenerative parkinsonism (as as- sessed by functional neuroimaging) may benefit from levodopa therapy. [15] Parkinsonism due to drugs such as tetrabenazine that deplete pre- synaptic dopamine may also be amenable to treatment with levodopa. [106] Resolution of the DIP may take considerable time, however. An alternative approach for refractory cases would be the use of electroconvulsive therapy when appro- priate, which temporarily ameliorates parkinson- ism and treats psychosis [107,108] and depression. [109] 9. Conclusions With increasing prevalence due to the ageing of the population and increasing polypharmaco- therapy in the elderly, DIP threatens to be a health problem of great magnitude in the future. The claim that second-generation antipsychotic agents cause less parkinsonismthan their predecessors has made many physicians believe that the atypical antipsychotics are safe and well tolerated in the elderly. It has been demonstrated that DIP is fre- quently misdiagnosed as iPD, and that in many cases dopaminergic treatment is given to patients who do not require it. The primary reason for fail- ure to recognize DIP relates to under-recognition of atypical antipsychotics as the possible cause. DIP is a reversible condition that adversely affects quality of life in the elderly. It can result in 114 Lopez-Sendon et al. 2012 Adis Data Information BV. All rights reserved. Drugs Aging 2012; 29 (2) falls and related hospitalizations, lead to nursing home placement, increased mortality and is re- versible when the causative agent is discontinued. In a study performed in a geriatric clinic, [21] 51% of 95 new cases of parkinsonism were associated with prescribed drugs, 25% of patients with DIP could not walk when first seen and 45% required hospital admission. The clinical features of DIP resolved permanently in two-thirds of cases in a mean of 7 weeks. It is essential for clinicians to be aware of the extrapyramidal side effects of medications, to pre- vent and manage DIP. The risk of side effects should be evaluated in each patient and the selec- tion of antipsychotic and antidepressant agents should be tailored according to the basal char- acteristics of each subject. For example, quetiapine and clozapine should be preferred to other atypi- cal and conventional antipsychotics when treat- ing psychosis in Parkinsons disease. 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