Neuroleptic-Induced Movement Disorders: Deconstructing Extrapyramidal Symptoms Richard M

Neuroleptic-Induced Movement Disorders: Deconstructing Extrapyramidal Symptoms Richard M. Trosch, MD

he neurological risks and benefits of atypical neurolep- to suggest that a particular neuroleptic possesses a risk of Ttics have received considerable attention in the medical causing TD, but isolated case reports do not instruct us on literature, but there have been few controlled studies ex- issues of relative risk or the incidence of TD from any par- amining these risks in elderly patients. Well-designed, long- ticular agent. In most patients, TD begins after prolonged term prospective studies are needed to identify the safest exposure to a neuroleptic agent, and reasonable estimates and most effective treatment regimens for elderly patients, of TD risk are best derived from the completion of pro- but until these studies are complete, clinicians will need to spective, long-term trials designed to specifically examine rely on available studies in making clinical decisions. This this issue. In the case of the atypical agents, no studies article is not an exhaustive systematic review of this topic; meeting these criteria have been conducted. Arguably, rather it is an attempt to integrate recent studies and the short-term Phase II and III industry-sponsored clinical trials author’s clinical experience to provide an approach to un- are primarily designed to measure efficacy of these agents in derstanding the risks of movement disorders associated psychosis and present a poor substitute for prospective, with the use of antipsychotic medications. long-term studies when assessing TD incidence. Inherent methodological flaws, including placebo-group contamina- NEUROLOGICAL RISKS AND BENEFITS OF tion, short duration of study, the use of inexperienced ATYPICAL NEUROLEPTICS movement disorder raters, and the lack of withdrawal- Within the field of geriatrics, neuroleptics (also called an- emergent assessments, further limit assessment of TD risk tipsychotics) are among the most commonly prescribed from clinical trials. Because of these limitations and the medications. In part, their popularity may be attributed to absence of prospective, long-term TD incidence studies, the growing list of difficult-to-manage psychiatric uses, on- current assumptions regarding the risk of TD or neuroleptic-induced parkinsonism (NIP) from the atypical neurolep- and off-label, for which these agents have potential benefit. 11 Also contributing to their increasing usage is the commonly tics remain speculative. held belief that atypical neuroleptics possess a lower risk of The common use of the term ‘‘extrapyramidal symp- tardive dyskinesia (TD) and other movement disorders, but toms’’ (EPS) when referring to some or all of the variety of whether all atypical neuroleptics are indeed safer or less abnormal movements associated with neuroleptic use has likely to induce movement disorders than typical neurolep- further obscured understanding of risk of neuroleptic-in- tic agents is unclear. Studies examining this issue are con- duced movement disorders. In the author’s experience, this flicting, and assumptions concerning the risks of movement term has taken on different meanings for different clinicians disorders associated with atypical neuroleptics remain spec- and has been used nonspecifically, in the psychiatric liter- ulative.1–5 ature and in the clinic, to denote all of the neuroleptic- When considering the risk of TD from the typical neu- induced movements, a single, specific type of reaction, or a roleptic agents, there is no clear distinction of risk between combination of several types of movements. This lack of the various agents.6 All typical neuroleptic agents are gen- specificity impedes the understanding of the relative safety erally held to cause TD with the same proclivity. Of the of the various neuroleptic agents by treating all neuroleptic- atypical neuroleptics, clozapine and quetiapine have not induced movements as equivalent, impeding any discrim- been reported to induce TD or parkinsonism in patients not ination of risk between the available agents. To illustrate this previously exposed to these neuroleptics, but case reports of point, consider a comparison of two agents, one associated new-onset TD have emerged in association with other with a 5% risk of acute dystonic reaction and another with a atypical neuroleptics.7–10 The reporting of multiple cases of 5% risk of neuroleptic malignant syndrome. If no other ad- typical TD after a singular neuroleptic exposure is sufficient verse effects were noted, then both agents could be considered to have an EPS risk of 5%, but the actual risk would be 5% of a brief, transient, and typically benign reaction from From the Parkinson’s Disease and Movement Disorder Center, Southfield, Michigan; and Department of Neurology, Wayne State University School the first agent versus a 5% risk of a fatal or potentially per- of Medicine, Southfield, Michigan. manently disabling reaction from the second. The differences Address correspondence to Richard M. Trosch, MD, 26400 West Twelve in risk between these two agents would be considerable, and Mile Road, Southfield, MI 48202. E-mail: [email protected] the practice of lumping all neuroleptic-induced movements

JAGS 52:S266–S271, 2004 r 2004 by the American Geriatrics Society 0002-8614/04/$15.00 JAGS DECEMBER 2004–VOL. 52, NO. 12 NEUROLEPTIC-INDUCED MOVEMENT DISORDERS S267 together as EPS serves to obscure the relative risk of dif- with other neuroleptic-induced movements. Reported risk ferent agents. When considered individually, the various factors include male sex, young age, neuroleptic dose and neuroleptic-induced adverse events, including TD, parkin- potency, prior acute dystonic reactions, and cocaine sonism, acute dystonic reactions, and neuroleptic malignant abuse.34–38 Younger patients, particularly boys in their first syndrome, are significant. These adverse events vary not 2 decades of life, are at greatest risk for this occurrence, only in their severity, but also in their associated risk fac- with incidence peaking during the first 2 decades of life tors, time to onset, duration, clinical presentation, and per- and decreasing after age 40. Elderly patients infrequently sistence. For these reasons, the risk of neuroleptic-induced suffer ADR.6 movement disorders are best assessed by considering the risk associated with each type of adverse event individually. Idiosyncratic Events To deconstruct the nosological term EPS, the neurolep- The idiosyncratic events consist of neuroleptic malignant tic-induced movement disorders may instead be organized syndrome (NMS), a rare medication-induced reaction char- into clinically meaningful categories based on their shared acterized by encephalopathy, rigidity, dystonia, fever, ele- clinical course and risk factors. vated creatine phosphokinase, autonomic lability, movement disorders, and a variety of transient or persist- A PARADIGM OF MEDICATION-RELATED ent neurological disorders.39 NMS affects patients of all MOVEMENT DISORDERS ages, but younger adults are reported to have a higher pre- 40 Each of the neuroleptic-induced movement disorders may dilection. Onset of symptoms often occurs after a first be placed into one of four categories: limited reactions, id- exposure to a neuroleptic. Most cases occur within the first iosyncratic events, toxic effects, and tardive syndromes 7 to 9 days of neuroleptic treatment, but patients may also 39,40 (Table 1). Each of these four categories shares a common develop NMS after years of exposure. Case reports cause of neuroleptic exposure but differs in its time to onset, have indicated that all available neuroleptic agents, inclu- 41–53 persistence, severity, and risk factors. Additionally, the risk sive of all atypical agents, cause NMS. Because NMS of causing different types of neuroleptic-induced movement incidence is low, affecting an estimated 1.0% of neurolep- 39,40,54–56 disorders appears to differ between the available agents, tic-exposed patients, data are insufficient to com- with some agents possessing no reported risk of inducing pare the relative risk of different neuroleptic agents. some of the categories of reactions. Neuroleptic dose has not been established as a risk factor for NMS, nor has NMS been reported as a feature of neuroleptic overdose.56 NMS may also rarely follow exposure CATEGORIES OF NEUROLEPTIC-RELATED to dopamine-depleting drugs57 and nonneuroleptic agents58 MOVEMENT DISORDERS and in Parkinson’s disease (PD) after an abrupt withdrawal 58–61 Limited Reactions of dopaminergic agents. Signs of NMS appear within days or weeks of starting a neuroleptic or after an increase Limited reactions, consisting of the acute dystonic reactions in dose, with symptoms rapidly evolving over 24 to 72 (ADR) oculogyric crisis and acute laryngospasm, have hours and persisting over a period of 1 to several weeks. been reported to follow exposure to each of the available Rates of mortality and morbidity from NMS remain high typical and atypical neuroleptics12–14 but may also result and may result from a variety of conditions, including pul- from the use of numerous nonneuroleptic medications, in- monary embolism, pneumonia, myoglobinuria with renal cluding several illicit drugs and over-the-counter medica- failure, and complication of autonomic lability.39,40 Per- tions.15–32 Some investigators found lower risk of an ADR sistent neurological residua may occur in some patients, with atypical neuroleptic use than with use of typical with reports of persistent dementia, ataxia, peripheral ne- agents.33 uropathy, parkinsonism, dyskinesia, and dystonia. With the The designation ‘‘limited’’ denotes a transient reaction, exception of the potential for neurological and end-organ distinguishing this category from the tardive or persistent residual damage, NMS shares with the limited reactions a reactions, which may share similar phenomenological fea- temporally discrete clinical course, followed by the eventual tures of dystonia, chorea, or stereotypy, but the term ‘‘lim- resolution of the acute syndrome. ited’’ does not describe their severity or imply that these reactions are mild or benign. ADR are typically intermittent or sustained, often painful, muscular spasms producing Toxic Effects twisting or abnormal postures of the eyes, jaw, face, neck, NIP and acute akathisia are distinguished as dose-related limbs, or axial structures. Severe events may produce phenomena, with their severity closely tied to the extent to 62 dysphagia, mandibular dislocation, or laryngeal obstruc- which the postsynaptic striatal D2 receptors are blocked. tion and may constitute a neurological emergency. The Studies are mixed on whether the limited reactions, idio- limited reactions are the first neuroleptic-induced move- syncratic reactions, or TD are dose related, and the impor- ments to appear, beginning within a few hours or days after tance of dose in the severity of these reactions remains exposure or dosage increase of an offending medication, controversial. Most clinicians are aware of this dose-related with practically all events occurring within a week of new association; neuroleptic dose reduction and substitution exposure.6 Limited reactions last from hours to weeks but with a lower-potency agent are strategies commonly used to are not persistent reactions. Although symptoms may be diminish symptom severity. The importance of neuroleptic distressing and temporarily painful or disfiguring, the lim- dose or potency for limited reactions, NMS, and the tardive ited reactions generally respond well to treatment. Because syndromes is less clear. After neuroleptic discontinuation, of their transience, most are relatively benign compared most patients become free of akathisia or parkinsonism S268 TROSCH DECEMBER 2004–VOL. 52, NO. 12 JAGS within a few weeks, but for some elderly patients Table 2. Recognized Tardive Syndromes parkinsonism may persist for several months or up to a year.63 Stereotypy (classical orobuccal lingual dyskinesia) Clinically, NIP can be difficult to distinguish from the Dystonia idiopathic form of the disease. Both conditions display the Akathisia same cardinal features of rigidity, tremor, postural instabil- Chorea ity, akinesia/bradykinesia/hypokinesia, simian posture, and Myoclonus motor blocks. Patients are considered to have parkinsonism Oculogyric deviations when two or more of these cardinal features are pre- Tic sent.64,65 Although idiopathic PD (IPD) progresses slowly Tremor and, in many cases, it takes several years for symptoms to Pain become debilitating, most cases of NIP occur within 20 days, and 90% occur within 72 days.66 Akinesia, an absence or poverty of movement, and bradykinesia, a slow- Excluding clozapine and quetiapine, the other atypical ness of movement, are the most common manifestations of neuroleptics are reported to cause NIP in patients not pre- NIP. In the author’s experience, limb rigidity is universally viously exposed to these neuroleptics.70–72 Their reported present in IPD but is frequently absent from NIP; this dis- tendency to worsen the motor symptoms in IPD or Lewy tinction may help differentiate NIP from IPD at the bedside. Body dementia further supports their potential to cause Reported estimates of NIP incidence and prevalence NIP. Several studies examining risperidone or olanzapine rates vary widely.66 This may, in part, be attributed to the use for psychosis in parkinsonism have demonstrated a characteristics of the patient cohort or which particular consistent worsening of parkinsonian symptoms.73–76 Ac- neuroleptic agents were studied. For example, older pa- cordingly, risperidone and olanzapine should be considered tients are observed to have a higher risk of NIP, and greater to be contraindicated in patients with parkinsonism or risk is associated with higher-potency neuroleptic agents. at risk for this condition. Conversely, clozapine and quetia- Documented risk factors for NIP include advanced age, fe- pine have been reported to treat symptoms of psychosis in male sex, underlying IPD, and the use of high-potency D2 parkinsonism effectively without worsening motor symp- receptor antagonists.66 One study67 proposed that the rate toms.76–78 at which a neuroleptic dissociates from the D2 receptor, identified as its dissociation constant, may predict the likelihood of that agent to cause NIP and TD. By this model, Tardive Syndromes drugs producing only a transient receptor blockade (fast A group of investigators first used the term tardive dissociation from the D2 receptor), which include the atyp- dyskinesia (TD) in 1952 to describe the late onset of per- ical neuroleptics clozapine and quetiapine, would permit a sistent orobuccal stereotypy occurring in three women 79 physiological stimulation of the striatal postsynaptic D2 within several months of neuroleptic exposure. The term receptor by endogenous dopamine. In turn, these agents tardive, or late, was used to draw a distinction between would pose lower risk of inducing TD or NIP movements than these cases and previously observed ADR. TD in the elderly agents producing a sustained D2 blockade or no risk at all. typically presents as an orobuccal-facial-lingual stereotypy. For NIP, incidence data from most Phase II and III trials Younger patients, in turn, are more likely to experience are difficult to interpret.68 Because of a lack of sufficient dystonic symptoms.80 The ‘‘tardive syndrome’’ actually re- washout (usually lasting only 4 to 14 days) at the start of a fers to several different varieties of hyperkinetic involuntary trial, there is contamination of the placebo group from the movements present concurrently in a patient. This may in- patient’s prior neuroleptic use. Additionally, reliance on the clude the tardive subsyndromes of dystonia, akathisia, cho- Simpson-Angus scale (SAS), a measure of NIP, may under- rea/athetosis, tremor, tic, myoclonus, or characteristic pain report NIP incidence.69 Scored items on the SAS favor the complaints (Table 2).6,81 Other investigators also described presence of rigidity, a feature typically absent in NIP. Fi- TD pain while reporting on 11 patients with chronic oral or nally, many studies report only a total EPS incidence, with- genital pain after neuroleptic use.82 The incidence of TD out a separate reporting of NIP incidence. pain is unknown, but because patients with schizophrenia or dementia commonly experience difficulties reporting their subjective complaints, it is likely that this TD subsyn- Table 1. Neurologic Paradigm of Medication-Related Move- drome is underreported. ment Disorders TD may be defined as a movement disorder beginning Limited reactions within 3 months, after an exposure to a striatal dopamine Acute dystonic reaction receptor blocking agent, and persisting despite discontinu- 83 Oculogyric crisis ation of the offending agent. In another study, TD was Acute laryngospasm divided into persistent (43 months) and chronic (46 84 Idiosyncratic events months). It is now recognized that TD can rarely occur Neuroleptic malignant syndrome acutely after a brief exposure to a neuroleptic, although in Toxic effects most instances, TD begins after chronic exposure of several Neuroleptic-induced parkinsonism months or years. More importantly, in contrast to other Acute akathisia neuroleptic-induced movements, TD is set apart by its per- Tardive syndromes sistence. Remissions of TD can occur but are uncommon, typically limited to younger patients or if the course of JAGS DECEMBER 2004–VOL. 52, NO. 12 NEUROLEPTIC-INDUCED MOVEMENT DISORDERS S269 neuroleptic exposure was brief.85 In the geriatric popula- TD in patients with a previous exposure to (an)other neu- tion, TD remissions are rare, and TD is typically a persistent roleptic agent(s) but not in previously neuroleptic-naı¨ve disorder.85,86 patients.98–100 The contribution of clozapine or quetiapine Many potential TD risk factors have been identified. to causing TD in these reports is difficult to establish be- Advancing age has been consistently found to correlate with cause of the possibility of a late unmasking of a TD syn- TD severity and prevalence.85–88 Elderly patients are also drome caused by a prior neuroleptic exposure. Aripiprazole more likely to develop TD early in their course of treatment has not been reported to cause TD either, although there is and less likely to remit after neuroleptic discontinuation. only limited clinical experience with this drug. Until the The importance of sex as a TD risk factor may be related to mechanisms responsible for causing TD and NIP are un- age. Women are at greater TD risk in the geriatric age derstood, it cannot be assumed that any neuroleptic is group, whereas an association between sex and TD is un- completely safe or devoid of potential for causing TD. Ac- clear in younger patients.89 Drug dose and potency have cumulated case reports, although not providing any insight long been suspected as contributing to TD risk, and it is a into the risk of these conditions, suggest that the risk of TD common practice among physicians to limit the dose of from the various atypical neuroleptics is not equal, with drug used in the hopes of diminishing a patient’s risk of TD. greater safety associated with clozapine and quetiapine. Recent studies have supported this assumption, finding a Unlike the typical neuroleptic drugs, no long-term pro- correlation between dose and TD risk in geriatric pa- spective studies have been conducted to examine the inci- tients.90 Several other reported TD risk factors remain con- dence of TD caused by the atypical neuroleptic agents. One troversial and include genetic factors, concurrent use of study compared the risk of an acute movement disorder anticholinergic medications, diabetes mellitus, affective after exposure to risperidone versus haloperidol in a pro- disorder, prior electroconvulsive therapy, smoking, and al- spective, short-term trial.5 Incidence rates of dyskinesia, cohol use.91–97 parkinsonism, akathisia, and dystonia were found to be All typical neuroleptics have been reported to cause the equivalent. Similarly, the Nithsdale survey, compared the tardive syndromes, and there are insufficient data to predict prevalence rates of TD, NIP, and akathisia before and after whether one agent is any worse or better than another in the introduction of atypical neuroleptics and found a lack in this regard.8,98–113 The reported incidence of TD with neu- anticipated reduction in the risk of these adverse events roleptics is highly dependent on the population studied and despite the introduction of atypical neuroleptics.3 Despite associated TD risk factors. A prospective observational claims of improved safety, empiric evidence collected out- study of neuroleptic-induced movements in recently diag- side of Phase II and III pharmaceutical company–sponsored nosed schizophrenic patients reported a 5% per year inci- trials have not confirmed a lower risk of TD with the newer dence of TD, increasing linearly over a period of 5 years of atypical agents as a class, and this widely held assumption exposure to a typical neuroleptic medication.87 Another remains controversial. prospective study of an elderly population of patients not previously exposed to these neuroleptics who were beginning typical neuroleptic treatment found that TD rates were SUMMARY three to five times the rates in younger patients, beginning at The use of neuroleptics remains vital to the management of 25% for the first year and 53% by Year 3, despite treatment an expanding number of psychiatric conditions but has the with smaller drug doses.88 The course of TD, once estab- potential to cause disabling and persistent movement dis- lished, is often progressive. A study80 of the natural history orders. Despite the common practice of lumping all of the of tardive dyskinesia dystonia (TDd) in 107 neuroleptic- neuroleptic-induced movement disorders under the rubric treated patients between 1972 and 1995 found that there of EPS, an examination of the differences in the temporal was no safe period of neuroleptic exposure (the onset of course, risk factors, phenomenology, and persistence of TDd was documented as early as after 4 days or as late as these movements suggests that splitting these movements after 23 years of neuroleptic use); men were younger than into the categories of limited reactions, idiosyncratic events, women at onset of TDd; specific psychiatric or medical ill- toxic events, and tardive syndromes adds precision to the nesses posed no additional risk; all typical neuroleptics were understanding of these disparate disorders. The use of implicated in causing TDd; for most patients, TDd pro- atypical neuroleptics, as suggested by Phase II and III clin- gressed over 1 to 2 years from a focal or segmental dystonia ical trials, may diminish the risk of neuroleptic-induced to a generalized state; discontinuation of dopamine-recep- movements, but long-term prospective incidence studies tor agonist treatment quadrupled the odds of remission; and have not been conducted with these drugs, and prevalence continued neuroleptic exposure after the onset of TDd studies have failed to demonstrate a difference between the symptoms diminished the likelihood of remission.80 The typical and atypical agents. TD and parkinsonism have not natural history of the other TD subsyndromes has not been been reported with clozapine or quetiapine use in previ- adequately studied, but given the potential for symptomatic ously neuroleptic-naı¨ve patients. These agents may repre- progression with continued neuroleptic exposure, once sent a unique class of atypical agent, providing a lower risk symptoms of any TD subsyndrome are recognized, meas- of neurological adverse effects. ures to reduce or eliminate further neuroleptic exposure are appropriate. Case reports of TD occurring in patients after a singular neuroleptic exposure have been reported in connection with ACKNOWLEDGMENTS risperidone, olanzapine, and ziprasidone use.7,8,101–113 The author is on AstraZeneca Pharmaceuticals’ speaker Clozapine and quetiapine have been implicated in causing bureau. S270 TROSCH DECEMBER 2004–VOL. 52, NO. 12 JAGS

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