REVIEW Antipsychotic-Related Movement Disorders: Drug- Induced Parkinsonism vs. Tardive Dyskinesia—Key Differences in Pathophysiology and Clinical Management Kristen M. Ward . Leslie Citrome Received: May 23, 2018 / Published online: July 19, 2018 Ó The Author(s) 2018 ABSTRACT Introduction: Drug-induced parkinsonism (DIP) and tardive dyskinesia (TD) are stigma- tizing movement disorders associated with exposure to dopamine receptor blocking agents such as antipsychotics, but they differ in their pathophysiology and clinical management. Treatment for one may worsen the other, and there are important diagnostic clues that assist in making an accurate assessment and institut- ing a rational treatment plan. Methods: A literature review was executed to identify articles relating to the presentation, pathophysiology, epidemiology, and manage- ment of DIP and TD. Results: DIP and TD prevalence estimates range from approximately 20 to 35% among antipsy- chotic users, but may be higher in select popula- tions. DIP often presents as bradykinesia and rigidity, as well as rhythmic tremor, and the majority of cases appear within hours to weeks of initiation of therapy with an antipsychotic, or if dosage of the antipsychotic is increased. TD onset is delayed, typically appearing after at least 3 months or longer of treatment, and patients will commonly present with involuntary, abnor- mal facial movements such as lip smacking, puckering, chewing, or tongue protrusion. DIP often resolves with discontinuation of the causa- tive agent, but TD may be permanent. Broadly, proposed mechanisms underlying these adverse events include decreased dopamine concentra- tions in the nigrostriatal pathway of the striatum and dopamine hypersensitivity, for DIP and TD, respectively. Pharmacologic treatment approa- ches for DIP have commonly included anti- cholinergic agents such as benztropine; however, anticholinergic medications can make TD worse. Switching the antipsychotic medication to one with lower propensity for DIP is an option for some patients. Amantadine, a non-anticholiner- gic agent used for the treatment of DIP, may be preferred in patients with comorbid DIP and TD. In TD, treatment options include the new rever- sible vesicular monoamine 2 transporter inhibi- tors, valbenazine and deutetrabenazine. Conclusions: It is important for clinicians to be able to recognize DIP and TD in patients using antipsychotics so that they can minimize the impact of these adverse events on their patients’ quality of life. Accurate diagnosis will drive the selection of the correct treatment. Plain Language Summary: Plain language summary available for this article. Enhanced digital content To view enhanced digital content for this article go to https://doi.org/10.6084/ m9.figshare.6736412. K. M. Ward University of Michigan College of Pharmacy, 428 Church Street, Ann Arbor, MI 48109, USA L. Citrome (&) Psychiatry and Behavioral Sciences, New York Medical College, Valhalla, NY, USA e-mail: [email protected]Neurol Ther (2018) 7:233–248 https://doi.org/10.1007/s40120-018-0105-0
Transcript
REVIEW
Antipsychotic-Related Movement Disorders: Drug-Induced Parkinsonism vs. Tardive Dyskinesia—KeyDifferences in Pathophysiology and ClinicalManagement
Kristen M. Ward . Leslie Citrome
Received: May 23, 2018 / Published online: July 19, 2018� The Author(s) 2018
ABSTRACT
Introduction: Drug-induced parkinsonism(DIP) and tardive dyskinesia (TD) are stigma-tizing movement disorders associated withexposure to dopamine receptor blocking agentssuch as antipsychotics, but they differ in theirpathophysiology and clinical management.Treatment for one may worsen the other, andthere are important diagnostic clues that assistin making an accurate assessment and institut-ing a rational treatment plan.Methods: A literature review was executed toidentify articles relating to the presentation,pathophysiology, epidemiology, and manage-ment of DIP and TD.Results: DIP and TD prevalence estimates rangefrom approximately 20 to 35% among antipsy-chotic users, but may be higher in select popula-tions. DIP often presents as bradykinesia andrigidity, as well as rhythmic tremor, and themajority of cases appear within hours to weeks of
initiation of therapy with an antipsychotic, or ifdosage of the antipsychotic is increased. TD onsetis delayed, typically appearing after at least3 months or longer of treatment, and patientswill commonly present with involuntary, abnor-mal facial movements such as lip smacking,puckering, chewing, or tongue protrusion. DIPoften resolves with discontinuation of the causa-tive agent, but TD may be permanent. Broadly,proposed mechanisms underlying these adverseevents include decreased dopamine concentra-tions in the nigrostriatal pathway of the striatumand dopamine hypersensitivity, for DIP and TD,respectively. Pharmacologic treatment approa-ches for DIP have commonly included anti-cholinergic agents such as benztropine; however,anticholinergic medications can make TD worse.Switching the antipsychotic medication to onewith lower propensity for DIP is an option forsome patients. Amantadine, a non-anticholiner-gic agent used for the treatment of DIP, may bepreferred in patients with comorbid DIP and TD.In TD, treatment options include the new rever-sible vesicular monoamine 2 transporter inhibi-tors, valbenazine and deutetrabenazine.Conclusions: It is important for clinicians to beable to recognize DIP and TD in patients usingantipsychotics so that they can minimize theimpact of these adverse events on their patients’quality of life. Accurate diagnosis will drive theselection of the correct treatment.Plain Language Summary: Plain languagesummary available for this article.
Enhanced digital content To view enhanced digitalcontent for this article go to https://doi.org/10.6084/m9.figshare.6736412.
K. M. WardUniversity of Michigan College of Pharmacy, 428Church Street, Ann Arbor, MI 48109, USA
L. Citrome (&)Psychiatry and Behavioral Sciences, New YorkMedical College, Valhalla, NY, USAe-mail: [email protected]
Antipsychotic medications are often used totreat serious mental illnesses, like schizophreniaand bipolar disorder. In some people, thesemedications cause uncontrollable movementsin the face and limbs. Two of the more commonmovement disorders are called drug-inducedparkinsonism (DIP) and tardive dyskinesia (TD).DIP usually starts within days to months afterstarting an antipsychotic, whereas TD maybegin months to years later. The more commonsigns of DIP are tremor and movements thatappear slow and stiff, and TD usually includesface movements like lip puckering or smacking,and chewing. These side effects are oftenembarrassing for the patient, can get in the wayof their daily activities, and may be permanent.It is important for clinicians to watch for theseside effects, and to understand the differenttreatment options because most medicationsused to treat DIP should not be used to treat TD.There are no medications used regularly toprevent TD. However, there are new medica-tions for the treatment of TD that have signifi-cant potential to help patients who developmovement side effects while takingantipsychotics.
INTRODUCTION
Movement disorders, or extrapyramidal sideeffects (EPS), are potential adverse events ofantipsychotic use that are often stigmatizing,and can impair patients’ ability to completeactivities of daily living. A study assessingquality of life among patients withstable schizophrenia symptoms on clozapine, ora typical antipsychotic, found that less EPS waspredictive of better quality of life scores in bothgroups [1]. Although movement disorders wereonce thought of primarily as a concern associ-ated with typical, or first-generation, antipsy-chotic use, increasing recognition is being given
to the possibility of most atypical, or second-generation, antipsychotics to precipitate move-ment disorders. As atypical antipsychotic use ishighly prevalent in the treatment of seriousmental illness, it is timely to discuss clinicalapproaches for treating two relatively commonantipsychotic-induced movement disorders:drug-induced parkinsonism (DIP) and tardivedyskinesia (TD). The aim of the following dis-cussion is to approach the review of theseadverse events with a focus on the similaritiesand differences of DIP and TD with respect totheir epidemiology, presentation, pathophysi-ology, and management. Understanding thedifferences between these two movement dis-orders is particularly important as the treatmentapproaches are distinct and rely on the accurateidentification of the underlying movementdisorder.
METHODS
On March 29, 2018, the PubMed database wassearched with the terms: antipsychotic AND(parkinson* OR ‘‘tardive dyskinesia*’’), and theresults were examined for articles pertaining tothe epidemiology, diagnosis, pathophysiology,and treatment of parkinsonism and tardivedyskinesia resulting from treatment withantipsychotics. This search was repeated onApril 19, 2018 to identify any new literaturepublished since the original query. Results werenotable for sparse primary literature supportingthe use of most medications (with the exceptionof valbenazine and deutetrabenazine) for thetreatment of antipsychotic-induced DIP or TD.This article reviews previously published mate-rial, and no new information from human par-ticipants or animal research conducted byeither of the authors was used in this article.
DRUG-INDUCED PARKINSONISM
Epidemiology
DIP is difficult to distinguish from Parkinson’sdisease, particularly in elderly patients, and isoften undiagnosed [2, 3]. These factors make it
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challenging to understand the scope ofantipsychotic-induced parkinsonism. Preva-lence rates in studies that include patients tak-ing typical and atypical antipsychotics rangefrom approximately 20 to 35% [4–6], but DIPoccurs at higher rates in elderly patients [7].Several studies have retrospectively assessedmedications as causes of identified parkinson-ism. In a review focused on the elderly, 46% ofthose with symptoms due to medications weredeemed to be caused by atypical antipsychotics[8]. This is contrasted by a recent report of a30-year epidemiologic study of parkinsonism,in which typical antipsychotics were identifiedas the culprit of the majority of all drug-inducedcases, with almost no contribution from atypi-cal antipsychotics [9]. These differences may bedue to varied populations and study design but,ultimately, they demonstrate that DIP is still aconcern of antipsychotic therapy despite thehope that it would abate with increased atypicalantipsychotic use.
Pathophysiology
The pathophysiology of DIP is related to drug-induced changes in the basal ganglia motorcircuit secondary to dopaminergic receptorblockade [2]. When dopamine D2 receptors inthe striatum are blocked, the gamma-aminobutyric acid (GABA)- and encephalin-containing striatal neurons are disinhibited,impacting the indirect pathway, and ultimatelyleading to a relative decrease in activity in tha-lamocortical circuitry (see Fig. 1a) [2, 10]. Thiseffect can be moderated by anticholinergicactivity of the antipsychotic [11, 12], as sup-ported by observations that clozapine, which isassociated with minimal-to-absent propensityto cause DIP [13], also has a high relative affin-ity for muscarinic cholinergic receptors [11].Decreased effective dopamine concentrations inthe striatum can also be caused by decreaseddopamine release into the synapse; as can beseen with the irreversible vesicular monoaminetransporter inhibitor, reserpine [12]. Medica-tions whose primary mechanism does notinvolve direct action on dopamine concentra-tions (valproic acid, calcium channel blockers)
can cause DIP through unclear mechanismsthat may involve modulating GABA activity ormitochondrial dysfunction [2, 12, 14]. A sum-mary of the basal ganglia direct and indirectpathways is presented in Box 1.
Presentation and Diagnosis
Relative to TD, DIP presents earlier in antipsy-chotic treatment, with approximately 50–75%of cases appearing within the first month, and90% of cases within the first 3 months [15].Table 1 highlights select differences betweenDIP and TD. Acute dystonic reactions can occurrelatively soon after administration of intra-muscular antipsychotic such as haloperidol[16, 17]. Where tremor is evident, it is rhythmic,occurring at a frequency of 3–6 Hz. Because DIPcan be associated with impairments of facialexpression, it is important to differentiatebetween negative symptoms in patients withschizophrenia, or the possibility of untreateddepression [18]. As mentioned previously, DIPcan be difficult to distinguish from Parkinson’sdisease. Characteristic symptoms, like bradyki-nesia, rigidity, and instable gait are present inboth disorders, and while some studies notedifferent prominence of symptoms between DIPand Parkinson’s disease (more bradykinesia,symmetry of symptoms, and rigidity in DIP),others suggest that these clues in presentationare inadequate for an accurate diagnosis[2, 12, 19, 20]. For example, abnormal move-ment patterns present asymmetrically in a sig-nificant minority of cases. Pieters et al. [21]recently noted asymmetrical symptoms in asmany as 20% of patients with DIP, as was alsoobserved by Savica et al. [9]. Furthermore,antipsychotic use may unmask Parkinson’s dis-ease, which contributes the difficulty of diag-nosing DIP in elderly patients [2].
Another difference in DIP and Parkinson’sdisease that may be useful in forming a diag-nosis is improvement when the causative med-ication’s dose is lowered or discontinued [22].Finally, dopamine transporter (DAT) imagingapproaches have been shown capable of differ-entiating DIP from Parkinson’s disease by
Neurol Ther (2018) 7:233–248 235
comparing symmetry of radiotracer uptake inthe striatum [2, 23, 24].
Akathisia can be observed alongside DIP, orin the absence of overt DIP. Akathisia is definedas a syndrome with subjective symptoms oftenaccompanied by objective findings [25]. Sub-jective symptoms include inner tension, anxi-ety, irritability, discomfort, restlessness, orsleeplessness. Objective findings that are oftenpresent include movements that are semivoli-tional, purposeful and suppressible, repetitive,complex, and stereotypical. The pathophysiol-ogy of drug-induced akathisia likely differs fromthat for DIP. Both can improve with reductionof antipsychotic dose; however, anticholinergicmedications are generally unhelpful in
managing akathisia [26]. Treatment of akathisiaincludes administration of either a beta-adren-ergic antagonist or a serotonergic 5HT2 receptorantagonist.
Risk Factors
A number of risk factors have been associatedwith DIP development, including: older age,female gender, previous EPS caused by antipsy-chotics, family history of PD, cognitive impair-ment, HIV infection, and higher potency andlonger duration antipsychotic use [9, 27]. Use ofadditional medications that may cause DIPinclude valproic acid, gut motility agents like
Fig. 1 Changes in basal ganglia-thalamocortical motorloop due to blockade of D2 receptors by DRBAs. Theblockage of D2 receptors by DRBAs in the striatum leadsto disinhibition of GABA- and encephalin-containingstriatal neurons at the origin of the indirect pathway,followed by a disinhibition of the subthalamic nucleus.This leads to increased GABAergic inhibition of thethalamocortical projection by facilitation of the inhibitoryprojection from the GPi/SNr (a). Chronic D2 receptorblockade also induces changes in the direct pathways of the
basal ganglia-motor loop to cause orolingual dyskinesia (b).DA dopamine, DRBAs dopamine receptor blocking agents,GABA gamma-aminobutyric acid, GPe globus pallidus parsexterna, GPi globus pallidus pars internal, SNc substantianigra pars compacta, SNr substantia nigra pars reticulata,STN subthalamic nucleus, TD tardive dyskinesia. Repro-duced as per the terms of the Creative CommonsAttribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0) from [2])
metoclopramide, antidepressants, and calciumchannel blockers like verapamil [12]. Impor-tantly, the vesicular monoamine transporter 2(VMAT2) inhibitor, tetrabenazine, treats TD butalso potentially contributes to DIP risk bydecreasing the amount of dopamine releasedinto the synapse, as observed in clinical trials forHuntington’s disease [12]. This is potentiallynot as concerning with the newer VMAT2inhibitors, valbenazine and deutetrabenazine,as observed in clinical trials for TD; however,patients with comorbid neurological conditionsthat could interfere with TD assessment wereexcluded from these trials [28, 29]. The productlabel for deutetrabenazine includes a warningregarding Parkinsonism, but this is directedtowards persons receiving the medication forHuntington’s disease, not TD [30].
Management
The necessary first step in managing DIP isrecognition through monitoring at an appro-priate frequency. The American PsychiatricAssociation (APA) recommends monitoring foracute onset extrapyramidal side effects weeklyduring initial treatment and until stable for2 weeks, then at every follow-up visit [18].Although clinical monitoring for signs andsymptoms of DIP may be adequate, a morestructured approach is the use of the Simp-son–Angus Extrapyramidal Side Effect scale,which is a quick 10-item measure that has
demonstrated efficacy in the early detection ofDIP [31–33], and is commonly used in clinicaltrials of antipsychotic medications.
Whenever possible, discontinuation of thecausative agent is the recommended treatmentstrategy for distressing DIP symptoms. Unlike inthe management of TD, where this approachresults in a transient worsening of symptoms, itwill lead to improvement of DIP symptomswithin days to months after stopping therapy.However, DIP symptoms have been observed topersist in 10–50% of patients [2]. It is often notpossible to discontinue antipsychotics, but theuse of any additional agents potentially con-tributing to DIP risk should be carefully recon-sidered. If reasonable in the course of thepatient’s treatment, it is appropriate to considerswitching to an antipsychotic with lesspropensity to cause DIP, such as from a typicalto an atypical agent. Quetiapine is often anagent of choice in this setting [34], but otheragents that have a lower propensity to cause DIP(as well as akathisia) include iloperidone andclozapine [35, 36]. When antipsychotic switch-ing is not a viable management strategy, addi-tional strategies include: (1) gradually loweringthe antipsychotic dose if clinically possible, (2)adding an anticholinergic medication, such asbenztropine or trihexyphenidyl, or (3) adding anon-anticholinergic agent such as amantadine.The use of potent dopaminergic medicationssuch as levodopa can exacerbate psychoticsymptoms [7].
Box 1 Summary of the basal ganglia direct and indirect pathways [74]
• The processing of movement in the basal ganglia involves a direct pathway and an indirect pathway
• The two pathways originate from distinct populations of striatal medium spiny neurons (MSNs) and project to different
output structures
• These circuits are believed to have opposite effects on movement: direct pathway MSNs promote movement but
activation of indirect pathway MSNs inhibit movement
Direct pathway Indirect pathway
Effect on motor thalamus Disinhibits Inhibits
Effect on thalamo-cortex Activates Inhibits
Effect on motor cortex Activates Inhibits
Effect on movement Facilitates Inhibits
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Anticholinergic medications, such as ben-ztropine, are used extensively, and often pro-phylactically, upon the initiation of antipsychoticmedication to manage DIP. However, thesemedications can increase the risk of developingTD, can worsen comorbid TD, and negativelyimpact cognition [37]. The deleterious impact ofbenztropine (and other anticholinergic medica-tion) on memory is not trivial, and can be aniatrogenic factor in the poor cognitive and func-tional outcomes commonly encountered in per-sons with schizophrenia [37]. Anticholinergicmedication should be avoided in the elderlyunless necessary due to an increased risk ofdelirium [7], especially if already receiving medi-cations with the potential for anticholinergic-in-duced adverse effects. In addition to alteredmentation, peripheral side effects such as blurredvision, dry mouth, constipation, and urinaryretention can be encountered. If prescribed, atypical duration of anticholinergic use is3 months, and they should be periodically stop-ped to assess the need for continued use [11]. Analternative to anticholinergic medications isamantadine. Amantadine works to improve DIP(and TD, discussed below) through unknownmechanisms that may involve dopamine and N-methyl-D-aspartate (NMDA) receptor antagonism[38]. It may be a more viable option than anti-cholinergic medications, particularly for elderlypatients, due to its reduced propensity for sideeffects, but having similar efficacy as anticholin-ergic medications when managing DIP [39]. Astudy of 44 patients with schizophrenia who wererandomized to benztropine or amantadine werefound to experience similar improvement insymptoms with less frequent side effects in theamantadine group [39]. Another small (n = 41),blinded, cross-over study comparing amantadineto trihexyphenidyl in the treatment of neurolep-tic-induced parkinsonism found similar results[40]. The most common side effects in clinicaltrials were insomnia, nausea, and dizziness(5–10%), with anticholinergic-like side effectsamong adverse events noted in 1–5% (anorexia,dry mouth, constipation) [38]. Amantadine is notexpected to worsen TD symptoms and there ismodest evidence to suggest that it may reducedyskinetic movements (see below). Extended-re-lease preparations of amantadine have recently
become available ‘‘for the treatment of dyskinesiain patients with Parkinson’s disease receivinglevodopa-based therapy, with or without con-comitant dopaminergic medications’’ [41] and for‘‘Parkinson’s disease and drug-induced extrapyra-midal reactions in adult patients’’ [42]. As with allamantadine-containing products, risk of exacer-bating psychosis will also need to be considered[38, 41, 42].
TARDIVE DYSKINESIA (TD)
Epidemiology
Similar to DIP, published TD prevalence andincidence rates may be falsely low [43]. In con-trast to DIP, this is likely not due to confusionwith an idiopathic disorder as much as to adecreased ability of providers to recognize theinsidious development of TD [44]. However, itdoes appear that TD prevalence and incidenceestimates vary with past antipsychotic expo-sure, antipsychotic class, and age. For example,a large meta-analysis conducted by Carbon et al.found that, in middle-aged patients, most ofwhom had a schizophrenia-spectrum disorder,the mean prevalence of TD among atypicalantipsychotic users was approximately 21%,compared to 30% among current typicalantipsychotic users [45]. However, more long-term studies that exclude patients with pasttypical antipsychotic use will be necessary todevelop a clearer picture of the impact of atyp-ical antipsychotics on TD risk [43]. On a cau-tionary note, in a real-world prospective study,the adjusted TD incidence rate-ratio for subjectstreated with atypical antipsychotics alone ver-sus typical antipsychotics alone was 0.68 [46].This suggests a small advantage for the neweragents, but the 95% confidence interval of0.29–1.64 implies that there may be no differ-ence [46]. Alarmingly, the severity of the TDwas only slightly lower among incident cases ofTD appearing after recent atypical antipsychoticexposure versus recent typical antipsychoticexposure.
The rates of TD increase with duration oftherapy, as in younger adults taking typicalantipsychotics, reported rates of TD were
238 Neurol Ther (2018) 7:233–248
approximately 4–5% annually, but this effect ismagnified by age [47]. For example, a longitu-dinal study of TD in elderly patients noted that31% (95% CI 20–42) of patients developed TDafter 43 weeks [48]. Prevalence rates becomemore complex when looking at symptom per-sistence in individuals diagnosed with TD. Inpatients taking typical antipsychotics, althoughabout 50% appear to have TD symptoms thatstagnate, 10–30% will experience remission orimprovement of symptoms, and another10–30% may have a worsening of symptoms[49].
Pathophysiology
Disruptions in a number of neurotransmittersystems and oxidative damage have been pro-posed as potential pathways underlying TD.These include dopamine receptor hypersensi-tivity, altered amino acid metabolism andGABA-containing neuron activity, and NMDAreceptor excitotoxicity [50]. Similar to DIP,there is also evidence that genetics are associ-ated with TD susceptibility [51]. Dopaminereceptor hypersensitivity is generally acceptedas playing a role in TD (Fig. 2) based on severalclinical observations, including temporaryimprovement in symptoms with increasedantipsychotic dose or potency, and symptomimprovement in some patients when adminis-tered VMAT2 inhibitors, such as tetrabenazine,which decrease the amount of dopamine that isultimately released into the synapse.
Presentation and Diagnosis
TD is a subset of tardive syndromes associatedwith antipsychotic drug use and is characterizedby involuntary, repetitive movements of theface that includes lip smacking or puckering,chewing, or tongue protrusion, but may alsoresult in uncontrolled movements in theextremities, like contraction or writhing [50].TD can worsen with stress. In contrast to DIP,the abnormal movements observed with TD aretypically arrhythmic. Further information
regarding the term tardive syndromes and rela-ted issues can be found elsewhere [52].
The Abnormal Involuntary Movement Scale(AIMS) is used clinically and in research toassess the abnormal movements associated withTD [53]. Measuring the AIMS dyskinesia itemsalone is inadequate, and questions regardingfunctional impairments attributable to TD needto be asked (e.g., interference with activitiessuch as eating, drinking, speaking, breathing,dressing oneself, writing, working, leisureactivities, being with others) [54].
The Schooler–Kane research criteria arecommonly used to identify probable antipsy-chotic-induced TD, and require that threecriteria are met: (1) symptoms occur after atleast 3 months of treatment with an antipsy-chotic, (2) abnormal, involuntary movementsmust occur in 2 or more body regions if mild,or 1 body region if moderate to severe, asdetermined by a rating scale such as the AIMS,and (3) there are no other conditions that maybe causing the abnormal movement patterns[55].
Risk Factors
Risk factors for TD are similar to those forDIP, and primarily include older age andincreased antipsychotic medication exposure(particularly typical antipsychotics), but alsoto some degree female sex, African Americanethnicity, preexisting mood disorder, cogni-tive disturbance, alcohol or substance abuse,use of lithium or antiparkinsonian agents,early occurrence of DIP, diabetes, and HIV[56–58].
Management
The APA recommends monitoring patients withschizophrenia for the development of TD every3–12 months, depending on the patient’s riskfactors and the type of antipsychotic prescribed[18]. Standards include every 6 months forpatients on a typical antipsychotic to every12 months for patients on an atypical antipsy-
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chotic, and to monitor twice as frequently forelderly patients and those with early, involun-tary, movement patterns after starting anantipsychotic [18]. These guidelines are likelyreasonable for most patients being treated withantipsychotics, regardless of diagnosis.
Once TD is diagnosed and treatment is ini-tiated, a baseline assessment should beobtained, and the AIMS examination is recom-mended for this purpose [54]. Advantages ofusing the AIMS include its ubiquity both in theclinic and in drug development, and that it can
Fig. 2 Hypothesized pathophysiology of tardive dyskinesia and the potential for vesicular monoamine transporter type 2inhibition to treat the condition (reproduced with permission from [75])
240 Neurol Ther (2018) 7:233–248
facilitate communication among providers.Follow-up assessments to assess the effective-ness of the intervention(s) should be carried outon a regular basis.
One of the first steps in the management ofTD should be to gradually discontinue anyanticholinergic medications, as they may wor-sen current symptoms [7]. In fact, symptomshave been noted to improve in up to 60% ofpeople with TD after discontinuing an anti-cholinergic [49, 59]. Unlike DIP, discontinuingan antipsychotic or switching from a typical toan atypical antipsychotic does not produce clearevidence of benefit in patients requiringantipsychotic use [60]. However, switchingantipsychotics, including a switch to clozapine,is generally supported by older treatment algo-rithms [61]. A recent review updatingthe American Academy of Neurology (AAN) TDtreatment guidelines ranks treatment optionsbased on available evidence from A to C, whereA corresponds to established efficacy, B corre-sponds to probable efficacy, and C correspondsto potential efficacy [60]. Level A evidence forefficacy exists for the two VMAT2 inhibitors,valbenazine and deutetrabenazine, both re-cently approved for the treatment of TD by theUnited States Food and Drug Administration(FDA), with a hypothesized mechanism ofaction related to dopamine D2 receptor hyper-sensitivity in the presence of chronic dopamineD2 receptor blockade (Fig. 2).
Valbenazine was the first medication tobe approved for TD in the United States, andimproves upon tetrabenazine by having a moretolerable side effect profile, potentially throughless off-site binding to dopaminergic, seroton-ergic, adrenergic, histaminergic, and muscarinicreceptors, in addition to a more convenientonce-daily dosing regimen [62]. In a Phase III,double-blind, randomized, 6-week, placebo-controlled study of 234 participants random-ized 1:1:1 to placebo or valbenazine 40 or80 mg/day, daily doses of 80 mg were shown toreduce AIMS total dyskinesia scores by - 3.2points (P\0.001 when compared tothe placebo change score of - 0.1 points) andby - 1.9 points in the 40 mg daily group(P = 0.002 when compared to placebo) after6 weeks of therapy [63]. The most common side
effects in the valbenazine group were somno-lence (5%), akathisia (3%), and dry mouth (3%),and discontinuation rates due to adverse eventswere 4% in the valbenazine group versus 3% inthe placebo group [63]. A 1-year extension ofthis study, which included 198 participants,demonstrated continued efficacy and tolerabil-ity, with the most common side effects beingheadache (7%) and urinary retention (7%), with16% discontinuing treatment due to an adversedrug event [64].
Although the target dose for valbenazine is80 mg/day (achieved after 1 week at40 mg/day), 40 mg daily should not be excee-ded in those with moderate to severe hepaticimpairment, or with concomitant use of strongCYP3A4 inhibitors [62]. This is because valbe-nazine is primarily metabolized by CYP3A4 toinactive metabolites, although CYP2D6 alsoplays a role in its metabolism [62]. In the case ofstrong CYP2D6 inhibitors, or known CYP2D6poor metabolizers, it is recommended to con-sider reducing the dose based on tolerability[62]. Valbenazine does not appear to impact thecommon CYP isoenzymes itself, but does inhi-bit P-glycoprotein, so digoxin should be moni-tored carefully in patients requiring bothmedications [62].
Valbenazine may prolong the electrocardio-graphic QT interval, but the degree of QT pro-longation is not clinically significant atconcentrations expected with recommendeddosing; nonetheless, valbenazine should beavoided in patients with congenital long QTsyndrome or with arrhythmias associated with aprolonged QT interval. For patients at increasedrisk of a prolonged QT interval, it is suggestedthat the QT interval be assessed before increas-ing the dosage (i.e., from 40 to 80 mg/day) [62].
Deutetrabenazine was the second VMAT2inhibitor approved by the FDA for the treat-ment of TD. Deutetrabenazine is a deuteratedformulation of tetrabenazine; deuterium atomsare substituted for hydrogen atoms at key loca-tions in the molecule, altering its pharmacoki-netics because deuterium–carbon chemicalbonds are many-fold stronger than hydro-gen–carbon bonds. Deuterium is naturallyoccurring ‘‘heavy hydrogen’’ and is notradioactive. Compared to tetrabenazine,
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metabolism is slowed, reducing the number ofdoses required per day, decreasing plasma levelvariability, and improving tolerability [30].Recommended dosing for deutetrabenazine istwice daily with food, starting at 6 mg twicedaily and increasing by 6 mg weekly up to amaximum dose of 24 mg twice daily, based ontolerability and reduction of TD [30]. In a PhaseII, 12-week, clinical trial (n = 117) whichallowed titration to optimal efficacy and toler-ability, the mean dose achieved was38.8 mg/day [65]. A Phase III, double-blind,12-week, placebo-controlled, randomized trialwas conducted to compare deutetrabenazine atdoses of 12, 24, and 36 mg/day to placebo in298 patients [66]. The randomizationscheme was 1:1:1:1 and the deutetrabenazinedose was increased over 4 weeks. The primaryend-point measure was change in AIMS scoresfrom baseline to week 12. At week 12, thetreatment difference from baseline (SE) was
- 1.4 in the placebo group and - 2.1 (P = 0.217when compared with placebo), - 3.2(P = 0.003) and - 3.3 (P = 0.001) for the 12-,24-, and 36-mg/day treatment groups, respec-tively [66]. The most common side effects in thedeutetrabenazine groups were headache (5%),anxiety (4%), and diarrhea (4%), and discon-tinuation due to side effects occurred in 4% ofthe treatment group and 3% of the placebogroup [66]. Deutetrabenazine metabolisminvolves CYP2D6; in the presence of CYP2D6inhibitors or in patients who are known poorCYP2D6 metabolizers, the total daily dosage ofdeutetrabenazine should not exceed 36 mg [30].Deutetrabenazine may prolong the QT intervaland use should be avoided in patients withcongenital long QT syndrome or with arrhyth-mias associated with a prolonged QT interval.For patients at increased risk of a prolonged QTinterval, it is suggested that the QT interval be
Table 1 Differentiating characteristics of drug-induced parkinsonism (DIP) versus tardive dyskinesia (TD)
Characteristic DIP TD
Onset Immediate (hours–days–weeks) after
initiation of an antipsychotic or after
dose is increased
Delayed (months–years) after initiation of an
antipsychotic
Motor symptoms observed Rhythmic tremor, rigidity, shuffling gait;
Table 2 A comparison of the key characteristics and recommended dosing considerations for valbenazine and deutetra-benazine use in the management of TD. Adapted from [30, 62, 75]
Valbenazine Deutetrabenazine
Brand name Ingrezza Austedo
Available dose formulation Capsules: 40 and 80 mg Tablets: 6, 9, and 12 mg
Other indications None Chorea associated with Huntington’s disease
Active metabolites [?]-a-HTBZ Deuterated a-HTBZ and b-HTBZ
Half-life Valbenazine and [?]-a-HTBZ: 15–22 h Total (a ? b)-HTBZ from
HTBZ dihydrotetrabenazine, TD tardive dyskinesia, MAOIs monoamine oxidase inhibitors, CNS central nervous system
Neurol Ther (2018) 7:233–248 243
assessed before and after increasing the totaldose above 12 mg BID [30].
Unlike valbenazine, deutetrabenazine is alsoapproved for the treatment of Huntington’sdisease, and contains language in its productlabel that is specific to tolerability concerns forthat population and differs from that for TD (forexample, there is a boxed warning for depres-sion and suicidality that has been observed inpatients with Huntington’s disease). Other dif-ferences between valbenazine and deutetra-benazine are summarized in Table 2.
Additional medication interventions for TDare not FDA-approved and carry lower levels ofevidence compared to valbenazine anddeutetrabenazine in the AAN guidelines. Level BAAN recommendations for the treatment of TDinclude Ginkgo biloba and clonazepam. Level Coptions that might be considered includeamantadine, tetrabenazine, and pallidal deepbrain stimulation [60]. Amantadine is uniqueamong medications used to treat DIP and TD, inthe respect that it has evidence supporting its usefor both indications. However, the therapeuticeffect for TD is modest. When compared to pla-cebo, amantadine has been shown to decreaseAIMS scores by approximately 15–22% in small,relatively short-term, placebo-controlled, cross-over studies [67, 68]. Drowsiness, fatigue,insomnia, constipation, and dizziness occurredmore frequently with amantadine than placeboin these studies [67, 68]. Tetrabenazine is usedoff-label for the treatment of TD in the UnitedStates; however, in other jurisdictions, such asthe UK, Canada, New Zealand, Australia, Ger-many, Italy, Israel, France, and Portugal, it isapproved for this purpose [69]. Two small, clin-ical trials were cited in the AAN recommenda-tion supporting the use of tetrabenazine for thetreatment of TD symptoms, as supported bysignificant reductions in AIMS scores [70, 71].Although tolerability was not a major issue inthese studies, clinical experience with side effectsof tetrabenazine that occur in more than 5% ofpatients in persons with Huntington’s disease(such as sedation, insomnia, depression, akathi-sia, parkinsonism, instability, irritability) [72],and the requirement to dose the medication upto 3 times per day, and assessing for CYP 2D6poor/extensive metabolizers if doses greater than
50 mg/day need to be used, led to the develop-ment of the two tetrabenazine alternatives, val-benazine and deutetrabenazine, discussedpreviously.
Co-occurrence of DIP and TD
It is possible for patients treated with antipsy-chotics to have both DIP and TD, with DIP pre-sumably preceding TD. Although themechanism is not fully understood, observationsregarding the differences in neural pathwaysbetween DIP and comorbid DIP and TD are pre-sented in Fig. 1 [2, 10, 73]. As compared toFig. 1a, Fig. 1b details relatively greater excitatorysignaling between the thalamus and the cerebralcortex, potentially explaining TD symptomsoccurring in the setting of DIP. For patientsexperiencing both disorders, treatment optionsinclude amantadine (with or without a VMAT2inhibitor), which may have some positiveimpact on both disorders. Anticholinergic med-ication should be avoided or minimized in orderto lessen potential adverse impact on TD symp-toms. Randomized controlled trials of VMAT2inhibitors in persons with co-occurring DIP andTD will help answer the question of whether ornot the decrease in dopamine release observedwith VMAT2 inhibition would have significantclinical impact on the severity of the DIP.
CONCLUSION
DIP and TD are potential adverse events ofantipsychotics that occur at significant rateswith both typical and atypical antipsychoticuse. DIP can be difficult to recognize and diag-nose, especially in the elderly, due to its simi-larity to Parkinson’s disease, but most oftenpresents within the first 3 months of therapy[27]. TD, however, typically does not developuntil after 3 months or longer of antipsychoticdrug use (although there may be the occasionalexception). Among the agents used to treat DIP,amantadine is expected to be better toleratedthan anticholinergics, particularly in theelderly. Valbenazine and deutetrabenazine arereasonable to consider as first-line pharma-cotherapy for TD.
244 Neurol Ther (2018) 7:233–248
ACKNOWLEDGEMENTS
Funding. No funding or sponsorship wasreceived for this study or publication of thisarticle.
Authorship. All named authors meet theInternational Committee of Medical JournalEditors (ICMJE) criteria for authorship for thisarticle, take responsibility for the integrity ofthe work as a whole, and have given theirapproval for this version to be published.
Disclosures. In the past 12 months, LeslieCitrome has served as a consultant to Acadia,Alkermes, Allergan, Intra-Cellular Therapeutics,Janssen, Lundbeck, Merck, Neurocrine, Noven,Otsuka, Pfizer, Shire, Sunovion, Takeda, Teva,Vanda and has served as a speaker for Acadia,Alkermes, Allergan, Janssen, Lundbeck, Merck,Neurocrine, Otsuka, Pfizer, Shire, Sunovion,Takeda, Teva, Vanda, owns stocks (small num-ber of shares of common stock) of Bristol-MyersSquibb, Eli Lilly, J & J, Merck, Pfizer purchased[10 years ago, and receives royalties fromWiley (Editor-in-Chief, International Journal ofClinical Practice), UpToDate (reviewer),Springer Healthcare (book). Kristen Ward hasnothing to disclose.
Compliance with Ethics Guidelines. Thisarticle was a review and commentary on previ-ously conducted studies. No information fromhuman participants or animal research con-ducted by either of the authors was used in thisarticle.
Data Availability. Data sharing is notapplicable to this article as no datasets weregenerated or analyzed during the current study.
Open Access. This article is distributedunder the terms of the Creative CommonsAttribution-NonCommercial 4.0 InternationalLicense (http://creativecommons.org/licenses/by-nc/4.0/), which permits any noncommer-cial use, distribution, and reproduction in anymedium, provided you give appropriate creditto the original author(s) and the source, provide
a link to the Creative Commons license, andindicate if changes were made.
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