Tardive Dyskinesia: Minimizing Risk and Improving Outcomes in Schizophrenia and Other Disorders

DECISION MAKER FORUM IN MANAGED CARE

DECEMBER 2007

FACULTY Leslie Citrome, MD, MPH Tardive Dyskinesia: Director, Clinical Research and Evaluation Facility Minimizing Risk and Nathan S. Kline Institute for Psychiatric Research Orangeburg, New York Improving Outcomes in Professor of Psychiatry New York University Schizophrenia and

Robert Dufresne, PhD, PhD, BCPS, BCPP Other Disorders Professor of Pharmacy Leslie Citrome, MD, MPH; Robert Dufresne, PhD, PhD, BCPS, BCPP; University of Rhode Island College and Judy M. Dyrud of Pharmacy Kingston, Rhode Island THE USE OF ANTIPSYCHOTIC AGENTS FOR PSYCHIATRIC DISORDERS In the United States, antipsychotic drugs are the cornerstone of treatment for schizo- This supplement to The American phrenia,1 for which about 2 million patients are treated annually.2 In addition, antipsychot- Journal of Managed Care is sponsored ic agents are widely used in the treatment of schizoaffective disorders and mood disorders by Eli Lilly and Company. with psychotic features. They are also sometimes prescribed for diagnoses that do not include a psychotic component.3 According to the US Department of Health and Human DISCLOSURES Services, 11 million antipsychotic prescriptions were paid by Medicaid in 1998, 51% of The faculty report the following which were for atypical antipsychotics.4 commercial disclosures: Psychosis can have a devastating impact on economic prospects, socialization, and qual- Dr Citrome: ity of life. Unfortunately, long-term treatment with antipsychotics carries the risk of seri- Consultant: Avanir, Bristol-Myers ous adverse effects, including tardive dyskinesia, which can have a substantial negative life Squibb, Eli Lilly, GlaxoSmithKline, impact.5 Because for many patients antipsychotics are the only effective treatment, clinicians Janssen, Jazz, Pfizer, Vanda; who prescribe them must be educated about their risks and guard against serious long-term Grant/research support: AstraZeneca, effects. Adverse effect risk can vary with individual patient vulnerabilities, treatment dura- Barr, Bristol-Myers Squibb, tion, dosage, and drug class (conventional/first-generation antipsychotics [FGAs] or atypi- Eli Lilly, Janssen, Pfizer; cal/second-generation antipsychotics [SGAs]). In schizophrenia, treatment is commonly life- Honoraria: Abbott, AstraZeneca, long; therefore the best treatment uses the antipsychotic agent with the best long-term effi- 6 Avanir, Bristol-Myers Squibb, Eli cacy-to-risk ratio for the individual patient. Lilly, GlaxoSmithKline, Janssen, MOTORIC ADVERSE EFFECTS Jazz, Pfizer, Vanda; Acute motoric adverse effects can begin to appear within the first few hours of antipsychotic Speaker’s bureau: Abbott, treatment. All antipsychotics can cause potentially fatal neuroleptic malignant syndrome, char- AstraZeneca, Eli Lilly, Pfizer. acterized by diffuse muscular rigidity, tremors, fever, labile blood pressure, and cognitive and Dr Dufresne: autonomic disturbances.7 Extrapyramidal symptoms (EPS) may develop in 50% to 60% of Consultant: Bristol-Myers Squibb, patients treated with FGAs.8 Dystonias appear as disturbances of muscle tone, whereas dyski- 9 Eli Lilly, JNJ (Janssen); nesias are disturbances of movement. Honoraria: Bristol-Myers Squibb, Eli Lilly, JNJ; Speaker’s bureau: Acute dystonia, involuntary and sometimes painful muscle contractions in neck, face, 10 10 Bristol-Myers Squibb, Eli Lilly, JNJ. tongue, or back, can usually be relieved with anticholinergic agents.

10 PUBLISHING STAFF Akathisia (motor restlessness) frequently manifests as pacing or inability to sit still. Acute akathisia does not always respond to antiparkinsonian drugs.11,12 Drug-induced Contributing Editor akathisia can be mistaken for psychotic agitation, sometimes leading clinicians to increase William H. Doutré, PharmD the antipsychotic dose.13 However, akathisia is best treated by reducing the dose or switch- Managing Editor ing antipsychotics.10,12 Elizabeth Turrin Design Director Drug-induced parkinsonism (tremors, rigidity, shuffling gait, extremely slow movement Michael Molfetto or paralysis)10 can be alleviated with antiparkinsonian agents including anticholinergics.10

Involuntary orofacial movements that seemed associated with neuroleptic treatment were A Supplement to described as early as 1957 and, along with limb and trunk movements described later, were called tardive dyskinesia (TD) in 1964.13 As the name “tardive” implies, TD was considered to be a result of months or years of exposure to antipsychotic drugs.13 Early reports consis- tently emphasized its persistence long after discontinuation of neuroleptics.13 These criteria remain today.

OL44132 TARDIVE DYSKINESIA: MINIMIZING RISK AND IMPROVING OUTCOMES IN SCHIZOPHRENIA AND OTHER DISORDERS

Training in the assessment of TD abnormal gait.25 It may affect neck elderly. In the Hillside study 23% of has decreased since prescribing prac- muscles first and present as an a subgroup of patients older than 55 tices have come to favor SGAs.14 abnormal head position.9 Some years developed TD within 2.2 years.15 Because many clinicians lack training authors contend that tardive dysto- Another prospective study of elderly in movement disorders and many nia can be mistaken for TD, and that patients found incidence of 59.8% patients do not complain of dyskine- TD identified within a year of after 3 years with FGAs.15 sias, TD may be underdiagnosed.15 antipsychotic initiation is usually tar- Whereas acute dystonia, akathisia, dive dystonia.26 No treatment for and drug-induced parkinsonism may tardive dystonia has been proven The incidence of TD is be transient and reversible with treat- generally effective. Tetrabenazine, higher in the elderly. ment, TD can be persistent.16,17 anticholinergics, clozapine, clon- Persistence is usually defined as sus- azepam, or the combination of cloza- tained TD symptoms >3 months after pine plus clonazepam have been Incidence of TD is also higher in withdrawal of the offending neurolep- helpful in some cases.9,25-28 In 1 mood disorders, sometimes even higher tic,9,18 but in some studies it can mean recent case, antipsychotics were dis- than in schizophrenia.32,33 TD incidence >3 months whether or not antipsy- continued and schizophrenia and may increase in the future as the use of chotic treatment continues.19 In up to severe tardive dystonia were man- antipsychotics increases for affective 50% of affected patients, TD becomes aged successfully with mood stabiliz- disorders and other nonschizophrenic chronic and irreversible.20 ers and benzodiazepines alone.29 indications.15 Akathisia was also noted in several Incidence and prevalence studies of the first reports of TD.13 Unlike that include outpatients may not con- In up to 50% of affected acute akathisia, tardive akathisia can trol for nonadherence. Up to 50% of worsen when the antipsychotic dose is outpatients fail to adhere to medica- patients, TD becomes lowered and can present with emergent tion schedules.2,18 In the context of chronic and irreversible. TD.12 In a study of chronic schizophre- nonadherence, patients may be devel- nia, discontinuation of antipsychotics oping TD with less total exposure to resulted in akathisia and withdrawal antipsychotics than is reported. Some dyskinesias described in the TD in a third of patients.12 When Another way to look at TD is in risk 1960s-1970s first appeared after neu- antipsychotics were restarted, the pa- related to years of neuroleptic expo- roleptic cessation but disappeared sev- tients who had exhibited akathisia at sure. The risk of TD is approximately eral weeks later.10,13 These symptoms, withdrawal persisted in exhibiting TD 5% per year of FGA exposure up to called withdrawal dyskinesia, reflect for up to 6 weeks, suggesting a rela- about 40 years of age.34 After age 40 the action of neuroleptics to suppress tionship between TD and late-onset years, the risk increases.34 In elderly or mask dyskinesia.21,22 akathisia.12 Tardive akathisia may be a patients, the risk in the first year of When TD first appears during preliminary stage of TD in some FGA exposure may be as high as antipsychotic use, withdrawal may ini- patients receiving long-term antipsy- 25%.14 However, the risk per year of tially worsen involuntary move- chotic treatment.12 SGA exposure has not been firmly ments.21,23 Later (sometimes in 1-2 established. A recent systematic review months) TD can remit spontaneously. INCIDENCE AND of current literature suggests annual Thus, withdrawal of antipsychotics, PREVALENCE OF TD TD incidence of about 1% per year when possible, is a primary treatment In an analysis of studies totaling with SGAs versus 5% per year with for TD.23 Dyskinesia that first appears nearly 35000 patients treated with FGAs.35 on withdrawal may be masked again if antipsychotics, the mean corrected antipsychotics are restarted. Then it is prevalence of TD was 18.5%.30 The CHARACTERISTICS AND important to avoid both FGAs, with incidence of TD in young adults is 4% PATHOPHYSIOLOGY OF TD their higher associated incidence of to 5% annually, but the risk increases TD is characterized by movements TD, and concomitant anticholinergic with age and duration of neuroleptic that are involuntary, repetitive, and medications for acute drug-induced treatment.31 purposeless.8 The movements may be movement disorders, with their poten- In the Hillside study, the first long- of 3 possible types: chorea (variable, tial to exacerbate TD.20,23 term prospective study of TD inci- rapid, jerky or fidgety), athetoses Dystonia that persisted 20 months dence,15 patients with no baseline TD (slow, writhing, irregular), or ballis- after discontinuation of phenoth- had a TD incidence of 14% after 4 mus (sudden, fast, flinging [eg, of iazines—in other words, tardive dys- years of cumulative FGA exposure.32 arms]).36 TD may present orofacially tonia—was described in 1962.13 In a The Hillside data on TD persistence or affect the limbs or trunk. recent study of long-term antipsy- suggest an FGA-related annual inci- chotic use, annual incidence of tar- dence of 3% for persistent TD (>3 Orofacial: dive dystonia was 0.7% versus months) and 2% for transient TD (<3 • Mouthing movements, chewing, 10.2% incidence of TD.24 Tardive months).15 Other prospective studies sucking, licking11,20 dystonia is characterized by some- have similarly shown annual incidence • Lip smacking11,16,20 times painful muscular contractions of 4% to 8% with spontaneous remis- • Grimacing, tongue protrusion, lip that may result in slow twisting sion up to 2.5%.15 puckering and pursing11,16,20 movements or dystonic postures and The incidence of TD is higher in the • Rapid eye blinking, brow wrinkling5,20

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• Likelihood of oral-lingual move- increase in the number of D2 receptors chotic treatment may be the “final ments increasing with age10 in the brain striatum, and resulting straw” that induces TD.40 spontaneous, random muscle contrac- A combination of factors and mech- Limbs: tions or movements, the hallmarks of anisms are most likely involved in TD, • Rapid movements of arms, legs, or TD.8,39 Over time the dopamine recep- with the highest risk in patients who trunk11 tor blockade may increase the sensitiv- have psychosis, advanced age, and • Flexion-extension movements in fin- ity to dopamine in the nigrostriatal long-term use of antipsychotics.40 gers, toes, ankles, or wrists20 dopamine receptor system.10,40 Ani- • Finger movements evoking guitar or mal models have demonstrated this RISK FACTORS FOR TD piano playing20 hypersensitivity and have shown TD occurs at higher rates in older • Symptoms in extremities more com- decreased dopamine turnover long patients,9,18,42-46 patients with affective mon in younger patients10 after cessation of neuroleptics, but do disorders,5,9,19,32,46,47 and patients with not account for all aspects of human a history of FGA use.44-46 Other iden- Trunk: TD.40 Human studies have not sup- tified risk factors have included dia- • Shoulder shrugging11,36 ported the hypersensitivity hypothesis; betes, ethnicity, negative symptoms of • Pelvic rocking (if abdominal in- they have not shown measurable dif- psychosis, cognitive dysfunction, sub- volvement)16 ferences in dopamine turnover in cere- stance abuse, early EPS, and use of • Grunting or other sounds with each bral spinal fluid or number of post- antiparkinsonian agents.42,46 Individ- breath (if diaphragmatic involve- mortem D2 receptors in patients with ual patients will present with varying ment)11,16,36 and without TD.40 risk factors for TD, some controllable and some not. TD carries secondary physical and GABA insufficiency in the anatom- psychiatric risks. Orofacial TD can ical loop that controls motor function Age: Advancing age is the most impair chewing and swallowing. Dental has also been proposed as a cause of accepted risk factor for development problems can develop and progress to TD.40 Some animal and human studies of TD.9,18,30,33,42-46 An analysis of 8 mouth infections. Nutritional intake, support altered GABA function or de- studies showed weighted mean preva- especially in the elderly, may become creased GABA-synthesizing enzymes lence 3 times higher in patients older insufficient.16,31 Orofacial and truncal with neuroleptic treatment and TD, versus younger than 40 years of age.18 TD are associated with unintelligible but others do not.40 In a prospective study of neuroleptic- speech.11,31 Severe limb or truncal dys- treated outpatients ages >45 years, the kinesia alters gait and can result in Metabolic problems may also con- incidence of TD at 1-, 2-, and 3-year falls.16,31 When the diaphragm is tribute to TD. This is supported by follow-up was 26%, 52%, and 60%, involved, respiratory distress can increased risk of TD in diabetes and respectively. The corresponding inci- result.11,37 Unintelligible speech, altered some treatment success with branched- dence in a study of younger adults was appearance, and falls can lead to shame chain amino acids (see page 9).40 5%, 19%, and 26%.43 Prevalence in and eventual depression.37 patients ages >65 years has been Severe TD can add considerably to Neurotoxicity and neuronal cell reported as 5 times greater than that in the stigma and social and employment loss could result from chronic anti- younger patients.15 Age can also be obstacles faced by persons with schiz- psychotic treatment and cause TD. considered a prognostic factor in TD; ophrenia. According to a 2002 con- Some brain imaging studies have as age advances, rates of spontaneous sensus conference assembled to devel- shown differences between patients remission decrease.15,46,48 op recommendations for physical with and without TD, but others have health monitoring of patients with not.40 Sex: Female sex has long been iden- schizophrenia, “Movement disor- tified as a risk factor for TD.9,15,39,46 ders…add to the stigmata associated Spontaneous dyskinesias, which The increase with advancing age may with schizophrenia and can provide can occur without the use of antipsy- be far greater in women than men.49,50 unnecessary obstacles to optimum chotics, sometimes appear in the elder- An analysis of 19 studies before 1981 social and vocational adjustment.”17 ly10,15,16,19 and in patients with schizo- showed weighted mean prevalence In short, TD is associated with in- phrenia.34,41 Before the advent of the 41% higher in women than in men. creased morbidity and poor quality of FGAs, abnormal involuntary move- However, in some of the studies, the life.38 ments similar to TD were described in women received longer and/or higher- The etiology and pathophysiology of some psychotic patients.40 Spontan- dose treatment than the men.18 Some TD have not been conclusively proved. eous dyskinesias have been document- incidence42 and prevalence studies6,23 Several theories of underlying mecha- ed in up to 40% of neuroleptic-naïve have not supported an increased risk nisms make sense given response to patients with schizophrenia34 and may of TD in women. The higher numbers antipsychotic drugs, but animal-model manifest the underlying cerebral of affected women in other studies and clinical data both support and pathology of schizophrenia.34,41 The may relate to methodology and refute the theories. schizophrenia disease process may age/sex demographics.6 The evidence increase vulnerability to TD from is inconclusive. Dopaminergic system: Antipsy- antipsychotic drugs.14,41 In psychotic chotics block dopamine D2 receptors. patients who do not experience spon- Ethnicity: Some data suggest a high- This may cause upregulation, an taneous dyskinesias, chronic antipsy- er risk for patients of African de-

3 TARDIVE DYSKINESIA: MINIMIZING RISK AND IMPROVING OUTCOMES IN SCHIZOPHRENIA AND OTHER DISORDERS

scent.24,31 One study found a cumula- amphetamines, antihistamines, and over longer periods. To allow for this tive annual TD incidence of 46.5% in tricyclic antidepressants) have been possibility, clinicians should keep African Americans and 27.2% in associated with dyskinesias over the doses as low as possible. whites.31 In another study, nonwhite long term.9 Anticholinergic agents However, evidence for cumulative patients (mostly African Americans) used to treat drug-induced parkinson- exposure as a risk factor for TD is were almost twice as likely to develop ism can worsen TD.5,23,44 If the mixed.19,23 At least 1 study found the TD.48 African descent has also pre- antipsychotic masks the emergence of amount of drug administered in any dicted poorer TD outcomes.46 TD symptoms, the anticholinergic one year was more predictive than the may be continued for the long term cumulative amount over many years.23 and exacerbate the latent TD. The TD Some authors have noted that with might not be detected until it is doubtful completeness and accuracy The schizophrenia disease advanced and difficult to reverse. In of records in chronic patients, it can be process may increase the CATIE study, patients who had difficult to establish total exposure vulnerability to TD from TD at baseline were more likely to be anyway.19 However, in the clinical set- receiving anticholinergics.44 ting, a new middle-aged or elderly antipsychotic drugs. patient with a longstanding diagnosis Antipsychotic use: Genetic vulnera- of schizophrenia and history of bility to movement disorders and the antipsychotic use most likely has sig- Affective disorders: Bipolar and use of antipsychotic medications com- nificant antipsychotic exposure and other affective disorders may carry a bine to create a high genetic risk of risk of TD. higher risk for TD than other psychi- TD.37 Although it is generally accept- atric diagnoses, including schizophre- ed that a lower FGA dose will carry a Early EPS: The risk of TD may be nia.5,9,19,32,33,46,47 Four studies of lower TD risk, the evidence that high higher in patients with EPS or a histo- antipsychotic-treated patients with dosing increases risk has been ry of early EPS.8,15,31,33,38,46,57 In the mood disorders found TD prevalence mixed.9,23 There is little evidence com- European Schizophrenia Outpatient of 26% to 64%.32,47 In the 2 studies paring the incidence of TD with low- Health Outcomes study, baseline EPS with schizophrenia comparator groups, versus high-potency FGAs.42 Because predicted later TD. In approximately the prevalence was 18% and 25% in TD appears to be related to duration half of patients who had TD after 1 schizophrenia versus 26% and 42% of treatment,18,23,44,45 clinicians should year of the study, it was preceded by in affective disorders.32,47 The ap- become more vigilant about TD over EPS.58 The CATIE study found that pearance of TD has been shown to time with antipsychotic use. The severity of EPS at baseline was signifi- relate to depression rather than mania Curacao Extrapyramidal Syndromes cantly related to TD prevalence.44 in bipolar disorder.47 In patients with Study demonstrated that patients However, the risk of TD posed by EPS schizophrenia, comorbid depression without TD after many years on has not been proved conclusively.9 It and even a family history of affective antipsychotics still were at risk for has not been determined whether EPS disorders can increase TD risk.47 The TD.24 Newly diagnosed TD occurred or its treatment with anticholinergics presence of an affective disorder can at an annual rate of 10.2% over 9 constitutes the greater risk.42 also predict poorer outcomes, with less study years.24 The mean antipsychotic Other reported risk factors for TD chance of reversal of TD.46 use duration of the patients with new- include baseline preclinical movement incident TD was 18 years.24 disorder or tremor,31 brain damage (eg, Diabetes mellitus has also long been TD takes from months to many from head trauma),37 mental retarda- considered a risk factor for TD.16,42,46 years to appear. The wide variation in tion,39 and history of electroconvul- Several studies over the past 15 years onset may relate in part to variations sive therapy.15,16 have demonstrated an association in cumulative antipsychotic exposure between pre-existing diabetes or insulin because of dosing variations and inter- DIFFERENTIAL RATES OF TD resistance and the development of TD mittent versus continuous treatment. WITH FGAs VERSUS SGAs in antipsychotic-treated patients.51-54 One study found duration of prior Although SGAs have fewer motor However, in other recent studies, dia- neuroleptic use at baseline and cumu- side effects than FGAs, all antipsy- betes did not predict TD.44,55 lative amount of high-potency neu- chotics carry some risk of development roleptics increased risk of TD by fac- of movement disorders.16 It is general- Alcoholism and substance abuse tors of 2.4 and 1.7, respectively.43 ly accepted that long-term FGA use may increase risk of TD.31,33,39,44,46 In Nomenclature in tobacco research bears a high risk of TD. With FGAs, 1 study of older patients, a history of presents an example of disease risks TD incidence has been approximately alcohol abuse increased TD risk by a related to cumulative exposure. In the 5% per year in adults and 25% to factor of 1.7.43 The schizophrenia “pack years” measurement, 3 pack 30% per year in elderly patients.38 Up study Clinical Antipsychotic Trials of years is the exposure produced by to 25% of patients with chronic psy- Intervention Effectiveness (CATIE) smoking 3 packs of cigarettes per day chosis who have been treated with found that substance abuse signifi- for 1 year, 1 pack per day for 3 years, FGAs may now have TD.46 After 20 cantly predicted TD.44 1/2 pack per day for 6 years, etc.56 years of FGA use, almost 70% of Similarly, it is possible that high-dose patients may have TD.8 Concomitant medications: Med- neuroleptics taken for a short time The Mount Sinai Conference on the ications other than neuroleptics (eg, may cause TD as easily as lower doses Pharmacotherapy of Schizophrenia

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issued the consensus opinion, “There is also have multiple receptor binding high doses of FGAs, and if the risk of sufficient evidence to conclude that characteristics, with a lower affinity TD is associated with cumulative expo- 35 SGAs are less likely to cause TD than for dopamine D2 receptors and greater sure, then it may be dose-related. A FGAs are.”57 This opinion is widely affinities for other neuroreceptors.1,37 meta-analysis of 31 randomized con- 6,8,45,59 supported. Trials of SGA effica- SGAs, via their 5HT2A antagonism, trolled trials comparing SGAs with cy and safety have suggested an inci- can reduce dopamine D2 blockade low-potency FGAs found that “opti- dence of approximately 1% per year activity in the nigrostriatal pathway.73 mum” doses of these FGAs were no with SGAs versus approximately 5% Meta-analyses have shown that all more likely to induce EPS than SGAs per year with FGAs.35 In a prospective SGAs at recommended doses have sig- were; the risk was significantly lower study of patients with borderline dys- nificantly lower rates of EPS and levels only with clozapine.15,75 kinesia at baseline, those treated with of antiparkinsonian medication use.17 SGAs have not existed long enough FGAs were approximately twice as Because SGAs have a lower risk of for the kinds of long-term studies that likely as those treated with SGAs to EPS,15 it may follow that SGAs carry a have shown FGAs cause TD eventual- develop definitive TD within 6 lower risk of TD.31 That was the con- ly in most patients. Because many months.60 A review of 11 controlled clusion of a meta-analysis of 11 SGAs have faster dissociation from the 38 15,35 studies found that in nongeriatric prospective studies of SGAs, but it D2 receptor than do FGAs, they adults, TD incidence was 0.8% with has not been proved unequivocally.15 might be expected to take longer to SGAs versus 5.4% with an FGA.38 The Most evidence of lower risk with SGAs cause any dopamine-related adverse CATIE study showed a significantly is based on studies not specifically de- effect. Most SGA studies have run for higher prevalence of TD in patients signed to assess TD risk. Comparative <2 years, not long enough to conclude receiving an FGA at baseline than in treatment with FGAs and SGAs was definitively that the risk of TD is low patients receiving an SGA alone.44 not always blinded or randomized and with long-term SGA treatment. Additional comparisons on rates of diagnosis of TD was rarely by neuro- TD can arise from years of FGA TD have been conducted between logic assessment.15 Although multiyear treatment even after discontinuation FGAs and SGAs, including in younger well-controlled studies are necessary to of the drugs; this has been called a and older patients.38,61-72 The review quantify long-term incidence, ethical “legacy of treatment.”41 Thus, if a pa- of the individual studies is beyond the concerns have dictated that TD inci- tient has been switched from FGAs to scope of this article. dence studies of 5 years have been an SGA, it is unclear whether emergence The first SGAs were called “atypi- naturalistic, with ≥less reliable data.74 of TD indicates harm from the SGA cal” because they reduced the risk of Naturalistic studies may not control for or “legacy” harm from the FGAs.74 EPS that typically occurred with nonadherent patients or physicians Although it implicates FGAs, legacy FGAs.15 All are associated with a lower who switch SGAs or combine 2 harm can nevertheless confound the incidence of EPS than FGAs.3,17 SGAs antipsychotics. Many studies used very results and conclusions of SGA studies

Table 1

Summary of Clinical Evidence Related to Atypical Antipsychotics and Risk of TD

Therapeutic Dimension Current Evidence Atypical antipsychotic with no risk of TD No Decreased TD in atypical compared with typical agents Yes (~1%/y vs ~5%/y) Mechanism(s) of action understood Unclear Evident when compared with low-dose typical agents Yes True for nonschizophrenic diagnoses Unknown True for specific subpopulations (eg, children, elderly) Yes Difference between atypical agents No Decrease maintained with atypical-typical combinations Unlikely Decrease maintained with atypical-atypical combinations Unknown Difference according to formulation (eg, oral compared with depot) No (limited data)

Antidyskinetic properties Yes Mechanism(s) of action understood Unclear Difference between atypical agents No Treatment (suppression) compared with cure Unclear

TD indicates tardive dyskinesia. Adapted with permission from Reference 35.

5 TARDIVE DYSKINESIA: MINIMIZING RISK AND IMPROVING OUTCOMES IN SCHIZOPHRENIA AND OTHER DISORDERS

Figure 1

Abnormal Involuntary Movement Scale (AIMS)

(A) Examination Procedure: Either before or after the examination procedure, observe the patient unobtrusively, at rest (eg, in waiting room). The chair to be used in this examination should be a hard, firm one without arms. 1. Ask the patient to remove shoes and socks. 2. Ask the patient if there is anything in his or her mouth (eg, gum, candy); if there is, remove it. 3. Ask the patient about the current condition of his or her teeth. Ask the patient if he or she wears dentures. Do teeth or dentures bother the patient now? 4. Ask the patient whether he or she notices any movements in mouth, face, hands, or feet. If yes, ask to describe and to what extent they currently bother the patient or interfere with his or her activities. 5. Have the patient sit in a chair with hands on knees, legs slightly apart and feet flat on floor. (Look at entire body for movements while in this position.) 6. Ask the patient to sit with hands hanging unsupported. If male, between legs; if female and wearing a dress, hanging over knees. (Observe hands and other body areas.) 7. Ask the patient to open mouth. (Observe tongue at rest in mouth.) Do this twice. 8. Ask the patient to protrude the tongue. (Observe abnormalities of tongue movement.) Do this twice. 9. Ask the patient to tap thumb, with each finger, as rapidly as possible for 10 to 15 seconds; separately with right hand, then with left hand. (Observe facial and leg movements.) 10. Flex and extend patient’s left and right arms (one at a time). (Note any rigidity.) 11. Ask the patient to stand up. (Observe in profile. Observe all body areas again, hips included.) 12. Ask the patient to extend both arms outstretched in front with palms down. (Observe trunk, legs, and mouth.) 13. Have the patient walk a few paces, turn and walk back to chair. (Observe hands and gait.) Do this twice. (B) Rating sheet Patient Name ______Rater Name ______Patient # ______Data Group: AIMS ______Evaluation Date______Instructions: Complete the above examination procedure before making ratings. For movement ratings, circle the highest severity observed. Code: 0: None 1: Minimal, may be extreme normal 2: Mild 3: Moderate 4: Severe 1. Muscles of Facial Expression 01234 • eg, movements of forehead, eyebrows, periorbital area, cheeks • Include frowning, blinking, smiling, and grimacing Facial and 2. Lips and Perioral Area 01234 Oral eg, puckering, pouting, smacking Movements 3. Jaw 0 1234 eg, biting, clenching, chewing, mouth opening, lateral movement 4. Tongue 01234 Rate only increase in movements both in and out of mouth, NOT the inability to sustain movement 5. Upper (arms, wrists, hands, fingers) 0 1234 • Include choreic movements (ie, rapid, objectively purposeless, irregular, Extremity spontaneous), athetoid movements (ie, slow, irregular, complex, serpentine) Movements • Do NOT include tremor (ie, repetitive, regular, rhythmic) 6. Lower (legs, knees, ankles, toes) 01234 eg, lateral knee movement, foot tapping, heel dropping, foot squirming, inversion and eversion of the foot Trunk 7. Neck, shoulders, hips 01234 Movements eg, rocking, twisting, squirming, pelvic gyrations 8. Severity of Abnormal Movements 0 1 2 3 4 Global 9. Incapacitation Due to Abnormal Movements 01234 Judgments 10. Patient’s Awareness of Abnormal Movements 01234 Rate only patient’s report. Dental 11. Current Problems with Teeth and/or Dentures 0: No 1: Yes Status 12. Does Patient Usually Wear Dentures? 0: No 1: Yes

Adapted from Reference 50.

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that include patients treated previous- movements. Movement Scale (AIMS)77 or the ly with FGAs.15,74 Longitudinal stud- • When initiating treatment or Simpson Abbreviated Dyskinesia ies of patients who never received increasing dose, monitor for EPS Rating Scale.49,78,79 Besides detecting FGAs would be necessary to deter- weekly until the dose has been stabi- emergent TD, periodic formal exami- mine the true risk of TD with SGAs.15 lized for 2 weeks. nations can also help to evaluate its Study results can also be confound- • With FGAs, examine for TD at course.22 Repeat instrumental assess- ed by mistaking spontaneous dyskine- least every 6 months. ments a few months after a TD diag- sia for TD, especially in the elderly, • With SGAs and no concomitant nosis can track the progress of treat- and by the masking of TD symptoms FGAs, examine for TD annually. ment or identify persistent TD.25 by antipsychotics.15 The risks of EPS • With patients at high risk for EPS Even with routine, careful examina- and the neuropharmacologic proper- (eg, older age, history of dystonic tion, TD can be difficult to detect ties of the different SGAs vary, there- reactions, akathisia, clinically signifi- early, because the antipsychotic agents fore the risks of TD may also vary.15 cant parkinsonism), examine every 3 that cause the underlying pathology Not all SGA study results support months with FGAs or 6 months with can also mask the emergence of symp- the idea of lower TD risk. In a natura- SGAs. toms. Some authors refer to an listic study of >20 000 elderly patients “induction period” of exposure to with dementia, no significant differ- Although some involuntary move- antipsychotics, followed by a “latent ence was found between FGAs and ments seem obvious, TD can be frus- period” when the pathology has SGAs in inducing a movement disor- tratingly difficult to diagnose accurate- begun, and finally a “clinical period” der within 1 year of treatment initia- ly. No clinical or laboratory test can when TD becomes detectable.42 tion.76 An 18-month schizophrenia diagnose or rule it out. Volitional or During long-term treatment with study found no significant differences psychotic mannerisms, tics, and drug- FGAs, clinicians have increased the in EPS or movement disorders among induced parkinsonism must be distin- dose to maintain efficacy. Dose groups receiving an FGA and various guished from TD and can coexist with increases might raise the risk of TD SGAs.1 In a cross-sectional study of TD in the same patients.10 The nature development,35,42 but the TD could nongeriatric patients who had received and severity of abnormal movements remain latent, its symptoms masked only SGAs, FGAs for <5 years, or may vary considerably over time.42 by the FGAs.21 FGAs for at least 5 years, the TD Clinicians should be vigilant because The National Institute of Mental prevalences were 19%, 19%, and patients may not complain of TD Health developed the AIMS examina- 42%, respectively; in other words, symptoms; many are unaware of their tion as a research tool.22 Because there was no difference between use of own dyskinesias.25 Studies have found AIMS can identify the presence and FGAs for <5 years and use of SGAs.74 a marked increase in identification of severity of choreoathetoid and other In summary, the preponderance of probable TD by the use of routine, for- movements typical of TD, it is widely evidence suggests that SGAs have a mal examinations with rating scales recommended for clinical screening low risk for TD relative to high-dose such as the Abnormal Involuntary for TD and follow-up of patients diag- FGAs, but the data are not entirely 35 conclusive (Table 1). Some authors Table 2 would classify use of FGAs versus SGAs as a risk factor for TD.35 Conditions That May Resemble TD RECOGNITION AND DIAGNOSIS Spontaneous dyskinesias occurring in the elderly19,37 and in Although persistent TD usually schizophrenia10,34,40* takes several years of antipsychotic 10,25 treatment to appear, some cases have Oral movements from ill-fitting dentures and other dental problems been documented in only 2 months Drug-induced dyskinesias from antiparkinsonian drugs or stimulants10,11,16 with FGAs.37 Whereas advanced TD is Autism16 largely untreatable, early detection can Chronic motor tic disorder37 enable possible reversal by discontinu- Huntington’s disease11,16,37 ing or reducing the dose of the antipsy- Meige’s syndrome37 chotic in some patients.22 A panel of Restless legs syndrome16 experts (see Mount Sinai consensus 16 statement) reviewed the quality and Rett’s syndrome quantity of data regarding the devel- Senile chorea37 opment of TD and recommended the Sydenham’s chorea37 following regarding the management Tourette syndrome37 of TD risk17,57: Wilson’s disease11,37

• Before initiating FGA or SGA treat- TD indicates tardive dyskinesia. ment, examine all patients for base- *If documented to have begun after initiation of antipsychotic treatment, line neurologic status, including spontaneous dyskinesias are more likely TD.13 parkinsonian signs and involuntary

7 TARDIVE DYSKINESIA: MINIMIZING RISK AND IMPROVING OUTCOMES IN SCHIZOPHRENIA AND OTHER DISORDERS

nosed with TD (Figure 1).22 more body area(s) or mild movements because it requires a complex differ- By itself, AIMS does not diagnose in 2 or more body areas ential diagnosis. TD.22 In 1982 Schooler and Kane • Absence of other conditions that TD is a diagnosis of exclusion developed 3 diagnostic criteria for might produce involuntary move- (Table 2); many other syndromes that TD22,25,80: ments. cause abnormal movements must be ruled out.42 When TD is mistaken for • At least 3 months cumulative expo- The AIMS is used to establish the certain other conditions (eg, resting sure to neuroleptics presence of the abnormal move- tremor), the results can be harmful (as • Presence of at least moderate abnor- ments. The third criterion is the most in treating the tremor with anticholin- mal involuntary movements in 1 or difficult to satisfy in clinical practice, ergics).20 A neurologist should be con-

Figure 2

Algorithm for the Management of TD

TD on classical agent

Switch gradually to an atypical TD improved: antipsychotic other than maintain atypical clozapine, and discontinue antipsychotic anticholinergic

TD persists

Switch to a second atypical TD improved: antipsychotic other than maintain atypical clozapine antipsychotic

TD persists

TD worse or the same: switch to clozapine

Consider suppression therapy with a classical agent in combination with an atypical agent (1st choice) or alone (2nd choice) or with tetrabenazine* (3rd choice) or consider adding BCAAs†

*Tetrabenazine use for the treatment of TD is considered experimental; tetrabenazine has orphan drug status in the United States. †BCAAs have been approved by the US Food and Drug Administration as a medical food for the indication of TD in males and had been marketed as Tarvil; the current availability of Tarvil is not known as the manufacturer has ceased its production, but BCAAs may be produced by a compounding pharmacy. TD indicates tardive dyskinesia; BCAAs, branched-chain amino acids. Adapted with permission from Reference 64.

8 DECISION MAKER FORUM IN MANAGED CARE

sulted if the clinician is unsure that the choice” for TD.10 TD may be mild Because TD is likely heterogeneous, no movements are TD or if signs of and reversible by withdrawing anti- single treatment will help all affected dementia are present, especially in a psychotics in one third of patients, patients.49 younger person. with higher rates in younger pa- Evidence has suggested an associa- Brief interruptions of neuroleptic tients.13,18,39 Some studies have shown tion between TD and impaired clear- treatment can unmask latent TD, that when TD was identified early, up ance of the large neutral amino acid thereby aiding early detection.5,81 to 90% of younger patients achieved phenylalanine, particularly in men.49 However, in vulnerable patients, a remission after discontinuing the BCAAs, a “medical food” (designed diagnostic drug-free interval long antipsychotic.13 In most cases, remis- for oral or enteral administration enough to unmask TD may risk sion can be predicted to occur within under physician supervision for a relapse into psychosis.5,81 Moreover, 3 months of withdrawal or not at specific condition with nutritional evidence suggests drug holidays or all.13 Unfortunately, discontinuing requirements), was approved for TD other drug-free intervals actually antipsychotics is not a viable option in males. BCAAs might improve TD increase the risk for TD.9,16,18 Because for most patients with chronic schizo- by decreasing amine neurotransmitter antipsychotics are the only effective phrenia and certain other disorders, synthesis. Ingesting BCAAs decreases treatment for schizophrenia, emer- who will always need antipsychotic availability of phenylalanine to the gence of TD during a drug-free inter- treatment.18,46 brain. One study gave high-dose val would not dictate immediate drug Thus, for patients receiving FGAs, BCAAs or placebo to men with long withdrawal, but other steps should be switching to an SGA is recommended histories of antipsychotic treatment taken (see following section).5,81 (Figure 2).16,45,64 If TD emerges in a and TD. TD movements decreased patient receiving an SGA, the clinician 36.5% in the BCAA group but PREVENTION AND can try lowering the dose or switching increased 3.4% in the placebo group. TREATMENT to another SGA. Decreasing the dose One third of the BCAA group had Advanced TD is usually irreversible will frequently help if the TD is iden- TD movement reductions of 60%.49 and no treatment has been shown to tified early enough.10,16,25 Discon- In a small uncontrolled trial, ≥the same be uniformly effective,6,8,16,18,26,32,72 tinuing any anticholinergics may also investigators gave BCAAs to children therefore the best treatment is preven- help.50,64 TD has improved in up to and adolescents, with resulting tion.8,26,45 Prevention of TD is easiest 60% of patients after ceasing anti- decreases of 40% to 65% in TD in patients who do not have schizo- cholinergics.82 symptoms.78 BCAAs were shown to phrenia or other disorders with psy- Open trials have sometimes shown be safe and tolerable in both stud- chotic features. For these patients, promise of particular agents to treat ies.49,78 Minor weight gain occurred, treatment alternatives other than anti- TD, but closer scrutiny in randomized but in the placebo-controlled study psychotics should be sought.18 In controlled trials show lack of benefit. there was no significant difference in patients who require antipsychotics, A systematic review of the TD treat- weight gain between the BCAA and SGAs should be first-line therapy ment literature shows no definitive placebo groups.49 BCAA formula- because they probably have lower risk treatment in well-done studies83; tions have not been tested in women for development of TD.8 Prevention however, the review did not include of childbearing age and are not rec- strategy should include using a single all possible interventions, such as ommended in patients with diabetes antipsychotic at the lowest dose effec- branched-chain amino acids (BCAAs). and other metabolic disorders, renal tive for the patient9,15,23,26,48 for the It was hoped that lithium used in disease, and certain other disorders.49 shortest term possible23 with regular combination with neuroleptics would Because no management strategies documented re-evaluations of anti- prevent TD, but this was not support- or treatments have been shown to pre- psychotic need, efficacy, and possible ed in controlled studies.9,23 Three vent or reverse all TD, more studies of dose reduction16,18,23,48 and regular studies demonstrated efficacy of tetra- incidence, risk factors, and potential examination for specific signs of dys- benazine,9,84 but it is less successful treatments are urgently needed. kinesia.15,23 Elderly patients are par- over the long term,9 the benefits Specifically required are long-term ticularly vulnerable to adverse effects reverse on discontinuation, and incidence studies in different popula- of any medication16 and therefore adverse effects (anxiety, depression) tions,10,42 for example, in countries require extra caution and lower dos- are common.64 Because anticholiner- with less antipsychotic drug use or dif- ing.18,30,31 Some authors suggest gics exacerbate TD, it was hoped ferent dosing than the United States.10 antiparkinsonian agents should be cholinergic agents (choline, deanol, Also required are well-designed SGA avoided, if possible, in all patients lecithin) could ameliorate it.9,23 They trials that include more women, receiving antipsychotics.18,23 If signs of helped in uncontrolled studies,9 but a minorities, and patients of all ages to TD appear during treatment with meta-analysis of randomized con- reach a better estimate of the true risk antiparkinsonian agents, they should trolled trials found that positive results of TD with these agents. These studies be tapered gradually to the minimum for cholinergic drugs did not reach sta- would provide stronger evidence if necessary to control parkinsonism, or tistical significance.85 Evidence is also they followed uniform standards38: ideally discontinued.9,45 limited, mixed, or anecdotal regarding The APA Task Force on Late benzodiazepines, baclofen, valproic • Randomized, double-blind, and >1 Neurological Effects of Antipsychotic acid, melatonin, vitamin B6, vitamin E, year long Drugs called discontinuing antipsy- levodopa, botulinum toxin, reserpine, • Examining for TD at 3-month inter- chotics the “theoretical treatment of ondansetron, and gabapentin.9,50,64,86 vals using AIMS

9 TARDIVE DYSKINESIA: MINIMIZING RISK AND IMPROVING OUTCOMES IN SCHIZOPHRENIA AND OTHER DISORDERS

• Including a final reassessment to understand TD and fail to detect its Further, psychotic symptoms and confirm diagnosis in patients who first early signs, or do not intervene to pre- response to antipsychotics can change met TD criteria at study endpoint vent progression when those signs over time.88 Some patients will not • Comparing SGAs head-to-head to appear, risk legal action.5 Since it has respond to an SGA, including cloza- establish differential effects (especially been generally accepted that SGAs have pine, or will respond initially but then in FGA-naïve patients) a lower risk of TD, the use of an FGA relapse even with a higher dose. If a • Using lower potency FGAs in low- before an SGA may now carry legal risk patient does not respond to trials of at to-medium doses for the prescriber. First-line treatment least 2 different SGAs, switching to an • Including adherence assessments to with an SGA is now widely considered FGA may then make sense. After treat- minimize intermittent treatment ef- the standard of care for schizophrenia.5 ment failure with SGAs, the potential fects and withdrawal dyskinesia In 2 classic malpractice cases involving benefit of antipsychotic efficacy would TD after antipsychotic treatment, the outweigh the increased risk of TD. ECONOMIC COST OF TD defense lacked 2 elements of good care: However, the ultimate decision Managed care programs usually informed consent and documentation belongs to the patient, who may require patients to seek care through of valid medical reasons for the antipsy- remain undisturbed by TD or prefer it primary care providers.16 As more chotic treatment decision, including to the risk of psychotic relapse inher- individuals are covered by managed adequate consideration of TD.87 ent in any medication switch.18,89 care plans, more antipsychotic pre- Informing family members about When an antipsychotic is prescriptions will come from primary care signs of TD can also aid in early scribed, documentation of the medical physicians.16 Yet primary care physi- detection.5 reasons is essential. Every time a cians do not receive adequate training patient is reassessed, a lack of adverse in the use of antipsychotics and the ETHICAL CONSIDERATIONS effects could be considered an oppor- need for periodic examination for IN RECOMMENDED tunity to lower the dose to reduce the TD.16 Clinicians need to be aware of ANTIPSYCHOTIC TREATMENT adverse effect risk.81 Therefore, the subtleties in prescribing and the poten- Most long-term incidence studies rationale not to change treatment tial costs of TD. have focused on FGAs and have clear- must be documented, as well as any Numerous costly studies over many ly linked TD with FGA use. However, decision to change it. years have failed to establish a univer- the link with SGA use has been neither The risk of TD with long-term use sally effective treatment, and research fully established nor disproved. Thus of antipsychotics, especially FGAs, is a costs continue. TD imposes costs of we are not certain about SGAs, but we concern for all clinicians who pre- medical care, disability, and lost produc- know FGAs carry a high risk of TD. scribe these powerful drugs. SGAs tivity. The economic costs of inadequate SGAs are generally recommended over have been shown to have lower risk solutions are accompanied by costs of FGAs except when the SGAs fail in for motoric adverse effects than FGAs, human suffering for patients and their efficacy, tolerability, or patient prefer- and have become the preferred first- families. Even if the incidence of TD is ence.45 Clinicians can choose agents line treatment for schizophrenia. lower with SGAs than FGAs, TD and its from the SGA class with differing risks Physicians, patients, and families need costs may continue to rise as the rate of and benefits according to the clinical education on TD risks, symptoms, utilization of antipsychotics rises. needs of a given patient. With the high- management, and outcomes. Clini- With the increased use of antipsy- er TD risk posed by FGAs, using SGAs cians must consider TD before pre- chotics, including off-label use, the as first-line treatment for antipsychot- scribing antipsychotics, examine for it costs and frequency of lawsuits that ic-naïve patients is recommended.8,45 periodically, and be prepared to modi- allege inappropriate prescribing have Every patient is different and treat- fy the treatment plan if the first signs increased.5 Clinicians who do not ment should always be individualized. emerge.

10 DECISION MAKER FORUM IN MANAGED CARE

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