TARDIVE SYNDROMES PHENOMENOLOGY, PATHOPHYSIOLOGY, AND MANAGEMENT

Cynthia Comella, MD, FAAN, FANA Professor of Neurological Sciences Rush University Medical Center Chicago, IL, USA Science never solves a problem without creating ten more George Bernard Shaw Objectives

 To describe the history of Tardive

 To discuss epidemiology, risk factors and possible pathophysiologic mechanisms of tardive syndromes

 To demonstrate the varied phenomenology of TD

 To discuss treatment options for TD RECEPTOR BLOCKING AGENTS (DRBA) AND TARDIVE DYSKINESIA

 Described in 1950’s within 5 yrs of development of for

 Initial descriptions were drug induced parkinsonism

 Subsequently orobuccal-lingual movements persisting beyond discontinuation

 Continuous persistent movements in other regions subsequently described (limbs, face

 Term “tardive dyskinesia” in 1964

Frei K, Truong D, Fahn S, Jankovic J, Hauser R. J Neurol Sci 2018 Factor et al. Lancet 2019 DOPAMINE RECEPTOR BLOCKING AGENTS: ASSOCIATED MOVEMENT DISORDERS

 Acute disorders  Acute  Oculogyric crisis

 Sub-acute disorders  Neuroleptic malignant syndrome   Parkinsonism

 Tardive disorders  /  Dystonia  Akathisia  (, , ) Dystonia Akathisia Neuroleptic Malignant Characteristic Tardive Dyskinesia Acute Tardive Acute Tardive Parkinsonism Syndrome Hours to Weeks to Days to Weeks to Days or weeks to Typical time to onseta Weeks to yearsb Hours to weeks days years months years years

Choreoathetotic (irregular, dancelike), athetotic (slow, writhing), Tremor and/or and/or stereotypic bradykinesia; also, (repetitive, purposeless) rigidity of neck, Pulling, twisting, sustained, movements of the mouth, trunk, and and repetitive movements or jaw, tongue, and face Inner feeling of restlessness extremities, Generalized “lead- postures that are usually (mouth/jaw chewing, with urge to move and hypomimia, reduced pipe” rigidity with focal, involving the head, tongue protrusion, inability to maintain seated; blink rate, reduced tremor (less Movement neck, eyes, mouth, jaw, grimacing, lip smacking or may be associated with arm swing, flexed frequently: various phenomenology tongue, and face (torticollis, pursing, blepharospasm); such as foot posture, and , trismus, jaw opening, also, and choreoathetotic tapping, shuffling, shifting shuffling or freezing dystonia, or grimacing, blepharospasm or and/or stereotypic weight, or rocking gait; also, rabbit myoclonus) oculogyric crisis, tongue movements of neck, trunk, syndrome (a protrusion, biting, or twisting) and extremities (piano- parkinsonian variant playing finger/hand that includes jaw movements, foot tapping, tremor) truncal rocking or thrusting)

Jankovic et al, CNS Spectrums 2020 submitted Tardive Dyskinesia: DSM-5

Tardive Dyskinesia: 333.85 (G24.01)

 Involuntary movements (lasting at least a few weeks)  generally of the tongue, lower face and jaw, and extremities  developing in association with the use of a neuroleptic medication for at least a few months.  Shorter exposure particularly in older individuals  Persistent movements after this time point consistent with Tardive dyskinesia  Withdrawal emergent dyskinesia can occur with dose reduction or discontinuation but resolve in 4-8 weeks

Tardive Dystonia 333.72 (G24.09) Tardive Akathisia (G25.71)

 Tardive syndrome involving other types of movement problems

American Psychiatric Association, 2013 Epidemiology

 Percent by phenomenology  Tardive dyskinesia: 30% of pts on (20- 50%)  Tardive akathisia: 20%  Tardive dystonia: 5-15%  Others are rare

 Long term risk  25% in 5 years  49% in 10 years  68% in 25 years Acquino and Lang. Parkinsonism Rel Disord 2014 Lerner et al. Psychiatr Clin Neurosci 2015 Type of agent

 3 year incidence of Tardive dyskinesia

Risk of TD Drug type Incidence of TD in 3 years HIGH Traditional antipsychotics 9%

MEDIUM 6%

LOW , , 3% ,

(Novick et al, 2010, Baldessarin and Gardner, 2011) Prevalance in US 2011-2015

Loughlin et al. PLOS ONE 2019 TD in the United States (2011-2015)

 Retrospective observational study Optum EHR Database  Review of 164,417 with new or repeat antipsychotic medication prescriptions  Documentation of TD if present  1314 identified through diagnosis in clinical notes  Annual prevalence TD in patients on DRBA 18-20 patients per 1000  79.8% received atypical antipsychotics  Quetiapine, risperidone, , olanzapine

Loughlin et al. PLOS ONE 2019 Prospective study comparing Olanzapine to conventional antipsychotics

 231 patients with dementia and psychosis without TD (mean age 78 years, 53 % women)

 Open label

 Randomized to olanzapine (2.5-20, 118 mg/day CPZ) or conventional antipsychotic (118 mg/day CPZ equivalents)

 Treatment for up to 1 year

 Primary outcome: persistent TD ( > 1 month)

Bruce J. Kinon et al. J Geriatr Neurol 2014;28:67-79 The Kaplan-Meier curves of time to tardive dyskinesia (TD) by varying degrees of dyskinesia severity and duration (P values are from log-rank exact test).

 Incidence of persistent TD of 2.5%. No difference OLZ vs CNV

Bruce J. Kinon et al. J Geriatr Psychiatry Neurol 2014;28:67-79 DRBA’s associated with TD

 Typical and some “atypical” antipsychotics  (chlorpromazine, , , )  Thioxanthenes (thiothixene (Navane®))  Butyrophenones (, (Haldol®))  Diphenyl butylpiperidine ( (Orap®))  Thiennobenzodiazepine: (olanzapine (Zyprexa®))  Pyrimidinones ( risperdone (Risperdal®), iloperidone (Fanapt®), ziprasidone (Geodone®)  Quinolinone (aripiprazole (Abilify®))

Martino et al. Can J Psych 2018 DRBA’s associated with TD

 DRBAs that are not considered antipsychotics but can cause TD  Substituted benzamides ( (Reglan))  Tricyclic antidepressant ( metabolites)  Calcium channel blockers (flunarizine, cinnarizine)

 General rule:  Drugs that can induce parkinsonism, can cause tardive dyskinesia with the exception of DA depletors. TD: risk factors

 Risk factors  Increasing age (except for tardive dystonia)  Increased incidence, prevalence  Worse severity  Less likely to resolve  Female gender especially for oral-lingual buccal movements  Longer duration of exposure  More potent DRBAs: High affinity for D2 receptors  Dose (chlorpromazine equivalents) TD: Clinical Characteristics

 Dyskinetic Movements:  Stereotypies  Chorea  Dystonia: usually focal or segmental  Retrocollis, opisthotnic posturing, truncal involvement  Oromandibular and lingual  Akathisia

 Often combinations of movement (complex) Tardive Dyskinesia: Chorea/stereotypy

 Distribution  Oral-lingual buccal movements  Distal limbs  Trunk  Respiratory

 Pattern  Complex chewing movements, tong popping, piano-playng fingers and toes, truncal rocking, marching in place, respiratory dyskinesia  Usually repetitive (stereotypy > chorea)  Movements often suppressed by voluntary tasks  Increased with stress  Variably distractible

 Disability  Significant disability, both functional and social with more severe symptoms  Dentition

Tardive dystonia

 Distribution  Sustained muscle contractions, frequently with twisting component  Abnormal postures, especially back arching and retrocollis  Often seen in association with classical lingual-facial-buchal movements  Extremities can be involved  Painful in many instances

 Pattern  Slow and sustained  Geste antagoniste can be present  In contrast to classical Tardive Dyskinesia, younger males are highest risk group  Action exacerbated.

 Disability  Can be painful and highly limiting in terms of sitting and walking  Much more concerning to patients than classical tardive dyskinesia movements

Tardive akathisia

 Distribution  Leg and body restlessness: patient volitionally moves to relieve symptoms  Often with classical lingual-facial buccal movements

 Pattern  Leg kicking, truncal rocking  Walking about and pacing relieves discomfort.

 Disability  Distressful and very uncomfortable for patients  Particular trouble sitting in a chair or standing in lines  Early reports linked tardive akathisia to suicide risk  Newer reports do not support links to suicide Tardive akathisia Tardive syndrome overlaps

 Combinations of dyskinesia/stereotypy, dystonia and akathisia frequent in tardive syndromes

 These combinations are of great diagnostic importance and highly suggestive of tardive syndromes. Diagnosis

 History of exposure DRBA for a few months

 Chorea, stereotypy, dystonia, akathisia usually in combinations temporally associated with DRBA

 Often worsens with reduction in DA blocker, improves with increased dose DA blocker

 Absence of other diagnoses

 Chorea/stereotypy type tardive dyskinesia  Huntington’s disease and other neurodegenerative conditions  Hepatolenticular degeneration  Stereotypies of psychosis  Edentulous dyskinesia  Paraneoplastic dyskinesias  Immune or metabolic dyskinesia  SLE, thyroid, pregnancy, Sydneham’s chorea  Infectious  HIV  Drugs causing dyskinesia (not tardive):  Levodopa, tricyclics and other antidepressants, lithium, phenytoin Differential diagnosis

 Tardive dystonia  Primary  Wilson’s disease  Secondary dystonias related to neurodegeneration  Drug induced

 Tardive akathisia  Primary akathisia  Restlessness related to psychosis  Restless leg syndrome Management: Prevention

 Very judicious use of DRBAs, including the not so atypical atypicals and metoclopramide

 Use of more atypical antipsychotics  Clozapine  Quetiapine  No antipsychotic is devoid of risk  Pimavanserin

 Caution in pediatric population

 Collaboration between psychiatrists and neurologists for early signs of TD in patients treated with DRBAs Management: Withdrawal and recurrence

 Antipsychotic withdrawal may be associated with withdrawal emergent dyskinesia that may improve or resolve  Up to 1 year

 Recurrence of TD following discontinuation of DRBA  Past studies suggested resolution in 37-40% patients  Most in these studies were continued on DRBAs

 Recent study in 108 patients with TD  Mood disorders (38%), GI illnesses (38%), psychotic disorders (6.48%)  Complete withdrawal of DRBA  Reversible TD in 13%  Only 2.8% resolved completely; up to 2.3 years for resolution

Zutshi, Cloud, Factor. Tremor Other Hyperkinet Mov 2014 Aquino, Lang. Parkinism and rel Disord 2014 Lerner et al. Psych Clin Neurosci 2015 Shireen et al. Exp Pharmacol, 2016 VMAT2 inhibitors for Tardive Dyskinesia

Vesicular monoamine transporter 2 (VMAT2) inhibitors: Mechanism of Action

Jankovic J. Nature Reviews Neurology 2017 Tetrabenazine

 Developed in 1950’s

 FDA approval Huntington disease related chorea

 Small controlled studies in TD  Improvement in movement

 Important adverse events  Sedation  Parkinsonism  Depression  Akathisia  suicidality

Scorr LM, Facot SA. J Neurol Sci 2018 Valbenazine FDA approved for TD April 2017

Bind 5-HT1, 5-HT2b, 5-HT7 Selective VMAT2 inhibition Inhibits D2 receptors

Gigoriadis et al. J Pharmacol Exp Therapeut, 2017 Seeberger and Hauser. Exp Opinion Pharmacother 2017 Kim ES. Drugs 2017 Davis et al, NEJM 2017 Kinect 3

. Inclusion:  , schizoaffective disorder, mood disorder  Moderate to severe tardive dyskinesia . Primary outcome: change in AIMS assessed by central video raters (experts in Movement disorders)  Videos randomized to study visit Kane et al. Psychopharmacol Bull 2017 Kinect 3: Valbenazine

Change in AIMS score (1-7) from baseline

Percent with > 50% improvement on AIMS

Hauser et al. Am J Psychiatr, 2017 Kinect 3: Valbenazine in TD

Davis et al. N Engl J Med, 2017 Kane et al. Psychopharmacol Bull 2017 Kinect 4: Safety

 Open label, 48 weeks treatment, 4 week wash out

 N= 167, 103 completed (26 discontinued for AE’s)

 Treatment related side effects in 65%

 UTI, headache.

 Discontinuation suicidal ideation (3), fatigue (2), schizophrenia (2)

Singer et al. Poster. PAS MDS Congress 2018 Marder et al. in press Move Disord 2018 Valbenazine: Safety Note

Valbenazine dose should be reduced to 40 mg/day in patients who are concomitantly receiving a potent CYP3A4 inhibitor (e.g., ketoconazole, itraconazole, clarithromycin). Coadministration with a potent CYP3A4 inducer (e.g., rifampin, phenytoin, carbamazepine, St. John’s wort) is not recommended because of the potential for reduced exposure. Deutetrabenzine FDA approved TD August 2017

Deuterated form doubles the half life of active metabolites of tetrabenazine • 2-fold increase in systemic exposure, decrease plasma fluctuations • Can give in lower doses than tetrabenazine Stamler et al. Neurology 2015 Deutetrabenazine in TD: AIM study (ARM study with similar results)

 DBPC, randomized

 3 doses DTB vs

placebo AIMS score AIMS  AIMS primary

 222 TD patients included

Anderson et al. Lancet Psychiatry, August 2017 Deutetrabenazine in TD: AIM study

Anderson et al. Lancet Psychiatry, August 2017 Mean change in AIMS score over the long-term treatment period.

Fernandez et al. J Neurol Neurosurg Psychiatry JNNP 2018 Percentage of patients at each deutetrabenazine dose level over the long-term treatment period.

Fernandez et al. J Neurol Neurosurg Psychiatry JNNP 2018 Metanalysis new VMAT2 agents

Salmi et al. Drug Des Devel Ther 2018 Summary

Tetrabenazine Valbenazine Deutetrabenazine Half Life Short Long Medium (T ½ = 4.8 hours) (T ½= 20 hours) (T ½ = 8.6 hours) Efficacy ++ +++ +++ Dosing tid nightly bid Side effects ++++ + + Sedation Sedation Headache Depression Sedation Suicidal ideation Akathisia Parkinsonism Prolonged QTc Orthostatic hypotension Treatment of persistent signs

 Decrease or stop anticholinergic drugs  Cholinesterase inhibitors (Donezepil successful in small series)  Switch to clozapine: mixed evidence (Factor and Friedman, 1997)  Amantadine-mild effect (Angus, 1997)  Levetiracetam (2000 mg/d) one report (Meco et al 2006)  : inconclusive evidence (Cochran Review, 2006)  E: 1200-1600 IU daily—inconclusive (Pierre, 2005)  Ginko baloba  Zolpidem in case series (Wahn and Jankovic. Mov Disord 2013) Factor et al. Lancet Neurology 2019 (in press) Maybe next year?