Tardive Dyskinesia and Drug-Induced
Parkinsonism Are Distinct:

Pathophysiology & Clinical Implications

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This newsletter is produced by Teva Pharmaceuticals and the patient pictured above has been compensated for the use of their image.

Mechanism of Disease
Exploring the Mechanisms Behind Tardive Dyskinesia and Drug-Induced Parkinsonism
Tardive Dyskinesia Overview
Tardive dyskinesia (TD) is a movement disorder characterized by involuntary, repetitive body movements that most often affect the mouth and face but can occur throughout the body.1 TD occurs in patients being treated with either typical or atypical antipsychotic drugs (APDs) primarily for psychosis, bipolar disorder, or major depressive disorder; it also occurs in patients taking certain prokinetic and antiemetic agents.2-5
Symptoms of TD occur with a delayed onset, and these clinical manifestations may be persistent, even when the causative agent is discontinued.6,7 Although TD is relatively common and occurs in approximately 30% of patients taking antipsychotics, it may go undiagnosed, resulting in impacts to the patient's psychiatric stability, psychosocial interactions, and physical and functional status.1
What Are Extrapyramidal Symptoms? EPS has been commonly used as a general term to describe antipsychotic-induced movement disorders including TD, drug-induced parkinsonism (DIP), akathisia, and dystonia.8 However, in the clinical setting, EPS commonly refers to DIP.8 DIP has a prevalence of 20% to 35% in patients taking APDs.9
It is important to be able to effectively distinguish DIP and TD as they are caused by largely opposite mechanisms, and thus require different treatment approaches.9 Choosing the wrong treatment based on an inaccurate diagnosis can make the patient's symptoms worse.9
The Roles of Dopamine and Acetylcholine
Within the brain, dopamine plays a central role in modulating both movement and mood/psychosis.10,11 Movement depends on two pathways that emerge from the striatum – the direct pathway (which "turns up" motor activity) and the indirect pathway (which "turns down" motor activity).12,13 Mood and psychosis are modulated via dopamine in the mesolimbic pathway.11,14,15
In addition to dopamine, acetylcholine also has significant activity within the motor pathways.16 Each of these neurotransmitters has an opposite effect on movement.17 The net result of increased dopaminergic activity within the two pathways is an increase in movement.16 Conversely, the net result of decreased dopaminergic activity in the two pathways is a decrease in movement.18 With respect to acetylcholine, the net result of increased cholinergic activity in the two pathways is a decrease in movement.19
The Opposing Mechanisms of TD and DIP
Although TD and DIP are both movement disorders, they occur due to opposite mechanisms within the dopaminergic pathways.9 TD can be considered a state of persistent hypersensitivity to dopamine and is thought to occur when the blockade of dopamine (as accomplished by APDs) upregulates the number of dopamine receptors in the motor pathways, subsequently increasing dopamine signaling.9,20 Due to the propensity of the brain to hyperrespond to the increase in dopamine signaling, hyperkinetic movements associated with TD may begin to appear.21 On the other hand, DIP occurs when the blockade of dopamine reduces dopamine signaling, subsequently resulting in hypokinetic movement such as bradykinesia.9 Each of these occurs on a different time scale – DIP typically occurs in the acute phases of treatment, whereas TD presents in a delayed fashion.9
Given their opposing mechanisms, effective management of TD and DIP requires an accurate diagnosis, lest the wrong treatment choice make the patient's symptoms worse.9 In addition, given the connection between mood/psychosis and movement, consideration needs to be given regarding any treatment decisions that may affect postsynaptic dopamine modulation within the mesolimbic pathway to ensure that the stability of the patient's mental health is not compromised.7,22

References
1. Caroff SN, Campbell EC, Carroll B. Pharmacological treatment of tardive dyskinesia: recent developments. Expert Rev Neurother. 2017;17(9):871-881. 2. Lehman AF, Lieberman JA, Dixon LB, et al; American Psychiatric Association Steering Committee on Practice Guidelines. Practice guideline for the treatment of patients with schizophrenia, second edition. Am J Psychiatry. 2004;161(2 suppl):1-56. 3. Hirschfeld RM, Bowden CL, Gitlin MJ, et al; American Psychiatric Association Steering Committee on Practice Guidelines. Practice guideline for the treatment of patients with bipolar disorder, second edition. Accessed January 29, 2020. http://psychiatryonline.org/pb/assets/raw/sitewide/practice_guidelines/guidelines/bipolar.pdf 4. Gelenberg AJ, Freeman MP, Markowitz JC, et al; American Psychiatric Association Steering Committee on Practice Guidelines. Practice guideline for the treatment of patients with major depressive disorder, third edition. Accessed January 29, 2020. http://psychiatryonline.org/pb/assets/raw/sitewide/practice_guidelines/guidelines/mdd.pdf 5. Avalos DJ, Sarosiek I, Loganathan P, McCallum RW. Diabetic gastroparesis: current challenges and future prospects. Clin Exp Gastroenterol. 2018;11:347-363. 6. Kim J, MacMaster E, Schwartz TL. Tardive dyskinesia in patients treated with atypical antipsychotics: case series and brief review of etiologic and treatment considerations. Drugs Context. 2014;3:212259. 7. Caroff SN, Miller DD, Dhopesh V, Campbell EC. Is there a rational management strategy for tardive dyskinesia? Decisions should be based on the course of TD and effective control of psychotic symptoms. Curr Psychiatry. 2011;10(10):22-32. 8. Frei K, Truong DD, Fahn S, Jankovic J, Hauser RA. The nosology of tardive syndromes. J Neurol Sci. 2018;389:10-16. 9. Ward KM, Citrome L. Antipsychotic-related movement disorders: drug-induced parkinsonism vs. tardive dyskinesia—key differences in pathophysiology and clinical management. Neurol Ther. 2018;7(2):233-248. 10. van Harten PN, Bakker PR, Mentzel C, Tijssen MA, Tenback DE. Movement disorders and psychosis, a complex marriage. Front Psychiatry. 2015;5:190. 11. Ruhé HG, Mason NS, Schene AH. Mood is indirectly related to serotonin, norepinephrine and dopamine levels in humans: a meta-analysis of monoamine depletion studies. Mol Psychiatry. 2007;12(4):331-359. 12. Shin JH, Kim D, Jung MW. Differential coding of reward and movement information in the dorsomedial striatal direct and indirect pathways. Nat Commun. 2018;9(1):404. 13. Zai CC, Maes MS, Tiwari AK, Zai GC, Remington G, Kennedy JL. Genetics of tardive dyskinesia: promising leads and ways forward. J Neurol Sci. 2018;389:28-34. 14. Yang AC, Tsai SJ. New targets for schizophrenia treatment beyond the dopamine hypothesis. Int J Mol Sci. 2017;18(8):1689. 15. Settell ML, Testini P, Cho S, et al. Functional circuitry effect of ventral tegmental area deep brain stimulation: imaging and neurochemical evidence of mesocortical and mesolimbic pathway modulation. Front Neurosci. 2017;11:104. 16. Lester DB, Rogers TD, Blaha CD. Acetylcholine-dopamine interactions in the pathophysiology and treatment of CNS disorders. CNS Neurosci Ther. 2010;16(3):137-162. 17. Howe M, Ridouh I, Allegra Mascaro AL, Larios A, Azcorra M, Dombeck DA. Coordination of rapid cholinergic and dopaminergic signaling in striatum during spontaneous movement. Elife. 2019:8:e44903. 18. Gobira PH, Ropke J, Aguiar DC, Crippa JA, Moreira FA. Animal models for predicting the efficacy and side effects of antipsychotic drugs. Braz J Psychiatry. 2013;35(suppl 2):S132-S139. 19. Hagino Y, Kasai S, Fujita M, et al. Involvement of cholinergic system in hyperactivity in dopamine-deficient mice. Neuropsychopharmacology. 2015;40(5):1141-1150. 20. Chouinard G, Samaha AN, Chouinard VA, et al. Antipsychotic-induced dopamine supersensitivity psychosis: pharmacology, criteria, and therapy. Psychother Psychosom. 2017;86(4):189-219. 21. Waln O, Jankovic J. An update on tardive dyskinesia: from phenomenology to treatment. Tremor Other Hyperkinet Mov (NY). 2013;3. pii: tre-03-161-4138-1. 22. Bhidayasiri R, Fahn S, Weiner WJ, Gronseth GS, Sullivan KL, Zesiewicz TA; American Academy of Neurology. Evidence-based guideline: treatment of tardive syndromes: report of the Guideline Development Subcommittee of the American Academy of Neurology. Neurology. 2013;81(5):463-469.

This newsletter is produced by Teva Pharmaceuticals and the patient pictured above has been compensated for the use of their image.

Clinical Insights
Clinical Implications of Tardive Dyskinesia and Drug-Induced Parkinsonism
The Impact of Growing Antipsychotic Use
In 1989, the first atypical antipsychotic drug (APD) was approved for treatment-resistant schizophrenia.1 It was postulated that the different D2-binding profile of atypical agents would result in less tardive dyskinesia (TD) and drug-induced parkinsonism (DIP), compared with the typical APDs that preceded them.2 However, since that time, studies have shown that atypicals may still contribute to the development of TD.3
In the United States, TD affects ∼785,000 patients and is growing
In an analysis of patients treated with APDs, the annualized incidence of TD across all typical APD treatment groups was 6.5%; the annualized incidence of TD across all atypical APD treatment groups was 2.6%.4 In a separate meta-analysis that involved the prevalence of TD in patients treated with atypical APDs, 7.2% of patients without prior typical APD use had TD compared with 30.2% of patients treated with typical APDs.5 Overall, 20.7% of patients treated with atypical APD monotherapy included in the meta-analysis had TD.5
In the early 2000s, there was a significant uptick in use of the atypical APDs due to US Food and Drug Administration (FDA) approvals for mood disorders.6 As a result, these agents are increasingly used to treat a variety of conditions beyond schizophrenia, including bipolar disorder (first approval in 2000) and major depressive disorder (first approval 2007).6-8 This heightened usage is evidenced by a >230% increase in the total number of patients prescribed APDs from 1997 (2.2 million patients) to 2022 (8.7 million patients).9-11
Today, despite the lower risk of TD seen with atypical APDs, the incidence of TD continues to increase and is estimated to affect approximately 785,000 patients in the United States.12
TD vs DIP: Treatment Considerations
In clinical practice, differentiating TD and DIP may be challenging, but it is very important from a management perspective.13
TD
DIP

This newsletter is produced by Teva Pharmaceuticals and the patients pictured above have been compensated for the use of their footage.

TD and DIP both result from APD use, but they arise from different mechanisms.13 As such, the appropriate treatment for each is different, which means that proper diagnosis is essential. An inaccurate diagnosis and subsequent choice of the wrong treatment may result in a worsening of the patient's movement disorder.13
According to the Diagnostic and Statistical Manual of Mental Disorders 5th edition diagnostic criteria for TD and DIP, the movement disorders have distinct differences.14
In patients with TD, decreasing the dosage of the antipsychotic therapy is unlikely to resolve the TD and can lead to destabilization of the patient's psychosis or mood disorder.15,16 Increasing the dosage of the antipsychotic therapy may temporarily improve symptoms by masking the effects of TD; however, over time, this is likely to make the TD worse.15,16
In comparison, patients with DIP may not respond well to increased dosages of antipsychotic therapy, and, due to further blockade of dopamine regulation, they may experience worsened symptoms of DIP.13 Conversely, decreasing the dosage of the antipsychotic therapy is likely to improve the symptoms13; however, as with decreasing the dose of the APD in patients with TD, this approach can again lead to destabilization of the patient's underlying mental health disorder.15
Vesicular monoamine transporter 2 (VMAT2) inhibitors are approved by the FDA for the treatment of TD,13,17 whereas anticholinergics are approved for treating patients with DIP.13 In some cases, using anticholinergics to treat patients with TD may worsen symptoms. Likewise, using VMAT2 inhibitors in patients with DIP may worsen their parkinsonian symptoms.13
VMAT2 inhibitors work by blocking the transporter that packages neurotransmitters, particularly dopamine, into presynaptic vesicles for release into the synaptic cleft.18 Using a VMAT2 inhibitor allows patients to treat their TD while continuing to receive optimal antipsychotic therapy.19 This option bypasses the situation where a physician might compromise the underlying psychiatric stability of the patient while simultaneously attempting to treat the TD.15
References
1. Sahni S, Chavan BS, Sidana A, Kalra P, Kaur G. Comparative study of clozapine versus risperidone in treatment-naive, first-episode schizophrenia: a pilot study. Indian J Med Res. 2016;144(5):697-703. 2. Divac N, Prostran M, Jakovcevski I, Cerovac N. Second-generation antipsychotics and extrapyramidal adverse effects. Biomed Res Int. 2014;2014:656370. 3. Cornett EM, Novitch M, Kaye AD, Kata V, Kaye AM. Medication-induced tardive dyskinesia: a review and update. Ochsner J. 2017;17(2):162-174. 4. Carbon M, Kane JM, Leucht S, Correll CU. Tardive dyskinesia risk with first- and second-generation antipsychotics in comparative randomized controlled trials: a meta-analysis. World Psychiatry. 2018;17(3):330-340. 5. Carbon M, Hsieh CH, Kane JM, Correll CU. Tardive dyskinesia prevalence in the period of second-generation antipsychotic use: a meta-analysis. J Clin Psychiatry. 2017;78(3):e264-e278. 6. Pillarella J, Higashi A, Alexander GC, Conti R. Trends in use of second-generation antipsychotics for treatment of bipolar disorder in the United States, 1998-2009. Psychiatr Serv. 2012;63(1):83-86. 7. Wenthur CJ, Lindsley CW. Classics in chemical neuroscience: clozapine. ACS Chem Neurosci. 2013;4(7):1018-1025. 8. Wang SM, Han C, Lee SJ, et al. Second generation antipsychotics in the treatment of major depressive disorder: an update. Chonnam Med J. 2016;52(3):159-172. 9. Stagnitti MD. Agency for Healthcare Research and Quality. Statistical Brief No. 275. 2010. 10. IQVIA Antipsychotic Data Report 2019. 11. Data on file. Teva Neuroscience, Inc. 12. Dhir A, Schilling T, Abler V, et al. Estimation of epidemiology of tardive dyskinesia incidence and prevalence in the United States. Presented at: The American Academy of Neurology 2017 Annual Meeting; April 22-28. 2017; Boston MA. 13. Ward KM, Citrome L. Antipsychotic-related movement disorders: drug-induced parkinsonism vs. tardive dyskinesia—key differences in pathophysiology and clinical management. Neurol Ther. 2018;7(2):233-248. 14. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Washington, DC; 2013. 15. Caroff SN, Mu F, Ayyagari R, Schilling T, Abler V, Carroll B. Hospital utilization rates following antipsychotic dose reductions: implications for tardive dyskinesia. BMC Psychiatry. 2018;18(1):306. 16. Bergman H, Rathbone J, Agarwal V, Soares-Weiser K. Antipsychotic reduction and/or cessation and antipsychotics as specific treatments for tardive dyskinesia. Cochrane Database Syst Rev. 2018;2:CD000459. 17. Mosley LL, Mosley JF, Fleischfresser JR, Reed T. Vesicular monoamine transporter type 2 (VMAT2) inhibitors in the management of tardive dyskinesia. Clin Med Rev Case Rep. 2017;4:198. 18. Karl B, Bergman H, Abd El Sayed S, Adams CE. Vesicular monoamine transporter inhibitors versus placebo for antipsychotic-induced tardive dyskinesia. Cochrane Database Syst Rev. 2018;3:CD012986. 19. Caroff SN. Overcoming barriers to effective management of tardive dyskinesia. Neuropsychiatr Dis Treat. 2019;15:785-794.
Treatment
AUSTEDO XR for Tardive Dyskinesia
Tardive Dyskinesia: A Brief Overview
Tardive dyskinesia (TD) is a movement disorder that occurs in patients treated with typical or atypical antipsychotic drugs (APDs),1 primarily for psychosis, bipolar disorder, or major depressive disorder.2-4 The condition typically presents with a delayed onset and may be irreversible.5,6 For these patients, APDs can be life changing; any presentation of TD may have a negative impact on patient lives and can complicate the management of mental health disorders.7,8
AUSTEDO XR is a VMAT2 inhibitor indicated for the treatment of TD in adults
AUSTEDO XR for TD in Adults
AUSTEDO XR is a vesicular monoamine transporter 2 (VMAT2) inhibitor indicated for the treatment of TD in adults.9 AUSTEDO XR contains deutetrabenazine, a deuterated form of tetrabenazine,9,10 and it is the first deuterated drug to be approved by the US Food and Drug Administration.11
VMAT2 Inhibition: Mechanism of Action
Maintaining a balance in the level of dopamine is essential for controlled movement.12 Dopamine signaling is facilitated by VMAT2, which transports monoamines, including dopamine, from the cytosol into synaptic vesicles, keeping them ready for subsequent release in response to an action potential.13
When an action potential reaches the nerve terminal of the presynaptic neuron, dopamine is released from the synaptic vesicles into the synaptic cleft and binds to receptors on the postsynaptic neuron, thereby signaling movement.14 Excess dopamine signaling manifests as abnormal involuntary movements.15
Deutetrabenazine binds to VMAT2 on the vesicle in the presynaptic neuron and inhibits the uptake of dopamine into synaptic vesicles.16 Dopamine molecules collect outside the blocked VMAT2 and are degraded in the cytosol by monoamine oxidase.16 Reducing dopamine levels in the presynaptic neuron results in less dopamine signaling to the postsynaptic neuron.17 Limiting dopamine signaling is believed to lead to fewer abnormal involuntary movements.17
See how the VMAT2 inhibition of AUSTEDO XR reduces dopamine levels:
Clinical Trials in TD
AUSTEDO has been studied in 2 pivotal, placebo-controlled clinical trials, Aim to Reduce Movements in Tardive Dyskinesia (ARM-TD) and Addressing Involuntary Movements in Tardive Dyskinesia (AIM-TD), to determine its effects on reducing involuntary movements in adult patients with TD (N=335).9,18,19 ARM-TD Trial (N=113) Flexible-dose trial in which patients were titrated to an individualized dose that reduced abnormal movements and was tolerated.9,18 The primary endpoint was the change from baseline (defined for each patient as the value from the day 0 visit) to Week 12 in the Abnormal Involuntary Movement Scale (AIMS) total score (sum of items 1 through 7), as assessed by blinded central video rating.9,18 Higher AIMS scores are indicative of more severe dyskinesia.9 ARM-TD Results Treatment with AUSTEDO resulted in a statistically significant greater improvement in AIMS total score compared with placebo.9,18 Patients receiving AUSTEDO improved by 3.0 points from baseline at Week 12, compared with 1.6 points for patients in the placebo group, for a treatment effect of −1.4 points (P=0.019).9,18
Change in AIMS Total Score From Baseline to Week 12 (N=113; P=0.019)
  • Baseline AIMS total scores were similar between AUSTEDO and placebo
      - AUSTEDO 9.7 (SD, 4.1)
      - Placebo 9.6 (SD, 3.8)
  • AUSTEDO significantly reduced AIMS total score by 3.0 points (vs 1.6 in the placebo group) at Week 12, (P=0.019, for a treatment effect of −1.4 points)
  • Mean AUSTEDO dose was 38.8 mg/day at the end of titration
The mean AUSTEDO dose among all patients in the modified intent-to-treat population was 38.8 mg/day at the end of the 6-week titration period and 38.3 mg/day at the end of treatment.18

Patients in the ARM-TD study received the AUSTEDO twice-daily (BID) formulation.
AIM-TD Trial (N=222) Fixed-dose, multi-arm trial in which patients were randomized 1:1:1:1 to 12 mg/day AUSTEDO, 24 mg/day AUSTEDO, 36 mg/day AUSTEDO, or placebo, respectively.9,19 The primary endpoint was the change in AIMS total score from baseline to Week 12 in the 36-mg/day group vs placebo, as assessed by blinded central video rating.9,19 AIM-TD Results Treatment with AUSTEDO significantly reduced the AIMS total score by 3.3 points from baseline in the 36-mg/day arm (vs 1.4 with placebo) at Week 12 (P=0.001 in the 36-mg/day group, treatment effect of −1.9 points).9,19 In an exploratory analysis, AIMS total score reduction was seen at 2 weeks.19
Change in AIMS Total Score From Baseline to Week 12 (N=222)
Patients in the AIM-TD study received the AUSTEDO BID formulation. Safety Results in Clinical Trials Across both pivotal trials, 4% of patients required dose reduction of AUSTEDO due to adverse events vs 2% of patients taking placebo.9 At baseline, 56% of patients treated with AUSTEDO across both studies were taking concomitant antidepressant therapy.20
ADVERSE REACTIONS REPORTED IN ≥2% OF PATIENTS TREATED WITH AUSTEDO20

Adverse reactions with AUSTEDO XR are expected to be similar to AUSTEDO.

In patients with TD, AUSTEDO demonstrated significant efficacy compared with placebo in reducing AIMS total score. In controlled clinical studies in patients with TD, the most common adverse reactions were nasopharyngitis and insomnia. AUSTEDO XR is a viable treatment option that allows for the continuation of antipsychotic treatment while concurrently treating the patient's TD.9,18,19
References
1. Loughlin AM, Lin N, Abler V, Carroll B. Tardive dyskinesia among patients using antipsychotic medications in customary clinical care in the United States. PLoS One. 2019;14(6):e0216044. 2. Lehman AF, Lieberman JA, Dixon LB, et al; American Psychiatric Association; Steering Committee on Practice Guidelines. Practice guideline for the treatment of patients with schizophrenia, second edition. Am J Psychiatry. 2004;161(2)(suppl):1-56. 3. Hirschfeld RM, Bowden CL, Gitlin MJ, et al. Practice guideline for the treatment of patients with bipolar disorder, second edition. Accessed February 11, 2020. http://psychiatryonline.org/pb/assets/raw/sitewide/practice_guidelines/guidelines/bipolar.pdf 4. Gelenberg AJ, Freeman MP, Markowitz JC, et al. Practice guideline for the treatment of patients with major depressive disorder, third edition. Accessed February 11, 2020. http://psychiatryonline.org/pb/assets/raw/sitewide/practice_guidelines/guidelines/mdd.pdf 5. Kim J, Macmaster E, Schwartz TL. Tardive dyskinesia in patients treated with atypical antipsychotics: case series and brief review of etiologic and treatment considerations. Drugs Context. 2014;3:212259. 6. Caroff SN, Miller DD, Dhopesh V, Campbell EC. Is there a rational management strategy for tardive dyskinesia? Decisions should be based on the course of TD and effective control of psychotic symptoms. Curr Psychiatry. 2011;10(10):22-32. 7. Caroff SN. Overcoming barriers to effective management of tardive dyskinesia. Neuropsychiatr Dis Treat. 2019;15:785-794. 8. McEvoy J, Carroll B, Gandhi S, et al. Effect of tardive dyskinesia on quality of life: patient-reported symptom severity is associated with deficits in physical, mental, and social functioning (143). Neurology. 2018;90(15)(suppl):89. 9. AUSTEDO® XR (deutetrabenazine) extended-release tablets/AUSTEDO® current Prescribing Information. Parsippany, NJ: Teva Neuroscience, Inc. 10. Meyer JM. Forgotten but not gone: new developments in the understanding and treatment of tardive dyskinesia. CNS Spectr. 2016;21(S1):13-24. 11. Dean M, Sung VW. Review of deutetrabenazine: a novel treatment for chorea associated with Huntington's disease. Drug Des Devel Ther. 2018;12:313-319. 12. Cepeda C, Murphy KP, Parent M, Levine MS. The role of dopamine in Huntington's disease. Prog Brain Res. 2014;211:235-254. 13. Lohr KM, Masoud ST, Salahpour A, Miller GW. Membrane transporters as mediators of synaptic dopamine dynamics: implications for disease. Eur J Neurosci. 2017;45(1):20-33. 14. Patri M. Synaptic Transmission and Amino Acid Neurotransmitters (chapter). IntechOpen. October 23, 2019. 15. Marsden CD. Dopamine and basal ganglia disorders in humans. Semin Neurosci. 1992;4(2):171-178. 16. Niemann N, Jankovic J. Treatment of tardive dyskinesia: a general overview with focus on the vesicular monoamine transporter 2 inhibitors. Drugs. 2018;78(5):525-541. 17. Stahl SM. Mechanism of action of vesicular monoamine transporter 2 (VMAT2) inhibitors in tardive dyskinesia: reducing dopamine leads to less "go" and more "stop" from the motor striatum for robust therapeutic effects. CNS Spectr. 2018;23(1):1-6. 18. Fernandez HH, Factor SA, Hauser RA, et al. Randomized controlled trial of deutetrabenazine for tardive dyskinesia: the ARM-TD study. Neurology. 2017;88(21):2003-2010. 19. Anderson KE, Stamler D, Davis MD, et al. Deutetrabenazine for treatment of involuntary movements in patients with tardive dyskinesia (AIM-TD): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Psychiatry. 2017;4(8):595-604. 20. Data on file. Teva Neuroscience, Inc.
Is It Tardive Dyskinesia or Drug-Induced Parkinsonism?
Leslie Citrome, MD, MPH

New York Medical College
Valhalla, New York

Q: Why is it important to accurately differentiate between tardive dyskinesia, or TD, and drug-induced Parkinsonism, or DIP?

A: The most important reason to differentiate between the two is that TD and DIP are treated differently—vesicular monoamine transporter 2, or VMAT2, inhibitor for TD and benztropine or an anticholinergic agent for DIP—and treatment for one can exacerbate the other.1 In addition, their prognoses are different—DIP will eventually resolve after discontinuation of the antipsychotic, which is not the case for TD.1

AUSTEDO XR may cause parkinsonism in patients with Huntington's disease or tardive dyskinesia. Parkinsonism has also been observed with other VMAT2 inhibitors. The risk of parkinsonism may be increased by concomitant use of dopamine antagonists or antipsychotics. If a patient develops parkinsonism, the AUSTEDO XR dose should be reduced; some patients may require discontinuation of therapy.

DIP movements are rhythmic and TD movements are irregular

Q: How can a clinician differentiate between TD and DIP?

A: There are a few simple ways to differentiate TD from DIP. First, carefully observe the movements—DIP movements are rhythmic while TD movements are choreoathetotic and irregular. Second, because DIP is frequently accompanied by rigidity,1 it is helpful to ask the patient to walk a few feet. If he/she demonstrates diminished arm swing, it is likely DIP.2 Also, TD and DIP have different onsets, with DIP typically occurring hours to weeks after antipsychotic initiation or dose increase and TD occurring months to years after antipsychotic initiation.1 In addition, if treatment with an anticholinergic agent improves symptoms, you can assume that it is DIP; if it worsens symptoms, it may be TD.1 Lastly, increasing the dose of the antipsychotic may temporarily improve TD but worsen DIP, while decreasing the dose will do the opposite.1

Q: How has benztropine historically been utilized in Psychiatry?

A: In some cases, psychiatrists have used benztropine prophylactically in order to prevent DIP; however, long-term use is not advisable because it can interfere with cognition, especially memory.1

Recent onset of rhythmic movement is suggestive of DIP

Q: In which situations would you refer a patient to a movement disorder specialist?

A: Let's consider an older patient, say over 60 years of age, who has been on an antipsychotic for many years with longstanding TD. A recent onset of rhythmic movements is suggestive of Parkinson's disease, or PD, rather than DIP if there has been no major change in the antipsychotic dose or if the patient is on a second-generation antipsychotic and if these symptoms continue upon a decrease in the dose or cessation of the antipsychotic drug.3 This would warrant a referral to a movement disorder specialist and, potentially, a DaTscan to rule out PD or a related condition involving neurodegeneration of the nigrostriatal neurons.4

Q: What is the role of AUSTEDO XR in the treatment of TD?

A: AUSTEDO XR, a VMAT2 inhibitor, is efficacious in the treatment of TD in adults.5 It is a viable treatment option that allows for the continuation of antipsychotic treatment while concurrently treating the patient's TD.5

References
1. Ward KM, Citrome L. Antipsychotic-related movement disorders: drug-induced parkinsonism vs. tardive dyskinesia—key differences in pathophysiology and clinical management. Neurol Ther. 2018;7(2):233-248. 2. Manage drug-induced parkinsonism through early recognition of the condition and discontinuation of the causative agent. Drugs Ther Perspect. 2012;28(12):20-23. 3. Shin HW, Chung SJ. Drug-induced parkinsonism. J Clin Neurol. 2012;8(1):15-21. 4. Cummings JL, Fine MJ, Grachev ID, et al. Effective and efficient diagnosis of parkinsonism: the role of dopamine transporter SPECT imaging with ioflupane I-123 injection (DaTscan™). Am J Manag Care. 2014;20(5 suppl):S97-S109. 5. AUSTEDO® XR (deutetrabenazine) extended-release tablets/AUSTEDO® current Prescribing Information. Parsippany, NJ: Teva Neuroscience, Inc.

This newsletter is produced by Teva Pharmaceuticals and Dr Citrome was compensated by Teva for his insights.

IMPORTANT SAFETY INFORMATION

Depression and Suicidality in Patients with Huntington's Disease: AUSTEDO XR and AUSTEDO can increase the risk of depression and suicidal thoughts and behavior (suicidality) in patients with Huntington's disease. Balance the risks of depression and suicidality with the clinical need for treatment of chorea. Closely monitor patients for the emergence or worsening of depression, suicidality, or unusual changes in behavior. Inform patients, their caregivers, and families of the risk of depression and suicidality and instruct them to report behaviors of concern promptly to the

Indications and Usage

AUSTEDO® XR (deutetrabenazine) extended-release tablets and AUSTEDO® (deutetrabenazine) tablets are indicated in adults for the treatment of chorea associated with Huntington's disease and for the treatment of tardive dyskinesia.

Important Safety Information

Depression and Suicidality in Patients with Huntington's Disease: AUSTEDO XR and AUSTEDO can increase the risk of depression and suicidal thoughts and behavior (suicidality) in patients with Huntington's disease. Balance the risks of depression and suicidality with the clinical need for treatment of chorea. Closely monitor patients for the emergence or worsening of depression, suicidality, or unusual changes in behavior. Inform patients, their caregivers, and families of the risk of depression and suicidality and instruct them to report behaviors of concern promptly to the treating physician. Exercise caution when treating patients with a history of depression or prior suicide attempts or ideation. AUSTEDO XR and AUSTEDO are contraindicated in patients who are suicidal, and in patients with untreated or inadequately treated depression.

Contraindications: AUSTEDO XR and AUSTEDO are contraindicated in patients with Huntington's disease who are suicidal, or have untreated or inadequately treated depression. AUSTEDO XR and AUSTEDO are also contraindicated in: patients with hepatic impairment; patients taking reserpine or within 20 days of discontinuing reserpine; patients taking monoamine oxidase inhibitors (MAOIs), or within 14 days of discontinuing MAOI therapy; and patients taking tetrabenazine or valbenazine.

Clinical Worsening and Adverse Events in Patients with Huntington's Disease: AUSTEDO XR and AUSTEDO may cause a worsening in mood, cognition, rigidity, and functional capacity. Prescribers should periodically re-evaluate the need for AUSTEDO XR or AUSTEDO in their patients by assessing the effect on chorea and possible adverse effects.

QTc Prolongation: AUSTEDO XR and AUSTEDO may prolong the QT interval, but the degree of QT prolongation is not clinically significant when AUSTEDO XR or AUSTEDO is administered within the recommended dosage range. AUSTEDO XR and AUSTEDO should be avoided in patients with congenital long QT syndrome and in patients with a history of cardiac arrhythmias.

Neuroleptic Malignant Syndrome (NMS), a potentially fatal symptom complex reported in association with drugs that reduce dopaminergic transmission, has been observed in patients receiving tetrabenazine. The risk may be increased by concomitant use of dopamine antagonists or antipsychotics. The management of NMS should include immediate discontinuation of AUSTEDO XR and AUSTEDO; intensive symptomatic treatment and medical monitoring; and treatment of any concomitant serious medical problems.

Akathisia, Agitation, and Restlessness: AUSTEDO XR and AUSTEDO may increase the risk of akathisia, agitation, and restlessness. The risk of akathisia may be increased by concomitant use of dopamine antagonists or antipsychotics. If a patient develops akathisia, the AUSTEDO XR or AUSTEDO dose should be reduced; some patients may require discontinuation of therapy.

Parkinsonism: AUSTEDO XR and AUSTEDO may cause parkinsonism in patients with Huntington's disease or tardive dyskinesia. Parkinsonism has also been observed with other VMAT2 inhibitors. The risk of parkinsonism may be increased by concomitant use of dopamine antagonists or antipsychotics. If a patient develops parkinsonism, the AUSTEDO XR or AUSTEDO dose should be reduced; some patients may require discontinuation of therapy.

Sedation and Somnolence: Sedation is a common dose-limiting adverse reaction of AUSTEDO XR and AUSTEDO. Patients should not perform activities requiring mental alertness, such as operating a motor vehicle or hazardous machinery, until they are on a maintenance dose of AUSTEDO XR or AUSTEDO and know how the drug affects them. Concomitant use of alcohol or other sedating drugs may have additive effects and worsen sedation and somnolence.

Hyperprolactinemia: Tetrabenazine elevates serum prolactin concentrations in humans. If there is a clinical suspicion of symptomatic hyperprolactinemia, appropriate laboratory testing should be done and consideration should be given to discontinuation of AUSTEDO XR and AUSTEDO.

Binding to Melanin-Containing Tissues: Deutetrabenazine or its metabolites bind to melanin-containing tissues and could accumulate in these tissues over time. Prescribers should be aware of the possibility of long-term ophthalmologic effects.

Common Adverse Reactions: The most common adverse reactions for AUSTEDO (>8% and greater than placebo) in a controlled clinical study in patients with Huntington's disease were somnolence, diarrhea, dry mouth, and fatigue. The most common adverse reactions for AUSTEDO (4% and greater than placebo) in controlled clinical studies in patients with tardive dyskinesia were nasopharyngitis and insomnia. Adverse reactions with AUSTEDO XR extended-release tablets are expected to be similar to AUSTEDO tablets.

Please see accompanying full Prescribing Information, including Boxed Warning.

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AUS-45467   April 2023
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