USHP Continuing Education November 1, 2018

USHP Continuing EducationNovember 1, 2018

Can’t Stop, Won’t Stop: Drug-Induced Movement Disorders

Lynsi Collins, PharmDPGY2 Internal Medicine Resident

University of Utah Health

DisclosureRelevant Financial Conflicts of Interest

• CE Presenter, Lynsi Collins:• None

• CE Mentor, Ryan McTish:• None

Off-label Uses of Medications• Propranolol• Cyproheptadine• Mirtazapine • Tetrabenazine• Baclofen• Clonazepam/Diazepam• Diphenhydramine• Donepezil

Pharmacist Objectives•Investigate the pathophysiology, risk factors, and medical management of drug-induced movement disorders

•Evaluate current treatment strategies and guideline recommendations for the management of drug-induced movement disorders

•Identify the clinical challenge of deciding how to manage drug-induced movement disorders

•Construct evidence-based recommendations for the management of drug-induced movement disorders

Technician Objectives

•Identify specific drugs and medication classes commonly associated with causing drug-induced movement disorders

•Analyze symptoms and complications of drug-induced movement disorders

•Recognize treatment strategies used in the management of drug-induced movement disorders

•Definition• Neuromuscular disorders caused by alterations in the central nervous system neurochemistry

•Overview• First discovered in the 1950s• Incidence up to 50%• Symptoms develop within hours to years of exposure• Caused by numerous medications• Can be uncomfortable, disfiguring, and functionally impairing

Drug-Induced Movement Disorders

Extrapyramidal Symptoms Extrapyramidal Symptoms

Neuroleptic Malignant SyndromeNeuroleptic Malignant Syndrome

Serotonin SyndromeSerotonin Syndrome

Types

•Akathisia

•Dystonia

•Parkinsonism

•Tardive Dyskinesia

Extrapyramidal Symptoms

AntipsychoticsAntipsychotics AntidepressantsAntidepressants AntiemeticsAntiemetics AnticonvulsantsAnticonvulsants

Antiparkinsonianagents

Antiparkinsonianagents AnxiolyticsAnxiolytics Antihistamines Antihistamines

Causative Agents

•Disturbance of chemicals in the brain• Dopamine (DA)

• Motor control, behavior regulation, stimulation, reward pathway

• Serotonin (5-HT)• Regulates anxiety, happiness, mood, sleep

• Gamma-aminobutyric acid (GABA)• Muscle tone, cognition, behavior, vision, anxiety

Pathophysiology

•Complex and multifactorial

•Exact mechanism is still unknown

•Theories• Blockage of dopamine receptors by dopamine

antagonists leading to an upregulation of dopamine receptor responsiveness

Pathophysiology

•Theories• Neurotoxicity from oxidative stress• Dopamine serotonin imbalance• GABA depletion/GABAergic neuron damage• Histamine receptor blockade• Genetic

Pathophysiology

Age

Causative agent

Gender

Neurological disorders

Risk Factors

Disabling and distressingDisabling and distressing

Can be permanent Can be permanent

Behavioral disturbancesBehavioral disturbances

Non‐adherence Non‐adherence

Reduce quality of lifeReduce quality of life

Complications

Under recognized and diagnosed Fluctuation of symptoms Therapies mask symptomsLack of standard guidelines

•Reduce dose of causative agent

•Switch to an agent with lower risk

•Discontinue causative agent

•Addition of anti-extrapyramidal agent

Important that careful evaluation is done on all patients treated with drugs with risk of movement disorders

Current Treatment Recommendations

Akathisia

SymptomsSymptoms• Motor restlessness• Inner restlessness• Distress• Discomfort

Onset Onset • Typically within 4 weeks• Earliest within 1 week

Diagnosis Diagnosis • Diagnostic and Statistical Manual of Mental Disorders (DSM) IV• Barnes Akathisia Rating Scale (BARS)

Akathisia

Beta Blockers

Akathisia Treatment

Study Intervention Outcomes Adverse Events

Lipinski et al. 1983

Propranolol 30mg

75% complete resolutionResponse within 24 hours

Not reported

Kramer et al. 1987

Propranolol 60mg vs placebo

Significant reduction in symptoms compared to placebo; P=0.006

No different in adverse effects

Poyurovsky et al. 2006

Propranolol 40mg BID vsplacebo

30% vs 7% responded with improved symptoms

17% developed orthostatic hypotension and bradycardia resulting in discontinuation

Cyproheptadine

Mirtazapine

Akathisia Treatment

Study Intervention Outcomes Adverse EventsPoyurovsky et al. 2001

Cyproheptadine 16mg

15/17 (88%) showed a 50% reduction in symptoms

Mild sedation, dry mouth, and blurred vision occurredSymptoms returned at discontinuation

Fischel et al.2001

Cyproheptadine 16mg vs propranolol 80mg

46% vs 42% reduction in symptom scores

Symptoms returned at discontinuation


Poyurovsky et al. 2006

Mirtazipine 15mg vs placebo

43% vs 7% respondedwith improved symptoms

Drowsiness and dizziness

Benzodiazepines

Trazodone

Akathisia Treatment


Stryjer et al. 2010 Trazodone 100mgvs placebo

50% response rate compared to 0% in placebo

Not reported


Lima et al. 2002 Clonazepam vsplacebo

Significant reduction in symptoms by 7-14 days

No difference seen

Akathisia Recommendations

Beta Blockers Cyproheptadine Mirtazapine Benzodiazepines Trazodone

Benefit YES YES YES YES YES

Side Effects Orthostatic

hypotension

Bradycardia

Sedation

Dry mouth

Blurry vision

Sedation

Dizziness

Weight gain

Sedation

Drug abuse or dependence

Cognitiveimpairment

Sedation

Dizziness

Confusion

Dystonia

SymptomsSymptoms• Sustained muscle contractions or spasms • Repetitive and twisting movements• Abnormal posturing• Difficulty with swallowing, breathing, and talking

Onset Onset • Within in 7 days• Can occur within 24 hours

DiagnosisDiagnosis• No scales have been developed specifically for dystonia• DSM-IV

Dystonia

Anticholinergics

Dystonia Prophylaxis/Treatment


Goff et al. 1991 Benztropine 2mg vsplacebo

14% vs 33% developed dystonia

Dry mouth and diminished sweat

Burke et al. 1986

Trihexyphenidyl 30mg vs placebo

71% had a clinically significant response

Blurred vision, dry mouth, and confusion

Tetrabenazine

Baclofen

Dystonia Treatment


Gerlach et al. 1978

Baclofen vsplacebo

Reduced frequency of symptoms, but did not change amplitude and increased duration

Sedation, weakness, and confusion in 50%


Jankovic et al. 1982

Tetrabenazine vs placebo

83% saw improvement in symptoms

Drowsiness, hypersalivation, insomnia, parkinsonism, hypotension

Kenney et al. 2007

Tetrabenazine 68% response rate Drowsiness, parkinsonism, depression, akathisia

Benzodiazepines

Antihistamines

Dystonia Treatment


Burke et al. 1982

Clonazepam or Diazepam

10% improvement in symptoms

Not reported


Burke et al. 1982

Diphenhydramine 13% improvement in symptoms

Not reported

Dystonia Recommendations

Anticholinergics Tetrabenazine Baclofen Benzodiazepines Antihistamines

Benefit YES YES YES YES YES

Side Effects Sedation

Dry mouth

Confusion

Blurry vision

Sedation

Parkinsonism

Akathisia

Depression/ Anxiety

Sedation

Confusion

Headache

Sedation


Cognitiveimpairment

Sedation

Dizziness

Parkinsonism

SymptomsSymptoms• Tremor• Muscle rigidity• Bradykinesia• Postural instability

Onset Onset • Within 7 days• Can be delayed > 30 days

Diagnosis Diagnosis • DSM-IV• Simpson-Angus Extrapyramidal Side Effect Scale

Parkinsonism

Anticholinergics

Amantadine

Parkinsonism Prophylaxis/TreatmentStudy Intervention Outcomes Adverse Events

McEvoy et al. 1983

Benztropine, trihexyphenidy, orphenadrine

Prophylaxis and treatment showed improved symptoms of rigidity and tremor, some reports of improved bradykinesia

Constipation, decreased sweating,blurred vision, impaired cognition, urinary retentionReports of worsened tardive dyskinesia with long-term use

Study Intervention Outcomes Adverse EventsDiMascio et al. 1976

Amantadine 400mg vs benztropine 16mg

Over 50% reduction in symptoms (tremor and rigidity) in both groups

Fewer SEs in amantadine group

Shannon etal. 1987

Amantadine 100-200mg vs placebo

55% had moderate reduction in symptoms after 2 months and 65% at 3 months

Nausea, dizziness, lightheadedness, and insomnia

Parkinsonism Recommendations

Anticholinergics Amantadine

Benefit YES YES

Side Effects Sedation

Dry mouth

Confusion

Blurry vision

Nausea

Anxiety/Depression

Dizziness

Insomnia

Tardive Dyskinesia

SymptomsSymptoms• Involuntary repetitive movements• Involves face, lips, tongue, trunk, and extremities • Irreversible in most patients

Onset Onset • Usually > 3 months• Can take > 1 year

Diagnosis Diagnosis • DSM-IV• Abnormal Involuntary Movement Scale (AIMS)

Tardive Dyskinesia

Vesicular Monoamine Transporter 2 (VMAT2) Inhibitors

Tardive Dyskinesia Treatment


Jankovic et al. 1982

Tetrabenazine vs placebo

100% saw improvement in symptoms

Drowsiness, hypersalivation, insomnia, parkinsonism,hypotension

Kenney et al. 2007

Tetrabenazine 84% response rate Drowsiness, parkinsonism, depression, akathisia

Bari et al. 2016 Valbenazine 50mg vs placebo

54% reduction in symptomsin 6 weeks

Drowsiness and fatigueNo serious side effects reported

Anderson et al. 2018

Deutetrabenazine12-48mg vsplacebo

Significant improvement in symptoms compared in placebo

90% of side effects were mild and occurred at a similar frequency to placebo

Amantadine



Pappa et al. 2010

Amantadine 100mg vs placebo

Significant reduction in symptoms and in severity

SEs included hallucinations, dizziness, syncope

Pahwa et al.2015

Amantadine XL 260mg, 340mg,420mg vs placebo

Superiority in improving both subjective and objective symptoms compared to placebo

Reported in 82% vs 80-95% of patients; 40% drop out in 420mg and 10-15% in the other groups

Benzodiazepines

Donepezil



Burke et al. 1982

Clonazepam vsplacebo

35% reduction in symptoms 26% developed tolerance and symptoms returned


Caroff et al. 2001

Donepezil 5-10mgvs placebo

Significantly reduced symptoms in 90% of patients

No significant side effects reported

Tardive Dyskinesia Recommendations

VMAT2 Inhibitors Amantadine Benzodiazepines Donepezil

Benefit YES YES YES YES

Side Effects Drowsiness

Hypersalivation

Insomnia

Parkinsonism

Suicidal Ideation

Hypotension

Syncope

Dizziness

Hallucinations

Sedation


Cognitiveimpairment

Nausea

Diarrhea

Dizziness

Fatigue

Extrapyramidal Symptoms Comparison Symptoms Onset Treatment

Akathisia Motor restlessnessInner restlessness

DistressDiscomfort

4 weeks PropranololCyproheptadine

MirtazapineBenzodiazepines

TrazodoneDystonia Sustained muscle

contractions/spasmsRepetitive and twisting movement

Abnormal posturingDifficulty swallowing, breathing,

talking

24 hours AnticholinergicsTetrabenazine

BaclofenBenzodiazepinesAntihistamines

Parkinsonism TremorMuscle rigidityBradykinesia

Postural instability

1 week AnticholinergicsAmantadine

Tardive Dyskinesia

Involuntary repetitive movementsLip smacking and chewing movement

Tongue protrusion Facial grimacing

> 3 months VMAT2 InhibitorAmantadine

BenzodiazepinesDonepezil

•Extrapyramidal symptoms are the most common drug-induced movement disorders

•They are serious side effects that are disabling and reduce patients overall quality of life

•Studies have demonstrated a reduction in symptoms and complete resolution of symptoms

•There is a lack of guidelines for treating drug-induced movement disorders

•Further clinical trials are needed to support the use of “anti-extrapyramidal” agents

Final Conclusions/Recommendations

•Recognize signs and symptoms of drug-induced movement disorders early on

•Identify common patient risk factors and causative agents with the movement disorder

•Educate patients and physicians on the risk of developing extrapyramidal symptoms

•Recommend appropriate therapy changes and initiations

Pharmacist Role and Future Directions

BT is a 67 year old female presenting to her primary care physician complaining of new restlessness and worsening anxiety. She states that she unable to sit still and constantly feels uncomfortable sitting and laying down.

Her primary care physician has been managing medication therapy for over 20 years. She has tried multiple antipsychotic medications in the past and is happy on chlorpromazine. Of note, her sertraline dose was increased from 100mg to 200mg 4 weeks ago.

On physical exam the patient is rocking in her chair and continuously tapping her left foot.

Past Medical History• Depression• Anxiety• HTN• Mixed bipolar/psychotic disorder• Hypothyroidism

Medication History• Sertraline 200 mg daily• Lisinopril-HCTZ 10mg/12.5mg daily• Chlorpromazine 50mg twice daily• Levothyroxine 88mcg daily before breakfast • Multivitamin daily

Patient Case 1

Based on BT’s current presentation and physical exam what extrapyramidal syndrome does she have?

A. Tardive Dyskinesia

B. Akathisia

C. Parkinsonism

D. Dystonia

Patient Case 1

What risk factors does BT have that are associated with akathisia?

A. Female

B. 67 years old

C. Mixed bipolar/psychotic disorder

D. All of the above

Patient Case 1

What medication(s) on BT’s list would most commonly cause an acute akathisia disorder?

A. Chlorpromazine

B. Levothyroxine

C. Sertraline

D. Lisinopril-HCTZ

Patient Case 1

With BT’s new diagnosis of drug-induced akathisia disorder which of the following would be the most appropriate treatment strategy?

A. Discontinue sertraline 200mg today and follow up in 4 weeks

B. Discontinue both sertraline and chlorpromazine and initiate lurasidone, an atypical antipsychotic

C. Initiate propranolol 10mg twice daily with follow up in 1 week with plans to taper as tolerated

D. Decrease sertraline back to 100mg daily and initiate clonazepam 1mg daily

Patient Case 1

JC is a 32 year old male with a history of schizophrenia. He was recently switched from olanzapine 60mg daily to paliperidone 324mg once monthly injection due to worsening symptoms of hallucinations, anxiety, repetitive movements, and disorganized speech.

He was given his first dose of paliperidone two days ago (8/12). Today (8/14) he is presenting with new muscle contractions of the neck and reports cramping of his feet. He speech seems unchanged and still reports hallucinations. He was given a dose of haloperidol 5mg to help control these symptoms. Over the next few days he required multiple doses of haloperidol with unchanged symptoms.

Patient Case 2

8/14 8/15 8/16 8/17 8/18

8:00am

12:00pm X X

17:00pm X X X

21:00pm X X X X

Based on JC’s presentation which of the following is likely occurring?

A. The patient is having an acute exacerbation of his schizophrenia

B. The patient is having an adverse drug reaction from his paliperidone injection

C. The patient is having withdrawal and relapse after discontinuing his olanzapine

D. All of the above

Patient Case 2

After requiring multiple doses of haloperidol with unchanged symptoms the patient was determined to have dystonia. What would be the best therapy to initiate to help treat his dystonia?

A. Baclofen

B. Diazepam

C. Benztropine

D. Diphenhydramine

Patient Case 2

HM is a 58 year old female with Parkinson’s disease who was recently diagnosed with tardive dyskinesia. Her levodopa-carbidopa dose was decreased to help with her tardive dyskinesia symptoms. Unfortunately this hasn’t helped and she is looking for another way to treat her tardive dyskinesia. Which of the following agents should be avoided?

A. Valbenazine

B. Clonazepam

C. Amantadine

D. Donepezil

Patient Case 3

• Lipinski JF, Zukenko GS, Barreira P, et al. Propranolol in the treatment of neuroleptic‐induced akathisia. Lancet 1983;1:685‐686.

• Kramer MS, Gorkin RA, Dijohnson C, et al. Propranolol in the treatment of neuroleptic‐induced akathisia (NIA) in schizophrenics: a double blind placebo controlled study. Biol Psychiatry. 1987;24:823‐827.

• Poyurovsky M, Pashinian R, Weizman A, et al. Low dose mirtazapine: a new option in the treatment of antipsychotic induced akathisia, a randomized, double‐blind, placebo and propranolol controlled trial. Biol Psychiatry. 2006;59:1071‐1077.

• Poyurovsky M, Weiman R, et al. Serotonin‐based pharmacotherapy for acute neuroleptic‐induce akathisia: a new approach to an old problem. Br J Psychiatry. 2001;179:4‐8.

• Fischel T, Hermesh H, Aizenberg D, et al. Cyproheptadine versus propranolol for the treatment of acute neuroleptic induced akathisia: a comparative double blind study. J Clin Psychopharm. 2001;6:612‐615.

• Lima AR, Soares K, Bacaltchuk J, et al. Benzodiazepines for neuroleptic‐induced acute akathisia. Cochrane database Syst Rev. 2002. CD001950.

• Stryjer R, Rosenzcwaig S, Bar F, et al. Trazodone for the treatment of neuroleptic‐induced acute akathisia: a placebo‐controlled double‐blind, crossover study. Clin Neuropharmacol. 2010;33:219‐222.

• Goff DC, Arana GW, Greenblatt DJ, et al. The effect of benztropine on haloperidol‐induced dystonia, clinical efficacy and pharmacokinetics: a prospective double blind trial. 1991;11(2):106‐112.

• Burke RE, Fahn S, Marsden CD, et al. Torsion Dystonia: double blind prospective trial of high dosage trihexphenidyl. Neurology .1986;36:160‐164.

• Jankovic J. Treatment of hyperkinetic movement disorders with Tetrabenazine: a double blind crossover study. Ann Neurol. 1982;11:41‐47.

• Kenney C, Hunter C, Jankovic J, et al. Long‐term tolerability of Tetrabenazine in the treatment of hyperkinetic movement disorders. Mov Disord. 2007;22(2):193‐197.

• Gerlach J, Rye T, Kristjansen P, et al. Effect of baclofen on tardive dyskinesia. Psychopharm. 1978;56(2):145‐151.

References

• Burke R, Fahn S, Jankovic J, et al. Tardive dystonia: late onset and persistent dystonia caused by antipsychotic drugs. Neurology. 1982;32:1335‐1346.

• McEvoy JP. The clinical use of anticholinergic drugs as treatment for extrapyramidal side effects of neuroleptic drugs. J Clin Psychopharm. 1983;3(5):288‐302.

• Cornett EM, Novitch BS, Kaye AD, et al. Medication induced tardive dyskinesia: a review and update. Ochsner Journal. 2017;00:162‐172.

• Hawthorne JM, Caley C. Extrapyramidal reactions associated with serotonerifc antidepressants. Annals of Pharmacotherapy. 2015;49(10):1136‐1152.

• Dimascio A, Bernardo DL, Greenblatt DJ, et al. A controlled trial of amantadine in drug induced extrapyramidal disorders. Arch Gen Psychiatry. 1976;33:599‐602.

• Shannon KM, Goetz CG, Carroll VS, et al. Amantadine and motor fluctuation in chronic Parkinson’s disease. Clin Neuropharmacol. 1987;10(6):522‐526.

• Bari M, Shiwach R, Roland J, et al. Open‐label extension of KINECT: phase 2 study of valbenazine for tardive dyskinesia. 2016;86(16).

• Anderson KE, Stamler D, Davis MD, et al. Deutetrabenazine for treatment of involumary movements in patients with tardive dyskinesia (AIM‐TD): a double‐blind, randomized, placebo‐controlled, phase 3 trial. Lancet Psychiatry. 2018;4:595‐604.

• Pappa S, Tsouli S, Apostolou G, et al. Effects of amantadine on tardive dyskinesia: a randomized double‐blind, placebo‐controlled study. ClinNeuropharmacol. 2010;33:271‐275.

• Pahwa R, Tanner CM, Hauser RA, et al. Amantadine extended release for levodopa‐induced dyskinesia in patkinson’s disease (EASED Study). MovDisord. 2015;30(6):788‐795.

• Caroff SN, Campell EC, Harvey J, et al. Treatment of TD with donepezil: a pilot study. J Clin Psychiatry. 2001;62(10):772‐775.

• Atlas SJ, Agboola F, Curfman G, et al. Effectiveness and Value of 2 Novel Treatments for Tardive Dyskinesia. JAMA Internal Medicine. 2018;178(8):1110‐1112.

References

Can’t Stop, Won’t Stop: Drug-Induced Movement Disorders

Lynsi Collins, PharmDPGY2 Internal Medicine Resident

University of Utah Health

USHP Continuing Education November 1, 2018

Documents

Transcript of USHP Continuing Education November 1, 2018