Antipsychotic Therapy: Managing Extrapyramidal Effects

John Lauriello, M.D.

Extrapyramidal Side Effects of Antipsychotic Medications

• Parkinsonism and Dystonia

• Tardive Dyskinesia• Akathisia • Neuroleptic Malignant

Syndrome

Effectiveness of a Particular Treatment

• Extent to which a particular treatment helps individuals afflicted with a particular illness in their lives

= Efficacy + Tolerability + Compliance

Rule#1: Efficacy FirstSide Effects Second

Rule #2: No Side EffectNo Effect

Side Effects of AntipsychoticsTolerability vs Safety

Tolerability• Nuisance (patient

comfort) vs life threatening

• Often time-limited• Often easily

managed• Mild-moderate EPS,

prolactin elevation, sexual dysfunction

Safety• Life threatening• Acute or chronic• Cardiovascular

disease, metabolic syndrome, diabetes

• NMS, laryngospasm

Mixed Safety & Tolerability• Akathisia • Weight gain• Metabolic risk

factors • Sedation

Adapted from Newcomer, JW. J Clin Psychiatry. 2007;68(suppl1):20-27.

Why Does EPS Matter?

0 10 20 30 40 50

Barriers to Medication Adherence in Schizophrenia

Hudson et al 2004 J Clin Psychitatry Patients (n=153 ) reporting barriers (%)

Homelessness / substance abuse

Adverse drug reactions

Stigma

Forgetfulness

Lack of social support

Afraid of medication

Denial of illness

Lack of trust in provider

Difficulty with regimen

Rank Order of Side Effects Eliciting Moderate-to-Severe Distress

Weiden PJ, Miller AL (2001), J Psychiatr Pract 7(1):41-47

Patients Reporting Moderate-to-Severe Distress (N=99)

Akinesia(N=49)

WeightGain

(N=58)

Anticho- linergic(N=45)

SexualProblems

(N=39)

MuscleRigidity(N=32)

Akathisia(N=38)

Per

cen

tP

erce

nt

40.037.3

30.8

18.8 18.4

33.2

0

10

20

30

40

50

Ziprasidone

Risperidone

Quetiapine

Olanzapine

Perphenazine

n=183

n=333

n=329

n=330

n=257

15

10

15

19

16

Lieberman JA et al. N Engl J Med. 2005;353:1209-1223.

Treatment Discontinuation in CATIE :Owing to Intolerability

Patients (%)

0 10 20 30 40 50

Mean modal dose

Ziprasidone 112.8 mg/day

Risperidone 3.9 mg/day

Quetiapine 543.4 mg/day

Olanzapine 20.1 mg/day

Perphenazine 20.8 mg/day

Patient Discontinuations in CATIE

0

5

10

15

20

25

30

35

40

45

50

Pat

ien

t d

isco

nti

nu

atio

ns

(%)

OLZ QTP RIS PER ZIP

*P=.001 vs other agents.

Lieberman JA et al. N Engl J Med. 2005;353:1209-1223.

Weight or metabolic effects EPS Sedation

Antipsychotics:A Dopamine Story

Modified DA Hypothesis of Schizophrenia

Normal State

Brain StemDA Neurons

Limbic Sites

PrefrontalCortex

Limbic Sites

PrefrontalCortex

Brain StemDA Neurons

Prefrontal DA Terminal Lesion

Pycock et al, 1981; Davis et al, 1991;Pycock et al, 1981; Davis et al, 1991; Weinberger DR. Arch Gen Psychiatry. 1987;44:660

• Dystonia• Akinesia • Rigidity • Tremor • Dyskinesia

• Negative symptoms• Cognitive impairment• Depression

Inoue A, Nakata Y (2001), Jpn J Pharmacol 86:376-380; Seesack SR, Carr DB (2002), Physiol Behavior 77:513-517

Nigrostriatal Pathway Disruption

Hypothalamic Disruption

Mesocortical Pathway Disruption

Disruption of Dopamine Pathways Leads to Predictable Effects

• Prolactin elevation• Amenorrhea • Galactorrhea • Sexual dysfunction

Mesolimbic Pathway Disruption• Agitation, psychosis, mania,

disorganization, thrill/drug seeking

D2 Occupancy Predicts Response

D2 occupancy predicts response on CGI (p<0.001); Predicts change in positive symptoms PANSS (p=0.07); Kapur S et al. (2000), Am J Psychiatry 157(4):514-520

% R

espo

nder

s (C

GI)

Striatal D2 Occupancy (%)

Responders

Nonresponders

100

80

60

40

20

0<60 >65

D2 Occupancy Predicts EPS/Akathisia

Kapur S et al. (2000), Am J Psychiatry 157(4):514-520

78%

Individual Participants

D2 O

ccup

ancy

(%

)

• No participant <78% showed EPS/akathisia

Schematic of D2 Occupancy, Antipsychotic Efficacy and EPS Liability

Dose

100

60

40

20

% R

ecep

tor

Occ

up

ancy

0

80 Χ

Signs of Motor EPSBegin

Dosing and Relative EPS Vulnerability

Jibson MD, Tandon R (1998), J Psychiatr Res 32(3-4):215-228

100

Olanzapine

Lik

elih

oo

d o

f EP

S (

%)

50

Therapeutic Dosing

Low Moderate High Very High

Haloperidol Risperidone

Ziprasidone

Quetiapine 0

Schematic Diagram of Dose and Relative EPS Liability

Aripiprazole Risperidone Olanzapine Quetiapine

Haloperidol Ziprasidone Clozapine

D2 0.34* 0.7 4 5 11 125 160

D2 Receptor Partial AgonistHigh D2 Affinity With Low D2 Side Effects

*Aripiprazole has high D2 affinity but not high D2 antagonism!

Data represented as Ki (nM); Bymaster FP et al. (1996), Neuropsychopharmacology 14(2):87-96; Seeger TF et al. (1995), J Pharmacol Exp Ther 275(1):101-113; Daniel DG et al. (1999), Neuropsychopharmacology 20(5):491-505; Arnt J, Skarsfeldt T (1998), Neuropsychopharmacology 18(2):63-101

Aripiprazole: The Exception

An Agonist Has Intrinsic Activity: Ability of a Compound to Activate Receptors

No activationAntagonist (haloperidol, etc.)

Partial activationPartial agonist (aripiprazole)

Full activationD2 receptor

Full agonist (dopamine)

Typical Atypical

Antipsychotics

Dose (mg/kg)

Effe

ct

Casey DE. Motor & Mental Aspects of EPS. Int Clin Psychopharmacol. 1995(Sept);10(suppl 3):105-114

0

25

50

75

100

Effe

ct

Dose (mg/kg)0.3 1 3 10 30

AEs(EPS)

(Antipsychotic) (Antipsychotic)

AEs(EPS)

25

50

75

100

0.3 1 3 10 300

Atypical Antipsychotics for SchizophreniaDrug Formulation (Approval) Dose Range

Aripiprazole Oral (2002) 10-30 mg/day

Olanzapine Oral (1996)10-20 mg/day; higher doses are often used if treatment refractory

Olanzapine LAI Long-acting IM (2009) 150-300 mg IM every 2 weeks

Quetiapine and Quetiapine XR Oral (1997, 2007)150-800 mg/day; higher doses are often used if treatment refractory

Risperidone Oral (1993) 4-16 mg/day

Risperidone LAI Long-acting IM (2003)25, 37.5 , or 50 mg IM every 2

weeks

Ziprasidone Oral (2001) 80-160 mg/day

Clozapine Oral (1989) 300-900 mg/day

Paliperidone Oral (2006) 6-12 mg/day

Paliperidone Long-acting IM (2009) 117 to 234 mg per month

Asenapine Oral – sublingual (2009) 5-10 mg twice daily

Iloperidone Oral (2009) 6-12 mg twice daily

Lurasidone Oral (2010) 40-80mg daily

TMAP Schizophrenia Clinician’s Manual. http://www.dshs.state.tx.us/mhprograms/pdf/SchizophreniaManual_060608.pdf. Accessed October 2010.FDA. http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Search_Drug_Name. Accessed October 2010.

Barriers to EPS Diagnosis

• Outdated notion that EPS is a therapeutic benefit • Difficulty getting accurate history • Acceptance of EPS as part of mental illness • Overlap between behavioral manifestations of EPS

and psychiatric symptoms • Lack of training in EPS diagnosis • Belief that atypical antipsychotics do not cause

EPS

Advantages of EPS Sparing Antipsychotics

Fewer MotorSide Effects

Less Dysphoria

CognitiveAdvantage

NegativeSymptomBenefit

Fewer EPSLess

Noncompliance

Lower Riskof TD

Tandon R et al. (1999), J Clin Psychiatry 60 Suppl 8:21-28

Parkinsonism

Frequency of Antipsychotic-Induced Parkinsonism (Conventional Antipsychotics)

Weiden P (1994), In: DSM-IV Sourcebook, vol. 1. Washington, D.C.: American Psychiatric Publishing, Inc.

Parkinson Type Incidence (%)

Any 61

Akinesia 33

Rigidity 52

Tremor 23

N= 40 58 161 195 194 245 183 *p0.01; Marder SR et al. (2003), Schizophr Res 61(2-3):123-136

(Simpson-Angus Scale)

Parkinsonism Rates of Aripiprazole vs. Haloperidol

-0.6

-0.4

-0.2

0

0.2

0.4

0.6

0.8

1

1.2

1.4

Placebo 2 mg Ari 10 mg Ari 15 mg Ari 20 mg Ari 30 mg Ari 10 mg HalS-A

Sco

re C

han

ge

Fro

m B

asel

ine

(Simpson-Angus Scale)

*p<0.05 vs. placebo; Arvanitis L, Miller BG (1997), Biol Psychiatry 42(4):233-246

Parkinsonism Rates: Quetiapine vs. Haloperidol

Placebo Quetiapine

*

0

10

20

30

40

50

75 150 300 600 750 12

Dose (mg/day)

Per

cen

t o

f P

atie

nts

Hal

Tardive Dyskinesia

Mean Rx length: 114.7 weeksAverage dose: 80 mg/day CPZ equivalentMean age: 76.9 yrs1-year incidence: 25%N = 261

The Risk of Tardive Dyskinesia Is Not Trivial

0

20

40

60

80

100

0 26 52 78 104 130 156 182 208 234 260

Weeks

% o

f P

atie

nts

wit

h T

D

Woerner MG, et al. Am J Psychiatry. 1998;155(11):1521-1528.

5-Year Prospective Incidence in Elderly with Conventional Antipsychotics

Cumulative Percent

95% CI

Patient population included dementia, major mood disorders, schizophrenia/schizoaffective disorder, anxiety disorders

120 150 180 210 240 270 300 330 365Days of Treatment

Risperidone

0

2

4

6

8

10

12

14

0 30 60

% o

f P

atie

nts

wit

h T

D Median Rx length: 273 daysMean modal dose: 0.96 mg/dayMean age: 82.5 years1-year incidence: 2.6%N = 330

Jeste DV, et al. Am J Psychiatry. 2000;157:1150-1155.

90

TD: 1-Year Prospective Incidence in the Elderly

Participants Treated With SGAs

Mean Weighted 1-Year Incidence Rates of Tardive Dyskinesia

*1 study reported separate rates for tardive dyskinesia in adults and the elderly Correll CU et al. (2004), Am J Psychiatry 161(3):414-425; 1Correll CU, Kane J (in press), J Child Adolesc Psychopharmacol

Mea

n R

ate

of T

ardi

ve

Dys

kine

sia

(%)

0.8

6.8

5.3

0.41

5.4

0

1

2

3

4

5

6

7

Children (N=783, 10 Trials)

Adults (N=1,964, 6 Trials*)

Adults and Elderly(N-207, 1 Trial)

Elderly (N=521,

4 Trials*)

Haloperidol-Treated Adults

(N=408, 3 Trials)

Author

Drug N

MeanAge

(Years)

MeanDose

(mg/Day) Exposure

(Days)Annualized

TD Incidence (%)

Glazer, 1999 Quetiapine 301 36 475 272 (mean) 0.74*Rein, 1999

AmisulprideHaloperidol

331106

3639

62414.6

359 (median)352 (median)

1.55.9

Beasley, 1999

OlanzapineHaloperidol

513114

3736

13.513.9

260 (median)259 (median)

0.52*7.4*

Sanger, 2001 Olanzapine 97 39 13.9 198 (mean) 0Csernansky, 2002

RisperidoneHaloperidol

177188

4040

4.911.7

364 (median)238 (median)

0.64.1

Chouinard, 2002

RisperidoneMicrospheres

587 42 55.2 350 (median) 0.71

Arato, 2002

ZiprasidonePlacebo

20771

5049

92.0-

206 (median) 72 (median)

6.835.7

Davidson, 2000 Risperidone 139 73 3.7 Not reported 13.4*Jeste, 1999 Quetiapine 85 76 172 365 (median) 2.72*

Jeste, 2000 Risperidone 255 82 0.96 273 (median) 2.6*

Incidence of TD with Second-Generation Antipsychotics in 1-Year Studies

Correll CU, Leucht S, Kane JM: Am J Psychiatry 2004 ; 161:414-425

Olanzapine vs. Haloperidol

Beasley et al. Randomized, double-blind comparison of the incidence of tardive dyskinesia in patients with schizophrenia during long-term treatment with olanzapine or haloperidol. Br J Psychiatry. 1999(Jan);174:23-30

14

0

2

4

6

8

10

12

0 42 100 200 300 400 500 600 700

Days of Treatment

% o

f P

atie

nts

with

TD Haloperidol

1-year incidence: 7.45%N=114

Olanzapine 1-year incidence: 0.52%N=513

p=0.002 olanzapine vs. haloperidol

TD: 1-Year Prospective Incidence

Akathisia

• Subjective Sense of Restlessness

• Objective Sense of Restlessness

• Associated Distress

• Often described as coming from the body

• Associated with medication use

• Is it really an EPS?

Causes of Restless Syndromes(Akathisia differential)

• Idiopathic• Antipsychotics• Antidepressants• Anti-emetics: Metoclopromide, Prochloperazine,

Promethazine • Stimulants: Amphetamines, Caffeine, Coffee

Antihistamines • Drug Withdrawal: Opiates, Barbiturates, Cocaine,

Benzodiazepines. Alcohol, Cannabis • Serotonin Syndrome • Chondromalacia patella

When Akathisia Is Missed

Akathisia

“Psychosis” Dose

Akathisia not diagnosed

Doctor responds to worsening of “psychosis”

Raise in dose worsens akathisia

Neuroleptic Malignant Syndrome

• NMS life-threatening (10%) complication of treatment with antipsychotic drugs

• Fever, severe muscle rigidity, and autonomic and mental status changes

• Estimates of the incidence once ran as high as 3% of patients treated with antipsychotics, more recent data suggest an incidence of 0.01%–0.02%

• Reintroduction of antipsychotics possibleStrawn et al Am J Psychiatry 164:870-876, June 2007

Neuroleptic Malignant Syndrome

• F – Fever

• A – Autonomic instability

• L – Leukocytosis

• T – Tremor

• E – Elevated enzymes (elevated CPK)

• R – Rigidity of muscles

NMS-Differential

• Encephalitis

• Status Epilepticus

• Heat Stroke

• Malignant Hyperthermia

• Serotonin Syndrome

• Drug Intoxication

Treatment of EPS

PORT Psychopharmacology Treatment Recommendations

• Evidence for differences among antipsychotic agents in the risk for developing EPS ranking is high-potency FGAs > mid-potency FGAs = risperidone > low-potency FGAs > olanzapine, ziprasidone > quetiapine > clozapine.

– There is currently insufficient evidence to rank aripiprazole nor to further refine the ranking of FGAs.

• FGA medications, prophylactic use of antiparkinson agents to reduce the incidence of EPS should be determined on a case by case basis. The use of prophylactic antiparkinson agents in people treated with SGA medications is not warranted.

• SGA medications, including clozapine, and several adjunctive agents have been evaluated for the treatment of TD. However, there is insufficient evidence to support a recommendation for the use of any specific agent to treat TD.

• NMS occurs rarely but has been associated with treatment with both FGA and SGA medications. Since the last update, there is additional evidence available on the risk of NMS with antipsychotic medications, including clozapine, and therefore, the previous recommendation to select clozapine as the first-line treatment for individuals with previous NMS is no longer being included. There is insufficient evidence to recommend the use of a specific antipsychotic medication for people who have previously developed NMS.

Buchanan et al Schizophrenia Bulletin 2010 Jan, 36 (1) 71-93

Reduce Dopamine Blocking Load

• EPS appears to be dose related

• Use lowest maintenance oral dose

• Consider switching to long acting antipsychotic agent

• Switch to a different antipsychotic

• Use an “antidote” medication

Switching to Reduce Parkinsonism

Switching to Quetiapine: Degree of EPS Reduction as a Function of Prior Antipsychotic

ITT population; *p<0.001 vs. baseline; †Mean PANSS total score baseline value; LSM = least square mean; LVCF = last value carried forward; De Nayer A et al. (2002), Poster presented at the 23rd Annual Meeting of the CINP, Montreal, Canada: June 23-27

-35

-30

-25

-20

-15

-10

-5

0

Previous Antipsychotic

OlanzapineMonotherapy

*

(N=60)

RisperidoneMonotherapy

*

(N=49)

All ConventionalMonotherapy

*

(N=161)

Improvement

Low-DoseHaloperidol

*

(N=38)

Agents for Treating EPS

Agent Dosage Indication

Amantadine 100-200 mg bid EPS

Benztropine.5mg-2mg bid po, IM

EPS, Dystonia

Biperiden2-6 mg tid po,IM

EPS, Dystonia

Diphenhydramine25-50 mg bid po,IM EPS, Dystonia

Procyclidine 2.5-5mg bid EPS

Agents for Treating Tardive Dyskinesia

• May be reversible but not guaranteed

• No proven medication treatment

• Agents that increase dopamine blockade temporarily help--”vicious cycle”

• Studies of Vitamin D, Omega 3 fatty acids have not held up to large scale studies

Agents for Treating Akathisia

Agent Dosage Indication

Clonzapam and other benzodiazepines

.5mg-1mg bid Akathisia

Propranolol and other Beta Blockers

20-40mg bid or

80-160mg LAAkathisia

Benztropine.5mg-2mg bid Akathisia

Diphenhydramine25-50 mg bid Akathisia

Procyclidine2.5-5mg bid Akathisia

Ropinirole (Requip) .25 mg-4 mg

Restless Leg Syndrome

Pramipexole (Mirapex) 1.5-4.5 mg

Restless Leg Syndrome

Agents for Treating NMS

• Benzodiazepines

• Amantadine 200-400 mg/day

• Bromocriptine 7.5mg-45 mg/day

• Dantrolene sodium 1-2.5mg IV initially and then 1mg q6hrs with eventual switch to oral

• ECT

Achieving Best Outcomes with Antipsychotics

• EFFECT FIRST! • Minimize impairment by side-effects

– NO EPS

– NO USE OF ANTICHOLINERGIC

– MINIMIZE OTHER ADVERSE EFFECTS

– INDIVIDUALIZE THERAPY

– MONITOR ON AN ONGOING BASIS

– AND THEN MAKE NECESSARY ADJUSTMENTS