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Off-Label Use of Atypical Antipsychotics: An Update Off-Label Use of Atypical Antipsychotics: An Update

Off-Label Use of Atypical Antipsychotics: An Update - PowerPoint Presentation

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Off-Label Use of Atypical Antipsychotics: An Update - PPT Presentation

Summary of the Agency for Healthcare Research and Quality AHRQ Report David L Fogelson MD Clinical Professor of Psychiatry David Geffen School of Medicine at UCLA And The Semel Institute for Neuroscience and Human Behavior at UCLA ID: 217505

olanzapine risperidone evidence confidence risperidone olanzapine confidence evidence quetiapine risk trials level aripiprazole effect patients nnh adverse effects amp

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Slide1

Off-Label Use of Atypical Antipsychotics: An Update

Summary of the Agency for Healthcare Research and Quality “AHRQ” Report

David L. Fogelson, M.D.

Clinical Professor of Psychiatry

David Geffen School of Medicine at UCLA

And The

Semel

Institute for Neuroscience and Human Behavior at UCLASlide2

Suggested Citation for most material in this presentation

Maglione

M,

Ruelaz

Maher A, Hu J, Wang Z,

Shanman

R,

Shekelle

PG, Roth

B, Hilton L,

Suttorp

MJ, Ewing BA,

Motala

A, Perry T.

Off-Label

Use of

Atypical Antipsychotics

: An Update. Comparative Effectiveness Review No. 43. (Prepared by

the Southern

California Evidence-based Practice Center under Contract No.

HHSA290-2007-10062-1

.) Rockville, MD: Agency for Healthcare Research and Quality. September 2011

.

Available at: www.effectivehealthcare.ahrq.gov/reports/final.cfm

.Slide3

What is the AHRQ Report?

A review of the expanding use of atypical antipsychotics for off label indications

Examined the efficacy, comparative effectiveness, benefits, and adverse effects

170 studies of efficacy or comparative effectiveness

180 studies of adverse effects

The review includes studies through May 2011

I have reviewed additional articles for this presentation

Intended to inform discussion of options and decision making

Not meant to be construed as a clinical guideline Slide4

What was Reviewed?

All extant

atypicals

were used as search terms

Searched all controlled trials comparing an atypical to placebo, to another atypical, or other pharmacotherapy, for off-label conditions

Conditions

Anxiety disorders

ADHD

Dementia & Agitation associated with Aging

Major Depression

Eating Disorders

Insomnia

OCD

PTSD

Personality Disorders

Substance Abuse

Tourette’s Syndrome

Observational Studies included if > 1,000 subjectsSlide5

What are FDA approved Atypicals?

Aripiprazole

(

Abilify

)

Asenapine

(

Saphris

)

Clozapine (

Clozaril

)

Iloperidone

(

Fanapt

)

Lurasidone

(Latuda)

Olanzapine (Zyprexa)

Paliperidone

(

Invega

)

Quetiapine

(Seroquel)

Risperidone

(Risperdal)

Ziprasidone

(Geodon)Slide6

Background

By 2001 96% of prescribed antipsychotics were

atypicals

90% prescribed to children are

atypicals

A class effect of

atypicals

cannot be assumed for any mental disorder

For most

atypicals

evidence lacking for effectiveness and comparative effectiveness for many indications

Risk benefit ratio must be considered

Adverse Effects may outweigh benefitSlide7

Conclusions about Efficacy, from most effective to least

Improve Behavioral Symptoms of Dementia

Several have approved indications in Depression and others show efficacy

Growing evidence for efficacy in:

Obsessive Compulsive Disorder

Combat-related PTSD

Generalized Anxiety Disorder

Evidence is too limited to estimate benefit in Borderline Personality Disorder

Evidence is insufficient for treatment of Tourette’sSlide8

Conclusions about Adverse Reactions

Risk of death in patients 65 and older increased by atypical and typical antipsychotics

Recent data contradicts this assertion

Weight Gain, most severe with olanzapine

Risks for endocrine/metabolic abnormalities & diabetes are less certain, but are present

Sedative Effects are common in all age groups

Urinary retention is found in the elderlySlide9

Conclusions about Inefficacy

Evidence is “stronger” that there is no increase in body weight in Anorexia Nervosa (even though weight gain is a common adverse side effect)

Evidence is “stronger” that there is inefficacy in Substance Abuse DisordersSlide10

Trends in Off-Label Use

Most Commonly Prescribed Off-Label

Risperidone

,

Quetiapine

, & Olanzapine

Most Commonly Studied for Off-Label use

Risperidone

, Olanzapine, &

Quetiapine

The Least Studied

Aripiprazole

,

Ziprasidone

Not studied for Off-Label use

Asenapine

,

Iloperidone

,

Lurasidone

, &

Paliperidone

Due to severe blood

dyscrasia

risk with Clozapine it was not included in this reviewSlide11

Trends in Off-Label Use

Since 2005 FDA regulatory warning about severe risks in elderly, use has declined in the elderly

Even so, atypical use is higher in long-term care settings than in the communitySlide12

Does Effectiveness/Harm vary by race, ethnicity, gender, or age?

Few studies adequately address this question

One study examined effect by gender

No studies stratified results by race, ethnicity

A couple studies did stratify by ageSlide13

Strength of Evidence for Efficacy or Inefficacy of Atypicals

for Off-Label Indications

AHRQ Report uses a 4 point “Strength of Evidence Scale” to indicate confidence in effect

Effect is defined as either “medication can improve symptoms or medication does not improve symptoms”

0: evidence unavailable or does not permit a conclusion

1: Low confidence that the evidence reflects the true effect; further research is likely to change confidence level and estimate of effect

2: Moderate confidence, evidence reflects true effect; further research may change confidence level and may change estimate of effect

3: High confidence evidence reflects true effect; further research very unlikely to change confidence level in the estimate of effect Slide14

Evidence Supports use of Five Atypicals

Aripiprazole

Olanzapine

Quetiapine

Risperidone

Ziprasidone

The next slides will review the Evidence of their Efficacy in specific disordersSlide15

Dementia, confidence levels

Rated Strength of Evidence in Overall (global scores) symptoms, Agitation, & Psychosis

Overall

Aripiprazole

2; Olanzapine 1;

Quetiapine

1;

Risperidone

3

Agitation

Aripiprazole

1; Olanzapine 2;

Quetiapine

no trials (a more recent meta-analysis suggests 1);

Risperidone

3

Psychosis

Aripiprazole

1; Olanzapine 1;

Quetiapine

no trials;

Risperidone

3Slide16

Dementia, comments on findings

General improvement in behavioral symptoms

Effect sizes are small

Less than .2 standard deviations of difference between treatment and control groups

No class effect

Risperidone

>

Aripiprazole

=Olanzapine>

QuetiapineSlide17

Major Depressive Disorder (MDD), confidence levels

Rated Strength of Evidence

for

M

onotherapy

and as Augmentation for MDD only; 36 trials

Monotherapy

, MDD

Aripiprazole

no trials;

Olanzapine

2

does not improve symptoms

;

Quetiapine

2, NNT =13, remission & 6 for response;

Risperidone

no trials

Augmentation of SSRI/SNRI, MDD

Aripiprazole

approved indication; Olanzapine Approved

Indication for Rx resistant;

Quetiapine

Approved Indication;

Risperidone

2, NNT = 8, remission & 7 for response;

Ziprasidone

1Slide18

Bipolar Depression (BPD)

Not part of AHRQ Review

Monotherapy

, BPD

Aripiprazole

not reviewed; Olanzapine not reviewed;

Quetiapine

Approved Indication;

Risperidone

not reviewed;

Lurasidone

Approved Indication

Augmentation, BPD

Aripiprazole

not reviewed; Olanzapine Approved Indication as

Symbyax

;

Quetiapine

not reviewed;

Risperidone

not reviewedSlide19

Obsessive Compulsive Disorder, Augmentation of SSRIs

Augmentation of SSRIs, response is a 30% improvement on YBOCS

Aripiprazole

no trials

Olanzapine, confidence level = 1

Quetiapine

, confidence level = 1, weak effect

Risperidone

, level = 2, NNT = 5, OR = 3.9

Ziprasidone

, level = 1, weak effectSlide20

Obsessive Compulsive Disorder, Comments about Findings

Risperidone

is

most effective

Olanzapine

and

Ziprasidone

have a weak effect

May have similar effect, confidence level = 1

Other meds have not been shown to be effective

Clozapine may exacerbate OCD Symptoms

Psychopharmacology (

Berl

).

 2013 May 10. [

Epub

ahead of

print]

Influence

of polymorphisms in genes SLC1A1, GRIN2B, and GRIK2 on clozapine-induced 

obsessive-compulsive symptoms.

Cai

J

Zhang W

Yi Z

Lu W

Wu Z

Chen J

Yu S

Fang Y

Zhang

C

.Schizophrenia

Program, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, 200030, People's Republic of China.Slide21

Post Traumatic Stress Disorder, Adjunctive

Ten trials

Aripiprazole

, no trials

Olanzapine

, evidence unavailable or does not permit a conclusion

Quetiapine

, evidence unavailable or does not permit a conclusion

Risperidone

, confidence level = 2, combat related (DOD guidelines disagree based on 2010 VA study in 247 veterans, found ineffective)Slide22

Comments about PTSD

Evidence insufficient to determine effect of

Risperidone

in abused women with PTSD

Evidence for Olanzapine and

Quetiapine

insufficient for analysisSlide23

Generalized Anxiety Disorder

Aripiprazole

, no trials

Olanzapine, no trials

Quetiapine

, confidence level = 2

Three large trials

26% greater likelihood of responding (> 50% improvement on HAMA) than placebo

Risperidone

, no trialsSlide24

Borderline Personality Disorder, confidence levels

12 trials in Personality Disorders

Aripiprazole

, 1

Olanzapine,

mixed results in 7 trials, does not permit a

conclusion

Quetiapine

, 1

Risperidone

, no trials

Ziprasidone

, 1, ineffectiveSlide25

Personality Disorders: Schizotypal

Two small trials with

Risperidone

One superior to placebo

One no difference from placebo

Unable to reach a conclusion, data insufficientSlide26

Anorexia Nervosa, body weight restitution, confidence levels represent inefficacy

Six Trials

Aripiprazole

, no trials

Olanzapine, 2, ineffective

Quetiapine

, 1, ineffective

Risperidone

, no trialsSlide27

Substance Abuse; confidence levels represent inefficacy

33 trials

Aripiprazole

, Alcohol-2, Methamphetamine-1

Olanzapine, Alcohol-1, Cocaine-1

Quetiapine

, Alcohol-1

Risperidone

, Cocaine-1, Methadone-1Slide28

Other Possible Indications

Tourette’s syndrome, data insufficient to permit conclusions

One small trial indicated

Risperidone

is at least as effective as

pimozide

or clonidine

Insomnia, very limited data, n = 13, of inefficacy for

QuetiapineSlide29

Attention Deficit Hyperactivity Disorder

ADHD, no co-occurring disorders

One trial showed

Risperidone

superior to placebo for aggression related to ADHD

Risperidone

may be efficacious

ADHD in the context of mental retardation

One trial showed

Risperidone

more effective than methylphenidate

Risperidone

may be more effective than methylphenidateSlide30

Autism Spectrum Disorders

Risperidone

, FDA approved

 treatment of irritability

Efficacy was established in 3 short-term trials in children and adolescents (ages 5 to 17 years

)

symptoms

of aggression towards others, deliberate self-injuriousness, temper tantrums, and quickly changing

moods

Aripiprazole

, FDA approved

Treatment of irritability

Efficacy

established in two 8-week trials in pediatric patients (aged 6 to 17 years)

symptoms

of aggression towards others, deliberate self-injuriousness, temper tantrums, and quickly changing

moodsSlide31

Adverse Effects, Elderly Patients: Dementia

Typical and Atypical Antipsychotics increase risk of death in elderly with dementia

Number Needed to Harm (NNH) = 100 for

Atypicals

(

Aripiprazole

, OLZ, QTP,

Risperidone

)

1/100 patients died due to treatment

Confidence Level 3

Typicals

elevated mortality rate

NNH not calculated

Confidence Level 2Slide32

Adverse Effects, Elderly Patients: Dementia

A recent publication argues differently, morbidity and mortality are related to mental illness and dementia severity, not medication side effects.

Am J Psychiatry.

 2013 Jul 30.

doi

: 10.1176/appi.ajp.2013.12081046. [

Epub

ahead of

print]

The

Long-Term Effects of Conventional and Atypical Antipsychotics in Patients With Probable 

Alzheimer'sDisease

.

Lopez

OL

Becker JT

Chang YF

Sweet RA

Aizenstein

H

Snitz

B

Saxton J

McDade

E

Kamboh

MI

Dekosky

ST

Reynolds CF

Klunk

WE

.Slide33

Adverse Effects, Elderly Patients: Dementia, Relative Risk

Risperidone

has increased risk of cerebrovascular accidents, NNH = 34

Risperidone

and Olanzapine have increased risk for cardiovascular events

Risperidone

, NNH = 53

Olanzapine, NNH = 48

Confidence level, 2Slide34

Adverse Events, Elderly: EPS, Sedation, & Urinary Infections and Incontinence

EPS is common in the elderly,

confidence level = 2

Risperidone

, NNH = 20

Olanzapine, NNH = 10

Sedative Effects, NNH = 8-16, confidence level =2

Fatigue, NNH = 18-21, confidence level = 2

Urinary Adverse Effects, confidence level = 1

Infections

incontinenceSlide35

Weight and Metabolic Adverse Events, Adults Aged > 64

Weight gain is more common in patients taking olanzapine or

risperidone

than placebo

One study shows no metabolic risks with

Risperidone

One study showed a trend toward increased risk for diabetes with olanzapine

Weight Gain in Children and Adolescents; increased risk in patients taking

Risperidone

in two placebo controlled studiesSlide36

Weight and Metabolic Adverse Events, Adults Aged 18-64

Most promote weight gain

Olanzapine has greatest risk

OLZ, NNH = 3 versus NNH = 16-35 for other

atypicals

, confidence level = 3

Could not estimate risk for

Ziprasidone

Increased Risk for Endocrine

Diabetes:

Quetiapine

,

Risperidone

,

Ziprasidone

, Olanzapine

Elevated Prolactin with

Risperidone

&

Lurasidone

Increased Risk for Metabolic Abnormalities

Olanzapine in particular

Magnitude of risk unknown

Confidence level = 1Slide37

EPS, Sedative, & Fatigue Adverse Events, Adults Aged 18-64

Elevated risk for EPS, confidence level 1

Aripiprazole

, NNH = 11,

akathisia

= 7

Quetiapine

, NNH = 36

Ziprasidone

, NNH = 11

Sedative Side Effects & Fatigue

Applies to

Aripiprazole

, Olanzapine,

Quetiapine

,

Risperidone

, &

Ziprasidone

Sedation NNH = 3-11, confidence level 2

Quetiapine

, fatigue, NNH = 14-19Slide38

What is known about the risk for tardive dyskinesia?

Woods SW et al in J

Clin

Psychiatry 2010; 71(4):

463-474

in

a naturalistic study found that patients exposed to

atypicals

have 55% of the risk of

conventionals

for TD.

Woods

literature review in the same article, found a lower risk, estimated to be 25%. Slide39

What is the risk for TD when combining atypicals

with conventional antipsychotic medication?

D

, Woods et al in J

Clin

Psychiatry 2010; 71(4):

463-474

naturalistic

study found

patients

treated with a combination of atypical plus conventional antipsychotic have more than twice the risk for developing TD compared to patients exposed to

conventionals

alone

While

it is common practice to employ this combination when

monotherapy

fails, one must consider the risk benefit of this therapy in light of the markedly increased risk for tardive

dyskinesia

Note that there is little

or no evidence that combination therapy is effective.

See

review

Antipsychotic

polypharmacy

in schizophrenia: benefits and risks.

Barnes TR, 

Paton

C

.CNS

Drugs. 2011 May;25(5):383-99. Slide40

Gaps in Knowledge

Evidence is insufficient to estimate effect of demographic related factors on outcomes of treatment

Race

Ethnicity

Age (with exception of ADRs in patients with dementia)

Evidence is insufficient to permit conclusions about optimal dosage and duration of treatment Slide41

Gaps in Knowledge

Few head to head comparisons of typical and atypical antipsychotics

Either within or between classes

For any indication

To permit estimating comparative efficacy

Adverse Event Reporting not Standardized

Unable to perform “global analysis”

Unable to understand RisksSlide42

What Shall we tell our Patients?

Explain limited evidence for off-label indications

Explain risk for adverse effects including Tardive Dyskinesia

Trade-offs for benefits and risks in Elderly with Dementia

Insufficient data to estimate risks based on 2013 data

Refers to death and stroke

Always consider non-pharmaceutical interventions first

Behavioral

environmentalSlide43

What Shall we tell our Patients?

High Risk for weight gain

Discuss nutritional considerations

Discuss benefits of exercise

Pharmacotherapy to prevent weight gain should be considered

Individualize treatment plans

No two patients are exactly alike

Consider patients’ and significant others’ preferences