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
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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