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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 UCLA
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.
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
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 subjects
What are FDA approved Atypicals?
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Aripiprazole (Abilify)
Asenapine (Saphris)
Clozapine (Clozaril)
Iloperidone (Fanapt)
Lurasidone (Latuda)
Olanzapine (Zyprexa)
Paliperidone (Invega)
Quetiapine (Seroquel)
Risperidone (Risperdal)
Ziprasidone (Geodon)
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 benefit
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’s
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 elderly
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 Disorders
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 review
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 community
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 age
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
Evidence Supports use of Five
Atypicals
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Aripiprazole
Olanzapine
Quetiapine
Risperidone
Ziprasidone
The next slides will review the Evidence of
their Efficacy in specific disorders
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 3
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>Quetiapine
Major Depressive Disorder (MDD),
confidence levels
• Rated Strength of Evidence for Monotherapy 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 1
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 reviewed
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 effect
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
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•
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.
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)
Comments about PTSD
• Evidence insufficient to determine
effect of Risperidone in abused
women with PTSD
• Evidence for Olanzapine and
Quetiapine insufficient for analysis
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 trials
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, ineffective
Personality Disorders: Schizotypal
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Two small trials with Risperidone
One superior to placebo
One no difference from placebo
Unable to reach a conclusion, data insufficient
Anorexia Nervosa, body weight
restitution, confidence levels
represent inefficacy
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Six Trials
Aripiprazole, no trials
Olanzapine, 2, ineffective
Quetiapine, 1, ineffective
Risperidone, no trials
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-1
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 Quetiapine
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
methylphenidate
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 selfinjuriousness, 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 selfinjuriousness, temper tantrums, and quickly changing moods
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 2
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.
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, 2
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
– incontinence
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
studies
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 = 1
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 = 14-19
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%.
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.
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
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 Risks
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
• environmental
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