Off-Label Use of Atypical Antipsychotics: An Update

1
Off-Label Use of Atypical Antipsychotics An
Update

• Prepared for
• Agency for Healthcare Research and Quality (AHRQ)
  
• www.ahrq.gov

2
Outline of Material

• Introduction to atypical antipsychotics and
  prescribing for other than approved indications
  (off-label)
• Systematic review methods
• The clinical questions addressed by the
  comparative effectiveness review (CER)
• Modes of statistical analysis and results
  reporting in the CER
• Results of studies and evidence-based conclusions
  about effectiveness and adverse effects of
  atypical antipsychotics used off-label
• Gaps in knowledge
• What to discuss with patients and their caregivers

Maglione M, Ruelaz Maher A, Hu J, et al.
Comparative Effectiveness Review No. 43.
Available at www.effectivehealthcare.ahrq.gov/offl
abelantipsych.cfm.
3
Introduction to Atypical Antipsychotics (1 of 4)

• Antipsychotics can be classified into two
  categories, based on the timeline of their
  development, pharmacology, and anticipated
  adverse effects profiles
• Typical antipsychotics, also called conventional
  or firstgeneration antipsychotics
• Atypical antipsychotics, also called
  secondgeneration antipsychotics
• Typical antipsychotics were the first successful
  pharmacological treatments for primary psychotic
  disorders, such as schizophrenia.
• Typical antipsychotics are associated with side
  effects that are difficult to manage and in some
  cases irreversible.
• Atypical antipsychotics were developed in
  response to avoid these adverse effects.

Maglione M, Ruelaz Maher A, Hu J, et al.
Comparative Effectiveness Review No. 43.
Available at www.effectivehealthcare.ahrq.gov/offl
abelantipsych.cfm.
4
Introduction to Atypical Antipsychotics (2 of 4)

• By 2001, 95.9 percent of antipsychotics
  prescribed to new users were of the atypical
  class.
• As of the date of this review, nine
  second-generation, atypical antipsychotic drugs
  have been approved by the U.S. Food and Drug
  Administration (FDA), some for indications other
  than primary psychoses.
• Aripiprazole (Abilify)
• Asenapine (Saphris)
• Clozapine (Clozaril, FazaClo)
• Iloperidone (Fanapt)
• Olanzapine (Zyprexa)
• Paliperidone (Invega)
• Quetiapine (Seroquel)
• Risperidone (Risperdal)
• Ziprasidone (Geodon)

Maglione M, Ruelaz Maher A, Hu J, et al.
Comparative Effectiveness Review No. 43.
Available at www.effectivehealthcare.ahrq.gov/offl
abelantipsych.cfm.
5
Introduction to Atypical Antipsychotics (3 of 4)

• Several atypical antipsychotics are approved by
  the FDA for indications in addition to primary
  psychoses, including autism spectrum disorders,
  bipolar disorder, and major depressive disorder.
• Aripiprazole (Abilify?) bipolar mania
• Olanzapine (Zyprexa?) manic or mixed episodes of
  bipolar I
• Quetiapine (Seroquel?) bipolar mania and bipolar
  depression
• Risperidone (Risperdal?) manic or mixed episodes
  of bipolar I irritability associated with autism
• Prescribing of atypical antipsychotics has
  expanded beyond these approved indications.

Maglione M, Ruelaz Maher A, Hu J, et al.
Comparative Effectiveness Review No. 43.
Available at www.effectivehealthcare.ahrq.gov/offl
abelantipsych.cfm.
6
Introduction to Atypical Antipsychotics (4 of 4)

• The FDA prohibits manufacturers from advertising
  or promoting the use of pharmaceuticals for
  indications that have not been approved by the
  FDA. To do so is illegal.
• Off-label prescribing by physicians is permitted.
• What is known about the efficacy or comparative
  effectiveness, benefits, and adverse effects of
  atypical antipsychotics when prescribed for
  unapproved (off-label) indications?

Maglione M, Ruelaz Maher A, Hu J, et al.
Comparative Effectiveness Review No. 43.
Available at www.effectivehealthcare.ahrq.gov/offl
abelantipsych.cfm.
7
Agency for Healthcare Research and Quality (AHRQ)
Comparative Effectiveness Review (CER) Development

• Topics are nominated through a public process,
  which includes submissions from health care
  professionals, professional organizations, the
  private sector, policymakers, members of the
  public, and others.
• A systematic review of all relevant clinical
  studies is conducted by independent researchers,
  funded by AHRQ, to synthesize the evidence in a
  report summarizing what is known and not known
  about the select clinical issue. The research
  questions and the results of the report are
  subject to expert input, peer review, and public
  comment.
• The results of these reviews are summarized into
  Clinician Research Summaries and Consumer
  Research Summaries for use in decisionmaking and
  in discussions with patients. The Summaries and
  the full report, with references for included and
  excluded studies, are available at
  www.effectivehealthcare.ahrq.gov/offlabelantipsych
  .cfm.

Maglione M, Ruelaz Maher A, Hu J, et al.
Comparative Effectiveness Review No. 43.
Available at www.effectivehealthcare.ahrq.gov/offl
abelantipsych.cfm.
8
Rating the Strength of Evidence From the
Comparative Effectiveness Review

• The strength of evidence was classified into four
  broad categories

High ??? Further research is very unlikely to change the confidence in the estimate of effect.
Moderate ??? Further research may change the confidence in the estimate of effect and may change the estimate.
Low ??? Further research is likely to change the confidence in the estimate of effect and is likely to change the estimate.
Insufficient ??? Evidence either is unavailable or does not permit estimation of an effect.
Maglione M, Ruelaz Maher A, Hu J, et al.
Comparative Effectiveness Review No. 43.
Available at www.effectivehealthcare.ahrq.gov/offl
abelantipsych.cfm.
9
Clinical Questions Addressed by theComparative
Effectiveness Review (1 of 2)

• Clinical questions addressed by the comparative
  effectiveness review include
• What are the leading off-label uses of atypical
  antipsychotics in utilization studies? How have
  trends in utilization changed in recent years,
  including inpatient versus outpatient use? What
  new uses are being studied in trials?
• What does the evidence show regarding the
  efficacy and comparative effectiveness of
  atypical antipsychotics for off-label
  indications?
• How do atypical antipsychotic medications compare
  with other drugs, including first-generation
  antipsychotics, for off-label indications?

Maglione M, Ruelaz Maher A, Hu J, et al.
Comparative Effectiveness Review No. 43.
Available at www.effectivehealthcare.ahrq.gov/offl
abelantipsych.cfm.
10
Clinical Questions Addressed by theComparative
Effectiveness Review (2 of 2)

• What are the potential adverse effects and/or
  complications involved with off-label prescribing
  of atypical antipsychotics? How do they compare
  within the class and with other drugs used for
  the conditions?
• What is the effective dose and time limit for
  atypical antipsychotics used in off-label
  indications?

Maglione M, Ruelaz Maher A, Hu J, et al.
Comparative Effectiveness Review No. 43.
Available at www.effectivehealthcare.ahrq.gov/offl
abelantipsych.cfm.
11
Clinically Significant Outcomes of Interestin
the Comparative Effectiveness Review (1 of 2)

• A variety of validated assessment instruments are
  used to measure outcomes of treatment with
  atypical antipsychotics, both in practice and in
  clinical studies. Remission rates and changes in
  symptom severity are reported. Response rate is
  defined as the proportion of participants
  achieving a degree of improvement on a rating
  scale that was specified a priori.

Indication Outcome Assessment Instruments
Dementia BEHAVE-AD Behavioral Pathology in Alzheimers Disease Rating Scale BPRS Brief Psychiatric Rating Scale NPI Neuropsychiatric Inventory Scale
Major Depressive Disorder HAM-D Hamilton Depression Rating Scale MADRS Montgomery-Asberg Depression Rating Score
Obsessive-Compulsive Disorder YBOCS Yale-Brown Obsessive Compulsive Scale
Eating Disorders BMI body mass index
Generalized Anxiety Disorder HAM-A Hamilton Anxiety Rating Scale
Maglione M, Ruelaz Maher A, Hu J, et al.
Comparative Effectiveness Review No. 43.
Available at www.effectivehealthcare.ahrq.gov/offl
abelantipsych.cfm.
12
Clinically Significant Outcomes of Interestin
the Comparative Effectiveness Review (2 of 2)

• A variety of validated assessment instruments are
  used to measure outcomes of treatment with
  atypical antipsychotics, both in practice and in
  clinical studies. Remission rates and changes in
  symptom severity are reported. Response rate is
  defined as the proportion of participants
  achieving an a priori-specified degree of
  improvement on a rating scale.

Indication Outcome Assessment Instruments
Personality Disorder (Borderline or Schizotypal) SCL-90-R Symptom Checklist 90 Revised CGI-BPD Clinical Global ImpressionsBPD HAM-A HAM-D MADRS BPRS PANSS Positive and Negative Symptoms Scale
Post-traumatic Stress Disorder (PTSD) CAPS Clinician Administered PTSD Scale
Substance Abuse CCQ Cocaine Craving Questionnaire ASI Addiction Severity Index
Tourettes Syndrome YGTS Yale Global Tic Severity CGI-I Clinical Global ImpressionsImprovement
Insomnia Sleep quality and onset
Maglione M, Ruelaz Maher A, Hu J, et al.
Comparative Effectiveness Review No. 43.
Available at www.effectivehealthcare.ahrq.gov/offl
abelantipsych.cfm.
13
Adverse Effects of Interest in theComparative
Effectiveness Review

• The adverse effect profiles of the atypical
  antipsychotics are not expected to vary according
  to indication (with the exception of dementia,
  which is associated with older age).
• Patient age is expected to influence the adverse
  effect profiles.
• Reported adverse events were evaluated according
  to age groups
• Adults 1864 years of age
• Elderly adults with dementia, aged 65 and older
• Key adverse events of interest are
• Mortality
• Weight gain
• Endocrine disorders and diabetes
• Cardiovascular events
• Extrapyramidal symptoms
• Sedation

Maglione M, Ruelaz Maher A, Hu J, et al.
Comparative Effectiveness Review No. 43.
Available at www.effectivehealthcare.ahrq.gov/offl
abelantipsych.cfm.
14
Summary of Study Characteristics Evaluated in the
Effectiveness Review PICOTS Framework

• Population adults
• All indications for which the intervention does
  not have formal approval
• Interventions atypical antipsychotics
• All formulations, routes of administration, and
  doses
• Comparators Other antipsychotics, other active
  interventions, placebo, or no active intervention
• Outcomes
• Symptom response and remission, general health
  and quality of life
• Key adverse effects mortality, weight gain,
  endocrine abnormalities/ diabetes, cardiovascular
  events, extrapyramidal symptoms, and sedation
• Timing any time point, ranging from lt6 weeks to
  months/years
• Setting All settings, including
  community-dwelling, nursing home, inpatient,
  Veterans Administration, and outpatient

Maglione M, Ruelaz Maher A, Hu J, et al.
Comparative Effectiveness Review No. 43.
Available at www.effectivehealthcare.ahrq.gov/offl
abelantipsych.cfm.
15
Summary of Studies Included in theComparative
Effectiveness Review (1 of 2)

• Studies of efficacy, effectiveness, benefits, and
  adverse effects of atypical antipsychotics as
  treatment for several off-label indications are
  reported in the clinical literature.
• There are no reports of studies of off-label use
  of the newer atypical antipsychotics asenapine,
  iloperidone, and paliperidone.
• The atypical antipsychotic clozapine was not
  included in the review clozapine can only be
  prescribed in a system that provides weekly
  monitoring for bone marrow-suppression disorders
  as a condition of receiving the treatment.

Maglione M, Ruelaz Maher A, Hu J, et al.
Comparative Effectiveness Review No. 43.
Available at www.effectivehealthcare.ahrq.gov/offl
abelantipsych.cfm.
16
Summary of Studies Included in theComparative
Effectiveness Review (2 of 2)

• Off-label indications of atypical antipsychotics
  that have been studied and reported in the
  clinical literature are
• Dementia
• Major depressive disorder (MDD)
• Obsessive-compulsive disorder (OCD)
• Borderline personality disorder (BPD)
• Post-traumatic stress disorder (PTSD)
• Substance abuse
• Eating disorders
• Anxiety
• Insomnia

Maglione M, Ruelaz Maher A, Hu J, et al.
Comparative Effectiveness Review No. 43.
Available at www.effectivehealthcare.ahrq.gov/offl
abelantipsych.cfm.
17
Modes of Results Reporting and Statistical
Analysis in the Comparative Effectiveness Review
(1 of 2)

• 95 Confidence Interval The range of
  statistically valid results that will include the
  true population mean in 95 of 100 repeated
  experiments.
• Mean Difference (MD) The difference between
  treatment and comparison group means.
• Standardized mean difference (SMD) is the mean
  difference expressed in units of standard
  deviations. It is a method for normalizing
  results to a uniform scale for pooled analysis,
  when different scales are used in trials.
• For MD and SMD, the result is statistically
  significant (p lt 0.05) when the 95 confidence
  interval does not include 0.0, which is the point
  of no difference between groups.
• Relative Risk (RR) The ratio of the rate
  (absolute risk, probability) of an event in the
  treatment group to the rate of the event in the
  comparison group.
• For RR, the result is statistically significant
  at p lt 0.05 when the 95 confidence interval does
  not include 1.0, which is the point of equal risk
  for both groups.

Maglione M, Ruelaz Maher A, Hu J, et al.
Comparative Effectiveness Review No. 43.
Available at www.effectivehealthcare.ahrq.gov/offl
abelantipsych.cfm.
18
Modes of Results Reporting and Statistical
Analysis in the Comparative Effectiveness Review
(2 of 2)

• Absolute Risk Difference The absolute value of
  the mathematical difference between the rates
  (risk) of an event in the treatment and
  comparison groups.
• ARD ARCART
• Number Needed To Treat or Harm (NNT, NNH) The
  number of patients to be treated to observe
  benefit or harm in one patient more than seen in
  the comparison group. The number of patients to
  be treated in order to find a benefit or harm
  attributable to the intervention.
• NNT or NNH ARCART-1 for a benefit or adverse
  event, respectively
• Number of attributable events per 1,000 1,000 x
  ARCART
• Effect sizes of 0.20 or smaller were considered
  small, sizes of 0.50 and greater were considered
  large, and those between were considered moderate.

Maglione M, Ruelaz Maher A, Hu J, et al.
Comparative Effectiveness Review No. 43.
Available at www.effectivehealthcare.ahrq.gov/offl
abelantipsych.cfm.
19
Results Atypical Antipsychotics for Dementia
Effect Size/Meta-analytic Result SMD and 95 CI, With Strength of Evidence Effect Size/Meta-analytic Result SMD and 95 CI, With Strength of Evidence Effect Size/Meta-analytic Result SMD and 95 CI, With Strength of Evidence
Atypical Antipsychotics in Placebo Comparisons Total Score/ Global Impressions Psychosis Agitation Strength of Evidence
Atypicals as a Class Combined result (18 studies, gt4,578 patientsa) 0.17 (0.08, 0.25) 0.12 (0.04. 0.19) 0.20 (0.12, 0.27) High ???
Olanzapine (4 studies, gt 840 patientsa) 0.12 (0.00, 0.25) NSD 0.19 (0.07, 0.31) Moderate ???
Risperidone (6 studies, 2,213 patientsb) 0.19 (0.00, 0.38) 0.20 (0.05, 0.36) 0.22 (0.09, 0.35) High ???
SMD Standardized mean difference the difference between the post-treatment mean scores of treatment and control groups. The scores from a variety of assessment instruments were standardized to a common scale (standard deviations) for meta-analysis. 95 CI 95-percent confidence interval the range of statistically valid results p 0.05 when the confidence interval crosses 0 (mean difference measures) or 1 (relative risk and odds ratios). NSD no statistically significant difference a Estimated One study of olanzapine did not report the number of patients. b Estimated The exact number of patients receiving either risperidone or placebo was not provided for three multiple treatment comparisons . SMD Standardized mean difference the difference between the post-treatment mean scores of treatment and control groups. The scores from a variety of assessment instruments were standardized to a common scale (standard deviations) for meta-analysis. 95 CI 95-percent confidence interval the range of statistically valid results p 0.05 when the confidence interval crosses 0 (mean difference measures) or 1 (relative risk and odds ratios). NSD no statistically significant difference a Estimated One study of olanzapine did not report the number of patients. b Estimated The exact number of patients receiving either risperidone or placebo was not provided for three multiple treatment comparisons . SMD Standardized mean difference the difference between the post-treatment mean scores of treatment and control groups. The scores from a variety of assessment instruments were standardized to a common scale (standard deviations) for meta-analysis. 95 CI 95-percent confidence interval the range of statistically valid results p 0.05 when the confidence interval crosses 0 (mean difference measures) or 1 (relative risk and odds ratios). NSD no statistically significant difference a Estimated One study of olanzapine did not report the number of patients. b Estimated The exact number of patients receiving either risperidone or placebo was not provided for three multiple treatment comparisons . SMD Standardized mean difference the difference between the post-treatment mean scores of treatment and control groups. The scores from a variety of assessment instruments were standardized to a common scale (standard deviations) for meta-analysis. 95 CI 95-percent confidence interval the range of statistically valid results p 0.05 when the confidence interval crosses 0 (mean difference measures) or 1 (relative risk and odds ratios). NSD no statistically significant difference a Estimated One study of olanzapine did not report the number of patients. b Estimated The exact number of patients receiving either risperidone or placebo was not provided for three multiple treatment comparisons . SMD Standardized mean difference the difference between the post-treatment mean scores of treatment and control groups. The scores from a variety of assessment instruments were standardized to a common scale (standard deviations) for meta-analysis. 95 CI 95-percent confidence interval the range of statistically valid results p 0.05 when the confidence interval crosses 0 (mean difference measures) or 1 (relative risk and odds ratios). NSD no statistically significant difference a Estimated One study of olanzapine did not report the number of patients. b Estimated The exact number of patients receiving either risperidone or placebo was not provided for three multiple treatment comparisons .
Maglione M, Ruelaz Maher A, Hu J, et al.
Comparative Effectiveness Review No. 43.
Available at www.effectivehealthcare.ahrq.gov/offl
abelantipsych.cfm.
20
Summary of Benefits Dementia

• Atypical antipsychotics, as a class, improve
  behavioral symptoms of dementia, although effect
  sizes are small.
• Strength of Evidence High
• When examined individually, some, but not all,
  atypical antipsychotics demonstrate statistically
  significant differences from placebo for some
  outcomes.
• Risperidone is superior to placebo on both
  agitation and psychosis subscales.
• Strength of Evidence High
• Olanzapine improves scores on agitation subscales
  but not psychosis scores.
• Strength of Evidence Moderate

Maglione M, Ruelaz Maher A, Hu J, et al.
Comparative Effectiveness Review No. 43.
Available at www.effectivehealthcare.ahrq.gov/offl
abelantipsych.cfm.
21
Results Atypical Antipsychotics for Major
Depressive Disorder (1 of 2)
Atypical Outcome Result NNT, SMD, and 95 CI SOE
Augmentation of SSRIs/SNRIs Augmentation of SSRIs/SNRIs Augmentation of SSRIs/SNRIs
Risperidone (3 studies, 645 patients) HAM-D remission rate One in every eight patients experienced remission attributable to risperidone treatment (score less than 7 or 8 over two visits). Moderate ???
Risperidone (3 studies, 645 patients) HAM-D response rate One in every seven patients responded with at least a 50 reduction in score attributable to risperidone. Moderate ???
Monotherapy Monotherapy Monotherapy Monotherapy
Quetiapine XR (5 studies, 2,454 patients) MADRS remission rate One in every 13 patients experienced remission attributable to olanzapine treatment (score less than 7 or 8 over two visits). Moderate ???
Quetiapine XR (5 studies, 2,454 patients) MADRS response rate One in every six patients responded with at least a 50 reduction in score attributable to quetiapine XR. Moderate ???
Olanzapine (3 studies, gt98 patients)a MADRS response and remission rates No statistically significant difference from placebo. Moderate ???
95 CI 95-percent confidence interval NNT number needed to treat SMD standard mean difference SNRI selective serotonin and norepinephrine reuptake inhibitor SOE strength of evidence SSRI selective serotonin reuptake inhibitor XR extended release a The number of patients was not reported in one study. 95 CI 95-percent confidence interval NNT number needed to treat SMD standard mean difference SNRI selective serotonin and norepinephrine reuptake inhibitor SOE strength of evidence SSRI selective serotonin reuptake inhibitor XR extended release a The number of patients was not reported in one study. 95 CI 95-percent confidence interval NNT number needed to treat SMD standard mean difference SNRI selective serotonin and norepinephrine reuptake inhibitor SOE strength of evidence SSRI selective serotonin reuptake inhibitor XR extended release a The number of patients was not reported in one study. 95 CI 95-percent confidence interval NNT number needed to treat SMD standard mean difference SNRI selective serotonin and norepinephrine reuptake inhibitor SOE strength of evidence SSRI selective serotonin reuptake inhibitor XR extended release a The number of patients was not reported in one study.
Aripiprazole, quetiapine XR, and combination
therapy with olanzapine and fluoxetine are FDA
approved for major depressive disorder.
Maglione M, Ruelaz Maher A, Hu J, et al.
Comparative Effectiveness Review No. 43.
Available at www.effectivehealthcare.ahrq.gov/offl
abelantipsych.cfm.
22
Summary of Benefits Atypical Antipsychotics for
Major Depressive Disorder

• Atypical antipsychotics increase the rate of
  response or remission when used as augmentation
  to SSRIs and SNRIs.
• Risperidone Strength of Evidence Moderate
• In monotherapy, quetiapine XR improves remission
  and response rates when compared with placebo,
  but olanzapine does not show efficacy.
• Strength of Evidence Moderate

MDD major depressive disorder SNRI selective
serotonin and norepinephrine reuptake inhibitor
SSRI selective serotonin reuptake inhibitor XR
extended release
Maglione M, Ruelaz Maher A, Hu J, et al.
Comparative Effectiveness Review No. 43.
Available at www.effectivehealthcare.ahrq.gov/offl
abelantipsych.cfm.
23
Results Atypical Antipsychotics
forObsessive-Compulsive Disorder

• Atypical antipsychotics are studied as
  augmentation of SSRIs and SNRIs in treating
  obsessive-compulsive disorder.

Atypical Outcome N Studies N Participants Effect Size/Meta-analysis Result Strength of Evidence
Augmentation of SSRIs/SNRIs, Placebo Comparisons Augmentation of SSRIs/SNRIs, Placebo Comparisons Augmentation of SSRIs/SNRIs, Placebo Comparisons Augmentation of SSRIs/SNRIs, Placebo Comparisons
Risperidone YBOCS response rate 3 97 One in every five patients demonstrated a response (improved YBOCS score) attributable to risperidone. Moderate ???
Comparative Effectiveness for Augmentation Comparative Effectiveness for Augmentation Comparative Effectiveness for Augmentation Comparative Effectiveness for Augmentation
Olanzapine Versus Risperidone YBOCS score 1 50 No statistically significant difference between olanzapine and risperidone. Low ???
SNRI selective serotonin and norepinephrine
reuptake inhibitor SSRI selective serotonin
reuptake inhibitor
Maglione M, Ruelaz Maher A, Hu J, et al.
Comparative Effectiveness Review No. 43.
Available at www.effectivehealthcare.ahrq.gov/offl
abelantipsych.cfm.
24
Summary of Benefits Atypical Antipsychotics for
Obsessive-Compulsive Disorder

• Risperidone improves symptoms of
  obsessive-compulsive disorder when used as an
  adjunct to selective serotonin reuptake
  inhibitors (SSRIs) for refractory patients.
• One in every five patients treated will show some
  benefit.
• Strength of Evidence Moderate
• Olanzapine and risperidone are similar in effect
  for augmentation of SSRIs.
• Strength of Evidence Low

Maglione M, Ruelaz Maher A, Hu J, et al.
Comparative Effectiveness Review No. 43.
Available at www.effectivehealthcare.ahrq.gov/offl
abelantipsych.cfm.
25
Results Atypical Antipsychotics for
Post-traumatic Stress Disorder
Atypical Versus Placebo Outcome N Studies N Participants Effect Size/Meta-analytic Result (95 Confidence Interval) Strength of Evidence
Risperidone Difference in CAPS score 4 151 (all causes) Score is 6.47 points lower with risperidone (from 0.32 to 12.61 lower) Moderate ???
Risperidone Difference in CAPS score 3 124 (combat-related) Score is 7.95 points lower with risperidone (from 1.06 to 14.84 lower) Moderate ???
Risperidone Difference in CAPS score (abused women) No summary result Insufficient???
Olanzapine Difference in CAPS score (all causes) No summary result Insufficient ???
Quetiapine Difference in CAPS score (all causes) No summary result Insufficient ???
PTSD post-traumatic stress disorder
Maglione M, Ruelaz Maher A, Hu J, et al.
Comparative Effectiveness Review No. 43.
Available at www.effectivehealthcare.ahrq.gov/offl
abelantipsych.cfm.
26
Summary of Benefits Post-traumatic Stress
Disorder

• Adjunctive treatment with risperidone reduces the
  symptoms of combat-related post-traumatic stress
  disorder (PTSD).
• Strength of Evidence Moderate
• The evidence for benefits of risperidone as
  treatment of abused women with PTSD is
  insufficient to determine an effect.
• Strength of Evidence Insufficient
• The evidence for olanzapine and quetiapine is
  insufficient for analysis.
• Strength of Evidence Insufficient

Maglione M, Ruelaz Maher A, Hu J, et al.
Comparative Effectiveness Review No. 43.
Available at www.effectivehealthcare.ahrq.gov/offl
abelantipsych.cfm.
27
Results and Summary of Benefits Atypical
Antipsychotics for Generalized Anxiety Disorder

• Quetiapine improves symptoms of generalized
  anxiety disorder.

Atypical Outcome N Studies N Participants Result (95 CI) Strength of Evidence
Quetiapine HAM-A percent responding 3 2,437 Response is 1.26-fold more likely with quetiapine than with placebo (from 1.02- to 1.56-fold). Response in 1 in 8 treated patients is attributable to quetiapine. Moderate ???
Olanzapine HAM-A percent responding 1 24 NSD Insufficient ???
Risperidone HAM-A percent responding 1 417 NSD Insufficient ???
95 CI 95-percent confidence interval NSD no
statistically significant difference
Maglione M, Ruelaz Maher A, Hu J, et al.
Comparative Effectiveness Review No. 43.
Available at www.effectivehealthcare.ahrq.gov/offl
abelantipsych.cfm.
28
Results and Summary of Benefits Atypical
Antipsychotics for Bipolar Personality Disorder

• Of seven studies of bipolar personality disorder
  (BPD), four showed statistically significant
  beneficial effects.
• Aripiprazole
• Two studies Strength of Evidence Low
• Olanzapine
• One study Efficacious at 510 mg/day but not at
  2.5 mg/day.
• Strength of Evidence Low
• Quetiapine
• One study Strength of Evidence Insufficient
• In summary, although there is some evidence for
  benefit from atypical antipsychotics for BPD, it
  is inadequate for a meta-analysis and conclusions
  about the statistical or clinical significance of
  the effect.

Maglione M, Ruelaz Maher A, Hu J, et al.
Comparative Effectiveness Review No. 43.
Available at www.effectivehealthcare.ahrq.gov/offl
abelantipsych.cfm.
29
Results and Summary of Benefits Atypical
Antipsychotics for Eating Disorders (Anorexia
Nervosa)

• Olanzapine and quetiapine do not increase BMI in
  patients with anorexia nervosa.

Atypical Outcome N Studies N Participants Result and 95 CI Strength of Evidence
Olanzapine BMI at 1 month 3 84 NSD (BMI may lie in a range from 0.56 kg lower to 0.57 kg higher) Moderate ???
Olanzapine BMI at 3 months 3 84 NSD (BMI may lie in a range from 0.34 kg lower to 0.84 kg higher) Moderate ???
Quetiapine BMI at 3 months 1 27 NSD (BMI may lie in a range from 1.74 kg lower to 1.54 kg higher) Low ???
95 CI 95-percent confidence interval BMI
body mass index NSD no statistically
significant difference
Maglione M, Ruelaz Maher A, Hu J, et al.
Comparative Effectiveness Review No. 43.
Available at www.effectivehealthcare.ahrq.gov/offl
abelantipsych.cfm.
30
Results Atypical Antipsychotics in Substance
Abuse Treatment

• Atypical antipsychotics are not effective as
  adjuncts in treating substance abuse.

Atypical Outcome No. Studies No. Participants Effect Size/Meta-analysis Summary Result and 95 CI Strength of Evidence
Alcohol Abuse Alcohol Abuse Alcohol Abuse Alcohol Abuse Alcohol Abuse
Aripiprazole Percentage completely abstinent 3 386 NSD The rate of abstinence with treatment lies between 2.8-fold more with placebo to 5.7-fold more with an atypical antipsychotic. Moderate ???
Quetiapine Percentage completely abstinent 3 386 NSD The rate of abstinence with treatment lies between 2.8-fold more with placebo to 5.7-fold more with an atypical antipsychotic. Moderate ???
Quetiapine Percentage completely abstinent 3 386 NSD The rate of abstinence with treatment lies between 2.8-fold more with placebo to 5.7-fold more with an atypical antipsychotic. Low ???
Cocaine Abuse Cocaine Abuse Cocaine Abuse Cocaine Abuse Cocaine Abuse
Olanzapine, Risperidone ASI composite score 3 129 NSD The score lies between 0.04 lower with treatment to 0.04 higher with treatment. Low ???
Cocaine or Opiate Abuse Cocaine or Opiate Abuse Cocaine or Opiate Abuse Cocaine or Opiate Abuse Cocaine or Opiate Abuse
Risperidone (with methadone treatment) ASI composite score 1 31 NSD The rate of reports of cocaine and opiate use did not differ between risperidone at 2 or 4 mg and placebo. Low ???
95 CI 95-percent confidence interval BMI
body mass index NSD no statistically
significant difference
Maglione M, Ruelaz Maher A, Hu J, et al.
Comparative Effectiveness Review No. 43.
Available at www.effectivehealthcare.ahrq.gov/offl
abelantipsych.cfm.
31
Results for Other Indications

• The evidence for efficacy of atypical
  antipsychotics is insufficient to permit
  conclusions for
• Tourettes syndrome
• Insomnia

Maglione M, Ruelaz Maher A, Hu J, et al.
Comparative Effectiveness Review No. 43.
Available at www.effectivehealthcare.ahrq.gov/offl
abelantipsych.cfm.
32
Adverse Effects of Atypical Antipsychotics

• The reviewed data were restricted to reports in
  studies of off-label use of atypical
  antipsychotics.
• With the exception of dementia, which is
  associated with older age, the adverse effects
  observed were not expected to be influenced by
  the diagnosis.
• Evidence was analyzed for two separate groups
• Elderly patients with dementia
• Adults aged 1864
• The atypical antipsychotic clozapine was not
  included in the review clozapine can only be
  prescribed in a system that requires weekly
  monitoring for bone marrow-suppression disorders
  before providing the drug.

Maglione M, Ruelaz Maher A, Hu J, et al.
Comparative Effectiveness Review No. 43.
Available at www.effectivehealthcare.ahrq.gov/offl
abelantipsych.cfm.
33
Adverse Effects in Elderly PatientsPlacebo
Comparisons (1 of 3)

• A previously published meta-analysis combined the
  results from 15 placebo comparisons of
  aripiprazole, olanzapine, quetiapine, and
  risperidone. The investigators found that, when
  compared with placebo, the risk of death in
  elderly patients (65 and older) with dementia was
  elevated during treatment with atypical
  antipsychotics.
• Typical antipsychotics are also associated with
  an increased risk of death among dementia
  patients, as revealed in a review of the
  literature reporting observational studies that
  was performed as part of the comparative
  effectiveness review.

Comparison N Studies N Participants Effect Size/Meta-analytic Result NNH Strength of Evidence
Atypical Antipsychotics vs. Placebo 15 5,204 Death of 1 in every 100 patients (over a 10- to 12-week course of treatment) is attributable to treatment with an atypical antipsychotic. High ???
Typical and Atypical Antipsychotics Cohort Studies 12 310,752 Elevated risk of death with both atypical and typical antipsychotics. Moderate ???
Schneider LS, Dagerman KS, Insel P. JAMA
20052941934-43. PMID16234500. NNH number
needed to harm (the number of patients that need
to be treated in order to find an adverse event
attributable to the drug)
Maglione M, Ruelaz Maher A, Hu J, et al.
Comparative Effectiveness Review No. 43.
Available at www.effectivehealthcare.ahrq.gov/offl
abelantipsych.cfm.
34
Adverse Effects in Elderly PatientsPlacebo
Comparisons (2 of 3)

• A meta-analysis for the comparative effectiveness
  review shows that among elderly patients (65 and
  older)
• Risperidone is associated with an increased risk
  of cerebrovascular accidents and cardiovascular
  adverse events.
• Olanzapine is associated with increased risk of
  cardiovascular adverse events.

Comparison N Studies N Participants Outcome Effect Size/Meta-analytic Result NNH Strength of Evidence
Risperidone vs. Placebo 4 1,852 Cerebrovascular accidents One in every 53 patients treated with risperidone will experience CVAs. Moderate ???
Risperidone vs. Placebo 6 2,767 Cardiovascular AE One in every 34 patients treated with risperidone will experience a cardiovascular AE. Moderate ???
Olanzapine vs. Placebo 5 1,218 Cardiovascular AE One in every 48 patients treated with olanzapine will experience a cardiovascular AE. Moderate ???
AE adverse events CVA cerebrovascular
accident NNH number needed to harm (the number
of patients that need to be treated in order to
find an adverse event attributable to the drug)
Maglione M, Ruelaz Maher A, Hu J, et al.
Comparative Effectiveness Review No. 43.
Available at www.effectivehealthcare.ahrq.gov/offl
abelantipsych.cfm.
35
Adverse Effects in Elderly PatientsPlacebo
Comparisons (3 of 3)
Meta-analytic Result NNH (N Studies N Participants) Meta-analytic Result NNH (N Studies N Participants) Meta-analytic Result NNH (N Studies N Participants) Meta-analytic Result NNH (N Studies N Participants)
Adverse Event Aripiprazole Olanzapine Quetiapine Risperidone SOE
EPSs NSD (4 1,080) 10 (1 242) NSD (3 609) 20 (5 1,477) Moderate ???
Sedation 16 (4 1,080) 9 (5 1,218) 4 (4 799) 10 (5 2,182) Moderate ???
Fatigue 22 (3 872) 34 (3 808) 34 (2 569) 34 (2 517) Moderate ???
Weight Gain NSD (2 695) 24 (3 808) NSD (1 236) 24 (2 517) High ???
EPSs extrapyramidal symptoms NSD no
statistically significant difference SOE
strength of evidence

• In summary, a meta-analysis of placebo comparison
  studies yielded the following results
• In elderly adults, extrapyramidal symptoms are
  common with risperidone and olanzapine.
• Strength of Evidence Moderate
• Atypical antipsychotics are associated with
  sedative effects and fatigue.
• Strength of Evidence Moderate
• Data not shown Atypical antipsychotics elevate
  the risk of urinary adverse effects in elderly
  patients (65), but the evidence is too limited
  to permit conclusions about the degree of risk.

Maglione M, Ruelaz Maher A, Hu J, et al.
Comparative Effectiveness Review No. 43.
Available at www.effectivehealthcare.ahrq.gov/offl
abelantipsych.cfm.
36
Summary of Adverse Effects in Elderly Patients (1
of 2)

• Antipsychotics increase the risk of death in
  elderly patients (65 and older) with dementia.
• For atypical antipsychotics, the death of 1 in
  100 patients can be attributed to the
  antipsychotic drug.
• Strength of Evidence High
• Risperidone is associated with an increased risk
  of cerebrovascular accidents.
• One in 34 patients will experience a
  cerebrovascular accident attributable to
  risperidone.
• Strength of Evidence Moderate
• Both risperidone and olanzapine are associated
  with increased risk of cardiovascular adverse
  events.
• For every 53 patients treated, 1 cardiovascular
  adverse event will occur due to risperidone.
• For every 48 patients treated, 1 cardiovascular
  adverse event will occur due to olanzapine.
• Strength of Evidence Moderate

Maglione M, Ruelaz Maher A, Hu J, et al.
Comparative Effectiveness Review No. 43.
Available at www.effectivehealthcare.ahrq.gov/offl
abelantipsych.cfm.
37
Summary of Adverse Effects in Elderly Patients (2
of 2)

• In elderly adults (65 and older), extrapyramidal
  symptoms are most common with risperidone and
  olanzapine.
• Strength of Evidence Moderate
• Atypical antipsychotics are associated with
  sedative effects and fatigue.
• Strength of Evidence Moderate
• Atypical antipsychotics elevate the risk of
  urinary adverse effects (infections,
  incontinence) in elderly patients, but the
  evidence is too limited to permit conclusions
  about the degree of risk.
• Strength of Evidence Low

Maglione M, Ruelaz Maher A, Hu J, et al.
Comparative Effectiveness Review No. 43.
Available at www.effectivehealthcare.ahrq.gov/offl
abelantipsych.cfm.
38
Adverse Effects in Adult PatientsPlacebo
Comparisons (1 of 2)

• The number of patients to be treated in order to
  observe an adverse effect on weight or appetite
  that is attributable to the intervention is
  lowest for olanzapine, being one in every three
  patients. In contrast, 1 of 35 patients treated
  with aripiprazole show the adverse effect. The
  strength of evidence for this finding is high.
• Endocrine and other lab test abnormalities are
  not as frequently examined or detected as is
  weight gain, although statistically significant
  increases when compared with placebo control
  groups are measurable.

NNH (N Studies N Participants) NNH (N Studies N Participants) NNH (N Studies N Participants) NNH (N Studies N Participants) NNH (N Studies N Participants) NNH (N Studies N Participants)
Aripiprazole Olanzapine Quetiapine Risperidone Ziprasidone SOE
Weight gain or appetite increase 35 (4 1,387) 3 (11 1,637) 16 (13 4, 733) 21 (4 434) Insufficient High ???
Endocrine and other metabolic lab test abnormalities Not Reported 12 (2 374) 18 (3 1,440) Not Reported Not Reported Low ???
Adults 1864 years of age. NNH number needed to harm SOE strength of evidence Adults 1864 years of age. NNH number needed to harm SOE strength of evidence Adults 1864 years of age. NNH number needed to harm SOE strength of evidence Adults 1864 years of age. NNH number needed to harm SOE strength of evidence Adults 1864 years of age. NNH number needed to harm SOE strength of evidence Adults 1864 years of age. NNH number needed to harm SOE strength of evidence Adults 1864 years of age. NNH number needed to harm SOE strength of evidence
Maglione M, Ruelaz Maher A, Hu J, et al.
Comparative Effectiveness Review No. 43.
Available at www.effectivehealthcare.ahrq.gov/offl
abelantipsych.cfm.
39
Adverse Effects in Adult PatientsPlacebo
Comparisons (2 of 2)

• As shown below, sedation is measurable with the
  use of all atypical antipsychotics studied, and
  fatigue may also be found.
• Strength of Evidence Moderate
• Extrapyramidal symptoms not found in
  placebo-treated groups are found with
  aripiprazole, quetiapine, and ziprasidone.
• Strength of Evidence Low

NNH (N Studies N Participants) NNH (N Studies N Participants) NNH (N Studies N Participants) NNH (N Studies N Participants) NNH (N Studies N Participants) NNH (N Studies N Participants)
Adverse Effect Aripiprazole Olanzapine Quetiapine Risperidone Ziprasidone Strength of Evidence
EPSs 11 (5 1,215) (Akathisia, NNH 7) NSD (3 136) 36 (7 2,566) NSD (1 25) 24 (3 482) Low ???
Sedation 8 (7 1,630) 6 (14 1,805) 3 (18 5,816) 11 (8 626) 6 (5 604) Moderate ???
Fatigue 15 (4 1,387) 19 (7 1,457) 18 (13 5,082) NSD (4 507) 14 (2 180) Moderate ???
Adults 1864 years of age. EPSs
extrapyramidal symptoms NNH number needed to
harm NSD no statistically significant
difference
Maglione M, Ruelaz Maher A, Hu J, et al.
Comparative Effectiveness Review No. 43.
Available at www.effectivehealthcare.ahrq.gov/offl
abelantipsych.cfm.
40
Summary of Adverse Effects in Adults (1 of 2)

• Antipsychotics in the atypical class generally
  promote weight gain in adults (ages 1864) and in
  the elderly (ages 65), but olanzapine is
  associated with greater risk than other
  atypicals.
• Olanzapine NNH 3 versus NNH 1635 for other
  atypical antipsychotics
• Strength of Evidence High
• Some atypical antipsychotics (olanzapine in
  particular) are associated with endocrine and
  metabolic abnormalities, but the degree of
  increased risk is not clear.
• Strength of Evidence Low

Maglione M, Ruelaz Maher A, Hu J, et al.
Comparative Effectiveness Review No. 43.
Available at www.effectivehealthcare.ahrq.gov/offl
abelantipsych.cfm.
41
Summary of Adverse Effects in Adults (2 of 2)

• The risk of extrapyramidal symptoms in adults
  (ages 1864) is elevated with aripiprazole (NNH
  11 akathisia, NNH 7), quetiapine (NNH 36),
  and ziprasidone (NNH 24)
• Strength of Evidence Low
• The risks of extrapyramidal symptoms with
  olanzapine and aripiprazole are about one-fourth
  of the risks for adult patients taking typical
  antipsychotics.
• Strength of Evidence Low
• In adults, atypical antipsychotics are associated
  with sedative effects and fatigue (sedation NNH
  3 for quetiapine, whereas others range from 611
  fatigue NNH 1419).
• Strength of Evidence Moderate

Maglione M, Ruelaz Maher A, Hu J, et al.
Comparative Effectiveness Review No. 43.
Available at www.effectivehealthcare.ahrq.gov/offl
abelantipsych.cfm.
42
Trends in Off-Label Use of Atypical Antipsychotics

• Since the FDA regulatory warning in 2005 about
  severe adverse events in the elderly (ages 65),
  the use of atypical antipsychotics for treating
  the elderly has declined. However, the
  statistical significance of the change is not
  known.
• Off-label use of atypical antipsychotics is
  higher in long-term care settings than in the
  community.
• No off-label use of the most recently approved
  atypical antipsychotics (asenapine, iloperidone,
  and paliperidone) has been reported in the
  literature.
• Risperidone, quetiapine, and olanzapine are the
  most commonly prescribed atypical antipsychotics
  for off-label indications.

Maglione M, Ruelaz Maher A, Hu J, et al.
Comparative Effectiveness Review No. 43.
Available at www.effectivehealthcare.ahrq.gov/offl
abelantipsych.cfm.
43
Gaps in Knowledge

• The evidence is insufficient to understand the
  effects of age (with the exception of adverse
  effects in patients with dementia), race,
  ethnicity, and baseline severity of disease on
  outcomes of treatment for off-label indications.
• For most drugs and indications, there are too few
  studies to permit conclusions about dosage and
  duration of treatment.
• There are few head-to-head comparisons of
  atypical and typical antipsychotics, either
  within or between classes, for treating off-label
  indications.
• Adverse event reporting is not standardized,
  which prevents global analysis and understanding
  of risks.
• Evidence about the effects of antipsychotics on
  endocrine function, metabolism, and blood glucose
  regulation is limited.

Maglione M, Ruelaz Maher A, Hu J, et al.
Comparative Effectiveness Review No. 43.
Available at www.effectivehealthcare.ahrq.gov/offl
abelantipsych.cfm.
44
Conclusions (1 of 3)

• Overall, a class effect of the atypical
  antipsychotics for each disorder cannot be
  assumed, and for most of these drugs, adequate
  supporting evidence for either efficacy or
  comparative effectiveness is still lacking for
  many indications.
• Atypical antipsychotics can improve behavioral
  symptoms of dementia, although the effect sizes
  are considered to be small in magnitude.
• Several atypical antipsychotics are approved for
  treating major depressive disorder, and
  additional members of the class show evidence of
  efficacy.
• There is a growing evidence base for the efficacy
  of individual atypical antipsychotics in treating
  these disorders
• Obsessive-compulsive disorder
• Post-traumatic stress disorder (combat-related)
• Generalized anxiety disorder

Maglione M, Ruelaz Maher A, Hu J, et al.
Comparative Effectiveness Review No. 43.
Available at www.effectivehealthcare.ahrq.gov/offl
abelantipsych.cfm.
45
Conclusions (2 of 3)

• The evidence for efficacy of atypical
  antipsychotics in treating borderline personality
  disorders is too limited to estimate benefits.
• Evidence is insufficient for treatment of
  Tourettes syndrome in adults (ages 1864).
• Evidence is stronger that atypical antipsychotics
  neither increase body weight in patients with
  anorexia nervosa nor do they reduce substance
  abuse.
• There is little evidence about optimal dosages or
  durations of treatment in off-label use.

Maglione M, Ruelaz Maher A, Hu J, et al.
Comparative Effectiveness Review No. 43.
Available at www.effectivehealthcare.ahrq.gov/offl
abelantipsych.cfm.
46
Conclusions (3 of 3)

• The risk of death in elderly patients (ages 65)
  is increased by both atypical and typical class
  antipsychotics.
• Adverse effects in both elderly and adult (ages
  1864) patients, not associated with age,
  include
• Increased risk of weight gain more common and
  severe with olanzapine
• Endocrine and metabolic abnormalities risks are
  measurable but less certain
• Sedative effects, fatigue
• Extrapyramidal symptoms
• The possibility of urinary adverse effects in
  elderly patients has appeared in studies of the
  atypical antipsychotics.

Maglione M, Ruelaz Maher A, Hu J, et al.
Comparative Effectiveness Review No. 43.
Available at www.effectivehealthcare.ahrq.gov/offl
abelantipsych.cfm.
47
What To Discuss With Your Patients andTheir
Caregivers

• The potential benefits of antipsychotics for
  treating disorders that are not psychoses
• The risks of adverse effects, including
  irreversible extrapyramidal symptoms, when
  antipsychotics are used
• The trade-offs between benefits and risks for
  death and stroke for elderly patients (ages 65)
  with dementia, and considerations of
  nonpharmaceutical interventions that might be
  undertaken before instituting drug treatment
• The likelihood of weight gain with these
  medicines and the implications for lifestyle
  changes that may be necessary
• Patient and caregiver preferences and values
  regarding treatment

Maglione M, Ruelaz Maher A, Hu J, et al.
Comparative Effectiveness Review No. 43.
Available at www.effectivehealthcare.ahrq.gov/offl
abelantipsych.cfm.