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/offlabelantipsych.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 first–
generation antipsychotics
 Atypical antipsychotics, also called second–generation
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/offlabelantipsych.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/offlabelantipsych.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/offlabelantipsych.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/offlabelantipsych.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/offlabelantipsych.cfm.

8. Rating the Strength of Evidence From the
Comparative Effectiveness Review
 The strength of evidence was classified into four broad
categories:
Maglione M, Ruelaz Maher A, Hu J, et al. Comparative Effectiveness Review No. 43. Available at www.effectivehealthcare.ahrq.gov/offlabelantipsych.cfm.

9. Clinical Questions Addressed by the
Comparative 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/offlabelantipsych.cfm.

10. Clinical Questions Addressed by the
Comparative 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/offlabelantipsych.cfm.

11. Clinically Significant Outcomes of Interest
in 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 Alzheimer’s Disease Rating Scale
BPRS: Brief Psychiatric Rating Scale
NPI: Neuropsychiatric Inventory Scale
Major Depressive HAM-D: Hamilton Depression Rating Scale
Disorder MADRS: Montgomery-Asberg Depression Rating Score
Obsessive- YBOCS: Yale-Brown Obsessive Compulsive Scale
Compulsive Disorder
Eating Disorders BMI: body mass index
Generalized Anxiety HAM-A: Hamilton Anxiety Rating Scale
Disorder
Maglione M, Ruelaz Maher A, Hu J, et al. Comparative Effectiveness Review No. 43. Available at www.effectivehealthcare.ahrq.gov/offlabelantipsych.cfm.

12. Clinically Significant Outcomes of Interest
in 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 SCL-90-R: Symptom Checklist 90 Revised
(Borderline or Schizotypal) CGI-BPD: Clinical Global Impressions–BPD
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
Tourette’s Syndrome YGTS: Yale Global Tic Severity
CGI-I: Clinical Global Impressions–Improvement
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/offlabelantipsych.cfm.

13. Adverse Effects of Interest in the
Comparative 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 18–64 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/offlabelantipsych.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 <6 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/offlabelantipsych.cfm.

15. Summary of Studies Included in the
Comparative 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/offlabelantipsych.cfm.

16. Summary of Studies Included in the
Comparative 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/offlabelantipsych.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 < 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 < 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/offlabelantipsych.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 = | ARC–ART |
 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 = |ARC–ART|-1 for a benefit or adverse event, respectively
 Number of attributable events per 1,000 = 1,000 x |ARC–ART|
 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/offlabelantipsych.cfm.

19. Results: Atypical Antipsychotics for Dementia
Effect Size/Meta-analytic Result: SMD and 95% CI,
With Strength of Evidence
Total Score/ Strength
Atypical Antipsychotics in Global of
Placebo Comparisons Impressions Psychosis Agitation Evidence
Atypicals as a Class High
Combined result 0.17 (0.08, 0.25) 0.12 (0.04. 0.19) 0.20 (0.12, 0.27) 
(18 studies, >4,578 patientsa)
Olanzapine Moderate
0.12 (0.00, 0.25) NSD 0.19 (0.07, 0.31)
(4 studies, > 840 patientsa) 
Risperidone High
0.19 (0.00, 0.38) 0.20 (0.05, 0.36) 0.22 (0.09, 0.35)
(6 studies, ≈2,213 patientsb) 
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/offlabelantipsych.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/offlabelantipsych.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
Risperidone HAM-D One in every eight patients experienced remission attributable to Moderate
remission rate risperidone treatment (score less than 7 or 8 over two visits). 
(3 studies,
645 patients) HAM-D One in every seven patients responded with at least a 50% reduction Moderate
response rate in score attributable to risperidone. 
Monotherapy
MADRS One in every 13 patients experienced remission attributable to Moderate
Quetiapine XR remission rate olanzapine treatment (score less than 7 or 8 over two visits). 
(5 studies,
2,454 patients) MADRS One in every six patients responded with at least a 50% reduction in Moderate
response rate score attributable to quetiapine XR. 
Olanzapine MADRS No statistically significant difference from placebo. Moderate
(3 studies, >98 response and 
patients)a remission rates
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/offlabelantipsych.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/offlabelantipsych.cfm.

23. Results: Atypical Antipsychotics for
Obsessive-Compulsive Disorder
 Atypical antipsychotics are studied as augmentation of
SSRIs and SNRIs in treating obsessive-compulsive disorder.
N Studies; Strength of
Atypical Outcome N Participants Effect Size/Meta-analysis Result Evidence
Augmentation of SSRIs/SNRIs, Placebo Comparisons
One in every five patients demonstrated a
YBOCS Moderate
Risperidone 3; 97 response (improved YBOCS score)
response rate 
attributable to risperidone.
Comparative Effectiveness for Augmentation
Olanzapine Low
No statistically significant difference
Versus YBOCS score 1; 50 
between olanzapine and risperidone.
Risperidone
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/offlabelantipsych.cfm.

24. Summary of Benefits: Atypical Antipsychotics for
Obsessive-Compulsive Disorder
Risperidone improves symptoms of obsessive-compulsive
 One in every five patients treated will show some benefit.
 Strength of Evidence = Moderate
Olanzapine and risperidone are similar in effect for
 Strength of Evidence = Low
Maglione M, Ruelaz Maher A, Hu J, et al. Comparative Effectiveness Review No. 43. Available at www.effectivehealthcare.ahrq.gov/offlabelantipsych.cfm.

25. Results: Atypical Antipsychotics for Post-
traumatic Stress Disorder
Atypical
Versus N Studies; Effect Size/Meta-analytic Result Strength of
Placebo Outcome N Participants (95% Confidence Interval) Evidence
4; 151 Score is 6.47 points lower with risperidone Moderate
(all causes) (from 0.32 to 12.61 lower) 
Difference in 3; 124 Score is 7.95 points lower with risperidone Moderate
Risperidone CAPS score (combat-related) (from 1.06 to 14.84 lower) 
Insufficient
(abused women) No summary result

Difference in Insufficient
Olanzapine CAPS score
(all causes) No summary result

Difference in Insufficient
Quetiapine CAPS score
(all causes) No summary result

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/offlabelantipsych.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/offlabelantipsych.cfm.

27. Results and Summary of Benefits: Atypical
Antipsychotics for Generalized Anxiety Disorder
Quetiapine improves symptoms of generalized anxiety disorder.
N Studies; Strength of
Atypical Outcome N Participants Result (95% CI) Evidence
• Response is 1.26-fold more likely
HAM-A with quetiapine than with placebo Moderate
Quetiapine percent 3; 2,437 (from 1.02- to 1.56-fold). 
responding • Response in 1 in 8 treated patients
is attributable to quetiapine.
HAM-A
Insufficient
Olanzapine percent 1; 24 NSD
responding 
Risperidone
HAM-A
NSD Insufficient
percent 1; 417 
responding
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/offlabelantipsych.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 5–10 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/offlabelantipsych.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.
N Studies; Strength of
Atypical Outcome N Participants Result and 95% CI Evidence
NSD
BMI at 1
3; 84 (BMI may lie in a range from 0.56
month
Olanzapine kg lower to 0.57 kg higher) Moderate

NSD
BMI at 3
3; 84 (BMI may lie in a range from 0.34
months
kg lower to 0.84 kg higher)
BMI at 3 NSD Low
Quetiapine 1; 27 (BMI may lie in a range from 1.74 
months
kg lower to 1.54 kg higher)
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/offlabelantipsych.cfm.

30. Results: Atypical Antipsychotics in Substance
Abuse Treatment
Atypical antipsychotics are not effective as adjuncts in treating substance abuse.
No. Studies; Effect Size/Meta-analysis Summary Strength of
Atypical Outcome No. Participants Result and 95% CI Evidence
Alcohol Abuse
Aripiprazole NSD: The rate of abstinence with Moderate
Percentage 
treatment lies between 2.8-fold more
completely 3; 386
Quetiapine with placebo to 5.7-fold more with an Low
abstinent
atypical antipsychotic. 
Cocaine Abuse
ASI NSD: The score lies between 0.04 Low
Olanzapine,
composite 3; 129 lower with treatment to 0.04 higher 
Risperidone
score with treatment.
Cocaine or Opiate Abuse
Risperidone NSD: The rate of reports of cocaine
ASI Low
(with and opiate use did not differ
composite 1; 31 
methadone between risperidone at 2 or 4 mg
score
treatment) and placebo.
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/offlabelantipsych.cfm.

31. Results for Other Indications
 The evidence for efficacy of atypical antipsychotics is
insufficient to permit conclusions for:
 Tourette’s syndrome
 Insomnia
Maglione M, Ruelaz Maher A, Hu J, et al. Comparative Effectiveness Review No. 43. Available at www.effectivehealthcare.ahrq.gov/offlabelantipsych.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 18–64
 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/offlabelantipsych.cfm.

33. Adverse Effects in Elderly Patients:
Placebo 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.
N Studies; Strength of
Comparison N Participants Effect Size/Meta-analytic Result: NNH Evidence
Death of 1 in every 100 patients (over a 10-
Atypical Antipsychotics to 12-week course of treatment) is High
15; 5,204 
vs. Placebo* attributable to treatment with an atypical
antipsychotic.
Typical and Atypical Moderate
Elevated risk of death with both atypical
Antipsychotics: 12; 310,752 
and typical antipsychotics.
Cohort Studies
* Schneider LS, Dagerman KS, Insel P. JAMA 2005;294:1934-43. PMID:16234500.
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/offlabelantipsych.cfm.

34. Adverse Effects in Elderly Patients:
Placebo 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.
N Studies; Strength of
Comparison N Participants Outcome Effect Size/Meta-analytic Result: NNH Evidence
Risperidone vs. Cerebrovascular One in every 53 patients treated with Moderate
4; 1,852 
Placebo accidents risperidone will experience CVAs.
Risperidone vs. One in every 34 patients treated with Moderate
6; 2,767 Cardiovascular AE 
Placebo risperidone will experience a cardiovascular AE.
Olanzapine vs. One in every 48 patients treated with olanzapine Moderate
5; 1,218 Cardiovascular AE 
Placebo will experience a cardiovascular AE.
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/offlabelantipsych.cfm.

35. Adverse Effects in Elderly Patients:
Placebo Comparisons (3 of 3)
Meta-analytic Result: NNH (N Studies; N Participants)
Adverse Event Aripiprazole Olanzapine Quetiapine Risperidone SOE
NSD (4;
EPSs 10 (1; 242) NSD (3; 609) 20 (5; 1,477) Moderate 
1,080)
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/offlabelantipsych.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/offlabelantipsych.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/offlabelantipsych.cfm.

38. Adverse Effects in Adult Patients:
Placebo 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*)
Aripiprazole Olanzapine Quetiapine Risperidone Ziprasidone SOE
Weight gain or 35 3 16 21 Insufficient High
appetite (4; 1,387) (11; 1,637) (13; 4, 733) (4; 434)

increase
Endocrine and Not 12 18 Not Not Low
other metabolic Reported (2; 374) (3; 1,440) Reported Reported

lab test
abnormalities
* Adults 18–64 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/offlabelantipsych.cfm.

39. Adverse Effects in Adult Patients:
Placebo 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*)
Adverse Strength of
Effect Aripiprazole Olanzapine Quetiapine Risperidone Ziprasidone Evidence
EPSs 11 (5; 1,215) NSD (3; 136) 36 (7; 2,566) NSD (1; 25) 24 (3; 482) Low
(Akathisia, 
NNH = 7)
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 18–64 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/offlabelantipsych.cfm.

40. Summary of Adverse Effects in Adults (1 of 2)
 Antipsychotics in the atypical class generally promote
weight gain in adults (ages 18–64) and in the elderly (ages
≥65), but olanzapine is associated with greater risk than
other atypicals.
 Olanzapine NNH = 3 versus NNH = 16–35 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/offlabelantipsych.cfm.

41. Summary of Adverse Effects in Adults (2 of 2)
 The risk of extrapyramidal symptoms in adults (ages 18–64) 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 6–11; fatigue NNH = 14–19).
 Strength of Evidence = Moderate
Maglione M, Ruelaz Maher A, Hu J, et al. Comparative Effectiveness Review No. 43. Available at www.effectivehealthcare.ahrq.gov/offlabelantipsych.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/offlabelantipsych.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/offlabelantipsych.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/offlabelantipsych.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 Tourette’s
syndrome in adults (ages 18–64).
 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/offlabelantipsych.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 18–64)
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/offlabelantipsych.cfm.

47. What To Discuss With Your Patients and
Their 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/offlabelantipsych.cfm.