off-label use of atypical antipsychotics: an update

Off-Label Use of Atypical Antipsychotics: An Update

Prepared for:

Agency for Healthcare Research and Quality (AHRQ)

www.ahrq.gov

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

Outline of Material

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

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.

Introduction to Atypical Antipsychotics (1 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®)



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.



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?



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.

Agency for Healthcare Research and Quality (AHRQ) Comparative Effectiveness Review (CER) Development


The strength of evidence was classified into four broad categories:

Rating the Strength of Evidence From the Comparative Effectiveness Review


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?

Clinical Questions Addressed by theComparative Effectiveness Review (1 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?

Clinical Questions Addressed by theComparative 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 a degree of improvement on a rating scale that was specified a priori.

Clinically Significant Outcomes of Interestin the Comparative Effectiveness Review (1 of 2)

Indication Outcome Assessment Instruments

Dementia BEHAVE-AD: Behavioral Pathology in Alzheimer’s Disease Rating ScaleBPRS: Brief Psychiatric Rating ScaleNPI: Neuropsychiatric Inventory Scale

Major Depressive Disorder

HAM-D: Hamilton Depression Rating ScaleMADRS: 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


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.

Clinically Significant Outcomes of Interestin the Comparative Effectiveness Review (2 of 2)

Indication Outcome Assessment Instruments

Personality Disorder(Borderline or Schizotypal)

SCL-90-R: Symptom Checklist 90 RevisedCGI-BPD: Clinical Global Impressions–BPDHAM-A HAM-DMADRSBPRSPANSS: Positive and Negative Symptoms Scale

Post-traumatic Stress Disorder (PTSD)

CAPS: Clinician Administered PTSD Scale

Substance Abuse CCQ: Cocaine Craving QuestionnaireASI: Addiction Severity Index

Tourette’s Syndrome YGTS: Yale Global Tic SeverityCGI-I: Clinical Global Impressions–Improvement

Insomnia Sleep quality and onsetMaglione M, Ruelaz Maher A, Hu J, et al. Comparative Effectiveness Review No. 43. Available at www.effectivehealthcare.ahrq.gov/offlabelantipsych.cfm.

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

Adverse Effects of Interest in theComparative Effectiveness Review


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

Summary of Study Characteristics Evaluated in the Effectiveness Review: PICOTS Framework


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.

Summary of Studies Included in theComparative Effectiveness Review (1 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

Summary of Studies Included in theComparative Effectiveness Review (2 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.

Modes of Results Reporting and Statistical Analysis in the Comparative Effectiveness Review (1 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.

Modes of Results Reporting and Statistical Analysis in the Comparative Effectiveness Review (2 of 2)


Results: Atypical Antipsychotics for Dementia

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, >4,578 patientsa)

0.17 (0.08, 0.25)

0.12 (0.04. 0.19)

0.20 (0.12, 0.27)

High

Olanzapine(4 studies, > 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 .


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

Summary of Benefits: Dementia


Results: Atypical Antipsychotics for Major Depressive Disorder (1 of 2)

Atypical Outcome Result: NNT, SMD, and 95% CI SOE

Augmentation of SSRIs/SNRIs

Risperidone(3 studies,

645 patients)

HAM-Dremission rate

One in every eight patients experienced remission attributable to risperidone treatment (score less than 7 or 8 over two visits).

Moderate

HAM-D response rate

One in every seven patients responded with at least a 50% reduction in score attributable to risperidone.

Moderate

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

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, >98

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.


Aripiprazole, quetiapine XR, and combination therapy with olanzapine and fluoxetine are FDA approved 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

Summary of Benefits: Atypical Antipsychotics for Major Depressive Disorder


MDD = major depressive disorder; SNRI = selective serotonin and norepinephrine reuptake inhibitor; SSRI selective serotonin reuptake inhibitor; XR = extended release

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

Results: Atypical Antipsychotics forObsessive-Compulsive Disorder

Atypical Outcome

N Studies;N Participants

Effect Size/Meta-analysis Result


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

Olanzapine Versus Risperidone

YBOCS score 1; 50No statistically significant difference between olanzapine and risperidone.

Low


SNRI = selective serotonin and norepinephrine reuptake inhibitor; SSRI = selective serotonin reuptake inhibitor

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

Summary of Benefits: Atypical Antipsychotics for Obsessive-Compulsive Disorder


Results: Atypical Antipsychotics for Post-traumatic Stress Disorder

Atypical VersusPlacebo Outcome


Effect Size/Meta-analytic Result(95% Confidence Interval)


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

3; 124(combat-related)

Score is 7.95 points lower with risperidone (from 1.06 to 14.84 lower)

Moderate

(abused women)

No summary resultInsufficient

Olanzapine


(all causes) No summary resultInsufficient

Quetiapine


(all causes) No summary resultInsufficient


PTSD = 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

Summary of Benefits: Post-traumatic Stress Disorder


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)


QuetiapineHAM-Apercent 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-Apercent responding

1; 24 NSDInsufficient

Risperidone

HAM-Apercent responding

1; 417NSD

Insufficient95% CI = 95-percent confidence interval; NSD = no statistically significant difference

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.

Results and Summary of Benefits: Atypical Antipsychotics for Bipolar Personality Disorder


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


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

BMI at 3 months 3; 84

NSD (BMI may lie in a range from 0.34 kg lower to 0.84 kg higher)

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

Results: Atypical Antipsychotics in Substance Abuse TreatmentAtypical 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


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

QuetiapineLow

Cocaine Abuse

Olanzapine, Risperidone

ASI composite score

3; 129NSD: The score lies between 0.04 lower with treatment to 0.04 higher with treatment.

Low

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

The evidence for efficacy of atypical antipsychotics is insufficient to permit conclusions for: Tourette’s syndrome Insomnia

Results for Other Indications


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.

Adverse Effects of Atypical Antipsychotics


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.

Adverse Effects in Elderly Patients:Placebo Comparisons (1 of 3)

Comparison


Effect Size/Meta-analytic Result: NNH


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; 310,752Elevated risk of death with both atypical and typical antipsychotics.

Moderate


* 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)

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


Risperidone vs. Placebo

4; 1,852Cerebrovascular accidents

One in every 53 patients treated with risperidone will experience CVAs.

Moderate

Risperidone vs. Placebo

6; 2,767Cardiovascular AE

One in every 34 patients treated with risperidone will experience a cardiovascular AE.

Moderate

Olanzapine vs. Placebo

5; 1,218Cardiovascular 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)

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.


Meta-analytic Result: NNH (N Studies; N Participants)

Adverse Event

Aripiprazole

Olanzapine

QuetiapineRisperidone

SOE

EPSsNSD (4; 1,080)

10 (1; 242)

NSD (3; 609)

20 (5; 1,477)

Moderate

Sedation16 (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

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

Summary of Adverse Effects in Elderly Patients (1 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

Summary of Adverse Effects in Elderly Patients (2 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.

Adverse Effects in Adult Patients:Placebo Comparisons (1 of 2)

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 18–64 years of age. NNH = number needed to harm; SOE = strength of evidenceMaglione M, Ruelaz Maher A, Hu J, et al. Comparative Effectiveness Review No. 43. Available at www.effectivehealthcare.ahrq.gov/offlabelantipsych.cfm.

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

Adverse Effects in Adult Patients:Placebo Comparisons (2 of 2)

NNH (N Studies; N Participants*)

Adverse Effect Aripiprazole

Olanzapine

Quetiapine

Risperidone

Ziprasidone


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 18–64 years of age. EPSs = extrapyramidal symptoms; NNH = number needed to harm; NSD = no statistically significant difference

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

Summary of Adverse Effects in Adults (1 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

Summary of Adverse Effects in Adults (2 of 2)


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.

Trends in Off-Label Use of Atypical Antipsychotics


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.

Gaps in Knowledge


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

Conclusions (1 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.



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.



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

What To Discuss With Your Patients andTheir Caregivers


off-label use of atypical antipsychotics: an update

Health & Medicine

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peer review

ruelaz maher

atypical class

label indications

approved indications

atypical antipsychotic

research questions