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Comparative Effectiveness Review Summary Guides for Clinicians [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2007-.

  • This publication is provided for historical reference only and the information may be out of date.

This publication is provided for historical reference only and the information may be out of date.

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Comparative Effectiveness Review Summary Guides for Clinicians [Internet].

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Off -Label Use of Atypical Antipsychotic Drugs

A Summary for Clinicians and Policymakers


Issued: .

Atypical antipsychotics are used primarily for schizophrenia and bipolar mania. They are also prescribed “off label” for symptoms like agitation, anxiety, psychotic episodes, and obsessive behaviors. These drugs can cause serious side effects. Evaluating research about how well atypical antipsychotics work for off-label conditions can help you weigh the benefits and risks of these drugs. A chart gives information on dosage and price.

Clinical Bottom Line

There is no strong evidence that atypical antipsychotics work for any off-label conditions, but there is some medium level evidence about their effectiveness for three off-label conditions and about harms.

  • Olanzapine (Zyprexa®) does not relieve depression for people who have not responded to serotonin reuptake inhibitors (SRIs). This applies to olanzapine (Zyprexa®) used alone or in combination with an SRI.
    Level of confidence Image clinantipsychfu2.jpg
  • Adding risperidone (Risperdal®) or quetiapine (Seroquel®) to an SRI helps people with obsessive-compulsive disorder who have not responded to standard SRI treatment.
    Level of confidence Image clinantipsychfu2.jpg
  • Quetiapine (Seroquel®), olanzapine (Zyprexa®), and risperidone (Risperdal®) reduce agitation and behavioral disturbances for people with dementia.
    Level of confidence Image clinantipsychfu2.jpg
  • Atypical antipsychotics increase the risk of death for elderly people with dementia.
    Level of confidence Image clinantipsychfu2.jpg
  • Risperidone (Risperdal®) and olanzapine (Zyprexa®) increase the risk of stroke for elderly people with dementia.
    Level of confidence Image clinantipsychfu2.jpg

Confidence Scale

The confidence ratings are derived from a systematic review of the literature. The level of confidence is based on the overall quantity and quality of clinical evidence.

Image clinantipsychfu3.jpg High There are consistent results from good quality studies.

Image clinantipsychfu2.jpg Medium Findings are supported, but further research could change the conclusions.

Image clinantipsychfu1.jpg Low There are very few studies, or existing studies are flawed.

Atypical Antipsychotics

Atypical antipsychotics are a newer class of antipsychotic drugs. Compared with the older, “typical,” antipsychotic drugs, such as haloperidol (Haldol®) and chlorpromazine (Thorazine®), atypicals are thought to cause fewer serious or long-term side effects.

The atypical antipsychotic drugs reviewed are:


AripiprazoleAbilify®2 mg daily$395
30 mg daily$555
OlanzapineZyprexa®2.5 mg daily$140
15 mg daily$590
20 mg daily$775
QuetiapineSeroquel®50 mg daily$105
200 mg daily$210
600 mg daily$550
RisperidoneRisperdal®0.25 mg twice a day$220
1 mg twice a day$255
2 mg twice a day$425
3 mg twice a day$500
ZiprasidoneGeodon®40 mg twice a day$330
80 mg twice a day$375

These drugs were evaluated in the systematic review.


No generics are available.


Doses are representative of the range used across conditions in the research studies.


Average Wholesale Price from Drug Topics Redbook, 2007.

Off-Label Use

“Off label” refers to using a drug for conditions not listed on the Food and Drug Administration (FDA) label of approved uses. Drugs are commonly prescribed off label when approved drugs cannot be used or do not work. Off-label uses may be supported by clinical evidence. This guide covers the off-label use of atypicals for these six conditions:

  • Dementia-related behavioral problems
  • Depression
  • Obsessive-compulsive disorder (OCD)
  • Post-traumatic stress disorder (PTSD)
  • Personality disorders
  • Tourette’s syndrome in children and adolescents

Using atypicals off label may help people with mental health conditions for which there are no FDA-approved alternatives. The chart on this page lists the results of research on the effectiveness of atypical antipsychotics for off-label conditions. There is insufficient evidence about many of these off-label uses because there are very few research studies, the studies are of poor quality, or study results are inconsistent.


OFF-LABEL CONDITION1EFFECTIVE (medium level of confidence) Image clinantipsychfu2.jpgNOT EFFECTIVE (medium level of confidence) Image clinantipsychfu2.jpgINSUFFICIENT EVIDENCE
Dementia-related behavioral problemsOlanzapine
Obsessive-compulsive disorderQuetiapine2
Depression (SRI resistant)OlanzapineAripiprazole
Depression (bipolar)All atypicals3
Depression (with psychotic features)All atypicals
Personality disordersAll atypicals
Post-traumatic stress disorderAll atypicals
Tourette’s syndrome in children and adolescentsAll atypicals

Treatment of adults unless otherwise specified.


When used in addition to an SRI for people with obsessive-compulsive disorder that does not respond to standard SRI therapy.


Bipolar depression was an off-label indication at the time of the research studies. In October 2006, the FDA approved quetiapine (Seroquel®) for bipolar depression.

SRI = serotonin reuptake inhibitor.

Risks for Elderly People with Dementia


All atypical antipsychotics increase the risk of death for elderly people with dementia:

  • 35 deaths per 1,000 elderly people taking atypicals.
  • 23 deaths per 1,000 elderly people taking placebo (inactive substance).
  • The risk may be similar when conventional antipsychotics are used for dementia symptoms.


Risperidone (Risperdal®) increases the risk of stroke for elderly people with dementia:

  • 43 strokes per 1,000 elderly people taking risperidone (Risperdal®).
  • 11 strokes per 1,000 elderly people taking placebo.

Olanzapine (Zyprexa®) increases the risk of stroke for elderly people with dementia:

  • 13 strokes per 1,000 elderly people taking olanzapine (Zyprexa®).
  • 4 strokes per 1,000 elderly people taking placebo.

Side Effects for Children and Adolescents

There is very little research about the side effects of atypical antipsychotics when used for children and adolescents with Tourette’s syndrome. Risperidone (Risperdal®) is the only drug for which we have research about the side effects.

  • Risperidone (Risperdal®) causes weight gain in children and adolescents. On average, children can gain from 4.5 to 8.5 pounds in 2–3 months of treatment.
  • Risperidone (Risperdal®) also causes gastrointestinal problems, increased salivation, fatigue, extrapyramidal symptoms (uncontrollable movements), and sleepiness.

Side Effects for Adults: Off-Label Conditions

All of the atypical antipsychotics cause side effects. The chart below shows the side effects for adults taking an atypical antipsychotic for an off-label condition compared with those taking placebo. There are fewer studies of off-label use for some of the atypicals, especially quetiapine (Seroquel®) and ziprasidone (Geodon®). Because most off-label studies lasted less than 6 months, there is limited evidence about longer term side effects.

Image clinantipsychfu4

Side Effects for Adults: The Catie Study

There is limited evidence comparing the side effects of atypicals when used off label, but we have comparative data about on-label use for people with schizophrenia. The Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) is a large randomized study. It compares side effects of four atypicals—olanzapine (Zyprexa®), quetiapine (Seroquel®), risperidone (Risperdal®), ziprasidone (Geodon®)—with perphenazine (Etrafon®, Trilafon®), a conventional (“typical”) antipsychotic. People were followed for up to 18 months.

  • Discontinuation due to extrapyramidal symptoms was 2–4 percent with the atypicals compared with 8 percent with the conventional antipsychotic perphenazine (Etrafon®, Trilafon®).
  • Sleepiness, dry mouth, and sexual side effects each occurred in 20–30 percent of people with all the study drugs.
  • All the study drugs caused weight gain. For some people, the gain was 7 percent or more of their baseline weight (14 lbs or more for someone weighing 200 pounds). The percentage of people gaining 7 percent or more was:
  • Discontinuation due to weight gain or metabolic effects was 9 percent in those using olanzapine (Zyprexa®) and 1–4 percent in people using the other study drugs.
  • Olanzapine (Zyprexa®) caused greater increases in glycohemoglobin (+ 0.4 percent) and triglycerides (+ 43mg/dl) than the other study drugs.

Still Unknown

  • There is no strong evidence on the effectiveness and safety of atypical antipsychotics compared to each other, to conventional (typical) antipsychotics, or to standard treatments for these six off-label conditions.
  • Long-term studies have not assessed whether the metabolic changes associated with olanzapine use lead to clinical diabetes.
  • We do not know about the long-term effects of off-label use of atypical antipsychotics, because most research studies last 25 weeks or less.

For More Information

For electronic copies of this summary and the full systematic review, visit this Web site:

For free print copies call:

The AHRQ Publications Clearinghouse

(800) 358–9295

A Summary for Clinicians and Policymakers, AHRQ Pub. No. 07-EHC003-2


The source material for this summary is a systematic review of over 100 research publications. The review, Efficacy and Comparative Effectiveness of Off-Label Use of Atypical Antipsychotics (2007), was prepared by the Southern California/RAND Evidence-based Practice Center. The Agency for Healthcare Research and Quality (AHRQ) funded the systematic review and this guide. The guide was developed using feedback from clinicians and policymakers who reviewed preliminary drafts.

AHRQ created the John M. Eisenberg Center at Oregon Health & Science University to make research useful for decisionmakers. This guide was prepared by Somnath Saha, M.D., Sandra Robinson, M.S.P.H., Theresa Bianco, Pharm.D., Martha Schechtel, R.N., and David Hickam, M.D., of the Eisenberg Center.


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