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.
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• Adding risperidone (Risperdal^®) or quetiapine (Seroquel^®) to an SRI helps people with obsessive-compulsive disorder who have not responded to standard SRI treatment.
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• Quetiapine (Seroquel^®), olanzapine (Zyprexa^®), and risperidone (Risperdal^®) reduce agitation and behavioral disturbances for people with dementia.
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• Atypical antipsychotics increase the risk of death for elderly people with dementia.
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• Risperidone (Risperdal^®) and olanzapine (Zyprexa^®) increase the risk of stroke for elderly people with dementia.
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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:

• Aripiprazole (Abilify^®)
• Olanzapine (Zyprexa^®)
• Quetiapine (Seroquel^®)
• Risperidone (Risperdal^®)
• Ziprasidone (Geodon^®)

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.

BENEFITS OF ATYPICALS FOR OFF-LABEL CONDITIONS

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OFF-LABEL CONDITION1	EFFECTIVE (medium level of confidence)	NOT EFFECTIVE (medium level of confidence)	INSUFFICIENT EVIDENCE
Dementia-related behavioral problems	Olanzapine Quetiapine Risperidone		Aripiprazole Ziprasidone
Obsessive-compulsive disorder	Quetiapine2 Risperidone2		Aripiprazole Olanzapine Ziprasidone
Depression (SRI resistant)		Olanzapine	Aripiprazole Quetiapine Risperidone Ziprasidone
Depression (bipolar)			All atypicals3
Depression (with psychotic features)			All atypicals
Personality disorders			All atypicals
Post-traumatic stress disorder			All atypicals
Tourette’s syndrome in children and adolescents			All atypicals

1

Treatment of adults unless otherwise specified.

2

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

3

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

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.

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:
  • 30 percent of people on olanzapine (Zyprexa^®).
  • 16 percent of people on quetiapine (Seroquel^®).
  • 14 percent of people on risperidone (Risperdal^®).
  • 7 percent of people on ziprasidone (Geodon^®).
  • 12 percent of people on perphenazine (Etrafon^®, Trilafon^®).
• 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: www.effectivehealthcare.ahrq.gov

For free print copies call:

The AHRQ Publications Clearinghouse

(800) 358–9295

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

Source

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.