1. Introduction

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. The table at the end of the summary gives information on drug dosage and price.

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

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2. Clinical Bottom Line

Confidence Scale

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

High

There are consistent results from good quality studies.

Medium

Findings are supported, but further research could change the conclusions.

Low

There are very few studies, or existing studies are flawed.

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3. Table - Benefits of Off-Label Use

Using atypicals off label may help people with mental health conditions for which there are no FDA-approved alternatives. The chart in this section 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.

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.

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4. Risks for Elderly People With Dementia

Death

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.

Stroke

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 a placebo.

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5. 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.

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6. Table - 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	Olanzapine (Zyprexa®)	Risperidone (Risperdal®)	Aripiprazole (Abilify®)	Quetiapine (Seroquel®)	Ziprasidone (Geodon®)
Weight gain
Cardiovascular problems
Stroke
Extrapyramidal symptoms (uncontrollable movements)
Agitation
Gait disturbance
Fatigue
Sleepiness
Headache
Cognitive problems
Pain
Gastrointestinal symptoms
Urinary symptoms
Skin problems
Dry mouth

The length of the bar indicates how many people typically experience the harmful effect.
	21-50%
	11-20%
	5-10%
	Less than 5%
	The harmful side effect occurred more often in people taking placebo (inactive substance) than in people taking the drug.
	Insufficient evidence.

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7. 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.

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8. 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.

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9. Dose and Price of Atypical Antipsychotics

¹These drugs were evaluated in the systematic review
²No generics are available.
³Doses are representative of the range used across conditions in the research studies.
⁴Average Wholesale Price from Drug Topics Red Book, 2007.

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10. 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 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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11. For More Information

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