Evidence Lacking To Support Many Off-Label Uses Of Atypical Antipsychotics
18 Jan 2007
antipsychotic medications approved to treat schizophrenia and bipolar
disorder are being prescribed to millions of Americans for depression,
dementia, and other psychiatric disorders without strong evidence that such
off-label uses are effective, according to a new analysis by HHS' Agency
for Healthcare Research and Quality.
The federally funded comparative effectiveness review of these drugs --
called atypical antipsychotics -- identified the medications' potential for
serious side effects while pointing to an "urgent need" for more research
into new treatments for the growing population of dementia patients who
display severe agitation.
"This report emphasizes the importance of understanding the risks and
benefits of different medicines," said AHRQ Director Carolyn M. Clancy,
M.D. "Caution is necessary in the off-label use of atypical antipsychotics,
especially when used in the elderly and when the evidence for effectiveness
is not good."
Atypical antipsychotics are second-generation medicines designed to
cause fewer neurological complications than conventional antipsychotics.
They include aripiprazole (sold as Abilify), olanzapine (Zyprexa),
quetiapine (Seroquel), risperidone (Risperdal), and ziprasidone (Geodon).
Each is approved by the Food and Drug Administration to treat schizophrenia
and bipolar disorder, and risperidone is also approved to treat
irritability in children ages 5 to 16 who have autism.
Some studies suggest that atypical antipsychotics may help patients
with mental health conditions for which there are no FDA-approved
alternatives. Risperidone and quetiapine, for example, help certain
patients with obsessive- compulsive disorder when used in conjunction with
antidepressants. Risperidone and olanzapine improve sleep problems,
depression, and other symptoms in men with combat-related post-traumatic
stress disorder when used to augment therapy with antidepressants or other
Overall, however, researchers found that much of the scientific
evidence for off-label use of antipsychotics was of insufficient quality
because studies were too small or lacked scientific rigor.
Review authors evaluating the potential benefits and risks of the
medications also found strong evidence that atypical antipsychotics can
increase chances of adverse events. Some of the drugs increase risks of
stroke, tremors, significant weight gain, sedation, and gastrointestinal
The new review was produced by AHRQ's Effective Health Care program. It
was authored by AHRQ's Southern California/RAND Evidence-based Practice
Center. The center examined 84 published studies on atypical antipsychotics
and summarized evidence about several conditions:
One analysis showed a small benefit for risperidone and
aripiprazole in the treatment of agitation and psychosis. Another
suggested olanzapine may help treat psychosis. But a large clinical
trial that explored whether risperidone, olanzapine, and quetiapine
controlled behavioral disturbances in Alzheimer's patients concluded
that the risks of adverse events offset the potential benefits.
Overall, analyses identified potential harms as a small increase in the
risk of death and increased chances of stroke, neurological problems
(such as tremors or muscle contractions), and weight gain.
For patients who don't benefit from selective serotonin
reuptake inhibitors (SSRIs), the supplemental use of atypical
antipsychotics was not helpful, according to research. No studies showed
the drugs provided a clear benefit for patients with major depressive
disorder with psychotic features. Evidence is conflicting for bipolar
Atypical antipsychotics significantly
helped patients who don't respond adequately to SSRI therapy, studies
showed. Overall, patients taking the drugs were about 2.7 times as
likely to improve as patients taking placebo. The chances of benefiting
were best for risperidone and quetiapine.
Post-Traumatic Stress Disorder:
Studies of men with combat-related PTSD
showed risperidone and olanzapine, when used with antidepressants or
other psychotropic medications, improved sleep quality, anxiety, and
other symptoms. Studies were inconclusive when measuring benefits for
For patients with borderline personality
disorder, one study suggested olanzapine was more effective than placebo
but showed little benefit when used to augment talk therapy. All studies
of olanzapine were very small, however, and patients experienced
significant weight gain. Two other small trials suggested risperidone
may benefit patients with schizotypal personality disorder, and
aripiprazole may help patients with borderline personality disorder.
Risperidone is more effective than placebo,
according to a small body of research. The benefits of ziprasidone are
Off-label prescribing is a common but relatively understudied practice
in health care. A 2001 AHRQ-funded study concluded that about 21 percent of
prescribed drug use was for conditions not indicated on the label. Cardiac
medications and anticonvulsants were the drugs most commonly used off
label. Most off-label use occurs without scientific support, the study
The report released today, Efficacy and Comparative Effectiveness of
Off- Label Use of Atypical Antipsychotics, is the newest analysis from
AHRQ's Effective Health Care program. That program represents the first
federal effort to compare alternative treatments for significant health
conditions and make the findings public. The program is intended to help
patients, doctors, nurses, and others choose the most effective treatments.
Information on the program, including full reports, can be found at