Antipsychotic drugs a last resort for these 5 conditions

The use of antipsychotic drugs to treat conditions not approved by the Food and Drug Administration has increased significantly in the last decade in children and adults. Conditions include anxiety, attention-deficit/hyperactivity disorder (ADHD), insomnia, post-traumatic stress disorder (PTSD), and some types of depression. (See Table 1 for list of drugs and their approved uses.)

This is known as “off-label” prescribing, which doctors can legally do. But in the case of these drugs, it’s a concern because our analysis shows that there is only limited research about the effectiveness and safety of antipsychotics drugs when used for these conditions, and that it’s unclear whether any potential benefit outweighs the risk of experiencing side effects.

Some of the possible side effects can be serious, and include: muscle rigidity, slow movement and involuntary tremors (known as extrapyramidal symptoms, some of which can be permanent), substantial weight gain, an increased risk of type 2 diabetes, and elevated cholesterol levels. Most people who start taking an antipsychotic medication will experience at least one side effect. Of those who do, up to 30 percent of people experience a serious or intolerable adverse effect, and stop taking the medicine within days, weeks, or a few months.

Because of the limited evidence for the eight antipsychotic medications evaluated and the complexities of treating the disorders, we have not chosen a Best Buy in this special analysis. Our medical advisers recommend that you discuss with your doctor first trying standard treatment options, including nondrug strategies if appropriate and medications that are FDA-approved for your condition. Carefully consider an antipsychotic drug only if those other options fail to improve your symptoms.

Antipsychotic drugs are also commonly used off-label in long-term-care settings to control agitation, aggression, hallucinations, and other behavioral symptoms in elderly patients with Alzheimer’s disease or other forms of dementia. But in 2005, the medications were found to be associated with an increased risk of death among elderly people with dementia, primarily due to strokes. As a result, all antipsychotic drug labels now carry a black box warning—the strongest kind—about this risk.

Table 1. Medications Evaluated in this Report

If you do decide to try an antipsychotic drug, carefully weigh the risks of the medication against the potential benefits, if any. Your doctor should monitor you for side effects. This includes assessing your weight, checking your muscles to make sure they are functioning well, and performing blood tests. If your symptoms don’t improve, you should stop taking the medication.

Cost might also be an important factor to take into account. Most of these antipsychotic drugs are expensive, so if you and your doctor decide that you should start taking one, find out how much of the price your insurance plan covers and how much you will have to pay out-of-pocket.

Another important issue to consider is that it is not clear from the available studies what dosage is correct for a person to take for the various off-label uses. We are unable to make any recommendation about how much a person should take, so you should discuss this with your physician. In some cases, a lower dose than is typically used to treat FDA-approved indications, such as schizophrenia, might be adequate for an off-label use.

For more about antipsychotic drugs, see these additional Best Buy Drugs reports.

■ Antipsychotic Drugs for Bipolar Disorder and Schizophrenia

■ Use of Antipsychotic Drugs in Children

■ Antipsychotic Drugs for Depression

It’s not known exactly how antipsychotic drugs work to help relieve symptoms. What is known is that they affect levels of chemicals in the brain called neurotransmitters, which play important roles in behavior, sleep, mood, attention, memory, learning, and other aspects of cognition. This might be how they reduce psychotic symptoms, such as hallucinations, delusions, disorganized thinking, and agitation in schizophrenia and bipolar disorder. But from the limited available evidence, it’s unclear how well they work for the treatment of attention-deficit/hyperactivity disorder (ADHD), generalized anxiety disorder (GAD), insomnia, major depressive disorder (MDD), and post-traumatic stress disorder (PTSD).

For each of those conditions, evidence directly comparing one newer antipsychotic medication to another is either extremely limited or nonexistent. Of the eight antipsychotic medications we evaluated, olanzapine, quetiapine, and risperidone are the most commonly prescribed for off-label uses.

There are no studies involving the off-label use of three of the newest antipsychotic drugs: asenapine, iloperidone, and paliperidone. And our analysis found almost no evidence of whether the effectiveness of antipsychotic medications for off-label conditions varies by sex, race, ethnicity, or pre-existing medical conditions of the person taking the drug. The evidence of how well these medications work for each condition is detailed below. 

Table 2. Evidence for Off-Label Use of Antipsychotic Drugs*

* No studies were identified that met the criteria for the Agency for Healthcare Research and Quality report that forms the basis of this report.

1. When the medication is used alone to treat depression. 

Clozapine (Clozaril, Fazaclo, and generic) was the first newer antipsychotic drug approved by the FDA. It was not included in our evaluation because it can cause serious side effects, including seizures and a blood disorder called agranulocytosis, which can lead to fatal infections and requires special monitoring by a doctor. The use of clozapine is generally limited to people with schizophrenia who have not responded to other antipsychotic medications. The other newer antipsychotic drugs are unlikely to cause those problems, but they carry the risk of the side effects listed above and described in more detail here.

Generalized anxiety disorder (GAD)—an excessive, irrational dread of everyday situations—affects about 6.8 million adults in the U.S., according to the National Institute of Mental Health. Twice as many women as men suffer from the condition. People with GAD have difficulty relaxing and concentrating, startle easily, and often have trouble sleeping. GAD can also cause other symptoms, including fatigue, headaches, muscle aches, and trembling. People with severe GAD can have difficulty functioning and carrying out daily activities.

GAD is usually treated with psychotherapy and, if necessary, antidepressant medications. In some cases, an antipsychotic drug might be used alone or in addition to an antidepressant. There’s limited research that suggests quetiapine might improve symptoms, but the other antipsychotic drugs appear to be ineffective or have not been studied for treating anxiety.

The results of three studies of quetiapine showed the drug was more effective than placebo in decreasing symptoms of generalized anxiety. Another study showed quetiapine reduced the risk of relapse. Studies involving ziprasidone, olanzapine, and risperidone found those medications were ineffective for treating generalized anxiety disorder.

The four other newer antipsychotic drugs—aripiprazole, asenapine, iloperidone, and paliperidone—have not been studied for treating generalized anxiety disorder.

Attention-deficit/hyperactivity disorder is one of the most common behavioral problems diagnosed among school-aged children in the U.S. The signs of ADHD include a persistent pattern lasting at least six months of abnormally high levels of physical activity (hyperactivity), impulsive behavior, and/or lack of ability to pay attention and focus or complete tasks. Boys and girls with ADHD are more likely to have low self-esteem, develop emotional and social problems, and underachieve at school. ADHD can also affect adults.

If you or your child have been diagnosed with ADHD, the usual treatment options include behavioral therapy, educational interventions, and stimulant medications, such as methylphenidate (Ritalin or generic) or amphetamine (Adderall or generic).

If those strategies fail to improve ADHD symptoms, your doctor might recommend trying one of the antipsychotic medications. Our Consumer Reports medical advisers recommend caution, though. As you can see below, there is little research on antipsychotic medications in the treatment of ADHD, and there is no clear evidence that they are effective.

Only two of the newer antipsychotic drugs—risperidone and aripiprazole—have been studied for treating ADHD in children. In one very small, short study, one in four children who received risperidone showed improvement in symptoms of aggression. The children who received risperidone were more likely to experience several side effects, including abdominal pain, agitation, and increased appetite. The study lasted only four weeks, and longer-term adverse effects were not reported. In another small study, risperidone decreased aggression more than methylphenidate in children with ADHD and mental retardation, but it was associated with weight gain.

In two studies involving aripiprazole in children with ADHD and bipolar disorder, the medication did not reduce ADHD symptoms.

See our FREE Best Buy Drugs report to learn more about ADHD.

Depression is a common health problem in the U.S., with 14.8 million adults suffering from the condition in any given year, according to the National Institute of Mental Health. Psychotherapy and, if necessary, antidepressant medication such as bupropion (Wellbutrin and generics), citalopram (Celexa and generics), and fluoxetine (Prozac and generics), can often help.

Antipsychotic drugs are used as “augmentation therapy,” or add-ons to treat depression that hasn’t been helped by antidepressants or other treatments. This is known as “treatment resistant” depression. Three of the antipsychotic medications—aripiprazole, olanzapine, and quetiapine—are FDA-approved for this; the other five are not. But the available evidence indicates that antipsychotics aren’t very effective as augmentation therapy for treating resistant depression.

Given the possible side effects they can cause, antipsychotic drugs aren’t the best choice for this use for most people. Other options, such as increasing the dose of your standard antidepressant or switching to a different one, are at least as effective and are safer. Combining two antidepressants may also be an option. These strategies should be tried first before adding any antipsychotic drug to your antidepressant.

Some doctors may prescribe antipsychotic drugs alone to treat depression, but it’s unclear from the evidence available which of these drugs, if any, should be used by themselves for relieving depression. Only a few studies have addressed using antipsychotic medications alone for treating depression.

Three studies of olanzapine found that it was not effective when used alone for depression. The combined results of five large trials of extended-release quetiapine found it helped relieve depression symptoms better than placebo, but the studies lasted 12 weeks or less, so it’s not clear whether the beneficial effects last over the long term or whether they outweigh the potential side effects, such as weight gain and increased risk of diabetes.

To learn more about treating depression with antidepressant medication, see our FREE Best Buy Drugs report here.

For more about augmentation therapy with antipsychotic drugs to treat depression, see our FREE Best Buy Drugs report here.

Insomnia—difficulty falling asleep or staying asleep—can lead to sleepiness and other problems during the daytime. The condition is quite common: one in three adults has insomnia occasionally, and one in 10 suffers from chronic insomnia, according to the National Heart, Lung, and Blood Institute (NHLBI).

Antipsychotic drugs have been used to treat insomnia because one of their side effects is drowsiness. But as discussed next, there is no clear evidence that they work to actually relieve insomnia. If you have persistent insomnia, instead first try improving your sleep habits, such as not watching TV or using computers in bed, sticking to a regular bedtime and wake-up time, and cutting back on caffeine and alcohol at night. Your doctor might also recommend cognitive behavioral therapy—a form of psychotherapy that can be just as helpful as, or more so, than medication. In some cases, judicious use of sleeping pills, such as zolpidem (Ambien and generic) or eszopiclone (Lunesta and generic), can often provide short-term relief.

Only two antipsychotic drugs—quetiapine and olanzapine—have been evaluated for the treatment of insomnia, and the limited results do not enable us to determine if they are effective. Quetiapine is the only newer antipsychotic medication to be evaluated in a clinical trial for the treatment of insomnia. That small trial found that it was no better than placebo. Four observational studies involving quetiapine indicated it improved insomnia symptoms, but because these types of studies are not as rigorous as clinical trials, it’s not clear how much of the benefit was attributable to the medication.

Two observational studies of olanzapine found that it might improve sleep, but again, it’s not clear how much of the benefit was due to the medication.

See our FREE Best Buy Drugs report for more details on treating insomnia.

PTSD can develop after the experience of a traumatic event, such as military combat, sexual or physical abuse or assault, and serious accidents, such as a car wreck or natural disaster. The symptoms of PTSD can include bad memories or nightmares about the traumatic event, fear, guilt, and avoidance of situations that remind you of the traumatic event. People with PTSD can also develop anxiety, depression, drinking or drug problems, chronic pain, and problems with employment and relationships.

The standard treatments for PTSD are psychotherapy, such as cognitive behavioral therapy, and medication, including antidepressants. Although antipsychotic medications have been used off-label to treat PTSD, there’s not enough evidence overall to draw conclusions about their effectiveness or which types of PTSD symptoms they should be used to treat. The available studies indicate that the medications help relieve symptoms in men who developed PTSD due to combat but not in women whose PTSD symptoms were due to noncombat incidences, such as domestic abuse.

Three newer antipsychotic drugs have been studied for treating PTSD: olanzapine, quetiapine, and risperidone. One trial indicated that olanzapine is effective for reducing combat-related PTSD symptoms when added to an antidepressant. One small, eight-week study of noncombat related PTSD also found that olanzapine by itself was helpful.

One trial of quetiapine found that when it was given with an antidepressant, the combination helped relieve PTSD symptoms (whether the PTSD was due to combat or something else was not reported).

The best evidence about risperidone comes from a study conducted by the U.S. Department of Veterans Affairs. That study, which is the largest conducted on risperidone for combat-related PTSD symptoms, found that, on average, the medication was no better than placebo at reducing PTSD severity or relieving symptoms, including depression and anxiety. People who took risperidone were more likely than those who took placebo to experience weight gain, fatigue, and drowsiness.

Newer antipsychotic drugs can cause significant side effects, some of which are serious (See Table 3). The side effects of these medications include death, weight gain, fatigue, sedation, restlessness (akathisia), muscle rigidity, and twitches or tremors (extrapyramidal symptoms, some of which can be permanent). Many people who start taking an antipsychotic drug do not take it for long, even if it reduces their symptoms, because they cannot or do not want to tolerate the side effects. So it’s important to take those into consideration when deciding whether to take one of these medications, especially if it’s for an off-label use, the benefits of which are uncertain.

Side effects associated with off-label use of these medications can include:

Death. Although death is a highly unlikely side effect, one large study that involved elderly people found higher rates of sudden death in those who took an antipsychotic drug. The risk was higher for those who took higher doses. The combined results of several studies found the risk of death is particularly increased for elderly people who have dementia and agitation.

Weight gain. Several antipsychotic drugs have been associated with weight gain, including aripiprazole, olanzapine, quetiapine, and risperidone. The pooled results of 85 trials found strong evidence that olanzapine poses a higher risk of weight gain than any other antipsychotic. Limited evidence indicates ziprasidone is not associated with weight gain.

Diabetes and high cholesterol. Olanzapine is more likely than the other new antipsychotic drugs to cause type 2 diabetes. Risperidone, quetiapine, olanzapine, and ziprasidone appear to increase the risk of high cholesterol, but aripiprazole does not. Studies have indicated that quetiapine can also increase triglycerides, which could increase the risk of heart disease.

Mental and muscular problems. All newer antipsychotic drugs increase the risk of mental side effects, which include confusion, dizziness, headaches, lightheadedness, sedation, seizure, and tinnitus. All of them, except for risperidone, are associated with fatigue. Olanzapine, risperidone, and quetiapine were also associated with cognitive decline in the elderly.

Only aripiprazole was associated with restlessness. Aripiprazole, quetiapine, and ziprasidone are associated with uncontrollable movements and tremors that resemble Parkinson’s disease (extrapyramidal symptoms). Olanzapine and risperidone increase the risk of other neuromuscular issues when compared with placebo.

Blood clots. One study found that all newer antipsychotic drugs increase the risk of blood clots, which can lead to serious complications and death if not treated. Older people have a higher risk.

Other side effects: Quetiapine is more likely than risperidone to cause agitation, decreased salivation, neurological events, and sedation. Studies in people with schizophrenia found that risperidone is the most likely of the newer antipsychotic drugs to increase a hormone called prolactin, which can result in women missing menstrual periods, diminished sex drive, and other sexual side-effects. But it is unclear if the lower doses of risperidone typically prescribed for off-label use increases prolactin. Paliperidone is closely related to risperidone and also has been shown to elevate prolactin levels.

Table 3. Side Effects Associated with Off-Label Use of Atypical Antipsychotic Drugs

The lack of comparative evidence for off-label use of the newer antipsychotic drugs makes it difficult to determine the effectiveness and safety of these medications under those circumstances. So we have not chosen a Best Buy antipsychotic drug for use in anxiety, ADHD, depression, insomnia, or PTSD.

Our Consumer Reports medical advisers recommend that you discuss with your doctor first trying standard treatment options for your condition, including nondrug and lifestyle strategies, if appropriate.

Consider an antipsychotic drug only if those other options fail to improve your symptoms. If you do decide to try an antipsychotic treatment, carefully weigh the risks of these drugs against any potential benefits.

In addition, the cost of the antipsychotics might be important to take into account. Most of these medications are very expensive, so before starting one, find out how much your insurance plan covers and how much your out-of-pocket costs will be.

Another important issue to be aware of is that it is not clear what dose of these medications is best for off-label uses. Our analysis found insufficient evidence about different dosages of the antipsychotic medications to draw conclusions about how much a person should take.

Often, the desired effects—for example, sedation to treat insomnia—can be achieved with a much lower dose of the medication than typically used to treat conditions for which the drug has been FDA-approved, such as schizophrenia.

If you decide to use a newer antipsychotic drug, your doctor should monitor you for side effects. This includes assessing your weight and muscle rigidity and blood-test results. And you should stop taking the medication if it doesn’t improve your symptoms.

Our evaluation is primarily based on an independent scientific review of the evidence on the effectiveness, safety, and adverse effects of the drugs included in this report. A team of physicians and researchers at the Southern California Evidence-Based Practice Center completed this analysis as part of a larger update on Off-Label Use of Atypical Antipsychotics, prepared for the Agency for Healthcare Research and Quality. This was a systematic review and meta-analysis comparing the effectiveness and safety of these medications. Members of the team had no financial interest in any pharmaceutical company or product.

A synopsis of that analysis, for selected conditions, along with expert opinion, forms the basis for this report. The full update (a long and technical document written for physicians) is available at www.ncbi.nlm.nih.gov/books/NBK66081/.

A consultant to Consumer Reports Best Buy Drugs is also a founder of Oregon Health & Science University’s Drug Effectiveness Review Project, or DERP, a first-of-its-kind multistate initiative to evaluate the comparative effectiveness and safety of hundreds of prescription drugs. The Oregon-based research team has no financial interest in any pharmaceutical company or product.

The Consumer Reports Best Buy Drugs methodology is described in more detail in the Methods section at www.CRBestBuyDrugs.org.

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