A Call for Caution in the Use of Antipsychotic Drugs - Dr. Richard A. Friedman is a professor of psychiatry at Weill Cornell Medical College

You will never guess what the fifth and sixth best-selling prescription drugs are in the United States, so I’ll just tell you: Abilify and Seroquel, two powerful antipsychotics. In 2011 alone, they and other antipsychotic drugs were prescribed to 3.1 million Americans at a cost of $18.2 billion, a 13 percent increase over the previous year, according to the market research firm IMS Health.Those drugs are used to treat such serious psychiatric disorders as schizophrenia, bipolar disorder and severe major depression. But the rates of these disorders have been stable in the adult population for years. So how did these and other antipsychotics get to be so popular?

Antipsychotic drugs have been around for a long time, but until recently they were not widely used. Thorazine, the first real antipsychotic, was synthesized in the 1950s; not just sedating, it also targeted the core symptoms of schizophrenia, like hallucinations and delusions. Later, it was discovered that antipsychotic drugs also had powerful mood-stabilizing effects, so they were used to treat bipolar disorder, too.

Then, starting in 1993, came the so-called atypical antipsychotic drugs like Risperdal, Zyprexa, Seroquel, Geodon and Abilify. Today there are 10 of these drugs on the market, and they have generally fewer neurological side effects than the first-generation drugs.

Originally experts believed the new drugs were more effective than the older antipsychotics against such symptoms of schizophrenia as apathy, social withdrawal and cognitive deficits. But several recent large randomized studies, like the landmark Catie trial, failed to show that the new antipsychotics were any more effective or better tolerated than the older drugs.

This news was surprising to many psychiatrists — and obviously very disappointing to the drug companies.

It was also soon discovered that the second-generation antipsychotic drugs had serious side effects of their own, namely a risk of increased blood sugar, elevated lipids and cholesterol, and weight gain. They can also cause a potentially irreversible movement disorder called tardive dyskinesia, though the risk is thought to be significantly lower than with the older antipsychotic drugs.

Nonetheless, there has been a vast expansion in the use of these second-generation antipsychotic drugs in patients of all ages, particularly young people. Until recently, these drugs were used to treat a few serious psychiatric disorders. But now, unbelievably, these powerful medications are prescribed for conditions as varied as very mild mood disorders, everyday anxiety, insomnia and even mild emotional discomfort.

The number of annual prescriptions for atypical antipsychotics rose to 54 million in 2011 from 28 million in 2001, an 93 percent increase, according to IMS Health. One study found that the use of these drugs for indications without federal approval more than doubled from 1995 to 2008.

The original target population for these drugs, patients with schizophrenia and bipolar disorder, is actually quite small: The lifetime prevalence of schizophrenia is 1 percent, and that of bipolar disorder is around 1.5 percent. Drug companies have had a powerful economic incentive to explore other psychiatric uses and target populations for the newer antipsychotic drugs.

The companies initiated dozens of clinical trials to test these drugs against depression and, more recently, anxiety disorders. Starting in 2003, the makers of several second-generation antipsychotics (also known as atypical neuroleptics) have received F.D.A. approval for the use of these drugs in combination with antidepressants to treat severe depression, which they trumpeted in aggressive direct-to-consumer advertising campaigns.

The combined spending on print and digital media advertising for these new antipsychotic drugs increased to $2.4 billion in 2010, up from $1.3 billion in 2007, according to Kantar Media. Between 2007 and 2011, more than 98 percent of all advertising on atypical antipsychotics was spent on just two drugs: Abilify and Seroquel, the current best sellers.

There is little in these alluring advertisements to indicate that these are not simple antidepressants but powerful antipsychotics. A depressed female cartoon character says that before she starting taking Abilify, she was taking an antidepressant but still feeling down. Then, she says, her doctor suggested adding Abilify to her antidepressant, and, voilà, the gloom lifted.

The ad omits critical facts about depression that consumers would surely want to know. If a patient has not gotten better on an antidepressant, for instance, just taking it for a longer time or taking a higher dose could be very effective. There is also very strong evidence that adding a second antidepressant from a different chemical class is an effective and cheaper strategy — without having to resort to antipsychotic medication.

A more recent and worrisome trend is the use of atypical antipsychotic drugs — many of which are acutely sedating and calming — to treat various forms of anxiety, like generalized anxiety disorder and even situational anxiety. A study last year found that 21.3 percent of visits to a psychiatrist for treatment of an anxiety disorder in 2007 resulted in a prescription for an antipsychotic, up from 10.6 percent in 1996. This is a disturbing finding in light of the fact that the data for the safety and efficacy of antipsychotic drugs in treating anxiety disorders is weak, to say nothing of the mountain of evidence that generalized anxiety disorder can be effectively treated with safer — and cheaper — drugs like S.S.R.I. antidepressants.

There are a small number of controlled clinical trials of antipsychotic drugs in generalized anxiety or social anxiety that have shown either no effect or inconsistent results. As a consequence, there is no F.D.A.-approved use of an atypical antipsychotic for any anxiety disorder.

Yet I and many of my colleagues have seen dozens of patients with nothing more than everyday anxiety or insomnia who were given prescriptions for antipsychotic medications. Few of these patients were aware of the potential long-term risks of these drugs.

The increasing use of atypical antipsychotics by physicians to treat anxiety suggests that doctors view these medications as safer alternatives to the potentially habit-forming anti-anxiety benzodiazepines like Valium and Klonopin. And since antipsychotics have rapid effects, clinicians may prefer them to first-line treatments like S.S.R.I. antidepressants, which can take several weeks to work.

Of course, physicians frequently use medications off label, and there is sometimes solid empirical evidence to support this practice. But presently there is little evidence that atypical antipsychotic drugs are effective outside of a small number of serious psychiatric disorders, namely schizophrenia, bipolar disorder and treatment-resistant depression.

Let’s be clear: The new atypical antipsychotic drugs are effective and safe. But even if these drugs prove effective for a variety of new psychiatric illnesses, there is still good reason for caution. Because they have potentially serious adverse effects, atypical antipsychotic drugs should be used when currently available treatments — with typically fewer side effects and lower costs — have failed.

Atypical antipsychotics can be lifesaving for people who have schizophrenia, bipolar disorder or severe depression. But patients should think twice — and then some — before using these drugs to deal with the low-grade unhappiness, anxiety and insomnia that comes with modern life.

Dr. Richard A. Friedman is a professor of psychiatry at Weill Cornell Medical College in Manhattan.

via nytimes.com

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