For more than 20 years, doctors have been prescribing powerful antipsychotic drugs-intended for the treatment of schizophrenia-for a wide range of other mental disorders, such as depression, dementia, personality disorders and even autism. Although the practice of using drugs for health problems for which they are not licensed to treat-known as 'off-label prescribing'-is not illegal, it should be done judiciously. How-ever, virtually all antipsychotic drug use has been off-label, making them the most prescribed drugs in medicine, representing 5 per cent of all drug spending in the US alone, and ringing up annual sales of $10 billion.
The drugs are, at best, useless against many of the conditions for which they're given, and they can cause a range of serious side-effects, such as diabetes and heart disease. In the US, reactions to these drugs have cost the health-care system billions of dollars in after-care treatment and employment losses, says Randall Stafford, professor of medicine at the Stanford School of Medicine Prevention Research Center in California.
As thousands of patients or their surviving relatives have filed lawsuits against the drug makers, the antipsychotics are now the single largest target of litigation filed under America's False Claims Act. As a result, drug companies have paid out hundreds of millions of dollars in damages, or are under investigation for skewing the results of trials, such that they may have falsely concluded that the drugs were effective for a wide range of mental problems or were safe to use.
Regulators are also investigating the "questionable marketing tactics" used by drug companies and their representatives to encourage doctors to prescribe antipsychotics off-label. Inducements have included gifts, PCs for the surgery and invitations to conferences at exotic locations. So compelling are these marketing ploys that many doctors don't even realize that they are prescribing off-label, says Stafford.
Stafford and his colleagues have tracked the off-label growth of antipsychotic use between 1995 and 2008, and found that such use nearly trebled in the US in those 13 years, by which time, 16.7 million prescriptions were being written every year. Of these, 9 million were off-label and, yet, there was no evidence that the drugs would work in 54 per cent of the conditions.
Translated into cash terms, the US healthcare system spent $6 billion for off-label prescribing of antipsychotics in 2008, of which $5.4 billion had "uncertain evidence" of effectiveness or safety (Pharmacoepidemiol Drug Saf, 2011; 20: 177-84).
Given the marked increase of off-label atypical antipsychotics throughout the 1990s, the US Food and Drug Administration (FDA) in 2005 issued its strongest possible alert-a 'black-box warn-ing'-that the use of antipsychotics to treat dementia, for example, could result in the patient's death. An analysis by researchers at the University of Michigan at Ann Arbor concluded that the FDA advisory was "associated with a significant acceleration in the decline" of off-label antipsychotic drug use (Arch Gen Psychiatry, 2011; 68: 190-7).
However, the FDA has hardly been the dragon at the gate. Not only has it turned a blind eye to antipsychotic misuse, it has even bowed to market pressures and expanded its 1989 approval of 'atypicals' (the second-generation antipsychotics) beyond treating only schizophrenia. Seroquel, the most prescribed antipsychotic in the US for some forms of bipolar disorder and depression, is also now commonly prescribed to treat anxiety and dementia.
Yet, despite the FDA's approval, independent studies are revealing that the risks of antipsychotics may outweigh the benefits even in schizophrenia. One US study has found that the drugs have signif-icant effects on brain tissue. When the researchers did MRI brain scans of 211 patients taking an antipsychotic, they discovered a consistent loss of gray and white matter over a seven-year period. At the very least, they concluded, doctors should be prescribing the lowest possible dose of these drugs (Arch Gen Psychiatry, 2011; 68: 128-37).
The drugs also increase the risk of blood clots. The atypicals are especially dangerous, say a team of UK researchers, who estimate that the drugs increase the risk of DVT (deep venous thrombosis) by 73 per cent vs 28 per cent with the older antipsychotics. The risk is greatest within the first two years of drug use (BMJ, September 21, 2010; 341: doi: 10.1136/bmj.c4245).
The FDA has recently bolstered its warning against antipsychotic use by pregnant women. Taking these drugs in the third trimester increases the risk of abnormal muscle symptoms in the newborn, including an inability to move (akinesia) and an inability to remain still (akathisia) (www.fda. gov/Drugs/DrugSafety/ucm243903.htm).
As Randall Stafford says: "Most people think that if the doctor prescribes the drug, it must be safe and effective. That's not true."
Factfile: Antipsychotics in the UK
These are the antipsychotic drugs approved for use in the UK:
u Abilify (aripiprazole)
u Clozaril (clozapine)
u Denzapine (clozapine)
u Invega (paliperidone)
u Risperdal/Risperdal Consta (risperidone)
u Solian (amisulpride)
u Zoleptil (zotepine)
u Zypreza (olanzapine)
WDDTY VOL. 22 NO. 1