Health Letter, April 2013
The use of psychiatric, or psychotropic, mind-affecting drugs in children has increased exponentially over the past two decades. An estimated 8 million U.S. children are now on at least one type of psychiatric medication for a behavioral disorder or mental illness.
Much of the increased use in recent years has involved a class of medicines called atypical antipsychotics. It is a troubling fact, but one that studies have repeatedly shown, that most of these risky antipsychotic drugs are being prescribed to children for unapproved — and unproven — uses. In other words, most of them are not psychotic.
Overview of atypical antipsychotics
The first antipsychotic medications, now known as first-generation or typical antipsychotics, were largely used to treat seriously mentally ill patients, such as those with schizophrenia, institutionalized in inpatient mental-health facilities. In the 1990s, a new class of drugs emerged. Called second-generation or atypical antipsychotics, these drugs had fewer side effects than the first-generation medicines, and their debut coincided with the continued transition of common mental-illness treatment from inpatient institutions to outpatient clinics. (Only one atypical antipsychotic, clozapine [Clozaril], was approved prior to the 1990s.) This timing resulted in the widespread use of atypical antipsychotics in the outpatient setting.
Sales of atypical antipsychotics have risen considerably in recent years, from 2.3 million prescriptions per month in November 2005 to 4 million prescriptions per month by September 2011. Sales of the drugs for children have followed a similar trend, increasing 62 percent between 2002 and 2007 in Medicaid-enrolled children.
Unproven, off-label use predominates in children
As of August 2012, atypical antipsychotics were approved by the Food and Drug Administration (FDA) in children only for treatment of bipolar disorder (for ages 10 to 17), schizophrenia (for ages 13 to 17), irritability associated with autism, and “tics and vocal utterances of Tourette syndrome.” Yet most atypical antipsychotic prescriptions written for children are not for these conditions. Instead, according to the federal Agency for Healthcare Research and Quality (AHRQ), the majority are for conditions for which the drugs have never been approved by the FDA.
A study of children in the Arkansas Medicaid program found that the most common conditions for which atypical antipsychotics were prescribed were attention deficit hyperactivity disorder (ADHD), followed by depression, conduct disorder, oppositional defiant disorder and adjustment reactions. According to the authors, 41 percent of the children had no diagnosis for which antipsychotic treatment was supported by any published study. Another large study of privately insured children found similar patterns of use, with atypical antipsychotics most commonly prescribed for behavioral or mood disorders (disruptive behavior disorder, followed by mood disorders and anxiety disorder).
There is no solid evidence that the drugs work for these most common off-label uses. Two systematic reviews conducted in 2006 and 2011 by AHRQ found only a handful of published trials that studied any off-label uses of antipsychotics in children. Only one drug, risperidone (Risperdal), demonstrated some benefit for ADHD, but the two trials in which this was shown were exceedingly small (70 children in total) and short-term (four weeks). Another drug, aripiprazole (Abilify), was shown to be ineffective in reducing ADHD symptoms in children with bipolar disorder in two other trials.
For all atypical antipsychotics other than risperidone, AHRQ researchers did not find a single trial evaluating the risks and benefits of any off-label uses for children. These two reviews demonstrated that there is no substantial evidence supporting the effectiveness of any atypical antipsychotic for any off-label use in children.
Drug risks without countervailing benefits
The fact that the drugs have not been proven effective for a large proportion of their uses in children puts their risks into sharp relief. The relative safety of atypical antipsychotics compared with their older counterparts is what launched them into widespread use, but the drugs come with serious and insidious side effects, including in otherwise healthy children.
Several atypical antipsychotics cause substantial weight gain, which is often associated with increases in blood glucose and cholesterol levels. In the largest study looking at metabolic side effects in first-time users of atypical antipsychotics, children on the drugs gained between 10 and 19 pounds on average, in some cases with accompanying increases in blood glucose and cholesterol levels, after just 12 weeks. Another, longer-term study found that children gained an average of 36 pounds on olanzapine (Zyprexa), 21 pounds on clozapine and 16 pounds on risperidone after approximately 10 months. These weight and metabolic changes can predispose patients to type 2 diabetes, as suggested in studies of adults taking the drugs. Neurological side effects, including conditions known as neuroleptic malignant syndrome and tardive dyskinesia, can be irreversible and potentially fatal in severe cases.
Questionable psychiatric diagnoses for children
A proliferation of new mental-health diagnoses in children of all ages is partly to blame for the increased antipsychotic drug use in children, with ADHD and bipolar disorder at the center of this trend.
ADHD was the first diagnosis for which psychotropic medications were specifically targeted in children, and it remains one of the most common conditions for which they are prescribed today. Attention deficit disorder (ADD), the precursor diagnosis to ADHD, was first added to the third version of the psychiatric Diagnostic and Statistical Manual (DSM) in 1980 to identify children with perceived attention problems in the home or school. (Hyperactivity was added to ADD more than a decade later, making up the current disease category of ADHD.)
In the past 20 years, rates of diagnosis of ADHD have increased exponentially. A 1995 study documented that the number of people with ADHD in the U.S. more than doubled from 1990 to 1993 alone. By 2011, the Centers for Disease Control and Prevention (CDC) reported that almost 1 in 10, or 9 percent, of all U.S. children under 18 were currently diagnosed with ADHD.
Bipolar disorder, characterized by extreme swings between depressed and manic moods, was first formally classified as a diagnosis in children in the fourth version of the DSM in 1994. Rates of bipolar disorder in children subsequently rose by a factor of 40 between 1994 and 2003 in youth 19 years or younger. By way of comparison, rates in adults increased by 86 percent over the same time period.
Accompanying this explosion of psychiatric diagnoses was a sevenfold increase in doctor visits for antipsychotic medications in children 13 and under between 1993 and 2009.
The sudden increase in the number of ADHD and bipolar disorder cases has made the diagnoses for so many children particularly controversial. Has there always been a silent epidemic of these diseases that went unrecognized until the mid-1990s? Or is the real epidemic the wave of overdiagnosis (and overtreatment) that predictably followed the diagnoses being formalized within the medical establishment?
There are undoubtedly legitimate cases of these disorders, in which the diagnoses represent increased awareness among physicians and parents of significant mental illness. But most of the new cases likely result from more dangerously liberal diagnostic standards — as well as outright misdiagnosis — within the medical community.
According to the National Institute of Mental Health (NIMH), some studies show that an overexcited and elated mood in normally subdued children can easily be misdiagnosed as bipolar disorder, as can the symptoms of other, less serious conditions, such as ADHD. The NIMH cited as an example a 2001 study in which nearly half of adolescents in inpatient facilities diagnosed with bipolar disorder were later reclassified as having other mental disorders.
Major Settlements With Pharmaceutical Manufacturers Over Allegations Of Illegal, Off-label Marketing of Antipsychotics for Use in Children
(including for other criminal and civil violations)**
|2007||Bristol-Myers Squibb||Abilify (aripiprazole)||$515 million|
|The U.S. Department of Justice (DOJ) alleged that from 2002 through 2005, Bristol-Myers Squibb knowingly promoted the atypical antipsychotic Abilify for sale and use in children (as well as to treat dementia-related psychosis), both of which uses were not FDA-approved.|
|2008||Otsuka Pharmaceutical||Abilify (aripiprazole)||$4 million|
|Otsuka initially developed Abilify and then partnered with Bristol-Myers Squibb to promote the drug, including the unlawful, off-label pediatric sale and use mentioned above. This 2008 penalty settled government charges against an Otsuka subsidiary for its role in the alleged marketing scheme.|
|2009||Eli Lilly||Zyprexa (olanzapine)||$1.4 billion|
|In 2009, drug company Eli Lilly settled civil and criminal allegations that the company persuaded doctors to prescribe the drug Zyprexa to children and geriatric adults. Not only was Zyprexa not approved by the FDA to sedate nursing home patients and treat disruptive children, but such uses were particularly risky in these two vulnerable populations.|
|2010||AstraZeneca||Seroquel (quetiapine)||$520 million|
|A press release issued on April 27, 2010, by the Department of Health and Human Services (HHS) stated that AstraZeneca agreed to pay $520 million to resolve government allegations that the company engaged in off-label promotion between 2001 and 2006. HHS stated that AstraZeneca “targeted its illegal marketing of the anti-psychotic Seroquel towards doctors who do not typically treat schizophrenia or bipolar disorder,” including those treating children and adolescents.|
|2012||Abbott Laboratories||Depakote (divalproex)||$1.5 billion|
|The DOJ alleged that between 1998 and 2008, Abbott illegally promoted the drug Depakote for a variety of unapproved uses, including pediatric and adolescent psychiatric conditions.|
|2012||Johnson & Johnson||Risperdal (risperidone)||$181 million|
|A subsidiary of Johnson & Johnson was accused by state and federal authorities of illegally promoting Risperdal for the treatment of bipolar disorder in children and adolescents, among other unapproved indications.|
* Parent companies are listed in all cases, including those involving allegations against subsidiaries of the company.
** Penalties include overall settlement totals for all alleged violations, including nonpediatric violations, involving the antipsychotic medication.
Clinical paradigms and pervasive marketing feed overdiagnosis
The propensity to overdiagnose some of these conditions may be particularly strong when dealing with psychiatric conditions with deep-seated social or economic roots that simply cannot be addressed fully in a 15-minute doctor visit. According to a 2011 national survey conducted by the CDC, children living in poverty or in a single-parent or foster home were substantially more likely than other children to be diagnosed with ADHD or a learning disability.
It should come as no surprise that a hungry child living in poverty, or one with an overworked or otherwise absent parent, might find it difficult to concentrate in school or might misbehave as a consequence of his or her situation. Addressing deep social or economic problems takes time that many pediatricians or psychiatrists are simply not given (or may be beyond the scope of their abilities) in a medical system that demands high patient turnover and discrete diagnoses that can be billed to insurers.
The drug industry also has played a decisive role in the overdiagnosis problem. Millions of newly diagnosed children represent a lucrative new market, and manufacturers of atypical antipsychotics have launched aggressive marketing campaigns to pressure physicians to prescribe the drugs. Because there are only a few FDA-approved conditions for the drugs in children, however, many of these promotional campaigns have apparently crossed the line into illegal, off-label marketing. Since 2007, seven different manufacturers of atypical antipsychotics have paid a total of
$4.3 billion in settlements with the federal and state governments over allegations including actively marketing the drugs for off-label uses in children.
Thanks to direct-to-consumer marketing campaigns for psychotropic drugs and media stories of an “epidemic” of mental illnesses (such as ADHD) in children, parents may be more prone to pathologize their children’s behavior and ask for medications themselves. Children formerly regarded as rambunctious or transiently sad are now often regarded as mentally ill and treated with a medication they may take for years — into adulthood and, in some cases, for life. Beyond the direct impact of ads, the current diagnostic paradigm might inherently appeal to busy and distressed parents looking for an immediate answer to a child’s misbehavior while alleviating them of any perceived (and in many cases unfounded) culpability for their child’s conduct.
Overprescribing displaces long-term solutions
The result of all these factors is that millions of children are receiving risky antipsychotic medications that have never been shown to provide any benefit to them. A fragmented medical system that encourages overdiagnosis and overmedication, combined with persistent marketing campaigns, fuels this unnecessary use and diverts attention from more effective long-term social interventions and economic policies to alleviate mental-health burdens in children and adolescents.