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Between 1996 and 2001, notes David Healy in : A Short History of , there was a fivefold increase in the use of in preschoolers and preteens. The second-generation atypicals (Zyprexa, Risperdal, Abilify, Seroquel, and others) were often prescribed off-label for a variety of indications, including , , mood stabilization, and behavioral control. From the outset, they were known to contribute to cardiovascular and metabolic problems, chiefly weight gain, tardive dyskinesia, and diabetes. But whether the drugs themselves were associated with an increased risk of death was, at least officially, unknown.

That is no longer the case. The first sizable (250,000-person) study on the subject was recently published online in JAMA , largely concerning children and teens diagnosed with ADHD. Led by Wayne A. Ray at the Vanderbilt University School of Medicine, the study controlled for multiple factors, including , suicide, and overdose. Of the three groups studied, it determined that the one receiving a higher dose of antipsychotic medication had a “significantly increased risk of unexpected death compared with the group that received control medication.”

Children taking a high dose of antipsychotics were found to be “1.8 times more likely to die of any cause,” medical reporter Peter Simons extrapolated, “3.5 times more likely to die of unexpected causes (not including overdose), and 4.29 times more likely to die of cardiovascular or metabolic problems.”

The findings are certain to raise concern about continued off-label prescribing for children and teens. As Washington University-based psychiatrist Barbara Geller wrote in an accompanying editorial, “Results in the study … heighten the already increased caution about prescribing antipsychotics to children and adolescents and emphasize the need to consider situational triggers of psychopathology to avoid medicating . Concerns about excess deaths are likely to increase because the prevalence of some disorders for which antipsychotics are prescribed off-label (e. ., ) and the number of prescriptions for indicated and off-label use are rising.”

“Instinctively,” she continues, “it might seem that children and adolescents who are physically healthy would sustain fewer and less serious adversities from antipsychotic medications than their adult counterparts. However, the opposite is true.” As evidence of their greater vulnerability, Geller references “more severe symptoms in children and adolescents because of their developmentally immature prefrontal cortices,” a reason for fundamental caution about prescribing in the first place.

The high risk of death associated with antipsychotics prescribed for the very young is understudied, fraught with controversy, but has in fact been known for some time. “Since the introduction of the antipsychotics,” Healy stated in an interview with this blog in 2009, “the rates of suicide have risen 10- or 20-fold.” He was referencing “Lifetime suicide rates in treated schizophrenia,” a 2006 study he and colleagues published in the British Journal of Psychiatry. The same year, the same journal also published “Schizophrenia, neuroleptic medication and mortality” and, in 2000, “Sudden unexplained death in psychiatric in-patients,” which opened by explaining: “Reports of sudden death in people with mental illness who are taking antipsychotic medication have been a source of public and professional controversy for three decades.”

“Long before the were linked with akathisia,” Healy extrapolated on “Side Effects,” “the antipsychotics were universally recognized as causing this problem. It was also universally accepted that the akathisia they induce risked precipitating the patient into or violence.”

In the mid-1990s, he underscored in Mania, almost half of all mood disorders were redefined as bipolar disorder rather than depression. The second-generation antipsychotics were aggressively promoted at the same time, to a greatly expanded market. Fears about SSRI-induced suicidality in children and teens would peak with the 2004 FDA decision to add a black-box warning to SSRIs, curbing pediatric prescribing, but also helping to present the atypicals as a safer alternative.

The consequences of such radical shifts remain as relevant as ever. As Healy noted in 2009, “Mood stabilization didnʼt exist before the mid-1990s. It canʼt be found in any of the earlier reference books and journals…. [And] bipolar disorder,” particularly in children, “itself is a somewhat mythical entity. As used now the term bears little relation to classic manic-depressive illness, which required people to be hospitalized with an episode of illness, either depression or mania.… While the term bipolar disorder was there since 1980, manic-depression was the term that was still more commonly used until the mid-1990s when it vanishes and is replaced by bipolar disorder. Nowadays, over 500 articles per year feature bipolar disorder in their titles.”

The lowering of age thresholds for bipolar disorder was accompanied by the upward expansion of ADHD, so adults could be diagnosed with it as well. Geller underscores the shift in treating adults and children as alike when asserting, “psychiatrically ill children are not adult ‘lite.’ Rather, they have the same disorders as adults, including those that have pediatric US Food and Drug Administration indications for antipsychotic use (e.g., schizophrenia, bipolar disorder)” (emphasis mine). But would the claim extend as readily to toddlers as to teens? And should either be given doses comparable to those prescribed adults if their “developmentally immature prefrontal cortices” are truly the center of concern?

The recent JAMA study recommends limiting pediatric use of antipsychotics to “indications for which there is good evidence of efficacy, an adequate trial of alternatives including psychosocial interventions when possible, cardio-metabolic assessments before treatment and monitoring after treatment, and limiting to the lowest dose and shortest duration possible.”

The problem there, at least in the UK, is that those diagnosed with first-episode or schizophrenia face prescribing guidelines that recommend continuous and indefinite use of antipsychotics. Geller, too, is emphatic in calling this last condition “lifelong” and thus potentially “requir[ing] decades of antipsychotic exposure.”

The latest study demands a rethink. With children taking a high dose of antipsychotics found to be more than four times more likely to die of cardiovascular or metabolic problems and almost twice as likely to die of any cause, the guidelines need adjusting, and soon.