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    ADHD: Are off-label atypical antipsychotics appropriate?

    The amount of off-label uses of atypical antipsychotic drugs (AAPs) prescribed for children with attention-deficit/hyperactivity disorder (ADHD) raises questions about the appropriateness of AAPs for this indication.

    In a recent study, investigators analyzed outpatient data from the National Ambulatory Medical Care Survey and the National Hospital Ambulatory Medical Care Survey. They found that between 1993 and 2010, AAP prescriptions written for patients aged between 4 and 18 years grew significantly, and that two-thirds of these prescriptions were written for off-label indications.1

    "It's concerning that such a high proportion of pediatric patients were taking AAPs off-label, and that a number of children are exposed to AAP side effects such as metabolic syndrome and diabetes, while the drugs' effectiveness on their psychiatric condition may not have been well-established," said study co-author Minji Sohn, PhD, in an interview. She is assistant professor of pharmaceutical sciences at Ferris State University's College of Pharmacy, Big Rapids, Michigan.

    Between 2007 and 2010, the most common mental disorder among AAP patients was ADHD, which accounted for 24% of total pediatric AAP visits but is not a US Food and Drug Administration (FDA)-approved indication for these drugs.

    Off-label AAP use remains controversial, write Sohn and colleagues, given the uncertainties regarding the effectiveness and safety of AAPs. Yet AAPs likely rank among the most increasingly prescribed classes of prescription drugs for children and adolescents, they say. A Medicaid study has shown that between 1996 and 2001, AAP use in children and adolescents increased 1.5- to 3-fold.2

    Investigators undertook their study to analyze recent trends in pediatric off-label AAP use, and to evaluate patient and provider characteristics associated with such use. They considered a visit to be an AAP visit if the provider prescribed risperidone, olanzapine, quetiapine, ziprasidone, aripiprazole, paliperidone, asenapine, or iloperidone, separately or in combination.

    Starting in 1995, overall AAP use in pediatrics grew slowly but steadily until 2000, when the average AAP prescription rate reached 0.9 per 100 visits—more than double the number prescribed in 1999 (0.4 per 100 visits). A similar doubling occurred between 2002 and 2003, when the average rate rose from 0.8 per 100 visits to 1.6 per 100 visits. After 2003, AAP usage in pediatrics showed a more fluctuating pattern, although investigators were able to divide their data into 3 different phases or eras based on approval of new AAP drugs and indications.

    From 1993 to 1999, when second-generation AAPs risperidone, olanzapine and quetiapine were approved to treat only schizophrenia, the average AAP prescription rate was 0.15 per 100 visits. By the study's final phase, 2003 to 2010, the average AAP prescription rate was 1.59 per 100 visits, which presents a statistically significant increase from phase II (0.81 per 100 visits, 2000-2002). The proportion of pediatric visits that included an AAP prescription peaked at more than 2 per 100 visits in 2009.

    In multivariate logistic regression analysis, factors that significantly increased the likelihood of a child with ADHD being prescribed an AAP included having Medicaid as the primary payer; having 4 or more non-AAP prescriptions; and having comorbid disorders such as approved AAP indications, psychoses, neurotic disorders, and disturbances.

    Whether on-label or off-label, AAP usage tended to spike, researchers discovered, with the approval of new AAPs, and particularly of new indications. Most of the usage increases came not from FDA-approved uses, they say, but from off-label usage.

    Between the study's first and second phases (1993 to 1999 vs 2000 to 2003), AAP visits for FDA-approved indications grew only 0.09 per 100 visits, whereas AAP visits for off-label uses increased by 0.57 per 100 visits. Drugs and indications approved in phase II included ziprasidone, aripiprazole, and bipolar I disorder. In the study's third phase (2003 to 2010), when the FDA-approved paliperidone, iloperidone, and asenapine, along with the additional pediatric indications schizophrenia, depression, bipolar I disorder, and autism, off-label prescriptions also far outstripped on-label uses.

    "Perhaps having approval for additional AAP indications impacted the AAP therapy decision-making process in a way that AAPs were regarded as useful for conditions other than currently approved indications," the researchers write.

    To prevent potential misuse, says Sohn, some payers require prior authorization or second opinions before dispensing AAPs. "But it would be best for pediatric providers to carefully weigh the benefits and risks before prescribing these drugs. We need more evidence that these off-label conditions are effectively managed and treated by AAPs."

    REFERENCES

    1. Sohn M, Moga DC, Blumenschein K, Talbert J. National trends in off-label use of atypical antipsychotics in children and adolescents in the United States. Medicine (Baltimore). 2016;95(23):e3784.

    2. Patel NC, Crismon ML, Hoagwood K, et al. Trends in the use of typical and atypical antipsychotics in children and adolescents. J Am Acad Child Adolesc Psychiatry. 2005;44(6):548-556.

    John Jesitus
    John Jesitus is a medical writer based in Westminster, CO.

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