Prescribing of psychotropic medications to children and adolescents: quo vadis?

Childhood and adolescence is a period of extraordinary biological, psychological and social growth. However, at such times, individuals are also vulnerable to disruptions of healthy development. In fact, a staggering 50% of all adult psychiatric disorders have manifested by age 14, with 75% manifesting by age 24 1. Moreover, two thirds of pediatric-onset psychiatric disorders are moderate or severe 2, and most continue into adulthood 3. Such patterns clearly indicate the importance of identifying and appropriately treating psychiatric disorders as early as possible to preserve healthy development and to reduce individual suffering and societal burden.

As eloquently described by J. Rapoport, there have been a number of groundbreaking developments in the management of pediatric psychiatric disorders. After decades of nearly exclusive reliance on psychological and behavioral interventions, psychopharmacologic advances have provided important biological management tools for severe pediatric psychiatric disorders. The advent of modern psychopharmacology, with its focus on parallel group, randomized controlled trials in large samples, has further informed the efficacy and tolerability of major psychotropic drug classes in youth 4. This progress has been facilitated by regulatory agencies encouraging and, more recently, requiring adequate studies of pharmacologic agents in pediatric patients.

Yet, as outlined by Rapoport, many challenges remain. There has been a far too narrow focus on short-term trials, with a lack of sufficient information on distal and lower frequency, but potentially serious adverse effects. Insufficient attention has also been devoted to the effects of commonly prescribed psychotropic medications on development, and too little is known about the safety and effectiveness of common off-label prescribing. Moreover, psychiatric drug development has been limited to relatively few and non-specific mechanisms of action, and much less is known regarding the efficacy of treatments for early illness manifestations compared to more chronic conditions. The rational development, of psychotropic medications is impeded by limited pathophysiological understanding of the disorders we aim to treat. In this context, the Research Domain Criteria project and other recent initiatives described by Rapoport may help to structure inquiries into underlying disease processes needed to identify new drug targets.

Although psychiatric disorders are now understood as having biological, psychological and social origins, requiring interventions in all domains, unilateral treatment approaches dominate in many countries and settings. Especially in the US, great concern has been raised about reductionist treatment approaches that focus too narrowly on pharmacologic management 5. Potential reasons include local and regional shortage of personnel trained in evidence-based psychosocial treatments, the absence of powerful and well-financed advocates for psychosocial treatments, ideological disagreements among psychotherapists, financial disincentives to providing psychotherapy under many public and private insurance plans, and the added time burden associated with psychological interventions. Many families are not willing to engage in therapy or are unable to attend appointments on a regular basis. Criticism has also focused on the tendency of some physicians to reach for a “quick fix”. Yet, all too often children and adolescents are brought to see a pediatric mental health clinician only at times of great distress and when urgently requiring interventions that reduce burdensome symptoms, improve disrupted functioning, or allow youth to stay in the current educational system or to advance to the next grade. In these instances, parents and school personnel may demand rapid results. Waiting lists for psychosocial treatment and longer periods to initial symptom control may further diminish the attractiveness of psycho therapy.

Although rising prescriptions do not permit distinguishing adequate treatment from overuse, concerns remain regarding overprescribing of psychotropic medications in youth, especially to those with behavioral symptoms and to pre-schoolers 5. These concerns focus on adverse drug effects, especially potentially life shortening cardiometabolic effects 6 that are only inadequately monitored and addressed, insufficient utilization of psychosocial treatments before, during or after psychotropic drug treatment, and use of psychotropic medications for conditions with a particularly underdeveloped evidence base.

Despite increasing private and public investments in research, the number of new drug classes entering clinical trials has fallen over the past two decades, as have overall new drug introductions worldwide 7. Many pharmaceutical companies have recently discontinued research on central nervous system disorders. While this is an understandable reaction to the availability of generic drugs, failed attempts at discovering new mechanisms of action, and narrowing profit margins, such decreased investment minimizes opportunities for much needed new treatments. In addition to the cutting-edge academic initiatives outlined by Rapoport, more emphasis should be paid to prevention targets and treatments in youth and adults. Given that first-onset disorders generally occur during childhood and adolescence, agents with neurotrophic, neuro-modulatory, anti-apoptotic and anti-inflammatory capacity and those countering oxidative stress should be investigated.

The move from immediate to intermediate phenotypes and the focus on biomarkers of illness as well as of treatment response will be important in realizing the critical goal of more personalized matching of patients to interventions. The decision by regulatory agencies to allow pharmaceutical companies to market companion tests if they can identify patient subgroups that are particularly likely to benefit from their treatments is a welcome step toward incentivizing the development of treatments for identifiable patient subgroups. Nevertheless, most of the next-generation progress in psychopharmacology and pediatric psychopharmacology will likely depend on the identification of mechanisms for illness development, persistence and progression.

It is hoped that increasingly sophisticated technological tools and neuroscientific methods will deliver new breakthroughs. Likewise, large registry data sets are as much needed to assess long-term safety in naturalistic settings, as are high-quality characterization of patients and clinical trial execution in order to successfully test and transfer new pharmacologic treatments into clinical care.