Outcomes in Child Psychiatry

“The good physician treats the disease; the great physician treats the patient who has the disease.”

—Sir William Osler

The longitudinal assessment of clinically relevant outcomes is necessary to inform diagnostic and prescribing decisions. Two recent articles (Santosh et al. 2017; Zito and Burcu 2017) in JCAP address the need for systematic outcomes research in pediatric psychopharmacology. Each article highlights gaps in current knowledge, as well as the complexity of measuring outcomes in child psychiatry.

Santosh et al. (2017) review the now widespread use of second-generation antipsychotic medications in youth, especially in the United States. Most antipsychotic prescriptions in children are for off-label indications, in particular disruptive behavior disorders and aggression. Increased prescribing can be attributed, at least in part, to marketing, expanding diagnostic categories (e.g., bipolar disorder, autism), and the perception of enhanced tolerability, compared to traditional neuroleptics.

As it stands, there is little evidence supporting the long-term efficacy and safety of second-generation antipsychotics in children, especially for off-label indications. As with all pediatric psychopharmacology, much of the support for using antipsychotic medications in children is based on short-term single-agent trials. Acute-phase treatment trials (typically 8 weeks or less) are important to first determine whether there is justification for longer maintenance treatment studies. However, short-term reductions in symptoms may not equate to long-term functional improvements, and significant safety concerns may only be evident after long-term exposure, for example, metabolic side effects. Furthermore, most clinical research trials use narrowly defined inclusion and exclusion criteria, thus limiting the generalizability of research findings to community settings. Also, given the lack of head to head medication trials, there is a lack of evidence regarding which agent is best to choose for any given clinical situation.

Santosh et al. (2017) raise two critical needs: (1) the identification of factors that predict whether (and for which youth) prescribed medications will significantly improve long-term functioning, including social, academic, and mental health outcomes and (2) the need to incorporate systematic medication monitoring into routine clinical practice. The Centre for Interventional Pediatric Psychopharmacology and Rare Diseases has developed a web-based health monitoring platform that gathers information regarding symptoms, treatment response, and side effects. These assessments, coupled with guidelines for standardized dosing and treatment monitoring, are designed to promote appropriate care and to provide clinicians with relevant long-term safety and effectiveness data to better guide clinical decision-making.

Zito and Burcu (2017) review the risk of adverse cardiovascular events with stimulant medications. Rare cases of sudden death in individuals exposed to mixed amphetamine salts have been linked to underlying cardiac structural abnormalities (which may go unrecognized in clinical settings) or to unexplained toxic drug levels on typical dosages (possibly rare genetic outliers). Population-based data vary in regard to whether stimulant use is statistically associated with an increased risk of sudden death, with differences in methods and the rarity of severe adverse outcomes likely explaining discrepant findings. More consistent associations are noted between stimulant use and other cardiac-related events, for example, syncope, alterations in pulse and blood pressure that result in emergency room visits.

The potential risk of cardiovascular side effects with stimulant medications supports the need for systematic monitoring of heart rate and blood pressure; routine assessment of medical problems and family medical history; and adequate informed consent. More intensive screening, such as electrocardiogram monitoring, should be considered for patients with known cardiovascular risks, or for patients on multiple agents, including combinations of stimulants, antidepressants, and antipsychotics.

Zito and Burcu (2017) highlight the need for longitudinal population-based monitoring to detect rare severe adverse events. These types of studies are complicated by the complexity and heterogeneity of clinical populations, including exposure to different agents, and the challenge of ascribing causal relationships to rare outcomes given a multitude of potential risk factors, known and unknown. Furthermore, there may be impediments or disincentives for reporting such findings given medico-legal concerns, the lack of a clear definitive relationship between treatment and any rare adverse event, and the implications within the larger debate regarding the relative risks and benefits of psychotropic agents in children.

Standard pediatric prescribing guidelines require the systematic assessment of symptoms, treatment response, and side effects (American Academy of Child and Adolescent Psychiatry 2009). Incorporating user-friendly and clinically relevant tools into routine practice helps engage patients in treatment and provides psychoeducational information in regard to expected treatment responses and self-monitoring. The longitudinal assessment and active surveillance of key outcomes in medical practice are important elements of healthcare reform, and will be increasingly required as part of managing and reimbursing care.

Yet, adoption of these strategies continues to lag given a lack of incentives and practitioner resistance. Incorporating standard checklists and monitoring strategies into routine care improves diagnostic accuracy, informs treatment decisions, facilitates the detection of potential adverse events, and enhances the therapeutic process. Prospective longitudinal studies of community cohorts are needed to better define the naturalistic course and outcomes of disorders, as well as identify determinants of treatment compliance, response, and long-term safety.

Flexner (1910) triggered substantial reforms by challenging medical education to prioritize scientific discovery over allegiance to traditional teaching methods built on apprenticeship and conventional wisdom. The observations of Flexner remain relevant today. Modern medicine requires evidence-based practitioners who prioritize clinical acumen, critical thinking, and complex decision-making, based on an understanding of pathophysiology and a holistic view of the patient, rather than adherence to rigid belief systems and common practice (Cooke et al. 2006).

Prescribing decisions should be informed by specific markers of treatment response and tolerability, and by the likelihood of improving clinically relevant long-term outcomes. Psychopharmacology research needs to prioritize clinical outcomes that matter. Demonstrating initial efficacy and safety is an important first step, but serious psychiatric illnesses tend to be chronic in nature. The goal of treatment is to enhance long-term functioning and well-being, not just provide a temporary relief of symptoms.

Most current pediatric psychopharmacology is short term, symptom driven, and lacks diagnostic specificity. Longitudinal treatment studies are limited, and what data are available raises questions regarding long-term effectiveness. For example, the behavioral improvements noted with stimulant medications are not unique to children with attention-deficit/hyperactivity disorder (ADHD), and are found in those with other conditions, as well as in normal children (Rapoport and Inoff-Germain 2002). Although medications significantly improved the core symptoms of ADHD in the randomized phase of the Multimodal Treatment of Attention Deficit Hyperactivity Disorder (MTA) trial, significant benefits were no longer apparent at the 3- and 8-year follow-up (Molina et al. 2009). Symptom and functional ratings tended to regress to the mean, regardless of treatment. Clinical experience suggests that some youth diagnosed with ADHD require long-term medication therapy. Yet, it is difficult to reconcile the fact that ∼10% of youth in the United States are prescribed stimulants (McCabe and West 2013) despite the lack of established long-term benefits.

Similarly, while there is substantial evidence that antipsychotic medications are superior to placebo for treating psychotic symptoms in persons with schizophrenia, most people (youth and adults) are not taking the same medication 12 to 18 months after initiating treatment, either due to lack of efficacy, side effects, or noncompliance (Lieberman et al. 2005; Findling et al. 2010). Although antipsychotic medications are clearly better than no treatment for schizophrenia spectrum disorders, their efficacy is limited and their tolerability problematic.

Psychiatric research must evolve to address extreme clinical and etiologic heterogeneity. Most psychotropic medication trials examine whether broadly defined groups of individuals respond better or worse to a time-limited course of active treatment, compared to those who receive no treatment, placebo, or an alternative therapy. In medicine, this approach has worked best for narrowly defined homogenous populations with predictable outcomes, for example, demonstrating whether a chemotherapeutic agent prolongs life for cancer patients. These methods are less informative for highly heterogeneous populations whose outcomes vary widely regardless of treatment.

For example, in a typical positive antidepressant trial, some patients respond to placebo, more respond to active treatment, and some fail to respond. Statistical differences between placebo and active treatment response may support the regulatory approval of the medication for treating depression. However, in an era of personalized medicine, the clinician must tailor treatment based on whether an individual patient requires a specific medication, a combination of treatments, or no treatment at all. Heterogeneous group differences do not inform individualized prescribing.

Despite enormous investments, the effectiveness of psychiatric interventions for severe mental disease has advanced very little over the past two decades (Insel and Gogtay 2014). In medicine, the most significant advances in prevention and treatment exploit biological causal mechanisms that when disrupted cause disease. As it stands, genetic and neurobiological mechanisms underlying complex neuropsychiatric disorders remain mostly unknown.

New approaches are needed to conceptualize psychiatric illness. A diagnostic tool is no more valid than the diagnoses themselves. The Diagnostic and Statistical Manual of Mental Health Disorders (DSM) nosology, although a useful communication tool, has limited utility for predicting treatment needs and outcomes, and lacks biological specificity. The National Institute of Mental Health (NIMH) Strategic Plan for Research outlines a series of goals designed to promote the understanding, intervention, and prevention of serious mental illness, including the delineation of mechanisms underlying complex psychiatric disorders, and defining trajectories of illness to target when, where, and how to intervene (Lieberman et al. 2005). Diagnostic and treatment-specific biomarkers, including specific disruptions in genetic pathways and neurocircuitry, are needed to advance the next generation of psychiatric therapeutics (McClellan and King 2010).

Mental health and substance abuse disorders contribute enormously to the global burden of disease (Whiteford et al. 2013). In the United States, hundreds of billions of dollars per year are spent on mental health services and treatment. The societal costs of mental disorder and its impact on other systems, including criminal justice, social welfare, and education, are staggering. Intervention research and development must focus on improving long-term outcomes that matter most, for example, ameliorating morbidity and mortality, enhancing academic achievement and economic independence, and reducing the risk of suicide, criminality, substance abuse, violence, and child maltreatment. We need better treatments.