Child neuropsychopharmacology: good news… the glass is half full
Authors: Celso Arango
Journal: World Psychiatry (2013)

J. Rapoport nicely illustrates the past and present of paediatric neuropsychopharmacology and – what is even more interesting – also speculates about the future of this field. She posits the debate as either more or less e.g., prescription of psychotropic drugs to children and adolescents than needed, with the relevant clinical implications and diagnostic controversies linked to it. I will address the debate from a complementary view, that of hazards and opportunities for child neuropsychopharmacology. Let's start with the empty part of the glass. I agree with Rapoport that we are far from discovering new drugs that cure or dramatically change the course of psychiatric disorders in children and adolescents. We first have to discover what needs to be fixed or repaired, i.e. the pathophysiology of psychiatric conditions at the molecular level. Only then will we be able to develop drugs targeted to altering a priori known biological mechanisms. This makes the field of neuropsychopharmacology a risky business: the old paradigms (e.g., monoamine release, dopamine blockade) seem to be exhausted, while the search for new mechanisms of action is uncertain, since in most cases we lack the science that should drive the development of such new drugs. This is even more true in times of economic crisis, when drug companies gravitate toward more secure markets, such as cancer and cardiovascular disease. This is a clear threat to the search for new treatments for very prevalent and disabling mental disorders. Big Pharma's pull-out from neuropsychopharmacology is a consequence of some of these problems 1. Turning now to the half-full part of the glass, we have to acknowledge that, while the field of child neuropsychopharmacology has always lagged behind that of adult neuropsychopharmacology, this has been changing in the last decade, as both the US Food and Drug Administration (Pediatric Research Equity Act, 2003) and the European Medicines Agency (regulations 1901/2006 and 1902/2006) have not only provided extension patents for drug companies that have pediatric plans, but also required companies to conduct clinical trials in children, if their drugs have the potential to be used in that population, when they are seeking approval for an indication in adults. For many years, drugs with proven efficacy in adults have been used in children with no evidence either for efficacy or safety and tolerability. This is not going to be the case anymore if these rules stay in place. The flip side of the coin is the difficulty drug companies face in recruiting patients for such clinical trials, and the economic burden added to the already extremely high cost of drug development. While it is clear that data from pediatric populations are needed, this should not come at the expense of making the business of developing drugs for mental disorders unaffordable. Nevertheless, we as a field should take advantage of the enormous amount of data generated by these pediatric clinical trials conducted for many psychiatric disorders 2. Some data are also valuable for assessing non-drug-related hypotheses, such as those concerning the clinical course and predictive markers in pediatric mental disorders provided by longitudinal trials with large patient samples. The high rate of prescription of drugs such as antipsychotics and stimulants in children reported in the US 3, 4 is in no way the rule in Europe, although prescription rates of psychotropics have also increased, to a much lesser extent, in some European Union countries 5. It is worrisome to see that the prescription rate of antipsychotics in the US is approximately five times the prevalence of psychotic disorders in the pediatric population. This clearly means that such drugs are prescribed without evidence or with only marginal evidence of efficacy, as is the case for conduct disorders without mental retardation. As many of these drugs are out of patent, more clinical trials need to be funded with public money. Since many patients need to be recruited for these trials and this is not an easy task, it seems very important to prioritize this type of studies among those launched at the initiative of the European Commission or the National Institute of Mental Health. Networks such as that on child and adolescent neuropsychopharmacology established by the European College of Neuropsychopharmacology are also a good way to improve recruitment at centres with a solid background in this field. Although mostly discovered by serendipity, as we lack the knowledge of the pathophysiology needed to direct the targets, some drugs used in child psychiatry have larger effect sizes than those used in other areas of medicine. For instance, drugs prescribed for asthma, headache or atopic dermatitis have lower effect sizes than those used to treat attention-deficit/hyperactivity disorder. Still, they are much less controversial. We should not allow the stigma related to mental disease to preclude us from providing the right treatment to our patients. If that were to happen, the stigma would have the dual deleterious effect of marginalizing our patients and depriving them of the benefit of drugs that have been shown to improve their quality of life and functioning. We are under close scrutiny, and some recent movements in the US e.g., (prescription of drugs to children under 7 years of age diagnosed as bipolar) work against us as a field. It has taken great effort and excellent professionals like J. Rapoport to arrive where we are now. We should take advantage of new opportunities, such as translational psychiatry studies that allow us to assess the behavioural effects of genetic variants or molecular induced changes. These include large cohort studies that will shed light on normal and abnormal development or the wealth of data on short- and long-term efficacy, safety and tolerability of new drugs that pharmaceutical companies are now requested to generate. One further opportunity is the increasingly accepted view that we should move towards early intervention and prevention and that most psychiatric conditions develop during childhood and adolescence 6. That should shift the target, not only of drug discovery but also of therapeutic approaches in general, toward a younger population than is typically included in clinical trials. We should not waste these opportunities or cook our own goose by diverging from evidence-based treatment algorithms. It is our children's mental health that is at stake.