New horizons in developmental neuropsychopharmacology
Recent studies in different neurodevelopmental disorders (such as Rett syndrome and fragile X) have had disappointing phase III results, even with very promising preclinical and early phase trial data and strong rationales based on sound mechanisms of action in known pathophysiologies. These studies were conducted with adults and adolescents. Should they have been conducted in subjects at a much younger age? It may be difficult to reverse 12-45 years of impaired function (and the resultant cascade effects) with only a few months of treatment.
We have plenty of good examples in medicine where response outside the therapeutic window does not predict response within the window (and vice versa). We know that, in children with congenital hypothyroidism, thyroid hormone replacement in the first two weeks after birth completely reverses the problem, but that given months later, it will not affect neurodevelopmental disorders resulting in intellectual disability. We also know that reperfusion therapy 12 hours after a myocardial infarction is already too late. There are hundreds of examples where drugs are effective for disease modification only within a given therapeutic window. However, developmental therapeutic windows have not been sufficiently factored into the design of trials of psychotropic drugs for mental disorders, many of which are neurodevelopmental disorders. We should devote more research to identifying the developmental stages at which individuals are most likely to respond to particular treatments.
During our annual ECNP Congress in Paris this year, we will have a regulatory update session to discuss guidelines for conducting clinical drug trials in autism spectrum disorders (ASD). It is clear that negative findings with drugs targeting core ASD symptoms in adults may not predict efficacy much earlier in life. In fact we may need to approach this from another direction, i.e. starting with trials in children when the proposed mechanism of action may improve dysfunction before deleterious effects are no longer amendable. We have good examples of studies showing that the same therapeutic ASD intervention had a five-times greater effect when provided before age 60 months compared with later administration. This interactive regulatory session with academic and industry participants promises to be an excellent opportunity for scientific and regulatory exchange.
Mounting evidence suggests that our field should move toward the more ambitious goals of primary and secondary prevention. Understanding the dynamic nature of the pathophysiological mechanisms underlying psychiatric disorders is crucial for the development of effective therapies. Recent insights into the pathophysiologies of mental disorders should inform different levels and stages of tailored interventions, including psychopharmacological approaches, to counteract early dysfunctions and prevent their future morbid consequences, especially during critical and sensitive neurodevelopmental periods.
Of course, all the above should be undertaken with the understanding that prudence and safety are the overriding considerations and that drugs should be tested first in the more vulnerable population of children and adolescents only when there is good rationale for doing so – and only after careful preclinical and phase I studies. An even higher level of caution must be exercised with such testing than in standard RCTs, in order to ensure maximum participant safety.
In March 2018, our annual innovation meeting in Nice will address the topic of developmental neuropsychopharmacology. On that occasion, we will focus on what Frederick Douglass said more than one hundred years ago: “It is easier to build strong children than to repair broken men”. And just as he escaped from slavery, we need to work toward new treatments that will help young people escape from chronic mental disorders.