Brain development and psychotropic drugs for children and adolescents

Increased use of psychotropic drugs for children and adolescents with psychiatric disorders is being reported from western countries in recent years. Some of these drugs may have not been approved for use in children. Physicians nevertheless who prescribe the drugs should be well informed not only about immediate side effects but also about possible problems related to brain development. The brain may be vulnerable to drugs during the stages of accelerating growth and development. Drugs, or other substances e.g. alcohol, may influence the mechanisms and processes that underlie the development of the brain. Brain development does not end upon birth. It continues to develop and mature at a high rate during the first year of life. Another important stage of development occurs at the time of passing from childhood to adolescence. At this stage, elimination of a large number of synapses (pruning) takes place, which coincides with the development of abstract thought. Deviation in the development of the brain may lead to permanent changes in the morphology of specific regions and alterations in the function of specific neurotransmitter pathways. Two neurotransmitters, serotonin and acetylcholine have been identified to have an important role in brain development. Serotonin has a dual role in the early stages of brain development: autoregulation of the serotonergic pathways and important role in overall in brain development. Acetylcholine plays a crucial role in the development of networks in the cortex and the hippocampus which support complex cognitive functions in the adult. Dysfunction of cholinergic neurons has been observed in cases of mental retardation.

Three categories of drugs have been approved and are currently in use in children and adolescents: stimulants (methylphenidate, dextroamphetamine) for the treatment of attention deficit-hyperactivity disorder, atypical antipsychotics (risperidone) for early onset schizophrenia and highly disruptive and aggressive behaviour, and SSRIs mainly for adolescents with depression and obsessive compulsive disorder. The prescription of atypical antipsychotics and SSRIs for children and adolescents is much wider than warranted by approved indications. The stimulants act on dopamine by blocking its transporter increasing thus its concentration in the striatum. Clinical trials of stimulants up to two years in duration have presented no evidence that these drugs may have adverse effects on brain development. The clinical trials of stimulants under the age of six years may not be considered adequate and these drugs may be prescribed with extreme caution. The clinical trials of the antipsychotic risperidone have not been long enough in duration to rule out possible interference with brain development. On the other hand a positive effect of risperidone may exist in restoring deviations in brain development that have been observed in early onset schizophrenia. Such a possible effect has not been explored yet. Risperidone blocks the dopamine D2 and serotonin 5-HT2A receptors. The SSRIs block selectively the 5-HT receptors and increase the levels of serotonin in the synaptic clef. Since serotonin has an important function at least at the early stages of brain development it is wise for the physician to avoid the prescription of SSRI to young children and to women during pregnancy. One recent study has reported toxic brain effects of SSRIs on newborn to mothers taking these drugs in the last three months of the pregnancy. Another study on laboratory animals has shown that high concentrations of SSRIs caused swelling and destruction of serotonergic neurons in the brain. The clinical relevance of this study cannot be determined. Drugs focusing on the cholinergic pathways, which are important in the development of cognitive related cortical areas, are not in use for children and adolescents, but may in the future be used to improve conditions associated with mental retardation.