Antidepressants and Adolescent Brain Development

Emily Karanges; Iain S McGregor


Future Neurology. 2011;6(6):783-808. 

In This Article

Future Perspective

Although developmental stage is an obvious mediator of neural response to antidepressants, the precise nature of these effects and their links to behavioral response is not yet clear. The mechanisms by which antidepressants produce their therapeutic effects are complex and largely unknown, thus further research is required, even in adult populations. Despite this, the current findings on antidepressant effects in adults can guide future research into effects on adolescent populations.

Thus far, there has been a strong focus on monoaminergic and neurotrophic mediators of adolescent response to antidepressants. However, there is increasing evidence that antidepressant action may be mediated by other systems and processes, many of which mature throughout adolescence. For example, glucocorticoid signaling is a recently recognized contributor to the antidepressant response,[166] and it is of particular interest given the susceptibility of the brain to glucocorticoids during adolescence.[43] Epigenetic mechanisms such as histone acetylation, histone deacetylation and DNA methylation have also been associated with chronic stress, depressive disorders and the antidepressant response.[189,190] Indeed, chronic fluoxetine stimulates the expression of methyl-CpG DNA binding domain proteins and histone deacetylase 2, repressing gene expression in GABAergic interneurons of the adult rat brain.[191] Epigenetic mechanisms have also been implicated in synaptic plasticity and the enduring neurobiological consequences of adolescent recreational drug use,[192] suggesting a potential role in the antidepressant response in adolescents. Other mechanisms of interest include glutamatergic[193] and GABAergic neurotransmission,[194] regulation of proinflammatory cytokines[195] and moderation of serotonergic signaling by miRNAs.[196]

Currently, there is a paucity of human research on the neural response of young people to antidepressants, although pharmacogenetic studies are emerging. Ultimately, the goal of pharmacogenetic research is personalized medicine, whereby clinicians tailor treatment to individual patients based on genetic indicators of a favorable response. Progress toward this goal, whether in pediatric or adult populations, requires replication of previous findings with adequately powered and well-controlled studies.[109,175]

Recent brain imaging studies have revealed neural correlates of adolescent psychopathology (e.g., [200]), but few have investigated correlates of antidepressant response in this population (but see [198,199]). Imaging studies have revealed regional effects of antidepressants on brain volume, neuronal activation and biochemistry in adults,[200] highlighting the need for corresponding studies in adolescents.


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