Antidepressants and Adolescent Brain Development

Emily Karanges; Iain S McGregor


Future Neurology. 2011;6(6):783-808. 

In This Article

Adolescent Neural Development

Adolescence is broadly defined in terms of the transition from childhood to adulthood, or dependence to independence, occurring approximately between the ages of 12 and 20 years in humans.[6] Other species have a corresponding developmental stage marked by similar behavioral and neural changes.[12] In male rodents, for example, adolescence occurs from around postnatal day (P)28 until P55, with sexual maturity occurring at approximately P45.[12,19] As in female humans, this life stage begins and ends slightly earlier in female rodents, spanning from approximately P25 until P42.[12]

Much of our knowledge of brain development in late childhood and adolescence comes from cross-sectional studies using rodents or from post-mortem human data.[20] More recently, however, the development of MRI technology has afforded the ability to noninvasively gather longitudinal data on overall structural and tissue-specific developmental trajectories.[21] Several comprehensive and recent reviews summarize these findings in detail (e.g., [6,13,20,22]); therefore, only the most salient features of adolescent brain development will be reviewed here.

Gross Structural Changes & Remodeling

Adolescent brain development can be reduced in its simplest form to five general processes: a 'deeper-to-higher' trajectory; a 'back-to-front' developmental trajectory; early overproduction of synapses followed by pruning; increased myelination and efficiency of signal transduction; and increased connectivity between and within regions. The first of these points refers to the fact that the adolescent brain does not develop in a uniform fashion. Rather, in keeping with the stereotypical adolescent behavioral characteristics of risk taking, novelty and sensation seeking, affective reactivity and increased social interaction,[23] maturation of 'deeper' subcortical brain regions precedes that of 'higher' cortical regions involved in cognitive control and decision making.[24] MRI studies demonstrate an inverted U-shaped developmental trajectory in gray matter volume, with maximal volume reached sometime in late childhood or early adolescence, depending on the lobe.[21] This growth and cortical thinning that follows proceeds in a 'back-to-front' fashion across the cortex: motor and sensory cortical regions mature first, followed by association regions, with higher cortical areas such as the prefrontal cortex (PFC) maturing later.[20,21,25] Cortical thinning and gray matter volume reduction encompasses, but is not limited to, processes of synaptic regression and pruning, particularly of excitatory glutamatergic cortical inputs.[12] Also contributing to the reduction in gray matter is a concurrent increase in myelination.[26] Volumetric increases in white matter occur fairly uniformly across the cortex and are accompanied by increases in anisotropy, facilitating efficient neuronal communication, particularly between subcortical and cortical regions.[7,27] Indeed, an important part of brain maturation is a remodeling and strengthening of connections between limbic regions and the PFC,[12] reflected in the marked increase in dopaminergic, serotonergic and cholinergic inputs to the PFC during adolescence.[6] Accordingly, synaptic plasticity,[28] neurogenesis[29] and dendritic spine proliferation[30] are elevated in the adolescent brain.

Monoaminergic Maturation

Changes at the level of individual neurotransmitter systems are of great relevance in considering the effects of psychotropic drugs on the adolescent brain, many of which work primarily through monoaminergic systems. Modern antidepressants typically inhibit the reuptake capabilities of the serotonin transporter (5-HTT; e.g., the selective serotonin-reuptake inhibitors [SSRIs]) and/or norepinephrine transporter (e.g., serotonin–norepinephrine-reuptake inhibitors [SNRIs] and the tricyclic antidepressants [TCAs]), while the majority of antipsychotics are antagonists of the dopamine and/or serotonin system.[31] Stimulants such as atomoxetine and methylphenidate have both dopaminergic and noradrenergic effects.[32]

The extensive functional connectivity between the monoamine systems means that alterations in one system can have consequences on the other systems, with potential developmental implications. For example, the inhibitory effects of serotonin (5-hydroxytryptamine [5-HT]) on dopaminergic outgrowth to the rodent medial PFC during late postnatal development has potential implications for the use of serotonergic drugs during this developmental period.[33] Similarly, 5-HT neurons in the raphe nucleus exert largely inhibitory effects on dopaminergic transmission in the substantia nigra and ventral tegmental area (VTA), key regions of the mesolimbic 'reward' pathway.[34] Thus, the SSRIs, despite their relative selectivity for the 5-HT system, have been shown to indirectly increase dopaminergic activity in these brain regions in adult rats.[35] Conversely, the SSRI escitalopram has inhibitory effects on the firing of noradrenergic neurons in the locus coeruleus (LC) through serotonergic mechanisms.[36]

Age-related changes to the monoamine systems vary considerably depending on the sex of the individual, brain region of interest and receptor subtype.[6,22] For example, in the striatum, an important area of the mesolimbic pathway, dopamine receptor expression follows an inverted U trajectory, peaking in early adolescence before declining to adult levels.[37] This is accompanied by a steady increase in striatal dopamine turnover, synthesis and transporter density.[6,12,38] By contrast, dopamine receptors in the frontal cortex rise to reach adult levels by mid-adolescence, while dopamine turnover and synthesis peak before decreasing.[6,12] These regional changes appear to reflect a functional shift in the balance of mesocortical to mesolimbic dopaminergic activity as adolescence progresses,[12] underscoring the malleability of the dopaminergic system during this epoch.

The serotonin system develops to near maturity early in life, with adult serotonergic innervation and serotonin synthesis capabilities obtained by the end of the third postnatal week in the rat.[39] However, maturational changes within the serotonin system occur throughout adolescence. Serotonin levels and 5-HT1A and 5-HT2A receptor densities are elevated in the adolescent brain,[6,39] while 5-HTT density and serotonin turnover is generally lower and increases towards adult levels as adolescence progresses.[6,40]

Development of the norepinephrine system lags behind that of the serotonin system, with adult concentrations of norepinephrine not obtained until mid-adolescence in the rat.[39] Although somewhat variable between brain regions, the inverted U function is apparent for adrenergic receptors,[41] synaptic density[39] and the norepinephrine transporter.[42]

Maintaining the Balance

Given the high levels of reorganization, growth and pruning occurring during adolescence both within and between brain systems, perturbations of the balance between these processes can have profound and lasting consequences. The adolescent brain is highly receptive to environmental signals, whether natural or synthetic, and becomes wired to match this input.[14] Adolescence is also a period of heightened susceptibility to stress[43] and development of psychopathologies[26] for which psychotropic drugs are the most common form of treatment. As such, it is vital to evaluate the safety and efficacy of such treatments in adolescent populations.


Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.
Post as: