Antidepressants and Adolescent Brain Development

Emily Karanges; Iain S McGregor


Future Neurology. 2011;6(6):783-808. 

In This Article

Pharmacogenetics of Adolescent Antidepressant Response

As mentioned earlier, antidepressant medications appear to be associated with efficacy or alternatively, with adverse effects, in certain subgroups of the adult and adolescent population. It has been hypothesized that genetic variation may play a role in determining treatment response, and pharmacogenetic approaches provide a means whereby such genotype–response associations can be investigated. Literature on the pharmacogenetics of the antidepressant response in adult populations is extensive (see [174–176] for recent reviews). Notable and replicated associations with treatment response include polymorphisms within the 5-HTT, BDNF, TPH1, 5-HT1A and 5-HT2A receptor subtype and CYP2D6 genes.[176] In addition, certain genes have been associated with adverse effects, particularly antidepressant-induced mania (e.g., 5-HTT polymorphisms) and treatment-emergent suicidal ideation (e.g., BDNF, FKBP5, CREB1 and GRIA3 polymorphisms).[174,177]

However, it is not possible to extend these findings to adolescent populations. Genes and their protein products can have different expression patterns, functions and interactions with other genes at different stages of development, thus associations between genes and treatment response may differ in younger populations. We have identified five pharmacogenetic studies of antidepressant response in children and adolescents (see Table 2), some of which have been reviewed previously.[109] All are of relatively small scale and most are open-label, therefore the findings within must be treated with caution until sufficiently replicated. Furthermore, treatment response is unlikely to be moderated extensively by any one gene, but rather by a combination of many environmental and genetic factors.[178] Regardless, these studies may inform future research by highlighting potential moderators of antidepressant response in pediatric and adolescent populations.

One of the most extensively researched polymorphisms in adult populations is the 5-HTT-linked polymorphic region (5-HTTLPR) within the promoter of the 5-HTT gene (SLC6A4). Studies have shown that the short (s) form of this variable-length repeat region is less transcriptionally active than the long (l) form, and has been associated with increased risk of major depressive disorder and other psychiatric diagnoses,[179] poorer antidepressant response,[180] and greater propensity to develop adverse effects,[176] at least in caucasian populations. Accordingly, this polymorphic region has been investigated in all five known pediatric studies on the pharmacogenetics of antidepressant response. Of these, two report an association between poorer response to citalopram and the s allele or ss genotype in children and adolescents with depression or anxiety disorders.[181,182] In addition, the ss genotype was associated with higher rates of suicidal ideation, although this was not restricted to treatment-emergent effects.[182] These studies suggest that reduced expression of the 5-HTT may contribute to poor treatment outcome in adolescents, as in adults. However, it should be noted that these two studies used patients from the same population pool, potentially limiting the generalizability of these results. Indeed, the 5-HTT polymorphism was not associated with treatment response,[183,184] suicidal events[183] or antidepressant-induced mania[185] in other pediatric populations. Interestingly, despite finding no association between 5-HTT polymorphism and treatment response in young patients with depression, Joyce et al. report an association between the ss genotype and poorer response to fluoxetine in patients older than 25 years.[184]

There are also other indications that variations in serotonergic function may influence SSRI response in children and adolescents. TPH2 is the rate-limiting enzyme in 5-HT biosynthesis, and there is some indication that polymorphisms in TPH2 may play a role in susceptibility to major depression, suicidal behavior and antidepressant response in adult populations, although these associations have not been replicated.[176] Similarly, there is some evidence that the TPH2 polymorphisms may predict antidepressant response in adolescents, whereby carriers of a T allele in the TPH2 promoter (G-703T; rs4570625) show a somewhat poorer antidepressant response to citalopram.[181] This study also demonstrates an additive effect of this TPH2 polymorphism and the 5-HTTLPR s allele in predicting lower remission rates.

Finally, results from the Treatment of SSRI-Resistant Depression in Adolescents (TORDIA) study point to a relationship between polymorphisms in the FKBP5 gene and onset of suicidal events during SSRI treatment.[183] The FKBP5 gene encodes a co-chaperone protein that moderates the sensitivity of the GR to glucocorticoids. Certain polymorphisms in this gene increase the GR-induced expression of FKBP5, decreasing the sensitivity of the GR to glucocorticoids and impairing negative-feedback regulation of the hypothalamic–pituitary–adrenal axis in healthy controls, with opposite effects in many clinical populations.[186] In adult populations, these alleles have been associated with major depressive disorder and other psychiatric diagnoses,[186] as well as treatment response to antidepressants.[187] However, while Brent et al. report associations between the FKBP5 rs1360780 TT genotype and suicidal events in the TORDIA population,[183] the T allele has been associated with better response to antidepressants in adults,[187,188] suggesting that these polymorphisms may have differential effects in different age groups.


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