The relationship between P-gp genotype and antidepressant function is complex. For example, quinidine(Drug information on quinidine), a P-gp inhibitor, has been shown to increase the absorption of amitriptyline(Drug information on amitriptyline),6,7 and similar effects may be involved with other drugs.8,9 Effects of drugs that are eliminated from tissues by this mechanism would then be expected to be enhanced by polymorphic variants that reduce the effect of P-gp.10 Alternatively, certain drugs appear to inhibit the activity of P-gp, which would be expected to increase brain concentrations.11
Inhibition of P-gp by antidepressants may exert inhibitory effects on hypothalamic-pituitary-adrenal (HPA) axis activity by decreasing glucocorticoid efflux.12 It has been proposed that reduced glucocorticoid efflux is associ- ated with increased glucocorticoid receptor (GR) expression, which exerts inhibitory effects on HPA activation.12 Mouse knockout studies of P-gp have shown that intact P-gp is required for the actions of desipramine on GR expression. Hence, the relationship between polymorphisms of P-gp and the activity of antidepressant drugs is complex.Other genetic polymorphisms
Polymorphic variants of other genes may also be associated with antidepressant drug response. For example, both coding and noncoding single nucleotide polymorphisms (SNPs) of the serotonin 2A gene (HTR2A) have been shown to be associated with reduced response to SSRIs.13-15
The largest of these studies was conducted by McMahon and colleagues15 using the STAR*D cohort. The study population comprised nearly 2000 patients who were divided between test and replication sets. A total of 768 SNPs from 68 genes were genotyped (a smaller subset were also characterized for polymorphic variants of HTR2A alone). The results showed a robust and reproducible association between response to citalopram(Drug information on citalopram) and an SNP in intron 2 of the HTR2A gene. Whether this SNP specifically reduces the effect of citalopram, or whether it is in linkage disequilibrium with another SNP is unknown.
Other genetic variants have been found to be associated with antidepressant response, although the results have been variable. These have included SNPs of the genes for brain-derived neurotrophic factor (BDNF),16 the norepinephrine(Drug information on norepinephrine) transporter,17 tryptophan(Drug information on tryptophan) hydroxylase 2,18,19 corticotrophin releasing hormone receptor 1,20 the glucocorticoid receptor,21 and the common promoter polymorphism of the serotonin transporter gene,19,22-26 among others. However, positive results have been in small-scale trials that have not been replicated; consequently, this area remains ambiguous.27Neuroanatomy and treatment response
Mood is regulated through a distributed network of brain areas, which involves functional connectivity between structures, such as the amygdala, anterior/ subgenual cingulate, nucleus accumbens, hippocampus, thalamus, hypothalamus, and frontal cortex.28 These pathways are regulated by the 3 major monoamine neurotransmitters affected by antidepressants: serotonin (from the raphe nucleus), norepinephrine (from locus caeruleus), and dopamine(Drug information on dopamine) (primarily from the ventral tegmental area). The functional connections between these structures mediate the experience of emotions. This complex interplay in brain regions is effective in regulating response to the external and internal environment. This is particularly true of conflicting choices, eg, approach versus avoidance of rewarding cues, or fight versus flight from threatening ones.29 However, it is also clear that these systems are prone to dysregulation, resulting in mood and anxiety disorders.
Antidepressant drugs exert their effects via modulation of regulatory pathways involving norepinephrine, serotonin, and, indirectly, dopamine. Moreover, they have both rapid and sustained actions. The effect of SSRIs is largely suppressive to the actions of structures such as the locus caeruleus and amygdala, which may account for the global effect of these drugs on anxious symptoms related to anxiety and depressive disorders.30 However, antidepressants also exert longer-range effects by stimulating the synthesis of certain proteins such as BDNF, which may account for neuroplastic actions.