Estradiol and progesterone modify the effects of the serotonin reuptake transporter polymorphism on serotonergic responsivity to citalopram.

Abstract

Individual vulnerability to psychopathologies is linked to a number of genetic polymorphisms including the serotonin transporter (5HTT) promoter polymorphic region (5HTTLPR). A single copy of the short variant (s-variant) allele of 5HTTLPR confers increased susceptibility to anxiety disorders and depression and decreased efficacy of serotonin-releasing agents in pharmacotherapy compared to the homozygous long 5HTTLPR variant (l/l). The data suggesting that the 5HTTLPR polymorphism modulates the efficacy of serotonin-releasing agents in pharmacotherapy is inconsistent. Other factors such as age, gender, and hormonal status could interact with 5HTTLPR genotype to affect individual physiological and behavioral responses to serotonin reuptake inhibitors such as citalopram. Indeed, estradiol and progesterone, the primary female steroid hormones, exert an array of effects on the serotonergic system, including 5HTT expression. The present study used ovariectomized female rhesus monkeys to determine the interaction between the 5HTTLPR polymorphism and the effects of mid-follicular levels of estradiol and luteal levels of progesterone on serotonergic responsivity to acute citalopram administration. The increase in serum prolactin, a surrogate measure of serotonin activity, following citalopram administration was significantly larger in l/l females than in s-variant females over the course of two hours during concurrent estradiol and progesterone hormone replacement only. These data suggest that ovarian function and the 5HTTLPR polymorphism interact to gate serotonergic reactivity in females, suggesting that clinicians should be aware of the ovarian status and 5HTTLPR genotype of women when considering serotonergic pharmacotherapy in women.

Treatment-resistant depression: are animal models of depression fit for purpose?

“…Similar results have been found in primates, as the short allele of the 5-HTTLPR gene increased the neuroendocrine response to separation stress in infant macaques (Barr et al 2004), increased sensitivity to social stress in adult rhesus monkeys (Jarrell et al 2008), and was also associated with a decreased hormonal response to acute administration of the SSRI citalopram (Michopoulos et al 2011). These results suggest that polymorphisms of the 5-HTTLPR gene may have similar effects on stress sensitivity and antidepressant responsiveness in humans and non-human primates.…”

Social subordination impairs hypothalamic–pituitary–adrenal function in female rhesus monkeys

“…This convention has been used by us and others to assess dominance status effects on a number of outcome measures in captive macaques (Kaplan et al, 1995; Kaplan et al, 1984; Kaplan et al, 2010; Kaplan and Manuck, 2008; Kaplan et al, 1982; Kaplan et al, 2002; Michopoulos et al, 2009; Michopoulos et al, 2011a; Michopoulos et al, 2010; Paiardini et al, 2009; Shively and Kaplan, 1984; Shively, 1998; Shively and Clarkson, 1994; Shively et al, 1997a; Shively et al, 1997b). The total number of subjects classified in this fashion was 16 dominant and 24 subordinate females.…”

Menopausal status could modulate the association between 5-HTTLPR and antidepressant efficacy in depressed women: a pilot study

“…Both estradiol and progesterone have been reported to inhibit the ability of the fluvoxamine to decrease the clearance of 5-HT (Benmansour et al 2009). Interestingly, Michopoulos et al (2011) reported an association with 5-HTTLPR and ovarian steroids considering antidepressant administration: increase in serum prolactin, a surrogate measure of serotonin activity, following citalopram administration was larger in LL than in S-variant females over the course of 2 h during concurrent estradiol and progesterone hormone replacement only in ovariectomized female rhesus monkeys, so ovarian function and the 5-HTTLPR polymorphism seem to interact to gate serotonergic reactivity in females.…”