Sex-related differences in antidepressant response: When to adjust treatment
How pharmacodynamic, pharmacokinetic, and hormonal factors impact prescribing
When prescribing antidepressants for pregnant women, a personalized discussion of the risks and benefits with each patient in the context of her psychiatric history, the developing fetus, and her value system is warranted. The potential consequences of antidepressant effect on patient and fetus, or lack there of, continues to be an evolving area; long-term data on prenatal exposure are limited.
Postpartum. The postpartum period—when depression can hit 10% to 15% of new mothers27—entails rapid shifts in many factors that may influence antidepressant response. Levels of gonadal hormones such as estrogen and progesterone decline, plasma volume contracts, and hepatic enzymatic metabolism and GFR return to pre-pregnancy levels. Together these changes may result in increased antidepressant blood levels postpartum, especially when the dosage used during pregnancy is held constant.19
The postpartum period is associated with a high risk for depression onset or worsening and is a time of great hormonal and pharmacokinetic change. Accordingly, a postpartum woman should be followed closely for changes in response and adverse effects, and her antidepressant dosage adjusted. Breastfeeding is a critical consideration in the postpartum. Meltzer-Brody et al28 provide a discussion of postpartum depression and what to tell patients who breast-feed.
Menopause. Despite evidence that reproductive-age women may respond better to SSRIs than men, the same findings have not been reproduced in postmenopausal women. For example, compared with men, postmenopausal women had no significant difference in SSRI treatment response in primary care clinics. In contrast, the same postmenopausal women had a significantly worse treatment response than premenopausal women.29
In considering why SSRI response among women would differ depending on reproductive stage or hormonal status, researchers examined the effect of estrogen on antidepressant response with the use of estrogen therapy (ET). As detailed in Box 3, estrogen has many serotonergic-enhancing properties. Early studies with TCAs and a retrospective analysis of SSRIs did not demonstrate improved antidepressant effect with the addition of ET in depressed women.30,31 In contrast, recent studies have demonstrated better SSRI response—regardless of which medication was used—in postmenopausal women on ET or ET with progesterone, compared with postmenopausal women taking placebo.32,33 Perhaps explaining the discrepancy, in a randomized, placebo-controlled trial, Rasgon et al34 found transdermal estrogen shortened time to response to sertraline in postmenopausal women, although it did not improve end response rate.
Human sexual dimorphism of the serotonergic system has been described for many years,a,b including estrogen’s sexually dimorphic effects on the brain.c Sex steroid receptors are found in mood-processing brain regions in men and womend and may influence sex differences in antidepressant response.
Estrogen has been found to augment serotonergic activitye by increasing serotonin synthesis and decreasing serotonin reuptakef as well as increasing serotonin 5-HT2A binding sites.g Estrogen therapy has been shown to increase the number of sites available for active transport of 5-HT into brain cells.h
References
a. Biver F, Lotstra F, Monclus M, et al. Sex difference in 5HT2 receptor in the living human brain. Neurosci Lett. 1996;204(1-2):25-28.
b. Nishizawa S, Benkelfat C, Young SN, et al. Differences between males and females in rates of serotonin synthesis in human brain. Proc Natl Acad Sci U S A. 1997;94(10):5308-5313.
c. Rubinow DR, Schmidt PJ, Roca CA. Estrogen-serotonin interactions: implications for affective regulation. Biol Psychiatry. 1998;44(9):839-850.
d. McEwen BS, Alves SE, Bulloch K, et al. Ovarian steroids and the brain: implications for cognition and aging. Neurology. 1997;48(5 suppl 7):S8-15.
e. Halbreich U, Rojansky N, Palter S, et al. Estrogen augments serotonergic activity in postmenopausal women. Biol Psychiatry. 1995;37(7):434-441.
f. Shors TJ, Leuner B. Estrogen-mediated effects on depression and memory formation in females. J Affect Disord. 2003;74(1):85-96.
g. Kendall DA, Stancel GM, Enna SJ. The influence of sex hormones on antidepressant-induced alterations in neurotransmitter receptor binding. J Neurosci. 1982;2(3):354-360.
h. Sherwin BB, Suranyi-Cadotte BE. Up-regulatory effect of estrogen on platelet 3H-imipramine binding sites in surgically menopausal women. Biol Psychiatry. 1990;28(4):339-348.
CASE CONTINUED: Dosage increase
After a detailed discussion with her psychiatrist about the potential benefits, known risks, and possible alternatives to using and increasing sertraline in pregnancy, Ms. C agrees to a dosage increase to 75 mg/d. Within 2 weeks she reports decreased anxiety and depression. Her depression remits for the remainder of the pregnancy and she gives birth to a full-term healthy infant. Ms. C’s sertraline dose is held at 75 mg/d during the early postpartum period, as she experienced no side effects at that dose, then reduced to 50 mg/d after a period of sustained euthymia.
