Sex-related differences in antidepressant response: When to adjust treatment
How pharmacodynamic, pharmacokinetic, and hormonal factors impact prescribing
With a history of panic disorder, perfectionistic tendencies, and depression, Ms. C, age 32, presents 29 weeks into her first pregnancy with a chief complaint that “the Zoloft is not working; my sadness and anxiety are increased and I feel dizzy, like when I miss a dose.” For the past 7 years, she has done well on sertraline, 50 mg/d; she has had no depressive symptoms and experienced minimal to manageable anxiety. Ms. C has found psychotherapy helpful for the last 2 years, including during her pregnancy.
After discussion with her obstetrician, Ms. C remained on sertraline through her early pregnancy. She did well until several weeks ago, when she noticed a return of sadness and incessant worry. She resumed an old habit of excessively cleaning her home. Ms. C denies missing doses but states she has the physical feeling as if she were—a lightheadedness that she clearly distinguishes from pregnancy symptoms.
Both men and women respond well to antidepressants, yet there are notable differences between the 2. Understanding why men and women may differ in response to antidepressants helps clinicians better tailor their treatment choice and dosing.
This article outlines some of differences—and lack thereof—in response rates to antidepressants. Our discussion of why these differences may occur is framed in the context of pharmacokinetics, pharmacodynamics, and the influence of gonadal hormones on antidepressant-related neurotransmitter systems. The second section focuses on major reproductive phases of adult women (the menstrual cycle, pregnancy, postpartum, and menopause) and how antidepressant response rates can influence clinical decision making, such as antidepressant timing, dose, and choice of potential adjunct treatments.
What the evidence says
Most studies look at sex differences in response to a single antidepressant, but several comparing sex differences among classes have produced fascinating results (Table 1). One of the most robust and replicated findings—although not universally reproduced1—is that compared with men, women are more likely to respond to selective serotonin reuptake inhibitors (SSRIs) than to tricyclic antidepressants (TCAs).2-4 Because of this and the fact that SSRIs are so commonly used, this article primarily will address SSRIs in women.
Initially, however, in reviewing non-SSRI anti depressants, monoamine oxidase inhibitors (MAOIs) are reported to produce a superior response in women than in men.5 Women are more likely to have atypical depression symptoms, which MAOIs often treat better than other antidepressants. In contrast, a recent meta-analysis of TCAs6 found no sex response difference within the class. However, 1 study reported women may be slower to respond to TCAs than men.2
Studies on the newer and more frequently prescribed antidepressants reveal some interesting sex differences. Although smaller studies initially did not find a sex difference in SSRIs,5,7 when response rates to citalopram were compared in 2,876 subjects in Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, women were more likely to reach remission and response than men.8 Younger women—generally those age <50—respond better to SSRIs than women age ≥50.2,3,9
There are less data concerning newer non-SSRI antidepressants. In the second stage of the STAR*D trial, when subjects who did not respond to citalopram were randomly assigned venlafaxine, bupropion, or sertraline, there was no sex difference in response.10 Pooled analysis of randomized controlled trials specifically looking at remission rates between the sexes for venlafaxine,9 bupropion,11 or duloxetine12 found no difference between men and women, regardless of age. No published sex differences in antidepressant response were found for mirtazapine.
Numerous studies have detailed sex differences in antidepressant pharmacokinetics (Box 1) and pharmacodynamics (Box 2), as well as human sexual dimorphism of the serotonergic system. Estrogen’s influence on the serotonergic system (Box 3) may be a component of men and women’s different responses to antidepressants, particularly across reproductive phases.
Sex differences in antidepressant response
Response: Male vs female
Monoamine oxidase inhibitors
Serotonin-norepinephrine reuptake inhibitors
Age <50: M< F
Sex differences in antidepressant pharmacokinetics
Medical literature has documented gender differences in antidepressant absorption, distribution, metabolism, and elimination.a-c Compared with men, women—especially premenopausal women—have slower gastric emptyingd and small bowel and colonic transit times.e,f Also, because antidepressants generally are lipophilic,a,g a lower ratio of lean muscle to adipose tissue in women compared with men may result in a greater volume of drug distribution (Vd).
Sex differences also have been reported in hepatic enzyme activity and may affect clinical response. Most medications, including antidepressants, undergo phase I metabolism, commonly via the cytochrome P450 (CYP450) pathway, and/or phase II conjugation reactions. Generally, phase I oxidative metabolism appears to be greater in women than in men; in contrast, phase II conjugation activity appears to be greater in men than in women.h
Lower CYP1A2 activity in womeni along with gonadal steroid inhibition of CYP1A2j,k may explain why clomipramine metabolic clearance is reduced in young womenl and mean steady state plasma levels of fluvoxamine are almost double in women than in men for the same dose.m In theory, greater CYP3A4 activity in womeni has the potential to accelerate metabolism and/or decrease plasma levels of some commonly used antidepressants metabolized via CYP3A4, such as nefazodone and (to some extent) sertraline and citalopram. In contrast, CYP2D6 and CYP2C9 do not show sex differences in metabolism.
Differences in antidepressant blood levels, however, are difficult to base solely on CYP metabolic route differences. Sex differences in plasma antidepressant levels likely reflect a summation of several sex-associated pharmacokinetic processes and may impact one of many factors that contribute to the small observed difference in antidepressant efficacy between men and women.
a. Yonkers KA, Kando JC, Cole JO, et al. Gender differences in pharmacokinetics and pharmacodynamics of psychotropic medication. Am J Psychiatry. 1992;149(5):587-595.
b. Kando JC, Yonkers KA, Cole JO. Gender as a risk factor for adverse events to medications. Drugs. 1995;50(1):1-6.
c. Bies RR, Bigos KL, Pollock BG. Gender differences in the pharmacokinetics and pharmacodynamics of antidepressants. J Gend Specif Med. 2003;6(3):12-20.
d. Hutson WR, Roehrkasse RL, Wald A. Influence of gender and menopause on gastric emptying and motility. Gastroenterology. 1989;96(1):11-17.
e. Sadik R, Abrahamsson H, Stotzer PO. Gender differences in gut transit shown with a newly developed radiological procedure. Scand J Gastroenterol. 2003;38(1):36-42.
f. Lorena SL, Tinois E, Hirata ES, et al. [Scintigraphic study of gastric emptying and intragastric distribution of a solid meal: gender differences]. Arq Gastroenterol. 2000;37(2):102-106.
g. Greenblatt DJ, Divoll M, Abernethy DR, et al. Physiologic changes in old age: relation to altered drug disposition. J Am Geriatr Soc. 1982;30(11 suppl):S6-10.
h. Anderson GD. Gender differences in pharmacological response. Int Rev Neurobiol. 2008;83:1-10.
i. Anderson GD. Sex and racial differences in pharmacological response: where is the evidence? Pharmacogenetics, pharmacokinetics, and pharmacodynamics. J Womens Health (Larchmt). 2005;14(1):19-29.
j. Lane JD, Steege JF, Rupp SL, et al. Menstrual cycle effects on caffeine elimination in the human female. Eur J Clin Pharmacol. 1992;43(5):543-546.
k. Pollock BG, Wylie M, Stack JA, et al. Inhibition of caffeine metabolism by estrogen replacement therapy in postmenopausal women. J Clin Pharmacol. 1999;39(9):936-940.
l. Gex-Fabry M, Balant-Gorgia AE, Balant LP, et al. Clomipramine metabolism. Model-based analysis of variability factors from drug monitoring data. Clin Pharmacokinet. 1990;19(3):241-255.
m. Hartter S, Wetzel H, Hammes E, et al. Nonlinear pharmacokinetics of fluvoxamine and gender differences. Ther Drug Monit. 1998;20(4):446-449.
Sex differences in antidepressant pharmacodynamics
Sexual dimorphisms in the localization and concentration of endogenous neurotransmitters such as serotonin and dopamine and their degradative enzymes and transporters have the potential to clinically affect antidepressant pharmacodynamics (eg, drug-receptor interactions).
Recent investigations report sex differences in some key monoaminergic enzymes in the brain, notably monoamine oxidase-A (MAO)a,b and catechol-O-methyltransferase (COMT).c-e
For example, estrogen has been found to inhibit MAO,f which is potentially clinically relevant in light of the finding that women respond better than men to MAO inhibitors. COMT—which is responsible for metabolism of norepinephrine, epinephrine, and dopamine—is down regulated by estradiole,g likely accounting for some sex effects. Recently, the sexually dimorphic effect of a COMT polymorphism was associated with a poorer fluoxetine response in men treated for major depression.h
a. Domschke K, Hohoff C, Mortensen LS, et al. Monoamine oxidase A variant influences antidepressant treatment response in female patients with major depression. Prog Neuropsychopharmacol Biol Psychiatry. 2008;32(1):224-228.
b. Yu YW, Tsai SJ, Hong CJ, et al. Association study of a monoamine oxidase a gene promoter polymorphism with major depressive disorder and antidepressant response. Neuropsychopharmacology. 2005;30(9):1719-1723.
c. Baune BT, Hohoff C, Berger K, et al. Association of the COMT val158met variant with antidepressant treatment response in major depression. Neuropsychopharmacology. 2008;33(4):924-932.
d. Harrison PJ, Tunbridge EM. Catechol-O-methyltransferase (COMT): a gene contributing to sex differences in brain function, and to sexual dimorphism in the predisposition to psychiatric disorders. Neuropsychopharmacology. 2008;33(13):3037-3045.
e. Jiang H, Xie T, Ramsden DB, et al. Human catechol-O-methyltransferase down-regulation by estradiol. Neuropharmacology. 2003;45(7):1011-1018.
f. Luine VN, Khylchevskaya RI, McEwen BS. Effect of gonadal steroids on activities of monoamine oxidase and choline acetylase in rat brain. Brain Res. 1975;86(2):293-306.
g. Xie T, Ho SL, Ramsden D. Characterization and implications of estrogenic down-regulation of human catechol-O-methyltransferase gene transcription. Mol Pharmacol. 1999;56(1):31-38.
h. Tsai SJ, Gau YT, Hong CJ, et al. Sexually dimorphic effect of catechol-O-methyltransferase val158met polymorphism on clinical response to fluoxetine in major depressive patients. J Affect Disord. 2009;113(1-2):183-187.
Change across reproductive phases
In contrast to men, women’s estrogen and progesterone status varies widely across a woman’s reproductive lifecycle (menstrual cycle, pregnancy, postpartum, premenopause vs post menopause). In men and women, androgen levels—including testosterone—tend to remain at steady levels, and then slowly decline with age.
Menstrual cycle. Hormone-related changes associated with the menstrual cycle may affect antidepressant absorption and distribution. During the luteal phase—second half of the menstrual cycle post-ovulation—and pregnancy, increased progesterone concentrations are associated with slowed gastrointestinal transit time13,14 compared with the follicular phase (preovulation).
Premenstrually, at the end of luteal phase, reduced serum antidepressant levels have been associated with breakthrough depressive symptoms.15,16 In these case reports, serum antidepressant levels returned to baseline and depressive symptoms resolved after menses ended. It is possible that women may be at increased risk of symptom recurrence before menses because of hormonally driven changes in drug absorption, distribution, and metabolism. Increased dosing of sertraline in the luteal phase has helped reduce premenstrual exacerbation of depression.17
Pregnancy. Dose requirements for the SSRIs citalopram, escitalopram, and sertraline,18 the serotonin-norepinephrine reuptake inhibitor venlafaxine,19 and the TCAs nortriptyline, clomipramine, and imipramine20 increase during the second half of pregnancy. This appears to be the result of increased drug metabolism. Altered cytochrome P450 (CYP450) enzymatic activity in pregnancy—likely mediated by elevated estrogen and progesterone—may have clinical effects on drug levels and treatment response. Studies indicate that CYP3A4—and possibly CYP2D6—are induced during pregnancy.21,22 Dose increases are necessary in two-thirds of pregnant women on antidepressant monotherapy, typically after 20 weeks gestation18,20,23 to treat symptom recurrence or maintain euthymia.
During pregnancy, drug elimination may increase because of higher renal blood flow and glomerular filtration rate (GFR).24 This could reduce blood levels of water-soluble active metabolites of some TCAs. Pregnancy-associated reductions in intestinal motility and gastric pH alone do not change medication bioavailability. Increased body fat could increase the volume of drug distribution for antidepressants, and, in theory, create a dilutional drop in free drug concentration, but this likely would have only a minor effect.
The range of antidepressant effectiveness among pregnant patients is wide, which reflects individual differences in pharmacokinetics and pharmacodynamics.25 Because we cannot predict which women will require dose changes during pregnancy or postpartum, patients should be monitored frequently for depressive symptom recurrence. Dose adjustments may be necessary to prevent relapse (eg, when net metabolism is increased) or pronounced side effects (eg, when net metabolism is reduced).18,26