User login
Pharmacokinetic considerations when prescribing during pregnancy
Sex-related differences in antidepressant response: When to adjust treatment
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.
Table 1
Sex differences in antidepressant response
| Class | Response: Male vs female |
|---|---|
| Monoamine oxidase inhibitors | M |
| Serotonin-norepinephrine reuptake inhibitors | M=F |
| Selective serotonin reuptake inhibitors | Age <50: M< F Age ≥50: M=F |
| Tricyclic antidepressants | M=F |
| References 1-12 | |
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.
References
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.
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
References
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
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.
Related resources
- Rubinow DR, Schmidt PJ, Roca CA. Estrogen-serotonin interactions: implications for affective regulation. Biol Psychiatry. 1998;44(9):839-850.
- Cohen LS, Nonacs RM, eds. Mood and anxiety disorders during pregnancy and postpartum. Arlington, VA: American Psychiatric Publishing, Inc.; 2005.
- Kornstein SG, Schatzberg AF, Thase ME, et al. Gender differences in treatment response to sertraline versus imipramine in chronic depression. Am J Psychiatry. 2000;157(9):1445-1452.
Drug brand names
- Bupropion • Wellbutrin
- Citalopram • Celexa
- Clomipramine • Anafranil
- Duloxetine • Cymbalta
- Escitalopram • Lexapro
- Estradiol • Estrace, Climara, others
- Fluoxetine • Prozac
- Fluvoxamine • Luvox
- Imipramine • Tofranil
- Mirtazapine • Remeron
- Nefazodone • Serzone
- Nortriptyline • Pamelor
- Sertraline • Zoloft
- Venlafaxine • Effexor
Disclosures
Dr. Marsh receives grant/research support from the University of Massachusetts.
Dr. Deligiannidis receives grant/research support from the Worcester Foundation for Biomedical Research and Forest Research Institute.
Acknowledgement
Dr. Deligiannidis’ contribution to this article was supported by the University of Massachusetts Medical School Department of Psychiatry and the University of Massachusetts Medical School Center for Psychopharmacologic Research and Treatment.
1. Parker G, Parker K, Austin MP, et al. Gender differences in response to differing antidepressant drug classes: two negative studies. Psychol Med. 2003;33(8):1473-1477.
2. Kornstein SG, Schatzberg AF, Thase ME, et al. Gender differences in treatment response to sertraline versus imipramine in chronic depression. Am J Psychiatry. 2000;157(9):1445-1452.
3. Baca E, Garcia-Garcia M, Porras-Chavarino A. Gender differences in treatment response to sertraline versus imipramine in patients with nonmelancholic depressive disorders. Prog Neuropsychopharmacol Biol Psychiatry. 2004;28(1):57-65.
4. Joyce PR, Mulder RT, Luty SE, et al. Melancholia: definitions, risk factors, personality, neuroendocrine markers and differential antidepressant response. Aust N Z J Psychiatry. 2002;36(3):376-383.
5. Quitkin FM, Stewart JW, McGrath PJ, et al. Are there differences between women’s and men’s antidepressant responses? Am J Psychiatry. 2002;159(11):1848-1854.
6. Wohlfarth T, Storosum JG, Elferink AJ, et al. Response to tricyclic antidepressants: independent of gender? Am J Psychiatry. 2004;161(2):370-372.
7. Hildebrandt MG, Steyerberg EW, Stage KB, et al. Are gender differences important for the clinical effects of antidepressants? Am J Psychiatry. 2003;160(9):1643-1650.
8. Young EA, Kornstein SG, Marcus SM, et al. Sex differences in response to citalopram: a STAR*D report. J Psychiatr Res. 2009;43(5):503-511.
9. Thase ME, Entsuah R, Cantillon M, et al. Relative antidepressant efficacy of venlafaxine and SSRIs: sex-age interactions. J Womens Health (Larchmt). 2005;14(7):609-616.
10. Rush AJ, Wisniewski SR, Warden D, et al. Selecting among second-step antidepressant medication monotherapies: predictive value of clinical, demographic, or first-step treatment features. Arch Gen Psychiatry. 2008;65(8):870-880.
11. Papakostas GI, Kornstein SG, Clayton AH, et al. Relative antidepressant efficacy of bupropion and the selective serotonin reuptake inhibitors in major depressive disorder: gender-age interactions. Int Clin Psychopharmacol. 2007;22(4):226-229.
12. Kornstein SG, Wohlreich MM, Mallinckrodt CH, et al. Duloxetine efficacy for major depressive disorder in male vs. female patients: data from 7 randomized, double-blind, placebo-controlled trials. J Clin Psychiatry. 2006;67(5):761-770.
13. Wald A, Van Thiel DH, Hoechstetter L, et al. Effect of pregnancy on gastrointestinal transit. Dig Dis Sci. 1982;27(11):1015-1018.
14. Datz FL, Christian PE, Moore J. Gender-related differences in gastric emptying. J Nucl Med. 1987;28(7):1204-1207.
15. Kimmel L, Gonsalvcs D, Youngs D, et al. Fluctuating levels of antidepressants premenstrually. J Psychosom Obstet Gynaecol. 1992;13:277-280.
16. Jensvold MF, Halbrich U, Hamilton JA. Psycho-pharmacology and women: sex, gender and hormones. Washington, DC: American Psychiatric Press, Inc.; 1996.
17. Miller MN, Newell CL, Miller BE, et al. Variable dosing of sertraline for premenstrual exacerbation of depression: a pilot study. J Womens Health (Larchmt). 2008;17(6):993-997.
18. Sit DK, Perel JM, Helsel JC. Changes in antidepressant metabolism and dosing across pregnancy and early postpartum. J Clin Psychiatry. 2008;69(4):652-658.
19. Klier CM, Mossaheb N, Saria A, et al. Pharmacokinetics and elimination of quetiapine, venlafaxine, and trazodone during pregnancy and postpartum. J Clin Psychopharmacol. 2007;27(6):720-722.
20. Wisner KL, Perel JM, Wheeler SB. Tricyclic dose requirements across pregnancy. Am J Psychiatry. 1993;150(10):1541-1542.
21. Wadelius M, Darj E, Frenne G, et al. Induction of CYP2D6 in pregnancy. Clin Pharmacol Ther. 1997;62(4):400-407.
22. Anderson GD. Pregnancy-induced changes in pharmacokinetics: a mechanistic-based approach. Clin Pharmacokinet. 2005;44(10):989-1008.
23. Hostetter A, Stowe ZN, Strader JR, Jr, et al. Dose of selective serotonin uptake inhibitors across pregnancy: clinical implications. Depress Anxiety. 2000;11(2):51-57.
24. Dunlop W. Serial changes in renal haemodynamics during normal human pregnancy. Br J Obstet Gynaecol. 1981;88(1):1-9.
25. Freeman MP, Nolan PE, Jr, Davis MF, et al. Pharmacokinetics of sertraline across pregnancy and postpartum. J Clin Psychopharmacol. 2008;28(6):646-653.
26. Wisner KL, Perel JM, Peindl KS, et al. Effects of the postpartum period on nortriptyline pharmacokinetics. Psychopharmacol Bull. 1997;33(2):243-248.
27. O’Hara MW, Schlechte JA, Lewis DA, et al. Controlled prospective study of postpartum mood disorders: psychological, environmental, and hormonal variables. J Abnorm Psychol. 1991;100(1):63-73.
28. Meltzer-Brody S, Payne J, Rubinow DR. Postpartum depression: what to tell patients who breast-feed. Current Psychiatry. 2008;7(5):87-95.
29. Pinto-Meza A, Usall J, Serrano-Blanco A, et al. Gender differences in response to antidepressant treatment prescribed in primary care. Does menopause make a difference? J Affect Disord. 2006;93(1-3):53-60.
30. Amsterdam J, Garcia-Espana F, Fawcett J, et al. Fluoxetine efficacy in menopausal women with and without estrogen replacement. J Affect Disord. 1999;55(1):11-17.
31. Shapira B, Oppenheim G, Zohar J, et al. Lack of efficacy of estrogen supplementation to imipramine in resistant female depressives. Biol Psychiatry. 1985;20(5):576-579.
32. Schneider LS, Small GW, Clary CM. Estrogen replacement therapy and antidepressant response to sertraline in older depressed women. Am J Geriatr Psychiatry. 2001;9(4):393-399.
33. Zanardi R, Rossini D, Magri L, et al. Response to SSRIs and role of the hormonal therapy in post-menopausal depression. Eur Neuropsychopharmacol. 2007;17(6-7):400-405.
34. Rasgon NL, Dunkin J, Fairbanks L, et al. Estrogen and response to sertraline in postmenopausal women with major depressive disorder: a pilot study. J Psychiatr Res. 2007;41(3-4):338-343.
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.
Table 1
Sex differences in antidepressant response
| Class | Response: Male vs female |
|---|---|
| Monoamine oxidase inhibitors | M |
| Serotonin-norepinephrine reuptake inhibitors | M=F |
| Selective serotonin reuptake inhibitors | Age <50: M< F Age ≥50: M=F |
| Tricyclic antidepressants | M=F |
| References 1-12 | |
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.
References
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.
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
References
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
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.
Related resources
- Rubinow DR, Schmidt PJ, Roca CA. Estrogen-serotonin interactions: implications for affective regulation. Biol Psychiatry. 1998;44(9):839-850.
- Cohen LS, Nonacs RM, eds. Mood and anxiety disorders during pregnancy and postpartum. Arlington, VA: American Psychiatric Publishing, Inc.; 2005.
- Kornstein SG, Schatzberg AF, Thase ME, et al. Gender differences in treatment response to sertraline versus imipramine in chronic depression. Am J Psychiatry. 2000;157(9):1445-1452.
Drug brand names
- Bupropion • Wellbutrin
- Citalopram • Celexa
- Clomipramine • Anafranil
- Duloxetine • Cymbalta
- Escitalopram • Lexapro
- Estradiol • Estrace, Climara, others
- Fluoxetine • Prozac
- Fluvoxamine • Luvox
- Imipramine • Tofranil
- Mirtazapine • Remeron
- Nefazodone • Serzone
- Nortriptyline • Pamelor
- Sertraline • Zoloft
- Venlafaxine • Effexor
Disclosures
Dr. Marsh receives grant/research support from the University of Massachusetts.
Dr. Deligiannidis receives grant/research support from the Worcester Foundation for Biomedical Research and Forest Research Institute.
Acknowledgement
Dr. Deligiannidis’ contribution to this article was supported by the University of Massachusetts Medical School Department of Psychiatry and the University of Massachusetts Medical School Center for Psychopharmacologic Research and Treatment.
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.
Table 1
Sex differences in antidepressant response
| Class | Response: Male vs female |
|---|---|
| Monoamine oxidase inhibitors | M |
| Serotonin-norepinephrine reuptake inhibitors | M=F |
| Selective serotonin reuptake inhibitors | Age <50: M< F Age ≥50: M=F |
| Tricyclic antidepressants | M=F |
| References 1-12 | |
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.
References
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.
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
References
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
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.
Related resources
- Rubinow DR, Schmidt PJ, Roca CA. Estrogen-serotonin interactions: implications for affective regulation. Biol Psychiatry. 1998;44(9):839-850.
- Cohen LS, Nonacs RM, eds. Mood and anxiety disorders during pregnancy and postpartum. Arlington, VA: American Psychiatric Publishing, Inc.; 2005.
- Kornstein SG, Schatzberg AF, Thase ME, et al. Gender differences in treatment response to sertraline versus imipramine in chronic depression. Am J Psychiatry. 2000;157(9):1445-1452.
Drug brand names
- Bupropion • Wellbutrin
- Citalopram • Celexa
- Clomipramine • Anafranil
- Duloxetine • Cymbalta
- Escitalopram • Lexapro
- Estradiol • Estrace, Climara, others
- Fluoxetine • Prozac
- Fluvoxamine • Luvox
- Imipramine • Tofranil
- Mirtazapine • Remeron
- Nefazodone • Serzone
- Nortriptyline • Pamelor
- Sertraline • Zoloft
- Venlafaxine • Effexor
Disclosures
Dr. Marsh receives grant/research support from the University of Massachusetts.
Dr. Deligiannidis receives grant/research support from the Worcester Foundation for Biomedical Research and Forest Research Institute.
Acknowledgement
Dr. Deligiannidis’ contribution to this article was supported by the University of Massachusetts Medical School Department of Psychiatry and the University of Massachusetts Medical School Center for Psychopharmacologic Research and Treatment.
1. Parker G, Parker K, Austin MP, et al. Gender differences in response to differing antidepressant drug classes: two negative studies. Psychol Med. 2003;33(8):1473-1477.
2. Kornstein SG, Schatzberg AF, Thase ME, et al. Gender differences in treatment response to sertraline versus imipramine in chronic depression. Am J Psychiatry. 2000;157(9):1445-1452.
3. Baca E, Garcia-Garcia M, Porras-Chavarino A. Gender differences in treatment response to sertraline versus imipramine in patients with nonmelancholic depressive disorders. Prog Neuropsychopharmacol Biol Psychiatry. 2004;28(1):57-65.
4. Joyce PR, Mulder RT, Luty SE, et al. Melancholia: definitions, risk factors, personality, neuroendocrine markers and differential antidepressant response. Aust N Z J Psychiatry. 2002;36(3):376-383.
5. Quitkin FM, Stewart JW, McGrath PJ, et al. Are there differences between women’s and men’s antidepressant responses? Am J Psychiatry. 2002;159(11):1848-1854.
6. Wohlfarth T, Storosum JG, Elferink AJ, et al. Response to tricyclic antidepressants: independent of gender? Am J Psychiatry. 2004;161(2):370-372.
7. Hildebrandt MG, Steyerberg EW, Stage KB, et al. Are gender differences important for the clinical effects of antidepressants? Am J Psychiatry. 2003;160(9):1643-1650.
8. Young EA, Kornstein SG, Marcus SM, et al. Sex differences in response to citalopram: a STAR*D report. J Psychiatr Res. 2009;43(5):503-511.
9. Thase ME, Entsuah R, Cantillon M, et al. Relative antidepressant efficacy of venlafaxine and SSRIs: sex-age interactions. J Womens Health (Larchmt). 2005;14(7):609-616.
10. Rush AJ, Wisniewski SR, Warden D, et al. Selecting among second-step antidepressant medication monotherapies: predictive value of clinical, demographic, or first-step treatment features. Arch Gen Psychiatry. 2008;65(8):870-880.
11. Papakostas GI, Kornstein SG, Clayton AH, et al. Relative antidepressant efficacy of bupropion and the selective serotonin reuptake inhibitors in major depressive disorder: gender-age interactions. Int Clin Psychopharmacol. 2007;22(4):226-229.
12. Kornstein SG, Wohlreich MM, Mallinckrodt CH, et al. Duloxetine efficacy for major depressive disorder in male vs. female patients: data from 7 randomized, double-blind, placebo-controlled trials. J Clin Psychiatry. 2006;67(5):761-770.
13. Wald A, Van Thiel DH, Hoechstetter L, et al. Effect of pregnancy on gastrointestinal transit. Dig Dis Sci. 1982;27(11):1015-1018.
14. Datz FL, Christian PE, Moore J. Gender-related differences in gastric emptying. J Nucl Med. 1987;28(7):1204-1207.
15. Kimmel L, Gonsalvcs D, Youngs D, et al. Fluctuating levels of antidepressants premenstrually. J Psychosom Obstet Gynaecol. 1992;13:277-280.
16. Jensvold MF, Halbrich U, Hamilton JA. Psycho-pharmacology and women: sex, gender and hormones. Washington, DC: American Psychiatric Press, Inc.; 1996.
17. Miller MN, Newell CL, Miller BE, et al. Variable dosing of sertraline for premenstrual exacerbation of depression: a pilot study. J Womens Health (Larchmt). 2008;17(6):993-997.
18. Sit DK, Perel JM, Helsel JC. Changes in antidepressant metabolism and dosing across pregnancy and early postpartum. J Clin Psychiatry. 2008;69(4):652-658.
19. Klier CM, Mossaheb N, Saria A, et al. Pharmacokinetics and elimination of quetiapine, venlafaxine, and trazodone during pregnancy and postpartum. J Clin Psychopharmacol. 2007;27(6):720-722.
20. Wisner KL, Perel JM, Wheeler SB. Tricyclic dose requirements across pregnancy. Am J Psychiatry. 1993;150(10):1541-1542.
21. Wadelius M, Darj E, Frenne G, et al. Induction of CYP2D6 in pregnancy. Clin Pharmacol Ther. 1997;62(4):400-407.
22. Anderson GD. Pregnancy-induced changes in pharmacokinetics: a mechanistic-based approach. Clin Pharmacokinet. 2005;44(10):989-1008.
23. Hostetter A, Stowe ZN, Strader JR, Jr, et al. Dose of selective serotonin uptake inhibitors across pregnancy: clinical implications. Depress Anxiety. 2000;11(2):51-57.
24. Dunlop W. Serial changes in renal haemodynamics during normal human pregnancy. Br J Obstet Gynaecol. 1981;88(1):1-9.
25. Freeman MP, Nolan PE, Jr, Davis MF, et al. Pharmacokinetics of sertraline across pregnancy and postpartum. J Clin Psychopharmacol. 2008;28(6):646-653.
26. Wisner KL, Perel JM, Peindl KS, et al. Effects of the postpartum period on nortriptyline pharmacokinetics. Psychopharmacol Bull. 1997;33(2):243-248.
27. O’Hara MW, Schlechte JA, Lewis DA, et al. Controlled prospective study of postpartum mood disorders: psychological, environmental, and hormonal variables. J Abnorm Psychol. 1991;100(1):63-73.
28. Meltzer-Brody S, Payne J, Rubinow DR. Postpartum depression: what to tell patients who breast-feed. Current Psychiatry. 2008;7(5):87-95.
29. Pinto-Meza A, Usall J, Serrano-Blanco A, et al. Gender differences in response to antidepressant treatment prescribed in primary care. Does menopause make a difference? J Affect Disord. 2006;93(1-3):53-60.
30. Amsterdam J, Garcia-Espana F, Fawcett J, et al. Fluoxetine efficacy in menopausal women with and without estrogen replacement. J Affect Disord. 1999;55(1):11-17.
31. Shapira B, Oppenheim G, Zohar J, et al. Lack of efficacy of estrogen supplementation to imipramine in resistant female depressives. Biol Psychiatry. 1985;20(5):576-579.
32. Schneider LS, Small GW, Clary CM. Estrogen replacement therapy and antidepressant response to sertraline in older depressed women. Am J Geriatr Psychiatry. 2001;9(4):393-399.
33. Zanardi R, Rossini D, Magri L, et al. Response to SSRIs and role of the hormonal therapy in post-menopausal depression. Eur Neuropsychopharmacol. 2007;17(6-7):400-405.
34. Rasgon NL, Dunkin J, Fairbanks L, et al. Estrogen and response to sertraline in postmenopausal women with major depressive disorder: a pilot study. J Psychiatr Res. 2007;41(3-4):338-343.
1. Parker G, Parker K, Austin MP, et al. Gender differences in response to differing antidepressant drug classes: two negative studies. Psychol Med. 2003;33(8):1473-1477.
2. Kornstein SG, Schatzberg AF, Thase ME, et al. Gender differences in treatment response to sertraline versus imipramine in chronic depression. Am J Psychiatry. 2000;157(9):1445-1452.
3. Baca E, Garcia-Garcia M, Porras-Chavarino A. Gender differences in treatment response to sertraline versus imipramine in patients with nonmelancholic depressive disorders. Prog Neuropsychopharmacol Biol Psychiatry. 2004;28(1):57-65.
4. Joyce PR, Mulder RT, Luty SE, et al. Melancholia: definitions, risk factors, personality, neuroendocrine markers and differential antidepressant response. Aust N Z J Psychiatry. 2002;36(3):376-383.
5. Quitkin FM, Stewart JW, McGrath PJ, et al. Are there differences between women’s and men’s antidepressant responses? Am J Psychiatry. 2002;159(11):1848-1854.
6. Wohlfarth T, Storosum JG, Elferink AJ, et al. Response to tricyclic antidepressants: independent of gender? Am J Psychiatry. 2004;161(2):370-372.
7. Hildebrandt MG, Steyerberg EW, Stage KB, et al. Are gender differences important for the clinical effects of antidepressants? Am J Psychiatry. 2003;160(9):1643-1650.
8. Young EA, Kornstein SG, Marcus SM, et al. Sex differences in response to citalopram: a STAR*D report. J Psychiatr Res. 2009;43(5):503-511.
9. Thase ME, Entsuah R, Cantillon M, et al. Relative antidepressant efficacy of venlafaxine and SSRIs: sex-age interactions. J Womens Health (Larchmt). 2005;14(7):609-616.
10. Rush AJ, Wisniewski SR, Warden D, et al. Selecting among second-step antidepressant medication monotherapies: predictive value of clinical, demographic, or first-step treatment features. Arch Gen Psychiatry. 2008;65(8):870-880.
11. Papakostas GI, Kornstein SG, Clayton AH, et al. Relative antidepressant efficacy of bupropion and the selective serotonin reuptake inhibitors in major depressive disorder: gender-age interactions. Int Clin Psychopharmacol. 2007;22(4):226-229.
12. Kornstein SG, Wohlreich MM, Mallinckrodt CH, et al. Duloxetine efficacy for major depressive disorder in male vs. female patients: data from 7 randomized, double-blind, placebo-controlled trials. J Clin Psychiatry. 2006;67(5):761-770.
13. Wald A, Van Thiel DH, Hoechstetter L, et al. Effect of pregnancy on gastrointestinal transit. Dig Dis Sci. 1982;27(11):1015-1018.
14. Datz FL, Christian PE, Moore J. Gender-related differences in gastric emptying. J Nucl Med. 1987;28(7):1204-1207.
15. Kimmel L, Gonsalvcs D, Youngs D, et al. Fluctuating levels of antidepressants premenstrually. J Psychosom Obstet Gynaecol. 1992;13:277-280.
16. Jensvold MF, Halbrich U, Hamilton JA. Psycho-pharmacology and women: sex, gender and hormones. Washington, DC: American Psychiatric Press, Inc.; 1996.
17. Miller MN, Newell CL, Miller BE, et al. Variable dosing of sertraline for premenstrual exacerbation of depression: a pilot study. J Womens Health (Larchmt). 2008;17(6):993-997.
18. Sit DK, Perel JM, Helsel JC. Changes in antidepressant metabolism and dosing across pregnancy and early postpartum. J Clin Psychiatry. 2008;69(4):652-658.
19. Klier CM, Mossaheb N, Saria A, et al. Pharmacokinetics and elimination of quetiapine, venlafaxine, and trazodone during pregnancy and postpartum. J Clin Psychopharmacol. 2007;27(6):720-722.
20. Wisner KL, Perel JM, Wheeler SB. Tricyclic dose requirements across pregnancy. Am J Psychiatry. 1993;150(10):1541-1542.
21. Wadelius M, Darj E, Frenne G, et al. Induction of CYP2D6 in pregnancy. Clin Pharmacol Ther. 1997;62(4):400-407.
22. Anderson GD. Pregnancy-induced changes in pharmacokinetics: a mechanistic-based approach. Clin Pharmacokinet. 2005;44(10):989-1008.
23. Hostetter A, Stowe ZN, Strader JR, Jr, et al. Dose of selective serotonin uptake inhibitors across pregnancy: clinical implications. Depress Anxiety. 2000;11(2):51-57.
24. Dunlop W. Serial changes in renal haemodynamics during normal human pregnancy. Br J Obstet Gynaecol. 1981;88(1):1-9.
25. Freeman MP, Nolan PE, Jr, Davis MF, et al. Pharmacokinetics of sertraline across pregnancy and postpartum. J Clin Psychopharmacol. 2008;28(6):646-653.
26. Wisner KL, Perel JM, Peindl KS, et al. Effects of the postpartum period on nortriptyline pharmacokinetics. Psychopharmacol Bull. 1997;33(2):243-248.
27. O’Hara MW, Schlechte JA, Lewis DA, et al. Controlled prospective study of postpartum mood disorders: psychological, environmental, and hormonal variables. J Abnorm Psychol. 1991;100(1):63-73.
28. Meltzer-Brody S, Payne J, Rubinow DR. Postpartum depression: what to tell patients who breast-feed. Current Psychiatry. 2008;7(5):87-95.
29. Pinto-Meza A, Usall J, Serrano-Blanco A, et al. Gender differences in response to antidepressant treatment prescribed in primary care. Does menopause make a difference? J Affect Disord. 2006;93(1-3):53-60.
30. Amsterdam J, Garcia-Espana F, Fawcett J, et al. Fluoxetine efficacy in menopausal women with and without estrogen replacement. J Affect Disord. 1999;55(1):11-17.
31. Shapira B, Oppenheim G, Zohar J, et al. Lack of efficacy of estrogen supplementation to imipramine in resistant female depressives. Biol Psychiatry. 1985;20(5):576-579.
32. Schneider LS, Small GW, Clary CM. Estrogen replacement therapy and antidepressant response to sertraline in older depressed women. Am J Geriatr Psychiatry. 2001;9(4):393-399.
33. Zanardi R, Rossini D, Magri L, et al. Response to SSRIs and role of the hormonal therapy in post-menopausal depression. Eur Neuropsychopharmacol. 2007;17(6-7):400-405.
34. Rasgon NL, Dunkin J, Fairbanks L, et al. Estrogen and response to sertraline in postmenopausal women with major depressive disorder: a pilot study. J Psychiatr Res. 2007;41(3-4):338-343.