Evidence-Based Reviews

Sex-related differences in antidepressant response: When to adjust treatment

Current Psychiatry. 2010 May;9(5):25-30

References

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.

Box 2

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 estradiol^e,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 time^13,14 compared with the follicular phase (preovulation).

Clinical Point

Hormone-related changes associated with the menstrual cycle may affect antidepressant absorption and distribution

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 gestation^18,20,23 to treat symptom recurrence or maintain euthymia.

Clinical Point

Dose increases are necessary in two-thirds of pregnant women on antidepressant monotherapy

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