Class | Response: Male vs female |
Monoamine oxidase inhibitors | M<F |
Serotonin-norepinephrine reuptake inhibitors | M=F |
Selective serotonin | Age <50: M< F |
Tricyclic antidepressants | M=F |
"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."
"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"
"Hormone-related changes associated with the menstrual cycle may affect antidepressant absorption and distribution"
"Dose increases are necessary in two-thirds of pregnant women on antidepressant monotherapy"
"Studies have shown better SSRI response in postmenopausal women receiving estrogen therapy compared with placebo"
"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"
Sex-related differences in antidepressant response: When to adjust treatment
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