madman
Super Moderator
Abstract
Various antidepressants are commonly used to treat depression and anxiety disorders, and sex differences have been identified in their efficacy and side effects. Steroids, such as estrogens and testosterone, both in the periphery and locally in the brain, are regarded as important modulators of these sex differences. This review presents published data from preclinical and clinical studies that measure testosterone and estrogen level changes during and/or after acute or chronic administration of different antidepressants. The majority of studies show an interaction between sex hormones and antidepressants on sexual function and behavior, or in depressive symptom alleviation. However, most of the studies omit to investigate antidepressants’ effects on circulating levels of gonadal hormones. From the data reviewed herein, it is evident that most antidepressants can influence testosterone and estrogen levels. Still, the evidence is conflicting with some studies showing an increase, others decrease or no effect. Most studies are conducted in male animals or humans, underscoring the importance of considering sex as an important variable in such investigations, especially as depression and anxiety disorders are more common in women than men. Therefore, research is needed to elucidate the extent to which antidepressants can influence both peripheral and brain levels of testosterone and estrogens, in males and females, and whether this impacts the effectiveness or side effects of antidepressants.
1. Introduction
The pharmacotherapy of mood and anxiety disorders relies heavily on drugs that modulate the monoaminergic neurotransmission (Yohn et al., 2017). Currently, selective serotonin reuptake inhibitors (SSRIs), comprising of citalopram/escitalopram, sertraline, fluoxetine, paroxetine, and fluvoxamine, is the most widely used class of such medications (Pirraglia et al., 2003). Serotonin and Norepinephrine Reuptake Inhibitors (SNRIs), namely venlafaxine and duloxetine, is another widely used category of antidepressants. Their common primary mechanism of action is the inhibition of the presynaptic reuptake of serotonin and/or norepinephrine neurotransmitters (Artigas et al., 2002). The older generation of tricyclic antidepressants (TCAs), i.e., amitriptyline, imipramine, desipramine, nortriptyline, is less frequently used nowadays, as their non-selective blockade was associated with more side-effects (Pacher et al., 2001). Several other compounds, such as agomelatine, bupropion, mirtazapine, and trazodone are considered atypical antidepressants. Atypical antidepressants’ mechanism involves modulation of dopamine neurotransmission, modulation of serotonin and melatonin receptors. Furthermore, recently esketamine was the first licensed antidepressant that acts on the NMDA receptors (Frazer, 1997; Garay et al., 2017).
Strong evidence supports the efficacy and safety of those medications in treating mainly depression and secondary anxiety disorders. However, in neuroscience and neuropsychopharmacology, there is a gradually increasing research interest regarding sex differences in the symptomatology, prevalence, etiology, and treatment of psychiatric disorders. Indeed, sex differences have been described in mood and anxiety disorders, in cognitive processes as well as in physiological and especially neuroendocrine mechanisms that present considerable differences among men and women (Dalla et al., 2010; Kokras and Dalla, 2014, 2017). Nonetheless, the study of both sexes in trials investigating psychiatric drugs is still problematic, potentially leading to inadequate evaluation of sex differences (Kokras et al., 2019). For instance, several studies have described gender differences in men's and women's pharmacokinetic profiles for several antidepressants. In particular, body weight, the volume of blood, enzyme activity, and clearance rates have been identified as potential sources of these differences (Kokras et al., 2011; Sramek et al., 2016).
Moreover, many studies suggest a significant interaction between sex hormones and antidepressants (Damoiseaux et al., 2014; Pawluski et al., 2020; Sramek and Cutler, 2011; Westlund Tam and Parry, 2003; Williams and Trainor, 2018) while focusing only on the aftereffect of antidepressants’ influences on sexual function and behavior. Unfortunately, the exploration of possible antidepressant-related changes in hormonal levels still remains significantly understudied. In particular, most studies focus on the possible synergistic effect of hormones and antidepressants, rather than investigating antidepressants’ effects on circulating levels of male and female hormones, such as testosterone and estrogens.
Therefore, the purpose of this review, following an exhaustive literature search, is to present preclinical and clinical studies that evaluate changes in testosterone and estrogen levels during and/or after acute or chronic administration of different antidepressants. Furthermore, we aim to elucidate the extent to which antidepressants can influence both serum and brain levels of testosterone and estrogens, in both males and females. Prompted by the extended relations between depression and alterations in the hormonal milieu, it is of great importance to determine the effects of antidepressants on testosterone and estrogen levels. Therefore, the aim of this review is to explore the drugs’ mechanisms of action and possibly further elucidate the pathophysiology of depression.
2. Testosterone
Testosterone is one of the major androgens biosynthesized during steroidogenesis from cholesterol (Figure 1) (Hu et al., 2010). Interestingly, some preclinical and clinical studies suggest that antidepressants can affect the hormonal milieu in both sexes, and data are presented herein.
2.1. Citalopram and escitalopram
2.2. Sertraline
2.3. Paroxetine
2.4. Fluoxetine
2.5. Venlafaxine
2.6. Duloxetine
2.7. Amitriptyline
2.8. Imipramine
2.9. Desipramine
2.10. Bupropion
2.11. Trazodone
2.12. Esketamine
3. Estrogens
Estrogen is a major reproductive hormone, responsible mostly for the female reproductive system. Aromatase (CYP19A) is the key enzyme in the estrogens’ biosynthesis, acting via androgens' aromatization. There are three major endogenous estrogens with estrogenic hormonal activity: estrone (E1), estradiol (E2), and estriol (E3) (Figure 1). Both men and women have lower levels of circulating estrogens compared to androgens, and although males have significantly lower levels of estrogens than females, they have important physiological roles in both sexes. Both preclinical and clinical studies have supported estrogens' involvement in the pathogenesis of depression and the augmentation of antidepressants’ effectiveness (Berlanga and Flores-Ramos, 2006; Bryant et al., 2006; Sramek et al., 2016). For instance, regarding the pathogenesis of depression, most prior research has described that estradiol decline is associated with depression and anxiety in postmenopausal women (Bromberger and Epperson, 2018; Freeman et al., 2006; Ryan et al., 2009; Soares et al., 2001)
3.1. Citalopram and escitalopram
3.2. Sertraline
3.3. Fluoxetine
3.4. Fluvoxamine
3.5. Venlafaxine
3.6. Amitriptyline
3.7. Imipramine
3.8. Desipramine
3.9. Agomelatine
3.10. Bupropion
3.11. Esketamine
Various antidepressants are commonly used to treat depression and anxiety disorders, and sex differences have been identified in their efficacy and side effects. Steroids, such as estrogens and testosterone, both in the periphery and locally in the brain, are regarded as important modulators of these sex differences. This review presents published data from preclinical and clinical studies that measure testosterone and estrogen level changes during and/or after acute or chronic administration of different antidepressants. The majority of studies show an interaction between sex hormones and antidepressants on sexual function and behavior, or in depressive symptom alleviation. However, most of the studies omit to investigate antidepressants’ effects on circulating levels of gonadal hormones. From the data reviewed herein, it is evident that most antidepressants can influence testosterone and estrogen levels. Still, the evidence is conflicting with some studies showing an increase, others decrease or no effect. Most studies are conducted in male animals or humans, underscoring the importance of considering sex as an important variable in such investigations, especially as depression and anxiety disorders are more common in women than men. Therefore, research is needed to elucidate the extent to which antidepressants can influence both peripheral and brain levels of testosterone and estrogens, in males and females, and whether this impacts the effectiveness or side effects of antidepressants.
1. Introduction
The pharmacotherapy of mood and anxiety disorders relies heavily on drugs that modulate the monoaminergic neurotransmission (Yohn et al., 2017). Currently, selective serotonin reuptake inhibitors (SSRIs), comprising of citalopram/escitalopram, sertraline, fluoxetine, paroxetine, and fluvoxamine, is the most widely used class of such medications (Pirraglia et al., 2003). Serotonin and Norepinephrine Reuptake Inhibitors (SNRIs), namely venlafaxine and duloxetine, is another widely used category of antidepressants. Their common primary mechanism of action is the inhibition of the presynaptic reuptake of serotonin and/or norepinephrine neurotransmitters (Artigas et al., 2002). The older generation of tricyclic antidepressants (TCAs), i.e., amitriptyline, imipramine, desipramine, nortriptyline, is less frequently used nowadays, as their non-selective blockade was associated with more side-effects (Pacher et al., 2001). Several other compounds, such as agomelatine, bupropion, mirtazapine, and trazodone are considered atypical antidepressants. Atypical antidepressants’ mechanism involves modulation of dopamine neurotransmission, modulation of serotonin and melatonin receptors. Furthermore, recently esketamine was the first licensed antidepressant that acts on the NMDA receptors (Frazer, 1997; Garay et al., 2017).
Strong evidence supports the efficacy and safety of those medications in treating mainly depression and secondary anxiety disorders. However, in neuroscience and neuropsychopharmacology, there is a gradually increasing research interest regarding sex differences in the symptomatology, prevalence, etiology, and treatment of psychiatric disorders. Indeed, sex differences have been described in mood and anxiety disorders, in cognitive processes as well as in physiological and especially neuroendocrine mechanisms that present considerable differences among men and women (Dalla et al., 2010; Kokras and Dalla, 2014, 2017). Nonetheless, the study of both sexes in trials investigating psychiatric drugs is still problematic, potentially leading to inadequate evaluation of sex differences (Kokras et al., 2019). For instance, several studies have described gender differences in men's and women's pharmacokinetic profiles for several antidepressants. In particular, body weight, the volume of blood, enzyme activity, and clearance rates have been identified as potential sources of these differences (Kokras et al., 2011; Sramek et al., 2016).
Moreover, many studies suggest a significant interaction between sex hormones and antidepressants (Damoiseaux et al., 2014; Pawluski et al., 2020; Sramek and Cutler, 2011; Westlund Tam and Parry, 2003; Williams and Trainor, 2018) while focusing only on the aftereffect of antidepressants’ influences on sexual function and behavior. Unfortunately, the exploration of possible antidepressant-related changes in hormonal levels still remains significantly understudied. In particular, most studies focus on the possible synergistic effect of hormones and antidepressants, rather than investigating antidepressants’ effects on circulating levels of male and female hormones, such as testosterone and estrogens.
Therefore, the purpose of this review, following an exhaustive literature search, is to present preclinical and clinical studies that evaluate changes in testosterone and estrogen levels during and/or after acute or chronic administration of different antidepressants. Furthermore, we aim to elucidate the extent to which antidepressants can influence both serum and brain levels of testosterone and estrogens, in both males and females. Prompted by the extended relations between depression and alterations in the hormonal milieu, it is of great importance to determine the effects of antidepressants on testosterone and estrogen levels. Therefore, the aim of this review is to explore the drugs’ mechanisms of action and possibly further elucidate the pathophysiology of depression.
2. Testosterone
Testosterone is one of the major androgens biosynthesized during steroidogenesis from cholesterol (Figure 1) (Hu et al., 2010). Interestingly, some preclinical and clinical studies suggest that antidepressants can affect the hormonal milieu in both sexes, and data are presented herein.
2.1. Citalopram and escitalopram
2.2. Sertraline
2.3. Paroxetine
2.4. Fluoxetine
2.5. Venlafaxine
2.6. Duloxetine
2.7. Amitriptyline
2.8. Imipramine
2.9. Desipramine
2.10. Bupropion
2.11. Trazodone
2.12. Esketamine
3. Estrogens
Estrogen is a major reproductive hormone, responsible mostly for the female reproductive system. Aromatase (CYP19A) is the key enzyme in the estrogens’ biosynthesis, acting via androgens' aromatization. There are three major endogenous estrogens with estrogenic hormonal activity: estrone (E1), estradiol (E2), and estriol (E3) (Figure 1). Both men and women have lower levels of circulating estrogens compared to androgens, and although males have significantly lower levels of estrogens than females, they have important physiological roles in both sexes. Both preclinical and clinical studies have supported estrogens' involvement in the pathogenesis of depression and the augmentation of antidepressants’ effectiveness (Berlanga and Flores-Ramos, 2006; Bryant et al., 2006; Sramek et al., 2016). For instance, regarding the pathogenesis of depression, most prior research has described that estradiol decline is associated with depression and anxiety in postmenopausal women (Bromberger and Epperson, 2018; Freeman et al., 2006; Ryan et al., 2009; Soares et al., 2001)
3.1. Citalopram and escitalopram
3.2. Sertraline
3.3. Fluoxetine
3.4. Fluvoxamine
3.5. Venlafaxine
3.6. Amitriptyline
3.7. Imipramine
3.8. Desipramine
3.9. Agomelatine
3.10. Bupropion
3.11. Esketamine
