David Baxter PhD
Late Founder
HT in Managing Depression in a Patient Using SSRIs
Claudio N. Soares, MD, PhD, FRCPC
12/20/2010
Case:
A 54-year-old woman presents to your office with complaints of depression. She is having minimal vasomotor symptoms since her hysterectomy 1 year ago, and is currently being treated with a selective serotonin reuptake inhibitor (SSRI) for depression by a psychiatrist. She has heard that hormone therapy (HT) may help her depression also and is asking for a prescription today. How would you proceed?
Commentary from Claudio N. Soares, MD, PhD, FRCPC
This case illustrates the worsening of a depressive disorder in the context of the menopause transition or early postmenopausal years. With the accumulating evidence on the interplay between physiological changes, psychological symptoms, and the hormonal milieu that may occur across the female life cycle, there is now little doubt that some women may develop mood symptoms during periods in life that are marked not only by hormonal variations but also by psychosocial stressors and changes in personal, family, and professional roles and responsibilities. These ?windows of vulnerability? represent a particular challenge to clinicians, and the menopause transition is perhaps a paramount example.[1]
The menopause transition is often accompanied by changes in metabolism, sexuality, lifestyle behaviors, and overall health, including greater susceptibility to cardiovascular events, metabolic syndrome, obesity, and hypertension. The occurrence of depression (new onset or recurrent episode) during this transition might constitute a compounded burden of health challenges, and physicians should consider tailoring their treatment strategies accordingly.
HT has long been considered the treatment of choice for menopause-related symptoms, particularly for vasomotor symptoms and sexual dysfunction. Conversely, antidepressants are the treatment of choice for the management of depression across the female life cycle. The menopause transition, however, offers a particular opportunity for the use of estrogen-based therapies for the management of depression?either as a monotherapy or as an add-on strategy in combination with antidepressants.
The effects of sex hormones on the brain areas and circuitry involved in the regulation of mood, behavior, and core body temperature have been well documented. For this particular case, it would be helpful to briefly review how estrogens could affect various mechanisms known to regulate mood and potentially alter response to antidepressants.[2]
Extensive preclinical studies demonstrate that estrogen can, in many ways, modulate molecular pathways involved in monoaminergic neurotransmission (serotonin [5-hydroxy-tryptamine receptors or 5-HT], norepinephrine [NE]); these systems are critical for mood and behavior regulation. Estradiol (E2) administration decreases the activity of monoamine oxidases (MAO-A and MAO-B), which are enzymes involved in 5-HT degradation; E2 also increases both isoforms of tryptophan hydroxylase, the rate-limiting enzyme of serotonin synthesis. Thus, E2 administration results in an overall increase in 5-HT synthesis and availability. E2 also regulates the 5-HT transporter, which plays an integral role in 5-HT reuptake from the synaptic cleft to the pre-synaptic neuron. Furthermore, by downregulating 5-HT1a autoreceptors and upregulating 5-HT2a receptors, E2 increases the amount of serotonin found in the synapse and increases the amount available for postsynaptic transmission. E2 is capable of inducing antidepressant effects in ovariectomized rats when administered in combination with subdoses of fluoxetine, which suggests that E2 can also augment antidepressant agents. In sum, estrogen appears to work via different pathways that ultimately result in increased serotonin production and transmission. Similarly, estrogens increase NE availability by decreasing expression of MAOs and increasing the activity of tyrosine hydroxylase, the rate-limiting enzyme in the synthetic pathway of catecholamine.
Clinically, E2 administration to depressed perimenopausal and early postmenopausal women demonstrated antidepressant effects of similar magnitude to that observed with antidepressant agents. Randomized, double-blind, placebo-controlled studies reported significantly greater reduction in depressive symptoms with the use of transdermal estradiol (17β-estradiol, 50-100 ?g), compared to placebo.[3] In some studies, the antidepressant effects of estrogen were observed even in the absence of concomitant vasomotor symptoms.[4] Notably, studies on E2 therapy for older, postmenopausal women suffering from depression resulted in small, nonsignificant reduction in depressive symptoms. Taken together, these observations suggest that:
Importantly, screening and management of risk factors for stroke should be imperative before considering HT. Moreover, I would particularly advise the use of transdermal estradiol because this route of administration accumulates more efficacy data for mood improvement and appears to have a more promising cardiovascular profile due to its neutral or beneficial effects on triglycerides and C-reactive protein levels and reduced risk for venous thromboembolism.[5]
From the NAMS Menopause e-Consult-newsletter released October 2010. For more, please visit User Log In
References
Claudio N. Soares, MD, PhD, FRCPC
12/20/2010
Case:
A 54-year-old woman presents to your office with complaints of depression. She is having minimal vasomotor symptoms since her hysterectomy 1 year ago, and is currently being treated with a selective serotonin reuptake inhibitor (SSRI) for depression by a psychiatrist. She has heard that hormone therapy (HT) may help her depression also and is asking for a prescription today. How would you proceed?
Commentary from Claudio N. Soares, MD, PhD, FRCPC
This case illustrates the worsening of a depressive disorder in the context of the menopause transition or early postmenopausal years. With the accumulating evidence on the interplay between physiological changes, psychological symptoms, and the hormonal milieu that may occur across the female life cycle, there is now little doubt that some women may develop mood symptoms during periods in life that are marked not only by hormonal variations but also by psychosocial stressors and changes in personal, family, and professional roles and responsibilities. These ?windows of vulnerability? represent a particular challenge to clinicians, and the menopause transition is perhaps a paramount example.[1]
The menopause transition is often accompanied by changes in metabolism, sexuality, lifestyle behaviors, and overall health, including greater susceptibility to cardiovascular events, metabolic syndrome, obesity, and hypertension. The occurrence of depression (new onset or recurrent episode) during this transition might constitute a compounded burden of health challenges, and physicians should consider tailoring their treatment strategies accordingly.
HT has long been considered the treatment of choice for menopause-related symptoms, particularly for vasomotor symptoms and sexual dysfunction. Conversely, antidepressants are the treatment of choice for the management of depression across the female life cycle. The menopause transition, however, offers a particular opportunity for the use of estrogen-based therapies for the management of depression?either as a monotherapy or as an add-on strategy in combination with antidepressants.
The effects of sex hormones on the brain areas and circuitry involved in the regulation of mood, behavior, and core body temperature have been well documented. For this particular case, it would be helpful to briefly review how estrogens could affect various mechanisms known to regulate mood and potentially alter response to antidepressants.[2]
Extensive preclinical studies demonstrate that estrogen can, in many ways, modulate molecular pathways involved in monoaminergic neurotransmission (serotonin [5-hydroxy-tryptamine receptors or 5-HT], norepinephrine [NE]); these systems are critical for mood and behavior regulation. Estradiol (E2) administration decreases the activity of monoamine oxidases (MAO-A and MAO-B), which are enzymes involved in 5-HT degradation; E2 also increases both isoforms of tryptophan hydroxylase, the rate-limiting enzyme of serotonin synthesis. Thus, E2 administration results in an overall increase in 5-HT synthesis and availability. E2 also regulates the 5-HT transporter, which plays an integral role in 5-HT reuptake from the synaptic cleft to the pre-synaptic neuron. Furthermore, by downregulating 5-HT1a autoreceptors and upregulating 5-HT2a receptors, E2 increases the amount of serotonin found in the synapse and increases the amount available for postsynaptic transmission. E2 is capable of inducing antidepressant effects in ovariectomized rats when administered in combination with subdoses of fluoxetine, which suggests that E2 can also augment antidepressant agents. In sum, estrogen appears to work via different pathways that ultimately result in increased serotonin production and transmission. Similarly, estrogens increase NE availability by decreasing expression of MAOs and increasing the activity of tyrosine hydroxylase, the rate-limiting enzyme in the synthetic pathway of catecholamine.
Clinically, E2 administration to depressed perimenopausal and early postmenopausal women demonstrated antidepressant effects of similar magnitude to that observed with antidepressant agents. Randomized, double-blind, placebo-controlled studies reported significantly greater reduction in depressive symptoms with the use of transdermal estradiol (17β-estradiol, 50-100 ?g), compared to placebo.[3] In some studies, the antidepressant effects of estrogen were observed even in the absence of concomitant vasomotor symptoms.[4] Notably, studies on E2 therapy for older, postmenopausal women suffering from depression resulted in small, nonsignificant reduction in depressive symptoms. Taken together, these observations suggest that:
- estrogen?s antidepressant effect may have a ?critical window? or optimal timing, possibly during the menopause transition and early postmenopausal years; and
- the potential benefits of E2 therapy for the improvement of mood symptoms may occur independent from changes or improvement of vasomotor symptoms. In sum, preclinical and clinical evidence suggest that estrogen-based therapies can contribute to greater therapeutic responses and potentially boost the response to traditional antidepressant agents, along with well-established benefits for vasomotor, sexual, and other menopause-related symptoms.
Importantly, screening and management of risk factors for stroke should be imperative before considering HT. Moreover, I would particularly advise the use of transdermal estradiol because this route of administration accumulates more efficacy data for mood improvement and appears to have a more promising cardiovascular profile due to its neutral or beneficial effects on triglycerides and C-reactive protein levels and reduced risk for venous thromboembolism.[5]
From the NAMS Menopause e-Consult-newsletter released October 2010. For more, please visit User Log In
References
- Soares CN, Maki PM. Menopausal transition, mood, and cognition: an integrated view to close the gaps. Menopause 2010;17:812-814.
- Lokuge S, Frey BN, Foster JA, et al. The rapid effects of estrogen: a mini-review. Behav Pharmacol 2010; 21:465-472.
- Soares CN, Almeida OP, Joffe H, et al. Efficacy of estradiol for the treatment of depressive disorders in perimenopausal women: a double-blind, randomized, placebo-controlled trial. Arch Gen Psychiatry 2001;58:529-534.
- Schmidt PJ, Nieman L, Danaceau MA, et al. Estrogen replacement in perimenopause-related depression: a preliminary report. Am J Obstet Gynecol 2000;183:414-420.
- Kopper NW, Gudeman J, Thompson DJ. Transdermal hormone therapy in postmenopausal women: a review of metabolic effects and drug delivery technologies. Drug Des Devel Ther 2009;2:193-202.
