Tailoring Treatment of Depression for Women Across the

Tailoring Treatment of Depression for Women Across the Reproductive Lifecycle: The Importance of Pregnancy, Vasomotor Symptoms, and Other Estrogen-Related

Events in PsychopharmacologyBy Dana D. Wise, PhD, Angela Felker, MA, and Stephen M. Stahl, MD, PhD

CNS Spectr 13:8 August 2008647CNS Spectr 13:8 August 2008647

NEW TREND IN PSYCHOPHARMACOLOGY

Compared with men, women are at increased

risk of depression, especially at several repro-

ductive-related lifecycle points. This may be

partially due to changing levels of estrogen, a

hormone that can affect levels of neurotransmit-

ters and neural proteins. As estrogen levels vary

throughout the lifespan, risk of depression in

women also varies, and not all treatments are

appropriate or effective at all times. In adoles-

cence, onset of depression may be associated

with onset of puberty, but treating underage

girls with antidepressants can risk suicidality. In

females of childbearing age, mood disturbances

associated with menstrual cycles signal a risk

for later full-blown major depressive disorder.

In depressed pregnant and postpartum women,

risks of treatment versus risks of nontreatment

are intricate and require case-by-case evalua-

tion. In perimenopause, vasomotor symptoms

may be harbingers of oncoming depression and

also may signal the presence of dysregulated

hormones and neurotransmitters. Relieving

vasomotor symptoms may be a necessary

dimension of treating depression. In postmeno-

pause, response to selected antidepressants

may depend on whether the patient is also tak-

ing hormone-replacement therapy. To attain opti-

mal outcomes, modern psychopharmacologists

must tailor treatment of depression to a wom-

an’s reproductive stage of life.

TRIMONOAMINE MODULATORS AND DEPRESSION

Clinicians often target the three neurotrans-mitters most implicated in depression—sero-tonin (5-HT), norepinephrine (NE), and dopamine (DA)—by using antidepressants to block reup-take at the respective neurotransmitter reup-take transporters.1 However, other agents can modulate all three neurotransmitters without

Dr. Wise is a senior medical writer at Arbor Scientia in Carlsbad, California. Ms. Felker is an associate medical writer at the Neuroscience Education Institute in Carlsbad. Dr. Stahl is adjunct professor of psychiatry in the Department of Psychiatry at the University of California–San Dr. Wise is a senior medical writer at Arbor Scientia in Carlsbad, California. Ms. Felker is an associate medical writer at the Neuroscience Education Institute in Carlsbad. Dr. Stahl is adjunct professor of psychiatry in the Department of Psychiatry at the University of California–San Dr. Wise is a senior medical writer at Arbor Scientia in Carlsbad, California. Ms. Felker is an associate medical writer at the Neuroscience

Diego in La Jolla. Education Institute in Carlsbad. Dr. Stahl is adjunct professor of psychiatry in the Department of Psychiatry at the University of California–San Diego in La Jolla. Education Institute in Carlsbad. Dr. Stahl is adjunct professor of psychiatry in the Department of Psychiatry at the University of California–San

Faculty Disclosures: Dr. Wise has written promotional materials for GlaxoSmithKline, Novartis, Organon, Pfizer, and Wyeth. Ms. Felker does not have an affiliation with or financial interest in any organization that might pose a conflict of interest. Dr. Stahl receives grant/research Faculty Disclosures: Dr. Wise has written promotional materials for GlaxoSmithKline, Novartis, Organon, Pfizer, and Wyeth. Ms. Felker does not have an affiliation with or financial interest in any organization that might pose a conflict of interest. Dr. Stahl receives grant/research Faculty Disclosures: Dr. Wise has written promotional materials for GlaxoSmithKline, Novartis, Organon, Pfizer, and Wyeth. Ms. Felker does

support from AstraZeneca, Biovail, Bristol-Myers Squibb, Cephalon, Cyberonics, Eli Lilly, Forest, GlaxoSmithKline, Janssen, Neurocrine not have an affiliation with or financial interest in any organization that might pose a conflict of interest. Dr. Stahl receives grant/research support from AstraZeneca, Biovail, Bristol-Myers Squibb, Cephalon, Cyberonics, Eli Lilly, Forest, GlaxoSmithKline, Janssen, Neurocrine not have an affiliation with or financial interest in any organization that might pose a conflict of interest. Dr. Stahl receives grant/research

Biosciences, Organon, Pfizer, Sepracor, Shire, Somaxon, and Wyeth; is a consultant to Acadia, Amylin, Asahi, AstraZeneca, Biolaunch, support from AstraZeneca, Biovail, Bristol-Myers Squibb, Cephalon, Cyberonics, Eli Lilly, Forest, GlaxoSmithKline, Janssen, Neurocrine Biosciences, Organon, Pfizer, Sepracor, Shire, Somaxon, and Wyeth; is a consultant to Acadia, Amylin, Asahi, AstraZeneca, Biolaunch, support from AstraZeneca, Biovail, Bristol-Myers Squibb, Cephalon, Cyberonics, Eli Lilly, Forest, GlaxoSmithKline, Janssen, Neurocrine

Biovail, Boehringer-Ingelheim, Bristol-Myers Squibb, Cephalon, CSC Pharma, Cyberonics, Cypress Bioscience, Eli Lilly, Epix, Fabre Kramer, Biosciences, Organon, Pfizer, Sepracor, Shire, Somaxon, and Wyeth; is a consultant to Acadia, Amylin, Asahi, AstraZeneca, Biolaunch, Biovail, Boehringer-Ingelheim, Bristol-Myers Squibb, Cephalon, CSC Pharma, Cyberonics, Cypress Bioscience, Eli Lilly, Epix, Fabre Kramer, Biosciences, Organon, Pfizer, Sepracor, Shire, Somaxon, and Wyeth; is a consultant to Acadia, Amylin, Asahi, AstraZeneca, Biolaunch,

Forest, GlaxoSmithKline, Jazz, Neurocrine Biosciences, NeuroMolecular, Neuronetics, Nova Del Pharma, Novartis, Organon, Otsuka, Biovail, Boehringer-Ingelheim, Bristol-Myers Squibb, Cephalon, CSC Pharma, Cyberonics, Cypress Bioscience, Eli Lilly, Epix, Fabre Kramer, Forest, GlaxoSmithKline, Jazz, Neurocrine Biosciences, NeuroMolecular, Neuronetics, Nova Del Pharma, Novartis, Organon, Otsuka, Biovail, Boehringer-Ingelheim, Bristol-Myers Squibb, Cephalon, CSC Pharma, Cyberonics, Cypress Bioscience, Eli Lilly, Epix, Fabre Kramer,

PamLab, Pfizer, Pierre Fabre, Sanofi-Synthelabo, Schering-Plough, Sepracor, Shire, Solvay, Somaxon, Takeda, Tetragenex, and Wyeth; and Forest, GlaxoSmithKline, Jazz, Neurocrine Biosciences, NeuroMolecular, Neuronetics, Nova Del Pharma, Novartis, Organon, Otsuka, PamLab, Pfizer, Pierre Fabre, Sanofi-Synthelabo, Schering-Plough, Sepracor, Shire, Solvay, Somaxon, Takeda, Tetragenex, and Wyeth; and Forest, GlaxoSmithKline, Jazz, Neurocrine Biosciences, NeuroMolecular, Neuronetics, Nova Del Pharma, Novartis, Organon, Otsuka,

is on the speaker’s bureau of Pfizer. PamLab, Pfizer, Pierre Fabre, Sanofi-Synthelabo, Schering-Plough, Sepracor, Shire, Solvay, Somaxon, Takeda, Tetragenex, and Wyeth; and is on the speaker’s bureau of Pfizer. PamLab, Pfizer, Pierre Fabre, Sanofi-Synthelabo, Schering-Plough, Sepracor, Shire, Solvay, Somaxon, Takeda, Tetragenex, and Wyeth; and

If you would like to comment on this column or submit a suggestion to Dr. Stahl for future columns, please e-mail [email protected].

Trends in Psychopharmacology


inhibiting their monoamine transporters. These “trimonoamine modulators”—such as thyroid hormone, lithium, L-methylfolate, and even psy-chotherapy—may be best utilized in combina-tion with a monoamine reuptake inhibitor, rather than as a monotherapy.1,2 These trimonoamine modulators theoretically work by boosting >1 of the monoamines, which may be useful in aug-menting the treatment of depressive episodes in patients who fail to remit with traditional antide-pressants.1 Another trimonoamine modulator—perhaps not always given proper consideration in psychopharmacology—is estrogen. This hor-mone, whether endogenous or exogenous, can affect the incidence and treatment of depression across a woman’s lifecycle.3-7

INCIDENCE OF DEPRESSION IN MEN AND WOMEN

Mood-altering hormones, such as estrogen and testosterone, can be found in men and women. However, women experience dramatic fluctuations in estrogen levels across their life-time, which mirror an incidence of depression that is higher than in men (Figure 1), who do not experience similar fluctuations in testoster-one (Figure 2). The risk of depression across the male lifespan rises in puberty and remains fairly constant throughout life, regardless of slowly declining levels of testosterone from 25 years of age forward (Figure 2). However, according to a study of 3,987 elderly men (71–89 years of age),8

those with levels of testosterone much lower than average (ie, those in the lowest quintile) are at a risk for depression nearly three times greater than men with higher levels of testosterone.

In contrast, the risk of depression in women is 2–3 times higher than in men during childbear-ing years; this may be due in part to fluctuat-ing levels of estrogen. The National Comorbidity Survey of 8,098 United States residents showed that women are ~1.7 times more likely than men to report a history of a major depressive epi-sode.9 The difference in prevalence between gen-ders begins in early adolescence and persists until women are in their mid-50s.9 Another study of 9,792 British adults10 found that, from 16–54 years of age, depression was twice as likely in women than in men, but depression in post-menopause-aged females (55–64 years) returned to levels similar to males of the same age.

A more recent population-based study (N=3,481)11 demonstrated that women not only

showed higher risk for onset of depression, but also experienced episodes that were ~20 weeks longer in duration and exhibited a nonsignificant tendency for higher risk of recurrence. Within this general lifetime trend, women also are at higher risk for depression at specific points in their life when reproductive hormones fluctu-ate: in puberty, when estrogen is first rising; in the premenstrual phase; in pregnancy or the postpartum period12; in association with infertil-ity, miscarriage, or perinatal loss; and/or in the perimenopausal period (Figure 3).3,13-15 Thus, men and women are only “equal” for risk of expe-riencing depressive episodes prior to puberty and in older age after women have experienced menopause.

ESTROGEN MODULATES NEUROTROPHIC FACTORS, MONOAMINES, GLUCOSE USAGE, AND NEURAL STRUCTUREUSAGE, AND NEURAL STRUCTURE

Action via the Nuclear Estrogen ReceptorIncidence reports are not the only data support-

ing a role for estrogen in depression; basic sci-ence also suggests a relationship.6 When estrogen binds to and activates its nuclear receptors, it regu-lates gene products such as brain-derived neuro-trophic factor,16,17 neurotransmitter-synthesizing enzymes, neurotransmitter-metabolizing enzymes,


FIGURE 1.Incidence of depression in women across the lifecycle*

* As estrogen levels rise, so does the risk of depression. When estrogen levels fall in conjunction with menopause, the risk of depression is also reduced. During childbearing years, the risk of depression is 2–3 times higher than in men of the same age.3

Stahl SM. Sex-specific and sexual function-related psychopharmacol-ogy. In: Essential Psychopharmacology. 2nd ed. New York, NY: Cambridge Essential Psychopharmacology. 2nd ed. New York, NY: Cambridge Essential PsychopharmacologyUniversity Press; 2000:539-568.

Wise DD, Felker A, Stahl SM. CNS Spectr. Vol 13, No 8. 2008.CNS Spectr. Vol 13, No 8. 2008.CNS Spectr

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and neurotransmitter receptors. Estrogen must penetrate both the neuronal membrane and the nuclear membrane to reach its receptors, which are located near the genes influenced by estro-gen (Figure 4A). Activation of these genes, termed estrogen response elements (Figure 4B), requires receptor dimerization (ie, coupling of two copies of the estrogen receptor) upon estrogen binding to produce an active transcription factor that is able to cause expression of estrogen response elements.3

Once estrogen receptors are activated as transcrip-tion factors, they bind to estrogen response ele-ments in the cell’s DNA and thus activate gene expression (Figure 4C).3

Estrogen theoretically exerts some of its mood-altering effects through estrogen recep-tors distributed in brain regions associated with symptoms of major depressive disorder (MDD). For example, the human brain contains estrogen receptors in the hippocampus and cerebral cortex, areas of the brain associated with the symptoms of depressed mood and cognitive dysfunction in MDD.18-20 In these brain regions, estrogen affects cellular spine density and related cognitive abili-ties.21 The human amygdala is especially rich in estrogen receptors.21 Anxiety is associated with the amygdala in humans22 and is a frequent symptom of MDD.23 Administration of estrogen to the amygdala of ovariectomized rats decreases anxious behaviors.22

Estrogen’s Trophic Properties Across the Menstrual Cycle

Evidence of estrogen’s trophic properties can be seen in hypothalamic and hippocampal neurons in adult female animals across a single menstrual cycle.24,25 Early in the menstrual cycle, estradiol levels rise, causing dendritic spines to form on pyramidal neurons and in the ventrome-dial hypothalamus, which is observable in adult female rats. This spine formation is at its height when both estrogen and progesterone peak, just after the first half of the cycle. Once estro-gen begins to fall and progesterone continues to rise, downregulation of these spines is triggered (Figure 5).3 The mechanism of this cyclical forma-tion and subsequent loss of dendritic spines is shown in Figure 6.1 As a possible behavioral cor-relate of this biological cycle, along with fewer spines and falling estrogen levels, mood also can slip downward—in extreme cases, manifesting as premenstrual dysphoric disorder (PMDD).

Estrogen and SerotoninEstrogen exerts generally positive effects on

serotonergic raphe neurons and on their corti-cal postsynaptic targets (Figure 7).4,6 In ovariec-tomized animals, estrogen treatment increases protein levels of tryptophan hydroxylase, the key synthetic enzyme for 5-HT,26 and also increases the 5-HT content in raphe neurons.27 Normally, 5-HT1A autoreceptors in the raphe exert negative

FIGURE 2.Men’s risk of depression increases dur-ing puberty. Then it gradually decreas-es over the lifespan, regardless of the declining level of testosterone begin-ning at 25 years age3



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FIGURE 3.The risk of depressive symptoms in women is affected by several occur-rences: puberty, menstrual cycles, post-partum period, and perimenopause*

* Puberty may be associated with first episodes of depression in women, whereas the greatest risk of depression may occur during postpartum period and perimenopause.3

PMS=premenstrual syndrome; ERT=estrogen-replacement therapy.



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feedback on the firing activity of 5-HT neurons. In rats, withdrawing estrogen (ovariectomy) upregu-lated these inhibitory 5-HT1A autoreceptors, while replacing estrogen downregulated them.28 The

expected functional outcome of this has also been observed: estrogen treatment increases the firing rate of rat raphe neurons.29 In humans, radiolabel neuroimaging showed that 10 weeks of estrogen treatment increased 5-HT2A receptors in the right prefrontal cortex of postmenopausal women and also improved verbal fluency and cognition.30

Estrogen and NorepinephrineEstrogen positively modulates the NE net-

work and its hypothalamic targets.4,6 In the locus coeruleus of female monkeys, an estrogen infu-sion increased the expression of messenger ribonucleic acid for tyrosine hydroxylase (the key synthetic enzyme for NE) and also caused dramatic release of NE into the hypothalamus.31

Hypothalamic NE is related to ingestive behav-ior32 and may therefore be related to the change of appetite in depressed patients. Activation

FIGURE 5.In the early phase of the menstrual cycle, estradiol levels rise, inducing dendritic spine formation and synaptogenesis*

* Spine formation is greatest just after the first half of the menstrual cycle, when estrogen is at its highest and progesterone peaks as well. After this point, estrogen levels begin to fall while progesterone continues to rise. This leads to a downregulation of dendritic spines and removal of formed synapses by the end of the cycle.3



loidartsE

Progesterone

enomroh gnizinietuL

Follicle stimulating hormone

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FIGURE 4.(A) Estrogen binds to estrogen receptors, modulating gene expression. Unlike neu-rotransmitter receptors, estrogen recep-tors are located in the neuronal cell nucle-us. Thus, the receptor is near the gene. (B) Estradiol activation of genes requires dimerization to initiate transcription. (C) Gene products expressed by this process include monoamine-regulating proteins and brain-derived neurotrophic factor3

E2=estradiol.



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of hypothalamic α1 receptors in rats is associ-ated with sexual receptivity33 and sleep.34 This is especially of interest because the hypothala-mus of depressed patients is implicated in their loss of sexual interest and sleeping problems.35

Moreover, administering estrogen to ovariecto-mized rats increased hypothalamic α1B norad-renergic receptors.

Estrogen and DopamineAnimal studies have demonstrated that DA

release and reuptake in the nucleus accumbens fluctuates over the estrous cycle; as estrogen levels peak, DA release also is increased, indi-cating a possible role for estrogen in facilitating DA release.36 Falling DA levels in the nucleus accumbens, a key pleasure-related area of the brain, are implicated in the loss of interest or

pleasure experienced by depressed patients.35

Moreover, estrogen can act like a reuptake inhibitor at the DA transporter37 in a manner similar to certain antidepressants.

Estrogen and Cellular Glucose Use Beyond the aforementioned specific changes

to the brain regions, estrogen also affects the glucose metabolism of nearly the entire brain. In animals, estrogen treatment increases glucose uptake and utilization in 42 out of 60 anatomically discrete brain regions within 2 hours.38 One way that estrogen exerts this effect is through the glu-cose transporter; estrogen increases expression of this transporter at the blood-brain barrier and on the membranes of neurons.39,40 Thus, estro-gen helps the brain to access and use glucose, enabling the brain to acquire energy.

TREATING DEPRESSION IN WOMEN ACROSS THE REPRODUCTIVE LIFECYCLE

It can be difficult to treat depressed females during adolescence, childbearing years, preg-nancy, breast-feeding and the postpartum period, perimenopause, and menopause (Figure 8). A psychopharmacologist must weigh the risks and benefits of using antidepressants to treat a depressive episode during these stages versus the alternative: no treatment and poten-tial increase in symptomatology.1,3 Each of the stages summarized in Figure 8 is examined in the sections that follow.

Treating Adolescent Onset of DepressionThe first episodes of depression experienced

by some females can coincide with puberty, though these episodes are often unrecognized and/or untreated by clinicians. Treatment with antidepressants in adolescents has become increasingly difficult due to the heightened awareness of suicidality risk with antidepres-sants in those <25 years of age. Furthermore, documented efficacy of many antidepressants in adolescents <18 years of age is lacking. Antidepressants are generally not approved for use in girls <18 years of age and may be less than ideal when considering a benefit-to-risk ratio up to 25 years of age.1,3 The American Academy of Child and Adolescent Psychiatry41

recommends psychotherapy as the first line of treatment for adolescent depression and recom-mends reserving antidepressants for those with

FIGURE 6.Estrogen regulates spine formation in a cyclical pattern*

* Initially, GABA inhibits pyramidal neurons, which are thus inactive. As the cycle continues, estrogen reduces GABA inhibition, leading to disinhibition of pyramidal neurons and a release of Glu. Glu acts on N-methyl-N-methyl-N D-aspar-tate receptors that, when in a sustained-activation state, cause changes in the postsynaptic neuron, including formation of dendritic spines. As the cycle ends, estrogen levels fall, Glu neurons become inactive, and spine formation is downregulated.1

GABA=γ-aminobutyric acid; Glu=glutamate.



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severe depression. In such cases, fluoxetine is the only antidepressant with documented effi-cacy and Food and Drug Administration approval for use in adolescents; its use should be coupled with careful monitoring and psychotherapy.41

Treating Premenstrual Dysphoric Disorder During the Fertile Years

Once women experience the onset of men-struation, some may be susceptible to PMDD.1,3

This disorder manifests primarily as irritability (or depressed mood, anxiety, or mood swings) during the late luteal phase just prior to menstrual flow and can potentially be incapacitating. Additionally, this end-of-cycle worsening of symptoms may actually be unmasking an underlying mood disor-der that may be present the entire cycle but only

becomes more obvious during “menstrual mag-nification.” Women who experience PMDD and/or menstrual magnification may be at increased risk for future onset of full-blown MDD14; therefore, symptomatic and preventive treatment are impor-tant. Two pharmacologic options have demon-strated efficacy for PMDD and are approved by the FDA: selective serotonin reuptake inhibitors (SSRIs), three of which are approved for PMDD, or a low-dose oral contraceptive pill containing estrogen and progestin.42 Due to the unique patho-physiology of the disorder, SSRIs can be effec-tively administered intermittently, with dosing limited to the luteal phase of the cycle (2 weeks prior to menses).42 Dopaminergic or noradrener-gic agents have not shown efficacy against PMDD, but GABAergic treatments, such as benzodiaz-epines, may be efficacious for PMDD.42

Treating Depression During PregnancyPregnant women requiring treatment for

depression pose a unique situation: the ben-efit-to-risk ratio must include consideration of the fetus (Table). Some antidepressants may be harmful to the fetus, especially when adminis-tered during the first trimester, whereas others may be more harmful if taken during the third trimester. Risks to the fetus include prematurity, low birth weight, long-term neurodevelopmental

FIGURE 7.Estrogen exerts generally positive effects on serotonergic raphe neurons and on their cortical postsynaptic targets*

* TpH is the key synthetic enzyme for 5-HT.

TpH=tryptophan hydroxylase; 5-HT=serotonin.


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FIGURE 8.Over the course of the female lifespan, appropriate pharmacotherapy use, including antidepressants and/or estro-gen, may vary by age or by reproduc-tive status3

E2=estradiol; SNRI=serotonin-norepinephrine reuptake inhibitor; ERT=estrogen-replacement therapy.



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abnormalities, and fetal withdrawal symptoms after birth. However, lack of treatment to the mother is not without its own risks—untreated depression may result in poor self-care, potential self-harm, or progressive worsening of symp-toms.1,3 In women with a history of depression, those who discontinue antidepressant treatment during pregnancy are at much higher risk for relapse than those who continue medication.43

In mild cases, psychotherapy may be sufficient; in severe depression, the benefits of treating the

mother may outweigh the risks. Women of child-bearing age should be educated on the risks of becoming pregnant while on an antidepressant and can be given the option of contraception during this time if so desired.

Treating Depression During the Postpartum Period

During pregnancy, estrogen levels skyrocket to much higher levels than even the peak of the cycle of estrogen in nonpregnant women of child-bearing age; after parturition, estrogen levels dra-matically plummet, which is considered a risk factor in the development of postpartum depres-sion.49 Regular hormonal cycles do not resume until after a woman stops nursing. Approximately 90% of postpartum depression episodes occur within the first 4 weeks after delivery.1 Women with any history of depression are twice as likely as never-depressed women to experience post-partum depression.12 Women with a history of postpartum depression have a 63% risk of recur-rence, whereas only one tenth of that risk exists if such patients take antidepressants.50

Treating depression during this postpartum period, when the mother may be breast-feeding the infant, may also be difficult and is considered high-risk. Nursing women who take antidepres-sants can pass some of the drug to the infant via breast milk. Thus, the key question for this particu-lar subgroup is not whether to treat, but whether to breast-feed. Estrogen, fluoxetine, sertraline, and venlafaxine supplementation all have been found effective against postpartum depression, and thy-roid levels also should be checked to see whether that system, which is susceptible to changes in pregnancy, needs treatment.49 The relative hyper-coagulative state of pregnant women may com-plicate treatment with estrogen in the immediate postpartum period, especially for women with thrombotic risks.50 For women who choose to remain medication-free, preferring the ability to breast-feed, psychotherapy in the postpartum period also has efficacy against depression.50

TREATING DEPRESSION IN WOMEN AFTER THE REPRODUCTIVE LIFECYCLE

Perimenopause, Vasomotor Symptoms, and Perimenopausal Depression

Perimenopause can be a time of chaotic change

TABLE.The Risks of Treating — and Not Treating — Pregnant Women*

Risks of Treatment

Risks to fetus/infant• Congenital cardiac malformations (first trimester;

paroxetine, modest risk)44

• Neural tube defects (first trimester; SSRIs, modest risk)45

• Newborn persistent pulmonary hypertension (third trimester; SSRIs, moderate risk)45

• Neonatal withdrawal syndrome (third trimester; SSRIs, especially paroxetine)46

• Prematurity, low birth weight47

• Long-term neurodevelopmental abnormalities

Risks to mother• Increased suicidality due to antidepressant use (up to

25 years of age)

Risks to physician• Medical-legal risks of prescribing antidepressants

Risks of No Treatment

Risks to fetus/infant48Risks to fetus/infant48Risks to fetus/infant• Poor prenatal care (due to unmotivated mother)• Disrupted mother-infant bonding• Low birth weight, developmental delay in children of

women with untreated depression• Harm to, or neglect of, infant (by depressed mother)

Risks to mother48Risks to mother48Risks to mother• Relapse of major depression43

• Increased suicidality due to abstinence from antidepressants

• Poor self-care• Self-harm

Risks to physician• Medical-legal risks of not prescribing antidepressants

* Use of antidepressants must be weighed according to benefit-to-risk ratio of harm to the mother and fetus on a per-case basis3

SSRIs=selective serotonin reuptake inhibitors.






for a woman’s body and mind. Some changes are easily observed, starting around 47 years of age51: first a woman’s period changes in length, and then whole cycles are skipped.52 Vasomotor symptoms, such as hot flashes and night sweats, mark these transitional years, particularly late peri-menopause and early postmenopause.52 Around 51 years of age, a woman’s final menstrual period occurs, although she cannot know it was her last until 1 year after the fact.51 The duration of each stage and age during occurrence are different for each woman. Whenever they occur, however, the hormonal fluctuations driving these physiologi-cal changes can put a woman at risk for depres-sion. Some women are at greater risk than others, including midlife women with a history of depres-sion, postpartum depression, or premenstrual syn-drome.14 However, even a woman with no history of depression is almost twice as likely to experi-ence an onset of MDD when she enters perimeno-pause than women of the same age who remain premenopausal.13 Diagnosis of perimenopausal MDD can be complicated due to the high degree of symptom overlap between perimenopause and depression (Figure 9).1

Vasomotor symptoms and depression are linked neurobiologically and clinically. Clinically, perimenopausal women with vasomotor symp-toms are four times more likely to be depressed than perimenopausal women without vasomo-tor symptoms.53 The elevated risk seems to sub-

side in postmenopause, when estrogen levels are low54,55 and when vasomotor symptoms also subside.52 This agrees with observations that risk for depression and for vasomotor symp-toms correlate with hormonal fluctuations, not absolute levels.15,52 Neurobiologically, both vaso-motor symptoms and depression are regulated

FIGURE 9.The symptoms of depression and peri-menopause often overlap due to simi-lar neurobiological links between these two conditions1

Stahl SM. Antidepressants. In: Stahl’s Essential Psychopharmacology. 3rd Stahl’s Essential Psychopharmacology. 3rd Stahl’s Essential Psychopharmacologyed. New York, NY: Cambridge University Press; 2008:511-666.


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FIGURE 10.Fluctuating levels of estrogen can lead to dysregulation of monoamines, lead-ing to depressive symptoms via mood circuits (upper figure) and vasomo-tor symptoms via hypothalamic circuits (lower figure)1

NE=norepinephrine; 5-HT=serotonin; VMPFC=ventromedial prefrontal cor-tex; DA=dopamine.



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(partially) by monoamine neurotransmitters. Thus, dysregulation of the monoaminergic neu-rotransmitter systems can lead to depression when the dysregulation occurs within mood-related circuits and can lead to vasomotor symp-toms when the dysregulation occurs within the hypothalamic thermoregulatory centers (Figure 10).1 Vasomotor symptoms are mediated via hypothalamic thermoregulatory centers, which are the homeostatic control sites for regulating internal core body temperature and integrating peripheral signals with vascular and neurochem-ical signals.56 Two key thermoregulatory signals are noradrenergic and serotonergic input to the hypothalamus; in monkeys, injecting 5-HT into the hypothalamus causes core body temperature to rise, and injecting NE into the hypothalamus causes internal body temperature to fall.57 Since estrogen fluctuations can cause dysregulation of both noradrenergic and serotonergic circuits, it

is not surprising that estrogen fluctuations could lead to both vasomotor symptoms and depres-sion, with substantial overlap in presentation.

Due to the association of vasomotor symp-toms with the onset or recurrence of a major depressive episode, experts now debate whether prescribers should identify and treat vasomo-tor symptoms as well as the traditional symp-toms of depression in perimenopausal women. Actually, the treatments for these two conditions overlap. Treating vasomotor symptoms could theoretically prevent a major depressive episode in vulnerable women. Furthermore, failure to treat vasomotor symptoms in a perimenopausal woman who also has a major depressive epi-sode may stand in the way of full remission of the major depressive episode or of sustaining


FIGURE 11.Irregular fluctuation of estrogen levels can interact with monoaminergic neu-rotransmitter projections to the hypo-thalamus, which can lead to the experi-ence of vasomotor symptoms*

* Administering estrogen can alleviate these vasomotor symptoms.1

E2=estradiol.



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FIGURE 12.Fluctuating levels of estrogen contrib-ute to dysregulation of monoaminer-gic neurotransmitters circuits mediating depressive symptoms, contributing to the potential development of a major depressive episode*

* In some cases, estrogen may be able to relieve depressive symptoms.1

NE=norepinephrine; VMPFC=ventromedial prefrontal cortex; 5-HT=serotonin; DA=dopamine.



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(continued on page 658)


that remission in the long run. That is, remission of the classic symptoms of depression while vasomotor symptoms persist is a likely signal that fluctuating estrogen levels are still affecting the brain and may continue to create vulnerabil-ity for relapse. Ongoing research seeks to deter-mine whether targeting vasomotor symptoms in women with depression or who are at risk for depression will achieve better outcomes.

Estrogen Treatment for Perimenopausal Depression and Vasomotor Symptoms

Vasomotor symptoms are the clinical indi-cation that estrogen levels are fluctuating irregularly and are increasingly recognized as the harbinger of onset or relapse of major depression during perimenopause. Fluctuating estrogen levels can theoretically create mono-aminergic dysfunction in the brain; when this dysregulation of monoaminergic control occurs in the hypothalamic thermoregulatory centers,

vasomotor symptoms could occur (Figure 11). In patients whose fluctuating estrogen levels are causing vasomotor symptoms via dysregula-tion of (>1) monoaminergic hypothalamic ther-moregulatory center(s), estrogen may restore monoamine function and thereby relieve vaso-motor symptoms (Figure 11). However, many women are not willing to take estrogen for vasomotor symptoms, and most prescribers are not willing to treat long-term with estrogen due to concerns over health risks. This has cre-ated the need for a nonhormonal treatment for vasomotor symptoms.

Because estrogen-replacement therapy is the recognized treatment option for vasomo-tor symptoms of perimenopause, estrogen may seem a natural therapeutic choice for perimeno-pausal depression as well (Figure 12).5 However, no type of hormonal therapy is yet approved for


FIGURE 13.Treatment of vasomotor symptoms with SSRIs has provided inconsistent results as to their efficacy in improving vaso-motor symptoms1

SSRIs=selective serotonin reuptake inhibitors.



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FIGURE 14.Treating vasomotor symptoms with an SNRI may be more efficacious than other forms of treatment*

* It is possible that actions on both serotonergic and noradrenergic systems are required to achieve hypothalamic thermoregulator control, necessitat-ing an SNRI or an SSRI with some noradrenergic activity (paroxetine).1

SNRI=serotonin-norepinephrine reuptake inhibitor; SSRI=selective sero-tonin reuptake inhibitors.



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(continued from page 655)


the treatment of perimenopausal depression, and the multitude of available formulations has long obscured any clear results, even in experi-mental literature. Low dosages (oral estrogen/progestin, 5 µg/1 mg/day, a formulation com-monly given for the alleviation of vasomotor symptoms) are insufficient against perimeno-pausal depression.58 A high dosage of transder-mal estradiol (100 µg/day) is effective against MDD in perimenopausal women59 but not in postmenopausal women.60 Add to this confu-sion the constantly changing and controversial reports about risk-benefit ratios of estrogen ther-apy, and a physician is left with an unapproved and uncertain therapy as well as possibly an unwilling patient.

Antidepressant Treatment for Perimenopausal Depression and Vasomotor Symptoms

SSRIs show inconsistent benefit for relief of vasomotor symptoms (Figure 13),56 although there are some positive results reported for par-oxetine,56 a compound that may, in fact, have some noradrenergic activity, making it a weak serotonin-norepinephrine reuptake inhibitor (SNRI). In contrast, full-fledged SNRIs may show a clearer benefit for relief of vasomotor symp-toms (Figure 14),61-64 although such agents are not approved for this use. Under investigation is whether SNRIs have the same effect size as estrogen and whether the benefits versus the risks of SNRIs justify their use in treating vaso-motor symptoms in perimenopausal women.

SSRIs have long been the first-line therapy for treatment of depression, and in young women,


FIGURE 15.Treating depressive symptoms with SSRIs is generally considered effica-cious, but results may differ when treat-ing postmenopausal women not taking estrogen-replacement therapy*

* It is suggested that the presence of estrogen may boost the efficacy of SSRIs and the absence of estrogen may reduce the efficacy of SSRIs in some women.1

SSRIs=selective serotonin reuptake inhibitors; NE=norepinephrine; VMPFC=ventromedial prefrontal cortex; 5-HT=serotonin; DA=dopamine.



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FIGURE 16.SNRIs appear to be efficacious in treat-ing depressive symptoms in women, irrespective of the presence of estrogen*

* The actions on both serotonergic and noradrenergic systems may be responsible for the ability of SNRIs to sustain efficacy even when estrogen levels are low.1

SNRIs=serotonin-norepinephrine reuptake inhibitors; NE=norepinephrine; VMPFC=ventromedial prefrontal cortex; 5-HT=serotonin; DA=dopamine.



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SSRIs may often be a good choice. In women less than ~40 years of age, depression is more responsive to SSRIs than to a tricyclic antide-pressant65 or to a norepinephrine reuptake inhib-itor.66 However, this advantage of SSRIs never exists in men of any age and is lost in women past ~44 years of age,65,66 which suggests the mode of action of SSRIs may benefit from the presence of estrogen (Figure 15). In contrast, SNRIs seem to be more efficacious for the treat-ment of depression across all ages and genders, including perimenopausal women, and also offer the aforementioned efficacy against vaso-motor symptoms (Figure 16). Venlafaxine, an SNRI, was more effective than SSRIs (fluoxetine, fluvoxamine, and paroxetine) against depres-sion in women both younger and older than 50 years of age.67 Similarly, duloxetine demon-strated consistent efficacy for depressed women in all age groups (<40, 40–55, and >55 years of age).68 Desvenlafaxine, a new SNRI, is approved for the treatment of depression and has been well studied but not yet approved for vasomotor symptoms.61,63 When tested specifically in peri-menopausal and postmenopausal women, these three SNRIs not only improved mood, but also relieved vasomotor symptoms.61-64 Since vaso-motor symptoms are a risk factor for (or marker of) perimenopausal depression, it is perhaps unsurprising that drugs effective against this particular kind of depression are also effective against vasomotor symptoms.

Treating Depression in Postmenopausal Women

Menopause is the final stage in the female lifecycle and can involve estrogen deficiency or, in some women, use of estrogen-replace-ment therapy. During this stage, the risk for depression is lower than during perimenopause. Although estrogen no longer fluctuates, vaso-motor symptoms are often still experienced. These vasomotor symptoms may arise from insufficient numbers of brain glucose transport-ers due to the lack of estrogen to induce their expression. The resultant inefficient transport of glucose to the brain would be detected by hypothalamic centers, which would react by trig-gering a noradrenergic and vasomotor response to increase blood flow to the brain and to gener-ate a compensatory increase in brain glucose transport.69 In women with diabetes and pre-diabetes, this situation could be exacerbated.69

Because SSRIs may work better in the presence of estrogen, which is diminished in menopause, SSRIs may not be as effective in postmeno-pausal women. However, SSRIs may be more effective in patients taking estrogen-replacement therapy than in those who are not.67,70 In contrast, SNRIs appear to offer consistent efficacy against MDD, regardless of estrogen level or estrogen-replacement therapy, age, or gender.67 Therefore, when choosing a treatment for depression in postmenopausal women, clinicians should con-sider presence of vasomotor symptoms and/or use of estrogen-replacement therapy and should consider SNRIs as a first-line treatment.

CONCLUSIONCompared with men, women are at an

increased risk of developing depression, espe-cially at several reproduction-related lifecycle points. This may partially be due to changing levels of estrogen, a hormone that can affect levels of neurotransmitters and neural proteins, which, theoretically, can result in symptoms of depression. As estrogen levels vary through-out the lifespan, risk of depression in women also varies, and not all treatments are appropri-ate or effective at all times. Thus, tailoring treat-ment to a woman’s reproductive stage of life aids in determining the best treatment option. SSRIs are beneficial in treating depression in younger women, but risks should be considered in pregnant women and in adolescents, and breast-feeding should be avoided in postpartum women if antidepressant pharmacotherapy is utilized. Psychotherapy may be more appropri-ate for youths and for pregnant or postpartum women. Hormonal control can sometimes offer relief of PMDD and postpartum or perimeno-pausal depression (and its comorbid vasomo-tor symptoms). SNRIs are currently the most efficacious nonhormonal treatment for vasomo-tor symptoms and also can effectively address depressive symptoms in older women, in whom SSRIs may be less efficacious. Clinicians who are aware of the varying risk levels for development of depression over the lifespan, as well as the risks and benefits of utilizing various therapies, can offer tailored and maximally effective treat-ments to bring their depressed female patients to remission of symptoms. CNS



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Tailoring Treatment of Depression for Women Across the