US Pharm. 2013;38(9):36-39.
ABSTRACT: Depression, like many other psychiatric illnesses, may
present differently in women versus men. These disparities go beyond the
depressive syndromes unique to women—namely, postpartum and menopausal
depression—and often manifest in women with major depressive disorder.
The STAR*D study found that women may be more prone to atypical symptoms
of depression. Also, some data indicate that women may respond more
robustly to selective serotonin reuptake inhibitors, whereas men may
favor tricyclic antidepressants. Additional treatment considerations
include variability in pharmacokinetics, effects on bone density, and
key drug interactions more likely in women. An understanding of the
etiology, presentation, and specific treatment of depression in women
will lead to a more successful outcome.
Cardiovascular disease, osteoporosis, autoimmune disease—these are
just a few of the conditions in which clinicians consider gender when
making a diagnosis or selecting therapy. So why isn’t gender necessarily
considered in the identification and treatment of psychiatric
disorders, which also can vary greatly between the sexes? One of the
most common examples of gender variation in psychiatric disorders is
major depressive disorder (MDD). MDD and similar depressive disorders do
not necessarily manifest identically in men and women. Prevalence,
comorbid disorders, and optimal therapy may differ between men and
women. Certainly, depressive symptoms occurring during the perinatal and
postmenopausal periods or as part of premenstrual dysphoric disorder
are recognized to be unique to women, but clinicians should be aware of
disparities seen outside of these specific conditions. For these
reasons, it is crucial for the clinician to anticipate and recognize
gender distinctions when evaluating female patients at risk for, or
diagnosed with, depression.
As much as 10% to 20% of the population will be diagnosed with depression.1
When the female population is specifically considered, this already
substantial percentage grows even larger. While rates of depression are
similar between the sexes during childhood and adolescence, women are
twice as likely as men to be diagnosed with depression.2 The
12-month prevalence rate for MDD in nonpregnant women aged 18 to 50
years is between 8% and 16%—roughly double the rate observed in men.3
Of even greater concern is that more than half of women who meet
criteria for MDD are not properly diagnosed. One explanation may be that
women and men present differently and nonpsychiatric clinicians have
difficulty recognizing depression in women.4
Various causes of—and factors contributing to—the higher rate of
depression in women have been considered. Hormonal fluctuations and
their role in depression are a natural starting point for elucidating
gender differences in this mood disorder. Indeed, estrogen may play some
role in differentiating depression in women. This hormone may initially
seem to be an outlier in the neurotransmitter model of MDD, but its
involvement becomes more evident upon closer examination.5
Estrogen is involved in modulating neurotransmitter turnover and
regulating receptor number and function. This affects serotonin and
possibly norepinephrine, two of the three most commonly targeted
neurotransmitters in the treatment of depression. Alterations in
estrogenic activity in women may lead to disruptions in these systems,
which may partially explain the increased rate of depression.5
Additionally, some studies suggest that certain estrogen receptor (ER)
polymorphisms may increase the risk of depression—particularly severe
depression—in women.6 Another link between estrogen and
depression involves possible activity between estrogens and monoamine
oxidase (MAO), the same enzyme on which the oldest class of
antidepressants exerts its effects.7
To date, however, there is no clear understanding of what causes
disparities in depression between genders. Most likely, it is a
combination of many factors: the hormonal and neurobiological variables
already discussed, as well as social and behavioral factors (e.g.,
burdens associated with caregiving or traumatic events and stressors
more likely encountered by women).8
Depressive disorders are identified primarily through subjective
patient symptoms. To fulfill a diagnosis, a depressed mood or lack of
interest in pleasurable activities for 2 weeks plus an additional five
or more symptoms must be present.9 These symptoms include,
but are not limited to, feelings of guilt and changes in weight, sleep,
energy, or concentration. On the surface, men and women may seem to meet
these criteria similarly. However, an examination of how these symptoms
present reveals marked differences between genders (TABLE 1).
STAR*D (Sequenced Treatment Alternatives to Relieve Depression), a
large, pragmatic study that evaluated multiple therapies for depression,
found that, compared with men, women typically had an earlier onset of
first major depressive episode, made an increased number of suicide
attempts, and reported symptoms correlating to a more severe depressive
episode. Women also were more likely to report increased appetite and
weight, reduced energy, and greater interpersonal sensitivity.10 These complaints are components of atypical depression (TABLE 2), a depressive subtype that occurs more often in women than in men.11
An awareness of the STAR*D findings will assist clinicians treating
female patients with depression who report a depressed mood or decreased
pleasure, but do not report (or are vague about) other common symptoms
of depression. Considering that all antidepressants have a similar
efficacy profile, these complaints are useful in driving therapy to
target specific symptoms.
Because the etiology of depression in women may sometimes be distinct
and women may present differently from men, it has been proposed that
effective treatments, particularly pharmacologic ones, may differ by
gender. However, supporting data are limited and sometimes conflicting.
Additionally, no major treatment guideline currently steers therapy
according to gender.4 Regardless, it is prudent to examine how pharmacotherapeutic efficacy may differ between men and women.
One of the better-studied gender-specific treatment comparisons for
depressed patients is selective serotonin reuptake inhibitors (SSRIs)
versus tricyclic antidepressants (TCAs). Multiple studies, such as one
by Baca and colleagues, have demonstrated that women may respond better
to SSRIs than to TCAs.12 In this study, women with
nonmelancholic depressive disorders who received sertraline had
significantly larger reductions on the Hamilton Rating Scale for
Depression (HAM-D) versus those receiving imipramine. Sertraline also
was better tolerated than imipramine, with imipramine being discontinued
more than three times as often as sertraline. Similarly, in an analysis
of STAR*D data, Trivedi and colleagues found that, compared with men,
women taking citalopram were more likely to show remission on the HAM-D,
a goal of therapy that is ideal but sometimes difficult to achieve.13
It is unclear why women may have a better response to SSRI therapy, but
one theory is the interaction between estrogen and serotonin activity,
which may cause women to respond better to medications that act solely
on the serotonergic system.2
Limited data indicate that women may have an inherent slight
preference for SSRIs over serotonin-norepinephrine reuptake inhibitors
(SNRIs). Keers and Atchison suggest this in an analysis of a review by
Khan and colleagues of 15 trials and six different antidepressants.2,14
Compared with men, women taking SSRIs were more likely to complete
therapy and responded better on the HAM-D scale; in subjects treated
with SNRIs, however, there was little difference between genders. The
clinical significance is questionable, but the finding is noteworthy
nonetheless, since both of these drug classes are considered first-line,
and occasionally one class is not more appropriate than the other for
initial treatment of depression.
If no single first-line agent is more suitable than another for a
female patient, it may be reasonable to select an SSRI, since women
taking SSRIs may be more likely to complete therapy. However, this has
not been fully determined, since evidence concerning preferential
pharmacotherapy by gender is conflicting. Studies such as that by Thiels
and colleagues failed to duplicate results favoring SSRIs in women.15 Furthermore, Yang and colleagues found that, regardless of type, women responded better to antidepressants than men did.16
Therefore, the extent to which gender should guide the choice between
SSRIs and SNRIs is unknown, and more traditional and better-studied
factors for determining appropriate therapy should be considered first.
As previously discussed, women are more likely to present with
symptoms congruent with atypical depression. This is a key
consideration, since this form of depression may respond more robustly
to SSRIs and MAO inhibitors (MAOIs) than to TCAs.2,17 SSRIs
are usually among the first agents chosen for depression because of
their favorable adverse-effect (AE) profile; MAOIs, however, are not (FIGURE 1). MAOIs are most often reserved for depression that is unresponsive to multiple other drug therapies.18
In treating depression in women with a confirmed atypical subtype, it
may be appropriate to consider MAOIs somewhat earlier in patients who
have failed other agents. In some studies, women responded better to
MAOIs than to TCAs, a class that is usually chosen before MAOIs in
depressed patients.7 Additionally, women with depression and coinciding panic attacks responded more favorably to MAOIs than to TCAs.7
Nonpharmacologic methods for treating depression, such as exercise
and psychotherapy, are key components of a treatment plan for patients
with depression. With these methods, there does not seem to be a
difference in response rate between genders.4 Therefore,
these treatment modalities should not be guided based on gender, whereas
pharmacotherapy may be somewhat influenced by gender.
Pharmacokinetic disparities may influence a patient’s response to
antidepressant treatment. The absorption and volume of distribution (VD)
of many drugs vary between the sexes because women have a higher
percentage of adipose tissue than men, resulting in increased VD of
lipophilic drugs, a property held by many antidepressants. Both
trazodone and bupropion have demonstrated a greater VD in women.7,19
Furthermore, clearance of antidepressants may be reduced in women,
since they secrete less gastric acid and exhibit decreased gastric
motility and emptying times.5
Differences in enzymatic activity may exist as well, since women are
known to have a smaller concentration of P-glycoprotein (Pgp) than men.7
This enzyme plays a crucial role in determining drug concentrations in
the gut and the central nervous system (CNS), largely by functioning as
an efflux transporter. In women, antidepressants—which are transported
by Pgp out of the CNS and into the circulation or out of the circulation
and into the gut—may be more highly concentrated in CNS tissue and
plasma because of an attenuated efflux. This could result in a greater
response or an increase in AEs.
The CYP450 system is not lacking in gender variances, either. Drugs
metabolized by CYP3A4 may clear faster in women, whereas substrates of
CYP2D6 may clear faster in men.5,19 Citalopram concentrations
are higher in women than in men, possibly owing to these factors or to
differences in hepatic blood flow. There also may be disparities in
enzymatic activity in glucuronidation and other pathways.7 The clinical significance of these parameters is undetermined.
Also to be considered in the appropriate treatment of depression in
women are the risk of osteoporosis with antidepressant use and possible
interactions with tamoxifen. SSRIs have been linked to decreased bone
mineral density (BMD), although the magnitude and clinical significance
remain unclear. One cohort study followed nearly 3,000 women for 5 years
to assess whether certain antidepressants reduced BMD. Subjects were
categorized as those taking TCAs, those taking SSRIs, and nonusers of
these classes. Subjects taking SSRIs, but not those taking TCAs, had a
significant reduction in hip BMD compared with nonusers.20
This is of particular concern given that antidepressant use may
predispose patients, particularly elderly ones, to falls and subsequent
Tamoxifen, a selective ER modulator, is a neoplastic agent often used
to treat ER-positive breast cancer. This agent is considered a prodrug;
the metabolites produced from various enzymes, including CYP2D6, have
much higher activity at ERs than the parent compound does. Accordingly,
patients with decreased CYP2D6 activity induced by genetic variability
or concurrent drug therapy may be at risk for reduced tamoxifen
effectiveness.23 Some antidepressants, including paroxetine,
fluoxetine, and duloxetine, are known to inhibit CYP2D6. Whether these
interactions produce significantly worse outcomes is unknown, since
studies have been inconsistent. If it is desirable to avoid this
interaction, an antidepressant with little CYP2D6 inhibition (e.g.,
venlafaxine, desvenlafaxine, mirtazapine) should be used.23
Women are disproportionately affected by depression. They are more
likely than men to be diagnosed, and depression in women may manifest
with earlier, more severe episodes that may involve a greater incidence
of suicidality. Although the reasons for this are unclear, it is evident
that women may present differently and may perhaps respond uniquely to
certain classes of drugs versus others. More information is necessary
before gender can play a large role in guiding pharmacotherapy for
depression; however, clinicians must always consider gender along with
many other individual factors when determining the most appropriate
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