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Abstract and Introduction
Despite the fact that women are the primary consumers of psychotropic
medication, little attention has been paid to sex differences in psychopharmacology.
Sex differences have been found in the absorption, metabolism, and excretion
of many medications. Women tend to respond more favorably to SSRIs than
to tricyclics, have more side effects with psychotropic medication, and
are more likely to develop tardive dyskinesia. They may also be more concerned
about certain side effects such as weight gain from neuroleptic medication.
In treating women patients, the clinician must be aware of the possible
effect of the menstrual cycle on serum levels of medications. It is also
essential to understand the effects of such medication during pregnancy
and the postpartum period. Tricyclic and SSRI antidepressants have not
been found to cause organic or behavioral teratogenesis when given in
pregnancy. Lithium has been associated with Ebstein's anomaly and carbamazepine
and valproic acid with the occurrence of neural tube defects. Although
small quantities of all psychotropic drugs pass through breast milk, they
do not appear to have an immediate effect on the infant. Women also take
exogenous hormones. Oral contraceptives differentially affect the blood
levels of various benzodiazepines, increasing levels of diazepam, and
decreasing levels of temazepam. Drugs such as carbamazepine can interfere
with the action of oral contraceptives. Postmenopausal women may require
lower doses of antipsychotics. Although hormone replacement therapy in
itself does not seem to be a treatment for depression, it may have some
benefit in augmenting the effects of antidepressant medication.
Women take more psychotropic medications than men. About two thirds of
antidepressants and tranquilizers dispensed in the United States are prescribed
to women. Also, more women than men take multiple medications.[1,2]
In general, women tend to have more side effects and adverse effects with
psychotropic medication than do men. Women's exposure to monthly variations
in gonadal hormones may alter the metabolism, distribution, elimination,
and, therefore, response to medication. In addition, women become pregnant,
breastfeed, go through menopause, and may take hormone replacement therapy
(HRT). All of these conditions may have an impact on the psychotropic
medication used, dosage required for efficacy, and response. Thus, it
is important for the clinician to understand how physiology at various
times in the female lifecycle may affect a woman's response to psychotropic
Physiologic Differences Between Women and Men
The effectiveness of
medication depends on how it is absorbed, metabolized, distributed, and
excreted in the body. There are numerous ways in which these processes
differ between men and women. Research is still being carried out to
determine how these processes work together or counteract each other in
the case of specific psychotropic medications.
Absorption and Bioavailability
The majority of studies show that premenopausal women have slower gastric
emptying times than men.[4,5] This results in delayed passage of the drug
into the small intestine, which has the greater absorptive capacity. In
turn, this can lead to slower absorption, delayed peak levels, and lower
peak serum concentrations of the drug. Women have also been found to have
lower basal gastric acid secretion as compared with men, which may
increase the absorption of bases, such as tricyclic antidepressants, benzodiazepines,
and phenothiazines, and decrease gastric absorption of acids such as phenytoin
Women on average weigh less than men and have lower body surface areas.
They tend to have lower total blood volumes than men. Adult women age
25-35, on average, have an absolute percentage of body fat that is 11%
higher than men in the same age range. For a given dosage of drug,
this may result in women initially having a lower serum concentration
compared with men. Over time, however, the gradual release of lipophilic
medications stored in fat tissue may lead to higher serum levels in women.
The rate of cerebral blood flow, which may be higher in women, may affect
the distribution of psychotropic drugs to the brain. Distribution
may also be affected by the degree of protein binding, although there
is no convincing evidence that this differs between men and women.
Metabolism and Elimination
The liver is the most important site of metabolism. There seem to be sex
differences in the activity of various drug-metabolizing systems involved
in the biotransformation of drugs. As well, sex differences in renal
clearance may mean that for drugs eliminated via the kidney, women could
have higher serum levels of drug than men for a given dosage.
Overall, women tend
to have greater bioavailability and slower clearance of drugs compared
with men, the consequence being that optimal doses for men may be relatively
high in women. This may be the reason that women generally experience
side effects of psychotropic drugs about twice as often as men. Reports
vary about the incidence of extrapyramidal side effects, with some finding
more dystonias in women and others finding fewer. Women have also
been found to have a higher rate than men of tardive dyskinesia.
in Women: Changes Throughout the Life Cycle
Menstrual Cycle Effects
Physiologic changes. Women's physiology changes throughout the menstrual
cycle. The majority of studies have found that there is a 28% to 36% decrease
in the rate of gastric emptying premenstrually.[17,18] The possible decreases
in serum level of drug as a result are likely offset by the slower, small
intestinal transit time, thereby tending to result in higher serum
levels of drugs premenstrually. As well, a decrease in gastric acid secretion
that probably also occurs premenstrually would increase blood levels
of base drugs such as tricyclic antidepressants.
Evidence remains inconclusive
that total body water changes over the course of the menstrual cycle.
However, in those women who retain water premenstrually, a decrease in
serum levels of water-soluble drugs may occur because of a dilution effect.
Although studies of renal elimination have also produced mixed results,
Hamilton and Yonkers found that the bulk of the evidence suggests there
may be a significant decline in renal clearance between the luteal and
early follicular phase. As well, for some women, changes in metabolism
or effects on central neurotransmitters or CNS receptor numbers or sensitivity
may vary throughout the menstrual cycle.
Women may suffer from premenstrual dysphoric disorder (PMDD) or have an
exacerbation of symptoms of another ongoing psychiatric illness during
the premenstrual phase. Selective serotonin reuptake inhibitors (SSRIs)[21,22]
and venlafaxine have been found to be effective in treating PMDD.
One should begin by giving the drug for the duration of a menstrual cycle.
It may take several cycles to assess the benefit of a particular dosage
of medication. Once an effective dosage is found, the individual may try
taking the drug only in the second part of the cycle beginning approximately
around ovulation time and continuing until a few days after the onset
In women with premenstrual
exacerbation of a major psychiatric illness, one should first try increasing
the dosage of the medication throughout the entire cycle. For women who
continue to be more symptomatic in the premenstrual phase, one may have
the option of further increasing the constant daily dose of the medication
for the whole cycle or increasing the dose for only 3-5 days before the
predicted onset of the increased symptoms, decreasing again 2-3 days after
the start of the menses.
Physiologic changes. The increase in total body water that occurs during
pregnancy may lower serum concentrations of drug. Total protein is also
reduced, however, thereby decreasing drug binding and thus increasing
its serum concentration. Drug absorption is altered by a decrease in the
emptying rate of the gastrointestinal tract as well as by a decrease in
gastric acid secretion. Glomerular filtration rates increase during pregnancy,
resulting in a faster excretion of some drugs, such as lithium, so higher
doses are required. In the second trimester of pregnancy, there is often
a physiologic drop in blood pressure, which may add to the orthostatic
hypotension effects of some antipsychotic and tricyclic antidepressant
drugs. Constipation, which is common in pregnancy, may be worsened by
medications with anticholinergic side effects. In general, higher
doses of medication are often required in pregnancy to achieve therapeutic
serum levels. Postdelivery, the dosage must be reviewed and usually decreased
to prevent toxicity.
Although, ideally, women who are trying to become pregnant should not
be taking any psychotropic medication, practically this is not always
possible. For women who are still being treated for past episodes of psychiatric
illness, it may be more harmful to them to cease taking medication and
thereby increase the risk of their developing a reoccurrence of illness
before or in the early stages of pregnancy. Neuroleptics and antidepressant
medications, such as imipramine, amitriptyline, and sertraline, can lead
to hyperprolactinemia, which may interfere with fertility. This, therefore,
should be considered if a woman is having difficulty becoming pregnant;
dosages may have to be lowered or drugs changed.
Detailed reviews of
the use of psychotropic drugs during pregnancy and lactation are found
elsewhere.[25-28] In general, because of the poor quality of much of the
research, it is impossible to guarantee that any psychotropic drug is
entirely safe during pregnancy. However, for a majority of drugs, there
is little evidence of either physical malformations or behavioral teratogenicity.
women who require psychotropic medication during pregnancy should receive
the lowest effective doses, and the medication should be given in divided
doses so that they have less effect on the fetus. During the first trimester,
high-potency agents tend to be preferred because they cause fewer autonomic
anticholinergic and cardiovascular effects as well as less hypotension
and sedation. The atypical antipsychotics have not been well studied.
Although monoamine oxidase inhibitors (MAOIs) can be teratogenic,
there is no clear evidence for such harm caused by tricyclics or SSRIs.
Recent studies of lithium
have suggested that it may be less teratogenic than previously thought,
although the risk of Ebstein's anomaly still seems to be 10-20 times as
common after first-trimester exposure than in the general population.
Unstable bipolar patients may be maintained on lithium with close monitoring
and targeted ultrasound and fetal echocardiograms at week 18 of gestation
to rule out cardiovascular malformation. Sodium-depleting diuretics
and low-salt diets should be avoided, and lithium levels should be monitored
monthly. Lithium should be given in divided doses to a maximum of 300
mg each. Carbamazepine has been associated with craniofacial defects
and neural tube defects, as has valproic acid when taken during
the first trimester of pregnancy. If carbamazepine or valproic acid is
required to stabilize the pregnant patient, she should also take 5 mg
daily of folic acid to decrease the risk of neural tube defects. Ultrasound
should be performed at weeks 10-19 of gestation to detect possible abnormalities.
of anxiety such as relaxation techniques, cognitive therapy, and psychotherapy
should be used when possible. If anxiolytics are needed, they should be
given in the lowest effective dose for the briefest possible period of
time. Generally, anxiety is better treated with antidepressant medication.
In the second and third
trimester, most psychotropic drugs seem to be safe. Although the central
nervous system continues to develop throughout pregnancy, no clear association
has been noted between the use of psychotropic drugs and the occurrence
of microcephaly or mental retardation. Pregnancy-related physiologic changes
may require an increased dosage of medication during the third trimester.
Lithium use during this time may infrequently cause a large goiter in
the fetus, ultimately necessitating a cesarean section. Although some
physicians have recommended lowering or discontinuing antidepressant medications
2 weeks before the expected date of delivery to reduce the possibility
of side effects, toxicity, and withdrawal in the newborn, others are concerned
that discontinuing drugs at this time may increase the risk of postpartum
Small doses of major
and minor tranquilizers have long been used by obstetricians during labor.
It is best to avoid long-acting benzodiazepines because they may adversely
affect the neonate. Lithium should be lowered or discontinued a couple
of weeks before delivery to avoid toxicity in the mother or in the baby
postdelivery. It is wise to have the patient restart the lithium very
soon after delivery, being careful to monitor blood levels, as there is
some evidence that prompt resumption of treatment can reduce the chances
of postpartum mania from 10% to 50% in vulnerable women.
Physiologic changes. Dramatic changes in hormone and electrolyte balance
and fluid volume level occur during labor and postpartum. Progesterone
and estradiol levels rapidly fall to prepregnancy levels by the third
day postpartum. Prolactin is no longer blocked and lactation begins. Plasma
corticosteroid levels decrease significantly within 4 hours postpartum.
Thyroid functions return to prepregnancy levels by approximately 4 weeks
after delivery. Plasma renin levels fall. Sodium excretion increases while
calcium secretion decreases. Rapid weight loss occurs.
The major concern about
drugs used in the postpartum period has to do with the effects on the
breastfeeding infant. Drugs pass into the milk in a nonionized form. As
milk is rich in fat and slightly acidic, drugs that are acidic, ionized,
protein-bound, or lipid insoluble will have high plasma to milk ratios.
Antipsychotic drugs, being highly protein-bound, will therefore have low
milk concentrations. As infants have little body fat, reduced protein
binding, and lower excretion rates, the effects of the drugs absorbed
through breastfeeding will tend to be increased.
Ten to fifteen percent of women suffer from a major depressive episode
during the postpartum period and .01% to .02% develop a psychotic illness
postpartum. Many of these mothers have chosen to breastfeed and may be
worried about the consequences of taking psychotropic medication during
It is always useful
to first ascertain whether the mother wishes to continue breastfeeding.
For some women, breastfeeding is the one positive thing they feel they
can give to their baby when, generally, they feel like very bad mothers
as a result of their depressed mood. For other women, breastfeeding may
become an agony when they are having difficulty coping with even simple
day-to-day tasks. If the mother wishes to continue breastfeeding, it is
important to be knowledgeable about the effects of various medications
on the infant.
The majority of psychotropic
medications pass from the maternal plasma to the breast milk in very small
quantities. A critical review of the literature found that amitriptyline,
nortriptyline, desipramine, clomipramine, and sertraline were not found
in quantifiable amounts in nursing infants, and no adverse effects were
reported. Infants older than 10 weeks showed no accumulation of doxepine
or fluoxetine and were at low risk for adverse effects. Stowe and colleagues
found no adverse short-term effects with maternal ingestion of paroxetine.
The effects of MAOIs are unknown. Overall, the American Academy of Pediatrics
does not preclude the use of non-MAOI antidepressants in breastfeeding
women but labels them as "drugs whose effects on nursing infants
are unknown but may be of concern." No data are available on the
long-term effects of breastfeeding while taking antidepressants; however,
infants exposed to fluoxetine or tricyclics during the first trimester
of pregnancy have now been followed up to school age with no evidence
of malformation or behavioral teratogenicity. This may suggest that
the small amounts taken in breastfeeding may be safe in the long term.
The quantity of major
tranquilizers found in breast milk is usually less than 30% of that found
in maternal plasma. Some minor short-term side effects have been noted,
such as drowsiness with chlorpromazine and galactorrhea with chlorpromazine
and thioridazine. One study showed that the breast milk of a mother on
haloperidol had 2/3 the maternal serum levels of the drug, although the
infant was developing normally at 6 and 12 months. Data on atypical
antipsychotics are limited to case studies. Breastfeeding mothers should
be on only 1 antipsychotic, at the lowest possible total dose, and should
take it in divided doses right after breastfeeding. Women who require
very high doses or more than 1 antipsychotic should avoid breastfeeding.
lead to lethargy, jaundice, and poor temperature regulation in the infant,
especially when taken during the first 6 weeks while the infant still
has difficulty metabolizing these agents. Sustained use of benzodiazepines
and those with a long half-life are contraindicated during breastfeeding.
Levels of lithium in
breast milk are 40% to 50% of those in maternal serum. It has been
shown to cause such toxic effects in the infant as cyanotic episodes,
lethargy, hypothermia, and hypotonia; breastfeeding mothers should
not take lithium. Both carbamazepine and valproic acid are found in
the serum of infants breastfed by mothers on these drugs, but levels are
lower than therapeutic levels for childhood epilepsy. Extensive reviews
have not found any long-term cognitive or behavioral adverse effects,
and these drugs are deemed compatible with breastfeeding by the American
Academy of Pediatrics. Newer anticonvulsants used to treat bipolar
illness (topiramate, lamotrigine, and gabapentin) all pass into breast
milk. Although information is still limited, there do not appear to be
any reports of immediate adverse effects or problems with long-term cognition
in infants breastfed by mothers on gabapentin or lamotrigine. Bar-Oz and
associates recommend allowing breastfeeding while monitoring the infant
for drug levels and side effects. The use of topiramate is not recommended
because of possible psychomotor slowing and somnolence.
Menopause and Age-Related
Physiologic changes. The majority of studies have poorly discriminated
between effects resulting from the menopausal transition and those of
aging. Aging tends to be associated with the following: decreased levels
of serum albumen, which increases the concentration of unbound active
drug; decreased lean body mass, which increases concentration of water-soluble
drugs; lower hepatic blood flow; decreased activity of hydroxylation or
conjugation; and decreased renal excretion and elimination. In women,
all of these processes may result in an increase in serum levels and half-lives
of many psychotropic drugs. Generally, however, age effects are less marked
in women than in men. The decreased ability in older men to clear
drugs produces psychopharmacokinetics more like those of younger women.
As women age, they may require even lower doses of psychotropic medication.
There is a greater prevalence of tardive dyskinesia with age; in addition,
women may present with more severe forms of this disorder. Hamilton
has proposed that this is due to diminishing levels of estrogen with age.
Women older than 50 years of age are also more likely than men to show
Effects of Exogenous
Nearly 27% of women of childbearing age in the United States use
OCs. These contain synthetic estrogen, progesterone, or a combination
of the two. Synthetic estrogen stimulates protein synthesis, which may
affect protein-binding of various drugs; inhibits various cytochrome P450
isoenzymes; and affects conjugation with glucuronic and sulfuric acid.
OCs increase the metabolism of some benzodiazepines, such as temazepam;
decrease that of chlordiazepoxide, diazepam, and nitrazepam; and have
no effect on alprazolam or lorazepam. Therefore, except for these
latter 2 drugs, one must be aware that differences in effects of benzodiazepines
may occur in the weeks on or off OCs. OCs decrease serum tricyclic levels
and may potentiate the prolactin response of antipsychotics. Carbamazepine
and phenobarbital may reduce OC efficacy. Patients need to be cautioned
about this possibility; they may require an increased dose of estradiol
or a switch to a different mood stabilizer such as valproic acid, which
does not tend to affect the efficacy of OCs.
More than 31 million prescriptions for HRT were dispensed in the United
States in 1992. As opposed to OCs, which use synthetic estrogens that
affect the cytochrome P450 oxidase system, some formulations of HRT contain
conjugated estrogens that do not affect that system. The levels of hormones
in HRT preparations are much lower than those in OCs. Progesterone on
its own has been thought to be associated with dysphoric moods; continuous
combined therapy with estrogen and progesterone may counteract this effect
Role of Estrogen
in Treatment of Mood Disorders
There is growing interest in the use of estrogen to treat depression,
although the results have been mixed. Klaiber and colleagues showed
statistical but not clinical improvement in a group of women treated with
supraphysiologic doses of estrogen. This group included both premenopausal
and postmenopausal women. Saletu and associates examined women with
laboratory-confirmed menopausal status and found that there was no benefit
of the estrogen compared with placebo. Zweifel and O'Brien carried
out a meta-analysis of 26 studies and concluded that estrogen may be of
some benefit for women with depressed mood or mild depressive symptoms
but not for women with a major depression. Yonkers and coworkers have
proposed that studies look more closely at the type of estrogen used,
as this might be an important variable.
Gregoire and colleagues
studied 61 women with postpartum depression who were treated with estradiol
for 3 months followed by 3 months with added cyclical dydrogesterone;
statistically and clinically significant reductions occurred in depressive
symptoms. Because at least half of these women were on concurrent antidepressant
medication, the beneficial effects of estrogen may have been an augmentation
of the antidepressant effects. There is some suggestion that estrogen
can increase tricyclic blood levels.
not taking HRT have been found to have an apparent desensitization of
serotonin receptors or a blunted serotonergic responsivity. Unfortunately,
the effect of estrogen on serotonergic responsivity in postmenopausal
women has not been well studied. Schneider and associates found that
women being treated with fluoxetine who were also taking concurrent HRT
had an improved response. The value of estrogen as an augmentor remains
unclear because many studies suffer from failure to determine menopause
status, lack of a double-blind, placebo-controlled trial design, and failure
to note the different types of estrogen used or to distinguish between
adding estrogen alone or estrogen and progesterone. , However, in the
face of treatment-resistant depression in a postmenopausal woman, the
addition of HRT (barring any contraindications) should be tried.
Choice of Antidepressants
There has been some limited research indicating that men and women
respond differently to different types of antidepressant. A meta-analysis
of 35 studies demonstrated that men respond more favorably to imipramine
than do women. In patients with atypical depression with panic attacks,
women responded better to MAOIs and men to tricyclic antidepressants.
In patients with chronic depression, Kornstein and colleagues showed
that premenopausal women were significantly more likely to respond to
sertraline than to imipramine. Women also responded more slowly to imipramine.
Postmenopausal women showed similar rates of response to the two medications.
Therefore, the clinician should be aware that men and women may respond
differently to a given antidepressant, and in women menopausal status
should be taken into account when choosing an antidepressant.
Women's compliance with recommended medications may be affected by a number
of sociocultural factors -- for example, male partners who do not agree
with the use of psychotropic medication and interfere with the woman's
using it. Many women are cautious about taking medication, having heard
for many years that women tend to be overmedicated and perhaps having
experienced overmedication personally. It is very important to differentiate
between the nature of antidepressant or antipsychotic medication and minor
tranquilizers. Many women are very afraid of becoming addicted to medication
and need careful explanations of the different qualities of these medications.
Proper attention to dosage in women is very important to prevent excessive
side effects. Women may need lower doses of antidepressant than men as
their physiology tends to result in higher serum levels of drug. On the
other hand, there may be times during the menstrual cycle, such as premenstrually,
when women require more medication.
Certain side effects
may be particularly worrisome for women. The atypical antipsychotics,
although very effective, are associated with a great deal of weight gain.
This can be horrifying and demoralizing for many women who may stop taking
the medication because of this side effect. As well, women may be troubled
by the sexual side effects that are associated with a number of antidepressant
medications. Often women are not informed that there is potential for
sexual side effects and experience their decreased interest or inability
to have an orgasm as another shortcoming on their part. It is important
to inform women about these effects and monitor their reactions to the
medication. Sildenafil, 50-100 mg, 1 hour before intercourse may be helpful.
Alternatively, a switch to an antidepressant such as bupropion or nefazedone
that is less likely to cause sexual problems may be indicated.
by antipsychotic medication can cause infertility, irregular menses, and
osteoporosis. The key clinical indicator of hyperprolactinemia is amenorrhea.
If this occurs, possibilities for management include decreasing the antipsychotic
dosage, switching to an antipsychotic with less effect on prolactin (such
as clozapine or quetiapine), treating with bromocriptine, or adding OC
medication to replenish estrogen.
The study of specific gender responses to medications is a relatively
new one. Women were habitually excluded from drug trials to avoid the
complications of their physiologic cycling and the risk of pregnancy.
However, women do have cycles, become pregnant, take exogenous hormones,
and still require psychotropic medication. Many of these issues remain
poorly researched. In the meantime, it is important for the physician
prescribing psychotropic medications to be aware of general physiologic
differences between women and men in relation to psychopharmacology, the
effects of menstrual cycles and reproductive events, and the possible
interactions with OCs and HRT.
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Dr. Robinson wishes to acknowledge Ryna Langer and Raisa Bohn for their
contributions to this article.
Gail Erlick Robinson, MD, D Psych, FRCP(C), has no significant financial
interests to disclose.
Erlick Robinson, MD, D Psych, FRCP(C), is Professor of Psychiatry
and Obstetrics/Gynecology, University of Toronto, and Director, Women's
Mental Health Program, University Health Network - Toronto General Site.