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Pharmacology: Gender-Specific

Considerations in the Use of

Psychoactive Medications

Sidney H. Schnoll, M.D., Ph.D., and Michael F. Weaver, M.D.

INTRODUCTION

This chapter focuses on considerations in prescribing psychoactive

medications for women. Women present to physicians more often and

have higher rates of anxiety and depression than do men. Psychotropic

medications are prescribed for women nearly twice as much as they are

for men, but there is little research information on the differences in

drug effects between men and women. Among the most frequently

prescribed drugs are the anxiolytics and sedative-hypnotics that often

fall into the benzodiazepine group and have high abuse potential.

Antidepressants and antipsychotics usually do not have abuse potential.

However, some anticholinergics, which are prescribed in conjunction

with antipsychotics to reduce side effects, can be abused. Stimulants,

which are often prescribed for weight control, also have potential for

abuse.

LACK OF TREATMENT

The high prescription rates of psychotropic drugs to women are

evidenced by data showing that psychiatric diagnoses are twice as

prevalent among women as among men (Cooperstock 1978). Women

tend to seek medical treatment more often than men, especially for

emotional problems. (Some studies show that men tend to deal

with their emotional problems by taking drugs on their own.) When

women are treated for psychiatric conditions, they often are treated

inappropriately (Vranas 1982).

An indication of inappropriate prescribing is demonstrated with

major depression, a common problem. Twenty-nine percent of those

who suffer from depression take anxiolytics, which can exacerbate

depression. Only 11 percent use antidepressant medication, and
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69 percent of depressed people receive no medication, even though

medication, particularly antidepressants, is known to be efficacious in

treating this disorder (Norman et al. 1992). Few women suffering from

anxiety syndromes are treated with medication. Even fewer receive

behavioral therapy for their problems because most of these problems

are treated by a primary care physician, not by a psychologist, psychiatrist,

or other psychiatric professional. Despite the concern about overprescribing, many women with psychological and psychiatric problems are not

receiving appropriate treatment or medication.

LIMITED RESEARCH ON WOMEN

Little research has been conducted on the effects of psychotropic

drugs on women. Most studies are done on laboratory animals. Animal

research provides evidence that pharmacologic and pharmacodynamic

differences exist between male and female animals when psychotropic

drugs are used. However, few studies of this sort are performed with

humans.

Most drugs studied in humans involve young men, usually male

medical students who volunteer to participate. However, differences exist

between men and women in muscle mass and adipose tissue distribution,

and all psychotropic drugs are lipophilic or fat-soluble. This is important

because the higher fat-to-muscle ratio in women allows more drugs to be

stored in body fat and prevent them from getting to the sites where they

are active. Therefore, important differences exist and should be considered in terms of how psychotropic drugs should be administered.

The reluctance of most pharmaceutical companies to include women

in studies for new medications results from the desire to avoid the potential liabilities that may occur with women (Kinney et al. 1981). There is

a fear of litigation, particularly with respect to studies with women of

childbearing age. Pharmaceutical companies are concerned about the

potential for a lawsuit if a woman were to become pregnant and teratogenesis occurred.

EFFECTS OF THE MENSTRUAL CYCLE

ON DRUG ACTION

In the study of drug use by women, the phases of the menstrual cycle

are rarely taken into account. The menstrual cycle has dramatic effects
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on a woman’s body, yet drugs are rarely given with consideration of this

fact. Because the hormonal fluctuation encountered during the menstrual cycle may affect the outcome of studies with a particular drug, the

desired positive effect might not result. Studies that test new drugs with

women usually are conducted with postmenopausal women. Although

elderly people often use drugs, high rates of anxiety and depression occur

more frequently in women of childbearing age, yet psychotropic drugs are

not studied adequately in the younger female population.

Gastrointestinal transit time changes during phases of the menstrual

cycle and also can affect how drugs are absorbed into the body. The time

sustained-release drugs spend in certain parts of the gastrointestinal tract

is critical for absorption. Time changes also can be critical to maintaining therapeutic blood levels in women during various menstrual cycle

phases.

Research has demonstrated that women are less responsive to

imipramine than are men for treatment of depression (Hamilton and

Parry 1983), yet this fact is seldom mentioned in discussions of treatment

of depression. Medical professionals also know that older women metabolize benzodiazepines much faster than older men (Greenblatt et al.

1980; Ochs et al. 1981). Women’s decrements of liver function are

different from men’s (Dawkins and Potter 1991). However, this is true

only of microsomal oxidation and not of glucuronidation, which is

important for the longer-acting benzodiazepines that are metabolized

to active metabolites. Some shorter-acting benzodiazepines like

oxazepam and lorazepam are directly metabolized to excretable forms;

glucuronidation is the process responsible. There is no evidence that

benzodiazepine metabolism is altered during the menstrual cycle.

Antipsychotics cause tardive dyskinesia and extrapyramidal effects

more frequently in women than in men (Halbreich et al. 1984); care

must be taken in prescribing these drugs for women.

DRUG TREATMENT DURING PREGNANCY

In treating women with medications, the major concern is pregnancy.

For a long time, the placenta was believed to be a protective organ for

the fetus and that drugs and other harmful substances would not get

through the placenta to the fetus; now it is known that this is not true

(Mortola 1989; Paxton 1981). Any drug that gets to the brain will
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cross the placenta because the same characteristics that allow a drug to

cross the blood-brain barrier also permit it to pass through the placenta.

Several critical issues must be addressed when psychoactive drugs

are prescribed to pregnant women. It is necessary to consider the effects

of the particular illness and its negative consequences, such as suicide,

violence, and decreased functioning, and to weigh these against the

potential side effects of the drugs. When women do not get treated for

certain disorders, fetal abuse, neonaticide, precipitous delivery, and

refusal of prenatal care can occur. The risks of prescribing must be

balanced against the risks of not prescribing.

Pregnancy is a continually evolving situation involving significant

changes in both the maternal and fetal systems. Those who prescribe

medications should keep in mind the importance of the placenta, how

it changes during pregnancy, and the profound effects fetal and maternal

system changes have on pharmacokinetics and pharmacodynamics.

For example, during methadone treatment, blood levels of methadone

drop precipitously in the later stages of pregnancy. Various approaches

have been taken to counteract this drop, from increasing the dose of

methadone to splitting the dose (Wittman and Segal 1991).

An institutional review board that wishes to study a drug in pregnant

women demands that the drug show clear efficacy in a nonpregnant

population first. Therefore, if phase 2 or phase 3 studies with a new drug

have not demonstrated efficacy, pregnant women are not included.

EFFECTS OF DRUGS ON THE FETUS

Neonatal withdrawal is primarily believed to be associated with

drugs like methadone, sedative-hypnotics, and alcohol; however, most

psychoactive drugs, including antidepressants and antipsychotics,

given to a woman during pregnancy will produce a kind of withdrawal

syndrome after the newborn is delivered.

When these drugs are prescribed for pregnant women, withdrawal

syndromes in neonates must be addressed because most psychoactive

drugs will produce withdrawal symptoms and the infants often are

premature and small for gestational age. It is vital to remember that

the use of drugs is riskiest to the fetus during days 18 to 55 of fetal

development (Schardein 1993, p. 5).
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THE FUTURE

Little is known and much must be learned about the relationship

between women and drugs. A review of the literature reveals how few

studies have examined the effects of psychotropic drugs on women,

particularly pregnant women. This field is wide open and needs more

work. Research in this area becomes even more important because, more

often than men, women have problems for which psychotropic drugs are

prescribed. How to treat women appropriately must be better understood.

A mixture of behavioral therapies and pharmacotherapies may provide

the best treatment for these problems and needs closer examination.

REFERENCES

Cooperstock, R. Sex differences in psychotropic drug use. Soc Sci Med

12(3B):179-186, 1978.

Dawkins, K., and Potter, W.Z. Gender differences in pharmacokinetics and

pharmacodynamics of psychotropics: Focus on women. Psychopharmacol

Bull 27(4):417-426, 1991.

Greenblatt, D.J.; Divoll, M.; Harmatz, J.S.; and Shader, R.I. Oxazepam kinetics:

Effects of age and sex. J Pharmacol Exp Ther 215:86-91, 1980.

Halbreich, U.; Asnis, G.; Goldstein, S.; Nathan, R.S.; Zander, K.; and Herne,

J.V. Sex differences in response to psychopharmacological interventions in

humans. Psychopharmacol Bull 20(3):526-530, 1984.

Hamiliton, J., and Parry, B. Sex-related differences in clinical drug response:

Implications for women’s health. J Am Med Wom Assoc 38(5):126-132,

1983.

Kinney, E.L.; Trautmann, J.; Gold, J.A.; Vessill, E.S.; and Zelis, R. Underrepresentation of women in new drug trials: Ramifications and remedies.

Ann Intern Med 95:495-499, 1981.

Mortola, J.F. The use of psychotropic agents in pregnancy and lactation.

Psychiatr Clin North Am 12(1):69-87, 1989.

Norman, T.R; Judd, F.K.; and Burrows, G.D. New pharmacological approaches

to the managment of depression: From theory to clinical practice. Aust

N Z J Psychiatry 26(1):73-81, 1992.

Ochs, H.R.; Greenblatt, D.J.; Divoll, M.; Abernethy, D.R.; Feyerbend, D.H.; and

Dinger, H.J. Diazepam kinetics in relation to age and sex. Pharmacology

23:24-20, 1981.

Paxton, J.W. Elementary pharmacokinetics in clinical practice. 4: Genetic,

environmental and age influences of pharmacokinetics. N Z Med J 94:423-

425, 1981.
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Schardein, J.L. Chemically Induced Birth Defects. 2d ed. New York: Marcel

Dekker, 1993.

Vranas, M. Psychiatric treatment of women: Standard of care? Med Trial

Tech Q 28(4):375-386, 1982.

Wittman, B.K., and Segal, S. A comparison of the effects of single- and splitdose methadone administration on the fetus: Ultrasound evaluation.

Int J Addict 26(2):213-218, 1991.

AUTHOR

Sidney Schnoll, M.D., Ph.D.

Professor

Departments of Internal Medicine and Psychiatry

Chairman

Division of Substance Abuse Medicine

(804) 828-9914 (Tel)

(804) 828-9906 (Fax)

sschnoll@gems.vcu.edu (E-mail)

Michael F. Weaver, M.D.

Clinical Research Fellow in

 Substance Abuse Medicine

Division of Substance Abuse Medicine

(804) 828-1283 (Tel)

(804) 828-9906 (Fax)

mfweaver@hsc.vcu.edu (E-mail)

Medical College of Virginia Hospitals

Box 980109

Richmond, VA 23298-0109