Over the course of a lifetime, depression occurs in approximately 20 percent of women compared with 10 percent of men.1 Although the exact reason for this difference is not known, the higher prevalence of depression in women is most likely due to a combination of gender-related differences in cognitive styles, certain biologic factors and a higher incidence of psychosocial and economic stresses in women.2 Possible biologic mechanisms may include differences in brain structure and function, genetic factors and the cognitive-behavioral or mood-related effects of female gonadal steroids on neurotransmitters and enzyme functions in vulnerable persons.3,4 Some risk factors for depression in women are listed in Table 1.5–7
|Family history of mood disorders|
|Personal past history of mood disorders in early reproductive years|
|Loss of a parent before the age of 10 years|
|Childhood history of physical or sexual abuse|
|Use of an oral contraceptive, especially one with a high progesterone content|
|Use of gonadotropin stimulants as part of infertility treatment|
|Persistent psychosocial stressors (e.g., loss of job)|
|Loss of social support system or the threat of such a loss|
The diagnostic criteria for major depression, as established in the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV), are the same for women and men (Table 2).8 The nine symptoms of depression are divided into two subgroups: psychologic (four symptoms) and physical (five symptoms). The diagnosis of depression requires the presence of depressed mood or the inability to experience pleasure, plus four other symptoms. Thus, five of nine symptoms must be present. Inclusion, exclusion and duration criteria must also be met.
|Reduction of interest and/or pleasure in activities, including sex|
|Feelings of guilt, hopelessness and worthlessness|
|Suicidal thoughts (recurrent)|
|Sleep disturbance (insomnia or hypersomnia)|
|Decreased energy or unexplained fatigue|
Although the same diagnostic criteria are used for both genders, the presentation and course of depression are sometimes different in women (Table 3).2,4,7,9 Compared with men, women may more often experience seasonal depression9 and symptoms of atypical depression (i.e., hypersomnia, hyperphagia, carbohydrate craving, weight gain, a heavy feeling in the arms and legs, evening mood exacerbations and initial insomnia).8 In addition, women more frequently have symptoms of anxiety, panic, phobia, eating disorders and dependent personality. Women also have a higher incidence of hypothyroidism, a condition that can cause depression.7 Thus, it is important to screen depressed female patients for hypothyroidism. Finally, exogenous and endogenous gonadal steroids may have a greater impact on mood in women than in men.
|Parameters||Differences in women compared with men|
|Lifetime prevalence rate||20 percent (10 percent in men)|
|Age of onset||May be earlier|
|Duration of episodes||May be longer|
|Course of illness||May more often be recurrent|
|Seasonal effect on mood||Greater|
|Association with stressful life events||More frequent|
|Atypical symptoms of depression (e.g., hypersomnia, hyperphagia)||Experienced more often|
|Severity of depression||May be greater if self-rated by the patient|
|Guilt feelings||May be experienced more often|
|Suicidal behavior||Suicide attempted more often but much less often successfully|
|Association of anxiety disorders, especially panic and phobic symptoms||Greater|
|Association of eating disorders||Greater|
|Association of alcoholism and substance use disorder||Usually less|
|Association of thyroid disease||Greater|
|Association of migraine headaches||Greater|
|Association of antisocial, narcissistic and obsessive-compulsive personalities||Less|
|Effect of exogenous and endogenous gonadal steroids on mood||Greater|
Depression and Suicide
Depression is a significant risk factor for suicidal behavior in both sexes. Women, especially those younger than 30 years of age, more often attempt suicide, whereas men more often complete the act of self-destruction.10 In fact, the male-to-female ratio for completed suicides is greater than 4:1,10 possibly because women frequently choose less lethal methods. In addition, women often attempt suicide to change the dynamics of interpersonal relationships. Significant risk factors for suicide by women are listed in Table 4.10–12
|Risk for suicide attempts|
|Age less than 30 years|
|Threatened loss of intimate relationship|
|Current psychosocial stressors (e.g., recent loss of job)|
|Personality disorder (e.g., borderline personality disorder)|
|Risk for completed suicide|
|Severe clinical depression, especially with psychosis|
|Past history of suicide attempts|
|Current active suicidal ideation or plan|
|Divorced or widowed status|
|One or more active or chronic medical illnesses|
|Feelings of hopelessness|
|Severe anxiety, especially if mixed with depression|
During the initial visit, every patient with depression should be screened for suicidal thoughts, intent and plan, as well as the availability and lethality of a method for committing suicide. This screening may provide an opportunity for lifesaving intervention.10
Self-poisoning is the method employed in 70 percent of all suicide attempts by women.11 Thus, at the initial visit with a depressed female patient, it is prudent to prescribe only one week of an antidepressant (especially one that is potentially lethal in overdose, such as a tricyclic agent). It is also important to enlist the aid of at least one of the patient's family members or friends to monitor intake of the prescribed antidepressant so that the patient does not hoard the medication for use in a suicide attempt.
Hospitalization is necessary for patients with severe depression, psychosis, substance abuse, severe hopelessness or limited social support. Patients should also be hospitalized if they articulate or display a strong urge to act on suicidal thoughts or if they have a specific suicide plan that is likely to be successful. Typically, such patients require management by a psychiatrist.
Outpatient management is appropriate for patients with less severe depression who have infrequent suicidal thoughts, who are willing to contract for safety and let go of their instrument of suicide, who have good social support and who are willing to return for regular follow-up.12
In addition to confirming the diagnosis of depression and evaluating suicide risk, the physician should identify any relationship between depression and menstruation, pregnancy, the perinatal period or the perimenopausal period. A possible relationship between depression and medications such as birth control pills or agents used in hormone replacement therapy must also be explored.7 If there is a link to any treatable cause of depression, it should be addressed first. If the patient's depression does not respond to this intervention, further treatment is required.
Psychosocial and pharmacologic treatments may be considered. Psychosocial therapies should address issues that particularly affect women, such as competing roles and conflicts.13 Commonly used treatments include psychotherapy to correct interpersonal conflicts and to help women develop interpersonal skills; cognitive-behavioral therapy to correct negative thinking and associated behavior; and couples therapy to reduce marital conflicts. In patients with mild to moderate depression, psychosocial therapies may be used alone for a limited period, or they may be used in conjunction with antidepressant medication.
The pharmacokinetics of antidepressant drugs differ somewhat in men and women (Table 5).2,7,14 Thus, standard pharmacotherapy may have to be modified for use in female patients. Currently, little is known about these pharmacokinetic differences because many more men than women have participated in investigational drug studies. Nonetheless, certain gender-related differences merit consideration.14
|Parameters||Differences in women compared with men|
|Frequency of seeking help||May be greater|
|Absorption of antidepressant||Greater|
|Ratio of body fat to muscle||Greater|
|Volume of drug distribution||Larger|
|Plasma concentration of antidepressant||May be higher|
|Antidepressant dosage||May need to be lower|
|Side effects of antidepressants||More frequent|
|Effect of progesterone||Increased microsomal and monoamine oxidase enzyme activity with decreased monoamine neurotransmitters|
|Effect of estrogens||Decreased microsomal and monoamine oxidase enzyme activity with increased monoamine neurotransmitters|
|Duration of therapy||May need to be longer|
|Efficacy of cognitive-behavioral and interpersonal therapy||Similar|
|Efficacy of combined medication and psychotherapy||Similar or may be greater|
|Need for treatment of comorbid anxiety, panic, phobic and eating disorders||Greater|
|Need for thyroid screening||More frequent|
Absorption of antidepressants may be enhanced in women because they secrete less gastric acid than men. In addition, gastrointestinal transit time may be slower in women, especially during high progesterone phases of the reproductive cycle. This slower transit time may also enhance the absorption of antidepressant medications. Another difference is the higher ratio of body fat to muscle in women; this ratio becomes even greater with age and increases the volume of distribution for many drugs. Finally, progesterone increases microsomal and monoamine oxidase enzyme activity, whereas estrogen decreases this activity; these actions affect monoamine neurotransmitters and drug metabolism.7
Because of these biologic differences, antidepressant plasma concentrations may be higher in women. Thus, female patients with depression may require lower dosages of antidepressants than their male counterparts. Women may also experience drug side effects more frequently. Although women frequently experience sexual side effects, they generally do not report these effects unless specifically asked.
Depression and the Lifetime Reproductive Cycle
PREMENSTRUAL DYSPHORIC DISORDER
The DSM-IV classifies premenstrual dysphoric disorder (PMDD) under research diagnostic criteria as depression not otherwise specified (Table 6).8 Mood and anxiety symptoms can occur only during the premenstrual period, or preexisting symptoms can become worse at this time. Identifying and treating symptoms that have a significant effect on patients is important; dismissing them as “simple” premenstrual symptoms deprives women of potentially beneficial treatment.
|A. Presence of five of 11 depressive, anxiety, cognitive or physical symptoms, with at least one of four specific symptoms experienced in most of the menstrual cycles for the past year. The symptoms may begin a week before menses and must completely remit within a few days after the onset of menses.|
|Depressive symptoms||Anxiety symptoms||Cognitive symptoms||Physical symptoms|
|Markedly depressed mood, feelings of hopelessness, self-deprecation†|
Suddenly feeling sad or tearful, with increased sensitivity to personal rejection†
Decreased interest in usual activities
Lethargy, fatigue, marked lack of energy
Marked changes in appetite and cravings for certain foods
Insomnia or hypersomnia
|Marked anxiety, tension, feeling of being “keyed up” or “on edge”†|
Persistent or marked irritability, anger, increased interpersonal conflicts†
Feeling overwhelmed or out of control
|Subjective sense of having difficulty concentrating||Breast tenderness or swelling, headaches, joint or muscle pain, weight gain, “bloated” feeling|
|B. Symptoms interfere with social, occupational, sexual or school functioning.|
|C. Symptoms are discretely related to menstrual cycle and are not merely worsening of preexisting depression, anxiety or personality disorder.|
|D. Criteria A, B and C must be confirmed prospectively by daily ratings for at least two consecutive menstrual cycles.|
PMDD is a severely distressing and debilitating condition that requires treatment. Between 3 and 5 percent of women meet the diagnostic criteria for this disorder, which presents with symptoms of depression and anxiety as well as cognitive and physical symptoms. The diagnosis of PMDD requires the presence of five of 11 symptoms, with at least one of the first four symptoms experienced during the last week of the luteal phase; in addition, remission of symptoms must occur within a few days of the onset of menstruation. The symptoms should not represent the exacerbation of preexisting anxiety, depression or personality disorder. Furthermore, duration, impairment and prospective diagnostic validation criteria must be met.
The literature shows a lack of consensus regarding the pathophysiology of PMDD and its relationship to neuroendocrine, hormonal or serotoninergic mechanisms.15 Many investigators have concluded that women with this disorder have an abnormal response to normal gonadal steroids.3 Longitudinal studies5,15,16 indicate that women who experience PMDD have a greater risk of future depression during pregnancy, the postpartum period and the perimenopausal period, thereby suggesting a biochemical relationship between depression and the disorder.
Both nonpharmacologic and pharmacologic measures have been employed in the treatment of PMDD (Table 7).17–24 Nonpharmacologic treatments such as aerobic exercise, caffeine restriction, complex carbohydrate consumption and moderation of alcohol intake have not been consistently beneficial in alleviating the symptoms of the disorder.17
|Consumption of complex carbohydrates and frequent meals|
|Pyridoxine (a form of vitamin B6)|
|Nonsteroidal anti-inflammatory drugs|
|Selective serotonin reuptake inhibitors ‡|
|Gonadotropin-releasing hormone agonists†|
Pharmacologic treatments for PMDD have included progesterone, antidepressants and antianxiety drugs.18–20 Progesterone therapy has been relatively ineffective.21 Although tricyclic antidepressants have been beneficial, side effects limit their use. Serotonergic antidepressants appear to be effective in reducing symptoms.22 Clomipramine (Anafranil), a tricyclic antidepressant, may also be effective.22 Gonadotropin-releasing hormone (GnRH) agonists such as leuprolide (Lupron) have been effective23; because GnRH agonists can cause menopausal symptoms, they should be used only in patients who are resistant to other forms of therapy. The results achieved with benzodiazepines, especially alprazolam (Xanax), have been mixed.20,24 The current literature indicates that if simpler, nonpharmacologic options are ineffective, selective serotonin selective reuptake inhibitors (SSRIs) may be used to treat patients with PMDD.22 The use of calcium supplementation to reduce symptoms has recently attracted interest.
DEPRESSION DURING PREGNANCY
In the past, pregnancy was viewed as a period of well-being that made women feel biologically “complete” and that provided “protection” against psychiatric disorders.25,26 However, the prevalence rates for depression are now known to be similar in pregnant and nongravid women.25,26 Factors such as a history of depression or PMDD, younger age, limited social support, living alone, greater number of children, marital conflict and ambivalence about pregnancy increase the risk of depression during pregnancy and the postpartum period.26 A history of depression during the antenatal phase remains one of the strongest predictors of future depression during pregnancy and the puerperium.
Pharmacotherapy for depression during pregnancy requires an assessment of the risks and benefits of treatment for both mother and fetus. The risks of treatment should be compared with the risks of not treating depression, which may include suicide, poor maternal and fetal nutrition, an adverse neonatal obstetric outcome and the continuation of depression into the postpartum period. Untreated depression may also affect mother-child bonding and may be a cause of chronic depression and treatment resistance.
A prospective European study27 of 689 women exposed to therapeutic dosages of tricyclic and noncyclic antidepressants during the first trimester of pregnancy found no causal relationship between in utero exposure to these drugs and adverse pregnancy outcomes. Similar findings were reported for another study of 400 pregnant women with documented exposure to tricyclic antidepressants.28
One study involving 228 pregnant women treated with fluoxetine during the first trimester found no increase in teratogenicity but did note perinatal neurobehavioral effects.29 Other investigators observed no effect on global intelligence quotient, language or behavioral development in preschool children exposed in utero to either tricyclic antidepressants or fluoxetine.30
No increase in teratogenic risk was reported in another prospective study31 of in utero exposure to the SSRIs (fluvoxamine, paroxetine and sertraline). In addition to being safe for use in pregnancy, these agents have favorable side effect profiles and therefore may be considered first-line therapy for depression severe enough to justify the use of medication during pregnancy. This recommendation is not consistent with the pregnancy ratings from the U.S. Food and Drug Administration32 (Table 8).11,27–35 Note, however, that experts in the field of teratology consider these ratings inadequate for determining safety in pregnancy.33
|Medication||Rating for use in pregnancy*||Adverse effects on breast-fed infants||Dosage range (mg per day)†||Cost (generic)‡|
|Amitriptyline (Elavil)||D||None||75 to 300||$ 29 (3 to 5)|
|Clomipramine (Anafranil)||C||None||75 to 300||45 (37 to 40)|
|Doxepin (Sinequan)||C||Apnea, drowsiness||75 to 300||32 (9 to 13)|
|Imipramine (Tofranil)||D||None||75 to 300||42 (3 to 10)|
|Trimipramine (Surmontil)||C||NA||75 to 300||65 for 25-mg tablets|
|Amoxapine (Asendin)||C||NA||100 to 600||65 (41 to 50)|
|Desipramine (Norpramin)||C||None||75 to 300||47 (18 to 22)|
|Nortriptyline (Pamelor)||D||None||50 to 200||57 (37 to 45)|
|Protriptyline (Vivactil)||C||NA||20 to 60||42 (34 to 37)|
|Bupropion (Wellbutrin)||B||None||225 to 450||62 for 75-mg tablets; 83 for 100-mg tablets|
|Maprotiline (Ludiomil)||B||NA||100 to 225||43 (32 to 33)|
|Mirtazapine (Remeron)||C||NA||15 to 45||59|
|Nefazodone (Serzone)||C||NA||300 to 600||58|
|Trazodone (Desyrel)||C||NA||150 to 600||115 (21 to 32)|
|Venlafaxine (Effexor)||C||NA||75 to 225||34|
|Selective serotonin reuptake inhibitors§¶|
|Fluoxetine (Prozac)||C||Gastrointestinal effects, irritability, insomnia||10 to 40||71|
|Fluvoxamine (Luvox)∥||C||NA||100 to 300||64|
|Paroxetine (Paxil)||C||NA||20 to 50||62|
|Sertraline (Zoloft)||C||None||50 to 150||65|
|Monoamine oxidase inhibitors|
|Phenelzine (Nardil)||C||NA||45 to 90||38|
|Tranylcypromine (Parnate)||C||NA||20 to 60||30|
|Lithium||D||Lithium toxicity||900 to 1,200||8 (2 to 7)|
Interpersonal and cognitive-behavioral therapies may have a special advantage in pregnant patients with less severe depression. These techniques can be helpful in resolving interpersonal and psychosocial conflicts, resulting in a positive outcome without exposing the mother or fetus to drugs. Such treatments can enhance pregnancy outcome.
Electroconvulsive therapy has been used to treat depression in pregnancy for over 50 years. This technique has been reported to be relatively safe in pregnant women with severe, refractory depression.36
DEPRESSION DURING THE POSTPARTUM PERIOD
Between 30 and 75 percent of women experience mild postpartum “blues” lasting four to 10 days. This postpartum depression is characterized by labile mood, tearfulness, irritability, anxiety, and sleep and appetite disturbances.34 Patient education and reassurance are generally adequate treatment measures.34 If physical symptoms (Table 2) and depressed mood persist for two weeks, patients should be evaluated for postpartum major depression, particularly if they have a history of depression.
Postpartum major depression is relatively common, with a prevalence rate approximately the same as that for major depression in nonpregnant women. Symptoms usually begin during the third trimester and are similar to those for major depression. In the United Kingdom, the Edinburgh Postnatal Depression Scale, a 10-item self-rating scale, is often used to detect postpartum depression.37 The risk of postpartum depression is increased in women with pregravid depression, a history of PMDD during pregnancy, primiparous status, negative life events during pregnancy, an inadequate social support system and marital problems.
Pharmacologic and nonpharmacologic techniques have been used in the treatment of postpartum major depression. Nonpuerperal and puerperal depression are treated similarly unless the mother is breast-feeding. Data regarding the excretion of antidepressants in breast milk are limited.32 The American Academy of Pediatrics Committee on Drugs35 concluded that “antidepressants are drugs whose effect on nursing infants is unknown but may be of concern.” Based on some reports, antidepressants considered to have no adverse effects on breast-fed infants (Table 8) may be considered for use in women with postpartum depression. Electroconvulsive therapy may be of value in patients who have severe depression with psychosis and an increased risk of suicide.
Some investigators have found that estrogen therapy may be effective in patients with post-partum major depression.38 Double-blind studies are necessary before this therapy can be recommended for general use.
Although pharmacotherapies for depression carry some risks, untreated depression may lead to significant problems. If depression is not treated, poor self-care, poor nutrition and newborn neglect may adversely affect infant development and maternal-child bonding.
DEPRESSION DURING THE PERIMENOPAUSAL PERIOD
Perimenopause has been viewed as a period of risk for depression. However, depressive disorders do not seem to cluster around this period of the reproductive cycle.2 Symptoms of menopausal depression often occur in conjunction with vasomotor instability as a result of declining ovarian function.
Depression during both nonmenopausal and menopausal phases is diagnosed and treated in a similar manner. Estrogen replacement alone can provide relief of vasomotor symptoms, and minor cognitive and mood symptoms. This therapy is also useful in preventing osteoporosis. However, hormone replacement therapy has limited benefit in the treatment of major depression unless patients receive concomitant antidepressant drug therapy and/or psychotherapy.
DEPRESSION ASSOCIATED WITH INFERTILITY, MISCARRIAGE OR PERINATAL LOSS
The grief reaction related to infertility, miscarriage or perinatal loss of an infant is usually self-limited. If this reaction persists beyond eight weeks and self-esteem is reduced, patients should be evaluated for an adjustment disorder with depressed mood or major depression. If diagnosed, these disorders should be treated.