Gender Issues in the Treatment of Mental Illness

Significant gender differences exist in the course and manifestation of schizophrenia. Although the incidence of schizophrenia has been widely reported to be approximately equal in men and women, a recent meta-analysis of the literature from the past two decades reported that the incidence risk ratio for men relative to women is between 1.31 and 1.42 (Aleman et al. 2003). The authors of this study suggested that these findings may reflect an increasing preponderance of schizophrenia in men in recent years. This increase may be related to the use of illicit drugs, which may precipitate the illness in genetically vulnerable men. Because oral contraceptives contain estrogen, which has dopamine-blocking effects in animal studies, the use of these agents may have had a protective effect in some women.

In men, rates of new-onset schizophrenia reach a peak between ages 15 and 24 years. For women, the peak occurs between ages 20 and 29 years. About 15% of women with schizophrenia do not develop the illness until their mid- or late 40s, possibly reflecting a response to the perimenopausal decline of estrogen (Aleman et al. 2003) (Table 1). For men, onset of the illness after age 40 years is rare. The diagnosis of schizophrenia is more likely to be delayed in women, in some cases possibly because of misdiagnosis of either major depression or bipolar disorder, as schizophrenia in women tends to be more affect-laden (Seeman 2004).

Other gender differences include a more favorable premorbid history in women and more favorable outcome, at least in the first 15 years after onset of the illness (Grigoriadis and Seeman 2002; Seeman 2004). Women with schizophrenia tend to experience more affective and positive symptoms and fewer negative symptoms (e.g., social withdrawal and lack of drive) than men. In addition, women who present initially with schizophrenia after age 45 years typically suffer fewer negative symptoms than either men of the same age with schizophrenia or age-matched women with early-onset schizophrenia (Lindamer et al. 1999). Structural brain abnormalities, such as increased ventricle size and decreased hippocampal volume, appear to be less common in women with schizophrenia than in men with the disorder (Cowell et al. 1996). Because relatives of women with schizophrenia are more likely to develop the illness, compared with relatives of men with schizophrenia, some researchers have suggested that schizophrenia is a more heritable illness in women and that environmental factors, such as birth complications, may be of more etiological significance in men (Castle and Murray 1991).

Issues in the treatment of women with schizophrenia are listed in Table 2. Some, but not all studies suggest that, compared with men, women respond better to treatment and may require lower doses of medication before menopause (Seeman 2004). Findings of a more favorable treatment response and course of illness in women have supported the speculation that estrogen may have a protective effect against schizophrenia (Szymanski et al. 1995). It is noteworthy that symptomatic exacerbation of schizophrenia and an increase in psychiatric hospital admission rates have been observed during the low-estrogen phases of the menstrual cycle (Bergemann et al. 2002; Choi et al. 2001; Seeman 1996; Szymanski et al. 1995) and in perimenopausal and postmenopausal years (Seeman 1986).

The menstrual patterns of women with schizophrenia should be monitored routinely. Careful clinical monitoring of symptoms in relation to the menstrual cycle, perhaps with the use of a diary, may be useful. If such monitoring indicates pre-menstrual worsening of symptoms, exacerbation of symptoms may be minimized by raising antipsychotic doses during the symptomatic pre-menstrual days. Women with schizophrenia should also be monitored carefully for worsening illness as they transition into menopause, as it may be necessary to increase antipsychotic doses at this time.

In a small double-blind, placebo-controlled study of acutely symptomatic premenopausal antipsychotic-treated women with schizophrenia, the use of transdermal estradiol as an adjunctive treatment resulted in significant improvement in psychotic symptoms (Kulkarni et al. 2001). Further studies are needed to determine whether estrogen may have a role as an adjunctive agent for the treatment of women with schizophrenia. Estrogen therapy in postmenopausal women has been associated with increased risks for cardiac events, pulmonary embolism, stroke, dementia, and breast cancer (Rossouw et al. 2002), and therefore estrogen therapy should not be used for the treatment of psychiatric symptoms unless its benefits clearly outweigh its risks.

Certain antipsychotic medications (e.g., risperidone, haloperidol, fluphenazine) can cause irregularities in the menstrual cycle by increasing levels of the pituitary hormone prolactin, which in turn inhibits release of follicle-stimulating hormone (FSH) from the pituitary. As FSH is necessary for maturation of the ovarian follicles, a hyperprolactinemic state can prevent ovulation. Furthermore, hyperprolactinemia and the ensuing hypoestrogenemia can lead to a reduction in bone mineral density (Seeman 2004). Amenorrhea (i.e., absence of the menstrual cycle) is not unusual when prolactin levels exceed 60 ng/mL (normal prolactin levels are 5–25 ng/mL) (Seeman 1983). Galactorrhea, or nipple discharge, may also occur with elevated prolactin levels. If prolactin levels exceed 100 ng/mL, a brain-imaging study (preferably magnetic resonance imaging [MRI]), should be performed to rule out a prolactin-secreting pituitary tumor. Additional causes of elevated prolactin include pregnancy, nursing, stress, weight loss, opiate use, and use of oral contraceptives (Marken et al. 1992). For women of childbearing age with menstrual cycle disturbances, β-human chorionic gonadotropin (β-HCG) levels should be measured to test for pregnancy. Other relatively common causes of irregularities in the menstrual cycle include hypothyroidism and primary hyperprolactinemia. If hyperprolactinemia is determined to be secondary to the use of an antipsychotic agent, the dose should be reduced or the medication should be replaced with one of the newer antipsychotic agents, such as olanzapine, ziprasidone, aripiprazole, or quetiapine, which do not tend to raise prolactin levels. As an alternative, dopamine agonists such as bromocriptine (2.5–7.5 mg bid) or cabergoline (0.5 mg/week) can be used to reduce prolactin levels. At these low doses, bromocriptine does not appear to exacerbate psychosis. The effect of cabergoline on psychotic symptoms has not been evaluated. Cabergoline requires only once or twice weekly dosing and produces few side effects, whereas bromocriptine must be taken daily and can cause significant nausea. To minimize the nausea, bromocriptine should be taken with food. A third strategy is initiation of an oral contraceptive. This approach returns the patient to regular menstrual cycling and, by restoring estrogen, protects against the long-term adverse effects of a hypoestrogenic state, such as osteoporosis. In addition, this approach has the advantage of providing contraception. Prolactin levels, however, may rise with use of oral contraceptives and thus should be monitored closely. If prolactin levels rise or amenorrhea persists, the woman should be referred for a gynecological and endocrinological evaluation.

Women with schizophrenia are at particular risk for pregnancy resulting from ineffective use of birth control and high rates of sexual assault. Even women with antipsychotic-induced amenorrhea may occasionally ovulate and thus can become pregnant. Teaching women with schizophrenia about methods for birth control and strategies for avoiding unwanted sexual advances is an important aspect of treatment. Women with schizophrenia who become pregnant are at increased risk for stillbirth, preterm delivery, and low-birth-weight babies, and their newborns are at increased risk for sudden infant death syndrome (Bennedsen et al. 2001; Nilsson et al. 2002; Jablonsky et al. 2005). Women with schizophrenia are also at increased risk for giving birth to an infant with cardiovascular congenital anomalies (Jablonsky et al. 2005). Although the reasons for these findings are not clear, research in obstetric clinics has found that pregnant women with schizophrenia typically attend fewer than 50% of prenatal care appointments (Kelly et al. 1999), and inadequate prenatal care significantly increases the relative risk of preterm birth and postnatal death (Vintzileos et al. 2002a, 2002b). Clinicians working with pregnant schizophrenia patients should strongly encourage them to obtain regular prenatal care in an effort to improve their birth outcomes.

Anxiety disorders are the most prevalent psychiatric disorders, affecting one of every 10 people in the United States (Robins et al. 1984; Wells et al. 1989). As a class, anxiety disorders are more prevalent in women than in men, and women with anxiety disorders are more likely than men to experience comorbid depression (Pajer 1995; Pigott 2003). Panic with agoraphobia and generalized anxiety disorder (GAD) are two to three times more common in women than in men (Bourdon et al. 1988; Robins et al. 1984; Schneier et al. 1992), and social phobia is three to four times as common in women than in men (Schwartz et al. 1996). The rates of generalized anxiety disorder are stable in both women and men between the ages of 25 and 34 years but increase more in women older than 34 years than in age-matched men. Thus, the prevalence of GAD increases from about 1.5% in young men ages 15–24 years to 3.6% in men older than 45 years. However, in women the prevalence increases from 2.5% at age 15–24 years to 10.3% in women older than 45 years (Halbreich 2003). The rate decreases in aging men but further increases in women as they age (Robins et al. 1984). Women with panic disorder are just as likely as men to recover but are twice as likely to have a subsequent recurrence of symptoms (Yonkers et al. 1998).

Women with alcoholism are more likely to have panic disorder with agoraphobia than are men with alcoholism (Task Force on Panic Anxiety and Its Treatments 1993). Whether agoraphobia is a precipitant for alcoholism in women is unclear. Although the prevalence rates for obsessive-compulsive disorder (OCD) are approximately equal for men and women, women appear to have a somewhat later onset than do men (average age of 25 years in women versus 20 years in men) (Flament and Rapoport 1984). Whereas the overall lifetime prevalence of exposure to traumatic events does not vary by gender (Breslau et al. 1997), lifetime rates of post-traumatic stress disorder (PTSD) are twice as high in women as in men (estimated at 10.4% for women and 5% for men) (Kessler et al. 1995). The reasons for the preponderance of anxiety disorders in women are not clear. Although genetic factors play a role in the transmission of anxiety disorders (Kendler et al. 1992, 1993), they have not been found to account for the gender differences in prevalence rates. Other possible causes for the preponderance of anxiety disorders in women include the increased prevalence rate of depression in women; the increased demands related to work and family that are currently placed on women; reproduction-related alterations in hormones; the relatively lower level of encouragement of self-sufficiency and self-confidence in girls, compared with boys; and histories of physical and sexual abuse (Pigott 2003; Zerbe 1995). With regard to PTSD, women may be culturally primed to experience traumatic events differently than men, rather than having an increased biological vulnerability. Thus, although women are more likely than men both to be molested and to subsequently develop PTSD, women are also more likely to develop PTSD after a physical assault despite the fact that men are much more likely to be victims of assault. However, although women are 10 times more likely than men to be raped, PTSD is more likely to result after this experience in men than in women (65% vs. 46%) (Yehuda 2002).

Evaluation for anxiety should first rule out medical conditions that present with anxious symptoms. In evaluating women patients for anxiety, the clinician should give particular attention to certain medical disorders. Although it appears that women with panic disorder are more likely to experience respiration-related difficulties than men with panic disorder (Sheikh et al. 2002), complaints of chest discomfort, diaphoresis, and tachycardia warrant a thorough diagnostic evaluation for heart disease. Women with these symptoms are more likely than men to be misdiagnosed as having an anxiety disorder and less likely than men to receive a cardiac assessment (Wenger et al. 1993). Mitral valve prolapse has been associated with panic disorder and is more prevalent in women (Yonkers and Gurguis 1995). The patient’s symptoms in relation to the menstrual cycle should also be evaluated, as women of reproductive age may experience premenstrual onset or worsening of anxiety. Patients with hypo- or hyperthyroidism may develop panic attacks with the onset of their thyroid condition. A thyroid panel should therefore be obtained in women reporting anxiety, tachycardia, diaphoresis, temperature intolerance, or tremor. Thyroid disease is more prevalent in women than in men, particularly in women older than age 40 years. Other medical illnesses that affect women more than men and that may present with symptoms of anxiety include systemic lupus erythematosus, iron deficiency anemia, and irritable bowel syndrome.

Nicotine and caffeine use should be assessed in women who report symptoms of anxiety and insomnia. Although in recent years the rate of cigarette smoking has declined in the general population, it has risen among teenage girls.

A full assessment of a patient’s medications should be part of the workup for an anxiety disorder. A number of medications may induce symptoms of anxiety, including decongestants, steroids, herbal supplements, and appetite suppressants.

The workup should also include an assessment of past and recent traumatic events. Women are more likely than men to experience rape and sexual assault, whereas men experience higher rates of nonsexual assault. Among women, rates of PTSD after sexual and nonsexual assault are estimated at 95% and 75%, respectively, within 2 weeks of the crime. Three months after the trauma, these rates diminish to approximately 50% for sexual assault and 25% for nonsexual assault. Female victims of sexual and nonsexual assault have been successfully treated with two forms of cognitive-behavioral treatment: prolonged exposure treatment and stress inoculation training (Foa 1997). Prolonged exposure treatment involves the patient’s repeated reliving of the trauma, combined with verbal recounting in therapeutic sessions, relaxation techniques, education about common reactions to trauma, and exposure to situations that remind the patient of the trauma. Stress inoculation training helps patients develop coping skills to deal with anxiety. These skills include muscle relaxation, breathing control, role-playing, thought-stopping, and self-dialogue.

Perimenopausal women may experience heat sensations, sweating, shortness of breath, and anxiety. For these women, vasomotor symptoms may be mistaken for panic or anxiety attacks (see Chapter 8, section titled “Physical changes”). A history of menstrual cycle alterations, measurement of the FSH level, and measurement of the estradiol level on day 2 or day 3 of the menstrual cycle (for women who are still cycling) can identify perimenopausal status. Hormone therapy rather than anxiolytic or antidepressant medication may suffice to resolve these symptoms if they are of vasomotor origin. Since estrogen and progestin therapy in post-menopausal women has been associated with increased risks for cardiac events, pulmonary embolism, stroke, dementia, and breast cancer, hormone therapy should be prescribed at the lowest effective dose for no more than 4–5 years (Rossouw et al. 2002).

Although women and men appear to have an equal prevalence of OCD, women seem to have more obsessions related to food and weight than do men, and women are also more likely to have comorbid anorexia (Kasvikis et al. 1986). It is therefore important to carefully evaluate all women with OCD for symptoms of restrictive-eating disorders.

Special considerations in the screening and treatment of substance-abusing women are listed in Table 7. Any woman who presents with complaints of depression, anxiety, insomnia, sexual dysfunction, job problems, or family and marital conflicts should be assessed for substance abuse. Of particular concern is the direct request for specific prescription medications. Women who report great preoccupation with their weight should be assessed for the use of diet pills or stimulants. Although a careful history is the most important part of the evaluation, the CAGE questionnaire (Table 8) is a helpful screening instrument for alcoholism (Ewing 1984). Laboratory values are not reliably useful in screening for alcoholism, but they can help confirm the diagnosis. Elevated results on liver function tests, primarily the level of γ-glutamyltransferase (GGT), and a high mean corpuscular volume (MCV) suggest a history of extensive drinking. Medical problems such as peptic ulcer, hypertension, anemia, and liver disease result from heavy alcohol consumption and should prompt investigation into drinking patterns.

Noting the presence of alcohol- and drug-related legal and employment problems is helpful in making a diagnosis of substance abuse, although more so in men than in women. Women who abuse alcohol or drugs, on the other hand, are more likely to have family, interpersonal, and health problems (Cyr and Moulton 1993). Because depression frequently precedes or is comorbid with substance abuse in women, all women with alcoholism or drug dependence should be assessed for current and previous depressive episodes. If a woman has a history of depression preceding her substance dependence, she is at risk for a depressive relapse as she recovers (Blume 1994; Ewing 1984; Griffin et al. 1989). Treatment of depression may reduce the likelihood that the patient will return to substance abuse. For the same reason, comorbid anxiety disorders should be treated. Addictive prescription medications are best avoided, because women with alcoholism are at risk for prescription drug abuse. An assessment for premenstrual symptoms is important, because up to two-thirds of women with alcoholism may drink to self-medicate premenstrual tension (Hendrick et al. 1996). Treatment of the premenstrual symptoms may reduce the alcohol use.

For any treatment plan to be effective, it is essential that the substance-abusing woman accept that she has an illness and recognize the interpersonal, psychological, and medical consequences of her drug use. Referrals to self-help groups—including Alcoholics Anonymous, Cocaine Anonymous, and Women for Sobriety, an all-woman support group—are important aspects of treatment. The woman’s family should be involved; family support and concern may help motivate the patient to remain in recovery. Family members can benefit from referrals to Al-Anon. Because a woman’s drinking or drug use pattern is greatly influenced by that of her partner, her likelihood of reaching sobriety is enhanced if her partner is sober. Thus, an evaluation of the partner’s drinking or drug use patterns is important. If the partner also has a substance use problem, he or she should be encouraged to obtain treatment. Family and marital conflicts may contribute to a woman’s drinking or drug use and should be explored. Attention should be given to child care needs that may interfere with a woman’s ability to obtain treatment.

Societal stigmatization of women drinkers may cause women to hide drinking problems. Women may also fear losing custody of their children if they reveal their alcoholism. It is therefore essential that women with alcoholism be treated in a non-judgmental and supportive manner. Group and individual therapy are helpful, particularly in addressing issues of shame and low self-esteem and in promoting assertiveness.

The combined prevalence of anorexia nervosa and bulimia nervosa is approximately 4%, with more than 90% of cases occurring in women (Leach 1995). These illnesses typically develop in puberty and are more common in industrialized societies. Anorexia nervosa is characterized by a body weight of less than 85% of the expected weight for age and height, intense fear of gaining weight, distorted body image, and (in postmenarcheal females) amenorrhea. Anorexia nervosa is categorized as one of two types: restricting type or binge-eating/purging type. Approximately 50% of cases fall into each category (Mickley 2000). Patients with bulimia nervosa engage in episodes of binge-eating, in which they experience a sense of lack of control over eating and are excessively concerned about body image. They attempt to compensate for their food intake by self-induced vomiting; use of laxatives, diuretics, and enemas; excessive exercise; or fasting. The DSM-IV-TR diagnosis of bulimia nervosa requires that the binge-eating and compensatory behaviors occur at least twice a week for at least 3 months. The disorder is categorized as either purging type (i.e., involving the use of self-induced vomiting, laxatives, diuretics, or enemas) or nonpurging type. Patients with bulimia are usually normal in weight. Anorexia and bulimia nervosa are frequently accompanied by mood, anxiety, personality, and substance use disorders. A history of substance use disorders and a longer duration of symptoms predict worse treatment outcomes (Keel et al. 1999).

The evaluation of women with eating disorders should include assessments of body image; eating habits; actual and desired weight; menstrual patterns; exercise; self-induced vomiting; presence of other psychiatric disturbance; use of laxatives, diuretics, enemas, emetics, and diet pills; and abuse of alcohol and illicit substances. A number of medical complications may result from anorexia and bulimia nervosa (Table 9) (Becker et al. 1999). Therefore, the evaluation should include a physical and dental examination and laboratory tests for albumin, total protein, and glucose levels to help assess nutritional status. Measurement of amylase levels gives an indication of the extent of self-induced vomiting. Measurement of electrolytes, blood urea nitrogen, and creatinine levels are essential for assessing fluid and electrolyte abnormalities. A complete blood count can reveal anemia from nutritional deficiency and from internal bleeding—for example, from esophageal tears resulting from self-induced vomiting. An electrocardiogram should be obtained because cardiac conduction abnormalities may occur as a result of electrolyte imbalance, malnutrition, and ipecac-induced cardiomyopathy.

The treatment of eating disorders should involve a multidisciplinary team including mental health professionals and a primary care physician, nutritionist, and dentist. The first priority for treatment is medical stabilization to correct malnutrition, electrolyte imbalance, and other serious medical problems. In life-threatening conditions, nasogastric tube feeding may be necessary. After medical stabilization, the treatment involves the establishment of healthful eating patterns and attention to the psychosocial precipitants of the condition (Leach 1995). Psychosocial interventions include family counseling, individual/couples psychotherapy, education, and group support. Two forms of structured, time-limited therapy have been effective in the treatment of bulimia nervosa: cognitive-behavioral therapy, which focuses on the relationship between thoughts, feelings, and behavior; and interpersonal therapy, which addresses the interpersonal stressors that precipitate disordered eating (Becker et al. 1999). Certain antidepressant medications, including fluoxetine, have been helpful for bulimia nervosa (Leach 1995). High doses (e.g., 60 mg/day) have been more effective than lower doses. Monoamine oxidase inhibitors (e.g., phenelzine, isocarboxazid) have also been effective but should be used only for patients who are able to avoid tyramine-containing foods. Antidepressant medications have been of little help in treating the symptoms of anorexia nervosa, although they are clearly indicated for associated mood and anxiety disorders. Tricyclic antidepressants can be helpful in promoting weight gain. Topiramate has been reported to be useful in reducing both bingeing and purging (Hoopes et al. 2003).

Most patients with anorexia nervosa will require intensive treatment in an inpatient setting or day program, where they can be supported in eating and weight gain restoration. Patients should be hospitalized if their body weight is 25% below normal, if they experience medical complications, or if they are refusing food. Weight gain should proceed at 2–3 lbs/week for inpatients and 1–2 lbs/week for outpatients. Patients with bulimia nervosa can usually be managed in outpatient settings. For both disorders, long-term maintenance therapy is recommended.

In 1995, the prevalence rate of chronic insomnia was 12%, with women having a rate 1.3 times higher than that of men (Millman 1999). The risk for sleep-related difficulties rises during certain reproductive phases of women’s lives: premenstrual bloating and cramping frequently disrupt sleep, as does the discomfort women experience in the third trimester of pregnancy, and night sweats produce sleep impairment in approximately one-third of perimenopausal women (Walsleben 1999).

Other common causes of insomnia include depression and anxiety disorders, side effects of medications (e.g., bronchodilators, blood pressure medications, decongestants), and use of alcohol, caffeine, nicotine, and illicit drugs. A number of medical conditions (e.g., asthma, chronic obstructive pulmonary disease, sleep apnea) produce insomnia by causing shortness of breath at night. Disruptions in circadian rhythm commonly caused by jet lag or rotating work shifts can produce insomnia. A restless limb syndrome, characterized by discomfort in the legs and sometimes in the arms, can also disrupt sleep.

A detailed history should be obtained to determine the etiology of the insomnia. If the underlying cause is a psychiatric or medical problem, the problem should be treated. The elements of sleep hygiene should be reviewed, including reduction in use of caffeine, nicotine, and alcohol; avoidance of napping during the day; maintenance of regular exercise; avoidance of excessive fluids in the evening; and maintenance of regular times for sleeping and waking up (Millman 1999). If sleep problems are associated with premenstrual phases, low-dose oral contraceptives may help, and short-term hormone therapy at the lowest effective dose will reduce night sweats that disrupt sleep in middle-aged women (Polo-Kantola et al. 1999). When sleep-promoting modalities are ineffective, it may be appropriate to prescribe a hypnotic agent. Benzodiazepines are the most common class of medications for the treatment of insomnia. A meta-analysis of controlled studies of the use of benzodiazepines for the treatment of insomnia revealed that both benzodiazepines and the non-benzodiazepine hypnotic zolpidem produced improvement in patients with chronic insomnia (Nowell et al. 1997). However, hypnotics should be generally prescribed only for short-term use, because long-term use raises concerns of addiction and rebound insomnia after withdrawal of the medication. Sedating antidepressants (e.g., trazodone, doxepin) can be used in place of traditional agents such as benzodiazepines to treat insomnia. Few studies have evaluated the efficacy and safety of these agents to treat insomnia over the long term.