6463_06_p1132-1140

JOURNAL OF WOMEN’S HEALTH
Volume 15, Number 10, 2006
Mary Ann Liebert, Inc.
Treatment Considerations in Women with Schizophrenia ABSTRACT
Schizophrenia is a challenging and complex psychiatric disorder. It is a chronic disorder of
thought, affect, and cognition that significantly disturbs the individual’s ability to function
in society and develop interpersonal relationships. The clinical presentation can be extremely
varied, with symptoms including delusional thinking, disorganized thoughts and speech, hal-
lucinatory behavior, and negative symptoms (e.g., blunted affect, avolition, alogia, anhedo-
nia). Approximately 1% of the population is affected by schizophrenia worldwide, and wo-
men may experience different symptoms, have a later age of onset, may respond to different
treatments, and may be more concerned about specific side effects than men. Women with
schizophrenia traditionally have been treated in the same way as men and have generally had
poorer comprehensive medical care. With the introduction of many new antipsychotic med-
ications in recent years, this review focuses on sex differences in schizophrenia, with an em-
phasis on differences in treatment and side effects. Additionally, it presents patient counsel-
ing issues in sexuality and health outcomes.
INTRODUCTION
cooperative and hostile, have impairments in self-care, and have difficulty initiating or maintaining SCHIZOPHRENIA IS A CHALLENGING and complex employment. Nevertheless, a woman with schizo-
psychiatric disorder. It is a chronic disorder phrenia must not be defined in terms of her dis- of thought, affect, and cognition that significantly ease; she requires and deserves comprehensive, disturbs the individual’s ability to function in so- ciety and develop interpersonal relationships.
The formal diagnostic criteria for schizophre- The clinical presentation can be extremely varied, and despite attempts in the media to portray astereotype, the stereotypic individual with schiz-ophrenia does not exist. It is a markedly hetero- THE GENDER FACTOR
geneous disorder, with symptoms includingdelusional thinking, disorganized thoughts and speech, hallucinatory behavior, and negativesymptoms (e.g., blunted affect, avolition, alogia, Considerable and convincing evidence sug- anhedonia). People with this disorder may be un- gests that there are sex differences in schizo- Department of Psychiatry, School of Medicine, Maryland Psychiatric Research Center, University of Maryland, Bal- TREATMENT CONSIDERATIONS IN SCHIZOPHRENIA
TABLE 1. DIAGNOSTIC CRITERIA FOR SCHIZOPHRENIA A. Characteristic symptoms: Two (or more) of the following, each present for a significant portion of time during a 1- month period (or less if successfully treated)a:• Delusions• Hallucinations• Disorganized speech (e.g., frequent derailment/incoherence)• Grossly disorganized/catatonic behavior• Negative symptoms (e.g., flat affect, alogia, avolition) B. Social/occupational dysfunction: For a significant portion of the time since the onset of the disturbance, one or more major areas of functioning, such as work, interpersonal relations, or self-care, are markedly below the levelachieved prior to onset (when onset is in childhood or adolescence, failure to achieve expected level ofinterpersonal, academic, or occupational achievement).
C. Duration: Continuous signs of disturbance persist for at least 6 months. This 6-month period must include at least 1 month of symptoms (or less if successfully treated) that meet criterion A (i.e., active-phase symptoms) and mayinclude periods of prodromal or residual symptoms. During these prodromal or residual periods, the signs of dis-turbance may be manifested by only negative symptoms or by two or more symptoms listed in category Apresent in an attenuated form (e.g., odd beliefs, unusual perceptual experiences).
• Schizoaffective and mood disorder exclusion: Schizoaffective disorder and mood disorder with psychotic fea- tures have been ruled out because either (1) no major depressive, manic, or mixed episodes have occurred con-currently with the active-phase symptoms or (2) if mood episodes have occurred during active-phasesymptoms, their total duration has been brief relative to the duration of the active and residual periods.
• Substance/general medical condition exclusion: The disturbance is not due to the direct physiological effects of a substance (e.g., drug of abuse, medication) or a general medical condition.
• Pervasive developmental disorder: If there is a history of autistic disorder or another pervasive developmental disorder, the additional diagnosis of schizophrenia is made only if prominent delusions orhallucinations are also present for at least a month (or less if successfully treated).
Adapted from American Psychiatric Association.1 aOnly one symptom from category A is required if delusions are bizarre or hallucinations consist of a voice main- taining a running commentary on the person’s behavior or thoughts or two or more voices conversing.
phrenia. There has recently been a resurgence in count for the lower rates of inpatient hospital- attention to sex differences in schizophrenia, re- ization in women than men for treatment of flecting the important contribution of these dif- ferences to the heterogeneity of schizophreniaphenomenology.2 Most data have focused on sex differences in the epidemiology and clinical ex-pression of schizophrenia. Many studies note an Another area of study addressing sex differ- overall prevalence of schizophrenia at approxi- ences in schizophrenia involves biological and mately 1%, consistently reporting a 2–3-fold neuroanatomical deficits. It is believed that male higher incidence of schizophrenia with an onset subjects with schizophrenia exhibit more struc- before age 45 years in men vs. women.3 Men with tural brain abnormalities than do women with schizophrenia also exhibit more negative symp- schizophrenia. Key neuroanatomical abnormali- tomatology than do women,4 whereas women of- ties include larger ventricle/brain ratios,11 re- ten experience more depressive and paranoid duced gray matter volume (particularly in tem- symptoms.5 Men typically experience their first porolimbic structures),6 and a lack of normal psychotic symptoms by 17–20 years of age, asymmetry.7 Males with schizophrenia also dis- whereas women may not experience symptoms play a higher rate of minor physical anomalies until 20 years of age (3–5 years later).6–8 Onset can and neurological soft signs than do female pa- also occur in postmenopausal women, although tients.8 In general, men show a greater disad- new cases typically do not occur in older men.
vantage than do women across neuropsycholog- Schizophrenia is still primarily a disease of the ical tests of cognitive function.12 More recent reproductive years.9 Women generally have bet- reports, however, have determined that women ter clinical outcomes than do men, that is, higher with schizophrenia have poorer verbal/spatial levels of social functioning, shorter hospital stays, memory and visual processing and more con- and lower relapse rates, and this may partially ac- ceptual impairments than men.13,14 Most impor- tant, however, are the differences in therapy and which are both metabolized primarily by the side effects that apply to the management of this cytochrome (CY) P450-1A2 enzyme. This enzyme is known to be less active in women than inmen.23,24 Additionally, smoking affects plasmalevels of clozapine and olanzapine, and smokers THERAPEUTIC CONSIDERATIONS
may have 40% lower plasma levels because of theinduction of liver enzymes from cigarette smoke.25 Plasma levels of the newer antipsy-chotics do not appear to differ significantly with As early as the 1960s, significant sex differences monotherapy in men vs. women, but women may need lower doses of clozapine and olanzapine.
noted.15 Other studies continued to suggest a su- Women are more likely than men to be using perior response in women taking conventional antidepressants and mood stabilizers that may in- antipsychotic medications, such as chlorpro- teract with antipsychotic metabolism, potentially mazine and haloperidol,16,17 although these early leading to increased/decreased antipsychotic studies did not generally take into account base- plasma levels. For example, antiepileptic drugs line differences, such as age of onset, when re- porting results, and diagnostic misclassifications haloperidol levels that are almost 30% lower than were likely. A more recent double-blind, ran- values in those not taking antiseizure drugs.26 domized study that matched clinical and demo- Carbamazepine has been found to reduce the graphic variables between men and women failed concentration/dose ratio of olanzapine by almost to find any differences in outcomes between the 40%.27 Selective serotonin reuptake inhibitors sexes when treating with conventional antipsy- (SSRIs) may lead to 4-fold increases in plasma chotics.18 In contrast, other studies that controlled levels of risperidone via competitive inhibition of for baseline variables have reported that women the CYP450-2D6 enzyme.28 Because no therapeu- are more likely to respond to these medica- tic range has been established for plasma con- tions,4,9,19 so women may have some benefits centrations of newer antipsychotics (except for over men in this area. No consensus has been clozapine at Ͼ350 ng/mL), sex-based dosage ad- reached. The second-generation antipsychotics justments are not always pertinent. However, ad- (SGAs) risperidone, olanzapine, quetiapine, justment may be required if side effects are evi- ziprasidone, and aripiprazole are now recom- dent in women that may be due to higher plasma mended as first-line therapy for both men and levels. Lower doses may be appropriate for wo- women, but none of these antipsychotics has men who are nonsmokers, or in the presence of demonstrated an advantage over the others in interacting medications that inhibit metabolism.
comparative clinical trials to date. One study Adipose tissue may lead to drug accumulation, showed no appreciable gender differences in ef- and adult women generally have an average adi- ficacy for risperidone,20 and another trial with posity of 33% compared with 20% in men. As olanzapine found a significantly greater response most antipsychotics are lipophilic and have large in women than in men.21 Thus, antipsychotic ef- volumes of distribution, maintenance depot in- ficacy is not generally different between the sexes.
jections of conventional antipsychotics should be Although women may have a more robust re- used less frequently in women than in men.29 sponse than men independent of the specificdrug, the most important consideration is the side effect profiles of the individual antipsychotics.
Such factors as genetics, height, weight, age, Women may be at increased risk of adverse lean/fat ratio, comorbid conditions, smoking, drug reactions from antipsychotic therapy, with and diet can contribute to differences in drug re- a 1.5–1.7-fold greater risk of side effects compared sponse and dosing. Because men and women of- with men.30 The incidence and severity of an- ten differ on all these variables, disparities may tipsychotic side effects most likely depend on be evident. As a group, women have higher drug plasma levels, so the factors that affect plasma levels of antipsychotics than men at the serum concentrations may contribute to the risk same dosage.22 This difference in plasma levels is of side effects. As a class, the conventional most evident with clozapine and olanzapine, antipsychotics (e.g., haloperidol, fluphenazine, TREATMENT CONSIDERATIONS IN SCHIZOPHRENIA
chlorpromazine) are relatively similar in their represent a high-risk group for diabetes occur- side effect profiles, with the most troubling ad- rence with new medications.34 Monitoring guide- verse effects being extrapyramidal symptoms lines have been developed, as this concern has be- and tardive dyskinesia. Acute dystonia was long thought to be more prevalent among youngermen under treatment, but a 10-week study at equivalent doses reported higher rates of dysto- Some antipsychotics have effects on electro- nia in first-episode women.31 Furthermore, el- cardiographic findings, especially on the cor- derly women generally have a higher risk of rected QT interval (QTc). Extending from the be- tardive dyskinesia from conventional antipsy- ginning of ventricular depolarization (QRS chotics.31,32 The newer class of antipsychotics (i.e., complex) to the end of repolarization (T wave), clozapine, risperidone, olanzapine, quetiapine, the QT interval is shorter with faster heart rates, ziprasidone, aripiprazole) are more heteroge- and longer with slower heart rates. Therefore, a neous in their side effect profiles, and each is as- correction for rate (QTc) is applied to make the sociated with unique pharmacological profiles in reporting of the interval more meaningful. The QTc intervals are generally considered to be pro-longed if they are Ͼ450 milliseconds in men or Weight gain and metabolic complications Ͼ470 milliseconds in women. In both sexes, QTc Antipsychotic-induced side effects may have prolongation Ͼ500 milliseconds may increase the different significance for men and women. Wo- risk of torsades de pointes. Women have longer QTc men tend to be more distressed by effects that de- intervals at baseline, which may predispose them tract from their appearance. Obesity is particu- to these phenomena. Postmenopausal women us- larly problematic for women, and drug-related ing estrogen therapy have significantly longer weight gain may be more prevalent in women QTc intervals than nonusers.36 Drug-induced than in men. Long-term morbidity and mortality QTc prolongation was found in one study to be from obesity and other metabolic effects of an- higher during ovulation than in the luteal phase tipsychotics (e.g., type 2 diabetes, cardiovascular of the menstrual cycle, corresponding to higher disease, hyperlipidemia) affect both men and wo- estrogen levels.36 Other factors that may pre- men, and family and individual risk factors dispose patients to a longer QTc interval are should be considered in overall management.
metabolic abnormalities (hypokalemia, hypo- Clozapine and olanzapine are associated with the magnesemia, hypothyroidism, hypocalcemia), greatest risk for weight and metabolic conse- hyperglycemia, alcoholism, bradycardia, and car- quences, with an estimated average weight gain diac disease.36 Moreover, QTc prolongation oc- in 10 weeks of 4–5 kg.33 Risperidone and queti- curs at routine doses to some degree with all the apine are associated with somewhat lower weight antipsychotics. Increases have been reported at 20 gain and risk for metabolic effects, and there is milliseconds for ziprasidone, 30 milliseconds for little evidence of an association for ziprasidone thioridazine, and 7–15 milliseconds for the other and aripiprazole. African American women may newer antipsychotics and haloperidol.36 Women TABLE 2. SIDE EFFECTS AND TOLERABILITY OF ATYPICAL ANTIPSYCHOTICS aϩ, increased effect; Ϫ, no effect; D, discrepant results.
bFewer drugs with limited long-term data.
Adapted from Allison and Casey.33 with risk factors and concurrent medications that male and female patients report that one of the inhibit ziprasidone metabolism may do best to areas with the highest proportion of unmet needs avoid this drug as first-line therapy.
is counseling about intimate relationships.42Studies addressing sexual issues have generally concluded that schizophrenia patients are pre-pared and willing to discuss sexual activity.43–45 One of the most prominent sex differences Thus, sex education should be an integral part of in antipsychotic side effects is the degree of the comprehensive treatment plan for patients prolactin elevations in women.37 Literature re- with schizophrenia. The primary care physician views indicate that prolactin concentrations can may be the patient’s only nonpsychiatric medical rise as high as 10 times normal levels in women contact and should always ask the patient if she during antipsychotic treatment; as a conse- has any questions or needs in this area.
Compared with emotionally healthy controls, studies experienced amenorrhea with or with- women with schizophrenia have been found to out galactorrhea.38 Antipsychotics with stronger have significantly less reproductive and contra- dopamine-binding properties (e.g., haloperidol, ceptive knowledge.46,47 In addition, schizophre- fluphenazine, risperidone) are associated with a nia patients often have poor judgment and may higher risk of prolactin elevation. Women taking be more likely to engage in risky sexual behav- medications that raise prolactin levels show de- iors that can increase their exposure to HIV and creased bone mineral density (BMD).39,40 Addi- other sexually transmitted diseases (STDs).48–52 A tionally, drug-related secondary hypoestro- history of sexual and physical abuse women with genism resulting from hyperprolactinemia may lead to osteoporosis.39,40 In women with long- term use of dopamine-blocking antipsychotics has been stabilized with medication may have and other risk factors for osteoporosis (e.g., fam- questions and concerns about childbearing. There ily history, poor diet, smoking, lack of exercise), is some evidence of a hereditary component in it may be beneficial to consider treatment with a schizophrenia, and genetic counseling may be ap- prolactin-sparing antipsychotic. A potential rela- propriate.54–56 There may be reduced fertility sec- tionship has been theorized between prolactin el- ondary to drug-induced hyperprolactinemia.57,58 evations and breast cancer, but no controlled data The SGAs are less likely to affect fertility, al- have been reported.29 Sexual dysfunction can also though patients and their families often are un- be related in part to elevations in prolactin. Ap- aware of this. As patients switch to these med- proximately 50% of both men and women using ications and regain libido, sexual function, and antipsychotics report sexual dysfunction when fertility, more pregnancies may occur; there are questioned directly. Men tend to be more dis- several cases in which switching patients from turbed by decreased sexual performance than do traditional antipsychotics to SGAs has resulted in women, but questioning patients about sexual unplanned pregnancy.59–61 The advent of newer function is an important component of treatment treatments that may increase fertility adds yet an- and outcomes. Prolactin-sparing antipsychotics other reason for providing appropriate education that do not produce sustained elevations include and counseling to women with schizophrenia.
clozapine, quetiapine, aripiprazole, and ziprasi- Contraceptive use in women with schizophre- nia has not been well characterized. Oral contra-ceptives (OCs) have been tried, although compli-ance is an issue in this population. The newer PSYCHOSOCIAL ISSUES AND
antipsychotics generally do not interact with PATIENT COUNSELING
OCs, but women with schizophrenia often useanticonvulsants and mood stabilizers that may decrease the effectiveness of OCs. Therefore, a Sexuality is a natural part of human behavior, full medication review is necessary before pre- and the nature of sexual behavior in the normal scribing OCs, and dosage adjustments may be re- population has been well addressed.41 In con- quired. Women with schizophrenia receive sig- trast, sexual functioning has received little atten- nificantly fewer gynecological services than do tion in the management of schizophrenia. Both other women, which also requires redress.62 TREATMENT CONSIDERATIONS IN SCHIZOPHRENIA
The use of antipsychotics in pregnancy and lac- of the general population.74,75 A meta-analysis of tation remains a risk/benefit decision. The risk of mortality rates showed that patients with schiz- psychotic relapse may be more detrimental to the ophrenia have a higher rate of death from natural mother and baby than the risks of drug use, and and unnatural causes than patients with other antipsychotics are often continued throughout mental disorders.76 Deaths from cardiovascular- pregnancy and postpartum. Essentially all of the related events are believed to occur more than 4 antipsychotic medications pass through the pla- times more frequently in patients with schizo- centa, and if possible, stopping antipsychotic use phrenia than in the normal population.77 It is for the first trimester is desirable.29 However, wo- believed that medical comorbidity may be rising men who experience a relapse in their psychotic as a result of newer treatments and that poor symptoms during pregnancy are at greater risk lifestyle habits contribute as well to increases in for birth complications.63 Therefore, the danger morbidity and mortality in people with schizo- of psychiatric relapse must be weighed against phrenia. These habits include lack of exercise and the risks of fetal drug exposure for individual sedentary lifestyle, poor diet and related obesity, medications. Most newer antipsychotic drugs smoking and related lung disease, and other pose little fetal risk, which appears to be no types of substance abuse.70,78,79 Therefore, wo- higher than in a nonschrizophrenic comparison men should be counseled about appropriate groups. Lower birth weights do occur, and spon- lifestyle choices such as diet and exercise, and re- taneous abortions, stillbirths, and a small, non- alistic goals should be set. Attempts to help wo- specific risk for organ malformations has been re- men with schizophrenia manage problems with ported.64,65 Antipsychotics are all excreted in substance abuse and smoking is an important breast milk, but breastfeeding is generally per- step in improving overall health concerns.
missible with many of the first-line antipsy-chotics.66 CONCLUSIONS
Medical comorbidities/overall health concerns Caring for women with schizophrenia presents risks of several chronic physical illnesses, and a difficult challenge to the clinician. Women will have a shorter life expectancy than women in the most likely experience symptoms at a later age general population.67 Approximately 50% of in- and may have a better prognosis than men. Wo- dividuals living with schizophrenia have been men are also more likely to have concomitant de- found to have serious co-occurring physical ill- pressive symptoms. Treatment should be indi- ness.67 Hypertension, epilepsy, lung diseases, di- vidualized in terms of patient risk and drug side abetes, and hepatitis are the most commonly oc- effect profiles (Table 3). Most importantly for wo- curring comorbid medical disorders,68–70 men, consideration should be given to weight contributing to the increased mortality rate of gain, risk of cardiovascular disease and type 2 di- persons with schizophrenia.71–73 This mortality abetes, hormonal disturbances and sexual dys- rate is estimated to be 2–3 times higher than that function, and other factors, such as concomitant TABLE 3. GUIDELINES FOR PRESCRIBING ANTIPSYCHOTICS IN WOMEN • Women generally require lower doses than men• Depot doses should be given at longer intervals in women than in men• Prolactin levels are higher in women• Obesity and weight gain are more of a problem in women• Women need regular mammography, electrocardiography, and bone densitometry• Women need diabetes and cardiovascular workups• Women need regular monitoring of lipid and glucose levels and weight• Dosages need to be modulated in aging women• Women require education in family planning and genetic counseling• Contraception should be offered to women with schizophrenia• During pregnancy and lactation, treatment must be subjected to risk/benefit analysis.
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14. Danielsson K, Flyckt L, Edman G. Sex differences in CONFLICT OF INTEREST
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Dr. Kelly has served as an advisor for Solvay, 15. Goldberg SC, Schooler NR, Davidson EM, Kayce MM.
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