MDIntroductionSchizophrenia is expressed differently in men and women with respect to the age at onset, symptom expression, course of illness, and outcomes. The sex differences may have etiologic implications, as demonstrated by recent studies showing a small but significantly higher incidence of schizophrenia among men compared with women when stringent classification criteria are applied.[1] Brain abnormalities and the genetics of schizophrenia are also influenced by sex. The Estrogen Protection HypothesisA key hypothesis put forward to explain the earlier age at onset of schizophrenia by 5-10 years in men compared with women is the "estrogen protection hypothesis."[2,3] Broadly, this hypothesis proposes that women are protected against the early onset of severe schizophrenia by estrogen. Furthermore, these researchers have suggested that women are vulnerable to relapses of established illness or their first-ever episode of schizophrenia in the perimenopausal period, when estrogen production diminishes. The hypothesis also encompasses early estrogen effects on the developing brain such that a structural effect of estrogen acting on brain maturation causes the delay of first-onset schizophrenia in females by raising the vulnerability threshold for schizophrenia. Following puberty, this putative structural effect is reinforced by a functional effect. Fading estrogen secretion around menopause causes women predisposed for schizophrenia, but who until then have been protected by estrogen, to fall ill with late-onset schizophrenia. The estrogen protection hypothesis rests on 3 main lines of work: epidemiologic studies, basic science studies using animal models, and clinical studies.[4] New epidemiologic data[5] from Mannheim, Germany, reinforce the later age at onset of early schizophrenia in women and another peak of onset in women aged 50 years and older. Early animal studies[6-8] showed that estradiol downregulated dopamine neurotransmission, while more recent studies[9-11] have shown that estrogen induces a significant increase in serotonin receptors. In this way, the actions of estrogen on the serotonin receptor (5-HT2A) and the dopamine receptor (D2) mimic the actions of the new antipsychotic drugs, such as risperidone and olanzapine. Clinical studies[12,13] showed that the symptoms of schizophrenia varied with the menstrual cycle phase in 32 acutely unwell women. Riecher-Rössler[12,13] found a significant excess of admissions to hospital during the premenstrual (ie, low-estrogen phase) compared with the high-estrogen phase. Seeman[14] reported that neuroleptic dose requirements in psychotic women rise as they approach menopause. Seeman attributed an increased vulnerability to psychosis in the postmenopausal period to the fall in circulating estrogen levels. Estrogen as Adjunct to Antipsychotic TherapyWith these lines of evidence for estrogen possibly having an inherent "antipsychotic" action, my colleagues and I have conducted clinical trials using estrogen as an adjunct to antipsychotic drug treatment.[15,16] Twelve women with acute schizophrenia received 100 micrograms (mcg) of transdermal estrogen plus a standardized dose of antipsychotic drug for 28 days and made a much faster and better recovery compared with 12 women who received 50 mcg of transdermal estrogen plus antipsychotic drug. Both groups, but especially the 100-mcg transdermal estrogen-treated group, made a much better and faster recovery than a matched group of 12 women who received a placebo patch plus antipsychotic drug. This study suggests that estrogen may play a useful role in the treatment of women with schizophrenia. In particular, women who have demonstrated monthly cyclical relapse in their illness may benefit from a modified form of estrogen replacement treatment (ERT). Furthermore, in women with established illness, ERT may be very useful as a preventive measure when these women approach their menopause. Estrogen has also been postulated to have a positive effect on short- and long-term verbal memory in postmenopausal women, as well as increasing the capacity for new learning.[17] Because cognitive deficits are a major problem for women with schizophrenia, ERT may have an added benefit for postmenopausal women with schizophrenia. Gender Differences in Quality of Life: Implications for TreatmentRecent studies on the gender differences in the quality of life of people with schizophrenia have shown that women are more likely to present with affective symptoms as part of their psychosis presentation.[5,18] Other differences include the finding that women have fewer negative symptoms (ie, anhedonia, apathy, alogia, and amotivational states) compared with men. This finding was also replicated in studies of first-episode psychosis patients.[19] In 350 patients with established schizophrenia, the Global Assessment of Function (GAF) scores were significantly better in women, although overall they were only in the mild to moderate range of function.[18] The gender difference in GAF scores may in fact reflect a difference in the premorbid functioning of patients, which may in turn be a product of the age difference. As discussed earlier, women generally experience the onset of schizophrenia in late adolescence before developing a career and family. The quality of life was measured by Kulkarni[18] in 350 patients with schizophrenia using the Quality of Life Scale (QLS). Women were found to generally have a higher quality of life, as per this scale, than men. In particular, women with schizophrenia scored better than men in the areas of interpersonal relations, instrumental role, and activities. There were no significant gender differences in life satisfaction, social needs, and basic needs. After 12 months, data on the quality of life of the same patients showed no significant difference in either men or women with schizophrenia. None of the QLS subsections on interpersonal relations, instrumental role, activities, and intrapersonal activities such as motivation, empathy, or curiosity had improved, although the actual psychotic symptoms had improved. These data suggest that current treatment strategies are targeting key illness symptoms, but psychosocial rehabilitation measures to improve the patient's quality of life are either not being implemented or else are not effective. The cost of managing patients with schizophrenia showed that women were significantly more expensive to treat than men.[18] This was mainly thought to be due to women receiving attention later than men, therefore being sicker and requiring longer inpatient stays. In the study of first-episode patients with schizophrenia,[19] data on magnetic resonance imaging were presented. The main gender differences were that males had more "immature" amygdala structures compared with women, suggesting a neurodevelopmental delay in young men with schizophrenia. There were no gender differences in hippocampal volumes in this first-episode psychosis group. Women experiencing their first episode of illness had longer duration of untreated psychosis compared with men. As with the more established schizophrenia group, young women with schizophrenia had fewer negative symptoms and better quality of life compared with young men. There were no gender differences in the positive psychotic symptoms (hallucinations, delusions, thought disorder) experienced by the young, early-onset-schizophrenia group. Both men and women received similar doses and type of antipsychotic medication.[19] Drug treatment available for women with schizophrenia includes a wide range of atypical and typical antipsychotic medications. B. Kinon,[20] Eli Lilly, Indianapolis, Indiana, presented data on hyperprolactinemia caused by antipsychotic drugs and the impact of high prolactin levels on the hypothalamic-pituitary-gonadal (HPG) axis. The study reported a decrease in the sex hormones that was significantly and inversely correlated with prolactin levels. The consequences of long-standing hyperprolactinemia in terms of osteoporosis and cardiovascular disease were discussed.
New Strategies for the Management of Women With SchizophreniaExpanding on the studies presented at the 1st World Congress on Women's Mental Health, new strategies for the management of women with schizophrenia were discussed. These include female-specific and individually tailored medication prescriptions, recognition of hormonal influences, the use of hormonal adjuncts, consideration of service delivery methods, and the development of better psychosocial rehabilitation programs to better meet women's needs. In more detail: Antipsychotic drugs are currently prescribed in standard doses, although women generally weigh much less than men and should be prescribed lower doses. Tailoring the dose of medication for weight and hormone effects would result in fewer side effects, better treatment adherence, and therefore better outcome in the longer term. Also, many women present with coexisting symptoms of depression or mania and psychosis. Hence, a tailored combination of antipsychotic drug plus mood-stabilizer may achieve better results for women with schizophrenia. Sex hormones play a major role through their effects on central brain neurotransmitters and may be an important key to the etiology of schizophrenia. The recognition of such hormonal influences during monthly cycles or at key lifetime hormonal events such as menopause in women may also lead to more effective treatments such as preventive ERT. Addition of estrogen to antipsychotic drug treatment may improve psychotic symptoms as well as assist with the management of hyperprolactinemia caused by some antipsychotic drugs. Currently, the mode of service delivery for people with schizophrenia comprises both inpatient wards and community- or home-based treatment. Women with established schizophrenia tended to obtain treatment later than men and were often sicker and required longer, more expensive inpatient treatment. In view of the female patients' better GAF scores and interpersonal relationships, it was thought that a home-based treatment model may suit women better. A poster presented by Bornheimer and Diethelm,[21] from Frankfurt, Germany, also described better outcomes for female patients treated at home, particularly with respect to women who have children. Finally, a yet-to-be-developed but much needed treatment strategy for women with schizophrenia is a female-specific psychosocial rehabilitation program. Such a program needs to incorporate psychotherapy designed to specifically help women patients and proven rehabilitation for women who are mothers and for women who want to return to or begin a career outside their homes. Female-focused rehabilitation would enable women with schizophrenia to capitalize on their current strengths and improve their quality of life after their psychotic symptoms improve.
References1. Goldstein JM, Lewine RRJ. Overview of sex differences in schizophrenia: where have we been and where do we go from here? In: Castle D, McGrath J, Kulkarni J, eds. Women and Schizophrenia. Cambridge, UK: Cambridge University Press; 2000. 2. Seeman M, Lang M. The role of estrogens in schizophrenia gender differences. Schizophr Bull. 1990;16:185-194. 3. Hafner H, Riecher A, Maurer K, et al. How does gender influence age at first hospitalization for schizophrenia? A transnational case register study. Psychol Med. 1989;19:903-918. 4. Hafner H, Maurer K, Loffler W, et al. The ABC Schizophrenia Study: a preliminary overview of the results. Soc Psychiatry Psychiatr Epidemiol. 1998;33:380-386. 5. Maurer K. Overview of the oestrogen protection hypothesis in schizophrenia 2001 [abstract S47]. Archives of Women's Mental Health. 2001;3(suppl 2):10. 6. Behrens S, Hafner H, De Vry J, Gattaz WF. Estradiol attenuates dopamine-medicated behaviour in rats. Implications for sex differences in schizophrenia. Schizophr Res. 1992;6:114. 7. Di Paolo T, Payet P, Labrie F. Effect of prolactin and estradiol on rat striated dopamine receptors. Life Sci. 1982;31:2921-2929. 8. Clopton J, Gordon JH. In vivo effects of estrogen and 2-hydroxy estradiol on D-2 dopamine receptor agonist affinity states in rat striatum. J Neural Transm. 1986;66:13-20. 9. Fink G, Sumner B, McQueen J, Wilson H, Rosie R. Sex steroid control of mood, mental state and memory. Clin Exp Pharmacol Physiol. 1998;25:764-765. 10. Fink G, Sumner B, Rosie R, Wilson H, McQueen J. Androgen actions on central serotonin neurotransmission: relevance for mood, mental state and memory. Behav Brain Res. 1999;105:53-68. 11. Fink G. Oestrogen-serotonin link: effects on mood, mental state and memory. Presentation at 1st World Congress on Women's Mental Health; March 27-31, 2001; Berlin, Germany. 12. Riecher-Rossler A, Hafner H, Maurer K, Stummbaum M, Schmidt R. Schizophrenic symptomatology varies with serum estradiol levels during menstrual cycle. Schizophr Res. 1992;6:114-115. 13. Riecher-Rossler A. Oestrogens and schizophrenia -- a brief overview. Presentation at 1st World Congress on Women's Mental Health; March 27-31, 2001; Berlin, Germany. 14. Seeman MV. Interaction of sex, age and neuroleptic dose. Compr Psychiatry. 1983;24:125-128. 15. Kulkarni J. Clinical adjunctive trials of estrogen in women with schizophrenia. Presentation at 1st World Congress on Women's Mental Health; March 27-31, 2001; Berlin, Germany. 16. Kulkarni J, de Castella A, Reidel A, Taffe J, Burger H, Fitzgerald P. Estrogen -- a potential treatment for schizophrenia. Schizophr Res. 2001;4. In press. 17. Sherwin B. Estrogen and cognitive functioning in postmenopausal women [abstract S228]. Archives of Women's Mental Health. 2001;3(suppl 2):50. 18. Kulkarni J. Gender differences in the quality of life of people with schizophrenia. Presentation at 1st World Congress on Women's Mental Health; March 27-31, 2001; Berlin, Germany. 19. McGorry P. Early psychosis -- gender aspects of treatment. Presentation at 1st World Congress on Women's Mental Health; March 27-31, 2001; Berlin, Germany. 20. Kinon B. Prevalence of hyperprolactinemia in a large cohort of schizophrenic patients treated with conventional antipsychotic drugs or risperidone [abstr S185]. Archives of Women's Mental Health. 2001;3(suppl 2):41. 21. Bornheimer B, Diethelm A. Psychiatric home treatment -- a new service preferably for women (?) [abstract P280]. Archives of Women's Mental Health. 2001;3(suppl 2):62
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