W
Niels Bergemann
Anita Riecher-Rössler (eds.)
Estrogen Effects in Psychiatric Disorders
SpringerWienNewYork
Dr. Dr. Niels Bergemann
Department of Psychiatry, University of Heidelberg, Germany
Prof. Dr. Anita Riecher-Rössler
Psychiatric Outpatient Department, University of Basel, Switzerland
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V
Introduction and Overview (N. Bergemann, A. Riecher-Rössler) ... VII
1 Estrogens in Neuropsychiatric Disorders: From Physiology to
Pathophysiology (H. Vedder, C. Behl) ... 1
2 Estrogens and Schizophrenia (A. Riecher-Rössler) ... 31
3 Gender Differences in Schizophrenia (H. Häfner) ... 53
4 Puberty and Schizophrenia Onset (R. Z. Hayeems, M. V. Seeman) ... 95
5 Clinical Estrogen Trials in Patients with Schizophrenia (J. Kulkarni) ... 107
6 Hypoestrogenism and Estrogen Replacement Therapy in Women Suffering from Schizophrenia (N. Bergemann, Ch. Mundt, P. Parzer, B. Runnebaum, F. Resch) ... 123
7 The Effect of Estrogens on Depression (L. S. Kahn, U. Halbreich) ... 145
8 Estrogens and Other Hormones in the Treatment of Premenstrual Syndromes (L. Born, M. Steiner) ... 175
9 Estrogens and Perinatal Disorders (A. Gregoire) ... 191
10 Estrogen Therapy in Perimenopausal Affective Disorders (G. Stoppe, M. Dören)... 207
11 The Effects of Estrogens on Cognition and Alzheimer’s Dementia (T. Edwin, U. Halbreich) ... 223
12 Effects of Hormone Therapy on Patterns of Brain Activation during Cognitive Activity: A Review of Neuroimaging Studies (P. M. Maki, S. M. Resnick) ... 239
13 Estrogens in Alzheimer’s Disease: A Clinical and Neurobiological Perspective (P. Schönknecht, J. Pantel, A. Hunt, M. Henze, T. Strowitzki, J. Schröder) ... 253
14 Estrogen Therapy: Interface Between Gynecology and Psychiatry (K. M. K. Ismail, G. V. Sunanda, P. M. S. O’Brien) ... 271
List of Contributors ... 289
Contents
VII
The study of the effects of gonadal hormones in the brain was focused mainly on reproductive actions for a long time. Meanwhile, however, it is well known that gonadal hormones, in particular estrogens, also have neuroprotective and psychoprotective pro- perties. They can obviously modulate many actions in the brain such as cognitive functions, pain regulation, motor coordination, epilepsy, as well as affective and psychotic disorders, to name just a few. In fact, during the past few years we have experienced a major change in our understanding of the endocrinologic aspects of psychiatric disorders. Endocrinologic irregularities in psychiatric patients are no longer viewed as pure epiphenomena but rather discussed as part of the pathomechanism of the disorders.
How exactly estrogens affect various disorders is a fascinating and intriguing aspect of this emerging field of non-reproductive brain actions of gonadal hormones. Among the estrogens, especially estra- diol appears to play an important and multimodal role in the brain.
Which of estradiol’s many membrane, intracellular, and genomic ac- tions matter most in psychiatric disorders, remains to be discovered.
The aim of this volume is to summarize the role estrogens play in major psychiatric disorders, such as schizophrenia, depression, and dementia, and to provide a state-of-the-art overview of current knowledge but also of open questions. We hope that it will be a useful resource for clinicians and readers who are interested in con- temporary research developments in this field.
Helmut Vedder and Christian Behl (“Estrogens in Neuropsychia- tric Disorders: From Physiology to Pathophysiology”) begin this volume with a chapter on the basic mechanisms of estrogens, also presenting an overview of the genomic and nongenomic effects of estrogens and of the modulatory effects of estrogens on the various neurotransmitter systems, particularly the glutaminergic, dopamin- ergic, serotonergic, and cholinergic systems. Furthermore, the neu- roprotective effects of estrogens and their immunological activation in the central nervous system during neurodegeneration and aging are discussed.
Introduction and Overview
N. Bergemann and A. Riecher-Rössler
The following twelve chapters are divided into three parts. The first part focuses on the impact of estrogens in schizophrenia and contains five chapters on the role of estrogens in the development and course of schizophrenia. This section starts with chapter 2 by Anita Riecher-Rösssler (“Estrogens and Schizophrenia”), which gives an overview on the impact of estrogens in schizophrenia. She first presents a historical view of this issue and then summarizes the findings from various trials on the “estrogen protection hypothesis”
and the “hypoestrogenism hypothesis” in schizophrenia. She closes her chapter with a discussion of the implications for therapy and pro- phylaxis. In chapter 3, Heinz Häfner gives a detailed review on
“Gender Differences in Schizophrenia”, in particular concerning the differences in diagnosis, subtypes and symptoms, lifetime risk and age at onset, risk factors, illness behavior and illness-specific defi- cits, and both course and outcome. In his review he refers to the fin- dings of the ABC study, which he conducted together with Anita Riecher-Rössler in a first-episode sample of schizophrenia. The data presented here are of major importance for the “estrogen protection hypothesis” in schizophrenia. Robin Z. Hayeems and Mary V. See- man (chapter 4: “Puberty and Schizophrenia Onset”) then report on a study showing the inverse relationship between onset of menarche and schizophrenia onset in women. In chapter 5, Jayashri Kulkarni and co-workers (“Clinical Estrogen Trials in Patients with Schizo- phrenia”) present findings which show that add-on therapy with est- radiol to the standard treatment of acute schizophrenia alleviates symptoms and shortens the acute hospital stay. Niels Bergemann and co-workers (chapter 6: “Hypoestrogenism and Estrogen Repla- cement Therapy in Women Suffering from Schizophrenia”) report on studies providing evidence for the “hypoestrogenism hypothesis”
that show menstrual irregularities and pathologically low estradiol blood levels throughout the menstrual cycle as well as anovulation in the majority of women suffering from schizophrenia. Furthermo- re, the results of estrogen replacement as a prophylactic adjunct to antipsychotics in women with schizophrenia are reported.
The second part of this book examines the role of estrogens in depression. Uriel Halbreich and Linda S. Kahn open this section with an overview on “The Effect of Estrogens on Depression.” They start with a summary of the gender differences in the prevalence of de- pression and regarding the response to psychotropic medication and then outline the role of estrogens in the treatment of major depres-
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N. Bergemann and A. Riecher-Rössler
IX
Introduction and Overview
sion and reproduction-related disorders in women. In the following chapter. 8, Leslie Born and Meir Steiner take a closer look at “Estro- gens and Other Hormones in the Treatment of Premenstrual Syn- dromes.” Alain Gregoire (chapter 9: “Estrogens and Perinatal Disor- ders”) gives an overview of the evidence for antidepressive effects of estrogens in postpartum disorders and summarizes the implications this has for research and clinical practice. Gabriela Stoppe and Mar- tina Dören (chapter 10) then critically discuss the current findings regarding “Estrogen Therapy in Perimenopausal Affective Disor- ders.”
The third part of the book focuses on the important association between estrogens and cognition and/or Alzheimer’s disease. Tony Edwin and Uriel Halbreich give a concise overview on “The Effects of Estrogens on Cognition and Alzheimer’s Dementia” (chapter 11).
Pauline M. Maki and Susan M. Resnick follow with a review of neuroimaging studies in this field (chapter 12: “Effects of Hormone Therapy on Patterns of Brain Activation during Cognitive Activity:
A Review of Neuroimaging Studies”). They conclude that neuro- imaging studies give evidence for a protective effect of estrogens on age-related changes in cognition and Alzheimer’s disease. Findings suggest that estrogens affect neural substrates of several cognitive functions. Peter Schönknecht and co-workers (chapter 13: “Estro- gens in Alzheimer’s Disease: A Clinical and Neurobiological Pers- pective”) elaborate on the question of whether estrogen might have a mediating effect on cerebral β-amyloid metabolism in Alzheimer’s disease.
Finally, the last chapter of this book by Khaled M. K. Ismail, G.V.
Sunanda and P. M. Shaughn O’Brien deals with the “Interface bet- ween Gynecology and Psychiatry” regarding estrogen therapy.
The present volume includes both reviews on the main topics and also chapters providing more detailed information on individual stu- dies. Thus, some overlap may occur and different views and inter- pretations of empirical findings become evident. It is not intended to rule out such discrepancies – on the contrary: different views may stimulate the ongoing discussion.
Overall, it is obvious that interest is growing in this area and that further research is required since clinical studies, especially inter- vention studies, are still rare. Results of larger-scale, controlled stu- dies are needed before recommendations for routine clinical appli- cation of estrogens can be made for psychiatric patients. In addition,
research needs to be undertaken on the best modality of hormone (replacement) therapy in psychiatric patients. Clearly, any decision for estrogen (replacement) therapy in women with psychiatric disor- ders must be made on the basis of an individual risk-benefit-assess- ment, evaluating the pros and cons. In this context, the results of the “Women’s Health Initiative” need to be considered, which should also include a critical evaluation of the study results and in- terpretations (Notman and Nadelson 2002; Schneider 2002; Writing Group for the Women’s Health Initiative Investigators 2002; Writing Group of the International Menopause Society Executive Commit- tee 2004; Turgeon et al. 2004).
We strongly believe that further research on the influence of estrogens in schizophrenia, affective disorders, and dementia will not only contribute to our understanding of the pathogenetic me- chanisms underlying some aspects of psychiatric disorders, but will also have direct therapeutic benefits for many women with these disorders.
Many people have contributed to this volume. In particular, we express our gratitude to our fellow authors. We also gratefully ack- nowledge the expert tutelage, guidance, and patience of the staff at SpringerWienNewYork, especially Raimund Petri-Wieder. Further- more, we owe many thanks to Sherryl Sundell for editing the ma- nuscripts.
Last but not least, the sponsoring of this volume by AstraZeneca- GmbH, Pfizer GmbH, and Lilly Deutschland GmbH through unre- stricted grants is greatly appreciated.
References
Notman MT, Nadelson CC (2002) The hormone replacement therapy controversy.
Arch Women Ment Health 5: 33-35
Schneider HPG (2002) The view of the International Menopause Society on the Women’s Health Initiative. Climacteric 5: 211-216
Turgeon JL, McDonnel DP, Martin KA, Wise PM (2004) Hormone therapy: physio- logical complexity belies therapeutic simplicity. Science 304: 1269-1273 Writing Group for the Women’s Health Initiative Investigators (2002) Risks and
benefits of estrogen plus progestin in healthy postmenopausal women. JAMA 288: 321-333
Writing Group of the International Menopause Society Executive Committee (2004) Guidelines for the hormone treatment of women in the menopause transition and beyond. Climacteric 7: 8-11
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N. Bergemann and A. Riecher-Rössler: Introduction and Overviews
