Psychiatric Times
"The onset of schizophrenia tends to be later in women," Schecter said. "During their premenopausal years, women seem to experience a less severe expression of the illness and to respond to lower neuroleptic doses than do either men or menopausal women."
In addition, Schecter pointed to research findings indicating that estrogen influences the sensitivity of dopamine receptors in much the same way that traditional neuroleptics are postulated to act.
http://www.psychiatrictimes.com/p950112.html
Psychiatric Times January 2004 Vol. XXI Issue 1
Hormones for Perimenopausal and Postmenopausal Depression
Victoria Hendrick, M.D.
Mood and well-being are believed to be regulated by mechanisms of estrogen and progesterone. How effective are they in the treatment of major and minor depression?
Estrogen and progesterone are believed to play a role in the regulation of mood and well-being. Several mechanisms have been proposed for this effect, including the hormones' influence on monoamine oxidase (MAO) metabolism. Estrogen inhibits MAO, thereby diminishing the degradation of norepinephrine and serotonin and thus increasing their activity, while progesterone has the reverse impact on MAO (Chakravorty and Halbreich, 1997; Luine and Rhodes, 1983). Allopregnanolone, a metabolite of progesterone, is a potent neuroactive steroid that modulates g-aminobutyric acid (GABA) receptors and may be anxiolytic (Majewska et al., 1986).
Estrogen
Estrogen's influence on mood has been studied significantly more than that of progesterone. While estrogen's mood-elevating effect is generally acknowledged, the clinical magnitude of this effect remains unclear. Unfortunately, many studies examining this question have been uncontrolled or retrospective or have used populations with only mild levels of depression. A meta-analysis of research done between 1970 and 1995 (mostly involving conjugated equine estrogen [Premarin]) reported moderate-to-large mood-elevating effects from estrogen administration, which diminished following addition of a progestogen (Zweifel and O'Brien, 1997). Interestingly, in this meta-analysis, perimenopausal women appeared more likely to benefit than postmenopausal women. The authors, however, cautioned that methodological shortcomings limited the generalizability of several of the studies.
Three controlled studies evaluated the use of estrogen for perimenopausal and postmenopausal women with major and minor depression. The first, which evaluated the effect of transdermal estrogen (17-ß estradiol) in a group of 31 women and used the Hamilton Rating Scale for Depression (HAM-D) and Center for Epidemiologic Studies, Depression Scale (CES-D), reported that 80% of subjects experienced a response to estradiol compared to 22% of the placebo group (Schmidt et al., 2000). The second study, which comprised 50 perimenopausal depressed women on transdermal estrogen, reported a 68% remission rate among the estradiol group compared to 20% in the placebo group as measured with the Montgomery-Asberg Depression Rating Scale (MADRS) (Soares et al., 2001). A third study, also using transdermal estrogen, reported remission of depression in six of nine (66.7%) perimenopausal women but only two of 11 (18%) postmenopausal women, as defined by ratings on the MADRS, Beck Depression Inventory (BDI) and Clinical Global Impression (CGI) scale (Cohen et al., 2003). In all three studies, the mood effect was independent of estrogen's relief of vasomotor symptoms. Most recently, the Women's Health Initiative evaluated 16,609 postmenopausal women with a brief rating scale composed of items from the CES-D and Diagnostic Interview Schedule (DIS) and reported no improvement of depressive symptoms from equine estrogen. These inconsistent findings may result from different formulations of estrogen ( Table 1 ), different menopausal status (perimenopausal versus postmenopausal), different methods of assessment of mood and/or different levels of depression among the subjects (major versus minor depression).
Unopposed estrogen produces substantial health risks, such as endometrial hyperplasia. Therefore, a progestogen must be added (except in women who have undergone a hysterectomy). Progestogen is an umbrella term for progesterone (which is natural) and progestins (which are synthetic). Progestogens, of which the most widely prescribed in the United States is medroxyprogesterone acetate (Provera), are administered either continuously (every day of the month) or cyclically (at a higher dose, 10 to 14 days of each month). Many studies have reported a worsening of mood following addition of a progestogen to the estrogen (Zweifel and O'Brien, 1997). One study did not find an adverse effect of medroxyprogesterone on mood; however, the study followed women on this regimen for only one week (Schmidt et al., 2000). The impact of progestogens on mood needs to be further examined using longer follow-up times and different formulations of progestogens (e.g., comparing progestins to natural progesterone).
A concern about the use of estrogen plus progestogen emerged last year following early results from the Women's Health Initiative, a randomized, controlled trial of the benefits and risks of hormone replacement therapy (HRT) (Rossouw et al., 2002). The study's duration had originally been planned for 8.5 years, but in 2002 the study's estrogen (Premarin) plus medroxyprogesterone acetate arm was abruptly discontinued after 5.2 years because preliminary findings showed that this hormone combination appeared to increase rather than decrease the risk of coronary heart disease. In addition, this hormone combination was associated with an elevated risk of invasive breast cancer compared to placebo. The estrogen alone arm continues as it remains uncertain whether the benefits outweigh the risks. The Women's Health Initiative has involved postmenopausal women aged 50 to 79, and its generalizability to younger, perimenopausal women remains unclear.
Testosterone
A number of studies have demonstrated a positive effect of testosterone administration on mood in men (Margolese, 2000). Few studies, however, have examined the effect of testosterone on mood in women (Davis and Tran, 2001). Testosterone is prescribed to enhance libido in perimenopausal and postmenopausal women, and it also helps relieve vasomotor symptoms, thereby reducing the amount of estrogen necessary. In the United States, testosterone is available to women as methyltestosterone (Estratest) and is prescribed in conjunction with HRT at 1.25 mg to 2.5 mg daily. Its use among perimenopausal and postmenopausal women is increasing and data on its psychological effects are therefore likely to expand. The sparse data currently available show that co-administration of testosterone with estrogen produces greater enhancement of well-being and energy than estrogen alone in perimenopausal and postmenopausal women (Brincat et al., 1984; Montgomery et al., 1987; Sherwin, 1988; Zweifel and O'Brien, 1997). Testosterone's use is limited by its androgenizing effects and its potentially negative influence on cardiolipids ( Table 2 ).
Conclusion
In sum, the data show that estrogen administration appears to benefit mood primarily in perimenopausal women with mild or moderate levels of depression. Further research is necessary to examine the benefit of estrogen for severe or recurrent depression in this population of women. Also, future studies should examine the use of estrogen as an augmentation agent for antidepressant medications, as no controlled studies exist to date on this treatment approach. Testosterone's role in improving mood in perimenopausal and postmenopausal women merits study in controlled trials. Particular attention should be given to possible adverse cardiovascular effects in aging women who may already be at risk for cardiovascular disease. There are additional questions that remain to be addressed. Do hormone formulations differ in their mood effects? Do certain women respond more favorably than others (e.g., women with histories of reproductive-related depressions)? What are the optimal hormone doses and durations of treatment that benefit mood while producing minimal health risks?
Dr. Hendrick is associate professor in the department of psychiatry and biobehavioral sciences at the University of California, Los Angeles, and medical director of the Women's Center, Augustus F. Hawkins Clinic.
References
Brincat M, Magos A, Studd JW et al. (1984), Subcutaneous hormone implants for the control of climacteric symptoms. A prospective study. Lancet 1(8367):16-18.
Chakravorty SG, Halbreich U (1997), The influence of estrogen on monoamine oxidase activity. Psychopharmacol Bull 33(2):229-233.
Cohen LS, Soares CN, Poitras JR et al. (2003), Short-term use of estradiol for depression in perimenopausal and postmenopausal women: a preliminary report. Am J Psychiatry 160(8):1519-1522.
Davis SR, Tran J (2001), Testosterone influences libido and well being in women. Trends Endocrinol Metab 12(1):33-37.
Luine VN, Rhodes JC (1983), Gonadal hormone regulation of MAO and other enzymes in hypothalamic areas. Neuroendocrinology 36(3):235-241.
Majewska MD, Harrison NL, Schwartz RD et al. (1986), Steroid hormone metabolites are barbiturate-like modulators of the GABA receptor. Science 232(4753):1004-1007.
Margolese HC (2000), The male menopause and mood: testosterone decline and depression in the aging male--is there a link? J Geriatr Psychiatry Neurol 13(2):93-101.
Montgomery JC, Appleby L, Brincat M et al. (1987), Effect of oestrogen and testosterone implants on psychological disorders in the climacteric. Lancet 1(8528):297-299.
Rossouw JE, Anderson GL, Prentice RL et al. (2002), Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial. JAMA 288(3):321-333 [see comments].
Schmidt PJ, Nieman L, Danaceau MA et al. (2000), Estrogen replacement in perimenopause-related depression: a preliminary report. Am J Obstet Gynecol 183(2):414-420.
Sherwin BB (1988), Affective changes with estrogen and androgen replacement therapy in surgically menopausal women. J Affect Disord 14(2):177-187.
Soares CN, Almeida OP, Joffe H, Cohen LS (2001), Efficacy of estradiol for the treatment of depressive disorders in perimenopausal women: a double-blind, randomized, placebo-controlled trial. Arch Gen Psychiatry 58(6):529-534[see comments].
Zweifel JE, O'Brien WH (1997), A meta-analysis of the effect of hormone replacement therapy upon depressed mood. [Published erratum Psychoneuroendocrinology 22(8):655.] Psychoneuroendocrinology 22(3):189-212.
http://psychiatrictimes.com/Women/showArticle.jhtml?articleID=175801906
Neuronal and Cognitive Effects of Oestrogens
Novartis Foundation Symposia
Published Online: 26 Sep 2003
Editor(s): Derek J. Chadwick, Jamie A. Goode
Series Editor(s): Novartis Foundation
Print ISBN: 9780471492030 Online ISBN: 9780470870815
Copyright © Novartis Foundation 2000
Ovarian Steroid Action in the Serotonin Neural System of Macaques
Chapter Authors: Cynthia L. Bethea, Chrisana Gundlah, Stephanie J. Mirkes
Summary
The serotonin neural system plays an important role in cognitive, emotional and endocrine processes. If the ovarian hormones, oestrogen and progesterone, alter serotonin neural transmission, then functional changes in all of these systems would follow. Therefore, information on the effects of oestrogen and progesterone at a molecular level in the serotonin neural system was sought using non-human primates. Serotonin neurons express nuclear oestrogen receptor (ER ) and progesterone receptors (PRs) which are gene transcription factors. Within serotonin neurons, the regulation of three genes related to serotonin neurotransmission was examined. The mRNA for tryptophan hydroxylase (TPH), the committal enzyme in serotonin synthesis, increased significantly with oestrogen treatment and remained elevated when progesterone was added to the oestrogen regimen. Serotonin reuptake transporter (SERT) mRNA decreased significantly with oestrogen treatment and addition of progesterone had no further effect. 5-HT 1A autoreceptor mRNA decreased significantly with oestrogen treatment and addition of progesterone caused a further decrease. Little or no regulation of postsynaptic 5-HT 1A , 5-HT 2A or 5-HT 2C receptor mRNAs was observed in hypothalamic target neurons. TPH protein is increased by oestrogen treatment and remains elevated with addition of progesterone in a manner similar to TPH mRNA. Medroxyprogesterone (MPA) blocked the stimulatory effect of oestrogen on TPH protein and tamoxifen reduced TPH protein levels below that observed in spayed monkeys. Together these data indicate that ovarian hormones and their synthetic analogues could modify cognitive and autonomic neural functions by acting on the serotonin neural pathway.
AUTHOR DETAILS
Cynthia L. Bethea 12, Chrisana Gundlah 12, Stephanie J. Mirkes 12
1Divisions of Reproductive Sciences and Neuroscience, Oregon Regional Primate Research Center, Beaverton, OR 97006, USA
2Department of Physiology/Pharmacology, Oregon Health Sciences University, Portland, OR 97201, USA
http://www3.interscience.wiley.com/cgi-bin/summary/105560241/SUMMARY?CRETRY=1&SRETRY=0
Journal of Clinical Psychopharmacology. 23(6):601-640, December 2003.
GABA and Schizophrenia: A Review of Basic Science and Clinical Studies.
Wassef, Adel MD *; Baker, Jeffrey PhD dagger;; Kochan, Lisa D. PhD dagger;
Abstract:
Background: A converging body of evidence implicates the [gamma]-aminobutyric acid (GABA) neurotransmitter system in the pathogenesis of schizophrenia.
Methods: The authors review neuroscience literature and clinical studies investigating the role of the GABA system in the pathophysiology of schizophrenia. First, a background on the GABA system is provided, including GABA pharmacology and neuroanatomy of GABAergic neurons. Results from basic science schizophrenia animal models and human studies are reviewed. The role of GABA in cognitive dysfunction in schizophrenia is then presented, followed by a discussion of GABAergic compounds used in monotherapy or adjunctively in clinical schizophrenia studies.
Results: In basic studies, reductions in GABAergic neuronal density and abnormalities in receptors and reuptake sites have been identified in several cortical and subcortical GABA systems. A model has been developed suggesting GABA's role (including GABA-dopamine interactions) in schizophrenia. In several clinical studies, the use of adjunctive GABA agonists was associated with greater improvement in core schizophrenia symptoms.
Conclusions: Alterations in the GABA neurotransmitter system are found in clinical and basic neuroscience schizophrenia studies as well as animal models and may be involved in the pathophysiology of schizophrenia. The interaction of GABA with other well-characterized neurotransmitter abnormalities remains to be understood. Future studies should elucidate the potential therapeutic role for GABA ligands in schizophrenia treatment.
(C) 2003 Lippincott Williams & Wilkins, Inc.
http://www.psychopharmacology.com/pt/re/jclnpsychopharm/abstract.00004714-200312000-00011.htm;jsessionid=GmVHmWlT7M4mMn2gT62nQ72CJ7TFTmpzRjnKH5dMxt3MwTSncylk!-1804036389!-949856145!8091!-1
Menopause. 9(4):253-263, July 2002.
Cummings, Jennifer A. MA 1; Brizendine, Louann MD 2
Comparison of physical and emotional side effects of progesterone or medroxyprogesterone in early postmenopausal women.
Abstract:
Objective: To compare the mood and somatic effects during the initial 2 months of medroxyprogesterone acetate (MPA) or progesterone combined with conjugated equine estrogen (CEE) in early postmenopausal women.
Design: Twenty-three nondepressed, early postmenopausal women (average age, 52.5 years) completed a 91-day, single-blind pilot study with the following sequence of treatments: 1 week of no substance; 2 weeks of placebo; 2 weeks of progestogen only; 1 week of placebo; and 2 months of "standard hormone replacement therapy cycles," which consisted of (in order) 2 weeks of 0.625 mg CEE, 2 weeks of CEE plus progestogen, 2 weeks of CEE, and 2 weeks of CEE plus progestogen. Ten women who completed the study received MPA (5 mg/day) as their progestogen, and 13 who completed the study received micronized, oil-suspended progesterone (200 mg/day) as their progestogen. All participants made daily assessments of mood using the Profile of Mood States and daily recordings of somatic symptoms. All subjects had plasma follicle-stimulating hormone of greater than 35 IU/L and had not had spontaneous vaginal bleeding for more than 1 year.
Results: None of the hormone treatments had a detectable effect on mood. MPA users reported more vaginal bleeding and breast tenderness than progesterone users.
Conclusions: In contrast with the widely held belief among psychiatrists that progesterone depresses mood, neither of the progestogens we used in normal, nondepressed and nonanxious women showed this effect. Absence of an effect on mood was also found when the results of the two progestogens were combined. The lesser side effects of the micronized progesterone-containing regimen suggest that some women may prefer it to an MPA-containing regimen.
(C)2002The North American Menopause Society
http://www.menopausejournal.com/pt/re/menopause/abstract.00042192-200207000-00006.htm;jsessionid=Gm2WxKcQvv11n0kqLxJ5kg2NWfns1HyQfTSLMpLYtf12fdnN9NyL!-1804036389!-949856145!8091!-1
European Journal of Neuroscience
Volume 16 Issue 1 Page 169Issue 1 - 173 - July 2002
doi:10.1046/j.1460-9568.2002.02084.x
The neurosteroid allopregnanolone increases dopamine release and dopaminergic response to morphine in the rat nucleus accumbens
Françoise Rougé-Pont,
Willy Mayo,
Michela Marinelli,
Mireille Gingras,
Michel Le Moal and
Pier Vincenzo Piazza
Psychobiologie des Comportements Adaptatifs, INSERM U259, Université Victor Segalen Bordeaux 2, Domaine de Carreire, Rue Camille Saint-Saëns, 33077 Bordeaux Cedex, France
Correspondence : Dr Pier Vincenzo Piazza, as above.
E-mail: pier-vincenzo.piazza@bordeaux.inserm.fr
Abstract
Neurosteroids are a subclass of steroids that can be synthesized in the central nervous system independently from peripheral sources. Clinical studies in humans have associated these hormones with depression and postpartum mood disorders. In rodents, allopregnanolone (AlloP) has been shown to have anxiolytic and rewarding properties. These observations suggest that neurosteroids could interact with mood and motivation. However, the possible neural substrates of these effects remain unknown. In this report, we have studied the action of AlloP on the activity of the mesencephalic dopaminergic (DA) projection to the nucleus accumbens, which is considered one of the biological substrates of motivation and reward. This study was conducted by measuring extracellular concentrations of dopamine (DA) in the nucleus accumbens by means of microdialysis in freely moving rats. We studied both the direct effect of AlloP and the influence of this hormone on the DA response to an injection of morphine. AlloP dose-dependently increased the release of DA in the nucleus accumbens. Furthermore, this hormone doubled the DA response to morphine. These effects were observed for AlloP doses of 50 and 100 pmol injected intracerebroventricularly. These results suggest that the stimulatory effect of AlloP on DA could mediate some of the behavioural effects of neurosteroids and, in particular, the interaction of these hormones with mood and motivation.
http://www.blackwell-synergy.com/links/doi/10.1046/j.1460-9568.2002.02084.x/abs/
