Imbalance between pro- and anti-inflammatory cytokines, and between Th1 and Th2 cytokines in depressed patients: the effect of electroacupuncture or fluoxetine treatment.

BACKGROUND: An increase in inflammatory response and an imbalance between T-helper (Th) 1 and 2 functions have been implicated in major depression. The aims of the present study were to 1) study the relationship between pro- and anti-inflammatory cytokines and between Th1 and Th2 produced cytokines in depressed patients and 2) evaluate and compare the effect of treatments with electroacupuncture (EA) and fluoxetine on these cytokines. METHODS: 95 outpatients with major depressive disorder were treated for 6 weeks with EA, fluoxetine or placebo. Hamilton Depression Rating Scale (HDRS) and Clinical Global Impression (CGI) were used to assess severity and therapeutic effects. 30 volunteers served as controls. Serum cytokine concentrations were measured by ELISA. RESULTS: Increased proinflammatory cytokine interleukin (IL)-1beta and decreased anti-inflammatory cytokine IL-10 were found in the depressed patients. By contract, Th1 produced proinflammatory cytokines, tumor necrosis factor (TNF)-alpha and interferon (IFN)-gamma were decreased, and Th2 produced cytokine IL-4 was significantly increased in depressed patients. The ratio of IFN/IL-4 was also increased. Both acupuncture and fluoxetine treatments, but not the placebo, reduced IL-1beta concentrations in responders. However, only acupuncture attenuated TNF-alpha concentration and INF-gamma/IL-4 ratio towards the control level. DISCUSSION: These results suggest that an imbalance between the pro- and anti-inflammatory cytokines (IL-1 and IL-10), and between Th1 and Th2 cytokines (INF-gamma or TNF-alpha and IL-4) occurred in untreated depressed patients. Both EA and fluoxetine had an anti-inflammatory effect by reducing IL-1beta. EA treatment also restored the balance between Th1 and Th2 systems by increasing TNF-alpha and decreasing IL-4.

Women's mental health in the Muslim world: cultural, religious, and social issues.

In Arab communities, several cultural factors, derived mainly from the subordinate position of women, have been shown to affect the prevalence, clinical picture, health seeking behaviour, course and management of psychopathology in women. Women are definitely at a greater risk of developing mental disorders such as depressive, somatoform, anxious or eating disorders, as well as suicidal behaviors. Furthermore, mentally ill women are more stigmatized, have less access to care and suffer from a worse social outcome. This paper describes a series of culture-related risk factors such as education, work, sexuality, marriage, and infertility, which significantly contribute to triggering mental disorders in females, or to worsen their course and outcome. The authors recommend that mental health providers should play a critical role by addressing the cultural as well as psychological conditions that create and maintain threats to women's mental health.

Mental health of Moroccan women, a sexual perspective.

Sexuality is a complex process coordinated with neurological, vascular, and endocrine systems. It incorporates family, societal, and religious beliefs and interpersonal relationships. Sexuality in the Muslim world is further complexed by tradition and discrimination of women. Studies conducted in Ibn Rushd University Psychiatric Center, Casablanca, Morocco, explored various aspects of sexuality in a traditional Muslim society: sexual behaviour (representative sample of Casablanca population n=728), sexual dysfunction (n=644), prevalence of abuse during childhood, effect of breast removal on sexuality (prospective study on 100 patients), effect of menopause on sexuality (comparative study between Moroccan and Tunisian samples, n=200), pregnancy and sexuality (follow up study in primary health care, n=100), and Ramadan and sexuality among healthy fasting people.

What does Chilean research tell us about postpartum depression (PPD)?

BACKGROUND: In Chile, a country with a so called emerging market-economy, where rapid social and life style changes are taking place, women and the more socially disadvantaged are more at risk of becoming depressed. METHODS: Results of several studies are summarized in the context of a review of the literature. RESULTS: A third of Chilean women have depressive and/or anxiety symptoms during midpregnancy, while prevalence figures both in the early and the late postpartum period increase up to 50% in most studies. If strict operational criteria describing well defined depressive disorders are used postnatally, differences in prevalence and incidence figures arise depending on socioeconomic status. Whereas incidence rates for postpartum depression (around 9%) are very similar to those found in the northern hemisphere and do not appear to vary across different socioeconomic levels, higher prevalence rates are found among women from lower socioeconomic status. LIMITATIONS: The studies focused on current diagnostic entities and did not consider different clusters or dimensions. CONCLUSION: A shared biological etiology may be triggered by the physiology of childbirth and account for similarities in incidence across different socioeconomic levels. In turn, we hypothesize that the higher prevalence of postpartum depression (PPD) in Chilean women from lower socioeconomic status is the result of pre-existing depression and is not caused by more new cases of the illness.

The diagnosis of premenstrual syndromes and premenstrual dysphoric disorder--clinical procedures and research perspectives.

Premenstrual syndromes (PMS) are quite prevalent among women of reproductive age. In up to 20% of women they are severe enough to warrant treatment, which is available and marketed as such. The impact of the cumulative burden of PMS is substantial and is in the same magnitude as affective disorders. Nevertheless, the definitions and diagnoses of PMS are still fragmented, not widely accepted and, if accepted, not always applied in day-to-day clinical practice. In the present paper, the current diagnostic entities are critically reviewed, problems with the current definitions are delineated and a unified definition is proposed. For clinical purposes, the recommended dinical practical diagnostic process and differential diagnosis are described. For clinical trials of medications for treatment of PMS/premenstrual dysphoric disorder, research diagnostic criteria, inclusion and exclusion criteria, as well as well-defined outcome measures, are of utmost importance; they are described here. The gaps of knowledge in the description and diagnosis of PMS are described, with suggestions for future directions for research.

Hormonal aspects of schizophrenias: an overview.

Although the lifetime risk and prevalence of schizophrenia are comparable for men and women, gender differences occur in various aspects of the disease, including age of onset, pathophysiology, symptoms, course, and response to treatment. These gender differences strongly suggest a key role played by gonadal hormones and their interactions with neurotransmitters. They may also suggest a key role for future applications of specific estrogens for improved treatment of schizophrenics.'Atypical' antipsychotics definitely improved the benefit/risk ratio of treatment of schizophrenic patients. However, they shift the reasons for noncompliance from extrapyramidal symptoms to hormonally related adverse effects, mostly weight gain and impaired sexual functions (which occur in men and women, but cause noncompliance mostly in men). Diabetes, dyslipidemia, and decreased bone mineral density, as well as some other adverse effects are more 'silent' but their long-term effects are detrimental. 'Hormone-friendlier' interventions might be needed.

The second-generation 'atypical' antipsychotics: similar improved efficacy but different neuroendocrine side effects.

The neuroendocrine aspects of schizophrenia generally receive little attention. This is in marked contrast to depressive disorders, where neuroendocrine issues are central to discussions of pathophysiology and treatment. Although the nature of neuroendocrine dysfunction is less well characterized in schizophrenia than in major depression, a number of neuroendocrine abnormalities have been described. Hypercortisolemia has been extensively documented in patients with schizophrenia, particularly during acute exacerbations, with persistent hypercortisolemia being associated with ventricular enlargement and poor outcome. Similarly, abnormalities in thyroid function, the hypothalamo-pituitary-gonadal axis, growth hormone, prolactin, neurotensin, and other neuroendocrine parameters have also been described in schizophrenia. While the precise neuroendocrine profile of schizophrenia is incompletely characterized, the impact of antipsychotic medications employed in its treatment on various endocrine parameters is better understood. Different conventional and atypical antipsychotics variably contribute to hyperprolactinemia, insulin resistance, and other abnormalities. A critical overview of neuroendocrine abnormalities in schizophrenia is provided and the differential impact of different antipsychotics in contributing to neuroendocrine dysfunction is discussed.

Elevated prolactin levels in patients with schizophrenia: mechanisms and related adverse effects.

The neurologic processes involved in schizophrenia are complex and diverse and the mechanisms through which antipsychotic agents exert their effects have been only partly elucidated. Hyperprolactinemia is a common side effect of treatment with many antipsychotics and is particularly associated with conventional ('typical') agents as well as the atypical antipsychotic risperidone. In contrast, other atypical agents introduced over the last decade do not elevate prolactin levels. This article discusses the regulatory mechanisms involved in prolactin secretion, the physiologic role of prolactin, and the etiology of hyperprolactinemia. Elevated prolactin levels may play important roles, both direct and indirect, in various pathologic states, including breast cancer, osteoporosis, cardiovascular disorders, and sexual disturbances. Antipsychotic-induced hyperprolactinemia may be associated with similar clinical manifestations; these are examined with particular reference to patients with schizophrenia.

Oral contraceptives and mood.

The past 40 years of research on the mood and behavioural effects of combined oral contraceptives (OCs) have yielded inconclusive results due to dramatic changes in the compounds and to methodological flaws inherent in studies undertaken to assess the effects of OCs. Since the late 1960s, the dosages of oestrogen and progestin in marketed OCs significantly declined and novel progestins were developed to deliver higher levels of progestogenic activity with a lower risk of adverse oestrogenic and androgenic effects. This review evaluates controlled, comparative studies that have focused on the efficaciousness of OCs as treatment for premenstrual syndrome (PMS) and those examining whether OCs may cause negative mood. It is suggested that the mood and behavioural effects of OCs might be attributed to different progestin compounds and possibly, their oestrogen ratios. There is a great need for more longitudinal, randomised, placebo-controlled studies to further clarify the mood and behavioural effects of OCs.

Role of estrogen in the aetiology and treatment of mood disorders.

Worldwide, the prevalence of depression in women is significantly greater than in men. Available data suggest that estrogen, or its absence, is strongly implicated in the regulation of mood and behaviour, as well as in the pathobiology of mood disorders. The multiple effects of estrogens and their complex interactions with the CNS and endocrine system have been well documented, although the specific, multifaceted role of estrogen in each dysphoric state has yet to be elucidated. Several facts suggest that estrogen plays a vital role in the precipitation and course of mood disorders in women. Gender differences in the prevalence of depression first appear after menarche, continue through reproductive age, and dissipate after perimenopause. Periods of hormonal fluctuations or estrogen instability (i.e. premenstrually, postpartum, perimenopausally) have been associated with increased vulnerability to depression among susceptible women. It is plausible that the phenotype of these depressions is distinguishable from those that are not associated with reproductive events or that occur in men. Based on current knowledge, estrogen treatment for affective disorders may be efficacious in two situations: (i) to stabilise and restore disrupted homeostasis - as occurs in premenstrual, postpartum or perimenopausal conditions; and (ii) to act as a psychomodulator during periods of decreased estrogen levels and increased vulnerability to dysphoric mood, as occurs in postmenopausal women. There is growing evidence suggesting that estrogen may be efficacious as a sole antidepressant for depressed perimenopausal women. It is still unclear whether estrogen is efficacious as an adjunct to selective serotonin reuptake inhibitors or as one of the paradigms to manage treatment-resistance depression in menopausal women, but such efficacy is plausible.

Are women with premenstrual dysphoric disorder prone to osteoporosis?

OBJECTIVE: The objective of this study was to examine whether bone mineral density (BMD) is reduced in women with premenstrual dysphoric disorder (PMDD). METHODS: Thirty-eight healthy women participated: 20 with prospectively confirmed PMDD and 18 without PMDD. Bone mass was measured using dual-energy x-ray absorptiometry at three sites: lumbar spine anteroposterior, lumber spine lateral, and femoral neck. Results from the PMDD and control groups were compared with each other and with age- and sex-matched normative data. RESULTS: The BMD of both groups was as expected for their age and sex, and groups did not differ in BMD or Z scores for any of the bone sites studied. CONCLUSIONS: If women with PMDD are at an increased risk of developing osteoporosis, this risk is not manifested in their BMD.

Effectiveness of St John's wort in major depression: a randomized controlled trial.

CONTEXT: Extracts of St John's wort are widely used to treat depression. Although more than 2 dozen clinical trials have been conducted with St John's wort, most have significant flaws in design and do not enable meaningful interpretation. OBJECTIVE: To compare the efficacy and safety of a standardized extract of St John's wort with placebo in outpatients with major depression. DESIGN AND SETTING: Randomized, double-blind, placebo-controlled clinical trial conducted between November 1998 and January 2000 in 11 academic medical centers in the United States. PARTICIPANTS: Two hundred adult outpatients (mean age, 42.4 years; 67.0% female; 85.9% white) diagnosed as having major depression and having a baseline Hamilton Rating Scale for Depression (HAM-D) score of at least 20. INTERVENTION: Participants completed a 1-week, single-blind run-in of placebo, then were randomly assigned to receive either St John's wort extract (n = 98; 900 mg/d for 4 weeks, increased to 1200 mg/d in the absence of an adequate response thereafter) or placebo (n = 102) for 8 weeks. MAIN OUTCOME MEASURES: The primary outcome measure was rate of change on the HAM-D over the treatment period. Secondary measures included the Beck Depression Inventory (BDI), Hamilton Rating Scale for Anxiety (HAM-A), the Global Assessment of Function (GAF) scale, and the Clinical Global Impression-Severity and -Improvement scales (CGI-S and CGI-I). RESULTS: The random coefficient analyses for the HAM-D, HAM-A, CGI-S, and CGI-I all showed significant effects for time but not for treatment or time-by-treatment interaction (for HAM-D scores, P<.001, P =.16, and P =.58, respectively). Analysis of covariance showed nonsignificant effects for BDI and GAF scores. The proportion of participants achieving an a priori definition of response did not differ between groups. The number reaching remission of illness was significantly higher with St John's wort than with placebo (P =.02), but the rates were very low in the full intention-to-treat analysis (14/98 [14.3%] vs 5/102 [4.9%], respectively). St John's wort was safe and well tolerated. Headache was the only adverse event that occurred with greater frequency with St John's wort than placebo (39/95 [41%] vs 25/100 [25%], respectively). CONCLUSION: In this study, St John's wort was not effective for treatment of major depression.

Imidazoline and alpha(2a)-adrenoceptor binding sites in postmenopausal women before and after estrogen replacement therapy.

BACKGROUND: Platelet alpha(2A)-adrenoceptors (alpha(2A)AR) and imidazoline binding sites (subtype I(1)) have been proposed as peripheral markers of brain stem receptors that mediate sympathetic outflow and are reported to be elevated in major depression. METHODS: In our study, p[(125)I]-iodoclonidine was used to assess platelet alpha(2A)AR and I(1) binding sites in healthy postmenopausal women (n = 34) compared with healthy women of reproductive age (n = 26). Receptor determinations were repeated in 19 postmenopausal women following 59-60 days of estrogen replacement therapy (ERT; 0.1 mg estradiol transdermal patches). RESULTS: I(1) binding sites were twofold higher in platelets of postmenopausal women compared with women of reproduction age but were down-regulated (normalized) after 59-60 days of ERT. All other binding parameters, including platelet alpha(2A)AR density, were not different between groups nor were they changed after ERT. Platelet I(1) densities after 59-60 days of ERT were positively correlated with plasma luteinizing hormone concentrations. CONCLUSIONS: It is suggested that increased imidazoline binding sites might be associated with mood and behavioral changes in postmenopausal women.

Psychosocial functioning in women with premenstrual dysphoric disorder before and after treatment with sertraline or placebo.

BACKGROUND: The objective of this study was to evaluate the pretreatment psychosocial functioning of women with premenstrual dysphoric disorder (PMDD) and the effect of sertraline treatment on psychosocial functioning in these patients. METHOD: Two hundred forty-three women recruited from 12 university-affiliated sites and meeting DSM-IV criteria for PMDD completed 1 cycle of single-blind placebo and were randomly assigned to flexible dose sertraline or placebo for 3 cycles. Psychosocial functioning was assessed by the Daily Record of Severity of Problems (DRSP), the Social Adjustment Scale (SAS), and the Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q). RESULTS: SAS scores during the follicular phase were similar to SAS scores of community norms, whereas the pretreatment SAS and Q-LES-Q scores during the luteal phase were similar to scores of women with depressive disorders. Sertraline was significantly more effective than placebo in improving psychosocial functioning as measured by the SAS, the Q-LES-Q, and the 3 DRSP items of impaired productivity, interference with social activities, and interference with relationships with others. Improvement in psychosocial functioning assessed by SAS and Q-LES-Q correlated with improvement in symptomatology assessed by the Clinical Global Impressions-Improvement (CGI-I) scale and the Hamilton Rating Scale for Depression (HAM-D). Remitters (CGI-I score of 1) were more likely to function better at baseline and showed larger improvements in functioning and quality of life with treatment compared with nonremitters. CONCLUSION: Sertraline was superior to placebo in improving psychosocial functioning in women with PMDD as reflected by SAS, Q-LES-Q, and DRSP measures. Functional improvement correlated with improvement in premenstrual symptomatology and was apparent by the second cycle of treatment. Comparison of pretreatment SAS scores in women with PMDD with the scores of other populations of women documents the degree of luteal phase functional impairment in women with PMDD and a relative absence of follicular phase impairment.

Selective oestrogen receptor modulators--current and future brain and behaviour applications.

Selective oestrogen receptor modulators (SERMs) are compounds that act as oestrogen agonists on selected targets while being oestrogen antagonists on others. The main targets of SERMs are oestrogen agonist activity on bone metabolism and several functions of the cardiovascular system, as well as oestrogen antagonism in the breast and uterus. They are indicated for the treatment and/or prevention of breast and endometrial cancer, osteoporosis and coronary heart disease. The extensive documentation of the multiple oestrogen effects on the CNS, greater understanding of the mechanisms of action, and especially the discovery of a second oestrogen receptor with differentiated distribution and mechanisms, have all led the way to the possibility of specific CNS-targeted SERMs. The demonstration that oestrogen selectively improves cognition, delays the appearance of Alzheimer's dementia, improves the feeling of well-being, as well as the response to antidepressant medications, provides targeted CNS indications for SERMs. The CNS effects of the currently marketed SERMs are not sufficiently explored yet. However, in postmenopausal women, tamoxifen and raloxifene probably show the most oestrogen agonist CNS effects. In women of reproductive age, competition with oestrogen probably exists, resulting in antagonist effects. Activity in men is still mostly unknown. It is quite safe to predict that the recent accumulation of knowledge, combined with the large, thirsty anticipated market for these 'designer oestrogens', will lead to clinical trials of CNS-targeted SERMs in the very near future.

Premenstrual syndromes: closing the 20th century chapters.

The need to re-evaluate premenstrual syndromes became apparent in 1997-1998 and early 1999. The success stories of some symptomatic treatment modalities and more sophisticated studies of pathobiology chart the pathways for future progress: the shift from a descriptive diagnosis to diagnoses based on etiology, the recognition of diversified vulnerabilities and their expression in particular situations, and specific treatment modalities.

Evaluation of women's mental health: delineation of the field, and needs and steps toward a consensus.

Mental health studies that investigate the behavior, mood, perception, cognition, and biology associated with specific conditions of women or with situations characterized by substantial gender differences are proliferating in number and progressing in quality, depth, and scope. To solidify the field, there is a need for a consensus on definitions and diagnostic criteria, standardized clinical assessment procedures, and large-scale interdisciplinary collaborative efforts to effectively study and illuminate the diversified aspects of women's mental health. Under a professional services contract with the National Institute of Mental Health, researchers who investigate women's mental health met during the American Psychiatric Association (APA) meeting in San Diego, California, on May 19, 1997. The 18 participants discussed key clinical and biological assessments and subsequently submitted papers reflecting scientific conclusions and recommendations for standardizing these assessments. It was agreed that a unified assessment instrument would be beneficial, but due to the widespread requirements and numerous factors that are critical in assessing all areas of women's health, situation-specific forms are often needed. The background, rationale, and process of the meeting are described here, whereas the details and recommendations are described in individual position papers.

Premenstrual syndromes.

Premenstrual syndromes (PMS) are a group of menstrually related, chronic, cyclical disorders manifested by emotional and physical symptoms in the second half of the menstrual cycle. A diagnosis of PMS is based on the timing and symptom pattern observed in daily symptom reports maintained by the patient. The etiology is unknown but is believed to involve genetic and dynamically evolving vulnerability, reproductive hormones, and neurotransmitters, as well as other brain processes. Effective medications have been identified for acute hormonal and symptomatic treatment of the disorder, but the time course and frequency of relapse and recurrence remain poorly understood. Further studies of PMS in all areas--etiology, pathobiology, diagnosis, course of illness, and treatment efficacy--are needed to increase the body of information about the menstrual cycle's effects on women's health and mood disorders.