(S)-S-adenosylmethionine in the treatment of pre-menstrual disorders in adult women: A protocol for an open-label pilot study.

Pre-menstrual disorders, including pre-menstrual syndrome and pre-menstrual dysphoric disorder, are highly prevalent disorders in women of reproductive age. Pre-menstrual disorders are associated with debilitating symptoms that onset in the days prior to menses. A complex interplay between hormonal fluctuations, cellular sensitivity, and psychosocial stressors likely underly the pathophysiology of pre-menstrual disorders. Current treatment options include selective serotonin reuptake inhibitors, hormonal therapies, and psychosocial support. There is growing evidence for oestrogen, progesterone, gonadotropin Releasing Hormone analogues and Complementary and Alternative Medicines in treating Pre-menstrual disorders. (S)-S-adenosylmethionine is a complementary and alternative medicine with postulated roles in the treatment of depression, with a rather rapid onset of action and minimal side effect profile. We propose a protocol for investigating the efficacy of (S)-S-adenosylmethionine in the treatment of pre-menstrual disorders. The proposed study is an open label pilot study, that will recruit thirty women between the ages of 18-45 who experience a pre-menstrual disorder. Daily and interval questionnaires will provide a quantification of symptoms across four menstrual cycles (16 weeks). During two consecutive menstrual cycles it is proposed that participants receive oral (S)-S-adenosylmethionine Complex 400 mg three times a day (total daily dose 1200 mg), during the pre-menstrual time-period (14 days prior to menses). Changes in pre-menstrual disorder symptoms between control and treatment cycles will assist in elucidating the clinical efficacy of (S)-S-adenosylmethionine. This study has the potential to support a larger double blinded, placebo controlled randomised control trial and aims to enrich the knowledge surrounding pre-menstrual disorders.

Estrogen and psychosis - a review and future directions.

The link between sex hormones and schizophrenia has been suspected for over a century; however, scientific evidence supporting the pharmacotherapeutic effects of exogenous estrogen has only started to emerge during the past three decades. Accumulating evidence from epidemiological and basic research suggests that estrogen has a protective effect in women vulnerable to schizophrenia. Such evidence has led multiple researchers to investigate the role of estrogen in schizophrenia and its use in treatment. This narrative review provides an overview of the effects of estrogen as well as summarizes the recent work regarding estrogen as a treatment for schizophrenia, particularly the use of new-generation selective estrogen receptor modulators.

Adjunctive agents to antipsychotics in schizophrenia: a systematic umbrella review and recommendations for amino acids, hormonal therapies and anti-inflammatory drugs.

QUESTION: This umbrella review and guidelines aimed to provide evidence to support the rational choice of selected adjunctive therapies for schizophrenia. STUDY SELECTION AND ANALYSIS: Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and World Federation of Societies of Biological Psychiatry (WFSBP)-grading recommendations, 63 randomised control trials (RCTs) (of which 4219 unique participants have completed the RCTs) and 29 meta-analyses were analysed. FINDINGS: Provisional recommendations (WFSBP-grade 1) could be made for two molecules in augmentation to antipsychotics: (1) N-acetyl-cysteine (NAC, 1200-3600 mg/day, for >12 consecutive weeks) in improving negative symptoms, general psychopathology (positive and negative syndrome scale for schizophrenia (PANSS) general psychopathology factor (G)-G subscale), with the RCTs with the longer duration showing the most robust findings; (2) polyunsaturated fatty acids (3000 mg/day of eicosapentaenoic acid, for >12 weeks) in improving general psychopathology. Weaker recommendations (ie, WFSBP-grade 2) could be drawn for sarcosine (2 g/day) and minocycline (200-300 mg/day) for improving negative symptoms in chronic schizophrenia (not early schizophrenia), and NAC for improving positive symptoms and cognition. Weak recommendations are not ready for clinical practice. There is provisional evidence that oestrogens and raloxifene are effective in some patients, but further research is needed to determine their benefit/risk ratio. CONCLUSIONS: The results of this umbrella review should be interpreted with caution as the number of RCTs included in the meta-analyses was generally small and the effect sizes were weak or medium. For NAC, two RCTs with low risk of bias have provided conflicting results and the WFSBP-grade recommendation included also the results of meta-analyses. These drugs could be provisionally prescribed for patients for whom no other treatments have been effective, but they should be discontinued if they prove ineffective.

Estrogen - A key neurosteroid in the understanding and treatment of mental illness in women.

The commentary is an invited brief about my contribution to Psychiatry Research. My work has built on the "estrogen hypothesis", as stated by Hafner, Riecher-Rossler and Seeman in the 1990's. This hypothesis was that estrogen provides 'protection' against the early onset of severe schizophrenia in women, and with decreasing brain estrogens at the menopause, mental ill health worsens in women. In this paper, results from clinical trials conducted over many decades, that involved administering exogenous estrogen in different types and doses, show an overall positive impact - with improved symptoms of schizophrenia in women. This led to the conduct of further successful clinical trials of gonadal hormone treatment in women with PMDD and menopausal depression, plus understanding more about depression caused by hormone contraceptives. The role of estrogens in stress vulnerability is reflected in the sex-dependent reaction to childhood trauma, which has led to our new work in the neurobiological effects of early life trauma in women.

Hormonal Agents for the Treatment of Depression Associated with the Menopause.

Perimenopause marks the transition from a woman's reproductive stage to menopause. Usually occurring between 42 and 52 years of age, it is determined clinically by the onset of irregular menstrual cycles or variable cycle lengths. Women are at an increased risk of depression and anxiety during perimenopause and the menopausal transition. Depressive symptoms experienced in perimenopause are often more severe compared to pre- and post-menopause. During menopausal transition, the impact of fluctuating estrogen in the central nervous system (CNS) can have negative psychological effects for some women. Traditional first-line management of menopausal depression involves antidepressants, with modest outcomes. The positive effects of estrogen treatment in the CNS are becoming increasingly recognised, and hormonal therapy (HT) with estrogen may have a role in the treatment of menopausal depression. In this review we will outline the prevalence, impact and neurochemical basis of menopausal-associated depression, as well as hormone-based approaches that have increasing promise as effective treatments.

A network meta-analysis of stress mediators in suicide behaviour.

Stress homeostatic mediators are the most consistently anomalous biomarkers observed in suicide and may therefore point to a common 'core biology' of stress susceptibility, and suicidal behaviour. Previously reported meta-analyses have demonstrated aberrant levels of stress cortisol and inflammatory cytokines in suicide patients compared to controls, and significant associations between the stress regulator FK506-binding protein 51 (FKBP5) gene and suicidal behaviour. Although these independent studies were investigated as separate entities in suicide, stress mediators interact in a dynamic system, collectively giving rise to system changes physiologically, and ultimately psychologically and behaviourally. It is therefore important to study the dynamic network these stress mediators. Network meta-analysis allows for the simultaneous comparison of more than two biological mediators, and for comparisons to be made between mediators that have not been directly compared before, using previously reported, pooled meta data. Such network approaches may help study the complex biological phenomena of suicide and may provide better prediction of biological risk of suicidal states. METHODS: This study aimed to establish the comparative relationships between key stress mediators in suicidal patients compared to non-suicidal controls using a random-effects network meta-analysis approach.. The key stress mediators included cortisol, six inflammatory markers (interleukin-6 (IL-6), interleukin-4 (IL-4), interleukin-2 (IL-2), tumour necrosis factor-a (TNF-α), interferon (IFN-y) and transforming growth factor ß (TGF-ß), and the FKBP5 single nucleotide polymorphism (SNP) allele. Data was derived from three previously published meta-analysis. The study population comprised of 1348 suicidal patients, defined as suicide attempters, completers, or patients with severe suicidal ideation, and 1750 non-suicidal controls, defined as healthy controls and psychiatric patients without suicidal ideation or previous attempts. RESULTS: Pair-wise indirect effects of stress mediators in suicide compared to controls demonstrated that relative to the effect of the FKBP5 risk SNP allele on suicide risk, the magnitude of differences (suicide vs control) for the levels of IL-2 (SMD -0.72; 95% CI, -0.135 to -0.09 and IL-4 (SMD -0.71; 95% CI, -1.34 to -0.08) were significantly smaller (with 95% confidence intervals not crossing the null). The comparative relationships between stress mediators in suicidal behaviour demonstrates that the dynamic stress network relationship is dysregulated in suicide patients when compared to controls. CONCLUSIONS: This model suggests that a genetic stress susceptibility with downstream abnormal cortisol stress axis functioning, together with anomalous interactions between the inflammatory system, may be one of the neurobiological correlates of suicide behaviour. This biological state may leave the individual physiologically susceptible and unable to cope with environmental stressors, which is consistent with the stress-diathesis hypothesis of suicide behaviour.

Sex hormones and cognition in aging.

Hormones of the hypothalamic-pituitary-gonadal axis that regulate reproductive function are also potent neurosteriods that have multiple effects on the development, maintenance and function of the brain. There is a growing body of evidence linking sex hormones to cognitive functioning across the lifespan. Both subjective and objective cognitive changes can occur with aging. For women, cognitive complains are commonly associated with the menopause transition-a time of significant hormone flux. Sex differences in neurodegenerative conditions associated with cognitive dysfunction, such as Alzheimer's disease and Parkinson's disease, suggest a potential link between sex hormones and cognitive decline. Evidence for the effects of hormone therapy on cognition is growing, but remains inconclusive. This chapter provides an overview of sex hormones and cognition in association with healthy aging, including a focus on the menopause transition, as well as reviewing findings linking sex hormones to cognitive decline associated with Alzheimer's disease and Parkinson's disease. An overview of hormone therapy and cognition is also provided.

Serum estradiol as a blood-based biomarker predicting hormonal treatment outcomes in women with schizophrenia.

Patients diagnosed with schizophrenia display substantial heterogeneity in terms of their clinical presentations, and treatment response. Accumulating research suggests that such high diversity may reflect distinct biological subtypes with differentially affected underlying neurobiology. Novel treatments, including sex hormone estradiol treatments, provide alternative efficacious treatment avenues but also should be studied within the context of potential heterogeneity. This repeated-measures study characterised the association between hormone levels (estrogen, progesterone, testosterone, prolactin, FSH, LH, DHEA) and symptom treatment outcomes (defined by The Positive and Negative Syndrome Scale (PANSS)) across a 56-day study of 200 ug adjunctive estradiol treatment in women with schizophrenia. Group-based trajectory models was used to account for potential heterogeneity (subgroups). Receiver operating characteristic (ROC) curves were evaluated to define the predictive value of endogenous estradiol levels as a treatment-response biomarker of estradiol treatment. The results generated two subgroups; a treatment-responder group who demonstrated decreasing PANSS scores across time, and a treatment non-responder group, demonstrating stable PANSS scores across time. The treatment-responder subgroup was significantly negatively predicted by estradiol blood level (b= -2.34, SE= 1.17, p = 0.047), while FSH blood level was positively associated with the treatment non-responders (b= 7.14, SE= 2.54, p = 0.008). ROC for day 28, 56 time points yielded area under the curve of 0.52 and 0.55, respectively. Harrell's C-statistic = 0.59. This is the first study to identify endocrine markers in blood serum predicting response to estradiol treatment in female schizophrenia patients, highlighting the existence of heterogeneity of response, indicative of molecular subtypes. Characterising the differential underlying biology of the subgroups may lead to better targeted, specific treatments in the future.(ClinicalTrials.gov Identifier: NCT00357006). https://www.clinicaltrials.gov/ct2/show/NCT00357006.

Family Violence: An Insight Into Perspectives and Practices of Australian Health Practitioners.

Family violence is threatening behavior carried out by a person to coerce or control another member of the family or causes the family member to be fearful. Health practitioners are well placed to play a pivotal role in identifying and responding to family violence; however, their perceived capacity to respond to patients experiencing family violence is not well understood. We aim to explore Australian health practitioners' current perspectives, practices, and perceived barriers in working with family violence, including perceived confidence in responding effectively to cases of family violence encountered during their work with patients. A total of 1,707 health practitioners primarily practicing in the wider Melbourne region were identified, and 114 health practitioners participated in the study between March 2016 and August 2016 by completing an investigator-developed questionnaire. Descriptive, qualitative, and thematic analyses were performed. The majority of participants recognized family violence to be a health issue and that family violence would impact the mental health of afflicted persons. Despite this, only a fifth of participants felt they were very confident in screening, supporting, and referring patients with family violence experiences. Perceived barriers to inquire about family violence included time constraints and greater importance placed on screening for other health issues. Health practitioners reported that additional training on screening, supporting, and referring patients would be beneficial. Australian health practitioners need to be upskilled. Recently, in Australia, state-relevant toolkits have been developed to provide succinct information about responding to initial patient presentations of family violence, how to inquire about family violence, and how to handle disclosures (and nondisclosures) by patients. Further resources could be developed to aid health practitioners in providing assistance to their patients as indicated. These initiatives would be a step toward addressing the concerns with regard to the lack of training and could possibly optimize outcomes for patients experiencing family violence.

Psychiatric comorbidities and adverse childhood experiences in women with self-reported polycystic ovary syndrome: An Australian population-based study.

PURPOSE: PCOS is associated with increased risk for depression and anxiety but its association with other psychiatric disorders is less clear, especially in community drawn populations. We aimed to investigate the prevalence of psychiatric disorders in women with PCOS and examine the factors associated with psychiatric disorders in this population. METHOD: A cross-sectional analysis of survey data was performed in community-recruited women born 1989-95 from the Australian Longitudinal Study of Women's Health (ALSWH). 760 and 7910 women with and without self-reported PCOS were included. The outcomes examined were self-reported depression, anxiety, post-traumatic stress disorder, bipolar affective disorder, obsessive compulsive disorder, borderline personality disorder and other disorders. The main explanatory variable was self-reported PCOS status. Other factors examined included adverse childhood experience scale (ACES), social support, perceived stress, sociodemographic and lifestyle factors. Chi-square tests were used to examine the differences in prevalence between groups. Logistic regression analyses were performed to assess factors associated with psychiatric disorders. RESULTS: Women with PCOS reported a significantly higher prevalence of the psychiatric disorders examined, compared with women without PCOS. PCOS was significantly associated with depression (adjusted odds ratio (OR) 1.4, 95 % confidence interval (CI) 1.2-1.7), anxiety (adjusted OR 1.2, 95 % CI 1.0-1.5), post-traumatic stress disorder (adjusted OR 1.5, 95 % CI 1.1-1.9) and obsessive compulsive disorder (adjusted OR 1.8, 95 % CI 1.2-2.5). More women with PCOS reported adverse childhood experiences (ACES ≥4: 19.3 % vs 9.2 %) and this was the strongest factor associated with psychiatric disorders (ACES ≥4: adjusted OR 2.9, 95 % CI 2.4-3.5). CONCLUSIONS: Women with PCOS had higher prevalence of various psychiatric conditions and adverse childhood experiences compared with women without PCOS. ACES was the strongest correlate of psychiatric disorders. These findings support PCOS is a reproductive, metabolic and psychological disorder and reinforces guideline recommendations to assess psychological wellbeing for in women with PCOS.

Do Genital Cosmetic Procedures Improve Women's Self-Esteem? A Systematic Review and Meta-Analysis.

BACKGROUND: The popularity of genital cosmetic procedures in women is increasing. These procedures are often assumed and promoted as having a positive effect on women's psychological well-being, particularly their self-esteem. Empirical support for these claims is lacking. OBJECTIVES: The aim of this study was to conduct a systematic review and meta-analysis of the impact of genital cosmetic procedures on self-esteem in women. METHODS: The authors performed a systematic literature review of MEDLINE, PreMEDLINE, Ebase, EMBASE, OVID, CINAHL, Cochrane, PsycINFO, and PubMed to identify articles that measured self-esteem in women after a genital cosmetic procedure. A meta-analysis was conducted to assess the pooled effect of these procedures on self-esteem. RESULTS: The authors identified 5 eligible studies for the meta-analysis, comprising 2 prospective and 3 retrospective studies. Labia minora reduction was the most commonly studied procedure. All 5 studies used different measures of self-esteem, with only 1 study employing a validated psychometric measure at both preoperative and postoperative time points. The meta-analysis results showed a pooled logit rate estimate of 1.230, indicating a positive effect of surgery on self-esteem. However, there was substantial heterogeneity across studies. CONCLUSIONS: Female genital cosmetic procedures, particularly labiaplasty, appear to have a positive effect on women's self-esteem. However, inconsistencies in study measures and methods limit our conclusions. Future research should involve the development of standardized outcome measures to more accurately assess the impact of these procedures on self-esteem, and on psychological well-being more generally.

Measuring Quality of Life in Female Genital Cosmetic Procedure Patients: A Systematic Review of Patient-Reported Outcome Measures.

BACKGROUND: In the subspecialty of female genital cosmetic procedures, patient satisfaction and quality of life are key outcome measures. As such, valid and reliable patient-reported outcome measures (PROMs) examining these outcomes are essential. OBJECTIVES: The authors sought to identify and scrutinize all PROMs developed for female patients undergoing genital cosmetic procedures. METHODS: The authors performed a systematic literature review utilizing MEDLINE, PreMEDLINE, Ebase, Embase, OVID, CINAHL, Cochrane Library, PsycINFO, PubMed, and Google Scholar to identify PROMs developed and validated for utilization in female genital cosmetic procedure patients. Instruments identified were assessed according to international guidelines for health outcome measures development and validation. RESULTS: The authors identified 50 outcome questionnaires employed in the female genital cosmetic procedure literature. Of these, 26 were ad hoc instruments (ie, had not been formally developed and tested) and 22 were generic instruments (ie, intended for use in broad groups of people, not only specific patient groups). Only 2 instruments have been validated in a female genital cosmetic procedure patient population. These were the Genital Appearance Satisfaction scale and the Cosmetic Procedure Screening Scale-Labiaplasty. Although both these scales had undergone fairly rigorous psychometric development and validation, both had content limitations. CONCLUSIONS: There is a lack of specific, valid, and reliable satisfaction and quality-of-life PROMs in the field of female genital cosmetic procedures. Future research should involve the development of such measures to more accurately assess the outcomes and benefits of these procedures.

Dissecting the syndrome of schizophrenia: Associations between symptomatology and hormone levels in women with schizophrenia.

Despite many studies implicating reproductive hormones in the development and outcome of schizophrenia, few have characterised the association between symptomatology and hormonal trajectories. To understand the influence of hormones on schizophrenia symptoms, serum steroids (estradiol, progesterone, follicular stimulating hormone (FSH), luteinising hormone (LH), and dehydroepiandrosterone (DHEA)) and psychopathology (The positive-and-negative-syndrome-scale(PANSS)) and depression (Montgomery-Asberg-Depression-Rating Scale(MADRS)) were collected across 12-weeks in 45 women (mean age 46) diagnosed with schizophrenia. To account for potential heterogeneity, Group-based-trajectory-modelling of psychopathology was used to identify distinct subgroups of individuals following a similar pattern of association between symptom score and hormone levels over-time. Two trajectories were identified for PANSS: one subgroup with lower symptom severity was associated with FSH, DHEA, LH, and another high severity subgroup associated with LH. Two trajectories were identified for MADRS: 'depressed' (associated with FSH), and non-depressed. The result delineates subpopulations with unique psychopathology and hormone associations that support the hypothesis that reproductive hormones play a role in the pathophysiology of schizophrenia, and that heterogeneity may exist in hormonal sensitivities in the schizophrenia population. Stratification of subjects according to biological phenotype may help improve existing treatments through personalised-medicine strategies. The endocrine system may be one such biological mechanism to continue dissecting the syndrome.

The influence of endogenous estrogen on high-frequency prefrontal transcranial magnetic stimulation.

BACKGROUND: The use of repetitive transcranial magnetic stimulation (rTMS) as both therapeutic and experimental tools has grown enormously over the past decade. However, variability in response to rTMS is one challenge that remains to be solved. Estrogen can impact neural plasticity and may also affect plastic changes following rTMS. The present study investigated whether estrogen levels influence the neurophysiological effects of high-frequency (HF) rTMS in the left dorsolateral prefrontal cortex (DLPFC). HYPOTHESIS: It was hypothesised that individuals with higher endogenous estrogen would demonstrate greater rTMS-induced changes in cortical reactivity. METHODS: 29 healthy adults (15M/14F) received HF-rTMS over left DLPFC. Females attended two sessions, one during a high-estrogen (HE) phase of the menstrual cycle, another during a low-estrogen (LE) phase. Males attended one session. Estrogen level was verified via blood assay. TMS-EEG was used to probe changes in cortical plasticity and comparisons were made using cluster-based permutation statistics and Bayesian analysis. RESULTS: In females, a significant increase in TMS-evoked P60 amplitude, and decrease in N45, N100 and P180 amplitudes was observed during HE. A less pervasive pattern of change was observed during LE. No significant changes in TEPs were seen in males. Between-condition comparisons revealed higher likelihood of the change in N100 and/or P180 being larger in females during HE compared to both females during LE and males. CONCLUSIONS: These preliminary findings indicate that a greater neuroplastic response to prefrontal HF-rTMS is seen in women when estrogen is at its highest compared to men, suggesting that endogenous estrogen levels contribute to variability in response to HF-rTMS.

An update on medication management of women with schizophrenia in pregnancy.

INTRODUCTION: Women with schizophrenia and their babies are at high risk of adverse outcomes in pregnancy and childbirth. A better understanding of the specific risks conferred by the illness itself and by the treatment provided will help guide more effective care of these women. AREAS COVERED: Herein, the authors review genetic, demographic, socioeconomic, nutritional and lifestyle risks associated with schizophrenia in pregnancy. They also cover specific risks associated with typical antipsychotic medications, specific risks associated with atypical antipsychotic medications, risks associated with polypharmacy and risks of developmental delay in children exposed to antipsychotic medications in utero. EXPERT OPINION: Our understanding of the risks that women with schizophrenia face in pregnancy from their illness and from the treatment they receive continues to evolve. As our ability to analyze data progresses, the risks conferred by antipsychotic medication treatment appear to lessen in clinical and statistical significance, whilst the true risks to these women and their babies from their experience of disadvantage continue to set them aside from the general population. Reducing polypharmacy and providing comprehensive and supportive care can minimize harm to women with schizophrenia and their babies.

Estrogens and SERMS as adjunctive treatments for schizophrenia.

More than thirty years have passed since sex and gender differences were noted in the age of onset, course and outcomes for schizophrenia. The 'estrogen hypothesis" was coined in the 1990's to describe neuroprotective effects of estrogen. Intervention studies in schizophrenia patients with estradiol and selective estrogen receptor modulators (SERMs) are promising but psychiatrists and other health practitioners do not generally take up this useful adjunctive treatment for their female patients with schizophrenia. The reasons for this are manifold, but overall a cultural shift in the practice of psychiatry is needed to recognise the specific needs of women with schizophrenia and tailor treatments, such as hormone adjuncts to improve the outcomes for this significant population. The two main aims of this article are to review the evidence and theory of estrogen treatments in schizophrenia and to recommend translation of adjunctive estrogen treatment into clinical practice for women with schizophrenia.

The influence of endogenous estrogen on transcranial direct current stimulation: A preliminary study.

Transcranial direct current stimulation (tDCS) is a non-invasive neuromodulatory technique. Responses to tDCS differ substantially between individuals. Sex hormones that modulate cortical excitability, such as estrogen, may contribute to this inter-individual variability. The influence of estrogen on tDCS after-effects has not yet been researched. This study aimed to investigate whether endogenous estrogen levels influence cortical response to tDCS. Data from 15 male and 14 female healthy adults were analyzed. Males completed one experimental session. Females completed two, one during the early follicular phase of the menstrual cycle when estrogen was low, one during the mid-luteal phase when estrogen was high. Each session comprised 15-min of anodal tDCS delivered to the left dorsolateral prefrontal cortex (DLPFC). Response to stimulation was assessed using electroencephalography with DLPFC transcranial magnetic stimulation (TMS) administered before, immediately after, and 20-min after tDCS. Changes in amplitudes of N120 and P200 components of TMS-evoked potentials over time were compared between males, women with low estrogen and women with high estrogen. Blood assays verified estrogen levels. Women with high estrogen demonstrated a significant increase in P200 amplitude at both time points and change over time was greater for the high estrogen group compared with males. No significant differences were observed between males and women with low estrogen, or between women with low and high estrogen. These preliminary results indicate that greater neuroplastic response to DLPFC tDCS is seen in highest compared with lowest estrogen states, suggesting that endogenous estrogen levels contribute to inter-individual variability of tDCS outcomes.

Tibolone improves depression in women through the menopause transition: A double-blind randomized controlled trial of adjunctive tibolone.

BACKGROUND: Many women with no past psychiatric history experience severe mood symptoms for the first time in their life during the menopausal transition, with debilitating long-term consequences. Women with a history of depression can experience a relapse or worsening of symptoms during the menopause transition. Traditional antidepressants, SSRIs or SNRIs, are commonly prescribed as the first line response. However, such treatment has shown only small improvements with side effects. Hormone therapies directly targeting the perimenopausal fluctuations in reproductive hormonal systems such as tibolone, have significant potential to treat perimenopausal depression. Our study investigated the use of adjunctive tibolone, selective tissue estrogenic activity regulator, to treat de-novo or relapsing depression occurring during the menopause transition period. METHODS: Women who were going through the menopause transition with depressive symptoms were invited to participate in a double-blind, 12 week randomized control trial with two arms: tibolone (2.5 mg oral/day) or oral placebo (NCT01470092). Forty-four women met inclusion/exclusion criteria; 22 were randomized to tibolone and 22 were randomized to oral placebo. Symptoms were measured with the 'Montgomery- Asberg depression rating scale' (MADRS) as the primary outcome measure. Latent growth curve analysis was used to assess the MADRS scores change over time. RESULTS: Participants in the tibolone group demonstrated a significant improvement in depression scores, as compared to the placebo group, without any significant side effects. LIMITATIONS: This trial only monitored tibolone's effects over 12 weeks. Future research should be conducted over an extended timeframe and explore whether the benefits of tibolone extend to other symptoms of perimenopausal depression. CONCLUSIONS: The use of hormone therapies such as tibolone provide exciting innovations for the treatment of depression during the menopause transition.