The menstrual cycle may not be limited to the endometrium but also may impact gut permeability.

OBJECTIVE: To examine associations between IgA responses to Gram-negative gut commensal bacteria and peri-menstrual symptoms and sex hormone levels during the menstrual cycle in women with and without premenstrual symptoms. METHODS: Forty women aged 18-45 years completed the Daily Record of Severity of Problems (DRSP) during all 28 consecutive days of the menstrual cycle. We assayed, in plasma, IgA responses to six Gram-negative bacteria, that is, Hafnei alvei, Pseudomonas aeruginosa, Morganella morganii, Klebsiella pneumoniae, Pseudomonas putida and Citobacter koseri, progesterone and oestradiol at days 7, 14, 21 and 28 of the menstrual cycle. RESULTS: Significant changes in Δ (actual - 1 week earlier) IgA to lipopolysaccharides (LPS) of the six Gram-negative bacteria during the menstrual cycle were observed with peak IgA levels at T4 (day 28) and lows at T1 or T2 (day 7 or 14). The ΔIgA changes in H. alvei, M. Morganii, P. putida during the menstrual cycle were significantly and positively associated with changes in the total DRSP score, and severity of physio-somatic, anxiety and breast-craving, but not depressive, symptoms. The changes in IgA responses to LPS were largely predicted by changes in progesterone and steady-state levels of progesterone averaged over the luteal phase. DISCUSSION: Menstrual cycle-associated changes in IgA directed against LPS and by inference bacterial translocation may be driven by the effects of progesterone on transcellular, paracellular and vascular pathways (leaky gut) thereby contributing to the severity of physio-somatic and anxiety symptoms as well as fatigue, breast swelling and food cravings.

In major affective disorders, early life trauma predict increased nitro-oxidative stress, lipid peroxidation and protein oxidation and recurrence of major affective disorders, suicidal behaviors and a lowered quality of life.

Early life trauma (ELT) may increase the risk towards bipolar disorder (BD) and major depression (MDD), disorders associated with activated neuro-oxidative and neuro-nitrosative stress (O&NS) pathways. It has remained elusive whether ELTs are associated with O&NS and which ELTs are associated with distinct affective disorder phenotypes. This case-control study examined patients with BD (n = 68) and MDD (n = 37) and healthy controls (n = 66). The Child Trauma Questionnaire (CTQ) was used to assess specific ELT. We measured malondialdehyde (MDA), lipid hydroperoxides (LOOH), superoxide dismutase (SOD), catalase, advanced oxidation protein products (AOPP); NO metabolites (NOx), paraoxonase 1 activity, zinc, albumin, high density lipoprotein cholesterol and -SH groups and computed z-unit weighted composite scores. Physical neglect significantly predicts higher z-unit weighted composite scores of LOOH+SOD, LOOH+SOD+NOx, LOOH+SOD+NOx + MDA and LOOH+SOD+NOx + AOPP. Sexual abuse was associated with a significantly lower composite score of zinc+albumin+SH. Emotional abuse was associated with severity of depression and anxiety, number of depressive and manic episodes, alcohol and hypnotics use, lifetime suicidal behavior and lowered quality of life. Sexual abuse was associated with an increased risk towards BD, but not MDD. ELT, especially physical neglect, may drive increased (nitro-)oxidative stress coupled with lipid and protein oxidation, which - together with emotional abuse - may play a role in severity of illness, lowered quality of life and MDD. ELTs are also associated with the onset of BD, but this link did not appear to be related to activated O&NS pathways. These novel findings deserve confirmation in prospective studies.

Natural regulatory IgM-mediated autoimmune responses directed against malondialdehyde regulate oxidative and nitrosative pathways and coupled with IgM responses to nitroso adducts attenuate depressive and physiosomatic symptoms at the end of term pregnancy.

AIM: We aimed to delineate the effects of immunoglobulin (Ig)M-mediated autoimmune responses directed against malondialdehyde (MDA) and nitroso (SNO) adducts on nitro-oxidative stress and depressive and physiosomatic symptoms (DPSS) at the end of term. METHODS: IgM responses to MDA, NO (nitroso) adducts formed by nitrosylation, and NO2 tyrosine formed by nitration were measured as well as hydroperoxides (ferrous oxidation xylenol orange), advanced protein oxidation products (AOPP), and NO metabolite (NOx) levels in women at the end of term pregnancy and in normal controls. RESULTS: IgM responses to MDA were significantly and inversely associated with AOPP, ferrous oxidation xylenol orange, and NOx and DPSS. IgM responses to NO adducts were significantly and inversely associated with DPSS and positively with NOx levels. There were significant associations between IgM responses to MDA, NO adducts, and NO2 tyrosine. The DPSS score was predicted by AOPP and a lifetime history of premenstrual syndrome (both positively) and IgM responses to NO adducts (inversely). Furthermore, 71.8% of the variance in the index of nitro-oxidative stress was explained by lowered IgM responses to MDA, antioxidant levels (zinc, total radical trapping parameter), and inflammatory mediators. CONCLUSION: Lowered levels of IgM responses to MDA during pregnancy are accompanied by a reduced regulation of nitro-oxidative processes thereby explaining increased oxidative and nitrosative stress biomarkers in association with DPSS. IgM responses to NO adducts, which reflect nitrosylation as a consequence of increased NO production, regulate DPSS symptoms at the end of term and are a trait marker of major depression. IgM responses to MDA are a key part of the compensatory anti-inflammatory responses system.

IgM-mediated autoimmune responses to oxidative specific epitopes, but not nitrosylated adducts, are significantly decreased in pregnancy: association with bacterial translocation, perinatal and lifetime major depression and the tryptophan catabolite (TRYCAT) pathway.

Immunoglubulin (Ig)M responses directed to oxidative specific epitopes (OSEs) and nitric oxide (NO)-adducts are significantly associated with major depression and physio-somatic symptoms. End of term serum IgM responses to OSEs and NO-adducts were assayed in pregnant women with (n = 24) and without prenatal depression (n = 25) as well as in 24 non-pregnant women. Associations of IgM/IgA responses to Gram-negative gut commensal bacteria (leaky gut index) and IgA/IgM responses to tryptophan catabolites (TRYCATs) were analyzed. IgM responses to OSEs, but not NO-adducts, were significantly reduced at the end of term. There were no significant associations between IgM responses to OSEs and perinatal depression, whilst IgM responses to NO-adducts, especially NO-cysteinyl, were significantly associated with a lifetime major depression. IgM responses to OSEs and NO-cysteinyl were significantly associated with IgA/IgM responses to Gram-negative bacteria, especially Morganella morganii, Klebsiella pneumoniae and Citrobacter koseri. IgM responses to NO-adducts and OSEs, especially malondialdehyde and myristic acid, and C-reactive protein (CRP) were inversely associated with TRYCAT pathway activity, whilst a lifetime depression and Pseudomonas putida were positively associated. The attenuation of natural IgM-mediated responses to OSEs at the end of term may indicate lowered activity of this part of the compensatory (anti-)inflammatory reflex system and may be partly explained by lowered bacterial translocation. Increased IgM responses to NO-cysteinyl is a biomarker of lifetime depression and may be induced by bacterial translocation. Natural IgM-mediated autoimmune responses, increased nitrosylation and higher CRP levels may have negative regulatory effects on the TRYCAT pathway.

Associated factors of prenatal depression among teenage pregnant women at King Chulalongkorn Memorial Hospital.

OBJECTIVE: Depression during pregnancy is associated with deteriorating maternal health and increasing risk of preterm birth, fetal growth restriction, and suicidal attempt. The problems may be worse in adolescents who are more vulnerable. This study was conducted to determine the percentage of depression among teenage mothers and its associated factors. MATERIAL AND METHOD: Two hundred teenage pregnant women aged between 13 and 19 years who visited King Chulalongkorn Memorial Hospital (KCMH) participated in the present study. They were asked to complete the validated Thai Edinburgh Postnatal Depression Scale (EPDS) questionnaire for depression screening. The cut-offscore of 11 was used for the diagnosis of prenatal depression. RESULTS: Ninety-two (46%) teenage pregnant women were found to have prenatal depression using the EPDS cut-off score of 11. The mean age of participants was 17.5 years with the mean gestational ages of 23 weeks. Most of the participants (67%) resignedfrom school and 16% had history of attempted abortion during current pregnancy. There was no significant association between prenatal depression and unplanned pregnancy, unemployment, leaving school, or trimester at screening. Logistic regression analyses showed that history of attempted abortion and inadequate income were significantly associated with prenatal depression (odd ratio = 8.03, 95% CI 1.59 to 40.37 and 4.16, 95% CI 1.35 to 12.83, respectively). CONCLUSION: Prenatal depression was common among teenage pregnant women who visited KCMH. Attempted abortion and inadequate income were found to be significantly associated with prenatal depression.

Prevalence of depression and anxiety in pulmonary tuberculosis patients and its association with unsuccessful treatment outcome: A prospective cohort study.

BACKGROUND: Pulmonary tuberculosis (TB) remains a major public health problem in Thailand. TB causes chronic disease which may cause physical disability, mental and socioeconomic problems in TB patients. Mental disorders may occur after TB infection or co-exist with the disease. This study assessed the prevalence of depression and anxiety among pulmonary TB patients and its association with treatment outcome. METHODS: This is a single-center prospective study. Pulmonary TB patients who were treated at a tertiary hospital, in both outpatient and in-patient settings, were enrolled into the study. Demographic data and Thai Hospital Anxiety and Depression Scale (HADS) score at baseline and at least 2 months after diagnosis were collected to evaluate the probability of depression and anxiety. Logistic regression model was used to analyze the data. Association between suspicious mental disorder and treatment outcome were evaluated at the end of each participant's treatment. RESULTS: One hundred and three participants were enrolled into the study on March 2018 to October 2019. The prevalence of probable depression and anxiety (Thai HADS score ≥11 from both test) were 7.8% and 6.8%, respectively. Unsuccessful treatment outcome rate was 10.7% (11/103). From the multivariate analysis, people previously treated/relapsed (aOR (95%CI): 7.04 (1.19-41.85), p = 0.03) and probable depression/anxiety with Thai HADS score ≥11 (10.12 (1.54-66.45), p = 0.02) were associated with unsuccessful treatment outcome. CONCLUSIONS: In this study, Thai HADS score could identify probable depression and anxiety among pulmonary TB patients, and its association with unfavorable treatment outcome. Clinicians should keep in mind that pulmonary TB can affect the mental status of the patients and therefore, should evaluate them and provide appropriate treatment.

Preoperative anxiety among patients who were about to receive uterine dilatation and curettage.

BACKGROUND: From our clinical experience, preoperative anxiety are quite common among women who were about to receive uterine dilatation and curettage (D&C). However these conditions have not yet been studied. The authors aimed to examine the prevalence of anxiety as well as the underlying specific concerns among this group of patients. MATERIAL AND METHOD: The authors assessed preoperative anxiety in 383 women who were about to receive D&C by using the Hospital Anxiety and Depression Scale and questionnaires to assess specific concern toward this operation. RESULTS: Prevalence of preoperative anxiety was 23.2%. Among the pregnant subjects, preoperative anxiety was associated with concern over being approached in lithotomy position and concern with the procedure. For the non-pregnant subjects, high preoperative pain score, marital status, having no medical expense reimbursement, distrust in medical personnel, concern over being approached in lithotomy position, and intra-operative pain are associated with anxiety. CONCLUSION: Preoperative anxiety is quite common among this group of patients. Understanding the underlying specific concern of women who are about to receive D&C will help medical personnel to provide more effective management strategies in making the patients more comfortable.

Biomarker Validation of a New Case Definition of Menstrual Cycle-Associated Syndrome (MCAS) Opinion Paper.

There are different case definitions of premenstrual syndrome, one proposed by the American College of Obstetricians and Gynecologists (ACOG) and another based on the Daily Record of Severity of Problems (DRSP) scores. Here we review our recent findings indicating that the gold-standard methods to assess PMS, including ACOG, provide a high degree of false-negative findings. We propose a new case definition of the Menstrual Cycle-Associated Syndrome (MCAS), which is characterized by increased DRSP scores during the menstrual cycle and symptom that increases the week prior to the menses. The MCAS case definition was externally validated by diverse biomarkers including plasma levels of progesterone and estradiol, chemokines (e.g. CCL2, CCL5 and CCL11), epidermal growth factor, hydroperoxides, paraoxonase 1 activity and complement C4. These biomarkers as well as IgA responses to Gram-negative bacteria are significantly associated with the DRSP and its subdomains including depression, anxiety, and physiosomatic symptoms(fatigue, pain). In conclusion, we propose, a) to use the MCAS diagnosis as an indicant of menstrual cycle-related symptoms; and b) to examine the associations of the time series in the DRSP and its subdomains and those in biomarkers including distributed lag models. Aberrations in the uterine-chemokine-brain-axis underpin the pathophysiology of MCAS whereby suboptimal pre-ovulatory follicular development coupled with a relative corpus luteum insufficiency may drive increased chemokine production, lowered antioxidant defenses, neuro-oxidative stress pathways, and increased bacterial translocation. As such, we have delineated new drug targets for the treatment of MCAS. This opinion paper reviews new possible treatments that should be trialed in MCAS.

Menstruation distress is strongly associated with hormone-immune-metabolic biomarkers.

OBJECTIVE: To examine the associations between menstruation features and symptoms and hormone-immune-metabolic biomarkers. METHODS: Forty-one women completed questionnaires assessing characteristic menstruation symptoms, duration of menstrual cycle and number of pads used/day and completed the Daily Record of Severity of Problems (DRSP) during the consecutive days of their menstrual cycle. Menses-related symptoms (MsRS) were computed from the sum of 10 pre- and post-menses symptoms and the menstruation blood and duration index (MBDI) was computed based on the daily number of pads and duration of menses. We assayed serum levels of various biomarkers at days 7, 14, 21, and 28 of the subjects' menstrual cycle. RESULTS: MBDI was significantly associated with a) MsRS including low abdominal cramps, and gastro-intestinal (GI) and pain symptoms (positively); b) plasma levels of haptoglobin (Hp), CCL5, insulin growth factor (IGF)-1, and plasminogen activator inhibitor (PAI)1 (all positively); and c) estradiol and paraoxonase (PON)1 arylesterase activity (both inversely). MsRS were significantly predicted by CCL5 and IGF-1 (both positively) and progesterone (inversely). Low-abdominal cramps, and gastro-intestinal and pain symptoms were associated with lower progesterone levels. The MBDI+MsRS score was significantly predicted by the cumulative effects of (in descending order of importance): Hp, IGF-1, PON1 arylesterase, estradiol and PAI. CONCLUSION: Menstruation-related features including estimated blood loss, duration of menses, cramps, pain, and gastro-intestinal symptoms are associated with hormone-immune-metabolic biomarkers, which mechanistically may explain those features. Future research should construct a cross-validated algorithm using MBDI+MsRS features in a larger study group to delineate a useful case-definition of menstruation-related distress.

The uterine-chemokine-brain axis: menstrual cycle-associated symptoms (MCAS) are in part mediated by CCL2, CCL5, CCL11, CXCL8 and CXCL10.

OBJECTIVE: To examine associations between chemokines and menstrual cycle associated symptoms (MCAS). METHODS: Forty-one women completed the Daily Record of Severity of Problems (DRSP) rating scale during 28 consecutive days of the menstrual cycle. MCAS is diagnosed when the total daily DRSP score during the menstrual cycle is > 0.666 percentile. We assayed plasma CCL2, CCL5, CCL11, CXCL8, CXCL10, EGF, IGF-1, and PAI-1 at days 7, 14, 21 and 28 of the menstrual cycle. RESULTS: CCL2, CCL5, CCL11 and EGF are significantly higher in women with MCAS than in those without. Increased CCL2, CXCL10, CXCL8, CCL11 and CCL5 levels are significantly associated with DRSP scores while CCL2 is the most significant predictor explaining 39.6% of the variance. The sum of the neurotoxic chemokines CCL2, CCL11 and CCL5 is significantly associated with the DRSP score and depression, physiosomatic, breast-craving and anxiety symptoms. The impact of chemokines on MCAS symptoms differ between consecutive weeks of the menstrual cycle with CCL2 being the most important predictor of increased DRSP levels during the first two weeks, and CXCL10 or a combination of CCL2, CCL11 and CCL5 being the best predictors during week 3 and 4, respectively. DISCUSSION: The novel case definition "MCAS" is externally validated by increased levels of uterus-associated chemokines and EGF. Those chemokines are involved in MCAS and are regulated by sex hormones and modulate endometrium functions and brain neuro-immune responses, which may underpin MCAS symptoms. As such, uterine-related chemokines may link the uterus with brain functions via a putative uterine-chemokine-brain axis.

The Role of Aberrations in the Immune-Inflammatory Response System (IRS) and the Compensatory Immune-Regulatory Reflex System (CIRS) in Different Phenotypes of Schizophrenia: the IRS-CIRS Theory of Schizophrenia.

Several lines of evidence indicate that aberrations in immune-inflammatory pathways may contribute to the pathophysiology of schizophrenia spectrum disorders. Here, we propose a novel theoretical framework that was previously developed for major depression and bipolar disorder, namely, the compensatory immune-regulatory reflex system (CIRS), as applied to the neuro-immune pathophysiology of schizophrenia and its phenotypes, including first-episode psychosis (FEP), acute relapses, chronic and treatment-resistant schizophrenia (TRS), comorbid depression, and deficit schizophrenia. These schizophrenia phenotypes and manifestations are accompanied by increased production of positive acute-phase proteins, including haptoglobin and α2-macroglobulin, complement factors, and macrophagic M1 (IL-1ß, IL-6, and TNF-α), T helper (Th)-1 (interferon-γ and IL-2R), Th-2 (IL-4, IL-5), Th-17 (IL-17), and T regulatory (Treg; IL-10 and transforming growth factor (TGF)-ß1) cytokines, cytokine-induced activation of the tryptophan catabolite (TRYCAT) pathway, and chemokines, including CCL-11 (eotaxin), CCL-2, CCL-3, and CXCL-8. While the immune profiles in the different schizophrenia phenotypes indicate the activation of the immune-inflammatory response system (IRS), there are simultaneous signs of CIRS activation, including increased levels of the IL-1 receptor antagonist (sIL-1RA), sIL-2R and tumor necrosis factor-α receptors, Th-2 and Treg phenotypes with increased IL-4 and IL-10 production, and increased levels of TRYCATs and haptoglobin, α2-macroglobulin, and other acute-phase reactants, which have immune-regulatory and anti-inflammatory effects. Signs of activated IRS and CIRS pathways are also detected in TRS, chronic, and deficit schizophrenia, indicating that these conditions are accompanied by a new homeostatic setpoint between upregulated IRS and CIRS components. In FEP, increased baseline CIRS activity is a protective factor that may predict favorable clinical outcomes. Moreover, impairments in the CIRS are associated with deficit schizophrenia and greater impairments in semantic and episodic memory. It is concluded that CIRS plays a key role in the pathophysiology of schizophrenia by negatively regulating the primary IRS and contributing to recovery from the acute phase of illness. Therefore, components of the CIRS may offer promising therapeutic targets for schizophrenia.

The role of immune and oxidative pathways in menstrual cycle associated depressive, physio-somatic, breast and anxiety symptoms: Modulation by sex hormones.

OBJECTIVE: To examine whether 1) immune and nitro-oxidative stress (IO&NS) biomarkers are associated with premenstrual syndrome (PMS); and 2) changes in IO&NS biomarkers during the menstrual cycle (MC) are associated with PMS symptoms and plasma estradiol and progesterone. METHODS: This longitudinal study examined 41 women who completed the Daily Record of Severity of Problems (DRSP) rating scale during 28 consecutive days and assayed plasma levels of complement C3 and C4, highly sensitive C-reactive protein (hsCRP), haptoglobin (Hp), advanced oxidation protein products (AOPP), lipid hydroperoxides (LOOH), nitric oxide metabolites (NOx), total radical-trapping antioxidant parameter (TRAP), sulfhydryl (-SH) groups and the activity of paraoxonase (PON)1 at days 7 (D7), 14 (D14), 21 (D21) and 28 (D28) of the MC. MC Associated Syndrome (MCAS) was diagnosed when the summed DRSP score during the MC is >0.666 percentile. RESULTS: All biomarkers, except hsCRP, showed significant alterations during the MC. Arylesterase (AREase) was lowered at D28, while LOOH increased at D14 and C4 at D21 in MCAS. Total DRSP scores were predicted by the combined effects of C4 (positively) and AREase and malondialdehyde (MDA) (both inversely associated). Progesterone lowered levels of LOOH, AOPP and C3 and estradiol lowered levels of Hp while both sex hormones increased 4-(chloromethyl)phenyl acetate (CMPA)ase and AREase activities and levels of -SH groups. CONCLUSION: PMS/MCAS is not accompanied by a peripheral inflammatory response. Lowered MDA and antioxidant defenses and increased C4 may play a role in MC symptoms while sex hormones may have a protective effect against oxidative stress toxicity.

Posttraumatic mental health establishment of the Tsunami survivors in Thailand.

The natural disaster known as "the Tsunami" occurred in Andaman coast of Thailand in December 2004, and there had been questions whether it could cause PTSD amongst the population who lives in the affected area and how to avoid PTSD condition to occur.The purpose of this study is to establish statistical results of psychosocial factors, and their correlation to PTSD and other mental disorders in order to generate the PTSD database. Cross sectional community surveys had been conducted in two phases from the same sampling group, the first phase is concerned with prevalence of PTSD, depression and related factors. Results were collected from 3,133 samples and shows that 33.6% suffered from PTSD, 14.27% with depression and 11.27% suffered from both. The second phase is focused on chronic PTSD and other mental disorders 2,573 samples were collected and only 21.6% were diagnosed with chronic PTSD.The statistical analysis has identified risks factors that could cause PTSD, and protective actions which could help to prevent PTSD.

Posttraumatic stress disorder of the Tsunami survivors in Thailand.

BACKGROUND: The natural disaster known as "the Tsunami" occurred in the Andaman sea coast of Thailand in December 2004, and there had been questions whether it could cause PTSD amongst the population who lives in the affected area and how to avoid PTSD condition to occur. OBJECTIVE: Establish statistical results of psychosocial factors, and their correlation to PTSD and other mental disorders to generate the PTSD database. MATERIAL AND METHOD: A cross-sectional community surveys from 3,133 samples had been conducted in two phases from the same sampling group. The first phase was concerned with prevalence of PTSD, depression, and related factors. The second phase included 2,573 samples from the first phase and focused on chronic PTSD and other mental disorders. RESULTS: The 3,133 samples used in the first phase show that 33.6% suffered from PTSD, 14.27% with depression, and 11.27% suffered from both. The 2,573 samples from the first phase were followed, collected the blood, and interview data only 21.6% were diagnosed with chronic PTSD. CONCLUSION: The statistical analysis has identified risks factors that could cause PTSD, and protective actions that could help to prevent PTSD. The prevalence of PTSD was still higher in the affected region six months after the Tsunami.

Lowered Plasma Steady-State Levels of Progesterone Combined With Declining Progesterone Levels During the Luteal Phase Predict Peri-Menstrual Syndrome and Its Major Subdomains.

BACKGROUND: It is unknown whether lowered steady state levels of sex hormones coupled with changes in those hormones during the menstrual cycle are associated with premenstrual syndrome (PMS). OBJECTIVE: To examine associations between levels of progesterone and oestradiol during the menstrual cycle and PMS considering different diagnostic criteria for PMS. METHODS: Forty-one women aged 18-45 years with a regular menstrual cycle completed the Daily Record of Severity of Problems (DRSP) for all 28 consecutive days of the menstrual cycle. Blood was sampled at days 7, 14, 21, and 28 to assay oestradiol and progesterone. RESULTS: We developed a new diagnosis of peri-menstrual syndrome, which is characterized by increased DRSP severity in pre and post-menstrual periods and increased scores on the major DRSP dimensions, i.e., depression, physio-somatic symptoms, breast tenderness and appetite, and anxiety. This new diagnosis performed better than classical diagnoses of PMS, including that of the American College of Obstetricians and Gynecologists (ACOG). Lowered steady state levels of progesterone, when averaged over the menstrual cycle, together with declining progesterone levels during the luteal phase predict severity of peri-menstrual symptoms. Steady state levels of oestradiol and declining oestradiol levels during the cycle are also related to DRSP severity although most of these effects appeared to be mediated by progesterone. CONCLUSION: A significant increase in menstrual-cycle related symptoms can best be conceptualized as "peri-menstrual syndrome" and may result from insufficient progesterone production (relative corpus luteum insufficiency), which, in part may result from lowered oestradiol production indicating suboptimal pre-ovulatory follicular development.

A neuro-immune, neuro-oxidative and neuro-nitrosative model of prenatal and postpartum depression.

A large body of evidence indicates that major affective disorders are accompanied by activated neuro-immune, neuro-oxidative and neuro-nitrosative stress (IO&NS) pathways. Postpartum depression is predicted by end of term prenatal depressive symptoms whilst a lifetime history of mood disorders appears to increase the risk for both prenatal and postpartum depression. This review provides a critical appraisal of available evidence linking IO&NS pathways to prenatal and postpartum depression. The electronic databases Google Scholar, PubMed and Scopus were sources for this narrative review focusing on keywords, including perinatal depression, (auto)immune, inflammation, oxidative, nitric oxide, nitrosative, tryptophan catabolites (TRYCATs), kynurenine, leaky gut and microbiome. Prenatal depressive symptoms are associated with exaggerated pregnancy-specific changes in IO&NS pathways, including increased C-reactive protein, advanced oxidation protein products and nitric oxide metabolites, lowered antioxidant levels, such as zinc, as well as lowered regulatory IgM-mediated autoimmune responses. The latter pathways coupled with lowered levels of endogenous anti-inflammatory compounds, including ω3 polyunsaturated fatty acids, may also underpin the pathophysiology of postpartum depression. Although increased bacterial translocation, lipid peroxidation and TRYCAT pathway activation play a role in mood disorders, similar changes do not appear to be relevant in perinatal depression. Some IO&NS biomarker characteristics of mood disorders are found in prenatal depression indicating that these pathways partly contribute to the association of a lifetime history of mood disorders and perinatal depression. However, available evidence suggests that some IO&NS pathways differ significantly between perinatal depression and mood disorders in general. This review provides a new IO&NS model of prenatal and postpartum depression.

Anxiety Disorders: Sex Differences in Serotonin and Tryptophan Metabolism.

INTRODUCTION: Anxiety disorders manifest in women more than in men by almost twofold. This narrative review aims to summarize the sex-related biological factors, which underpin anxiety, focusing on the interactions of sex and tryptophan/serotonin with anxiety. METHODS: A literature search was conducted using Google Scholar, PubMed/MEDLINE, Scopus, and EMBASE databases from inception until December 31, 2017. RESULTS: This review shows that sex may interact with many serotonin functions thereby modulating anxiety, including 5-HT1A and 5-HT2C receptors, 5-HT transporter and central 5-HT concentrations and metabolism. Sex-steroids modulate the expression of serotonin transporter genes, creating a difference in serotonin availability. Sex and estrous cycle phases lead to varying anxiety responses to tryptophan depletion. Testosterone, progesterone and estrogen are important factors in mediating sex differences in serotonin responses to anxiety-generating behavioral tests. At prenatal levels, there are sexrelated differences in the reciprocal relationships between serotonin and the HPA-axis, which modulate anxiety-like behaviors. Activated immune-inflammatory pathways induce indoleamine-2,3-dioxynease (IDO) and the tryptophan catabolite (TRYCAT) pathway thereby increasing tryptophan degradation and increasing the production of TRYCATs including kynurenine and quinolinic acid, which may create an overall anxiogenic effect. The effects of immune activation on IDO are significantly more pronounced in women than men, and therefore, females may show increased levels of anxiogenic TRYCAT following immune challenge. Aberrations in the IDO-activated TRYCAT pathway are found in pregnant females and parturients and are associated with increased anxiety levels in the postnatal period. CONCLUSION: The results of this review underscore the necessity of studying the associations between serotonin and anxiety in both sexes taking into account the effects of immune activation on IDO and production of anxiogenic TRYCATs. Future anxiety research should focus on the interactions between serotonin/tryptophan and sex, sex hormones, the menstrual cycle, pregnancy, the HPA axis and the immune system through the production of anxiogenic TRYCATs.

Body image dissatisfaction in pregnant and non-pregnant females is strongly predicted by immune activation and mucosa-derived activation of the tryptophan catabolite (TRYCAT) pathway.

OBJECTIVES: The aim of the present study is to delineate the associations between body image dissatisfaction in pregnant women and immune-inflammatory biomarkers, i.e., C-reactive protein (CRP), zinc and IgA/IgM responses to tryptophan and tryptophan catabolites (TRYCATs). METHODS: We assessed 49 pregnant and 24 non-pregnant females and assessed Body Image Satisfaction (BIS) scores at the end of term (T1), and 2-4 days (T2) and 4-6 weeks (T3) after delivery. Subjects were divided in those with a lowered BIS score (≤ 3) versus those with a higher score. RESULTS: Logistic regression analysis showed that a lowered T1 BIS score was predicted by CRP levels and IgA responses to tryptophan (negative) and TRYCATs (positive), perinatal depression, body mass index (BMI) and age. The sum of quinolinic acid, kynurenine, 3-OH-kynurenine and 3-OH-anthranilic acid (reflecting brain quinolinic acid contents) was the single best predictor. In addition, a large part of the variance in the T1, T2 and T3 BIS scores was explained by IgA responses to tryptophan and TRYCATs, especially quinolinic acid. CONCLUSIONS: Body image dissatisfaction is strongly associated with inflammation and mucosa-derived IDO activation independently from depression, pregnancy, BMI and age. IgA responses to peripheral TRYCATs, which determine brain quinolinic acid concentrations, also predict body image dissatisfaction.

Common Environmental Factors May Underpin the Comorbidity Between Generalized Anxiety Disorder and Mood Disorders Via Activated Nitro-oxidative Pathways.

Generalized Anxiety Disorder (GAD) commonly co-occurs with mood disorders, especially Major Depressive Disorder (MDD) and bipolar disorder (BD), which are accompanied by activated neuro-immune and neuro-oxidative pathways. The aim of this narrative review is to review the phenomenological similarities and dissimilarities and the shared pathways between GAD and mood disorders. We searched PubMed, Scopus, and Google Scholar for articles published in English from 1980 to present. GAD and mood disorders, either MDD or BD, show some phenomenological overlaps and a high degree of comorbidity, especially between GAD and MDD. Both GAD and mood disorders are also frequently comorbid with other anxiety disorders, substance use disorders and medical conditions, including cardio- vascular disorder (CVD). Mood disorders have a worse prognosis when GAD is present. GAD and mood disorders are associated with female sex and may partly share genetic variants of risk. Moreover, both GAD and mood disorders frequently share similar environmental risks factors including Early Life Time Trauma (ELT) and Psychological Stressors in Adulthood (PSA). Increased nitro-oxidative stress and lipid peroxidation coupled to lowered lipid-associated antioxidant defenses are evident in GAD, MDD and type I bipolar patients. Patients with comorbid GAD and MDD show significantly higher nitro- oxidative biomarkers as compared with patients presenting with either GAD or MDD as well as patients with BD with or without co-occurring GAD. Activated immune-inflammatory processes characterized by increased levels of CRP and pro-inflammatory cytokines are other shared pathways that underpin GAD and mood disorders. Moreover, these pathways may explain comorbidities with medical disorders including CVD. Aberrations in HPA-axis, GABA and glutamate neurotransmission, NMDA and mu opioid-receptors and neuroimaging fields have yielded more inconsistent findings. In conclusion, here we propose a new model explaining GAD and the comorbidity between GAD and mood disorders. Common triggers such as ELT/PSA may underpin GAD and its comorbidity with mood disorders via activated neuro-oxidative, neuro-nitrosative and neuro-immune pathways.

Associations between severity of anxiety and clinical and biological features of major affective disorders.

Patients with major affective disorders (MAFD) with comorbid anxiety show a greater functional impairment than those without anxiety. The aim of this study is to delineate the associations between severity of anxiety in MAFD, namely bipolar disorder (BD) and major depression (MDD), and MAFD characteristics and serum high-density lipoprotein (HDL)-cholesterol levels. Recruited were 82 participants with anxiety disoders and 83 without anxiety disoders, including 101 MAFD patients and 51 healthy controls. We used the Hamilton Anxiety Rating Scale (HAM-A) to measure severity of anxiety and made the diagnoses of posttraumatic stress disorder (PTSD), obsessive compulsive disorder (OCD), panic disorder (PD), generalized anxiety disorder (GAD) and phobias. The HAM-A score is significantly predicted by higher number of depressive episodes, GAD and phobias, childhood trauma, tobacco use disorder, metabolic syndrome and lowered HDL-cholesterol. Increased HAM-A scores are, independently from severity of depression, associated with lowered quality of life, increased disabilities and suicidal ideation. Lithium treatment significantly lowers HAM-A scores. It is concluded that severity of anxiety significantly worsens the phenomenology of MAFD. Therefore, treatments of MAFD should target increased severity of anxiety and its risk factors including low HDL-cholesterol, metabolic syndrome, childhood trauma and tobacco use disorder.