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Rationale: Valproic acid (VPA) is commonly used as a second-line mood stabilizer or augmentative agent in severe mental illnesses. However, population pharmacokinetic studies specific to psychiatric populations are limited, and clinical predictors for the precision application of VPA remain undefined., Objectives: To identify steady-state serum VPA level predictors in pediatric/adolescent and adult psychiatric inpatients., Methods: We analyzed data from 634 patients and 1,068 steady-state therapeutic drug monitoring (TDM) data points recorded from 2015 to 2021. Steady-state VPA levels were obtained after tapering during each hospitalization episode. Electronic patient records were screened for routine clinical parameters and co-medication. Generalized additive mixed models were employed to identify independent predictors., Results: Most TDM episodes involved patients with psychotic disorders, including schizophrenia (29.2%) and schizoaffective disorder (17.3%). Polypharmacy was common, with the most frequent combinations being VPA + quetiapine and VPA + promethazine. Age was significantly associated with VPA levels, with pediatric/adolescent patients (< 18 years) demonstrating higher dose-adjusted serum levels of VPA (β = 7.6±2.34, p < 0.001) after accounting for BMI. Women tended to have higher adjusted VPA serum levels than men (β = 5.08±1.62, p < 0.001). The formulation of VPA (Immediate-release vs. extended-release) showed no association with VPA levels. Co-administration of diazepam exhibited a dose-dependent decrease in VPA levels (F = 15.7, p < 0.001), suggesting a potential pharmacokinetic interaction., Conclusions: This study highlights the utility of population-specific pharmacokinetic data for VPA in psychiatric populations. Age, gender, and co-administration of diazepam were identified as predictors of VPA levels. Further research is warranted to establish additional predictors and optimize the precision application of VPA in psychiatric patients., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background and Objectives : Fibromyalgia syndrome (FMS) is defined as a chronic pain syndrome that is characterized by widespread pain, tenderness, and diffuse stiffness. In addition, neuropsychological symptoms such as fatigue, sleep disorders, poor mood, cognitive impairment, and headaches are often reported. Many reports have addressed the coexistence of affective disorders and anxiety with FMS, yet few have focused on its association with obsessive compulsive disorder (OCD). We investigated the occurrence of classical patterns of OCD in participants with FMS and assessed their effect on pain perception and functional impairment. Material and Methods : The research population included 37 patients diagnosed with FMS, treated at the Rheumatology Clinic in the Sheba Medical Center, Tel-Hashomer, Israel. We used validated questionnaires including a demographic questionnaire, a questionnaire on average and maximal pain intensity, the Eysenck Personality Questionnaire-Revised (EPQ-R), the Perceived Stress Scale, the Pain Catastrophizing Scale, the Pain Obsessive questionnaire, and the Yale-Brown Obsessive Compulsive Scale (Y-BOCS). Results : Patients with FMS were found to have intrusive and obsessive thoughts regarding pain for several hours every day, causing a high degree of anxiety and high levels of pain, catastrophizing, and magnification, leading to helplessness and functional impairment. In total, 27% of the patients reported severe malfunction due to pain and pain ideation, and 49% demonstrated mild obsessive compulsive symptoms that were strongly correlated with pain intensity and functional impairment. Conclusions : Obsessive compulsive thinking patterns contribute to pain magnification and to the cognitive aspects of fibromyalgia syndrome.

Introduction: Neurofeedback (NF) therapy is brain training using operant conditioning including real-time displays of brain activity to teach people how to regulate their brain function. We would like to present a treatment for a patient who experienced severe traumatic events on 7/10 including physical injury accompanied by difficulty sleeping for two months, nightmares, intrusive thoughts, difficulties in emotional regulation and difficulty in concentrating. Due to the complexity and difficulties in emotional regulation accompanied by severe sleep disturbances, it was decided to treat with medication in combination with neurofeedback. After several training sessions in addition to pharmaceutical treatment, significant relaxation was observed, there was an improvement in concentration and the patient was able to return to his work and normal social functioning. In addition, intrusive thoughts decreased in intensity and frequency.

We conducted a prospective, single arm, multisite, multinational, open label trial assessing the safety and efficacy of a novel amygdala derived neurofeedback treatment, designated Amygdala-Derived-EFP, for chronic PTSD. Participants, including veterans and civilians, underwent screening, training, 15 neurofeedback sessions over 8 weeks and; baseline, termination (8 weeks) and 3 month post treatment assessments with validated measures. The primary endpoint was more than 50 % of the participants demonstrating a Minimally Clinically Important Difference (MCID) defined as a 6-point reduction, on the Clinician Administered PTSD Scale (CAPS-5) total score at 3 months. Secondary measures included the PCL-5, ERQ, PHQ-9, and CGI. Statistical analyses were performed using SAS®V9.4. The primary endpoint was met, with a CAPS-5 MCID response rate of 66.7 %. The average reduction in CAPS-5 total scores at 3 month follow up was 13.5 points, more than twice the MCID. Changes from baseline in CAPS-5, PCL-5, PHQ-9 scores at 8 weeks and the 3 month follow-up demonstrated statistically significant improvements in response and; demonstrated effect sizes ranging from 0.46 to 1.07. Adverse events were mild and resolved after treatment. This study builds on prior research demonstrating similar outcomes using amygdala-derived neurofeedback. Positive attributes of this therapy include monitoring by non-physician personnel, affordability, accessibility, and tolerability., Competing Interests: Declaration of competing interest Jeffrey Voigt is a reimbursement consultant for GrayMatters, the developer and manufacturer of the Prism technology. Charles Marmar has received support from: National Institute on Alcohol Abuse and Alcoholism, National Institute of Mental Health, Department of Defense- CDMRP * US Army Research Office * DARPA, Bank of America Foundation, Brockman Foundation, Cohen Veterans Bioscience, Cohen Veterans Network, McCormick Foundation, Home Depot Foundation, New York City Council, New York State Health, Mother Cabrini Foundation, Tilray Pharmaceuticals, and Ananda Scientific. Lenard Adler has received support from: Supernus Pharmaceuticals, Otsuka Pharmaceuticals, Bracket/Signant, SUNY and, Takeda Pharmaceuticals. Len Adler also receives royalties as an inventor from licensing agreements with the NYU Grossman School of Medicine. Lisa Deutsch is a statistician for hire and received compensation from GrayMatters for statistical analysis. Nadav Goldenthal and Raz Gross receive research support from GrayMatters. Eyal Fruchter, Shulamit Grinapol, Amital Daniela, Nitsa Nacasch, and Eiran Harel, have nothing to disclose., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Introduction: The exact pathogenesis of fibromyalgia (FM) syndrome is unclear. However, various infectious have been implicated with the development of FM after their acute phase. We aimed to investigate the incidence of FM syndrome among convalesced individuals following hospitalization for Acute Coronavirus Disease-2019 (COVID-19)., Methods: We performed a cross-sectional study on patients who were discharged after COVID-19 hospitalization from the Sheba Medical Center, Israel, between July 2020 to November 2020. A phone interview was performed consisting of the following questionnaires: the Fibromyalgia Survey Diagnostic Criteria Questionnaire, Sense of Coherence Questionnaire to evaluate resilience, and the Subjective Traumatic Outlook Questionnaire to assess the associated psychological aspects of the trauma. The incidence of post-COVID FM was calculated and regression models were performed to identify predictors., Results: The study population consisted of 198 eligible patients who completed the phone interview. The median age was 64 (52-72) and 37% were women. The median follow-up was 5.2 months (IQR 4.4-5.8). The incidence of FM was 15% (30 patients) and 87% (172 patients) had at least one FM-related symptom. Female gender was significantly associated with post-COVID FM (OR 3.65, p = 0.002). In addition, high median Subjective Traumatic Outlook scores and low median Sense of Coherence scores were both significantly associated with post-COVID FM (OR 1.19, p<0.001 and OR 0.92, p<0.001, respectively)., Conclusions: FM is highly prevalent among COVID-19 convalescent patients. Our finding suggests that a significant subjective traumatic experience and a low resilience are highly associated with post-COVID FM., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Savin et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Statin-induced myalgia is defined as muscle pain without elevation of serum creatine phosphokinase levels and is a well-known complaint among statin users. Chronic pain syndromes affect a high percentage of the population. These pain syndromes may confound the reports of statin-induced myalgia., Objectives: To compare the occurrence of chronic pain among patients on statin therapy who developed myalgia with those who did not., Methods: This study included 112 statin-treated patients, who were followed at the lipid center at Sheba Medical Center. Fifty-six patients had a diagnosis of statin-associated muscle symptoms (SAMS) and 56 did not. Verified questionnaires were used to assess the diagnoses of fibromyalgia, pain intensity, functional impairment, anxiety, and depression in the study population., Results: Patients with statin myalgia were more likely to fulfil the diagnostic criteria for fibromyalgia than patients without statin myalgia (11 [19.6%] vs. 0, respectively). Patients in the SAMS group exhibited higher levels of anxiety and depression compared with the control group. Female sex, higher scores on the Brief Pain Inventory pain intensity scale, and a Hamilton rating scale level indicative of an anxiety disorder were found to be significant predictors for fibromyalgia in patients presenting with statin myalgia., Conclusions: A significant percentage of patients diagnosed with statin myalgia fulfilled the diagnostic criteria for fibromyalgia depression or anxiety disorder. Detection of these patients and treatment of their primary pain disorders or psychiatric illnesses has the potential to prevent unnecessary cessation of effective statin therapy.

Background: Behçet's disease (BD) is a chronic vasculitic multi-systemic disease of unknown etiology. BD is characterized by recurrent attacks of oral aphthae, genital ulcers, and uveitis. BD is a multisystemic disorder and as such it may provoke various psychiatric manifestations, including depression., Objectives: To evaluate the association between BD and depression, adjusting for established risk factors for depression., Methods: We executed a cross-sectional study based on the Clalit Health Services database, the largest healthcare organization in Israel, serving over 4.4 million members. For this study 873 BD patients were detected and matched with 4369 controls by age and sex., Results: The rate of depression was higher among the BD patients compared with the control group (9.39% vs 5.49%, respectively, odds ratio [OR] 1.79, 95% confidence interval [95%CI] 1.37-2.31, P < 0.001). An association between BD and depression was also observed on multivariable analysis (OR 1.83, 95%CI 1.39-2.39, P < 0.001). When stratifying the data, according to established risk factors, the association between BD and depression was prominent in the youngest age group (18-39 years of age), low and high socioeconomical status, and non-smokers., Conclusions: Establishing the association between BD and depression should influence the attitude and the treatment of BD patients, as this relationship requires a more holistic approach and a multidisciplinary treatment regimen for all patient needs.

Background: Mood disorders, such as anxiety and depression, are extremely prevalent among patients with rheumatoid arthritis (RA). In this study, we assessed the impact of treatment with tocilizumab (TCZ), an IL-6 antagonist, upon anxiety and depressive symptoms in a cohort of RA patients., Materials and Methods: Study participants were adults diagnosed with RA who received a weekly subcutaneous injection of tocilizumab for 24 weeks. We used the Hamilton Depression (HDRS) and Anxiety (HAMA) scores in order to assess the severity of depression and anxiety, respectively. RA disease activity indices and depression and anxiety levels were assessed at baseline, 4 weeks and study completion., Results: Ultimately, 91 patients were included in the study. The mean age was 54 years, and the majority were female (79%). The mean score in all disease activity indices as well as depression and anxiety levels decreased dramatically from baseline to study completion. Sixty patients (66%) demonstrated a significant decrease in anxiety and/or depression levels. When logistic regression was performed, an HDRS score indicative of depression at study baseline demonstrated an independent association with a significant psychiatric response whilst older age and increased baseline weight were negatively associated. HAMA and HDRA scores correlated with the following RA disease activity parameters, respectively; HAQ-DI (r = .4, .42), DAS28 (r = .29, .32) and CDAI (0.28 and 0.33), all of them were statistically significant (P < .01)., Conclusions: This study has demonstrated a favourable impact of TCZ therapy on parameters reflecting depression and anxiety severity in patients with RA., (© 2020 Stichting European Society for Clinical Investigation Journal Foundation. Published by John Wiley & Sons Ltd.)

Objective: To identify predicators of patients with fibromyalgia (FM) that are associated with a severe COVID-19 disease course., Methods: We utilized the data base of the Clalit Health Services (CHS); the largest public organization in Israel, and extracted data concerning patients with FM. We matched two subjects without FM to each subject with FM by sex and age and geographic location. Baseline characteristics were evaluated by t-test for continuous variables and chi-square for categorical variables. Predictors of COVID-19 associated hospitalization were identified using univariable logistic regression model, significant variables were selected and analyzed by a multivariable logistic regression model., Results: The initial cohort comprised 18,598 patients with FM and 36,985 matched controls. The mean age was 57.5± 14.5(SD), with a female dominance of 91%. Out of this cohort we extracted the study population, which included all patients contracted with COVID-19, and consisted of 571 patients with FM and 1008 controls. By multivariable analysis, the following variables were found to predict COVID-19 associated hospitalization in patients with FM: older age (OR, 1.25; CI, 1.13-1.39; p<0.001), male sex (OR, 2.63; CI, 1.18-5.88; p<0.05) and hypertension (OR, 1.75; CI, 1.04-2.95; p<0.05)., Conclusion: The current population-based study revealed that FM per se was not directly associated with COVID-19 hospitalization or related mortality. Yet classical risk factors endangering the general population were also relevant among patients with FM., Competing Interests: NO authors have competing interests

Background: Familial Mediterranean Fever (FMF) is an autosomal recessive autoinflammatory disease associated with various systemic comorbidities. Recent research regarding the association with depression and anxiety has yielded conflicting results. The current study aims were to examine whether such an association exists using big data analysis methodology., Methods: This study was conducted as a cross-sectional analysis based on the Clalit Health Services database. We compared the proportions of depression and anxiety in patients diagnosed with FMF and age- and sex- matched controls. We used the Chi-square test and T-test for univariate analysis. Multivariate logistic regression was then applied to control for possible confounding variables., Results: The study included 7,670 patients with FMF and 7,670 matched controls. The prevalence of both depression and anxiety was found to be higher in the FMF group as compared to controls (6.22% and 4.58%, respectively, p<0.001, and 4.93% and 3.14%, respectively, p<0.001). These proportions remained significant after adjusting for important confounders, such as smoking and socioeconomic status., Limitations: Temporal association does not indicate a causal relationship, the validity of the diagnoses relies on clinical records and is not based on formal classifications or diagnostic criteria, information regarding disease duration and other parameters were not accessible., Conclusions: Our data imply that FMF is independently associated with both depression and anxiety. These findings highlight the importance of raising awareness for these comorbidities., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Fibromyalgia is a common pain syndrome treated by physicians of many disciplines and presents with many co-morbidities. We reviewed the complexities in assessing disabilities in fibromyalgia patients and the complex interrelationships between patients, their working places, and the medical community regarding preserving productivity. Flexibility is essential to keep the patients functional and productive. Job loss is costly to both society and patients and joint measures are needed to prevent unemployment.

Aims: This study aimed to examine a possible association between BMI levels, smoking and socio-economic status and the existence of fibromyalgia., Background: Obesity is a worldwide epidemic with devastating impacts on the public's health. There are several indications that obesity might also be involved in the pathogenesis of chronic pain syndromes such as fibromyalgia., Methods: Patients who were diagnosed with fibromyalgia were compared to population-based controls, matched in age and gender (by a ratio of 1:5). Body mass indices, smoking status and socioeconomic strata were retrieved from computerized medical records of the Clalit Health Services database. Body mass index was classified in WHO categories of underweight, normal, overweight and obese (<18.5, 18.5-<25, 25.0-<30, ≥30.0 kg/m2); χ2, t-tests, and logistic regression models were used to compare the study groups and assess the association between obesity and fibromyalgia., Results: The study included 14,296 patients with fibromyalgia and 71,324 controls. Among patients with fibromyalgia the average BMI (body mass index) was higher than that of the controls 29.1± 6.2 vs. 28.0± 6.01, p<0.001) with every increment of 1 unit of the BMI score, there was an increment of 2.7% of the odds of having coexistent fibromyalgia. The chances of having fibromyalgia was 56% higher among subjects with obesity compared to individuals of normal weight. The data revealed that patients with fibromyalgia smoke more and belong to lower socioeconomic levels., Conclusions: Our findings demonstrate that obesity is significantly associated with a higher proportion of fibromyalgia. This finding underlines the role that obesity plays in inflammation and chronic pain.

Background: Fibromyalgia is a syndrome of unknown etiology that is characterized by widespread pain, which severely impairs quality of life. Several forms of occupational and alternative therapy have demonstrated beneficial effects in fibromyalgia patients., Objectives: To assess the effects of participation in a floral design course on physical and psychiatric symptoms in a cohort of fibromyalgia patients., Methods: This study was conducted as an observational study. Women diagnosed with fibromyalgia over the age of 18 were recruited to participate in one of two 12-week flower design (floristry) courses. Demographic details, disease activity indices, and anxiety and depression scores were calculated for all participants at baseline, week 12, and study completion. Physical and mental health of the two groups were compared throughout the study time-points., Results: The study was completed by 61 female fibromyalgia patients who were included in the final analyses; 31 patients participated in the first floristry course and 30 in the second. Significant improvements in the 36-Item Short Form Survey physical and mental health components, visual analog scale, Fibromyalgia Impact Questionnaire, Hamilton Anxiety Rating Scale, and Hamilton Depression Rating Scale scores for the entire study population and for each group separately could be seen following participation in each floristry course., Conclusions: Participation in a floristry course may lead to a significant improvement in pain and psychiatric symptoms in fibromyalgia patients. These findings highlight the potential benefit of utilizing occupational therapy programs, such as a floristry course, for improving quality of life in fibromyalgia.

Background: Systemic sclerosis (SSc) can clinically present with psychological symptoms, including pain, depression, and distress about disfigurement, physical and social functioning. The existing small studies have reported a prevalence of depression ranging from 36% to 65% among SSc patients, likely reflecting the disease impact on the patient's self-image and function., Aim of the Study: To investigate the association between SSc and depression using big data analysis methods., Methods: We designed a nation-wide epidemiological survey relying on a large database of 2500 SSc patients and explored the relationship between SSc and depression, but also the impact of depression on the survival of SSc patients. Chi-squared and t-tests were used for univariate analysis and a logistic regression model was used for multivariate analysis., Results: The proportion rate of depression among SSc patients was significantly higher than controls (16.2% vs 10.9%), and this proportion was even higher in female SSc patients and of low socioeconomic status. At the multivariate logistic regression, SSc was found to be an independent risk factor for depression with an OR of 1.55 (95%CI 1.29-1.88, p < 0.0001). No significant association was found between SSc-specific autoantibodies (anti-centromere, anti-Scl-70, anti-RNA polymerase III and anti-RNP) status and the risk of depression. Depression was not found to have a significant impact on the survival of SSc patients with an HR of 1.06 (0.80-1.42)., Conclusions: This study provides further support for the high prevalence of depression in SSc patients and therefore, SSc patients may benefit from a screening approach and a broad supportive care program., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Fibromyalgia (FM) is a chronic pain syndrome associated with significant distress and numerous unpleasant consequences. Mental health problems in people with FM have been reported in many studies. People with mental disorders are thought to be at higher risk of FM than the general population, but the prevalence has not been established., Objective: We aimed to investigate the prevalence of FM in a representative sample of inpatients with non-psychotic mental disorders. Additionally, we aimed to assess the psychometric properties of the Fibromyalgia Rapid Screening Tool (FiRST) in the Russian-speaking population of people with mental disorders., Methods: Consecutive inpatients admitted to the Moscow Research and Clinical Center for Neuropsychiatry for treatment of non-psychotic mental disorders were evaluated for FM by a neurologist and completed the FiRST, Beck Depression Inventory (BDI), and State and Trait Anxiety Inventory (STAI)., Results: Of the 1168 patients evaluated 9.0% met the diagnostic criteria for FM. FM was associated with being female, having a diagnosis of unipolar depression, and having higher total scores on the BDI and STAI. The psychometric properties of the FiRST were good (McDonald's omega 0.79, corrected item-total correlation greater than 0.45). An optimal cut-off point with the highest Yuden's index (J = 0.75) was >3 (AUC of 0.89)., Conclusion: FM is a common comorbidity in people with non-psychotic mental disorders, associated with being female, having a diagnosis of unipolar depression, and having more severe anxiety and depression. The FiRST can be used for the FM screening with its cut-off >3 in people with non-psychotic mental disorders., Significance Statement: It is the first study to determine the prevalence of FM in people with non-psychotic spectrum mental disorders. The study design included a consecutive sample in a real-life setting to avoid bias. In addition, we evaluated the psychometric properties of the FM screening instrument in a population of people with mental disorders and established the cut-off. The specificity of this subpopulation is explained by both the high prevalence of pain symptoms and the overlap of some psychiatric and FM symptoms., (© 2024 European Pain Federation ‐ EFIC ®.)

Several observations indicate that cytokine concentrations might also relate to the severity of the psychosis. In this study we assessed whether inflammatory and anti-inflammatory cytokine concentrations are associated with the degree of the psychotic manifestations. A group of 41 patients with schizophrenia suffering from an acute psychosis leading to hospitalization in a psychiatric ward were assessed for the intensity of their psychotic manifestations by the PANSS score. Serum IL-2R, IL-6, IL-8, IL-10 were analyzed by commercial ELISA kits. These patients were compared to controls without schizophrenia. At the univariate analysis, statistically significant elevated levels of the cytokines IL-6, IL-2R and IL-8 were detected in the sera of the patients with schizophrenia compared to controls. At the multivariate analysis, statistically significance held only for IL-2R concentration. Furthermore, positive correlation was found between symptom severity as measured by the PANSS and IL-6 levels as well as IL-2R levels. In Conclusion, our data indicate that elevated serum concentrations of IL-6, IL-8 and IL-2R are associated with severe clinical symptoms measured by the total, general, negative and positive scores of the PANSS scale., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Little is known about the relationship between epilepsy and SSc. Our study included 2431 SSc patients and 12,710 age- and sex-matched controls. In 209 controls (1.6%) and 66 SSc patients (2.7%), epilepsy diagnosis was made (not significant). In the multivariate logistic regression analysis, higher age (OR 1.01 [95% CI 1.00-1.02], p = 0.0207) was associated with an increased risk of epilepsy, whereas high vs low socioeconomic status (SES) (OR = 0.62 [95% CI 0.42-0.92], p = 0.0189) was associated with a low risk of epilepsy. In the Cox multivariate survival analysis, higher age (HR = 1.06 [95% CI 1.06-1.07], p < 0.0001), epilepsy (HR = 2.28 [95% CI 1.77-2.94], p < 0.0001) and SSc (HR = 2.37 [95% CI 2.07-2.71], p < 0.0001) were independent risk factors for all-cause mortality. In contrast, BMI >30 kg/m 2 vs BMI <20 kg/m 2 (HR = 0.69 [95% CI 0.59-0.81, p < 0.0001]), female gender (HR = 0.73 [95% CI 0.65-0.83], p < 0.0001) and high SES (HR = 0.72 [95% CI 0.63-0.82], p < 0.0001) were protective factors for mortality. SSc-related autoantibodies were not associated with the risk of epilepsy. In conclusion, whilst epilepsy and SSc are not significantly associated, epilepsy is a predictor of mortality in SSc patients., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Fibromyalgia is a complex disorder, and its diagnosis often comprises a challenge for physicians. We aimed to assess the time from the appearance of early symptoms to the definite diagnosis of fibromyalgia and to delineate patient and physician factors associated with this delay. The database of a large healthcare services provider was searched for all fibromyalgia patients (age 21 years or more) diagnosed during 2008-2011. Patients with a diagnosis confirmed by a physician with a relevant specialization were compared with age- and sex-matched nonfibromyalgia controls to retrospectively identify an initial complaint pattern characteristic of fibromyalgia. The time from initial complaints to fibromyalgia diagnosis, as well as the fraction of time while the patient was treated continuously by the same primary physician as at time of diagnosis, was assessed among all eligible fibromyalgia patients. An initial complaint pattern was identified in 67.9% of 2,055 patients with confirmed fibromyalgia vs. 27.6% of 9,172 controls. Among 2,369 (69.0%) of all 3,434 eligible patients with fibromyalgia, mean (SD) total time to diagnosis was 6.42 (3.57) years and mean (SD) time while treated by the same primary physician as at diagnosis was 3.75 (3.26) years. Comorbidity, younger patient, and older physician age were associated with longer time to diagnosis. By analysis of "real-world" data, fibromyalgia remains a complex and elusive diagnosis, taking years to be properly diagnosed. There is a need to increase the awareness of this syndrome among physicians, especially of older age., (Copyright © 2019. Published by Elsevier Ltd.)

The role of physical and psychological trauma precipitating fibromyalgia is often encountered by physicians, yet a proper systematical review of this association is lacking. Literature searches identified 51 studies which examined the association of fibromyalgia with a preceding traumatic event of physical or emotional nature. The overall quality of evidence of studies included, as assessed by the GRADE criteria, was low, however the majority of studies described a significant association between prior physically traumatic events and the onset of chronic widespread pain or fibromyalgia. Elevated rates of psychological trauma in fibromyalgia patients were demonstrated across the literature and several studies indicate a mediating effect of post-traumatic stress disorder. Potential biological mechanisms for conversion of traumatic events into a chronic pain syndrome, such as fibromyalgia, are discussed., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Israel represents a complex and pluralistic society comprising two major ethno-national groups, Israeli Jews and Israeli Arabs, which differ in terms of religious and cultural values as well as social constructs. According to the so-called "diversification hypothesis", within the framework of e-health and in the era of new information and communication technologies, seeking online health information could be a channel to increase health literacy, especially among disadvantaged groups. However, little is known concerning digital seeking behavior and, in particular, digital mental health literacy. This study was conducted in order to fill in this gap. Concerning raw figures, unadjusted for confounding variables (time, population size, Internet penetration index, disease rate), "depression" searched in Hebrew was characterized by 1.5 times higher search volumes, slightly declining throughout time, whereas relative search volumes (RSVs) related to "depression" searched in Arabic tended to increase over the years. Similar patterns could be detected for "phobia" (in Hebrew 1.4-fold higher than in Arabic) and for "anxiety" (with the searches performed in Hebrew 2.3 times higher than in Arabic). "Suicide" in Hebrew was searched 2.0-fold more than in Arabic (interestingly for both languages search volumes exhibited seasonal cyclic patterns). Eating disorders were searched more in Hebrew: 8.0-times more for "bulimia", whilst "anorexia" was searched in Hebrew only. When adjusting for confounding variables, association between digital seeking behavior and ethnicity remained statistically significant ( p -value < 0.0001) for all psychiatric disorders considered in the current investigation, except for "bulimia" ( p  = 0.989). More in details, Israeli Arabs searched for mental health disorders less than Jews, apart from "depression". Arab and Jewish Israelis, besides differing in terms of language, religion, social and cultural values, have different patterns of usage of healthcare services and provisions, as well as e-healthcare services concerning mental health. Policy- and decision-makers should be aware of this and make their best efforts to promote digital health literacy among the Arab population in Israel., Competing Interests: The authors declare there are no competing interests.

Objective: Systemic lupus erythematosus (SLE) is a chronic autoimmune disease affecting a wide range of systems including the peripheral and central nervous system. Cognitive impairment leading to dementia is one of the harmful central nervous system afflictions of SLE. The aim of this study was to investigate the association of SLE with dementia., Methods: A cross-sectional study was conducted using Clalit Health Care database, the largest health maintenance organization in Israel with more than 4.4 million enrollees. Systemic lupus erythematosus patients were compared in a 1:5 ratio to age- and sex-matched controls. Chi-square and t tests were used for univariate analysis, and a logistic regression model was used for multivariate analysis., Results: The study included 4886 SLE patients and 24 430 age-frequency- and sex-frequency-matched controls without SLE. The proportion of dementia was higher among SLE patients compared to controls (1.56% and 0.51%, respectively; P < .001). This finding was consistent across all age groups by univariate analysis. In a multivariate logistic regression analysis, SLE was significantly associated with dementia (odds ratio = 1.51, 95% confidence interval, 1.11-2.04)., Conclusion: Systemic lupus erythematosus is significantly associated with dementia. This finding should give rise to search for SLE in patients with an ambiguous cause for dementia, especially those with an early onset cognitive decline., (Copyright © 2017 John Wiley & Sons, Ltd.)

Background: The fibromyalgia syndrome (FMS) is a chronic condition consisting of widespread musculoskeletal pain and tenderness together with mood and cognitive dysfunction. Diabetes mellitus (DM) is a common condition causing significant and detrimental morbidity and mortality. Data on the association between the two conditions is scarce and mainly based on small populations therefore lack solid evidence., Objectives: To evaluate the association of FMS with DM., Material and Methods: This cross-sectional study used the Clalit Health Services database, the largest Health Maintenance Organization in Israel, serving 4,400,000 members. FMS patients were compared to age- and sex-matched controls regarding chronic comorbid conditions. χ 2 and student's t-tests were used for univariate analysis., Results: The study included 14,296 FMS patients and 71,324 age- and sex-matched controls. The FMS group had a significantly higher proportion of DM patients compared to non-FMS controls (19.8% and 17.4 respectively; OR 1.17 , 95% CI: 1.12-1.23, p < 0.001)., Conclusions: DM was found to be more common amongst FMS patients compared to matched controls to suggest that the pathophysiology of DM might lead a patient to develop FMS. Consequently, physicians treating DM patients should be aware of the possible risk and asses for clinical signs of FMS in order to diagnose and treat it in time to better their patients' quality of life and disease management., Competing Interests: The rest of the authors declare no conflict of interest.

Introduction: Fibromyalgia syndrome (FMS) is a complex chronic pain condition that negatively impacts women's daily lives, particularly their roles as mothers and wives. A phenomenological qualitative study was conducted to explore the lived experiences of motherhood and daily life among women diagnosed with fibromyalgia., Methods: A sample of 10 women affected by FMS was recruited between January and February 2020. Participants were interviewed in a face-to-face, in-depth interview using a semi-structured interview guide. Data were collected until saturation, and Colaizzi's method was used to analyse data., Results: This qualitative analysis identified five themes: A trauma preceding diagnosis, Pervasive feelings of misunderstanding, A struggle to maintain strength among limitations, Challenges in fulfilling maternal roles, and Persistent sexual discomfort. The latter two themes emerged as the most prominent., Conclusion: These findings highlight the significant impact of fibromyalgia on women's family lives and suggest the need for a more comprehensive care programme., (© 2024 John Wiley & Sons Ltd.)

Background: Mounting data are indicating that major depression is related to diverse functions of the immune system. Several observations indicate that cytokine concentrations might also relate to the intensity of depressive manifestations. In this study we assessed whether inflammatory and anti-inflammatory cytokine concentrations are associated with the intensity of the depressive features in a cohort of patients with major depression and in healthy normal controls., Methods: A group of 25 patients with major depression all suffering from an acute deterioration of their mental status and all hospitalized in a psychiatric ward were assessed for the intensity of their depressive manifestations according to the Hamilton rating scale for depression and by the clinical global impression scale (CGI). In parallel, concentrations of serum IL-2R, IL-6, IL-8, IL-10 were analyzed by commercial ELISA kits. As comparators, a group of 25 healthy controls was analyzed., Results: The levels of IL-6 were higher among patients with depression. A high degree of correlation was found between the scores measured by the Hamilton and CGI scales by which the intensity of depressive symptoms were ranked. Interestingly, within the group of patients with depression a negative correlation was detected between the IL-6 concentrations and the CGI scores while a positive correlation was found between the IL-10 concentration and IL-6 concentration., Conclusions: Our data indicate that the patients with depression differ from healthy individuals by their cytokine profile. Within this group of patients depressive features have a specific pattern and linkage to inflammatory and anti-inflammatory scores.

Introduction: This review deals with the neuropsychiatric disorders resulting from systemic lupus erythematosus (SLE). SLE is a chronic autoimmune disease that impacts all systems in the human body, including the central nervous system. Neuropsychiatric symptoms in SLE are a common complication of the disease. This complication has significant implications for the severity of the illness. In most cases no thorough psychiatric assessment is performed during initial evaluation of the disease and no protocol or clear guidelines for treating the psychiatric symptoms in SLE are available. Early diagnosis of the psychiatric symptoms in SLE is critical since absence of treatment may result in severe psychiatric complications. Clinical pharmacological studies are needed in order to develop guidelines for treating psychiatric symptoms in SLE.

Objective: To assess 1-year persistence and adherence rates with drug therapy among patients with fibromyalgia (FM) and to identify factors associated with therapy discontinuation., Methods: This retrospective, cohort study included members ≥ 21 years old from the Maccabi Healthcare Services, a large health maintenance organization in Israel, who were diagnosed with FM from 2008 through 2011. Medications of interest included the anticonvulsant pregabalin, antidepressants [selective serotonin reuptake inhibitor (SSRI), serotonin/norepinephrine reuptake inhibitor (SNRI)], and tricyclic antidepressants (TCA). Time to treatment discontinuation and proportion of days covered (PDC) with FM-specific therapies during the year from first dispensed were analyzed. PDC < 20% was considered low adherence and PDC ≥ 80% was considered high adherence. Logistic regression models were constructed for multivariable analyses., Results: Overall, 3932 patients with FM were included; 88.7% were female. Pre-diagnosis use of medication of interest was documented in 41% of the study population. Of the remaining 2312 patients, 56.1% were issued a prescription, 45.0% were dispensed at least 1 medication in the year following diagnosis, and only 28.8% had prescriptions filled twice within the first year from diagnosis. Among newly prescribed patients, 1-year discontinuation was highest for TCA (91.0%) and lowest for SSRI/SNRI antidepressants (73.7%). Over half of the patients (60.5%) had fewer than 20% of the days covered by any medication during the year and only 9.3% were very adherent (PDC ≥ 80%)., Conclusion: This study clearly shows that in an Israeli "real-life" population of patients with FM, persistence and adherence with FM therapy in the year following diagnosis is remarkably low.

Fibromyalgia is a chronic disease, characterized by pain, fatigue, and poor sleep quality. Patients and mainly those with chronic diseases tend to search for health-related material online. Google Trends (GT), an online tracking system of Internet hit-search volumes that recently merged with its sister project Google Insights for Search (Google Inc.), was used to explore Internet activity related to fibromyalgia. Digital interest in fibromyalgia and related topics searched worldwide has been reported in the last 13 years. A slight decline in this interest has been observed through the years, remaining stable in the last 5 years. Fibromyalgia web behavior exhibited a regular, cyclic pattern, even though no seasonality could be detected. Similar findings have been reported among rheumatoid arthritis and depression. However, differently from rheumatoid arthritis and depression, the focus of the fibromyalgia-related queries was more concentrated on drug side effects and the "elusive" nature of fibromyalgia: is it a real or imaginary condition? Does it really exist or is it all in your head? A tremendous amount of information on fibromyalgia and related topics exist online. Still many queries have been raised and repeated constantly by fibromyalgia patients in the last 13 years. Therefore, physicians should be aware of the common concerns of people or patients regarding fibromyalgia in order to give a proper answers and education.

Aims: Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease involving multiple organs, including the central nervous system. Evidence of immune dysfunction exists also in schizophrenia, a psychiatric illness involving chronic or recurrent psychosis. The aim of our study was to investigate if there is an epidemiological association between SLE and schizophrenia., Method: A cross-sectional study was conducted comparing patients with SLE with age and gender-matched controls regarding the proportion of patients with comorbid schizophrenia. χ 2- and t-tests were used for univariate analysis, and interaction of schizophrenia with SLE across strata of covariates was checked. A logistic regression model was used for multivariate analysis. The study was performed utilising the medical database of Clalit Health Services in Israel., Results: The study included 5018 patients with SLE and 25 090 controls. SLE patients had a female predominance, and a higher proportion of smoking compared with age and sex-matched controls. In multivariate analysis, SLE was found to be independently associated with schizophrenia while controlling for age, gender, socioeconomic status (SES) and smoking (OR 1.33, p = 0.042)., Conclusions: We found a positive association between SLE and schizophrenia across patients of different age, gender and SES. This association can contribute to understanding the pathophysiology of the two disorders and may also have clinical implications for earlier as well as better diagnosis and treatment.

Background: Systemic lupus erythematosus (SLE) is a chronic, autoimmune disease that has a wide variety of physical manifestations, including neuropsychiatric features. Bipolar disorder (BD) is a chronic, episodic illness, that may present as depression or as mania. The objective of this study was to investigate the association between SLE and BD using big data analysis methods., Methods: Patients with SLE were compared with age- and sex-matched controls regarding the prevalence of BD in a cross-sectional study. Chi-square and t-tests were used for univariate analysis and a logistic regression model was used for multivariate analysis, adjusting for confounders. The study was performed utilizing the chronic disease registry of Clalit Health Services medical database., Results: The study included 5018 SLE patients and 25,090 matched controls. BD was found in a higher prevalence among SLE patients compared to controls (0.62% vs. 0.26%, respectively, P<0.001). BD patients had a greater prevalence of smokers compared to non-BD patients (62.5% vs 23.5%, respectively, P<0.001). In a multivariate analysis, smoking and SLE were both found to be significantly associated with BD., Conclusions: SLE was found to be independently associated with BD. These findings may imply that an autoimmune process affecting the central nervous system among SLE patients facilitates the expression of concomitant BD., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

Background: Psychiatric disorders occur in a considerable proportion of patients with rheumatoid arthritis (RA), often reflecting the difficulties of these patients in coping with a chronic debilitating disorder., Aim of the Study: To evaluate the proportion of anxiety disorder in RA patients using a large database analysis., Methods: The study was designed as a case-control population-based study using data from the Clalit Health Services (CHS) database. Patients were defined as having RA or anxiety disorder when there was at least one documented diagnosis identified by the International Classification of Diseases-9 (ICD-9) from the medical records. The proportion of anxiety disorder was compared between RA patients and controls. A logistic regression model was used to estimate the association between RA and anxiety disorder in a multivariate analysis adjusted for age, gender and socioeconomic status (SES)., Results: The study included 11,782 patients with RA and 57,973 age- and sex-frequency matched controls. The proportion of anxiety in RA patients was higher than in controls (7.1% vs 6.3%, p=0.001). In multivariate analysis, RA was found to be independently associated with anxiety (OR 1.11 [95%CI 1.03-1.20], p=0.01). Our study has some shortcomings, as its cross-sectional nature does not allow to make inferences about a causal relationship between RA and anxiety., Conclusion: Our study confirms the higher proportion of anxiety in RA patients, especially young women with low SES. Physicians should be aware of such findings and, therefore, apply proper screening strategies., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background/aims: Rheumatoid arthritis (RA) is a chronic, debilitating autoimmune disease that affects the joints and it is known to be associated with cardiovascular morbidity. However, the association between RA and stroke among different age groups has not been explored. The objective of our study was to evaluate the association between RA and stroke in different age strata., Methods: Cross-sectional study, utilizing the database of Israel's largest healthcare provider. The proportion of stroke was compared between patients diagnosed with RA and age- and gender-matched controls. The study sample was divided into 2 age groups: young (≤65 years) and elderly (>65 years). Multivariable analysis was performed using logistic regression., Results: The study included 11,782 RA patients and 57,973 age- and gender-matched controls. RA patients, primarily young, had more cardiovascular risk factors than controls. Stroke rates were significantly elevated among young RA patients in comparison with controls (3.74 vs. 2.20%, respectively, p < 0.001). In multivariate analysis, RA was found to be independently associated with stroke (OR 1.18, 95% CI 1.09-1.28)., Conclusion: RA is independently associated with stroke, especially among RA patients under 65 years, for whom cardiovascular risk factors were more prominent. Physicians should advise RA patients to manage their risk factors strictly., (© 2017 S. Karger AG, Basel.)

Introduction: There are mixed data regarding the effect of emotional distress on diabetes risk, especially among young adults. This study assessed the effect of self-perceived emotional distress on diabetes incidence among young men., Methods: Incident diabetes during a mean follow-up of 6.3 (4.3) years was assessed among 32,586 men (mean age, 31.0 [5.6] years) of the Metabolic, Lifestyle, and Nutrition Assessment in Young Adults cohort with no history of diabetes between 1995 and 2011. Emotional distress was assessed by asking participants as part of a computerized questionnaire: Are you preoccupied by worries or concerns that affect your overall wellbeing? Time-dependent Cox models were applied. Data analysis took place between 2014 and 2015., Results: There were 723 cases of diabetes during 206,382 person-years. The presence of distress was associated with a 53% higher incidence of diabetes (95% CI=1.08, 2.18, p=0.017) after adjustment for age, BMI, fasting plasma glucose, family history of diabetes, triglyceride and high-density lipoprotein cholesterol levels, education, cognitive performance, white blood cell count, physical activity, and sleep quality. These results persisted when distress, BMI, physical activity, and smoking status were treated as time-dependent variables (hazard ratio=1.66, 95% CI=1.21, 2.17, p=0.002). An adjusted hazard ratio of 2.14 (95% CI=1.04, 4.47, p=0.041) for incident diabetes was observed among participants persistently reporting emotional distress compared with those persistently denying it., Conclusions: Sustained emotional distress contributes to the development of diabetes among young and apparently healthy men in a time-dependent manner. These findings warrant awareness by primary caregivers when stratifying diabetes risk., (Copyright © 2016 American Journal of Preventive Medicine. Published by Elsevier Inc. All rights reserved.)

Objectives: Current therapeutic approaches to fibromyalgia syndrome (FMS) do not provide satisfactory pain control to a high percentage of patients. This unmet need constantly fuels the pursuit for new modalities for pain relief. This randomised, double-blind, controlled study assessed the efficacy and safety of adding etoricoxib vs. placebo to the current therapeutic regimen of female patients with FMS., Methods: In this double-blind, placebo-controlled study, female patients were randomised to receive either 90 mg etoricoxib once daily or placebo for 6 weeks. Several physical and mental parameters were assessed throughout the study. The primary end-point was the response to treatment, defined as ≥ 30% reduction in the average Brief Pain Inventory score. Secondary outcomes were changes in the Fibromyalgia Impact Questionnaire, SF-36 Quality of Life assessment questionnaire and Hamilton rating scales for anxiety and depression., Results: Overall, 73 patients were recruited. Although many outcome measures improved throughout the study, no difference was recorded between the etoricoxib- and placebo-treated groups. The Brief Pain Inventory, Fibromyalgia Impact Questionnaire, The Hamilton Anxiety and Depression scores did not differ between the two groups., Conclusions: This is the first randomised, double-blind study assessing the effect of adding etoricoxib to pre-existing medications for female patients with FMS. Although being mildly underpowered this study clearly has shown that etoricoxib did not improve pain scores and did not lead to any beneficial mental or physical effects., (© 2016 John Wiley & Sons Ltd.)

Background: Rheumatoid arthritis (RA) is a chronic inflammatory disease associated with systemic comorbidities. Recent data suggests that patients with RA have increased prevalence of the bipolar disorder. The current study investigates the association between RA and bipolar disorder., Methods: A case-control study was conducted as Patients with RA were compared with age- and gender-matched controls regarding the prevalence of bipolar disorder. Pearson χ(2) test was used for univariate analysis and a logistic regression model was used for multivariate analysis. The study was performed utilizing the medical database of Clalit Health Services., Results: The study included 11,782 patients with RA and 57,973 age- and gender-matched controls. The prevalence of Bipolar disorder in patients with RA was increased compared with the prevalence in controls (0.6% and 0.4% respectively, p=0.036). However, in a multivariate analysis the association between RA and Bipolar disorder was not significant, whereas smoking is positively correlated with Bipolar disorder (p<0.001)., Conclusions: By univariate analysis our data implied that patients with RA have a greater prevalence of bipolar disorder than matched controls. However, our analysis suggests that this association may have been confounded by smoking status. Further research is warranted before making inferences about this association in the level of clinical practice., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Patients with autoimmune diseases often present with olfactory impairment. The aim of the study was to assess the olfactory functions of female patients with fibromyalgia (FM) compared with patients with systemic sclerosis (SSc) and with healthy female controls. Olfactory functions were assessed in 24 patients with FM, 20 patients with SSc and 21 age-matched healthy controls. The sense of smell was evaluated using the Sniffin' Sticks test including the three stages of smell: threshold, discrimination, and identification (TDI) of the different odors. The severity of fibromyalgia was assessed using the fibromyalgia impact questionnaire (FIQ). The short form 36 (SF-36) questionnaire was also completed in order to seek a relationship between the patients perception of quality of life and the different aspects of the smell sense. Depression was evaluated in both FM and SSc patients utilizing the Beck depression inventory-II (BDI-II) questionnaire. Patients with FM had significantly lower TDI smell scores compared with both SSc patients and healthy controls (p < 0.005, One-Way ANOVA). Hyposmia (defined as TDI scores below 30) were observed in 14 of 24 (42 %) patients with FM compared to 3 of 20 (15 %) patients with SSc and 1 of the healthy controls (4.3 %) (p < 0.02). FM patients had significantly lower thresholds of smell compared to both healthy controls and patients with SSc (p < 0.001), whereas for patients with SSc only the ability to discriminate between odors was impaired (p < 0.006). We could not detect any statistical correlation between smell abilities and clinical manifestation of SSc or the FIQ and SF-36 scores among FM patients. However the correlation between depression, defined by the BDI-II score, and the sense of smell differed between patients with FM and patients with SSc. As only among SSc patients a lower sense of smell correlated with a higher BDI-II score (p = 0.02). Our findings suggest that there is a decrease in the sense of smell both in FM and SSc patients compared with healthy controls. However these impairments differ between patients group and might represent different mechanisms that affect the sense of smell.

Background: Little is known about the extent to which a family history of major depression (MD) affects residual depressive symptoms in responder and non-responder patients suffering from MD., Methods: Nine hundred eighty-six patients with MD were recruited within the context of a large multicenter project. Information about the family history of MD, as well as about total depressive symptoms and specific depressive clusters, was collected and analyzed., Results: No significant difference was observed in overall depressive symptoms between patients with and those without a family history of MD. However, non-responder patients with a family history of MD showed significantly higher scores in core symptoms as compared with responder patients without a family history of MD., Conclusions: Non-responder MD patients with a positive family history of MD could represent a slightly different sub-group of MD patients with more consistent core depressive symptoms as compared with responder patients without a family history of MD. However, taking into account the retrospective assessment of data, the use of positive or negative family history as a dichotomous indicator of familial loading and the cross-sectional design of the present study, further research is needed to draw more definitive conclusions., (© 2014.)

Over the past years, considerable progress has been made in understanding the pathogenesis of the fibromyatgia syndrome and the evidence based approach to the diagnosis and management has been significantty extended. The purpose of the current project is to develop practicat and evidence based guidetine recommendations for the Israeli health care system. A panet of physicians with clinical and research experience in the fibromyalgia field was convened under the auspices of the Israeli Rheumatology Association. A systematic review was performed on the current literature regarding the diagnosis and treatment of fibromyalgia. Using an interactive discussion procedure, recommendations were reached and expert opinion was introduced where evidence was considered incomplete. The panel recommendations underline the importance of concomitant and integrated medical therapy, such as serotonin and noradrenaline reuptake inhibitor (SNRI) anti-depressants or gamma-aminobutyric acid (GABA) related anti-epileptics, with regular aerobic physical exercise.

Background: Patients with major depression (MD) show reduced social adjustment when compared with healthy controls. However, even among treatment responders, significant differences in social adjustment occur. The main aim of the present work is to study several socio-demographic and clinical variables possibly influencing social adjustment in MD patients who responded to treatment., Methods: Two hundred and eleven MD patients experiencing a depressive episode who responded to their current treatment were recruited within the context of a large European multicentre project. Our primary outcome measure was the association between 19 socio-demographic and clinical variables and total social adjustment scores, as measured with the Social Adjustment Scale (SAS). Secondary outcome measures included the associations between the same variables and SAS sub-scales, and the associations between these variables and self-esteem, as measured with the Rosenberg Self-Esteem Scale., Results: A co-morbidity with anxiety disorders and the severity of residual depression symptoms were the strongest independent factors associated with poorer social adjustment, in terms of total and most sub-areas' SAS scores. Other variables associated with total and sub-areas' SAS scores were identified as well, although some variations across different areas were observed., Limitations: The cross-sectional design, the retrospective assessment of data and the lack of a placebo control group., Conclusions: Our results confirm that a co-morbidity with anxiety disorders and higher residual depression symptoms could reduce social adjustment among responder MD patients. Further longitudinal studies are needed to confirm our results., (© 2013 Elsevier B.V. All rights reserved.)

Background: Social adjustment is impaired in depressed patients. The difficulty to adjust to social circumstances has been hypothesized to be one of the causes of depression, as well as a consequence of the disorder. Genetic variation in the serotonin transporter gene has been previously associated with social adjustment levels in patients with mood disorders., Methods: We investigated whether variations on the HTR1A (rs6295) and HTR2A (rs7997012) genes were associated with levels of social adjustment using the Social Adjustment Scale in two samples of depressed patients (total n=156)., Results: Patients carrying the GG genotype of the HTR2A-rs7997012 showed better social adjustment in areas of work and family unit bonding., Limitations: These findings did not survive correction for multiple testing and should be interpreted with caution., Conclusion: Our finding is in line with previous observations that have associated the G allele of the HTR2A-rs7997012 with higher rate of antidepressant response. The HTR2A-rs7997012 is worthy of further investigation in studies examining factors that are related to depression course and outcome., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Co-morbid physical illness has been suggested to play an important role among the factors contributing to treatment resistance in patients with major depressive disorder. In the current study we compared the rate of physical co-morbidity, defined by ICD-10, among a large multicenter sample of 702 patients with major depressive disorder. A total of 356 of the participants were defined as treatment resistant depression (TRD) patients-having failed two or more adequate antidepressant trials. No significant difference was found between TRD and non-TRD participants in the prevalence of any ICD-10 category. This finding suggests that although physical conditions such as diabetes, thyroid dysfunction, hypertension, ischemic heart disease, and peptic diseases are often accompanied by co-morbid MDD, they do not necessarily have an impact on the course of MDD or the likelihood to respond to treatment. Marginally higher rates of co-morbid breast cancer, migraine and glaucoma were found among TRD participants. Possible explanations for these findings and their possible relation to TRD are discussed., (Copyright © 2012 Elsevier B.V. and ECNP. All rights reserved.)

Treatment resistant depression (TRD) is a significant clinical and public health problem. Among others, neuroplasticity and inflammatory pathways seem to play a crucial role in the pathomechanisms of antidepressant efficacy. The primary aim of this study was to investigate whether a set of single nucleotide polymorphisms (SNPs) within two genes implicated in neuroplasticity and inflammatory processes (the mitogen activated protein kinase 1, MAPK1 (rs3810608, rs6928, rs13515 and rs8136867), and the cyclic AMP responsive element binding protein 1, CREB1 (rs889895, rs6740584, rs2551922 and rs2254137)) was associated with antidepressant treatment resistance (according to two different definitions), in 285 Major Depressive Disorder (MDD) patients. As secondary aims, we investigated the genetic modulation of the same SNPs on response, remission and other clinical features both in MDD patients and in a larger sample including 82 Bipolar Disorder (BD) patients as well. All patients were screened in the context of a European multicenter project. No association between both the investigated genes and treatment resistance and response was found in MDD patients. However, considering remission, higher rates of CREB1 rs889895 GG genotype were reported in MDD patients. Moreover, MAPK1 rs8136867 AG genotype was found to be associated with remission in the whole sample (MDD and BD). Present results suggest that some genetic polymorphisms in both CREB1 and MAPK1 could be associated with treatment remission. Although further research is needed to draw more definitive conclusions, such results are intriguing since suggest a potential role of two genes implicated in neuroplasticity and inflammatory processes in symptom remission after antidepressant treatment., (Copyright © 2013 Elsevier Inc. All rights reserved.)

The extent to which a family history of mood disorders and suicide could impact on clinical features of patients suffering from major depression (MD) and bipolar disorder (BD) has received relatively little attention so far. The aim of the present work is, therefore, to assess the clinical implications of the presence of at least one first- and/or second-degree relative with a history of MD, BD and suicide in a large sample of patients with MD or BD. One thousand one hundred and fifty-seven subjects with MD and 686 subjects with BD were recruited within the context of two large projects. The impact of a family history of MD, BD, and suicide-considered both separately and together-on clinical and socio-demographic variables was investigated. A family history of MD, BD, and suicide was more common in BD patients than in MD patients. A positive family history of mood disorders and/or suicide as well as a positive family history of MD and BD separately considered, but not a positive history of suicide alone, were significantly associated with a comorbidity with several anxiety disorders and inversely associated with age of onset. The clinical implications as well as the limitations of our findings are discussed.

Background: Adverse life events are precipitating and maintenance factors for mood and anxiety disorders. However, the impact of such events on clinical features and treatment response is still unclear., Sampling and Methods: The aim of this study was to investigate whether specific adverse events (early parental loss and physical abuse) influence clinical features in a sample of 1,336 mood disorder patients, and whether genetic parameters interact with adverse events to influence treatment outcomes in a subsample of 252 subjects. Participants were collected in the context of a European multicenter study and treated with antidepressants at adequate doses for at least 4 weeks. We focused on two genes (BDNF and CREB1) due to prior evidence of association with treatment outcomes in the same sample., Results: Patients with a history of physical abuse had higher suicidal risk (including history of attempts), comorbid panic disorder, posttraumatic stress disorder and alcohol dependence compared to non-abused patients. Experience of early parental loss was a less detrimental type of life stressor. Treatment response was not affected by adverse events. No gene-environment interaction was found with genetic variations, using a corrected significance level., Conclusions: A limitation of the present study is that the subsample is too small for detecting gene-environment interactions. The clinical message of our findings is that mood disorder patients with a history of physical abuse showed a worse clinical profile, characterized by higher comorbid Axis I psychopathology and increased suicidal behavior., (Copyright © 2013 S. Karger AG, Basel.)

Cancer patients often complain about weakness, fatigue, and pain. The aim of this study was to assess the features of the fibromyalgia syndrome (FMS) characteristics in patients with non-metastatic breast cancer. The study group included 40 women whose age ranged from 40 to 70 years with Stages 0-3 breast cancer. The control group included 40 healthy women matched by age. A diagnosis of FMS was established based on medical history, physical examination, and the Fibromyalgia Impact Questionnaire (FIQ). Pain measures and functional factors were evaluated by the Brief Pain Inventory and the Sheehan Questionnaire. Resilience was assessed by Antanovsky's Sense of Coherence Questionnaire. Psychiatric disturbances were tested by the MINI Questionnaire and Hamilton questionnaires for depression and anxiety. The prevalence of chronic pain was higher in the study group. Statistically significant differences were also found between the group regarding pain, fatigue, and functional measures. The prevalence of depressive or anxious mood, measured by the Hamilton questionnaires, was strongly related to FMS characteristics reflected by FIQ scores (r = 0.79 between FIQ and the Hamilton Depression Index and r = 0.75 between FIQ and the Hamilton Anxiety Scale). The sense of coherence measure for these patients demonstrated an inverse correlation with pain, fatigue, and functional capability. Women with breast cancer tend to develop chronic widespread pain syndromes more often than do healthy women.

Background: Observations that antagonists of the N-methyl-d-aspartate (NMDA) receptor of glutamatergic neurons can mimic symptoms of schizophrenia have raised the hope that NMDA agonists can improve symptoms. On the basis of encouraging results of trials in which NMDA agonists were added to antipsychotics, we conducted an adequately powered randomized controlled trial adding d-serine, an NMDA modulator, to antipsychotics., Method: This study was a 195-patient, multicenter, double-blind, randomized, placebo-controlled, 16-week trial of d-serine 2 g/d as an add-on treatment to antipsychotics. Subjects had DSM-IV schizophrenia or schizoaffective disorder and were inpatients or outpatients stabilized on antipsychotics, with persistent negative symptoms. The primary outcome measures were changes in negative symptoms and cognition as measured by the Scale for the Assessment of Negative Symptoms (SANS) and the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) battery, respectively. The study was performed between 2003 and 2007., Results: Mean total Positive and Negative Syndrome Scale scores at baseline were 75.5. Subjects receiving d-serine and placebo improved in scores on the SANS and MATRICS, but no significant differences were observed between groups: improvement on SANS was 11.4% for d-serine vs 14.8% for placebo, F1,147=1.18, P=.32; and improvement on MATRICS was 6.8% for d-serine vs 6.1% for placebo, F1,125=0.96, P=.39, respectively. d-Serine was well tolerated., Discussion: This study did not find a significant difference between drug and placebo. However, the results are limited by a relatively large placebo response and somewhat lower-achieved doses than in prior studies. Future studies will administer higher doses and will attempt to affect the NMDA receptor using other mechanisms, such as agonists of the presynaptic metabotropic glutamate 2/3 receptor or glycine reuptake inhibitors., Trial Registration: ClinicalTrials.gov identifier: NCT00138775., (© Copyright 2012 Physicians Postgraduate Press, Inc.)

Background: On 4 February 2008, two terrorists armed with suicide bombs arrived atthe open market in the southern Israeli city of Dimona. One detonated his bomb at approximately 10:30 a.m. causing multiple casualties. Short-term emotional effects and acute stress reactions usually appear among survivors after such incidents., Objectives: To compare the differences in emotions and in disturbances of daily life activities that emerge a couple of days following such an event and to identify patterns of stress development among resilient and low-resilient members of the population in Dimona and in the general population of Israel., Methods: A telephone survey of two randomly selected representative samples of adults (428 Israeli residents and 250 Dimona residents) was conducted 2 days afterthe event., Results: A higher prevalence of stress and fear and a lower prevalence of joy were reported among the population of Dimona compared to the general population in Israel (P < 0.05). Differences were also recorded when the population of Dimona was categorized by its personal degree of resilience (P < 0.05). A higher prevalence of disturbances in daily life activities and changes in leisure activity was found in the low-resilient population in Dimona (P < 0.01)., Conclusions: This study demonstrates that following a public terror event, self-reported low-resilient subjects have a higher prevalence of disturbances in daily life activities, as well as adverse emotional responses. These differences must be addressed by the relevant social service agencies for immediate public intervention.