The effect of caloric restriction on working memory in healthy non-obese adults.

OBJECTIVE: We aim to evaluate the effect of caloric restriction (CR) in cognition by comparing performance in neuropsychological tests for working memory between a group of non-obese healthy subjects doing CR for 2 years with another consuming ad libitum diet (AL). METHODS: This study was part of a larger multicenter trial called CALERIE that consisted of a randomized clinical trial with parallel-group comparing 2 years of 25% CR and AL in 220 volunteers with a BMI between 22 and 28 kg/m2, across 3 sites. The cognitive tests used were the Cambridge Neuropsychological Tests Automated Battery (CANTAB) for Spatial Working Memory (SWM) including the total number of errors (SWMTE) and strategy (SWMS). Included as possible moderators were sleep quality, mood states, perceived stress, and energy expenditure. Analyses were performed at baseline and months 12 and 24. RESULTS: After adjustments, there was a significantly greater improvement in working memory assessed by the SWM for CR individuals, compared to AL. At month 24, it was related mostly to lower protein intake, compared to other macronutrients. Changes in SWM were moderated by changes in sleep quality, physical activity, and energy expenditure. CONCLUSION: On the long term, CR in healthy individuals seems to have a slightly positive effect on working memory. The study of brain CR targets opens new possibilities to prevent and treat cognitive deficits.

Insight into the Influence of Cultivar Type, Cultivation Year, and Site on the Lignans and Related Phenolic Profiles, and the Health-Promoting Antioxidant Potential of Flax (Linum usitatissimum L.) Seeds.

Flaxseeds are a functional food representing, by far, the richest natural grain source of lignans, and accumulate substantial amounts of other health beneficial phenolic compounds (i.e., flavonols, hydroxycinnamic acids). This specific accumulation pattern is related to their numerous beneficial effects on human health. However, to date, little data is available concerning the relative impact of genetic and geographic parameters on the phytochemical yield and composition. Here, the major influence of the cultivar over geographic parameters on the flaxseed phytochemical accumulation yield and composition is evidenced. The importance of genetic parameters on the lignan accumulation was further confirmed by gene expression analysis monitored by RT-qPCR. The corresponding antioxidant activity of these flaxseed extracts was evaluated, both in vitro, using ferric reducing antioxidant power (FRAP), oxygen radical absorbance capacity (ORAC), and iron chelating assays, as well as in vivo, by monitoring the impact of UV-induced oxidative stress on the lipid membrane peroxidation of yeast cells. Our results, both the in vitro and in vivo studies, confirm that flaxseed extracts are an effective protector against oxidative stress. The results point out that secoisolariciresinol diglucoside, caffeic acid glucoside, and p-coumaric acid glucoside are the main contributors to the antioxidant capacity. Considering the health benefits of these compounds, the present study demonstrates that the flaxseed cultivar type could greatly influence the phytochemical intakes and, therefore, the associated biological activities. We recommend that this crucial parameter be considered in epidemiological studies dealing with flaxseeds.

Vitex agnus castus for premenstrual syndrome and premenstrual dysphoric disorder: a systematic review.

The objective of this study was to evaluate whether Vitex agnus castus is a safe and effective treatment for PMS and premenstrual dysphoric disorder (PMDD) and to discuss the implications of these findings for clinical practice. A systematic review of literature was conducted using PubMed and Scielo databases. The inclusion criteria were randomized controlled trials (RCT) using V. agnus castus in individuals with PMS or PMDD that compared this intervention with placebo or an active comparator and included a description of blinding and dropouts/withdrawals. The search was conducted by two independent investigators who reached consensus on the included trials. A total of eight RCTs were included in this study. Most studies focused on PMS, and the diagnostic criteria of PMS and PMDD changed over the years. Three different preparations of V. agnus castus (VAC) were tested, and there was significant variability in the measurement of treatment outcomes between the studies. Nevertheless, all eight studies were positive for VAC in the treatment of PMS or PMDD and VAC was overall well tolerated. Main limitations were differences in definition of diagnostic criteria, the instruments used as main outcome measures, and different preparations of VAC extracts limit the comparison of results between studies. In conclusion, the RCTs using VAC for treatment of PMS/PMDD suggested that the VAC extract is a safe and efficacious alternative to be considered for the treatment of PMS/PMDD symptoms.

Mice deficient for the epidermal dermokine ß and γ isoforms display transient cornification defects.

Expression of the human dermokine gene (DMKN) leads to the production of four dermokine isoform families. The secreted α, ß and γ isoforms have an epidermis-restricted expression pattern, with Dmkn ß and γ being specifically expressed by the granular keratinocytes. The δ isoforms are intracellular and ubiquitous. Here, we performed an in-depth characterization of Dmkn expression in mouse skin and found an expression pattern that was less complex than in humans. In particular, mRNA coding for the δ family were absent. Homozygous mice null for the Dmkn ß and γ isoforms had no obvious phenotype but only a temporary scaly skin during the first week of life. The pups null for the Dmkn ß and γ isoforms had smaller keratohyalin granules and their cornified envelopes were more sensitive to mechanical stress. At the molecular level, amounts of profilaggrin and filaggrin monomers were reduced whereas amino acid components of the natural moisturizing factor were increased. In addition, the electrophoretic mobility of involucrin was modified, suggesting post-translational modifications. Finally, the mice null for the Dmkn ß and γ isoforms strongly overexpressed Dmkn α. These data are evocative of compensatory mechanisms relevant to the temporary phenotype. Overall, we improved the knowledge of Dmkn expression in mouse and highlighted a role for Dmkn ß and γ in cornification.

Corneodesmosomes and corneodesmosin: from the stratum corneum cohesion to the pathophysiology of genodermatoses.

Corneodesmosin (CDSN) was identified 20 years ago by raising monoclonal antibodies against human plantar stratum corneum. The protein is specific to corneodesmosomes, cell-junction structures that, in humans, are found in the epidermis, the hard palate epithelium, and the inner root sheath of the hair follicles. Synthesized by the granular keratinocytes and secreted via the lamellar bodies, CDSN is incorporated into the desmoglea of the desmosomes, shortly before their transformation into corneodesmosomes during cornification. CDSN displays adhesive properties, mostly attributable to its N-terminal glycine-rich domain, and is sequentially proteolyzed as corneocytes migrate towards the skin surface prior to desquamation. The recent inactivation of Cdsn in mice induced a lethal epidermal barrier disruption and hair follicle degeneration, related to corneodesmosome dysfunction. That confirmed the essential role of the protein in maintaining integrity of the epidermis and the hair follicle. The CDSN gene is located in PSORS1, the major psoriasis susceptibility locus on the chromosome 6, but to date its involvement in the disease pathophysiology is not clear. By contrast, two different monogenic diseases associated with nonsense mutations in CDSN, were recently identified. First, hypotrichosis simplex of the scalp in which mutated CDSN accumulates in the dermis and forms amyloid deposits; then, peeling skin disease in which the genetic defect induces dyscohesion of the stratum corneum, responsible for abnormal desquamation and increased skin penetration of allergens.

Quantifying arsenic post-depositional mobility in lake sediments impacted by gold ore roasting in sub-arctic Canada using inverse diagenetic modelling.

Lake sediments are widely used as environmental archives to reconstruct past changes in contaminants deposition, provided that they remain immobile after deposition. Arsenic (As) is a redox-sensitive element that may be redistributed in the sediments during early diagenesis, for instance along with iron and manganese, and thus depth profiles of As might not provide a reliable, unaltered record of past deposition. Here, we use inverse diagenetic modelling to calculate fluxes of As across the sediment-water interface and interpret As sedimentary records in eight lakes along a 80 km transect from the Giant and Con mines, Northwest Territories, Canada. The sediment cores were dated using 210Pb methods and analyzed for solid-phase and porewater As, Fe, Mn and organic C concentrations. We reconstructed the history of As deposition by correcting for the varying mobility patterns and calculated contemporary As deposition fluxes. Correction for diagenesis was substantial for three of the eight lakes, suggesting that lakes with lower sedimentation rates, which allows longer residence of As within the reactive zones defined by the model, enhance the influence of diagenesis. Results show that solid phase As peaks coincides with the period of high emissions from past gold ore roasting activities. Results also show that sediments sustained present-day As fluxes to the water column of study lakes within 50 km of the mines, while sediment in study lakes further than 50 km acted as As sinks instead.

Barriers to care and psychopathology among Bolivian migrants living in São Paulo, Brazil.

The objective of this study was to investigate barriers to appropriate mental health care in a sample of Bolivian migrants living in São Paulo and to examine the association between barriers of care and the presence of symptoms of non-psychotic psychiatric disorders in this population. Considering that treatment usually reduces symptoms, it could be hypothesized that individuals reporting more barriers to care also will report more symptoms. The sample comprised 104 individuals born in Bolivia, with Bolivian nationality and living in São Paulo for at least 30 days prior to enrolling in the study, between 18 and 80 years of age and able to read and write in Spanish or Portuguese. The symptoms of mental disorders were assessed using the Self-Reporting Questionnaire (SRQ-20) and barriers to appropriate mental health care were evaluated using the Barriers to Assessing Care Evaluation (BACE). A multiple linear regression analysis was performed to determine the predictive effect of the BACE total score (independent variable) in the SRQ-20 score (dependent variable), including in the model, and the variables that were significantly correlated with the BACE total score or SRQ-20. Our results indicate that more than a half of the sample of Bolivian migrants living in Sao Paulo, Brazil, especially females, presented significant non-psychotic psychopathology. Individuals reporting more barriers to care, especially instrumental and attitudinal barriers, also have a higher risk of psychiatric symptoms, independently of sex, age and family income. Our results suggest that actions to increase availability of mental health services, especially culturally sensitive services, could reduce barriers to care and improve mental health among migrants.

A Green Ultrasound-Assisted Extraction Optimization of the Natural Antioxidant and Anti-Aging Flavonolignans from Milk Thistle Silybum marianum (L.) Gaertn. Fruits for Cosmetic Applications.

Silybum marianum (L.) Gaertn. (aka milk thistle) constitutes the source of silymarin (SILM), a mixture of different flavonolignans and represents a unique model for their extraction. Here we report on the development and validation of an ultrasound-assisted extraction (UAE) method of S. marianum flavonolignans follow by their quantification using LC system. The optimal conditions of this UAE method were: aqueous EtOH 54.5% (v/v) as extraction solvent, with application of an ultrasound (US) frequency of 36.6 kHz during 60 min at 45 °C with a liquid to solid ratio of 25:1 mL/g dry weight (DW). Following its optimization using a full factorial design, the extraction method was validated according to international standards of the association of analytical communities (AOAC) to ensure precision and accuracy in the quantitation of each component of the SILM mixture. The efficiency of this UAE was compared with maceration protocol. Here, the optimized and validated conditions of the UAE allowed the highest extraction yields of SILM and its constituents in comparison to maceration. During UAE, the antioxidant capacity of the extracts was retained, as confirmed by the in vitro assays CUPRAC (cupric ion reducing antioxidant capacity) and inhibition of AGEs (advanced glycation end products). The skin anti-aging potential of the extract obtained by UAE was also confirmed by the strong in vitro cell-free inhibition capacity of both collagenase and elastase. To summarize, the UAE procedure presented here is a green and efficient method for the extraction and quantification of SILM and its constituents from the fruits of S. marianum, making it possible to generate extracts with attractive antioxidant and anti-aging activities for future cosmetic applications.

The landscape genetics of yellow perch (Perca flavescens) in a large fluvial ecosystem.

Landscape genetics is being increasingly applied to elucidate the role of environmental features on the population structure of terrestrial organisms. However, the potential of this framework has been little explored in aquatic ecosystems such as large rivers. Here, we used a landscape genetics approach in order to (i) document the population structure of the yellow perch (Perca flavescens) by means of genetic variation at microsatellite markers, (ii) assess to what extent the structure was explained by landscape heterogeneity, and (iii) interpret the relevance of interactions between genetics and landscape for management and conservation. Analysis of the genetic variation among 1715 individuals from 16 localities and distributed over 310 km in the freshwater section of the Saint Lawrence River (Québec, Canada) revealed a relatively modest level of genetic structuring (F(ST) = 0.039). Application of the Monmonier's algorithm combining geographical and genetic information identified three zones of restricted gene flow defining four distinct populations. Physical barriers played a more important role on gene flow and genetic structure than waterway geographical distance. We found correlations between genetic differentiation and presence of distinct water masses in the sector of Lake Saint-Louis (r = 0.7177, P = 0.0340) and with fragmentation of spawning habitats in the sector of Lake Saint-Pierre (r = 0.8578, P = 0.0095). Our results support the treatment of four distinct biological units, which is in contrast with the current basis for yellow perch management. Finally, this study showed that landscape genetics is a powerful means to identify environmental barriers to gene flow causing genetic discontinuities in apparently highly connected aquatic landscapes.

Stress, trauma, and posttraumatic stress disorder in migrants: a comprehensive review.

OBJECTIVE: There is growing evidence supporting the association between migration and posttraumatic stress disorder (PTSD). Considering the growing population of migrants and the particularities of providing culturally sensitive mental health care for these persons, clinicians should be kept up to date with the latest information regarding this topic. The objective of this study was to critically review the literature regarding migration, trauma and PTSD, and mental health services. METHODS: The PubMed, SciELO, LILACS, and ISI Web of Science databases were searched for articles published in Portuguese, English, Spanish, or French, and indexed from inception to 2017. The following keywords were used: migration, mental health, mental health services, stress, posttraumatic stress disorder, and trauma. RESULTS: Migration is associated with specific stressors, mainly related to the migratory experience and to the necessary process of acculturation occurring in adaptation to the host country. These major stressors have potential consequences in many areas, including mental health. The prevalence of PTSD among migrants is very high (47%), especially among refugees, who experience it at nearly twice the rate of migrant workers. CONCLUSIONS: Mental health professionals must be trained to recognize and provide appropriate care for posttraumatic and/or stress-related disorders among migrants.

The differential association between history of childhood sexual abuse and body mass index in early and late stages of bipolar disorder.

BACKGROUND: History of distal stressors such as childhood trauma is a well-established, non-specific vulnerability factor for multiple mental illnesses. The objective of this study was to investigate the possible association between history of childhood trauma and body mass index (BMI) in individuals in early and late stages of bipolar disorder (BD) and to verify is there was any difference in the association of sexual abuse history and obesity in early versus late stages of BD. METHODS: Seventy-one euthymic BD-type I patients and eighty-one healthy controls were evaluated using the Childhood Trauma Questionnaire (CTQ) and body mass index (BMI). The association between BMI and CTQ total and subscores were evaluated dividing BD population in early-stage BD-I (less than 10 years since onset of disease) or late-stage BD (more than 10 years). RESULTS: BD individuals had higher rates of history of childhood trauma than HC, especially sexual and emotional abuse, after adjusting for confounders. We observed a moderating effect of group on the association between BMI and sexual abuse (SA), but not on other modalities of childhood trauma, after adjustments for age, gender, ethnicity, education, alcohol and tobacco use. LIMITATIONS: Our sample included a predominance of female individuals. The study cross-sectional design does not allow concluding a cause-effect relationship. In dividing the BD subgroups in relation with the time since the onset, we supposed that the natural course of BD is linear. The CTQ is subject to recall bias. CONCLUSION: There is a relationship between childhood sexual abuse and BMI, but the direction of the association varies across the different stages of BD-I.

Determinants of adherence to treatment in first-episode psychosis: a comprehensive review.

OBJECTIVE: To conduct a comprehensive review of current evidence on factors for nonadherence to treatment in individuals with first-episode psychosis (FEP). METHODS: MEDLINE, LILACS, PsycINFO, and SciELO databases were searched with the keywords first episode psychosis, factor, adherence, nonadherence, engagement, disengagement, compliance, and intervention. References of selected studies were consulted for relevant articles. RESULTS: A total of 157 articles were screened, of which 33 articles were retained for full review. The factors related to nonadherence were: a) patient-related (e.g., lower education level, persistent substance use, forensic history, unemployment, history of physical abuse); b) environment-related (e.g., no family involved in treatment, social adjustment difficulties); c) medication-related (e.g., rapid remission of negative symptoms when starting treatment, therapeutic alliance); and d) illness-related (e.g., more positive symptoms, more relapses). Treatment factors that improve adherence include a good therapeutic alliance and a voluntary first admission when hospitalization occurs. CONCLUSION: The results of this review suggest that nonadherence to treatment in FEP is multifactorial. Many of these factors are modifiable and can be specifically targeted in early intervention programs. Very few studies have assessed strategies to raise adherence in FEP.

Development and validation of an efficient ultrasound assisted extraction of phenolic compounds from flax (Linum usitatissimum L.) seeds.

Flaxseed accumulates in its seedcoat a macromolecular complex composed of lignan (secoisolariciresinol diglucoside, SDG), flavonol (herbacetin diglucoside, HDG) and hydroxycinnamic acids (p-couramic, caffeic and ferulic acid glucosides). Their antioxidant and/or cancer chemopreventive properties support their interest in human health and therefore, the demand for their extraction. In the present study, ultrasound-assisted extraction (UAE) of flaxseed phenolic compounds was investigated. Scanning Electron Microscopy imaging and histochemical analysis revealed the deep alteration of the seedcoat ultrastructure and the release of the mucilage following ultrasound treatment. Therefore, this method was found to be very efficient for the reduction of mucilage entrapment of flaxseed phenolics. The optimal conditions for UAE phenolic compounds extraction from flaxseeds were found to be: water as solvent supplemented with 0.2N of sodium hydroxide for alkaline hydrolysis of the SDG-HMG complex, an extraction time of 60 min at a temperature of 25°C and an ultrasound frequency of 30 kHz. Under these optimized and validated conditions, highest yields of SDG, HDG and hydroxycinnamic acid glucosides were detected in comparison to other published methods. Therefore, the procedure presented herein is a valuable method for efficient extraction and quantification of the main flaxseed phenolics. Moreover, this UAE is of particular interest within the context of green chemistry in terms of reducing energy consumption and valuation of flaxseed cakes as by-products resulting from the production of flax oil.

Determinants of adherence to treatment in bipolar disorder: a comprehensive review.

OBJECTIVE: Comprehensively review studies evaluating factors associated with adherence to treatment in bipolar disorder (BD), as well as the results of interventions developed to enhance adherence in this population. METHODS: The following search engines were consulted: PubMed, Scielo, LILACS and PsycINFO. The keywords used were "Bipolar Disorder", "Factor", "Adherence", "Nonadherence", "Compliance" and "Intervention". In addition, references list of selected studies were consulted searching for relevant articles. RESULTS: Adherence has been defined in various ways, with some considering adherence vs. nonadherence, and other including a "partial" adherence measure. In addition, methods to assess adherence differ for each study. Several factors were related to poor adherence, including patient-related factors (e.g. younger age, male gender, low level of education, alcohol and drugs comorbidity), disorder-related factors (e.g. younger age of onset, severity of BD, insight and lack of awareness of illness) and treatment-related factors (e.g. side effects of medications, effectiveness). To improve adherence, the main recommendations are to provide customized interventions focusing on the underlying causes of nonadherence, strong therapeutic alliance and different modalities based on psychoeducation. CONCLUSION: Our results indicate that nonadherence is a multicausal phenomenon and strategies to prevent and approaches them must include enhanced therapeutic alliance, flexible topics, early intervention, group setting, and psychoeducation. LIMITATIONS: Different definitions and measures of adherence in the literature currently moderate the generalization of the findings in this review. Further studies are necessary regarding factors of adherence in BD and interventions to improve it, especially on social factors like stigma and family.

Stress, trauma, and posttraumatic stress disorder in migrants: a comprehensive review

Objective: There is growing evidence supporting the association between migration and posttraumatic stress disorder (PTSD). Considering the growing population of migrants and the particularities of providing culturally sensitive mental health care for these persons, clinicians should be kept up to date with the latest information regarding this topic. The objective of this study was to critically review the literature regarding migration, trauma and PTSD, and mental health services. Methods: The PubMed, SciELO, LILACS, and ISI Web of Science databases were searched for articles published in Portuguese, English, Spanish, or French, and indexed from inception to 2017. The following keywords were used: migration, mental health, mental health services, stress, posttraumatic stress disorder, and trauma. Results: Migration is associated with specific stressors, mainly related to the migratory experience and to the necessary process of acculturation occurring in adaptation to the host country. These major stressors have potential consequences in many areas, including mental health. The prevalence of PTSD among migrants is very high (47%), especially among refugees, who experience it at nearly twice the rate of migrant workers. Conclusions: Mental health professionals must be trained to recognize and provide appropriate care for posttraumatic and/or stress-related disorders among migrants.

Recognition of bipolar disorder type I before the first manic episode: challenges and developments.

Bipolar disorder (BD) usually follows a neurobiological progression pathway, but a relatively long interval between the first symptoms of the disorder and the correct diagnosis and treatment takes place in most patients. Strategies used to recognize BD at an early stage and even prior to the first manic episode could help identify the risk and modifying factors that influence the onset and course of disease, and improve outcomes. Drawing on current research results, this article presents considerations on risk factors for the development of BD, including genetic/familial risk, endophenotypes and clinical characteristics. Taken together, this article provides a framework and tools for research on the BD prodrome, as well as for the early recognition and timely treatment of patients prior to and immediately after the emergence of BD.

Impact of peripheral levels of chemokines, BDNF and oxidative markers on cognition in individuals with schizophrenia.

OBJECTIVE: To investigate possible differences in peripheral levels of chemokines, BDNF and oxidative markers between patients with Schizophrenia (SZ) and matched healthy controls, and investigate the correlation of these biomarkers with cognitive performance. METHODS: Thirty individuals with SZ and 27 healthy controls were included and the following plasmatic biomarkers' levels were determined according to manufacturers' instructions: BDNF, TBARS, protein carbonyl content (PCC) and the chemokines CXCL-10/IP-10, CXCL-8/IL-8, CCL-11, CCL-24/Eotaxin-2, CCL-2/MCP-1, CCL-3/MIP-1. Selected neuropsychological tasks were administered to assess verbal learning (Hopkins Verbal Learning Test), verbal fluency (FAS test), working memory (Visual Working Memory Task, Keep Track Task, Letter Memory Task), set shifting (Plus-minus task, Number-letter task), inhibition (Computerized Stroop Task, Semantic Generation Task) and complex executive function tasks (Tower of London and the shortened version of the WCST-64). RESULTS: Compared with the healthy control group, individuals with SZ presented significantly higher levels of BDNF and the chemokine CCL-11, and lower levels of TBARS and the chemokine CXCL-10/IP-10. When we examined only the SZ group, BDNF levels were positively correlated with semantic generation tasks. Working memory ability was negatively correlated with PCC. Regarding chemokines, CCL-11 was negatively correlated to performance in working memory test, and positively correlated with cognitive flexibility task. CXCL-8/IL-8 was positively correlated with verbal fluency. CCL-24/Eotaxin-2 was positively correlated with semantic generation ability and letter memory task. CONCLUSIONS: Our results indicate that cognitive performance in SZ is associated with mediators of neuroplasticity that can be measured peripherally.

The ubiquitous dermokine delta activates Rab5 function in the early endocytic pathway.

The expression of the recently identified dermokine (Dmkn) gene leads to four families of proteins with as yet unknown functions. The secreted α, ß and γ isoforms share an epidermis-restricted expression pattern, whereas the δ isoform is intracellular and ubiquitous. To get an insight into Dmknδ function, we performed yeast two-hybrid screening and identified the small GTPases Rab5 as partners for Dmknδ. The Rab5 proteins are known to regulate membrane docking and fusion in the early endocytic pathway. GST pull-down assays confirmed the direct interaction between Rab5 and Dmknδ. Transient expression of Dmknδ in HeLa cells led to the formation of punctate structures colocalized with endogenous Rab5 and clathrin, indicating Dmknδ involvement in the early steps of endocytosis. Dmknδ indeed colocalized with transferrin at early stages of endocytosis, but did not modulate its endocytosis or recycling kinetics. We also showed that Dmknδ was able to bind both inactive (GDP-bound) and active (GTP-bound) forms of Rab5 in vitro but preferentially targeted GDP-bound form in HeLa cells. Interestingly, Dmknδ expression rescued the Rab5S34N-mediated inhibition of endosome fusion. Moreover, Dmknδ caused the enlargement of vesicles positive for Rab5 by promoting GTP loading onto the small GTPase. Together our data reveal that Dmknδ activates Rab5 function and thus is involved in the early endosomal trafficking.

Determinants of adherence to treatment in first-episode psychosis: a comprehensive review

Objective: To conduct a comprehensive review of current evidence on factors for nonadherence to treatment in individuals with first-episode psychosis (FEP). Methods: MEDLINE, LILACS, PsycINFO, and SciELO databases were searched with the keywords first episode psychosis, factor, adherence, nonadherence, engagement, disengagement, compliance, and intervention. References of selected studies were consulted for relevant articles. Results: A total of 157 articles were screened, of which 33 articles were retained for full review. The factors related to nonadherence were: a) patient-related (e.g., lower education level, persistent substance use, forensic history, unemployment, history of physical abuse); b) environment-related (e.g., no family involved in treatment, social adjustment difficulties); c) medication-related (e.g., rapid remission of negative symptoms when starting treatment, therapeutic alliance); and d) illness-related (e.g., more positive symptoms, more relapses). Treatment factors that improve adherence include a good therapeutic alliance and a voluntary first admission when hospitalization occurs. Conclusion: The results of this review suggest that nonadherence to treatment in FEP is multifactorial. Many of these factors are modifiable and can be specifically targeted in early intervention programs. Very few studies have assessed strategies to raise adherence in FEP. .