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Objectives The Retrospective Assessment of the Lithium Response Phenotype Scale (Alda scale) is the most widely used clinical measure of lithium response phenotypes. We assess its performance against recommended psychometric and clinimetric standards. Methods We used data from the Consortium for Lithium Genetics and a French study of lithium response phenotypes (combined sample >2500) to assess reproducibility, responsiveness, validity, and interpretability of the A scale (assessing change in illness activity), the B scale, and its items (assessing confounders of response) and the previously established response categories derived from the Total Score for the Alda scale. Results The key findings are that the B scale is vulnerable to error measurement. For example, some items contribute little to overall performance of the Alda scale (eg, B2) and that the B scale does not reliably assess a single construct (uncertainty in response). Machine learning models indicate that it may be more useful to employ an algorithm for combining the ratings of individual B items in a sequence that clarifies the noise to signal ratio instead of using a composite score. Conclusions This study highlights three important topics. First, empirical approaches can help determine which aspects of the performance of any scale can be improved. Second, the B scale of the Alda is best applied as a multidimensional index (identifying several independent confounders of the assessment of response). Third, an integrated science approach to precision psychiatry is vital, otherwise phenotypic misclassifications will undermine the reliability and validity of findings from genetics and biomarker studies.

Bipolar disorder is a heritable mental illness with complex etiology. We performed a genome-wide association study of 41,917 bipolar disorder cases and 371,549 controls of European ancestry, which identified 64 associated genomic loci. Bipolar disorder risk alleles were enriched in genes in synaptic signaling pathways and brain-expressed genes, particularly those with high specificity of expression in neurons of the prefrontal cortex and hippocampus. Significant signal enrichment was found in genes encoding targets of antipsychotics, calcium channel blockers, antiepileptics and anesthetics. Integrating expression quantitative trait locus data implicated 15 genes robustly linked to bipolar disorder via gene expression, encoding druggable targets such as HTR6, MCHR1, DCLK3 and FURIN. Analyses of bipolar disorder subtypes indicated high but imperfect genetic correlation between bipolar disorder type I and II and identified additional associated loci. Together, these results advance our understanding of the biological etiology of bipolar disorder, identify novel therapeutic leads and prioritize genes for functional follow-up studies. © 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.

IMPORTANCE: Being born small for gestational age (SGA) is a leading cause of perinatal morbidity and mortality with no effective prevention or therapy. Maternal suboptimal nutrition and high stress levels have been associated with poor fetal growth and adverse pregnancy outcomes. OBJECTIVE: To investigate whether structured interventions based on a Mediterranean diet or mindfulness-based stress reduction (stress reduction) in high-risk pregnancies can reduce the percentage of newborns who were born SGA and other adverse pregnancy outcomes. DESIGN, SETTING, AND PARTICIPANTS: Parallel-group randomized clinical trial conducted at a university hospital in Barcelona, Spain, including 1221 individuals with singleton pregnancies (19-23 weeks' gestation) at high risk for SGA. Enrollment took place from February 1, 2017, to October 10, 2019, with follow-up until delivery (final follow-up on March 1, 2020). INTERVENTIONS: Participants in the Mediterranean diet group (n = 407) received 2 hours monthly of individual and group educational sessions and free provision of extra-virgin olive oil and walnuts. Individuals in the stress reduction group (n = 407) underwent an 8-week stress reduction program adapted for pregnancy, consisting of weekly 2.5-hour sessions and 1 full-day session. Individuals in the usual care group (n = 407) received pregnancy care per institutional protocols. MAIN OUTCOMES AND MEASURES: The primary end point was the percentage of newborns who were SGA at delivery, defined as birth weight below the 10th percentile. The secondary end point was a composite adverse perinatal outcome (at least 1 of the following: preterm birth, preeclampsia, perinatal mortality, severe SGA, neonatal acidosis, low Apgar score, or presence of any major neonatal morbidity). RESULTS: Among the 1221 randomized individuals (median [IQR] age, 37 [34-40] years), 1184 (97%) completed the trial (392 individuals assigned to the Mediterranean diet group, 391 to the stress reduction group, and 401 to the usual care group). SGA occurred in 88 newborns (21.9%) in the control group, 55 (14.0%) in the Mediterranean diet group (odds ratio [OR], 0.58 [95% CI, 0.40-0.84]; risk difference [RD], -7.9 [95% CI, -13.6 to -2.6]; P = .004), and 61 (15.6%) in the stress reduction group (OR, 0.66 [95% CI, 0.46-0.94]; RD, -6.3 [95% CI, -11.8 to -0.9]; P = .02). The composite adverse perinatal outcome occurred in 105 newborns (26.2%) in the control group, 73 (18.6%) in the Mediterranean diet group (OR, 0.64 [95% CI, 0.46-0.90]; RD, -7.6 [95% CI, -13.4 to -1.8]; P = .01), and 76 (19.5%) in the stress reduction group (OR, 0.68 [95% CI, 0.49-0.95]; RD, -6.8 [95% CI, -12.6 to -0.3]; P = .02). CONCLUSIONS AND RELEVANCE: In this randomized trial conducted at a single institution in Spain, treating pregnant individuals at high risk for SGA with a structured Mediterranean diet or with mindfulness-based stress reduction, compared with usual care, significantly reduced the percentage of newborns with birth weight below the 10th percentile. Due to important study limitations, these findings should be considered preliminary and require replication, as well as assessment in additional patient populations, before concluding that these treatments should be recommended to patients. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03166332.

Accuracy of dietary assessment instruments such as food frequency questionnaire (FFQ) is crucial in the evaluation of diet-disease relationships. Test-retest reliability and concurrent and construct validity of a FFQ were evaluated in 150 pregnant women at high risk to develop fetal growth restriction randomly selected from those included in the improving mothers for better prenatal care trial Barcelona (IMPACT BCN). The FFQ and dietary records were performed at baseline and 34-36 weeks of gestation. Test-retest reliability of the FFQ for 12 food groups and 17 nutrients was moderate (ICC = 0.55) and good (ICC = 0.60), respectively. Concurrent validity between food, nutrients and a composite Mediterranean diet score (MedDiet score) and food records was fair for foods and nutrients (? average = 0.38 and 0.32, respectively) and moderate (r = 0.46) for the MedDiet score. Validation with biological markers ranged from poor (r = 0.07) for olives to moderate (r = 0.41) for nuts. A fair concordance between methods were found for nutrients (weighted ? = 0.22) and foods (weighted ? = 0.27). The FFQ-derived MedDiet score correlated in anticipated directions with intakes of nutrients and foods derived by food records. The FFQ showed a moderate test-retest reliability and reasonable validity to rank women according to their food and nutrient consumption and adherence to the Mediterranean diet.

Impairments in a broad range of cognitive domains have been consistently reported in some individuals with first-episode psychosis (FEP). Cognitive deficits can be observed during the prodromal stage. However, the course of cognitive deficits is still unclear. The aim of this study was to identify cognitive subgroups over time and to compare their sociodemographic, clinical and functional profiles. A total of 114 patients with Schizophrenia Spectrum Disorders were included in the present study. We assessed subjects through psychiatric scales and eight neuropsychological tests at baseline and at two-year follow-up visit. We performed the Partition Around Medoids algorithm with all cognitive variables. Furthermore, we performed a logistic regression to identify the predictors related to the different cognitive clusters at follow-up. Two distinct subgroups were found: the first cluster characterized by cognitive impairment and a second cluster had relatively intact cognition in comparison with norms. Up to 54.7% of patients with cognitive deficits at baseline tended to improve during the first two years of treatment. Patients with intact cognition at follow-up had a higher socioeconomic status, later age of onset, lower negative symptoms and a higher cognitive reserve (CR) at baseline. CR and age of onset were the baseline variables that predicted cognitive impairment. This research allows us to obtain a better understanding of the heterogeneous profile of psychotic disorders. Identifying the characteristics of patients who will present a cognitive impairment could improve early detection and intervention. These results suggest that enhancing CR could contribute to improving the course of the illness. © 2021 Elsevier B.V.

Background: Bipolar disorder is associated with circadian disruption and a high risk of suicidal behavior. In a previous exploratory study of patients with bipolar I disorder, we found that a history of suicide attempts was associated with differences between winter and summer levels of solar insolation. The purpose of this study was to confirm this finding using international data from 42% more collection sites and 25% more countries. Methods: Data analyzed were from 71 prior and new collection sites in 40 countries at a wide range of latitudes. The analysis included 4876 patients with bipolar I disorder, 45% more data than previously analyzed. Of the patients, 1496 (30.7%) had a history of suicide attempt. Solar insolation data, the amount of the sun’s electromagnetic energy striking the surface of the earth, was obtained for each onset location (479 locations in 64 countries). Results: This analysis confirmed the results of the exploratory study with the same best model and slightly better statistical significance. There was a significant inverse association between a history of suicide attempts and the ratio of mean winter insolation to mean summer insolation (mean winter insolation/mean summer insolation). This ratio is largest near the equator which has little change in solar insolation over the year, and smallest near the poles where the winter insolation is very small compared to the summer insolation. Other variables in the model associated with an increased risk of suicide attempts were a history of alcohol or substance abuse, female gender, and younger birth cohort. The winter/summer insolation ratio was also replaced with the ratio of minimum mean monthly insolation to the maximum mean monthly insolation to accommodate insolation patterns in the tropics, and nearly identical results were found. All estimated coefficients were significant at p < 0.01. Conclusion: A large change in solar insolation, both between winter and summer and between the minimum and maximum monthly values, may increase the risk of suicide attempts in bipolar I disorder. With frequent circadian rhythm dysfunction and suicidal behavior in bipolar disorder, greater understanding of the optimal roles of daylight and electric lighting in circadian entrainment is needed. © 2021, The Author(s).

Introduction: There is evidence that early intervention contributes to improving the prognosis and course of first-episode psychosis (FEP). However, further randomised treatment clinical trials are needed. Objectives: The aim of this study was to compare the efficacy of a combined clinical treatment involving Cognitive Behavioural Therapy (CBT) as an adjunctive to treatment-as-usual (TAU) (CBT+TAU) versus TAU alone for FEP. Patients and methods: In this multicentre, single-blind, randomised controlled trial, 177 participants were randomly allocated to either CBT+TAU or TAU. The primary outcome was post-treatment patient functioning. Results: The CBT+TAU group showed a greater improvement in functioning, which was measured using the Global Assessment Functioning (GAF) and Functioning Assessment Short Test (FAST), compared to the TAU group post-treatment. The CBT+TAU participants exhibited a greater decline in depressive, negative, and general psychotic symptoms; a better awareness of the disease and treatment adherence; and a greater increase in brain-derived neurotrophic factor levels than TAU participants. Conclusions: Early intervention based on a combined clinical treatment involving CBT as an adjunctive to standard treatment may improve clinical and functional outcomes in FEP.

Background: Offspring of patients diagnosed with bipolar disorder and schizophrenia (Off-BDSZ) have a high genetic risk of developing a mental illness. The aim of this project is to develop and investigate the efficacy of an intervention aimed at this population, based on the concept of cognitive reserve. Methods: This is a multicenter randomized trial with an experimental test–retest design study with control group. Two groups will be included: a community comparison group (CC) and a Off-BDSZ group. A total of 108 Off-BDSZ and 65 CC aged between 6 and 25 years will be recruited. Off-BDSZ participants will be randomized to receive either Cognitive Reserve EnhAncement ThErapy (CREATE) (n = 54), or a supportive approach (n = 54). The CC group will be assessed at baseline. The duration of the intervention will be 3 months, with 12 weekly group sessions. The primary outcome will be the improvement in CR measured according to change in the Cognitive Reserve Assessment Scale in Health (CRASH) and Cognitive Reserve scale for Adolescents (CORE-A). All participants will be blindly evaluated using clinical, cognitive and neuroimaging measures at baseline, at three months (after the psychological intervention), and at twelve-month follow-up after treatment completion. Discussion: The results will provide insight into whether the CREATE-Offspring version may enhance cognitive reserve (CR) in child, adolescent and young adult Off-BDSZ as well as advance knowledge about changes in clinical manifestations, neuropsychological performance and brain structure and function associated with improving CR. This novel and cost-effective intervention represents an advance in the framework of preventive interventions in mental health. Trial registration: Clinicaltrials.gov, NCT03722082. Registered on 26 October 2018. © 2021 SEP y SEPB

Functional impairment is a defining feature of psychotic disorders. The Functional Assessment Short Test (FAST) is one of the most widely used instruments to measure psychosocial functioning. However, cut-offs of impairment have been well-established for bipolar disorders, but not for other clinical populations. This study aims to analyse psychometric properties of the FAST and establish their corresponding cut-off values for the different severity gradations in a first-episode of non-affective psychosis (FEP) patients. Global Assessment Functioning (GAF) and FAST ratings from 212 non-affective FEP and 204 healthy controls were analyzed. The psychometric properties of FAST (internal consistency, concurrent validity, discriminant validity, factorial analyses and sensitivity to change) were analyzed. The severity gradations of the FAST were defined by the congruence between two grading methods: linear regression analysis (LRA) and percentiles. The FAST showed strong psychometric properties. LRA with the GAF scores yielded the following equation: GAF(score) = 80.83 - 0.639*FAST(score). The FAST ranges in non-affective FEP patients derived from LRA and percentiles, were as follows: 0-9 (No impairment); 10-19 (Minimal impairment); 20-34 (Mild impairment); 35-45 (Moderate impairment); 46-72 (Severe impairment). Patients with no functional impairment had a higher socioeconomic status, fewer depressive and negative symptoms, lower severity of illness and higher cognitive reserve level than the others groups. In conclusion, the FAST shows optimal psychometric properties which corroborate its applicability in FEP populations. It is a well-demonstrated valid instrument and the present cut-off scores could be implemented in clinical and research practice to assess properly the psychosocial functional outcome of non-affective FEP populations. (C) 2021 Elsevier B.V. and ECNP. All rights reserved.

BACKGROUND: Fetal growth restriction (FGR) affects 7-10% of all pregnancies resulting in a higher risk of perinatal morbidity and mortality, long-term disabilities, and cognitive impairment. Due to its multifactorial etiology, changes in maternal lifestyle, including suboptimal maternal diet and stress, have increasingly been associated with its prevalence. We present a protocol for the Improving Mothers for a better PrenAtal Care Trial Barcelona (IMPACT BCN), which evaluates two different maternal lifestyle strategies (improved nutrition by promoting Mediterranean diet and stress reduction program based on mindfulness techniques) on perinatal outcomes. The primary objective is to reduce the prevalence of FGR. Secondary aims are to reduce adverse perinatal outcomes and to improve neurodevelopment and cardiovascular profile in children at 2 years of age. METHODS: A randomized parallel, open-blind, single-center trial following a 1:1:1 ratio will select and randomize high-risk singleton pregnancies for FGR (N=1218), according to the criteria of the Royal College of Obstetricians and Gynaecologists (19.0-23.6 weeks' gestation), into three arms: Mediterranean diet, mindfulness-based stress reduction program, and usual care without any intervention. Compliance to the interventions will be randomly tested in 30% of participants with specific biomarkers. Maternal socio-demographic, clinical data, biological samples, and lifestyle questionnaires will be collected at enrollment and at the end of the interventions (34.0-36.6 weeks' gestation), together with a fetoplacental ultrasound and magnetic resonance. Fetoplacental biological samples and perinatal outcomes will be recorded at delivery. Postnatal follow-up is planned up to 2 years of corrected age including neurodevelopmental tests and cardiovascular assessment. Intention-to-treat and population per-protocol analysis will be performed. DISCUSSION: This is the first randomized study evaluating the impact of maternal lifestyle interventions during pregnancy on perinatal outcomes. The maternal lifestyle interventions (Mediterranean diet and mindfulness-based stress reduction program) are supported by scientific evidence, and their compliance will be evaluated with several biomarkers. TRIAL REGISTRATION: ClinicalTrials.gov NCT03166332 . Registered on April 19, 2017.

Introduction The role of Olanzapine therapeutic drug monitoring is controversial. The present study explores the associations of Olanzapine plasma concentrations with clinical response and metabolic side effects in first episode psychosis (FEP) after 2 months of treatment. Methods Forty-seven patients were included. Improvement in clinical symptomatology was assessed using the PANSS. Metabolic assessment included weight, blood pressure, waist circumference, blood glucose, total cholesterol, high-density lipoprotein, low-density lipoprotein, and triglycerides. Results The Olanzapine plasma concentrations after 2 months of treatment were positively correlated with weight gain (r = 0.49, p = 0.003), and a concentration > 23.28 ng/mL was identified as a positive predictor of weight gain (>= 7%). The Olanzapine concentration to dose (C/D) ratio was positively correlated with the percentage of improvement in the total PANSS (r = 0.46, p = 0.004), and a C/D ratio > 2.12 was identified as a positive predictor of a good response (percentage of improvement > 30%) after 2 months of treatment. We also identified several factors that could alter Olanzapine pharmacokinetics: gender (p = 0.03), diagnosis (p = 0.05), smoking habit (p = 0.05), and co-medications such as valproic acid (p = 0.05) and anxiolytics (p = 0.01). Discussion In conclusion, our results suggest that therapeutic drug monitoring of Olanzapine could be helpful to evaluate therapeutic efficacy and metabolic dysfunction in FEP patients treated with Olanzapine.

Objective The period immediately after the onset of first-episode psychosis (FEP) may present with high risk for suicidal ideation (SI) and attempts, although this risk may differ among patients. Thus, we aimed to identify trajectories of SI in a 2-years follow-up FEP cohort and to assess baseline predictors and clinical/functional evolution for each trajectory of SI. Methods We included 334 FEP participants with data on SI. Growth mixture modeling was used to identify trajectories of SI. Putative sociodemographic, clinical, and cognitive predictors of the distinct trajectories were examined using multinomial logistic regression. Results We identified three distinct trajectories: Non-SI trajectory (85.53% sample), Improving SI trajectory (9.58%), and Worsening SI trajectory (6.89%). Multinomial logistic regression model revealed that greater baseline pessimistic thoughts, anhedonia, and worse perceived family environment were associated with higher baseline SI followed by an Improving trajectory. Older age, longer duration of untreated psychosis, and reduced sleep predicted Worsening SI trajectory. Regarding clinical/functional evolution, individuals within the Improving SI trajectory displayed moderate depression at baseline which ameliorated during the study period, while the Worsening SI subgroup exhibited persistent mild depressive symptoms and greater functional impairment at follow-up assessments. Conclusion Our findings delineated three distinct trajectories of SI among participants with FEP, one experiencing no SI, another in which SI might depend on acute depressive symptomatology, and a last subset where SI might be associated with mild but persistent clinical and functional impairments. These data provide insights for the early identification and tailored treatment of suicide in this at-risk population.

Few studies have used a multidimensional approach to describe lifestyle changes among undergraduate students during the COVID-19 pandemic or have included controls. This study aimed to evaluate lifestyle behaviors and mental health of undergraduate students and compare them with an age and sex-matched control group. A cross-sectional web survey using snowball sampling was conducted several months after the beginning of COVID-19 pandemic in Spain. A sample of 221 students was recruited. The main outcome was the total SMILE-C score. Students showed a better SMILE-C score than controls (79.8 + 8.1 vs. 77.2 + 8.3; p < 0.001), although these differences disappeared after controlling for covariates. While groups did not differ in the screenings of depression and alcohol abuse, students reported lower rates of anxiety (28.5% vs. 37.1%; p = 0.042). A lower number of cohabitants, poorer self-perceived health and positive screening for depression and anxiety, or for depression only were independently associated (p < 0.05) with unhealthier lifestyles in both groups. History of mental illness and financial difficulties were predictors of unhealthier lifestyles for students, whereas totally/moderate changes in substance abuse and stress management (p < 0.05) were predictors for the members of the control group. Several months after the pandemic, undergraduate students and other young adults had similar lifestyles.

Objectives Clinical staging is widely used in medicine to map disease progression, inform prognosis, and guide treatment decisions; in psychiatry, however, staging remains a hypothetical construct. To facilitate future research in bipolar disorders (BD), a well-defined nomenclature is needed, especially since diagnosis is often imprecise with blurred boundaries, and a full understanding of pathophysiology is lacking. Methods Under the auspices of the International Society of Bipolar Disorders, a Task Force of international experts was convened to review, discuss, and integrate findings from the scientific literature relevant to the development of a consensus staging model and standardize a terminology that could be used to advance future research including staging of BD and related disorders. Results Consensus opinion and areas of uncertainty or difference were identified in regard to terms referring to staging as it may apply to BD, to at-risk status and subthreshold stages, and to various clinical stages of BD as it is currently diagnosed. Conclusion The use of a standardized nomenclature about the clinical stages of BD will facilitate communication about research on clinical and pathological components of this heterogeneous group of disorders. The concepts presented are based on current evidence, but the template provided allows for further refinements as etiological advances come to light.

BACKGROUND: This study aimed to compare self-reported changes on lifestyle behaviors during two phases of the COVID-19 pandemic in Spain, and to evaluate clinical and sociodemographic factors associated with lifestyles. METHODS: Two cross-sectional web surveys were conducted during lockdown (April 15-May 15, 2020) and seven months later (November 16-December 16, 2020). Lifestyle behaviors were self-reported by a multidimensional scale (SMILE-C). Two separate samples of respondents were analyzed. A multivariate regression model was performed to evaluate the association of SMILE-C scores with demographic and clinical variables. RESULTS: The sample comprised, 3412 participants from the first survey (S1) and in the S1 and 3635 from the second (S2). SMILE-C score decreased across surveys (p

Psychotic disorders typically manifest from late adolescence to early adulthood, and an earlier onset might be associated with greater symptom severity and a worse long-term prognosis. This study aimed to compare the cognitive characteristics of patients with first-episode psychosis (FEP) by their age at onset. We included 298 patients diagnosed with FEP and classified them as having an early onset (EOS), youth onset (YOS), or adult onset (AOS) based on age limits of = 25 years (N = 116), respectively. Socio-demographic and clinical variables included age at baseline, gender, socio-economic status, antipsychotic medication, DSM-IV diagnoses assessed by clinical semi-structured interview, psychotic symptom severity, and age at onset. Neuropsychological assessment included six cognitive domains: premorbid intelligence, working memory, processing speed, verbal memory, sustained attention, and executive functioning. The EOS group had lower scores than the YOS or AOS groups in global cognition, executive functioning, and sustained attention. Although the scores in the YOS group were intermediate to those in the EOS and AOS groups for most cognitive factors, no statistically significant differences were detected between the YOS and AOS groups. Age at onset results in specific patterns of cognitive interference. Of note, impairment appears to be greater with EOS samples than with either YOS or AOS samples. A longitudinal study with a larger sample size is needed to confirm our findings.

Altres ajuts: Fundació "La Caixa" (ID 100010434, LCF/PR/GN18/50310006); European Social Fund; Fondo Europeo de Desarrollo Regional (FEDER); CIBER of Mental Health (CIBERSAM); Generalitat de Catalunya (CERCA Programme); Departament de Salut de la Generalitat de Catalunya (PERIS SLT006/17/00357, SLT006/17/00345); Project B2017/BMD-3740 Ayudas I + D en Biomedicina de la Comunidad de Madrid. The aim of the present study was to evaluate the contribution of family environment styles and psychiatric family history on functioning of patients presenting first-episode psychosis (FEP). Patients with FEP and healthy controls (HC) were assessed at baseline and after 2 years. The Functional Assessment Short Test (FAST) was used to assess functional outcome and the Family Environment Scale (FES) to evaluate family environment. Linear regressions evaluated the effect that family environment exerts on functioning at baseline and at 2-year follow-up, when FEP patients were diagnosed according to non-affective (NA-PSYCH) or affective psychoses (A-PSYCH). The influence of a positive parents' psychiatric history on functioning was evaluated through one-way between-groups analysis of covariance (ANCOVA) models, after controlling for family environmental styles. At baseline, FEP patients presented moderate functioning impairment, significantly worse than HC (28.65±16.17 versus 3.25±7.92; p