The Mood and Resilience in Offspring (MARIO) project: a longitudinal cohort study among offspring of parents with and without a mood disorder.

BACKGROUND: One of the most robust risk factors for developing a mood disorder is having a parent with a mood disorder. Unfortunately, mechanisms explaining the transmission of mood disorders from one generation to the next remain largely elusive. Since timely intervention is associated with a better outcome and prognosis, early detection of intergenerational transmission of mood disorders is of paramount importance. Here, we describe the design of the Mood and Resilience in Offspring (MARIO) cohort study in which we investigate: 1. differences in clinical, biological and environmental (e.g., psychosocial factors, substance use or stressful life events) risk and resilience factors in children of parents with and without mood disorders, and 2. mechanisms of intergenerational transmission of mood disorders via clinical, biological and environmental risk and resilience factors. METHODS: MARIO is an observational, longitudinal cohort study that aims to include 450 offspring of parents with a mood disorder (uni- or bipolar mood disorders) and 100-150 offspring of parents without a mood disorder aged 10-25 years. Power analyses indicate that this sample size is sufficient to detect small to medium sized effects. Offspring are recruited via existing Dutch studies involving patients with a mood disorder and healthy controls, for which detailed clinical, environmental and biological data of the index-parent (i.e., the initially identified parent with or without a mood disorder) is available. Over a period of three years, four assessments will take place, in which extensive clinical, biological and environmental data and data on risk and resilience are collected through e.g., blood sampling, face-to-face interviews, online questionnaires, actigraphy and Experience Sampling Method assessment. For co-parents, information on demographics, mental disorder status and a DNA-sample are collected. DISCUSSION: The MARIO cohort study is a large longitudinal cohort study among offspring of parents with and without mood disorders. A unique aspect is the collection of granular data on clinical, biological and environmental risk and resilience factors in offspring, in addition to available parental data on many similar factors. We aim to investigate the mechanisms underlying intergenerational transmission of mood disorders, which will ultimately lead to better outcomes for offspring at high familial risk.

Clinical profiles of subsequent stages in bipolar disorder: Results from the Dutch Bipolar Cohort.

INTRODUCTION: The manifestation of bipolar disorder (BD) is hypothesized to be determined by clinical characteristics such as familial loading, childhood abuse, age at onset, illness duration, comorbid psychiatric disorders, addiction, treatment resistance, and premorbid cognitive functioning. Which of these are associated with a more severe course and worse outcome is currently unknown. Our objective is to find a combination of clinical characteristics associated with advancement to subsequent stages in two clinical staging models for BD. METHODS: Using cross-sectional data from the Dutch Bipolar Cohort, staging was applied to determine the progression of bipolar-I-disorder (BD-I; N = 1396). Model A is primarily defined by recurrence of mood episodes, ranging from prodromal to chronicity. Model B is defined by level of inter-episodic functioning, ranging from prodromal to inability to function autonomously. For both models, ordinal logistic regression was conducted to test which clinical characteristics are associated with subsequent stages. RESULTS: For model A, familial loading, childhood abuse, earlier onset, longer illness duration, psychiatric comorbidity, and treatment resistance were all predictors for a higher stage in contrast to addiction and cognitive functioning. For model B, childhood abuse, psychiatric comorbidity, cognitive functioning, and treatment resistance were predictors for a more severe stage, whereas age at onset, illness duration, and addiction were not. DISCUSSION/CONCLUSIONS: Differences in clinical characteristics across stages support the construct validity of both staging models. Characteristics associated with a higher stage largely overlapped across both models. This study is a first step toward determining different clinical profiles, with a corresponding course and outcome.

Characterisation of age and polarity at onset in bipolar disorder.

BACKGROUND: Studying phenotypic and genetic characteristics of age at onset (AAO) and polarity at onset (PAO) in bipolar disorder can provide new insights into disease pathology and facilitate the development of screening tools. AIMS: To examine the genetic architecture of AAO and PAO and their association with bipolar disorder disease characteristics. METHOD: Genome-wide association studies (GWASs) and polygenic score (PGS) analyses of AAO (n = 12 977) and PAO (n = 6773) were conducted in patients with bipolar disorder from 34 cohorts and a replication sample (n = 2237). The association of onset with disease characteristics was investigated in two of these cohorts. RESULTS: Earlier AAO was associated with a higher probability of psychotic symptoms, suicidality, lower educational attainment, not living together and fewer episodes. Depressive onset correlated with suicidality and manic onset correlated with delusions and manic episodes. Systematic differences in AAO between cohorts and continents of origin were observed. This was also reflected in single-nucleotide variant-based heritability estimates, with higher heritabilities for stricter onset definitions. Increased PGS for autism spectrum disorder (ß = -0.34 years, s.e. = 0.08), major depression (ß = -0.34 years, s.e. = 0.08), schizophrenia (ß = -0.39 years, s.e. = 0.08), and educational attainment (ß = -0.31 years, s.e. = 0.08) were associated with an earlier AAO. The AAO GWAS identified one significant locus, but this finding did not replicate. Neither GWAS nor PGS analyses yielded significant associations with PAO. CONCLUSIONS: AAO and PAO are associated with indicators of bipolar disorder severity. Individuals with an earlier onset show an increased polygenic liability for a broad spectrum of psychiatric traits. Systematic differences in AAO across cohorts, continents and phenotype definitions introduce significant heterogeneity, affecting analyses.

Genetic analysis of activity, brain and behavioral associations in extended families with heavy genetic loading for bipolar disorder.

BACKGROUND: Disturbed sleep and activity are prominent features of bipolar disorder type I (BP-I). However, the relationship of sleep and activity characteristics to brain structure and behavior in euthymic BP-I patients and their non-BP-I relatives is unknown. Additionally, underlying genetic relationships between these traits have not been investigated. METHODS: Relationships between sleep and activity phenotypes, assessed using actigraphy, with structural neuroimaging (brain) and cognitive and temperament (behavior) phenotypes were investigated in 558 euthymic individuals from multi-generational pedigrees including at least one member with BP-I. Genetic correlations between actigraphy-brain and actigraphy-behavior associations were assessed, and bivariate linkage analysis was conducted for trait pairs with evidence of shared genetic influences. RESULTS: More physical activity and longer awake time were significantly associated with increased brain volumes and cortical thickness, better performance on neurocognitive measures of long-term memory and executive function, and less extreme scores on measures of temperament (impulsivity, cyclothymia). These associations did not differ between BP-I patients and their non-BP-I relatives. For nine activity-brain or activity-behavior pairs there was evidence for shared genetic influence (genetic correlations); of these pairs, a suggestive bivariate quantitative trait locus on chromosome 7 for wake duration and verbal working memory was identified. CONCLUSIONS: Our findings indicate that increased physical activity and more adequate sleep are associated with increased brain size, better cognitive function and more stable temperament in BP-I patients and their non-BP-I relatives. Additionally, we found evidence for pleiotropy of several actigraphy-behavior and actigraphy-brain phenotypes, suggesting a shared genetic basis for these traits.

Whole blood transcriptome analysis in bipolar disorder reveals strong lithium effect.

BACKGROUND: Bipolar disorder (BD) is a highly heritable mood disorder with complex genetic architecture and poorly understood etiology. Previous transcriptomic BD studies have had inconsistent findings due to issues such as small sample sizes and difficulty in adequately accounting for confounders like medication use. METHODS: We performed a differential expression analysis in a well-characterized BD case-control sample (Nsubjects = 480) by RNA sequencing of whole blood. We further performed co-expression network analysis, functional enrichment, and cell type decomposition, and integrated differentially expressed genes with genetic risk. RESULTS: While we observed widespread differential gene expression patterns between affected and unaffected individuals, these effects were largely linked to lithium treatment at the time of blood draw (FDR < 0.05, Ngenes = 976) rather than BD diagnosis itself (FDR < 0.05, Ngenes = 6). These lithium-associated genes were enriched for cell signaling and immune response functional annotations, among others, and were associated with neutrophil cell-type proportions, which were elevated in lithium users. Neither genes with altered expression in cases nor in lithium users were enriched for BD, schizophrenia, and depression genetic risk based on information from genome-wide association studies, nor was gene expression associated with polygenic risk scores for BD. CONCLUSIONS: These findings suggest that BD is associated with minimal changes in whole blood gene expression independent of medication use but emphasize the importance of accounting for medication use and cell type heterogeneity in psychiatric transcriptomic studies. The results of this study add to mounting evidence of lithium's cell signaling and immune-related mechanisms.

The characteristics of psychotic features in bipolar disorder.

BACKGROUND: In a large and comprehensively assessed sample of patients with bipolar disorder type I (BDI), we investigated the prevalence of psychotic features and their relationship with life course, demographic, clinical, and cognitive characteristics. We hypothesized that groups of psychotic symptoms (Schneiderian, mood incongruent, thought disorder, delusions, and hallucinations) have distinct relations to risk factors. METHODS: In a cross-sectional study of 1342 BDI patients, comprehensive demographical and clinical characteristics were assessed using the Structured Clinical Interview for DSM-IV (SCID-I) interview. In addition, levels of childhood maltreatment and intelligence quotient (IQ) were assessed. The relationships between these characteristics and psychotic symptoms were analyzed using multiple general linear models. RESULTS: A lifetime history of psychotic symptoms was present in 73.8% of BDI patients and included delusions in 68.9% of patients and hallucinations in 42.6%. Patients with psychotic symptoms showed a significant younger age of disease onset (ß = -0.09, t = -3.38, p = 0.001) and a higher number of hospitalizations for manic episodes (F11 338 = 56.53, p < 0.001). Total IQ was comparable between groups. Patients with hallucinations had significant higher levels of childhood maltreatment (ß = 0.09, t = 3.04, p = 0.002). CONCLUSIONS: In this large cohort of BDI patients, the vast majority of patients had experienced psychotic symptoms. Psychotic symptoms in BDI were associated with an earlier disease onset and more frequent hospitalizations particularly for manic episodes. The study emphasizes the strength of the relation between childhood maltreatment and hallucinations but did not identify distinct subgroups based on psychotic features and instead reported of a large heterogeneity of psychotic symptoms in BD.

Brain network analysis reveals affected connectome structure in bipolar I disorder.

The notion that healthy brain function emerges from coordinated neural activity constrained by the brain's network of anatomical connections--i.e., the connectome--suggests that alterations in the connectome's wiring pattern may underlie brain disorders. Corroborating this hypothesis, studies in schizophrenia are indicative of altered connectome architecture including reduced communication efficiency, disruptions of central brain hubs, and affected "rich club" organization. Whether similar deficits are present in bipolar disorder is currently unknown. This study examines structural connectome topology in 216 bipolar I disorder patients as compared to 144 healthy controls, focusing in particular on central regions (i.e., brain hubs) and connections (i.e., rich club connections, interhemispheric connections) of the brain's network. We find that bipolar I disorder patients exhibit reduced global efficiency (-4.4%, P =0.002) and that this deficit relates (r = 0.56, P < 0.001) to reduced connectivity strength of interhemispheric connections (-13.0%, P = 0.001). Bipolar disorder patients were found not to show predominant alterations in the strength of brain hub connections in general, or of connections spanning brain hubs (i.e., "rich club" connections) in particular (all P > 0.1). These findings highlight a role for aberrant brain network architecture in bipolar I disorder with reduced global efficiency in association with disruptions in interhemispheric connectivity, while the central "rich club" system appears not to be particularly affected.

Real-time personalized feedback in mHealth for adolescents.

Mobile Health (mHealth) interventions have the potential to improve early identification, prevention, and treatment of mental health problems. Grow It! is a multiplayer smartphone app designed for youth aged 12-25, allowing them to monitor their emotions and engage in daily challenges based on Cognitive Behavioral Therapy (CBT) principles. Recently, a personalized mood profile was added to improve the app. We investigated whether real-time personalized feedback on mood enhances app engagement, user experience, and the effects on affective and cognitive well-being. Sample A (N = 1269, age = 18.60 SD = 3.39, 80.6% girls, 95.4% Dutch) played the original app without feedback on their mood, and an independent Sample B (N = 386, age = 16.04 SD = 3.21, 67.6% girls, 82.9% Dutch) received the renewed version with personalized real-time feedback on their mood. Participants who received personal feedback did not have higher app engagement (t(1750,400) = 1.39, P = .206, d = 0.07; t(692,905) = 0.36, P = .971, d = 0.0) nor higher user experience (t(177,596) = 0.21, P = .831, d = 0.02; (t(794) = 1.28, P = .202, d = 0.12; χ2 (659,141) = 2.83, P = .091). Players of the renewed version (Sample B) experienced significant improvements in affective (t(175) = 3.01, P = .003, d = 0.23) and cognitive well-being (t(175) = 3.48, P = <.001, d = 0.26) over the course of three weeks. The renewed version Grow It! has the potential to enhance youths' affective and cognitive well-being. However, adding real-time insights did not seem to affect app engagement nor user experience.

Just-in-time adaptive interventions for adolescent and young adult health and well-being: protocol for a systematic review.

INTRODUCTION: Health behaviours such as exercise and diet strongly influence well-being and disease risk, providing the opportunity for interventions tailored to diverse individual contexts. Precise behaviour interventions are critical during adolescence and young adulthood (ages 10-25), a formative period shaping lifelong well-being. We will conduct a systematic review of just-in-time adaptive interventions (JITAIs) for health behaviour and well-being in adolescents and young adults (AYAs). A JITAI is an emerging digital health design that provides precise health support by monitoring and adjusting to individual, specific and evolving contexts in real time. Despite demonstrated potential, no published reviews have explored how JITAIs can dynamically adapt to intersectional health factors of diverse AYAs. We will identify the JITAIs' distal and proximal outcomes and their tailoring mechanisms, and report their effectiveness. We will also explore studies' considerations of health equity. This will form a comprehensive assessment of JITAIs and their role in promoting health behaviours of AYAs. We will integrate evidence to guide the development and implementation of precise, effective and equitable digital health interventions for AYAs. METHODS AND ANALYSIS: In adherence to Preferred Reporting Items for Systematic Review and Meta-Analysis guidelines, we will conduct a systematic search across multiple databases, including CENTRAL, MEDLINE and WHO Global Index Medicus. We will include peer-reviewed studies on JITAIs targeting health of AYAs in multiple languages. Two independent reviewers will conduct screening and data extraction of study and participant characteristics, JITAI designs, health outcome measures and equity considerations. We will provide a narrative synthesis of findings and, if data allows, conduct a meta-analysis. ETHICS AND DISSEMINATION: As we will not collect primary data, we do not require ethical approval. We will disseminate the review findings through peer-reviewed journal publication, conferences and stakeholder meetings to inform participatory research. PROSPERO REGISTRATION NUMBER: CRD42023473117.

A Smartphone Serious Game for Adolescents (Grow It! App): Development, Feasibility, and Acceptance Study.

BACKGROUND: Anxiety and mood problems in adolescents often go unnoticed and may therefore remain untreated. Identifying and preventing the development of emotional problems requires monitoring and effective tools to strengthen adolescents' resilience, for example, by enhancing coping skills. OBJECTIVE: This study describes the developmental process, feasibility, and acceptance of Grow It!, a multiplayer serious game app for adolescents aged 12-25 years. The app consists of the experience sampling method (ESM) to monitor thoughts, behaviors, and emotions in daily life to enhance self-insight and daily cognitive behavioral therapy-based challenges to promote adaptive coping. METHODS: Our approach entails an iterative game design process combined with an agile method to develop the smartphone app. The incorporated game features (ie, challenges, chat functionality, and visual representation) in the Grow It! app were co-designed with adolescent end users to increase participant engagement and adherence. RESULTS: The Grow It! app was delivered for Android and iOS in May 2020. Grow It! was offered to adolescents during the COVID-19 crisis between May and December 2020. Participants of the Grow It! COVID-19 study (sample 1: N=685; mean age 16.19, SD 3.11 years; 193/685, 28.2% boys; sample 2: N=1035; mean age 18.78, SD 3.51 years; 193/1035, 18.64% boys) completed 31.5% (13.2/42) to 49.5% (10.4/21) of challenges. Compliance of ESM was suboptimal (35.1/210, 16.7% to 32.5/105, 30.9%). Follow-up questionnaires indicated an overall score of the app of 7.1 out of 10. Moreover, 72.6% (278/383) to 75.6% (487/644) would recommend the app to friends. CONCLUSIONS: To our knowledge, Grow It! is the first gamified ESM app that both measures individual differences in emotional dynamics and offers an integrated cognitive behavioral therapy-based intervention. Our findings support the feasibility and acceptance, and therefore applicability, of the Grow It! app in adolescents. Further iterations of this serious game app will focus on the increase of compliance and on providing participants feedback through their personal mood profiles.

Exome sequencing in bipolar disorder identifies AKAP11 as a risk gene shared with schizophrenia.

We report results from the Bipolar Exome (BipEx) collaboration analysis of whole-exome sequencing of 13,933 patients with bipolar disorder (BD) matched with 14,422 controls. We find an excess of ultra-rare protein-truncating variants (PTVs) in patients with BD among genes under strong evolutionary constraint in both major BD subtypes. We find enrichment of ultra-rare PTVs within genes implicated from a recent schizophrenia exome meta-analysis (SCHEMA; 24,248 cases and 97,322 controls) and among binding targets of CHD8. Genes implicated from genome-wide association studies (GWASs) of BD, however, are not significantly enriched for ultra-rare PTVs. Combining gene-level results with SCHEMA, AKAP11 emerges as a definitive risk gene (odds ratio (OR) = 7.06, P = 2.83 × 10-9). At the protein level, AKAP-11 interacts with GSK3B, the hypothesized target of lithium, a primary treatment for BD. Our results lend support to BD's polygenicity, demonstrating a role for rare coding variation as a significant risk factor in BD etiology.

Resilience and mental health in children and adolescents: an update of the recent literature and future directions.

PURPOSE OF REVIEW: In order to promote optimal development of children and adolescents at risk for psychiatric disorders, a better understanding of the concept resilience is crucial. Here, we provide an overview of recent work on clinical and epidemiological correlates of resilience and mental health in children and adolescents. RECENT FINDINGS: Our systematic literature search revealed 25 studies that unanimously show that higher levels of resilience are related to fewer mental health problems, despite the heterogeneity of study populations and instruments. Correlates of resilience included multisystem factors, such as social, cultural, family and individual aspects, which is in line with the multisystem approach as described by recent resilience theories. Longitudinal studies are scarce but confirm the dynamical character of resilience and mental health. The application of longitudinal studies and innovative measurement techniques will improve our understanding on the cascade effects of stressors on resilience and mental health outcomes. SUMMARY: Resilience is strongly associated with mental health in children and adolescents and deserves a more prominent role in research, prevention programs and routine clinical care. Including social, cultural and family context in the evaluation of resilience is of great value, as this can identify targets for early and preventive interventions.

Bipolar episodes after reproductive events in women with bipolar I disorder, A study of 919 pregnancies.

BACKGROUND: Women with bipolar I disorder are at high risk for severe episodes after childbirth, but there is no study that provides an overview on bipolar episode risk both during pregnancy and after childbirth, miscarriage and induced abortion. The aim of this study was to determine the episode risk during all pregnancy outcomes subdivided by first and subsequent pregnancies. METHODS: Participants were 436 women with bipolar I disorder from the Dutch Bipolar Cohort, having 919 pregnancies of which 762 resulted in a live childbirth, 118 ended in a miscarriage and 39 ended in induced abortion. Women reported on the occurrence of manic or depressed episodes during the perinatal period. Information about medication use was obtained by questionnaires. RESULTS: Episode risk was 5.2% during pregnancy, and 30.1% in the postpartum period, with a peak in the early postpartum period. Risk of an episode was highest after live birth (34.4%), and lower after miscarriage (15.2%) and induced abortion (27.8%). Women with an episode during pregnancy or postpartum were less likely to have a second child compared to women with an uneventful first pregnancy (cOR=0.34; 95%CI: 0.22-0.51; p<0.001); if they had a second child their risk of an episode was significantly elevated with a subsequent pregnancy (cOR=6.17; 95%CI: 3.64-10.45; p<0.001). LIMITATIONS: Retrospective cross-sectional design with assessment (partial) through self-report in a homogeneous population. CONCLUSIONS: Women with bipolar I disorder have a six times higher risk of an episode after delivery compared to during pregnancy, therefore preventive strategies are particularly important immediately after delivery.

Comparing ecstasy users and non-users in a population-based and co-twin control design across multiple traits.

OBJECTIVE: Ecstasy is one of the most commonly used illicit substances in Western countries. The aim of this study is to identify characteristics of ecstasy users in a large population-based sample of adults aged 18-45 years. METHOD: With generalized estimating equation models we explored the association between self-reported lifetime ecstasy use and urbanicity, educational attainment, health, wellbeing, stress, other substance use, personality traits and psychopathology in a Dutch twin sample (N = 9578, 66.8% female, 18-45 years). We also explored the nature of the association (underlying genetic factors, shared environmental factors or a causal relationship) with the co-twin control method. RESULTS: Lifetime ecstasy users (N = 945, 9.9%) were more often male, younger, living more often in urban areas, higher educated, less satisfied with life and more stressed than non-users. Ecstasy users scored differently on most personality and psychopathology scales compared to non-users and were more likely to have used every other substance we investigated. Whereas smoking tobacco and alcohol use often preceded first use of ecstasy, first ecstasy use often preceded first use of other illicit substances. A combination of scenarios (both causal and environmental/genetic) explained the strong associations between ecstasy and substance use. CONCLUSIONS: Ecstasy users differ on many characteristics from non-users, and especially on illicit substance use. Our results indicate that causal effects may play a role in explaining the relationship between ecstasy use and other illicit substance use.

Higher cortisol levels may proceed a manic episode and are related to disease severity in patients with bipolar disorder.

BACKGROUND: Regulation of the hypothalamic-pituitary-adrenal (HPA) axis is implicated in the pathogenesis of bipolar disorder (BD). However, the relationship between HPA-activity and disease severity is not fully elucidated. In this pilot study we aimed to explore the temporal relationship between HPA-activity and the risk of a manic episode in BD patients type I, by assessing long-term hair cortisol concentrations (HCC). Second, we explored the relation between HCC and the number of previous episodes. METHODS: Hair samples were collected from 45 BD I patients in euthymic or manic state and compared to 17 controls. From each participant, two hair samples of 3 cm length were used to measure long-term cortisol, reflecting retrospect time frames of 1-3 months and 4-6 months respectively prior to sampling. RESULTS: HCC in the BD group was slightly higher than in the control group in both hair segments (p = 0.049 and 0.03; after adjustment for age, sex, BMI and hair washing frequency p = 0.222 and 0.139). A significant peak in hair cortisol was observed prior to a manic episode (p = 0.036). Furthermore, we found a positive correlation between the number of mood episodes HCC (p = 0.03). CONCLUSIONS: Our results indicate that long-term cortisol levels are slightly higher in BD, and in particular elevated in the months prior to a manic relapse. In addition HCC are positively associated with the number of previous mood episodes in the course of BD type I.

Lithium Use during Pregnancy and the Risk of Miscarriage.

Recent studies have provided new data on the teratogenicity of lithium. Less is known about the risk of miscarriage after lithium use during pregnancy. The aim of this study was to investigate the association between lithium use during pregnancy and miscarriage. Participants were women with bipolar I disorder and one or more pregnancies, of which information on medication use and pregnancy outcome was available (n = 443). The unadjusted odds ratios for miscarriage after lithium use during pregnancy was calculated. Multilevel logistic regression was used to calculate the odds ratio, adjusted for the age at conception and the clustering of pregnancies per woman. Miscarriages occurred in 20.8% of the lithium-exposed pregnancies (16/77), compared with 10.9% of the unexposed pregnancies (40/366) (OR = 2.14; 95% CI: 1.13-4.06). The adjusted odds ratio of miscarriage after lithium use during pregnancy was 2.94 (95% CI: 1.39-6.22). Lithium use during pregnancy may increase the risk of miscarriage.

Extensions of Multiple-Group Item Response Theory Alignment: Application to Psychiatric Phenotypes in an International Genomics Consortium.

Large-scale studies spanning diverse project sites, populations, languages, and measurements are increasingly important to relate psychological to biological variables. National and international consortia already are collecting and executing mega-analyses on aggregated data from individuals, with different measures on each person. In this research, we show that Asparouhov and Muthén's alignment method can be adapted to align data from disparate item sets and response formats. We argue that with these adaptations, the alignment method is well suited for combining data across multiple sites even when they use different measurement instruments. The approach is illustrated using data from the Whole Genome Sequencing in Psychiatric Disorders consortium and a real-data-based simulation is used to verify accurate parameter recovery. Factor alignment appears to increase precision of measurement and validity of scores with respect to external criteria. The resulting parameter estimates may further inform development of more effective and efficient methods to assess the same constructs in prospectively designed studies.

Psychopathological symptoms associated with synthetic cannabinoid use: a comparison with natural cannabis.

BACKGROUND: Synthetic cannabinoids (SCs) are a class of new psychoactive substances that have been rapidly evolving around the world throughout recent years. Many different synthetic cannabinoid analogues are on the consumer market and sold under misleading names, like "spice" or "incense." A limited number of studies have reported serious health effects associated with SC use. In this study, we compared clinical and subclinical psychopathological symptoms associated with SC use and natural cannabis (NC) use. METHODS: A convenience sample of 367 NC and SC users was recruited online, including four validated psychometric questionnaires: The Drug Use Disorders Identification Test (DUDIT), Insomnia Severity Index (ISI), Altman Mania Scale (Altman), and Brief Symptom Inventory (BSI). The two groups were compared with analysis of variance (ANOVA) and covariance (ANCOVA), chi2 tests, and logistic regression when appropriate. RESULTS: The SC user group did not differ in age from the NC user group (27.7 years), but contained less females (21% and 30%, respectively). SC users scored higher than NC users on all used psychometric measures, indicating a higher likelihood of drug abuse, sleep problems, (hypo)manic symptoms, and the nine dimensions comprising the BSI, somatization, obsessive-compulsive behavior, interpersonal sensitivity, depression, anxiety, hostility, phobic anxiety, paranoid ideation, and psychoticism. Odds ratios (95% CI) for the SC user group vs NC user group were, respectively, drug dependence 3.56 (1.77-7.16), (severe) insomnia 5.01 (2.10-11.92), (hypo-)mania 5.18 (2.04-13.14), and BSI psychopathology 5.21 (2.96-9.17). DISCUSSION: This study shows that SC use is associated with increased mental health symptomatology compared to NC use.

White matter disruptions in patients with bipolar disorder.

Bipolar disorder (BD) patients show aberrant white matter microstructure compared to healthy controls but little is known about the relation with clinical characteristics. We therefore investigated the relation of white matter microstructure with the main pharmacological treatments as well its relation with IQ. Patients with BD (N = 257) and controls (N = 167) underwent diffusion tensor imaging (DTI) and comprehensive clinically assessments including IQ estimates. DTI images were analyzed using tract-based spatial statistics. Fractional anisotropy (FA) and Mean Diffusivity (MD) were determined. Patients had significantly lower FA and higher MD values throughout the white matter skeleton compared to controls. Within the BD patients, lithium use was associated with higher FA and lower MD. Antipsychotic medication use in the BD patients was not associated with FA but, in contrast to lithium, was associated with higher MD. IQ was significantly positively correlated with FA and negatively with MD in patients as well as in controls. In this large DTI study we found evidence for marked differences in FA and MD particularly in (but not restricted to) corpus callosum, between BD patients and controls. This effect was most pronounced in lithium-free patients, implicating that lithium affects white matter microstructure and attenuates differences associated with bipolar disorder. Effects of antipsychotic medication intake were absent in FA and only subtle in MD relative to those of lithium. The abnormal white matter microstructure was associated with IQ but not specifically for either group.

Is online information on ecstasy tablet content safe?

BACKGROUND AND AIMS: In recent years, the prevalence of ecstasy use has increased in most European countries. Users can acquire information on ecstasy tablet composition through the internet. This study compares online information from two websites, Pillreports and Partyflock, to the validated Dutch Drugs Information and Monitoring System (DIMS) database, and aims to measure its accuracy and potential danger or value. DESIGN, SETTING, PARTICIPANTS: The drug-related information posted on Pillreports.net and Partyflock.nl between 1 January 2014 and 31 December 2015 was investigated for accuracy and several information characteristics such as picture inclusion and dose range inclusion. In total, 471 informatory statements on ecstasy tablet content were analysed relative to the Dutch ecstasy market. MEASUREMENTS: Informatory statements on the content of specific ecstasy tablets were scored as 'too high' or 'too low' if their concentrations deviated > 10 mg from the entries in the DIMS database within a 12-week time-frame, and scored as 'dangerous' if their concentration was > 40 mg too low. Unreported substances were scored as 'dangerous' if listed as an illegal or dangerous substance in the DIMS database and if present in relevant quantities. Also scored were the report characteristics 'picture inclusion', 'spread inclusion' and 'website source', which were tested for their association with report safety/danger. FINDINGS: On average, reports on ecstasy tablets from Pillreports and Partyflock show concentrations which are 10.6 mg too high [95% confidence interval (CI) = 6.7-14.4]. Qualitatively, 39.7% of the reports scored as 'too high' (95% CI = 35.2-44.4), 17.6% scored as 'too low' (95% CI = 14.0-21.2) and 15.5% had 'unreported substances' (95% CI = 12.3-18.9), resulting overall in 15.3% of the reports being scored as 'dangerous' (95% CI = 11.9-18.5). The report characteristic 'spread inclusion' associated inversely with report danger [Exp(b) = 0.511, 95% CI = 0.307-0.850, P = 0.01]. CONCLUSION: Information from the popular Pillreports and Partyflock websites tends to overestimate 3,4-methylenedioxymethamphetamine (MDMA) concentrations in ecstasy tablets. In addition, 15.3% of the reports omit the relevant concentration spread, fail to report additional illegal or dangerous substances contained in the tablets or underestimate MDMA concentration by > 40 mg.