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Obesity is highly prevalent and disabling, especially in individuals with severe mental illness including bipolar disorders (BD). The brain is a target organ for both obesity and BD. Yet, we do not understand how cortical brain alterations in BD and obesity interact.
We obtained body mass index (BMI) and MRI-derived regional cortical thickness, surface area from 1231 BD and 1601 control individuals from 13 countries within the ENIGMA-BD Working Group. We jointly modeled the statistical effects of BD and BMI on brain structure using mixed effects and tested for interaction and mediation. We also investigated the impact of medications on the BMI-related associations.
BMI and BD additively impacted the structure of many of the same brain regions. Both BMI and BD were negatively associated with cortical thickness, but not surface area. In most regions the number of jointly used psychiatric medication classes remained associated with lower cortical thickness when controlling for BMI. In a single region, fusiform gyrus, about a third of the negative association between number of jointly used psychiatric medications and cortical thickness was mediated by association between the number of medications and higher BMI.
We confirmed consistent associations between higher BMI and lower cortical thickness, but not surface area, across the cerebral mantle, in regions which were also associated with BD. Higher BMI in people with BD indicated more pronounced brain alterations. BMI is important for understanding the neuroanatomical changes in BD and the effects of psychiatric medications on the brain.
Anorexia nervosa (AN) is a psychiatric disorder with complex etiology, with a significant portion of disease risk imparted by genetics. Traditional genome-wide association studies (GWAS) produce principal evidence for the association of genetic variants with disease. Transcriptomic imputation (TI) allows for the translation of those variants into regulatory mechanisms, which can then be used to assess the functional outcome of genetically regulated gene expression (GReX) in a broader setting through the use of phenome-wide association studies (pheWASs) in large and diverse clinical biobank populations with electronic health record phenotypes.
Here, we applied TI using S-PrediXcan to translate the most recent PGC-ED AN GWAS findings into AN-GReX. For significant genes, we imputed AN-GReX in the Mount Sinai BioMe™ Biobank and performed pheWASs on over 2000 outcomes to test the clinical consequences of aberrant expression of these genes. We performed a secondary analysis to assess the impact of body mass index (BMI) and sex on AN-GReX clinical associations.
Our S-PrediXcan analysis identified 53 genes associated with AN, including what is, to our knowledge, the first-genetic association of AN with the major histocompatibility complex. AN-GReX was associated with autoimmune, metabolic, and gastrointestinal diagnoses in our biobank cohort, as well as measures of cholesterol, medications, substance use, and pain. Additionally, our analyses showed moderation of AN-GReX associations with measures of cholesterol and substance use by BMI, and moderation of AN-GReX associations with celiac disease by sex.
Our BMI-stratified results provide potential avenues of functional mechanism for AN-genes to investigate further.
Response to lithium in patients with bipolar disorder is associated with clinical and transdiagnostic genetic factors. The predictive combination of these variables might help clinicians better predict which patients will respond to lithium treatment.
To use a combination of transdiagnostic genetic and clinical factors to predict lithium response in patients with bipolar disorder.
This study utilised genetic and clinical data (n = 1034) collected as part of the International Consortium on Lithium Genetics (ConLi+Gen) project. Polygenic risk scores (PRS) were computed for schizophrenia and major depressive disorder, and then combined with clinical variables using a cross-validated machine-learning regression approach. Unimodal, multimodal and genetically stratified models were trained and validated using ridge, elastic net and random forest regression on 692 patients with bipolar disorder from ten study sites using leave-site-out cross-validation. All models were then tested on an independent test set of 342 patients. The best performing models were then tested in a classification framework.
The best performing linear model explained 5.1% (P = 0.0001) of variance in lithium response and was composed of clinical variables, PRS variables and interaction terms between them. The best performing non-linear model used only clinical variables and explained 8.1% (P = 0.0001) of variance in lithium response. A priori genomic stratification improved non-linear model performance to 13.7% (P = 0.0001) and improved the binary classification of lithium response. This model stratified patients based on their meta-polygenic loadings for major depressive disorder and schizophrenia and was then trained using clinical data.
Using PRS to first stratify patients genetically and then train machine-learning models with clinical predictors led to large improvements in lithium response prediction. When used with other PRS and biological markers in the future this approach may help inform which patients are most likely to respond to lithium treatment.
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.
To examine the genetic architecture of AAO and PAO and their association with bipolar disorder disease characteristics.
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.
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 (β = −0.34 years, s.e. = 0.08), major depression (β = −0.34 years, s.e. = 0.08), schizophrenia (β = −0.39 years, s.e. = 0.08), and educational attainment (β = −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.
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.
Cross-sectional studies have found impaired cognitive functioning in patients with bipolar disorder, but long-term longitudinal studies are scarce.
The aims of this study were to examine the 6-year longitudinal course of cognitive functioning in patients with bipolar disorder and healthy controls. Subsets of patients were examined to investigate possible differences in cognitive trajectories.
Patients with bipolar I disorder (n = 44) or bipolar II disorder (n = 28) and healthy controls (n = 59) were tested with a comprehensive cognitive test battery at baseline and retested after 6 years. We conducted repeated measures ANCOVAs with group as a between-subject factor and tested the significance of group and time interaction.
By and large, the change in cognitive functioning between baseline and follow-up did not differ significantly between participants with bipolar disorder and healthy controls. Comparing subsets of patients, for example those with bipolar I and II disorder and those with and without manic episodes during follow-up, did not reveal subgroups more vulnerable to cognitive decline.
Cognitive performance remained stable in patients with bipolar disorder over a 6-year period and evolved similarly to healthy controls. These findings argue against the notion of a general progressive decline in cognitive functioning in bipolar disorder.
Socioeconomic factors can affect healthcare management.
The aim was to investigate if patient educational attainment is associated with management of bipolar disorder.
We included patients with bipolar disorder type 1 (n = 4289), type 2 (n = 4020) and not otherwise specified (n = 1756), from the Swedish National Quality Register for Bipolar Disorder (BipoläR). The association between patients’ educational level and pharmacological and psychological interventions was analysed by binary logistic regression. We calculated odds ratios after adjusting for demographic and clinical variables.
Higher education was associated with increased likelihood of receiving psychotherapy (adjusted odds ratio 1.34, 95% CI 91.22–1.46) and psychoeducation (adjusted odds ratio 1.18, 95% CI 1.07–1.46), but with lower likelihood of receiving first-generation antipsychotics (adjusted odds ratio 0.76, 95% CI 0.62–0.94) and tricyclic antidepressants (adjusted odds ratio 0.76, 95% CI 0.59–0.97). Higher education was also associated with lower risk for compulsory in-patient care (adjusted odds ratio 0.79, 95% CI 0.67–0.93).
Pharmacological and psychological treatment of bipolar disorder differ depending on patients’ educational attainment. The reasons for these disparities remain to be explained.
There have been reports of long-term subjective memory worsening after electroconvulsive therapy (ECT).
To study the prevalence and risk factors of long-term subjective memory worsening among patients receiving ECT in routine clinical practice.
Patients (n = 535, of whom 277 were included in the final analysis) were recruited from eight Swedish hospitals. Participants' subjective memory impairment was assessed before ECT and a median of 73 days after ECT using the memory item from the Comprehensive Psychopathological Rating Scale. Participants also rated their pre-ECT expectations and post-ECT evaluations of the effect of ECT on memory on a 7-point scale. We used ordinal regression to identify variables associated with subjective memory worsening and negative evaluations of the effect of ECT on memory.
Comparisons of pre- and post-ECT assessments showed that subjective memory worsened in 16.2% of participants, remained unchanged in 52.3% and improved in 31.4%. By contrast, when asked to evaluate the effect of ECT on memory after treatment 54.6% reported a negative effect. Subjective memory worsening was associated with negative expectations before ECT, younger age and shorter duration of follow-up.
Although subjective memory improved more often than it worsened when assessed before and after ECT, a majority of patients reported that ECT had negative effects on their memory when retrospectively asked how ECT had affected it. This might suggest that some patients attribute pre-existing subjective memory impairment to ECT. Clinicians should be aware that negative expectations are associated with subjective worsening of memory after ECT.
Variation in the CACNA1C gene has been associated with bipolar disorder in several genome-wide association studies. This gene encodes the alpha 1C subunit of L-type voltage-gated calcium channels, which play an essential role in neurons. We analysed 39 biomarkers in either cerebrospinal fluid or serum in relation to six different CACNA1C variants in 282 patients with bipolar disorder and 90 controls. We report associations of CACNA1C risk alleles with serum levels of BDNF as well as tissue plasminogen activator, which converts pro-BDNF to mature BDNF. This sheds light on links between CACNA1C genetic variants and pathophysiological mechanisms in bipolar disorder.
Electroconvulsive therapy (ECT) is effective for unipolar depression but relapse and suicide are significant challenges. Lithium could potentially lower these risks, but is used only in a minority of patients.
This study quantifies the effect of lithium on risk of suicide and readmission and identifies factors that are associate with readmission and suicide.
This population-based register study used data from the Swedish National Quality Register for ECT and other Swedish national registers. Patients who have received ECT for unipolar depression as in-patients between 2011 and 2016 were followed until death, readmission to hospital or the termination of the study at the end of 2016. Cox regression was used to estimate hazard ratios (HR) of readmission and suicide in adjusted models.
Out of 7350 patients, 56 died by suicide and 4203 were readmitted. Lithium was prescribed to 638 (9%) patients. Mean follow-up was 1.4 years. Lithium was significantly associated with lower risk of suicide (P = 0.014) and readmission (HR 0.84 95% CI 0.75–0.93). The number needed to be treated with lithium to prevent one readmission was 16. In addition, the following factors were statistically associated with suicide: male gender, being a widow, substance use disorder and a history of suicide attempts. Readmission was associated with young age, being divorced or unemployed, comorbid anxiety disorder, nonpsychotic depression, more severe symptoms before ECT, no improvement with ECT, not receiving continuation ECT or antidepressants, usage of antipsychotics, anxiolytics or benzodiazepines, severity of medication resistance and number of previous admissions.
More patients could benefit from lithium treatment.
The efficacy of psychoeducation for bipolar disorder has been demonstrated in clinical trials, but it is not known if the results translate into effectiveness in routine clinical practice. The aim was to determine the effectiveness of psychoeducation for bipolar disorder in a routine clinical setting.
We identified 2819 patients with at least three registrations in the Swedish Quality Assurance Register for Bipolar Disorder. Among those, 402 had not been exposed to psychoeducation at the first visit, but received psychoeducation during any of the following registrations. Using within-individual analyses, the risk of recurrence after having received psychoeducation was compared with the risk prior to psychoeducation.
In adjusted within-individuals comparisons, periods after psychoeducation was associated with decreased risks of any recurrence [odds ratio (OR) 0.57, 95% CI 0.42–0.78], (hypo-)manic or mixed episodes (OR 0.54, 95% CI 0.39–0.76), depressive episodes (OR 0.63, 95% CI 0.47–0.86), and inpatient care (OR 0.54, 95% CI 0.33–0.86) relative to periods prior to psychoeducation. There was no association with rates of involuntary sectioning or suicide attempts.
The results suggest that psychoeducation for bipolar disorder reduces the risk of mood episodes and inpatient care also when implemented in routine clinical practice.
Maternal polycystic ovary syndrome (PCOS) has been proposed as a model for investigating the role of prenatal androgen exposure in the development of neuropsychiatric disorders. However, women with PCOS are at higher risk of developing psychiatric conditions and previous studies are likely confounded by genetic influences.
A Swedish nationwide register-based cohort study was conducted to disentangle the influence of prenatal androgen exposure from familial confounding in the association between maternal PCOS and offspring attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorders (ASD), and Tourette's disorder and chronic tic disorders (TD/CTD). PCOS-exposed offspring (n = 21 280) were compared with unrelated PCOS-unexposed offspring (n = 200 816) and PCOS-unexposed cousins (n = 17 295). Associations were estimated with stratified Cox regression models.
PCOS-exposed offspring had increased risk of being diagnosed with ADHD, ASD, and TD/CTD compared with unrelated PCOS-unexposed offspring. Associations were stronger in girls for ADHD and ASD but not TD/CTD [ADHD: adjusted hazard ratio (aHR) = 1.61 (95% confidence interval (CI) 1.31–1.99), ASD: aHR = 2.02 (95% CI 1.45–2.82)] than boys [ADHD: aHR = 1.37 (95% CI 1.19–1.57), ASD: aHR = 1.46 (95% CI 1.21–1.76)]. For ADHD and ASD, aHRs for girls were stronger when compared with PCOS-unexposed cousins, but slightly attenuated for boys.
Estimates were similar when accounting for familial confounding (i.e. genetics and environmental factors shared by cousins) and stronger in girls for ADHD and ASD, potentially indicating a differential influence of prenatal androgen exposure v. genetic factors. These results strengthen evidence for a potential causal influence of prenatal androgen exposure on the development of male-predominant neuropsychiatric disorders in female offspring of women with PCOS.
Clinical trials have examined the efficacy of drugs to prevent relapse in
patients with bipolar disorder, however, their design often limits
generalisation to routine clinical practice.
To estimate the effectiveness of drugs used for maintenance treatment in
We used national registers to identify 35022 individuals diagnosed with
bipolar disorder and information on lithium, valproate, carbamazepine,
lamotrigine, quetiapine and olanzapine treatment from 2006 to 2009. The
main outcome was psychiatric hospital admissions. We used stratified cox
regression to compare periods on and off medication within the same
Medication with lithium, valproate, lamotrigine, olanzapine and
quetiapine was associated with reduced rates of admission to hospital.
Lithium was more effective than quetiapine and olanzapine. The effects of
specific drugs depended on the polarity of the mood episode.
Our findings complement results from randomised controlled trails, but
suggest that lithium is more effective than both quetiapine and
olanzapine in routine clinical practice.
Bipolar disorder is a highly heritable polygenic disorder. Recent
enrichment analyses suggest that there may be true risk variants for
bipolar disorder in the expression quantitative trait loci (eQTL) in the
We sought to assess the impact of eQTL variants on bipolar disorder risk
by combining data from both bipolar disorder genome-wide association
studies (GWAS) and brain eQTL.
To detect single nucleotide polymorphisms (SNPs) that influence
expression levels of genes associated with bipolar disorder, we jointly
analysed data from a bipolar disorder GWAS (7481 cases and 9250 controls)
and a genome-wide brain (cortical) eQTL (193 healthy controls) using a
Bayesian statistical method, with independent follow-up replications. The
identified risk SNP was then further tested for association with
hippocampal volume (n = 5775) and cognitive performance
(n = 342) among healthy individuals.
Integrative analysis revealed a significant association between a brain
eQTL rs6088662 on chromosome 20q11.22 and bipolar disorder (log Bayes
factor = 5.48; bipolar disorder P =
5.85×10–5). Follow-up studies across multiple independent
samples confirmed the association of the risk SNP (rs6088662) with gene
expression and bipolar disorder susceptibility (P =
3.54×10–8). Further exploratory analysis revealed that
rs6088662 is also associated with hippocampal volume and cognitive
performance in healthy individuals.
Our findings suggest that 20q11.22 is likely a risk region for bipolar
disorder; they also highlight the informative value of integrating
functional annotation of genetic variants for gene expression in
advancing our understanding of the biological basis underlying complex
disorders, such as bipolar disorder.
Several genome-wide association studies and case–control studies have
associated the single nucleotide polymorphism (SNP) rs1006737, situated in
CACNA1C encoding the alpha 1C subunit of the L-type
voltage-gated calcium channel, with bipolar disorder and other psychiatric
disorders. However, the causal pathway linking genetic variants in
CACNA1C with increased risk for developing brain
disorders remains unclear. Here, we explored the association between the
rs1006737 SNP and cerebrospinal fluid (CSF) markers. We found a significant
association between the risk allele in rs1006737 and a decreased CSF
hyperphosphorylated tau/total tau ratio in patients with bipolar disorder,
thus linking variation in the CACNA1C gene to a
neurochemical marker of neuroaxonal plasticity in those with this
Acute intermittent porphyria (AIP) has been associated with schizophrenia in
some studies, but prior research is limited by the absence of comparison
populations. Here, we linked Swedish registers to examine the risk of
schizophrenia and bipolar disorder in 717 individuals diagnosed with AIP and
their first-degree relatives, compared with matched individuals without AIP
and their first-degree relatives. Individuals with AIP had a fourfold
increased risk of schizophrenia or bipolar disorder. Similarly, relatives of
individuals with AIP had double the risk of schizophrenia or bipolar
disorder, suggesting that these associations may be as a result of common
Premenstrual dysphoria (PMD) is a severe form of premenstrual syndrome, causing a marked reduction in the quality of life for about 5% of all women of fertile age. The cardinal symptoms are irritability and anger, which surface regularly between ovulation and menstruation and disappear completely within a few days after the onset of menstruation. Other frequent symptoms are depressed mood, affect lability, tension, and carbohydrate craving. In placebo-controlled trials, the serotonin reuptake inhibitors (SRIs) clomipramine, fluoxetine, sertraline, paroxetine, and citalopram have proven very effective for PMD, with a response rate of 60% or higher; in contrast, nonserotonergic antidepressants are not effective. The onset of action of SRIs is rapid, allowing for intermittent administration during luteal phases only. The impressive effect of SRIs for PMD is probably not equivalent to the antidepressant effect of these drugs, but is more likely to be a manifestation of the well-established influence of serotonin on aggression and irritability. It strongly reinforces the assumption that a major function of serotonergic neurons in the brain is to modulate sex-steroid—driven behavior.
Neurodevelopmental disorders affect a substantial minority of the general population. Their origins are still largely unknown, but a complex interplay of genetic and environmental factors causing disturbances of the central nervous system's maturation and a variety of higher cognitive skills is presumed. Only limited research of rather small sample size and narrow scope has been conducted in neurodevelopmental disorders using a twin-differences design. The Roots of Autism and ADHD Twin Study in Sweden (RATSS) is an ongoing project targeting monozygotic twins discordant for categorical or dimensional autistic and inattentive/hyperactive-impulsive phenotypes as well as other neurodevelopmental disorders, and typically developing twin controls. Included pairs are 9 years of age or older, and comprehensively assessed for psychopathology, medical history, neuropsychology, and dysmorphology, as well as structural, functional, and molecular brain imaging. Specimens are collected for induced pluripotent (iPS) and neuroepithelial stem cells, genetic, gut bacteria, protein-/monoamine, and electron microscopy analyses. RATSS's objective is to generate a launch pad for novel surveys to understand the complexity of genotype-environment-phenotype interactions in autism spectrum disorder and attention-deficit hyperactivity disorder (ADHD). By October 2013, RATSS had collected data from 55 twin pairs, among them 10 monozygotic pairs discordant for autism spectrum disorder, seven for ADHD, and four for other neurodevelopmental disorders. This article describes the design, recruitment, data collection, measures, collected pairs’ characteristics, as well as ongoing and planned analyses in RATSS. Potential gains of the study comprise the identification of environmentally mediated biomarkers, the emergence of candidates for drug development, translational modeling, and new leads for prevention of incapacitating outcomes.
Attention-deficit hyperactivity disorder (ADHD) is associated with bipolar disorder and schizophrenia, and it has been suggested that combined bipolar disorder and ADHD is aetiologically distinct from the pure disorders.
To clarify whether ADHD shares genetic and environmental factors with bipolar disorder and schizophrenia.
By linking longitudinal Swedish national registers, we identified 61 187 persons with ADHD (the proband group) and their first- and second-degree relatives, and matched them with a control group of people without ADHD and their corresponding relatives. Conditional logistic regression was used to determine the risks of bipolar disorder and schizophrenia in the relatives of the two groups.
First-degree relatives of the ADHD proband group were at increased risk of both bipolar disorder (odds ratio (OR) = 1.84−2.54 for parents, offspring and full siblings) and schizophrenia (OR = 1.71−2.22 for parents, offspring and full siblings). The risks of bipolar disorder and schizophrenia among second-degree relatives were substantially lower than among full siblings.
These findings suggest that the co-occurrence of ADHD and bipolar disorder as well as ADHD and schizophrenia is due to shared genetic factors, rather than representing completely aetiologically distinct subsyndromes.
Motor retardation is a characteristic feature of bipolar depression, and is also a core feature of Parkinson's disease. Within the framework of the functional deafferentiation theory in Parkinson's disease, we hypothesised that motor retardation in bipolar depression is mediated by disrupted subcortical activation, leading to decreased activation of cortical motor areas during finger tapping.
We used functional magnetic resonance imaging to investigate neural activity during self-paced finger tapping to elucidate whether brain regions that mediate preparation, control and execution of movement are activated differently in subjects with bipolar depression (n = 9) compared to healthy controls (n = 12).
An uncorrected whole-brain analysis revealed significant group differences in dorsolateral and ventromedial prefrontal cortex. Corrected analyses showed non-significant differences in patients compared to controls: decreased and less widespread activation of the left putamen and left pallidum; increased activity in the left thalamus and supplementary motor area; decreased activation in the left lateral pre- and primary motor cortices; absence of activation in the pre-supplementary motor area; activation of the bilateral rostral cingulate motor area.
Both movement preparation and execution may be affected in motor retardation, and the activity in the whole left-side motor circuit is altered during self-initiated motor performance in bipolar depression.