Genetic analysis of the PCSK9 locus in psychological, psychiatric, metabolic and cardiovascular traits in UK Biobank.

The association between severe mental illness (SMI) and cardiovascular and metabolic disease (CMD) is poorly understood. PCSK9 is expressed in systems critical to both SMI and CMD and influences lipid homeostasis and brain function. We systematically investigated relationships between genetic variation within the PCSK9 locus and risk for both CMD and SMI. UK Biobank recruited ~500,000 volunteers and assessed a wide range of SMI and CMD phenotypes. Initially we used genetic data from white British ancestry individuals of UK Biobank. Genetic association analyses were conducted in PLINK, with statistical significance defined by the number of independent SNPs. Conditional analyses and linkage disequilibrium assessed the independence of SNPs and the presence of multiple signals. Two genetic risk scores of lipid-lowering alleles were calculated and used as proxies for putative lipid-lowering effects of PCSK9. PCSK9 variants were associated with central adiposity, venous thrombosis embolism, systolic blood pressure, mood instability, and neuroticism (all p<1.16x10-4). No secondary signals were identified. Conditional analyses and high linkage disequilibrium (r2 =0.98) indicated that mood instability and central obesity may share a genetic signal, which was confirmed using trans-ancestry data from UK Biobank. Genetic risk scores suggested that the lipid-lowering effects of PCSK9 may be causal for greater mood instability and higher neuroticism. This is the first study to implicate the PCSK9 locus in mood-disorder symptoms and related traits, as well as the shared pathology of SMI and CMD. PCSK9 effects on mood may occur via lipid-lowering mechanisms. Further work is needed to understand whether repurposing PCSK9-targeting therapies might improve SMI symptoms and prevent CMD.

The Neurometabolic Basis of Mood Instability: The Parvalbumin Interneuron Link—A Systematic Review and Meta-Analysis

The neurobiological bases of mood instability are poorly understood. Neuronal network alterations and neurometabolic abnormalities have been implicated in the pathophysiology of mood and anxiety conditions associated with mood instability and hence are candidate mechanisms underlying its neurobiology. Fast-spiking parvalbumin GABAergic interneurons modulate the activity of principal excitatory neurons through their inhibitory action determining precise neuronal excitation balance. These interneurons are directly involved in generating neuronal networks activities responsible for sustaining higher cerebral functions and are especially vulnerable to metabolic stress associated with deficiency of energy substrates or mitochondrial dysfunction. Parvalbumin interneurons are therefore candidate key players involved in mechanisms underlying the pathogenesis of brain disorders associated with both neuronal networks’ dysfunction and brain metabolism dysregulation. To provide empirical support to this hypothesis, we hereby report meta-analytical evidence of parvalbumin interneurons loss or dysfunction in the brain of patients with Bipolar Affective Disorder (BPAD), a condition primarily characterized by mood instability for which the pathophysiological role of mitochondrial dysfunction has recently emerged as critically important. We then present a comprehensive review of evidence from the literature illustrating the bidirectional relationship between deficiency in mitochondrial-dependent energy production and parvalbumin interneuron abnormalities. We propose a mechanistic explanation of how alterations in neuronal excitability, resulting from parvalbumin interneurons loss or dysfunction, might manifest clinically as mood instability, a poorly understood clinical phenotype typical of the most severe forms of affective disorders. The evidence we report provides insights on the broader therapeutic potential of pharmacologically targeting parvalbumin interneurons in psychiatric and neurological conditions characterized by both neurometabolic and neuroexcitability abnormalities.

Mood instability, depression, and anxiety in pregnancy and adverse neonatal outcomes

Background Antenatal women experience an increased level of mood and anxiety symptoms, which have negative effects on mothers’ mental and physical health as well as the health of their newborns. The relation of maternal depression and anxiety in pregnancy with neonate outcomes is well-studied with inconsistent findings. However, the association between antenatal mood instability (MI) and neonatal outcomes has not been investigated even though antenatal women experience an elevated level of MI. We sought to address this gap and to contribute to the literature about pregnancy neonate outcomes by examining the relationship among antenatal MI, depression, and anxiety and neonatal outcomes. Methods A prospective cohort of women (n = 555) participated in this study at early pregnancy (T1, 17.4 ± 4.9 weeks) and late pregnancy (T2, 30.6 ± 2.7 weeks). The Edinburgh Postnatal Depression Scale (EPDS) was used to assess antenatal depressive symptoms, anxiety was measured by the EPDS anxiety subscale, and mood instability was measured by a visual analogue scale with five questions. These mood states together with stress, social support, as well as lifestyle were also examined in relation to neonatal outcomes using chi-square tests and logistic regression models. Results Mood instability, depression, and anxiety were unrelated to adverse neonatal outcomes. Only primiparous status was associated with small for gestational age after Bonferroni correction. Conclusions We report no associations between antenatal mood symptoms including MI, depression, and anxiety and neonatal outcomes. More studies are required to further explore the relationship between antenatal mood instability, depression, and anxiety and neonatal outcomes.

Development and Validation of the Mood Instability Questionnaire-Trait (MIQ-T)

Background and objectives: Mood instability (MI) is a stable trait associated with psychiatric disorders, yet there is a lack of tools to measure MI. The purpose of this study was to develop and validate the Mood Instability Questionnaire-Trait (MIQ-T) to evaluate MI in mood disorder patients. Material and methods: Items were taken from various established questionnaires to create an initial list of MIQ-T questions. Data from 309 psychiatric patients (n = 309; 62 major depressive disorder, 58 bipolar I disorder, and 189 bipolar II disorder) were gathered from their medical records and were utilized in an exploratory factor analysis to clarify the underlying components of MI. Then, anonymous survey data from 288 individuals from the general population were included in the analysis as a comparison group. Associations between MIQ-T and other previously validated clinical instruments for mood disorders were examined to test external validity. Results: The exploratory factor analysis demonstrated that the five-factor structure (Lability, Upward Tendency, Downward Tendency, Childhood Instability, and Seasonality) of 59 items was the most appropriate with clear, cohesive features. MIQ-T exhibited high internal consistency (α = 0.96) and moderate to strong correlations with other previously validated clinical instruments, which were consistent with theoretical predictions, providing evidence of criterion validity. Short forms were also created to address the high internal consistency value, which can indicate redundancy, and to increase the approachability of the measure. We found that the patients with bipolar II disorder had higher MIQ-T scores than the patients with bipolar I disorder or major depressive disorder and the comparison group. Conclusion: Together, these findings validate the newly developed MIQ-T as an instrument of mood instability. MIQ-T can be a potential research tool for mood disorder.

Genome-wide association analysis reveals extensive genetic overlap between mood instability and psychiatric disorders but divergent patterns of genetic effects

Mood instability (MOOD) is a transdiagnostic phenomenon with a prominent neurobiological basis. Recent genome-wide association studies found significant positive genetic correlation between MOOD and major depression (DEP) and weak correlations with other psychiatric disorders. We investigated the polygenic overlap between MOOD and psychiatric disorders beyond genetic correlation to better characterize putative shared genetic determinants. Summary statistics for schizophrenia (SCZ, n=105,318), bipolar disorder (BIP, n=413,466), DEP (n=450,619), attention-deficit hyperactivity disorder (ADHD, n=53,293) and MOOD (n=363,705), were analysed using the bivariate causal mixture model and conjunctional false discovery rate methods to estimate the proportion of shared variants influencing MOOD and each disorder, and identify jointly associated genomic loci. MOOD correlated positively with all psychiatric disorders, but with wide variation in strength (rg=0.10-0.62). Of 10.4K genomic variants influencing MOOD, 4K-9.4K were estimated to influence psychiatric disorders. MOOD was jointly associated with DEP at 163 loci, SCZ at 110, BIP at 60 and ADHD at 25, with consistent genetic effects in independent samples. Fifty-three jointly associated loci were overlapping across two or more disorders (transdiagnostic), seven of which had discordant effect directions on psychiatric disorders. Genes mapped to loci associated with MOOD and all four disorders were enriched in a single gene-set, synapse organization. The extensive polygenic overlap indicates shared molecular underpinnings across MOOD and psychiatric disorders. However, distinct patterns of genetic correlation and effect directions of shared loci suggest divergent effects on corresponding neurobiological mechanisms which may relate to differences in the core clinical features of each disorder.

Association of alcohol dependence syndrome with clinical and psychological characteristics of suicidal behavior in individuals with organic mental disorders and aggressive behavior (moral and ethical features)

Purpose of the study: to study the association of alcohol dependence syndrome with the clinical and psychological characteristics of patients with organic mental disorders, aggressive behavior, and suicidal attempts. Materials and methods: we examined 842 patients with organic mental disorders, addictive disorders and aggressive behavior who made a suicide attempt from 1991 to 2018 in the Tyumen region, which were divided into two groups: 1) 421 patients who were diagnosed with an organic mental disorder (in categories F06.6, F06.7, F06. 8, F07.8): 201 men and 220 women; 2) 421 people with organic mental disorders of the above categories and alcohol dependence (F10.242, F10.252, F10.262): 208 men and 213 women. Results and discussion. According to the data of the clinical conversation, the structure of subjective indicators characterizing various disorders of the neuropsychiatric state was described in individuals with high and low levels of factors contributing to the development of suicidal behavior. When assessing the relative risk of factors contributing to the development of suicidal activity, when comparing the indicators of the clinical and mental status of men and women of the studied groups, a 95% confidence interval was determined: mood instability (1.34), psychosomatic complaints (1.03), sleep disorders (1.09), interpersonal interaction problems (1.02), psychopathic (1.48), depressive (1.11) reactions and self-esteem inadequacy (1.05). Conclusions: when comparing the indicators of the neuropsychiatric status in persons with organic mental disorders, aggressive behavior and addictive disorders who have committed suicide attempts, more than half (75.6%) of the examined persons revealed a high level of factors for the development of suicidal activity: 38.0% of women and 37.6% of men. Clinical and psychological parameters were significantly (p < 0.001) characterized by: mood instability (12.4%), difficulties in interpersonal interaction (11.6%), prenosological neurotic (8.5%), psychopathic (8.9%) and depressive (6.2%) reactions. The results obtained can be used to develop effective prevention and rehabilitation measures using digital resources.

Associations between the cortisol awakening response and patient-evaluated stress and mood instability in patients with bipolar disorder: an exploratory study

Objective The Cortisol Awakening Response (CAR) measured as the transient increase in cortisol levels following morning awakening appears to be a distinct feature of the HPA axis. Patients with bipolar disorder (BD) experience daily stress, mood instability (MI) and studies have shown disrupted HPA-axis dynamics. Aims: to evaluate (1) patient-evaluated stress against the CAR, (2) associations between the CAR and mood symptoms, and (3) the effect of smartphone-based treatment on the CAR. Methods Patients with BD (n = 67) were randomized to the use of daily smartphone-based monitoring (the intervention group) or to the control group for six months. Clinically rated symptoms according to the Hamilton Depression Rating Scale 17-items (HDRS), the Young Mania Rating Scale (YMRS), patient-evaluated perceived stress using Cohen’s Perceived Stress Scale (PSS) and salivary awakening cortisol samples used for measuring the CAR were collected at baseline, after three and six months. In the intervention group, smartphone-based data on stress and MI were rated daily during the entire study period. Results Smartphone-based patient-evaluated stress (B: 134.14, 95% CI: 1.35; 266.92, p = 0.048) and MI (B: 430.23, 95% CI: 52.41; 808.04, p = 0.026) mapped onto increased CAR. No statistically significant associations between the CAR and patient-evaluated PSS or the HDRS and the YMRS, respectively were found. There was no statistically significant effect of smartphone-based treatment on the CAR. Conclusion Our data, of preliminary character, found smartphone-based patient-evaluations of stress and mood instability as read outs that reflect CAR dynamics. Smartphone-supported clinical care did not in itself appear to disturb CAR dynamics.