Transcriptome Changes in Three Brain Regions during Chronic Lithium Administration in the Rat Models of Mania and Depression.

Lithium has been the most important mood stabilizer used for the treatment of bipolar disorder and prophylaxis of manic and depressive episodes. Despite long use in clinical practice, the exact molecular mechanisms of lithium are still not well identified. Previous experimental studies produced inconsistent results due to different duration of lithium treatment and using animals without manic-like or depressive-like symptoms. Therefore, we aimed to analyze the gene expression profile in three brain regions (amygdala, frontal cortex and hippocampus) in the rat model of mania and depression during chronic lithium administration (2 and 4 weeks). Behavioral changes were verified by the forced swim test, open field test and elevated maze test. After the experiment, nucleic acid was extracted from the frontal cortex, hippocampus and amygdala. Gene expression profile was done using SurePrint G3 Rat Gene Expression whole transcriptome microarrays. Data were analyzed using Gene Spring 14.9 software. We found that chronic lithium treatment significantly influenced gene expression profile in both mania and depression models. In manic rats, chronic lithium treatment significantly influenced the expression of the genes enriched in olfactory and taste transduction pathway and long non-coding RNAs in all three brain regions. We report here for the first time that genes regulating olfactory and taste receptor pathways and long non-coding RNAs may be targeted by chronic lithium treatment in the animal model of mania.

A miRNome analysis of drug-free manic psychotic bipolar patients versus healthy controls.

The lifetime presence of psychotic symptoms is associated with more clinical severity, poorer outcome and biological changes in patients affected by bipolar disorder (BD). Epigenetic mechanisms have been evoked to explain the onset of psychotic symptoms in BD as well as the associated biological changes. The main objective of the present study was to evaluate the expression profiles of circulating microRNAs (miRNAs) in drug-free manic psychotic bipolar patients versus healthy controls (HC), to identify possible non-invasive molecular markers of the disorder. 15 drug-free manic psychotic bipolar patients and 9 HC were enrolled and 800 miRNAs expression profile was measured by Nanostring nCounter technology on plasma samples and validated through qPCR. Overall, twelve miRNAs showed a significantly altered expression between the two groups (p < 0.05). Functional annotation of predicted miRNAs targets by MultiMIR R tool showed repression in bipolar patients of genes with a role in neurodevelopment and neurogenesis, and upregulation of genes involved in metabolism regulation. We identified a signature of circulating miRNA characteristic of manic psychotic bipolar patients, suggesting a possible role in neurodevelopment and metabolic processes regulation.

Association of Etiological Factors for Hypomanic Symptoms, Bipolar Disorder, and Other Severe Mental Illnesses.

Importance: Subsyndromal hypomanic symptoms are relatively common in the general population and are linked to the onset of bipolar disorder. Little is known about their etiology and whether this is shared with the etiology of bipolar disorder or other mental illnesses. Objective: To examine the genetic and environmental architecture of hypomanic symptoms in a nonclinical youth sample and compare estimates at varying severity levels and their association with diagnosed bipolar disorder. Design, Setting, and Participants: This cohort study used phenotypic and genetic data from the Child and Adolescent Twin Study in Sweden and included individuals with International Statistical Classification of Diseases and Related Health Problems, Tenth Revision diagnosis of psychiatric disorders from national registries for residents of Sweden. Associations between hypomania and polygenic risk scores for bipolar disorder, major depressive disorder and schizophrenia were also investigated. Analysis began November 2018 and ended October 2021. Main Outcomes and Measures: Hypomanic symptoms were assessed using the parent-rated Mood Disorders Questionnaire when the twins were aged 18 years. Bipolar disorder diagnosis and/or lithium prescription were ascertained from national registries for residents of Sweden. Polygenic risk scores for psychiatric disorders were calculated using independent discovery genetic data. Results: A total of 8568 twin pairs aged 18 years (9381 [54.7%] female) were included in the study. The hypomania heritability estimate was 59% (95% CI, 52%-64%) for male individuals and 29% (95% CI, 16%-44%) for female individuals. Unique environmental factors accounted for 41% (95% CI, 36%-47%) of the hypomania variance in male individuals and 45% (95% CI, 40%-50%) in female individuals. Shared environmental factors were only detected for female individuals and explained 26% (95% CI, 13%-38%) of the variance. The heritability estimates were fairly consistent across different hypomania severity groups. Moderate genetic (0.40; 95% CI, 0.21-0.58) and shared environmental (0.41; 95% CI, 0.03-0.75) correlations between hypomania and diagnosed bipolar disorder were found. Hypomania was significantly associated with the polygenic risk scores for schizophrenia (ß = 0.08; SE = 0.026; P = .002) and major depressive disorder (ß = 0.09; SE = 0.027; P = .001) but not bipolar disorder (ß = 0.017; SE = 0.03; P = 0.57) (bipolar disorder I [ß = 0.014; SE = 0.029; P = .64] or bipolar disorder II [ß = 0.045; SE = 0.027; P = .10]). Conclusions and Relevance: Higher heritability for hypomania was found for male compared with female individuals. The results highlight the shared etiologies between hypomanic symptoms, bipolar disorder, major depression, and schizophrenia in youths. Future research should focus on identifying specific shared genetic and environmental factors. These findings support a possible dimensional model of bipolar disorder, with hypomania representing a continuous trait underlying the disorder.

A prospective study to explore the relationship between MTHFR C677T genotype, physiological folate levels, and postpartum psychopathology in at-risk women.

BACKGROUND: The etiology of postpartum psychopathologies are not well understood, but folate metabolism pathways are of potential interest. Demands for folate increase dramatically during pregnancy, low folate level has been associated with psychiatric disorders, and supplementation may improve symptomatology. The MTHFR C677T variant influences folate metabolism and has been implicated in depression during pregnancy. OBJECTIVE: To conduct a prospective longitudinal study to explore the relationship between MTHFR C677T genotype, folate levels, and postpartum psychopathology in at-risk women. HYPOTHESIS: In the first three months postpartum, folate will moderate a relationship between MTHFR genotype and depression, with TT homozygous women having more symptoms than CC homozygous women. METHODS: We recruited 365 pregnant women with a history of mood or psychotic disorder, and at 3 postpartum timepoints, administered the Edinburgh Postnatal Depression Scale (EPDS); Clinician-Administered Rating Scale for Mania (CARS-M) and the Positive and Negative Symptom Scale (PANSS) and drew blood for genotype/folate level analysis. We used robust linear regression to investigate interactions between genotype and folate level on the highest EPDS and CARS-M scores, and logistic regression to explore interactions with PANSS psychosis scores above/below cut-off. RESULTS: There was no significant interaction effect between MTHFR genotype and folate level on highest EPDS (p = 0.36), but there was a significant interaction between genotype, folate level and log(CARS-M) (p = 0.02); post-hoc analyses revealed differences in the effect of folate level between CC/CT, and TT genotypes, with folate level in CC and CT having an inverse relationship with symptoms of mania, while there was no relationship in participants with TT genotype. There was no significant interaction between MTHFR genotype and folate level on the likelihood of meeting positive symptom criteria for psychosis on the PANSS (p = 0.86). DISCUSSION: These data suggest that perhaps there is a relationship between MTHFR C677T, folate level and some symptoms of postpartum psychopathology.