Increased expression of splicing factor SRp20 mRNA in bipolar disorder patients

BACKGROUND: Variations and defects in alternative splicing are well known to be associated with a variety of human diseases and the stress response. We previously reported a decrease in glucocorticoid receptor (GR) alpha, but not GRbeta in mood disorder patients, suggesting an aberrant alternative splicing mechanism. To examine whether altered RNA splicing may underlie the pathophysiology of mood disorder, we evaluated the expression of a variety of SR protein splicing factors, a family of proteins indispensable for proper alternative splicing, in mood disorder patients. METHODS: We used quantitative real-time PCR to measure expressions of SRp20, SRp30c, SC35, SRp40, SRp46, SRp54, SRp55, SRp75, ASF/SF2, and 9G8 mRNA in peripheral white blood cells of 33 mood disorder patients during a depressive episode. In addition, the expressions of SRp20 and SC35 mRNA were quantified for 78 mood disorder patients in a remissive state, and 32 the first-degree relatives of these mood disorder patients. RESULT: A significant correlation was observed between SRp30c and the GRbeta/GRalpha ratio in control subjects, but not in mood disorder patients. Increased expression of SRp20 but not SRp30c mRNA was observed in bipolar disorder patients in both the depressive and remissive states. Major depressive disorder patients did not show any significant change in mRNA levels of SR proteins. LIMITATION: Subjects were Japanese adults. Patient treatment was not standardized. CONCLUSIONS: These results suggest that aberrant alternative splicing machinery caused by increased SRp20 mRNA expression would be associated with the pathophysiology of bipolar disorder.     

Frequency of narcolepsy symptoms and other sleep disorders in narcoleptic patients and their first-degree relatives

Narcolepsy is a rare neurological sleep disorder affecting around 0.05% of the general population. Genetic factors are known to have an important role in narcolepsy. However, because of its very low prevalence, it is difficult to have groups of comparison between first-degree relatives and general population subjects in order to identify a specific spectrum of disorders in these families. Consequently, from 157 Italian patients with narcolepsy, 263 first-degree relatives were recruited, two refused to participate. These family members were compared with a matched group of 1071 subjects selected from a sample of 3970 subjects representative of the general population of Italy (46 million inhabitants). Finally, 68 spouses of narcoleptic patients were used to assess for possible role of environmental factors. All subjects were interviewed by telephone using the Sleep-EVAL system. Nineteen cases of narcolepsy were discovered among the first-degree relatives of 17 probands (10.8%). Compared with the general population subjects, the relative risk of narcolepsy among female first-degree relatives was of 54.4 and of 105.1 among male first-degree relatives. First-degree relatives were also at higher risk for idiopatic hypersomnia (OR: 23.0), obstructive sleep apnea syndrome (OR: 6.8), adjustment sleep disorder (OR: 4.0), insufficient sleep syndrome (OR: 7.0), circadian rhythm disorders (OR: 2.5), REM behavior disorder (OR: 4.4), and sleep talking (OR: 2.0). The vulnerability to sleep disorders is very high in first-degree relatives and the link with different expressivity and severity of hypersomnia can be confirmed.     

Neuroendocrine, polysomnographic and psychometric observations in healthy subjects at high familial risk for affective disorders: the current state of the 'Munich vulnerability study'

The present article summarizes the main results of the cross-sectional part of the 'Munich Vulnerability Study' in which healthy first-degree relatives of patients with an affective disorder were investigated by assessing their neuroendocrine, polysomnographic and psychometric status. As patients with an acute episode of a major depression, the group of the healthy relatives exhibited signs of a hyperactive hypothalamic-pituitary-adrenocortical system verified by the combined dexamethasone corticotropin-releasing hormone (DEX/CRH) test, as well as a slow wave sleep deficit in the first sleep cycle and an increased amount of rapid eye movements during REM sleep. The psychometric profile of the healthy relatives was characterised by elevated scores on the scales measuring 'Rigidity' and 'Autonomic Lability'. On a single-case level, 32% of the healthy first-degree relatives of patients with an affective disorder exhibited 'depression-like' features or conspicuous findings in at least two of the three (i.e. neuroendocrine, polysomnographic, psychometric) areas assessed. Whether the relatives with the neurobiological and psychometric abnormalities we identified have a higher risk for developing an affective disorder than those without has to be answered by the still ongoing prospective part of the study.     

Mood disorder service genetic database: Morbidity risks for mood disorders in 3,942 first-degree relatives of 671 index cases with single depression,recurrent depression,bipolar I,or bipolar II

There is increasing evidence that genetic factors play a role in the etiology of mood disorders. As a result, relatives of affected individuals are more often asking about their own risks to develop a mood disorder. From 1988 to 1990, all consecutive, unrelated inpatients and outpatients (index cases) presenting to the Mood Disorders Service, Department of Psychiatry, University of British Columbia, had detailed family histories taken, thus creating the Mood Disorders Service Genetic Database. Diagnoses for index cases and their first-degree relatives were made according to Research Diagnostic Criteria and Family History Research Diagnostic Criteria respectively. Morbidity risks for mood disorders were calculated for first-degree relatives (parents, siblings, children—aged 10 and above) of all index cases with a diagnosis of single depression, recurrent depression, bipolar I, or bipolar II disorder. Morbidity risks were calculated using the maximum likelihood approach. Morbidity risk data are presented according to the sex and diagnosis for the index case in an easy reference format for risk counselling. The risks are presented twice, including and excluding data for “high-risk” families whose genetic pedigree is suggestive of “autosomal dominant” inheritance. © 1994 Wiley-Liss, Inc.     

Personality of recovered patients with bipolar affective disorder

Personality traits of 45 patients with bipolar affective disorder who were fully recovered were compared with those of 78 patients with unipolar affective disorder (also fully recovered) and with those of 1172 never mentally ill first-degree relatives. The most striking finding is the similarity in personality between the recovered bipolar and unipolar patients, who both differed substantially from the never-ill group on measures of emotional strength. Bipolar men had normal levels of extraversion, whereas bipolar women, like unipolar women, were introverted.     

A family study of bipolar I disorder in adolescence. Early onset of symptoms linked to increased familial loading and lithium resistance

Lifetime rates of psychiatric illness were compared in relatives of adolescent probands with bipolar I disorder and in relatives of age-matched schizophrenic controls. Familial aggregation of major affective disorders was observed in bipolar probands, the rate of bipolar I disorder greatly exceeding that reported in relatives of adult bipolar probands. Adolescent probands with childhood onset of psychiatric disturbance were distinguished from probands who had no premorbid childhood psychiatric abnormality in two ways: (1) significantly increased aggregation of bipolar I disorder in first-degree relatives; and (2) poorer antimanic response to lithium carbonate. These data underscore important heterogeneity in adolescent-onset bipolar disorder.     

Lower high-density lipoprotein cholesterol and increased omega-6 polyunsaturated fatty acids in first-degree relatives of bipolar patients

BACKGROUND: Lower serum high-density lipoprotein cholesterol and increased ratio of omega-6/omega-3 fatty acids have been reported in unipolar and bipolar depressed patients. Changes in cholesterol and fatty acids have been suggested to affect membrane viscosity and consequently serotonergic neurotransmitter expression. The goal of this study was to investigate whether lower baseline cholesterol and increased omega-6 and lower omega-3 fatty acids are present in healthy first-degree relatives of bipolar patients compared with controls and whether these changes were associated with neuroendocrine responses to an i.v. tryptophan challenge or mood. METHOD: Baseline cholesterol, fatty acids and mood were determined in healthy first-degree relatives of patients with bipolar disorders (N = 30) and healthy matched controls (N = 15) (parallel-group design). Prolactin and cortisol were measured following tryptophan infusion. RESULTS: First-degree relatives showed significantly lower plasma high-density lipoprotein cholesterol and increased total omega-6 fatty acids in phospholipids. Lower total omega-3 and higher total omega-6 fatty acids in phospholipids were positively correlated with peak prolactin response to tryptophan. Lower total omega-3 fatty acids in phospholipids and cholesteryl esters were associated with lower mood. CONCLUSIONS: Abnormalities of lower plasma high-density lipoprotein cholesterol and increased total omega-6 fatty acids in phospholipids in these subjects are in agreement with findings in bipolar and major depressed patients. Changes in fatty acids show an association with central serotonergic parameters. It is suggested that these abnormalities in cholesterol and fatty acids may constitute a trait marker for bipolar disorders.     

Affective temperaments as measured by TEMPS-A in patients with bipolar I disorder and their first-degree relatives: a controlled study

BACKGROUND: The aims of this study were to identify the dominant affective temperamental characteristics of patients with bipolar disorder (BP) and their clinically well first-degree relatives and to compare the prevalence rates of these temperaments with those in healthy control subjects. METHODS: One hundred bipolar I probands and their 219 unaffected first-degree relatives were enrolled in the study. The control group consisted of healthy subjects without any personal or family history of bipolar disorder, matched with the age and gender of the probands and first-degree relatives. To identify the dominant affective temperaments, the Turkish version of TEMPS-A scale was used. RESULTS: At least one dominant temperament was found in 26% of the proband group, in 21.9% of the relative group, and 6.0% and 10.0% of the control groups, respectively. The most noteworthy finding was that both the probands and their relatives had significantly higher frequency of hyperthymic temperament than the controls. LIMITATIONS: Temperament had not been assessed premorbidly in the probands with bipolar disorder. CONCLUSIONS: The study supports the familial, possibly genetic, basis for the hyperthymic temperament in the genesis of bipolar I dosorder. That the cyclothymic temperament was not similarly represented, may be due to the higher specificity of the cyclothymic temperament to the bipolar II sybtype (which we did not study). More research is needed on the relevance of cyclothymic and other temperaments to the genetics of bipolar disorders selected by rigorous subtyping along the clinical spectrum of bipolarity.     

Expressed emotion as a predictor of outcome among bipolar patients undergoing family therapy

BACKGROUND: Levels of expressed emotion (EE) in relatives are consistent predictors of relapse among bipolar and other mood disordered patients followed naturalistically. However, few studies have examined whether levels of EE predict the course of illness for patients engaged in psychosocial interventions. METHODS: This study examined whether EE levels among caregivers moderated the success of family-based psychosocial interventions for patients with bipolar disorder. EE was examined as a predictor of symptomatic outcome in two groups: (1) bipolar patients receiving family-focused psychoeducational treatment (FFT) or integrated family and individual treatment (IFIT), and (2) bipolar patients receiving crisis management (CM), a less intensive intervention designed to emulate community care. Bipolar patients (N = 125) began the study in an acute illness episode, were stabilized on standard pharmacotherapy regimens, and followed for up to 2 years. RESULTS: Family EE status was not associated with time to relapse in either group. However, patients with high EE relatives reported higher levels of depression over the 2-year term of follow-up, regardless of treatment condition. An examination of the dimensions of EE (critical comments and emotional overinvolvement) indicated that a higher frequency of critical comments predicted higher levels of mania and depression at follow-up. Additionally, the association between EE criticism and levels of mania symptoms was stronger among patients in CM than among patients in family treatment. LIMITATIONS: The participants were recruited from two separate treatment protocols. Patients in the IFIT protocol were not randomly assigned to treatments. CONCLUSIONS: EE is a predictor of symptom severity among bipolar patients undergoing pharmacological and psychosocial treatments, but family intervention may mitigate this association.     

Cognitive functioning in patients with familial bipolar I disorder and their unaffected relatives

BACKGROUND: Impairments in verbal learning and memory, executive functions and attention are manifest in some euthymic patients with bipolar disorder (BPD). However, evidence is sparse on their putative role as aetiologically important genetic vulnerability markers for the disorder. This population-based study examined the cognitive functions of affected and unaffected individuals in families with BPD. The aim was to discover whether any cognitive function would indicate genetic liability to the disorder and could thus be regarded as endophenotypes of BPD. METHOD: A diagnostic interview and a neuropsychological test battery were administered to 32 familial bipolar I disorder patients, 40 of their unaffected first-degree relatives and 55 controls, all representing population-based samples. RESULTS: Unaffected first-degree relatives showed impairment in psychomotor performance speed and slight impairment in executive function. Bipolar patients were impaired in verbal learning and memory compared with unaffected relatives and controls. They also differed from controls in tasks of executive functions. There were no difference between the groups in simple attention and working memory tasks. CONCLUSIONS: Impaired psychomotor performance speed and executive function may represent endophenotypes of BPD, reflecting possible underlying vulnerability to the disorder. Verbal memory impairments appear to be more related to the fully developed disorder.     

Migraine life-time prevalence in mental disorders: concurrent comparisons with first-degree relatives and the general population

The authors quantified the prevalence of migraine in subjects with mental disorders, first-degree relatives and the adult general population (GP) in Mérida, Venezuela. After validation, a modified, short version of the Lipton's diagnostic scale was administered to consecutively admitted in- and out-patients (n = 1059), their first-degree relatives (n = 445) and a probabilistic sample of the GP (n = 516). In the GP, the frequency of migraine (percentage and 95% confidence interval) was 14.9 (11.8-17.9). The migraine frequencies were (percentage and odd ratio probability against the GP: bipolar disorder (15.7%, p = 0.5), schizophrenia (8.3%, p = 0.08), depression and dysthimia (24.4%, p = 0.2), anxiety disorders (10.0%, p = 0.02), personality disorders (11.4%, p = 0.15), all other disorders (15.5%, p = 0.4), relatives of bipolar patients (4.4%, p < 0.001), relatives of schizophrenia patients (3.5%, p = 0.003), and relatives of patients with all other mental disorders (12.8%, p = 0.4). Migraine was more common in women (p < 0.001), and the bipolar patients presented the highest female to male ratio (8:1). A high variability was observed in migraine prevalence among the diagnostic categories, but it was particularly high in subjects with affective disorders, mainly in women, who thus deserve special attention from clinicians.     

The Munich Vulnerability Study on Affective Disorders: risk factors for unipolarity versus bipolarity

BACKGROUND: An individual with a high genetic load for psychiatric disorders is subject to a considerable risk factor for an affective illness. Family studies usually try to distinguish between bipolar and unipolar disorders since it was suggested that they might show different modes of inheritance. The aim of this study was to differentiate between healthy members of unipolar and bipolar families without a previous history of any psychiatric disorder according to the neurobiological and psychometric findings. METHODS: We first analysed the results obtained from neurobiological and psychometric measurements taken from 75 healthy subjects who had at least two close relatives with a unipolar and a bipolar disorder. In a second step we examined the subjects with a parental affective disorder; finally, we compared the members of 'pure' unipolar, bipolar and of mixed families to each other. RESULTS: The first-degree relatives of unipolar patients showed a significantly higher REM density and scored higher on scales of 'neuroticism' and 'vegetative lability' than the controls. No significant differences could be noticed between the relatives of unipolar and bipolar patients, either when considering the degree of relationship, or the parental type of affective disorder and the 'purity' of the respective families. CONCLUSIONS: We found some distinct neurobiological and psychometric differences between the relatives of unipolar patients and the control probands. No obvious differences, however, were ascertained between relatives of unipolar and bipolar patients. Therefore, we consider it to be possible that these findings represent potential vulnerability markers for affective disorders in general.     

Personal and family history of affective illness in patients with multiple sclerosis

There is a high prevalence of affective illness, both depression and bipolar disorder, in patients with multiple sclerosis. In this study, the family history method was used to assess the prevalence of affective illness in first-degree relatives of patients with multiple sclerosis. There was not an excess of affective illness in the relatives suggesting that affective disorder associated with multiple sclerosis does not have a familial pattern similar to primary affective disorder. Clinical and theoretical implications of these findings are discussed.     

Early and late onset bipolar disorders: two different forms of manic-depressive illness?

BACKGROUND: Conflicting results in genetic studies of bipolar disorders may be due to the clinical and genetic heterogeneity of the disease. Age at onset of bipolar disorders may be a key indicator for identifying more homogeneous clinical subtypes. We tested whether early onset and late onset bipolar illness represent two different forms of bipolar illness in terms of clinical features, comorbidity and familial risk. METHODS: Among a consecutively recruited sample of 210 bipolar patients, we compared early onset (n=58) and late onset (n=39) bipolar patients; the cut-off points were age at onset before 18 years and after 40 years for the two subgroups. The subgroups were compared by independent t tests and a contingency table by raw chi-square test. Morbid risk among first-degree relatives was measured by the survival analysis method. RESULTS: The early onset group had the most severe form of bipolar disorder with more psychotic features (P=0.03), more mixed episodes (P=0.01), greater comorbidity with panic disorder (P=0.01) and poorer prophylactic lithium response (P=0.04). First degree relatives of early onset patients also had a higher risk of affective disorders (P=0.0002), and exhibit the more severe phenotype, i.e bipolar disorder. CONCLUSION: Our data suggest that early and late onset bipolar disorders differ in clinical expression and familial risk and may therefore be considered to be different subforms of manic-depressive illness.     

Evidence supporting the independent inheritance of primary affective disorders and primary alcoholism in the families of bipolar patients

Background: This study explored the nature of the association between bipolar disorder and alcoholism. Methods: The authors studied 814 first-degree relatives of 121 bipolar patients, divided on the basis of response to lithium prophylaxis. Logistic regression analysis was used to analyze the contribution of demographic, familial and clinical variables to the risk of primary alcoholism in the relatives. Results: The risk of primary alcoholism in relatives was not related to the degree of affective loading in the family or to the proband's lithium response. Conclusion: This study does not support a shared genetic liability between bipolar disorder and alcoholism. Limitations: This study lacked a control group, but the analysis accounted for this. Clinical Relevance: These disorders are not alternative forms of the same illness.     

Alterations in the steroid biosynthetic pathways in the human prefrontal cortex in mood disorders: A post‐mortem study

Altered levels of steroids have been reported in the brain, cerebral spinal fluid and plasma of patients with mood disorders. Neuroimaging studies have reported both functional and structural alterations in mood disorders, for instance in the anterior cingulate cortex (ACC) and dorsolateral prefrontal cortex (DLPFC). In order to determine whether the endogenous production of steroids is altered in the ACC and DLPFC of patients with major depressive disorder (MDD) or bipolar disorder (BPD), quantitative real‐time PCR was performed to detect mRNA expression level of key enzymes in the steroid biosynthetic pathways. In MDD, a significant decrease in mRNA level of cytochrome P450 17A1 (CYP17A1, synthesizing C19 ketosteroids) in the ACC and a significant increase in mRNA levels of hydroxysteroid sulfotransferase 2A1 [SULT2A1, catalyzing the sulfate conjugation of dehydroepiandrosterone (DHEA)] were observed in the DLPFC, suggesting alterations in DHEA and its sulfate metabolite DHEAS levels. Decreased intensity and distribution of CYP17A1 immunohistochemical staining was found in the ACC of MDD patients. Interestingly, there was a significant positive correlation between the mRNA levels of CYP17A1 and tyrosine‐related kinase B (TrkB) full length isoform. In a unique post‐mortem human brain slice culture paradigm, BDNF mRNA expression was found to be significantly increased following incubation with DHEA. Together, these data indicate a close relationship between DHEA and BDNF‐TrkB pathways in depression. Furthermore, in the DLPFC, higher mRNA levels of 11β‐hydroxysteroid dehydrogenase‐1 (HSD11B1, reducing cortisone to the active hormone cortisol) and steroidogenic acute regulatory protein (STAR, facilitating the shuttle of cholesterol through the intermembrane space) were found in the MDD patients and BPD patients, respectively. In conclusion, this study suggests the presence of a disturbance in the endogenous synthesis of DHEA and DHEAS in mood disorders, which has a close relationship with BDNF‐TrkB signaling.     

Serum neurotrophin-3 is increased during manic and depressive episodes in bipolar disorder

Accumulating evidence suggest that neural changes and cognitive impairment may accompany the course of bipolar disorder. Such detrimental effects of cumulative mood episodes may be related to changes in neurotrophins that take place during mood episodes but not during euthymic phases. The present study investigated serum neurotrophin-3 (NT-3) levels in patients with bipolar disorder during manic, depressed, and euthymic states, using an enzyme-linked immunosorbent assay (sandwich-ELISA). Serum NT-3 levels were increased in manic (p<0.001) and depressed (p<0.001) BD patients, as compared with euthymic patients and normal controls. These findings suggest that the NT-3 signaling system may play a role in the pathophysiology of BD.     

Malignancy of recurrent, early-onset major depression: a family study.

Coordinated efforts to identify susceptibility genes for unipolar major depressive disorder (MDD) and related disorders are now underway. These studies have focused on recurrent, early-onset MDD (RE-MDD), the most heritable form of this disorder. The goal of this study was to characterize the burden of MDD and other mood disorders, comorbid mental disorders, and excess mortality in RE-MDD families. A total of 81 families were identified through probands over the age of 18, who met criteria for recurrent (> or = 2 episodes), early-onset (< or = 25 years), nonpsychotic, unipolar MDD (RE-MDD), and included 407 first-degree relatives and 835 extended relatives. Psychiatric diagnoses for probands and their family members who provided blood samples were formulated from structured personal interviews, structured family history assessments, and available medical records. The remaining family members who participated and those who were deceased were evaluated through the family history method augmented by available medical records. Best estimate diagnoses were made during a consensus conference according to established diagnostic criteria. Approximately half of the first-degree relatives and a quarter of extended relatives of RE-MDD probands suffered from at least one mood disorder, typically MDD. As commonly observed for other oligogenic, multifactorial disorders, the severity of MDD reflected by age at onset and number of episodes attenuated with increasing familial/genetic distance from the proband. A substantial fraction of RE-MDD probands and their first-degree relatives met diagnostic criteria for additional psychiatric disorders that include prominent disturbances of mood. The deceased relatives of RE-MDD probands died at a median age that was 8 years earlier than for the local population; over 40% died before reaching age 65. These differences in mortality statistics resulted from a shift toward younger ages at death across the lifespan, including a fivefold increase in the proportion of individuals who died in the first year of life. Several-fold increases in the proportion of deaths by suicide, homicide, and liver disease were observed among the relatives of RE-MDD probands. However, the rank order of the three most common causes of death-heart disease, cancer, and stroke-remained unchanged and differences in the proportions of deaths from the remaining causes were small. RE-MDD is a strongly familial condition with a high rate of psychiatric comorbidity, whose malignant effects have a significant negative impact on the health and longevity of patients and their family members.