Replication of functional serotonin receptor type 3A and B variants in bipolar affective disorder: a European multicenter study.

Serotonin type 3 receptors (5-HT(3)) are involved in learning, cognition and emotion, and have been implicated in various psychiatric phenotypes. However, their contribution to the pathomechanism of these disorders remains elusive. Three single nucleotide polymorphisms (SNPs) in the HTR3A and HTR3B genes (rs1062613, rs1176744 and rs3831455) have been associated with bipolar affective disorder (BPAD) in pilot studies, and all of them are of functional relevance. We performed a European multicenter study to confirm previous results and provide further evidence for the relevance of these SNPs to the etiology of neuropsychiatric disorders. This involved analysis of the distribution of the three SNPs among 1804 BPAD cases and 2407 healthy controls. A meta-analysis revealed a pooled odds ratio of 0.881 (P = 0.009, 95% confidence intervals = 0.802-0.968) for the non-synonymous functional SNP HTR3B p.Y129S (rs1176744), thereby confirming previous findings. In line with this, the three genome-wide association study samples BOMA (Bonn-Mannheim)-BPAD, WTCCC (Wellcome Trust Case Control Consortium)-BPAD and GAIN (Genetic Association Information Network)-BPAD, including >3500 patients and 5200 controls in total, showed an overrepresentation of the p.Y129 in patients. Remarkably, the meta-analysis revealed a P-value of 0.048 (OR = 0.934, fixed effect model). We also performed expression analyses to gain further insights into the distribution of HTR3A and HTR3B mRNA in the human brain. HTR3A and HTR3B were detected in all investigated brain tissues with the exception of the cerebellum, and large differences in the A:B subunit ratio were observed. Interestingly, expression of the B subunit was most prominent in the brain stem, amygdalae and frontal cortex, regions of relevance to psychiatric disorders. In conclusion, the present study provides further evidence for the presence of impaired 5-HT(3) receptor function in BPAD.

Excess of allele1 for alpha3 subunit GABA receptor gene (GABRA3) in bipolar patients: a multicentric association study.

The available data from preclinical and pharmacological studies on the role of gamma amino butyric acid (GABA) support the hypothesis that a dysfunction in brain GABAergic system activity contributes to the vulnerability to bipolar affective disorders (BPAD). Moreover, the localization of the alpha3 subunit GABA receptor GABRA3 gene on the Xq28, a region of interest in certain forms of bipolar illness, suggests that GABRA3 may be a candidate gene in BPAD. In the present study, we tested the genetic contribution of the GABRA3 dinucleotide polymorphism in a European multicentric case-control sample, matched for sex and ethnogeographical origin. Allele and genotype (in females) frequencies were compared in 185 BPAD patients and 370 controls. A significant increase of genotype 1-1 was observed in BPAD females compared to controls (P=0.0004). Furthermore, when considering recessivity of allele 1 (females with genotype 1-1 and males carrying allele 1), results were even more significant (P= 0.00002). Our findings suggest that the GABRA3 polymorphism may confer susceptibility to or may be in linkage disequilibrium with another gene involved in the genetic etiology of BPAD.

Lack of association between GABRA3 and unipolar affective disorder: a multicentre study.

Available data on gamma amino butyric acid (GABA) support the hypothesis that a dysfunction in the brain GABAergic system activity contributes to vulnerability to affective disorders (AD), including bipolar disorder (BPAD) and unipolar disorder (UPAD). The localization of the alpha3 subunit GABA receptor (GABRA3) gene in Xq28, a region of interest for BPAD suggests that GABRA3 may be a relevant candidate gene. In the present study, we tested the genetic contribution of the GABRA3 dinucleotide polymorphism in a European multicentre UPAD case-control sample [UPAD (n = 106), controls (n = 212)]. Our negative results suggest that GABRA3 does not confer susceptibility nor is it in linkage disequilibrium with another close gene involved in the genetic aetiology of UPAD.

Variability of 5-HT2C receptor cys23ser polymorphism among European populations and vulnerability to affective disorder.

Substantial evidence supports a role for dysfunction of brain serotonergic (5-HT) systems in the pathogenesis of major affective disorder, both unipolar (recurrent major depression) and bipolar.(1) Modification of serotonergic neurotransmission is pivotally implicated in the mechanism of action of antidepressant drugs(2) and also in the action of mood stabilizing agents, particularly lithium carbonate.(3) Accordingly, genes that code for the multiple subtypes of serotonin receptors that have been cloned and are expressed in brain,(4) are strong candidates for a role in the genetic etiology of affective illness. We examined a structural variant of the serotonin 2C (5-HT2C) receptor gene (HTR2C) that gives rise to a cysteine to serine substitution in the N terminal extracellular domain of the receptor protein (cys23ser),(5) in 513 patients with recurrent major depression (MDD-R), 649 patients with bipolar (BP) affective disorder and 901 normal controls. The subjects were drawn from nine European countries participating in the European Collaborative Project on Affective Disorders. There was significant variation in the frequency of the HT2CR ser23 allele among the 10 population groups included in the sample (from 24.6% in Greek control subjects to 9.2% in Scots, chi(2) = 20.9, df 9, P = 0.01). Logistic regression analysis demonstrated that over and above this inter-population variability, there was a significant excess of HT2CR ser23 allele carriers in patients compared to normal controls that was demonstrable for both the MDD (chi(2) = 7.34, df 1, P = 0.006) and BP (chi(2) = 5.45, df 1, P = 0.02) patients. These findings support a possible role for genetically based structural variation in 5-HT2C receptors in the pathogenesis of major affective disorder.

Tryptophan hydroxylase polymorphism and suicidality in unipolar and bipolar affective disorders: a multicenter association study.

BACKGROUND: Being the rate-limiting enzyme in the biosynthesis of serotonin, the tryptophan hydroxylase gene (TPH) has been considered a possible candidate gene in bipolar and unipolar affective disorders (BPAD and UPAD). Several studies have investigated the possible role of TPH polymorphisms in affective disorders and suicidal behavior. METHODS: The TPH A218C polymorphism has been investigated in 927 patients (527 BPAD and 400 UPAD) and their matched healthy control subjects collected within the European Collaborative Project on Affective Disorders. RESULTS: No difference of genotype distribution or allele distribution was found in BPAD or UPAD. No statistically significant difference was observed for allele frequency and genotypes counts. In a genotype per genotype analysis in UPAD patients with a personal history of suicide attempt, the frequency of the C-C genotype (homozygosity for the short allele) was lower in UPAD patients (24%) than in control subjects (43%) (chi(2) = 4.67, p =.03). There was no difference in allele or genotype frequency between patients presenting violent suicidal behavior (n = 48) and their matched control subjects. CONCLUSIONS: We failed to detect an association between the A218C polymorphism of the TPH gene and BPAD and UPAD in a large European sample. Homozygosity for the short allele is significantly less frequent in a subgroup of UPAD patients with a history of suicide attempt than in control subjects.

Women, war and trauma: a study description.

The last few decades have seen a sharp increase in research into the psychological, psychiatric and social consequences of war. However the bulk of this research relates to male veterans and refugees. There is a serious dearth of literature on female civilians, particularly where the research is being performed in the country of trauma origin. This study aims to explore the psychosocial effects of war on women. One hundred and fifty female civilians participated in this study, conducted in the city of Sarajevo and surrounding refugee settlements in Bosnia. The subjects were divided into three groups: domestic women residing in Sarajevo during and after the war, displaced: women forced to leave their homes, and staying in refugee settlements, returness: women who have returned to Sarajevo from exile. Each woman was interviewed extensively by local psychiatrists. This interview contained the Harvard Trauma Scale for the screening of PTSD and Social Functioning, and the Hopkins Checklist for Anxiety and Depression. Both these tests have been revised, translated and validated for the Bosnian population. The Rosenberg Self-Esteem Scale and the Lazarus Coping scale examine psychological aspects of self-esteem and coping. A questionnaire containing demographic information was devised for the purposes of this study.

[Reconstruction of mental health services in Bosnia and Herzegovina]. / Rekonstrukcija sluzbe za zastitu mentalnog zdravlja u Federaciji Bosne i Hercegovine.

Psychiatric services in Bosnia-Herzegovina before the war disaster was fairly developed and one of the best organized services amongst the republics of the former Yugoslavia. The psychiatric care system was based on psychiatric hospitals and small neuropsychiatric wards within general hospitals, accompanied by psychiatric services in health centers. The onset of war in B&H brought devastation and destruction in all domains of life, including the demolition and closing of numerous traditional psychiatric institutions, together with massive psychological suffering of the whole civilian population. Already during the war, and even more so after the war, the reconstruction and reorganization of the mental health services was undertaken. The basis of mental health care for the future is designed as a system where majority of services is located in the community, as close as possible to the habitat of the patients. The key aspect of the system of the comprehensive health care is primary health care and the main role is assigned to family practitioners and mental health professionals working in the community. Large psychiatric institutions were either closed or devastated, or have their capacities extensively reduced. There will be no reconstructions or reopening of the old psychiatric facilities, nor the new ones will be built. The most integrated part of the psychiatric system are the Community based mental health centers. Each of these centers will serve a particular geographic area. The centers will be responsible for prevention and treatment of psychiatric disorders, as well as for the mental health well being. Chronic mental health patients without families and are not able to independently live in the community will be accommodated in designated homes and other forms of protected accommodation within their communities. The principal change in mental health policy in B&H was a decision to transfer psychiatric services from traditional facilities into community, much closer to the patients. Basic elements of the mental health policy in B&H are: Decentralization and sectorization of mental health services; Intersectorial activity; Comprehensiveness of services; Equality in access and utilization of psychiatric service resources; Nationwide accessibility of mental health services; Continuity of services and care, together with the active participation of the community. This overview discusses the primary health care as the basic component of the comprehensive mental health care in greater detail, including tasks for family medicine teams and each individual member. 1. Comprehensive psychiatric care is implemented by primary health care physicians, specialized Centers for community-based mental health care, psychiatric wards of general hospitals and clinical centers in charge of brief, "acute" inpatient care; 2. Primary mental health care is implemented by family practitioners (primary care physicians) and their teams; 3. Specialized psychiatric care in community is performed professional teams specialized mental health issues' within Mental health centers in corresponding sectors; 4. A great deal of relevance is given to development of confidence and utilization of links between primary health care teams and specialized teams in Mental health centers and psychiatric in patient institutions; 5. Psychiatric wards within general cantonal hospitals, departments of psychiatric clinics in Sarajevo, Tuzla, and Mostar, and Cantonal Psychiatric hospital in Sarajevo (Jagomir) shall admit acute patients as well as chronic (with each new relapse). Treatment in these facilities is brief an patients are discharged to return to their homes, with further treatment referral to their family practitioner or designated Mental health center; 6. Chronic mental patients with severe residual impairment in social, psychological, and somatic functioning, shall live in the community with their families or independently. Those chronic patients without families and economic and other resources to live independently shall be placed in supervised Homes in the communities where they live. The above delineated strategy of mental health care program in B&H has several fundamental and specific objectives, among which the most important are: Reduction of incidence and prevalence of some mental disorders, particularly war stress-related disorders and suicide; Reduction of level of functional disability caused by mental disorders through improvement of treatment and care of individuals with mental health problems; Improvement of psychosocial well being of people with mental health problems, through implementation of comprehensive and accessible service for community mental health care; and Respect of basic human rights of individuals with mental health disabilities. The program has been updated since 1996, after the two-year pilot program. The main goals for current two- and five-year period are: Implement the mental health care reform program by launching all 38 Mental health centers in the Federation of BiH by 2002; Complete the 10-day education and re-education of at least 50% of all professionals employed in mental health services in FB&H by 2002; and Achieve that 80 percent of all mental health problems are treated by family medicine teams (primary care practitioners) and specialized mental health services (Community mental health care centers) by 2005.

A European multicenter association study of HTR2A receptor polymorphism in bipolar affective disorder.

The available data on the role of 5-HT in a variety of behaviors support the hypothesis that a dysfunction in brain serotoninergic system activity contributes to vulnerability to major depression. The diversity in the electrophysiological actions of 5-HT in the central nervous system can now be categorized according to receptor subtypes and their respective effector mechanisms. In particular, the implication of central postsynaptic 5-HT2A receptor in affective disorders has been supported by findings consistent with the hypothesis of 5-HT2A receptor up-regulation in depression. For these reasons, the 5-HT2A receptor (HTR2A) gene can be considered as a candidate gene in bipolar affective disorder (BPAD). We tested the possible genetic contribution of the polymorphic DNA variation T102C in exon 1 of HTR2A (chromosome 13q14-21) gene in a large European multicentric case-control sample. Allele and genotype frequencies, as well as homo-heterozygote distributions were compared between the two groups of 309 bipolar affective disorder patients and 309 matched controls. No significant differences were observed in the allelic and genotypic (also for homo-heterozygote) distribution between BPAD and controls. These results indicate that, in our sample, the 5-HT2A receptor polymorphism studied is unlikely to play a major role in the genetic susceptibility to BPAD. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:136-140, 2000.

Allelic distribution of CTG18.1 in Caucasian populations: association studies in bipolar disorder, schizophrenia, and ataxia.

CTG18.1 is a highly polymorphic and unstable CTG repeat within an intron of the SEF2-1 gene. We tested the CTG18.1 repeat length in affective disorder, schizophrenia, and nonspecific ataxia; these diseases all have shown clinical evidence for anticipation. There was no difference in the allele frequencies comparing the controls and disease groups. The most common allele contains 11 CAGs (35%) followed by alleles with 14-17 CAGs (35%). There was no difference in the distribution of the alleles in the cases vs controls for ataxia (P = 0.11), affective disorders (P = 0.21), or schizophrenia (P = 0.26). The frequency of unstable CTG18.1 alleles was approximately 3% in a population of N. European descent and is not related to the phenotypes tested.

Psychotic symptoms and comorbid psychiatric disorders in Croatian combat-related posttraumatic stress disorder patients.

AIM: To investigate the prevalence rate of post-traumatic stress disorder (PTSD) comorbid psychiatric disorders and to explore psychotic symptoms in patients with combat-related current PTSD. METHOD: The sample included Croatian war veterans (N=41) who were hospitalized at the University Department of Psychiatry of the Vrapèe Psychiatric Hospital during the 1995-1996 period and fulfilled the DSM-IV criteria for the current and chronic PTSD. The Schedule for Affective Disorder and Schizophrenia (SADS-L) was applied for the assessment of current and lifetime psychiatric disorders. Only three subjects had a prewar Axis I psychiatric disorder. One third of the patients met the criteria for personality disorder. RESULTS: After severe combat trauma, the majority of PTSD patients (33/41) had at least one comorbid psychiatric diagnosis on Axis I. In those with personality disorders the most frequent was alcohol dependence, whereas in those without personality disorders it was major depressive disorder. Psychotic symptoms occurred in 8 out of 41 PTSD patients. None of them had a primary psychotic disorder or a personality disorder. In all the patients, psychotic symptoms were different from flashbacks. They were symbolically related to the trauma and resistant to antipsychotic treatment. Psychotic symptoms were associated with depression in 5 out of 8 patients with psychotic symptoms. CONCLUSION: Severe and prolonged combat trauma may be followed by the co-occurrence of PTSD and psychotic symptoms, forming the atypical clinical picture of PTSD.

[Reconstruction of mental health services in the Federation of Bosnia-Herzegovina]. / Rekonstrukcija sluzbe za mentalno zdravlje na teritoriji Federacije Bosne i Hercegovine.

The war in Bosnia and Herzegovina has caused severe suffering of the population, and left behind destruction and misery. Hundreds of thousands were killed, ten thousands were severely injured, and almost the whole population has endured severe psychological traumas. The consequences today are numerous stress related psychical disorders, and especially PTSD. The war has almost destroyed the system of psychiatric services, and lead to lack of professional staff. Because of this, after the war, Federal Ministry of Health of Bosnia and Herzegovina has decided to carry out a complete reconstruction of psychiatric services based on new principles. Comprehensive care for improvement of mental health; prevention of mental illness, treatment and rehabilitation of mentally ill, should be transferred from institutions into the community. Consequently Ministry of Health have designed 38 Community Mental Health Centers in the Federation of Bosnia and Herzegovina in connection with already existing Primary Health Care centers (Dom zdravljas). Each of these centers is responsible for mental health in general within a catchment area of 50,000-80,000 inhabitants. A network of Community Mental Health Centers has started to operate. An efficient and useful training of the staff going to work in these centers have been carried out. Nevertheless, there is still significant resistance towards this new approach to mental health services and treatment of people with mental illness in the community. However, many problems related to this new program of community psychiatry have been identified and are under consideration.

Tyrosine hydroxylase polymorphism and phenotypic heterogeneity in bipolar affective disorder: a multicenter association study.

Tyrosine hydroxylase (TH), the rate-limiting enzyme in the metabolism of catecholamines, is considered a candidate gene in bipolar affective disorder (BPAD) and has been the subject of numerous linkage and association studies. Taken together, most results do not support a major gene effect for the TH gene in BPAD. Genetic and phenotypic heterogeneity may partially explain the difficulty of confirming the exact role of this gene using both association and linkage methods. Four hundred one BPAD patients and 401 unrelated matched controls were recruited within a European collaborative project (BIOMED1 project in the area of brain research, European Community grant number CT 92-1217, project leader: J. Mendlewicz) involving 14 centers for a case-control association study with a tetranucleotide polymorphism in the TH gene. Patients and controls were carefully matched for geographical origin. Phenotypic heterogeneity was considered and subgroup analyses were performed with relevant variables: age at onset, family history, and diagnostic stability. No association was observed in the total sample or for subgroups according to age at onset (n = 172), family history alone (n = 159), or high degree of diagnostic stability and a positive family history (n = 131). The results of this association study do not confirm the possible implication of TH polymorphism in the susceptibility to BPAD.

Psychotic symptoms in post-traumatic stress disorder.

Although many coexisting disorders have been reported with post-traumatic stress disorder (PTSD), little reference has been made to the presence of psychotic symptoms. Psychotic symptoms are not included in the Diagnostic and Statistical Manual of Mental Disorders IV or International Classification of Diseases 10 diagnoses of PTSD. The hallucinations and delusions described here in two cases of PTSD were accompanied by psychotic symptoms. These symptoms clearly differ from flashbacks but have a strong symbolic relationship to the trauma, and they do not respond to antipsychotic drugs. The question is whether there are two separate diagnoses or if psychotic symptoms are an integral part of PTSD. More systematic studies are required to explore the possibility of changing the current classifications of PTSD to include a diagnosis of PTSD with psychotic features.

Genetics of mood disorders--an overview. Part two.

The present article reviews the recent molecular findings in mood disorders. Results of linkage and association studies are discussed in regard to the main limitations of these approaches in psychiatric disorders. On the whole linkage and association studies contributed to the localisation od some potential vulnerability genes for Bipolar disorder (BP) on chromosomes 11, 4, 21 and X. The hypothesis of anticipation in mood disorders is also considered in light of interesting results with trinucleotide repeat expansions.

Genetics of mood disorders--an overview. Part one.

Mood disorders are severe and common psychiatric diseases with two main clinical forms: Bipolar disorder, type 1 (BP1), and Unipolar disorder (UP). This paper provides an overview of the Literature on genetics of BP1 and UP disorders. We described the problems of diagnostic definitions, and statistical methods for studying the genetic etiology of these disorders. Epidemiological and quantitative genetic studies are reviewed. Interactions of susceptibility genes and environmental factors in this disorders are also fundamental and has to be properly investigated. The understanding of genetic aspects of BP1 and UP disorders has benefited from recent findings with DNA markers. Therefore we also provide an overview of linkage and association studies that reveal several chromosomal regions, candidate genes and dynamic mutations which may play role in BP1 and UP disorders.

Association analysis of the 5-HT2C receptor and 5-HT transporter genes in bipolar disorder.

We selected 42 patients with bipolar disorder type I (BPI) and 40 healthy controls for genetic analysis of DNA polymorphisms in the serotonin receptor 2c (5-HTR2c) and serotonin transporter (5-HTT) genes. No significant associations were found in the total patient sample. However, when the individuals were divided according to gender, trends for association with both polymorphisms (P = 0.051 for 5-HTR2c and P = 0.049 for 5-HTT) in female patients were observed. These results suggest that variations in these genes may be responsible for a minor increase in susceptibility for bipolar disorder in women.

Analysis of the tyrosine hydroxylase and dopamine D4 receptor genes in a Croatian sample of bipolar I and unipolar patients.

We selected 83 patients with bipolar disorder type I or unipolar recurrent major depression and 71 healthy controls for genetic analysis of the tyrosine hydroxylase and the dopamine D4 receptor gene. No significant association was found between bipolar disorder type I and unipolar recurrent major depression and the polymorphisms located near these genes. Therefore, the hypothesis that the tyrosine hydroxylase and the dopamine D4 receptor genes may be involved in the etiology of bipolar disorder and unipolar recurrent major depression is not supported in our study.

Positive association between the GABRA5 gene and unipolar recurrent major depression.

The gamma-aminobutyric acid (GABA) neurotransmitter system has been implicated in the pathogenesis of mood disorders. To test this hypothesis we carried out an association study between a dinucleotide repeat polymorphism in the GABAA receptor alpha 5 subunit gene and bipolar and unipolar mood disorders. Our results suggest a possible involvement of this gene in unipolar but not in bipolar disorder.