George N. Papadimitriou

A meta-analysis and transmission disequilibrium study of association between the dopamine D3 receptor gene and schizophrenia

We performed a meta-analysis of over 30 case-control studies of association between schizophrenia and a bi-allelic, BalI polymorphism in exon 1 of the dopamine D3 receptor gene. We observed a significant excess of both forms of homozygote in patients (P = 0.0009, odds ratio (OR) = 1.21, 95% Confidence Interval (CI) = 1.07–1.35) in the combined sample of 5351 individuals. No significant heterogeneity was detected between samples and the effects did not appear to be the product of publishing bias. In addition we undertook an independent, family-based association study of this polymorphism in 57 parent/proband trios, taken from unrelated European multiplex families segregating schizophrenia. A transmission disequilibrium test (TDT) showed a significant excess of homozygotes in schizophrenic patients (P = 0.004, odds ratio (OR) = 2.7, 95% CI = 1.35–5.86). Although no significant allelic association was observed, a significant association was detected with the 1–1 genotype alone (P = 0.02, OR = 2.32, 95% CI = 1.13–4.99). In addition when the results of the family-based association study were included in the meta-analysis, the homozygosity effect increased in significance (P = 0.0002, OR = 1.23, 95% CI = 1.09–1.38). The results of the meta-analysis and family-based association study provide independent support for a relationship between schizophrenia and homozygosity at the BalI polymorphism of the D3 receptor gene, or between a locus in linkage disequilibrium with it.

Association between COMT (Val158Met) functional polymorphism and early onset in patients with major depressive disorder in a European multicenter genetic association study.

The available data from preclinical and pharmacological studies on the role of the C-O-methyl transferase (COMT) support the hypothesis that abnormal catecholamine transmission has been implicated in the pathogenesis of mood disorders (MD). We examined the relationship of a common functional polymorphism (Val108/158Met) in the COMT gene, which accounts for four-fold variation in enzyme activity, with ‘early-onset’ (EO) forms (less than or equal to 25 years) of MD, including patients with major depressive disorder (EO-MDD) and bipolar patients (EO-BPD), in a European multicenter case–control sample. Our sample includes 378 MDD (120 EO-MDD), 506 BPD (222 EO-BPD) and 628 controls. An association was found between the high-activity COMT Val allele, particularly the COMT Val/Val genotype and EO-MDD. These findings suggest that the COMT Val/Val genotype may be involved in EO-MDD or may be in linkage disequilibrium with a different causative polymorphism in the vicinity. The COMT gene may have complex and pleiotropic effects on susceptibility and symptomatology of neuropsychiatric disorders.

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 drugs2 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, χ2 = 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 (χ2 = 7.34, df 1, P = 0.006) and BP (χ2 = 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.

Sleep disturbance in anxiety disorders

Many patients suffering from the majority of anxiety disorders complain about their sleep by reporting difficulties in initiating and maintaining it. Polysomnographic studies have shown that, in comparison to normal subjects, the sleep of patients with panic disorder is characterized by longer sleep latency, increased time awake and reduced sleep efficiency. Sleep architecture is normal and there are no significant changes in REM sleep measures. Nocturnal panic attacks are non-REM-related events and occur without an obvious trigger in 18–45% of panic disorder patients. Regarding generalized anxiety disorder, the patients complain of ‘trouble sleeping’ in 60–70%, while polysomnography has shown increased sleep latency and decreased sleep continuity measures. The findings in REM sleep and sleep architecture generally do not show any aberration to exist. In patients with obsessive-compulsive disorder (OCD) and post-traumatic stress disorder (PTSD), results from the sleep laboratory do not seem to support the subjective complaints of poor sleep. The early reports of shortened REM latency in OCD could not be replicated by recent studies. A dysregulation of the REM sleep control system has been reported for patients with PTSD. Finally, no significant differences were found in all sleep parameters between social phobia patients and controls.

Apathy, cognitive deficits and functional impairment in schizophrenia

INTRODUCTION Apathy has been repeatedly highlighted as a core component of negative symptoms especially with regard to functional outcome of schizophrenia. The purpose of this study was to explore the relationships between apathy, cognitive deficits, and psychosocial functioning in chronic patients with schizophrenia. METHODS Thirty-six chronic patients with schizophrenia and an equal number of matched healthy participants were assessed with the clinician version of Apathy Evaluation Scale (AES-C) along with a comprehensive battery of neuropsychological measures. Functioning was assessed with the Personal and Social Performance scale (PSP) and other symptoms were measured with the Positive and Negative Syndrome Scale and the Calgary Depression Scale for Schizophrenia. RESULTS Apathy was strongly and specifically associated with poorer performance on executive tests in patient group. AES-C was significantly correlated with PSP total score as well as its subscales for social useful activities, personal and social relationships, and self-care. Multiple regression analysis revealed that apathy was the most robust predictor of current psychosocial functioning, accounting for 70% of the variance in functioning, independently of co-existent cognitive deficits. Moreover, executive dysfunction did not predict functional impairment, independently of the effect of apathy. CONCLUSION Our findings confirm that apathy has a stronger relationship to functional impairment than cognitive deficits on a cross-sectional basis in schizophrenia. Moreover, they suggest that apathy and executive dysfunction might represent different manifestations of the same syndrome, probably sharing a common neural substrate.

The neuropsychiatry of multiple sclerosis: Focus on disorders of mood, affect and behaviour

Neuropsychiatric symptoms are common in multiple sclerosis (MS). They include two broad categories of disturbances: abnormalities in cognition, and abnormalities of mood, affect and behaviour. The present review deals with the epidemiology, clinical features, etiology and treatment of disturbances included in the second category, i.e., major depression, fatigue and sleep disorders, bipolar disorder, euphoria, pathological laughing and crying, anxiety, psychosis and personality changes. Major depression is one of the most common neuropsychiatric disorders in MS with an approximate 50% lifetime prevalence rate. Early recognition and management of depression in MS is of major importance because it is a key predictor of morbidity, mortality, quality of life, possibly physical outcome and disease exacerbations, adherence to immunomodulatory treatments and suicide risk in MS patients, as well as of the caregivers distress and quality of life. The etiopathogenesis of neuropsychiatric disorders in MS has been incompletely investigated. It is postulated that a complex interplay of biological, disease-related, behavioural and psychosocial factors contribute to the pathophysiology of most of them. Management of neuropsychiatric symptoms in MS is often effective, although commonly based on evidence provided by case studies and uncontrolled trials. A comprehensive biopsychosocial neuropsychiatric approach is essential for the optimal care of patients with MS.

Family study of panic disorder: Comparison with generalized anxiety disorder, major depression and normal subjects

Family studies have demonstrated that genetic factors are involved in panic and other anxiety disorders. In order to investigate these factors, 25 probands with panic disorder (PD) were compared with three other groups (age and sex matched): patients with generalized anxiety disorder (GAD), major depressive disorder (MDD), and normal subjects. About 75% of all first-degree relatives were personally interviewed. Age-corrected morbidity risk (MR) was calculated according to the Stromgren method. The distribution of psychopathology in first-degree relatives showed significantly greater MR for PD in the relatives of PD probands in comparison with all groups. For all anxiety disorders and various psychiatric disorders, relatives of PD patients also showed greater MR than controls. The frequency of GAD and MDD in relatives did not discriminate between the groups. The results of this study validate PD as a separate illness from GAD, the differentiation of PD from MDD, and support the hypothesis of a genetic contribution to the predisposition of PD.

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.

EEG Sleep Studies in Patients With Generalized Anxiety Disorder

Sleep polygraphic recordings were performed during 3 consecutive nights in 12 inpatients with generalized anxiety disorder (GAD) in comparison with age- and sex-matched groups of patients with major depressive disorder (MDD) and normal subjects. GAD patients differed significantly from those with MDD. A lower number of awakenings and stage shifts in night 1 and the mean of the 3 nights and a shorter rapid eye movement (REM) duration in night 1 but longer REM latency in the mean of the 3 nights were observed in GAD in comparison to MDD. GAD patients also showed a significantly longer sleep onset latency and shorter duration of total sleep time and Stage 2 than control subjects. Electroencephalographic sleep recordings, as well as other laboratory tests, may help the clinician to differentiate anxiety from depressive disorders.

Genomewide linkage scan of schizophrenia in a large multicenter pedigree sample using single nucleotide polymorphisms

A genomewide linkage scan was carried out in eight clinical samples of informative schizophrenia families. After all quality control checks, the analysis of 707 European-ancestry families included 1615 affected and 1602 unaffected genotyped individuals, and the analysis of all 807 families included 1900 affected and 1839 unaffected individuals. Multipoint linkage analysis with correction for marker–marker linkage disequilibrium was carried out with 5861 single nucleotide polymorphisms (SNPs; Illumina version 4.0 linkage map). Suggestive evidence for linkage (European families) was observed on chromosomes 8p21, 8q24.1, 9q34 and 12q24.1 in nonparametric and/or parametric analyses. In a logistic regression allele-sharing analysis of linkage allowing for intersite heterogeneity, genomewide significant evidence for linkage was observed on chromosome 10p12. Significant heterogeneity was also observed on chromosome 22q11.1. Evidence for linkage across family sets and analyses was most consistent on chromosome 8p21, with a one-LOD support interval that does not include the candidate gene NRG1, suggesting that one or more other susceptibility loci might exist in the region. In this era of genomewide association and deep resequencing studies, consensus linkage regions deserve continued attention, given that linkage signals can be produced by many types of genomic variation, including any combination of multiple common or rare SNPs or copy number variants in a region.