Marie-Chantal Bourdel

Brain Derived Neurotrophic Factor (BDNF) gene variants association with age at onset and therapeutic response in schizophrenia

Schizophrenia is a heterogeneous disease involving genetic and environmental factors. The frequency of structural brain abnormalities1, 2 or physical anomalies3supports a neurodevelopmental etiology, especially in early onset schizophrenia.4Brain-Derived-Neurotrophic-Factor (BDNF) is involved in the neurodevelopment of dopaminergic (DA)-related systems5, 6 and interacts with the meso-limbic DA systems,7, 8, 9, 10 involved in the therapeutic response to antipsychotic drugs11 and substance abuse.12 In addition, BDNF promotes and maintains dopamine D3 receptor (DRD3) expression.13 In a French Caucasian population, we found no statistical difference in allele or genotype distribution of the BDNF gene dinucleotide repeat polymorphism (166–174 bp)14 between the whole group of schizophrenic patients and controls. By contrast, an excess of the 172–176 bp alleles was found in patients with late onset, in neuroleptic-responding patients and in non-substance-abusing patients. BDNF gene variants thus appear to be associated with developmental features of schizophrenia. In addition, this association with good treatment responding was independent from the association found with the DRD3 BalI gene polymorphism in the same population.15 These results suggest an independent contribution of each gene to a treatment-sensitive form of schizophrenia.

Prevalence of smoking in psychiatric patients

Compelling evidence that tobacco-smoking is a form of drug addiction exists. The aim of this study is to determine the following: (1) prevalence of tobacco-smoking and of nicotine dependence in French psychiatric patients; (2) rates and patterns of tobacco smoking and of nicotine dependence according to diagnosis; (3) relationship between current smoking status and antipsychotic medications; and (4) relationship between cigarette smoking and neurological side effects induced by neuroleptics. A population of 711 psychiatric in- and outpatients was assessed using: (1) a detailed smoking self-questionnaire for smoking history and nicotine dependence; and (2) a questionnaire for staff covering treatments and DSMIII-R diagnoses. Data were analyzed using chi2 analysis of variance (ANOVA) tests (one factor) for quantitative comparisons between groups of patients, and analysis of covariance (ANCOVA) test with age covariate was performed for age-dependent variables. Prevalence of smoking in the population of psychiatric patients was significantly higher than in the French general population. Diagnoses among current smokers were mainly substance-related disorder and schizophrenia. The authors established correlations between prevalence of smoking and age, sex, marital and socioeconomic status, alcohol use, coffee consumption and other psychoactive substance use or abuse. The authors did not find relationship between smoking prevalence and institutionalization. Neuroleptic neurological side effects were significantly fewer among smokers compared to nonsmokers. However, the rate of smokers was significantly higher in psychiatric patients receiving neuroleptic drugs. Nicotine abuse in psychiatric patients, and especially in schizophrenic patients, could support the hypothesis that smoking is consistent with self-medication.

The cortical serotonin2 receptors studied with positron-emission tomography and [18F]-setoperone during depressive illness and antidepressant treatment with clomipramine.

BACKGROUND Changes in serotonin (5-HT)2 receptor densities were reported in depression by postmortem studies and following treatment with tricyclic antidepressants in animal studies. Here, 5-HT2 receptors were studied in vivo in depressed patients. METHODS Cortical 5-HT2 receptors were investigated prospectively using positron-emission tomography and [18F]-setoperone in 7 depressed patients, before and after at least 3 weeks of clomipramine (CMI), 150 mg daily. They were compared to 7 age-matched controls. RESULTS There was no significant difference between the untreated patients and the controls, except in the frontal region, where the [18F]-setoperone specific binding was slightly lower in patients. After CMI treatment, depression scores significantly improved and [18F]-setoperone specific binding decreased in cortical regions, suggesting receptor occupancy and/or receptor regulation, by CMI; however, no clinical score correlated with the 5-HT2 receptor measurements either in the untreated or in the treated conditions. CONCLUSIONS These data substantiate the view that tricyclic antidepressants such as clomipramine significantly interact with cortical 5-HT2 serotoninergic receptors in actual therapeutic situations.

Absence of association between a polymorphic GGC repeat in the 5' untranslated region of the reelin gene and autism

Autism is a complex neurodevelopmental disorder with severe cognitive and communication disabilities, that has a strong genetic predisposition.1 Reelin, a protein involved in neuronal migration during development, is encoded by a gene located on 7q22,2 within the candidate region on 7q showing increased allele sharing in previous genome scans.3–8 A case/control and family-based association study recently reported a positive association between a trinucleotide repeat polymorphism (GGC) located in the 5′ untranslated region (UTR) of the reelin gene and autism.9 We performed a transmission disequilibrium test (TDT) analysis of the 5′UTR polymorphism in 167 families including 218 affected subjects (117 trios and 50 affected sib pairs) and found no evidence of linkage/association. Our results do not support previous findings and suggest that this GGC polymorphism of the reelin gene is unlikely to be a major susceptibility factor in autism and/or genetic heterogeneity.

Homozygosity at the dopamine D3 receptor gene is associated with opiate dependence

Anatomical, pharmacological and human post-mortem studies suggest the dopamine D3 receptor (DRD3) gene as a candidate for drug dependence. We thus performed an association study of the Bal I polymorphism at the DRD3 gene, including 54 opiate addicts and 70 controls. Opiate addicts had a higher sensation-seeking score (on the Zückerman scale) than controls (P = 0.001), particularly a subgroup (70%) who had a distinctly higher score, exceeding 24. There were no marked differences in genotypes between patients as a whole and controls. However, patients with a sensation-seeking score above 24 were more frequently homozygotes for both alleles than patients with a sensation-seeking score under 24 (P = 0.038) or controls (P = 0.034). Although obtained in a sample of limited size, these results suggest that the DRD3 gene may have a role in drug dependence susceptibility in individuals with high sensation-seeking scores. This hypothesis is consistent with the role of DRD3 in mediating responses to drugs of abuse in animals and the association of homozygosity at the Bal I polymorphism with drug abuse in schizophrenic patients (see companion article by Krebs et al).

Dopamine D3 receptor gene variants and substance abuse in schizophrenia

In an association study of the Bal I polymorphism in the dopamine D3 receptor (DRD3) gene in a French Caucasian population, global comparison of patients with schizophrenia (n = 89, DSM-III-R criteria) and controls (n = 52) led to non-significant differences. However, the homozygosity was significantly more frequent in schizophrenic patients with lifetime substance abuse comorbidity (n = 36) as compared to patients with no history of substance abuse (P = 0.010) or to controls (P = 0.047) and in neuroleptic responder patients as compared to treatment-refractory patients (n = 19; P = 0.037). The combined characteristics treatment response and lifetime substance abuse were strongly associated with homozygosity. We propose that homozygosity for the Bal I polymorphism DRD3 gene is associated with predisposition to substance abuse and/or the pharmacosensitive characteristic of schizophrenia rather than with schizophrenia itself, an hypothesis in agreement with the positive association of this polymorphism with opiate dependence (see companion article by Duaux et al) and the involvement of DRD3 in both pharmacodependence mechanisms and antipsychotic effects of neuroleptics.

Neurological soft-signs and minor physical anomalies in schizophrenia: differential transmission within families

Markers of vulnerability have been identified in schizophrenia, and among them, neurological soft-signs (NSS) and minor physical anomalies (MPAs) also seem to occur in biological relatives. The similarities of these developmental markers within families may depend on either genetic or non-genetic factors. The aim of the study was to investigate the intra-familial similarities of NSS and MPAs within 18 nuclear families (18 probands with schizophrenia and 36 of their non-psychotic parents). A general linear model showed similarities within families for NSS (intra-class coefficient [ICC] = 0.64; F = 2.6; df = 17.17; p = 0.02) but not for MPAs (ICC = -0.10; F = 0.7; df = 17.17; ns). We thus found a direct evidence for the intra-familial transmission of NSS but not of MPAs, suggesting that this morphological phenotypic trait could be more dependent on epigenetic influences.

Population-based and family-based association study of 5'UTR polymorphism of the reelin gene and schizophrenia

Reelin is a glycoprotein involved in the migration and positioning of proliferating neurons and synaptic connectivity during neurodevelopment. It may also modulate neuronal plasticity throughout life. Therefore, the reelin gene is a candidate gene for schizophrenia. We examined the association of the CGG repeat polymorphism in the 5′‐untranslated region of the reelin gene with schizophrenia in 266 unrelated French Caucasian patients, 156 of their parents, and 103 controls. We found no difference in the allele distribution between patients and controls although there was a significant higher prevalence of the genotype 8‐8 in controls (CLUMP T3: χ2 = 6.3, P = 0.035). There was no significant transmission disequilibrium in intrafamilial analysis. To refine our phenotypic characterization and in accordance with converging evidence suggesting that treatment resistance is associated with indices of abnormal neurodevelopment, we studied the association between reelin gene polymorphism and response to antipsychotics. Patients who responded to antipsychotics had a higher frequency of both the (CGG)10 allele and (CGG)10‐containing genotypes (P = 0.02; P = 0.006, respectively), with an odd ratio for genotypes of 4.2 (CI = [1.4;12.4]). Our results weakly support an association of reelin gene variants with schizophrenia as a whole, yet suggest that reelin could be associated with treatment‐resistant schizophrenia.

Plasma melatonin and cortisol in patients with obsessive–compulsive disorder: relationship with axillary temperature, physical activity, and clinical symptoms

BACKGROUND Many studies have found biological abnormalities in obsessive-compulsive disorder (OCD), although most of them have not been replicated. The investigation of melatonin rhythm may thus provide an indirect clue to neurotransmitter alterations, and allow a biological comparison with depression. METHODS The circadian variations of plasma melatonin, plasma cortisol, axillary temperature, motor activity, and obsessive-compulsive symptoms have been documented on a circadian basis in 8 patients with OCD compared to 8 paired healthy volunteers. RESULTS The circadian pattern of axillary temperature was slightly different in OCD patients when compared to control subjects. No significant difference between the two groups could be observed for any other variable studied. CONCLUSIONS The discrepancies with previous studies are discussed on the basis of the methods used (patients and control subjects samples, biological measurement procedures). An alteration of temperature circadian rhythm hypothesis is suggested.

Impairment of predictive saccades in schizophrenia.

Using infrared oculography, we compared saccades toward predictable and pseudo-random visual targets in 19 neuroleptic-free patients with schizophrenia (including 13 neuroleptic-naïve patients) and in 29 age- and gender-matched healthy volunteers. Externally driven saccades were not different between patients and controls, whether or not the target was predictable. Anticipated saccades were specifically less accurate in the patients compared to the controls. The difference between primary gain of anticipated and non-anticipated saccades was markedly higher in the patients compared to controls (p = 0.003). These results point to a deficit in the early step of internally driven oculomotor planning in schizophrenia.