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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.Molecular Psychiatry (2005) 10, 598-605. doi:10.1038/sj.mp.4001615 Published online 7 December 2004 [ABSTRACT FROM AUTHOR]

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 α3 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. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article on HTR2C (cys23ser) polymorphism influences early onset in bipolar patients in a large European multicenter association study.

THIS STUDY PROVIDE A LITERATURE REVIEW TO BETTER UNDERSTAND THE INVOLVEMENT OF THE CEREBELLUM IN COGNITION. ANIMAL TESTING HAS HELPED, FIRST, TO HIGHLIGHT THE CONNECTIONS BETWEEN THE CEREBELLUM AND THE FRONTAL CORTEX. THEN, IN HEALTHY SUBJECTS, BRAIN ANATOMY COULD BE BEST DESCRIBED THANKS TO NEW IMAGING TECHNIQUES AS FMRI: PEOPLE SHOW CEREBELLAR ACTIVATIONS DURING TASKS INVOLVING EXECUTIVE FUNCTIONS. PATIENTS WITH CEREBELLAR PATHOLOGY PRESENT AN IMPAIRMENT OF EXECUTIVE FUNCTIONS. SOME ABNORMALITIES WERE ALSO FOUND IN PATIENTS WITH PSYCHIATRIC DISORDERS, ESPECIALLY IN ADHD AND BIPOLAR DISORDER: THERE IS A REDUCTION IN THE VOLUME OF THE CEREBELLUM; AND IN ADHD, A HYPOACTIVATION IN TASKS INVOLVING WORKING MEMORY IN FMRI. WORK DONE DURING THE LAST DECADE ON THE CEREBELLUM DESCRIBES AND EXPLAINS PART OF ITS INVOLVEMENT IN COGNITION. [ABSTRACT FROM AUTHOR]

Abstract: Many association studies have reported associations between the catechol-O-methyltransferase (COMT) gene and psychiatric disorders including major depression (MDD). The COMT gene has further been associated with suicidal behaviour, as well as with treatment response, although with conflicting results. In the present study, we further elucidate the impact of COMT in treatment response in MDD patients with suicide risk and/or a personal history of suicide attempts. Two hundred fifty MDD patients were collected in the context of a European multicentre resistant depression study and treated with antidepressants at adequate doses for at least 4weeks. Suicidality was assessed using Mini International Neuropsychiatric Interview (MINI) and the Hamilton Rating Scale for Depression (HAM-D). Treatment response was defined as HAM-D≤17 and remission as HAM-D≤7 after 4weeks of treatment with antidepressants at adequate dose. Genotyping was performed for seven SNPs (rs4680, rs2075507, rs737865, rs6269, rs4633, rs4818 and rs165599) within the COMT gene. With regard to suicide risk and personal history of suicide attempts, neither single marker nor haplotypic association was found with any SNP after multiple testing correction. In non-responders, we found significant single marker and haplotypic association with suicide risk, but not in responders. The same holds true for both remitters and non-remitters, and when testing for association with a personal history of suicide attempts and treatment response phenotypes. In conclusion, we found significant association of COMT SNPs with suicide risk in MDD patients not responding to antidepressant treatment. Larger well-defined cohorts will be required to dissect this further. [Copyright &y& Elsevier]

Abstract: Controversial evidence exists regarding the presence of the phenomenon of anticipation in affective disorder. To further evaluate this hypothesis on the unipolar pattern of the disease, we examined 21 two-generation pairs of first and second degree relatives with unipolar recurrent major depression. Biases from index-patient and from unaffected sibs were taken into consideration. A significant difference in the age at onset and episode frequency (as measure of disease severity) between parental and offspring generation was observed. The median age at onset of the parental generation was 37±8.2 years compared to 22±8.3 years in the offspring generation (p=0.001). The offspring generation also experienced an episode frequency two times greater than the parent generation (p=0.001). Anticipation was demonstrated in 95% of pairs regarding age at onset and in 84% of pairs in episode frequency. However, the observation of a birth cohort effect may possibly explain the differences in age at onset between generations in our sample. [Copyright &y& Elsevier]

We previously identified 18q21-q22 as a candidate region for bipolar (BP) disorder and constructed a yeast artificial chromosome (YAC) contig map. Here we identified three potential CpG islands using CCG/CGG YAC fragmentation. Analysis of available genomic sequences using bioinformatic tools identified an exon of 3639 bp downstream of a CpG island of 1.2 kb containing a putative transcription initiation site. The exon contained an open reading frame coding for 1212 amino acids with significant homology to the SART-2 protein; weaker homology was found with a series of sulphotransferases. Alignment of cDNA sequences of corresponding ESTs and RT-PCR sequencing predicted a transcript of 9.5 kb which was confirmed by Northern blot analysis. The transcript was expressed in different brain areas as well as in multiple other peripheral tissues. We performed an extensive mutation analysis in 113 BP patients. A total of nine single nucleotide polymorphisms (SNPs) were identified. Five SNPs predicted an amino acid change, of which two were present in BP patients but not in 163 control individuals. [ABSTRACT FROM AUTHOR]

Self-esteem (SE) and social adjustment (SA) are often impaired during the course of affective disorders; this impairment is associated with suicidal behaviour. The aim of the present study was to investigate SE and SA in unipolar or bipolar patients in relation to demographic and clinical characteristics, especially the presence of suicidality (ideation and/or attempt). Forty-four patients, 28 bipolar and 16 unipolar, in remission for at least 3 months, and 50 healthy individuals were examined through a structured clinical interview. SE and SA were assessed by the Rosenberg self-esteem scale and the social adjustment scale, respectively. The results have shown that bipolar patients did not differ from controls in terms of SE, while unipolar patients had lower SE than bipolars and controls. No significant differences in the mean SA scores were found between the three groups. Suicidality during depression was associated only in bipolar patients with lower SE at remission; similar but not as pronounced was the association of suicidality with SA. It is concluded that low SE lasting into remission seems to be related to the expression of suicidality during depressive episodes of bipolar patients, while no similar pattern is evident in unipolar patients. [Copyright &y& Elsevier]

Cloninger's Temperament and Character Inventory (TCI) personality profile was used to compare alcohol-dependent patients with non-psychiatric control subjects, and a search made for sub-types of alcoholics with different TCI profiles, using the criteria age of onset of alcohol-related problems, paternal dependence on alcohol and familial antecedents of alcohol dependence. Alcohol-dependent patients (n = 38) were characterized by higher Novelty-Seeking [corresponding to Diagnostic and Statistical Manual of Mental Disorders (4th edition) group B personality type] and lower Self-Directedness than non-psychiatric control subjects (n = 47). Lower Self-Directedness indicates a higher probability of personality disorder in the alcohol-dependent population. Only age of onset of alcohol-related problems delineated the two sub-populations with different TCI profiles: early-onset alcoholics (≤25 years of age, n = 19), but not late-onset ones (n = 16), in comparison with control subjects, were associated with higher Novelty-Seeking. Both early and late-onset patients scored lower on Self-Directedness than control subjects. Self-Directedness and Cooperation scores were lower in early-onset than in late-onset patients. These results in part support Cloninger's typology, and the TCI data add to evidence concerning a higher probability of personality disorder in alcohol-dependent patients, particularly those with early-onset. [ABSTRACT FROM AUTHOR]

Studies the variability of the serotonin 5-HT2C receptor csy23ser polymorphism among European populations and vulnerability to affecive disorder. Implication of the modification of serotonergic neurotransmission in the mechanism of action of antidepressant drugs; Result of the logistic regression analysis; Significance of the findings in the pathogenesis of major affective disorder.

A letter to the editor is presented about acute Balint's syndrome.

A letter to the editor is presented about a case of an isolated progressive amnesia associated with the London mutation Val717Ile in the amyloid precursor protein gene.

Describes the case of a 14-year-old girl presenting with akinetic catatonia. Regional cerebral glucose metabolism; Decrease of metabolism in a large prefrontal area, the right anterior cingulate and the right medial frontal cortices; Relative increase of metabolism in primary motor cortices.

Many association studies have reported associations between the brain-derived neurotrophic factor (BDNF) gene and psychiatric disorders including major depression (MDD). The BDNF gene has further been associated with suicidal behaviour, as well as with treatment response, although with conflicting results. In the present study, we further elucidate the impact of BDNF in MDD patients with suicide risk and/or a personal history of suicide attempts. Two hundred fifty MDD patients were collected in the context of a European multicentre resistant depression study and treated with antidepressants at adequate doses for at least 4 weeks. Suicidality was assessed using Mini International Neuropsychiatric Interview (MINI) and Hamilton Rating Scale for Depression (HAM-D). Treatment response was defined as HAM-D≤17 and remission as HAM-D≤7 after 4 weeks of treatment with antidepressants at adequate dose. Genotyping was performed for eight SNPs within the BDNF gene. With regard to suicide risk and personal history of suicide attempts, neither single marker nor haplotypic association was found with any SNP after multiple testing correction. However, in gender-specific analyses, we found haplotypic association with suicide risk in males, but not in females (rs925946-rs10501087-rs6265, rs10501087-rs6265-rs122733). The only single-marker association with suicide risk in males (rs908867) did not resist multiple testing correction. No significant associations were found in gender-specific analyses with regard to a personal history of suicide attempts. In conclusion, we found two BDNF haplotypes significantly associated with suicide risk in male MDD patients. However, replication in larger well-defined cohorts is required to dissect this further. [ABSTRACT FROM AUTHOR]

Suicidal behaviour runs in families and the existence of genetic vulnerability to suicidality is well-established. Mental disorders, especially depression, are present in more of 90% of suicides. The incidence of treatment emergent suicidal ideation in major depression (MDD) varies from 4% to 20%, depending on the definition of suicidal ideation and sample characteristics. In the present study, we further elucidated the impact of depression candidate genes in treatment emergent suicidal ideation in MDD. One hundred-seventy MDD patients were collected in the context of a resistant depression study and treated with antidepressants at adequate doses for at least 4 weeks. MDD subjects were genotyped for SNPs within the COMT gene, BDNF, DTNBP1, 5HT1A, 5HT2A, GNB3, GRIK4, PTGS1, PTGS2, CREB, and cytochrome P450 CYP1A2, CYP2C9, CYP2C19 and CYP2D6 gene. Response, remission and treatment resistance, as well as suicidality information derived from Mini International Neuropsychiatric Interview (MINI) and Hamilton Rating Scale for Depression (HAM-D) were recorded. A quantitative and measure of suicidal behaviour was defined using the Hamilton rating scale (score 0 to 4) and the MINI-item (yes/no) on suicidality in a large cohort of depression cases. In addition, we tested for association with ‘serious suicidal attempts’ corresponding to a HAMD score of 4 (discrete trait analyses). Results of this candidate gene approach in treatment emergent suicidal ideation in MDD will be presented and discussed. [ABSTRACT FROM AUTHOR]