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Genetic anticipation, a phenomenon characterized by increased severity of symptoms and earlier age at onset of a disease in successive generations, is believed to be present in schizophrenia. In several neurodegenerative diseases showing anticipation, the mutation causing the disease is an expanded trinucleotide repeat. Therefore, genes containing trinucleotide repeats prone to expansion have become a suitable family of candidate genes in schizophrenia. A human calcium-activated potassium channel gene (hSKCa3), possibly mapping to chromosome 22q11-13, a region previously linked to schizophrenia, was recently described. This gene contains two contiguous expressed CAG repeat stretches. Recently, long allelic variants of one of these CAG repeats were found to be overrepresented in schizophrenic patients compared to normal controls. In this study we attempted to replicate this result and to study the relationship between the length of this CAG repeat on the one hand and the severity and age at onset of the disease on the other hand. No association with the disease or correlation with the severity of schizophrenia was identified. In addition, hSKCa3 was mapped to chromosome 1. Our results do not support the involvement of this particular CAG repeat-containing gene in schizophrenia.

Although genes play a major role in the etiology of schizophrenia, no major genes involved in this disease have been identified. However, several genes with small effect have been reported, though inconsistently, to increase the risk for schizophrenia. Recently, the 5HT2A 2 allele (T102C polymorphism) was reported to be over-represented in patients with schizophrenia. Other reports have found an excess of allele 2(C) only in schizophrenic patients who are resistant to clozapine, not in those who respond to clozapine. In this study, the 5HT2A receptor allele 2 frequencies were compared between 2 groups of patients with schizophrenia (39 responders and 63 nonresponders) based on long-term outcome and response to typical neuroleptics. A control group of 90 healthy volunteers screened for mental disorders was also included. Genotype 2/2 tended to be more frequent in patients with schizophrenia with poor long-term outcome and poor response to typical neuroleptics (Bonferroni corrected p = 0.09). This difference was significant in men (Bonferroni corrected p = 0.054) but not in women. In addition, the age at first contact with psychiatric care was significantly younger in the patients with schizophrenia with genotype 2/2 than in patients with genotype 1/1. These result suggest that the 5HT2A-receptor gene may play a role in a subset of schizophrenia characterized by poor long-term outcome and poor response to neuroleptics.

A number of association studies have investigated the role of the monoamine oxidase A (MAOA) gene in the susceptibility to bipolar disorder. Although some studies have reported positive findings, there remains some controversy, because results from different studies have not been consistent. A common explanation for inconsistencies between studies is genetic heterogeneity. We have focused on lithium responsive bipolar disorder as a way to reduce heterogeneity. In this study, we investigated the role of MAOA in lithium responsive bipolar patients using association and linkage study designs. The investigation used 138 patients and 108 normal controls. In addition, 25 families were also studied. Our results were not supportive of a major role of MAOA in the predisposition to bipolar disorder.

Genetic anticipation, manifested by increased severity and earlier age-at-onset of the disease over successive generations, is reported in schizophrenia. The molecular basis of anticipation in several neurodegenerative diseases is unstable coding CAG repeat expansions. Anticipation was reported in schizophrenia. Recently, studies suggested that enlarged CAG/CTG repeats are over represented in schizophrenic patients compared to normal controls. Together, these observations suggest that unstable CAG repeats may play a role in the etiology of schizophrenia. The purpose of this study is to test for the presence of polyglutamine-expanded tracts, encoded by CAG repeats, in total protein extracts derived from lymphoblastoid cell lines of schizophrenic patients. Proteins from schizophrenic patients (n = 59) and normal controls (n = 73) were separated by means of SDS-polyacrylamide gel electrophoresis, wet blotted onto nitrocellulose membrane and probed with a monoclonal antibody (mab 1C2) recognizing expanded polyglutamine arrays. Three abnormal bands corresponding to protein(s) of molecular weight of approximately 50 kDa were identified in two unrelated schizophrenic patients and in a sibling of one of these patients. None of the normal controls tested positive for this abnormal band. These results suggest that expanded polyglutamine-containing proteins, though rare, may play a role in the pathogenesis of schizophrenia.

Several studies have indicated that patients with bipolar disorder (BD) who respond well to lithium prophylaxis constitute a biologically distinct subgroup. Lithium is thought to stabilize mood by acting at the phosphoinositide cycle. We have investigated a polymorphism located in the gene (PLCG1) that codes for a gamma-1 isozyme of phospholipase (PLC), an enzyme that plays an important role in the phosphoinositide second messenger system. A population-based association study and a family-based linkage study were carried out on patients who were considered excellent responders to lithium prophylaxis. Response to lithium was evaluated prospectively with an average follow-up of 14.4 +/- 6.8 years. The PLCG1 polymorphism was investigated in 136 excellent lithium responders and 163 controls. In addition, the segregation of this marker was studied in 32 families ascertained through lithium-responsive bipolar probands. The allele distributions between lithium-responsive bipolar patients and controls were different, with a higher frequency of one of the PLCG1 polymorphisms in patients (chi2 = 8.09; empirical P = 0.033). This polymorphism, however, confers only a small risk (OR = 1.88, CI 1.19-3.00). Linkage studies with the same marker yielded modest support for the involvement of this gene in the pathogenesis of BD when unilineal families were considered (Max LOD = 1.45; empirical P = 0.004), but not in the whole sample. Our results provide preliminary evidence that a PLC isozyme may confer susceptibility to bipolar disorder, probably accounting for a fraction of the total genetic variance. Whether this polymorphism is implicated in the pathogenesis of BD or in the mechanism of lithium response remains to be determined.

Tyrosine hydroxylase (TH) is a candidate gene extensively explored in several association studies of bipolar disorder (BD). However, because of conflicting results of independent studies and low statistical power of individual studies to detect small differences between cases and controls, reliable conclusions are difficult to formulate. A method to obtain more reliable conclusions about the involvement of the TH locus in the etiology of BD is meta-analysis. We undertook a meta-analysis of studies that investigated the association between BD and TH genetic markers. The studies were identified by means of computerized searches of several databases, and the scanning of review articles and the reference lists of the primary articles identified. More than 60 publications were reviewed, and 9 relevant articles were included in this meta-analysis, with an overall sample of 1,069 subjects (547 cases and 522 normal controls). The overall odds ratio (and confidence interval) based on combining the results of the studies was 1.02 (0.68-1.54). Test of the null hypothesis that the mean log odds ratio equals zero (chi2 = 0.11; 5 df; P > 0.05) indicated that there was no overall association between bipolar disorder and tyrosine hydroxylase.

Several studies have recently reported genetic linkage between markers located on the short arm of chromosome 6 and schizophrenia. Valid conclusions, however, are difficult to formulate because chromosomal markers that yielded positive results span a relatively large region of chromosome 6, and studies did not necessarily obtain consistent results with regard to the particular loci tested. Here, we report a meta-analysis of the results of linkage studies of schizophrenia that used chromosome 6p markers. After conducting a systematic search, nine different studies were selected for the analysis using defined criteria. Pooled P values were obtained for all common markers investigated and provided additional support for a major susceptibility locus for schizophrenia in this region. In addition, two markers located 2 cM apart, D6S274 and D6S285, provided the most significant results. These findings may help narrow the chromosomal region in the search for a major gene implicated in schizophrenia.

Although clozapine (CLZ) is effective in resistant schizophrenia, it fails in some cases leading to a therapeutic problem. Authors report a case of schizophrenia which resists several neuroleptic trials (including haloperidol, chlorpromazine and thioproperazine) and responds to a sequence of CLZ and amisulpride. These two atypical neuroleptics have the same main target (mesolimbic system) but have different and complementary affinities to neuromediator receptors: CLZ has strong serotoninergic and anticholinergic action, noradrenergic alpha 1 affinity and moderately active dopaminergic antagonism; amisulpride has a high and specific dopaminergic D2 antagonism when used at high posology. This clinical improvement can be related to "second treatment effect", described by Goldman in 1966: his study included two groups of refractory schizophrenic patients who received successively during two 6 months periods, 2 neuroleptics (fluphenazine and trifluperazine). Without initial therapeutic response, he noted a significant improvement only after change of neuroleptic medication. Tricyclic antidepressants may turn to be effective, after an initial failure, when they are given after an uneffective ECT trial. The same model may be applied and the clozapine-amisulpride sequence is proposed as an alternative treatment in resistant schizophrenia: even if CLZ is uneffective, it may produce carryover effects which ease the action of amisulpride. The hypothesis of an action on 5HT2-D2 antagonism is advanced. It leads to the general question of the opportunity of neuroleptic sequential prescription in resistant schizophrenia as a therapeutic option.

Through a review of the literature, the average mortality in schizophrenia is twice higher than among the population. This over mortality is highest among the 20-40 years range of age and added risk tends to disappear after 60 years. All studies stress the unnatural causes of death, suicide or accidental deaths. However several studies found an over mortality caused by natural death. The pathologies most often involved are: infections, lung, gastrointestinal, urogenital and cardiovascular diseases. Cancer mortality in schizophrenic patients is still debated. Some studies point out a reduced mortality compared to the general population whereas other studies find similar or over mortality. Nevertheless mortality ratio is found to be near 1 in the majority of studies. So it can be admitted that schizophrenic patient do really not differ from the general population in regard to cancer mortality. Premature death is highly linked to suicide. The epidemiological indicators that enable us to estimate the importance of suicide mortality are: the rate of suicide per 105 patients per year varies between 150 and 500, the percentage of death by suicide range between 10 and 15 percent. Suicide risk factors are numerous. Some of them are accepted as valid and others are still discussed. The former are: male gender, young and medium age ten first years of the illness course, associated depressive symptoms, past history of suicide attempts, iterative relapses and post hospital discharge period. The latter are: social isolation, celibacy, unemployment, high level of instruction, delusional and hallucinatory activity and familiar rejection.

The place of electroconvulsive therapy (ECT) in the treatment of affective disorders is presently important and even inequaled in some depressive illness forms. But ECT is still controversial and its indications in the treatment of schizophrenia remain debated. In order to evaluate the place of this "vielle thérapeutique du futur" (39) in the treatment of schizophrenia, we reviewed the literature of the two last decades and tried to answer these questions. 1) Is ECT effectiveness in treatment of schizophrenic symptoms proved? 2) What is the effectiveness of ECT compared with other efficacious treatment? 3) Does the ECT + neuroleptic combination provide some advantage? and in which cases? The literature provides many studies in the topic. However, a considerable proportion of these studies make no use of modern methodological criteria. We only consider papers which: --give a clear diagnostic definition in patients groups and control groups, --use a standardized method of treatment, --use quantitative tools to evaluate results, --randomize treatment and use, when possible, double blind design. 1) Curative effects of ECT in schizophrenic symptoms: Brandon et al. (14) compare two groups of schizophrenic patients diagnosed according to PSE for schizophrenia and receiving equivalent doses of neuroleptics. The first group receives ECT when the other one receives simulate ECT. The former improved significantly better than the later. The difference persists but is no longer significant from the forth week of treatment.(ABSTRACT TRUNCATED AT 250 WORDS)