Shared and specific susceptibility loci for schizophrenia and bipolar disorder: a dense genome scan in Eastern Quebec families.

The goal of this study was to identify susceptibility loci shared by schizophrenia (SZ) and bipolar disorder (BP), or specific to each. To this end, we performed a dense genome scan in a first sample of 21 multigenerational families of Eastern Quebec affected by SZ, BP or both (N=480 family members). This probably constitutes the first genome scan of SZ and BP that used the same ascertainment, statistical and molecular methods for the concurrent study of the two disorders. We genotyped 607 microsatellite markers of which 350 were spaced by 10 cM and 257 others were follow-up markers in positive regions at the 10 cM scan. Lander and Kruglyak thresholds were conservatively adjusted for multiple testings. We maximized the lod scores (mod score) over eight combinations (2 phenotype severity levels x 2 models of transmission x 2 analyses, affected/unaffected vs affected-only). We observed five genomewide significant linkages with mod score >4.0: three for BP (15q11.1, 16p12.3, 18q12-q21) and two for the shared phenotype, that is, the common locus (CL) phenotype (15q26,18q12-q21). Nine mod scores exceeded the suggestive threshold of 2.6: three for BP (3q21, 10p13, 12q23), three for SZ (6p22, 13q13, 18q21) and three for the CL phenotype (2q12.3, 13q14, 16p13). Mod scores >1.9 might represent confirmatory linkages of formerly reported genomewide significant findings such as our finding in 6p22.3 for SZ. Several regions appeared to be shared by SZ and BP. One linkage signal (15q26) appeared novel, whereas others overlapped formerly reported susceptibility regions. Despite the methodological limitations we raised, our data support the following trends: (i) results from several genome scans of SZ and BP in different populations tend to converge in specific genomic regions and (ii) some of these susceptibility regions may be shared by SZ and BP, whereas others may be specific to each. The present results support the relevance of investigating concurrently SZ and BP within the same study and have implications for the modelling of genetic effects.

A search for specific and common susceptibility loci for schizophrenia and bipolar disorder: a linkage study in 13 target chromosomes.

We report the first stage of a genome scan of schizophrenia (SZ) and bipolar disorder (BP) covering 18 candidate chromosomal areas. In addition to testing susceptibility loci that are specific to each disorder, we tested the hypothesis that some susceptibility loci might be common to both disorders. A total of 480 individuals from 21 multigenerational pedigrees of Eastern Québec were evaluated by means of a consensus best-estimate diagnosis made blind to diagnoses in relatives and were genotyped with 220 microsatellite markers. Two-point and multipoint model-based linkage analyses were performed and mod scores (Z, for max Z(max)) are reported. The strongest linkage signals were detected at D18S1145 (in 18q12; Z = 4.03) for BP, and at D6S334 (in 6p 22-24; Z(het) = 3.47; alpha = 0.66) for SZ. Three other chromosomal areas (3q, 10p, and 21q) yielded linkage signals. Chromosomes 3p, 4p, 5p, 5q, 6q, 8p, 9q, 11q, 11p, 12q, 13q, 18p and 22q showed no evidence of linkage. The 18q12 results met the Lander and Kruglyak (1995) criterion for a genome-wide significant linkage and suggested that this susceptibility region may be shared by SZ and BP. The 6p finding provided confirmatory evidence of linkage for SZ. Our results suggest that both specific and common susceptibility loci must be searched for SZ and BP.

Clinical and methodological factors related to reliability of the best-estimate diagnostic procedure.

OBJECTIVE: The reliability and accuracy of the best-estimate diagnostic procedure were examined, and factors associated with reliability were determined. METHOD: The subjects were 134 members of large multigenerational pedigrees densely affected by bipolar disorders or schizophrenia. Three best-estimate diagnoses were derived: first, by a research psychiatrist and research assistant unblind to the relatives' diagnoses; second, by two blind independent psychiatrists; third, by a panel of four blind psychiatrists. The subjects were characterized on several clinical and methodological variables, which were used to compare the agreements of two types of best-estimate diagnoses with the disagreements. RESULTS: There was satisfactory agreement between the unblind and blind consensus best-estimate diagnoses and between the two blind independent psychiatrists. Latent class analyses revealed that limited sensitivity was the main source of imperfect reliability. Confusability analyses revealed that the most problematic diagnostic distinctions involved schizoaffective disorder, which was confused with schizophrenia, bipolar I disorder, and schizophreniform disorder. Blindness significantly affected diagnostic outcome in latent class analyses. Moreover, for diagnostic disagreements, unblind diagnoses had greater continuity with the most predominant diagnosis in the pedigree than did blind diagnoses. Diagnostic disagreements were associated with the presence of mixed affective and psychotic symptoms, less diagnostic certainty, and shorter duration of illness. CONCLUSIONS: These results suggest that it is possible to identify cases that are more likely to lead to diagnostic disagreements in family and epidemiological studies and that blind diagnoses may help to prevent false positive diagnoses, which may be particularly detrimental to genetic linkage analyses.

6p24-22 region and major psychoses in the Eastern Quebec population. Le Groupe IREP.

Recent reports of a linkage trend in 6p24-22 for schizophrenia (SZ), in different samples, were tempered by the concurrent evidence of negative reports in other samples. In the studies showing positive results, different definitions of affection and a wide spectrum of diagnoses were used. Our objectives were not only to test for linkage at 6p24-22 in the Eastern Quebec population, but also to test whether this putative vulnerability locus was either selectively linked to schizophrenia (SZ), or to bipolar disorder (BP), or to both major psychoses. Parametric and nonparametric linkage analyses with 12 microsatellite markers in 6p24-p22 were performed on a sample of 18 large multigenerational pedigrees (N = 354) either affected by SZ, or by BP, or equally affected by both major psychoses (i.e., mixed pedigrees). Three affection definitions were usually tested in our program: one on schizophrenia (SZ), one on bipolar disorder (BP), and one that comprised SZ and BP under the hypothesis of a susceptibility locus common to both in major psychoses (common locus, CL). The results of parametric analyses did not support a major gene hypothesis. However, in one large mixed pedigree (#151), we observed with the common locus phenotype (CL) lod scores of 2.49 and 2.15, respectively, at the D6S296 and D6S277 loci under a dominant model. Our data suggest the presence of a potential vulnerability locus at 6p24-22 that could be related to both schizophrenia and bipolar affective disorder. These results may be seen as congruent with former studies that used schizoaffective as well as schizophrenia diagnoses as entry criteria for the affected families, and used an affection definition that comprised affective psychoses as well as schizophrenia.

Linkage results on 11Q21-22 in Eastern Quebec pedigrees densely affected by schizophrenia.

The 11q21-22 region is of interest for schizophrenia because several candidate genes are located in this section of the genome. The 11q21-22 region, including DRD2, was surveyed by linkage analysis in a sample (N = 242) made of four large multigenerational pedigrees densely affected by schizophrenia (SZ) and eight others by bipolar disorder (BP). These pedigrees were ascertained in a large area of Eastern Quebec and Northern New Brunswick and are still being extended. Family members were administered a "consensus best-estimate diagnosis procedure" (DSM-III-R criteria) blind to probands and relatives' diagnosis and to pedigree assignment (SZ or BP). For linkage analysis, 11 microsatellite polymorphism (CA repeat) markers, located at 11q21-22, and comprising DRD2, were genotyped. Results show no evidence of a major gene for schizophrenia. However, a maximum lod score of 3.41 at the D11S35 locus was observed in an affected-only analysis of one large SZ family, pedigree 255. Whether or not the positive linkage trend in pedigree 255 reflects a true linkage for a small proportion of SZ needs to be confirmed through the extension of this kindred and through replication.

Negative, psychoticism, and disorganized dimensions in patients with familial schizophrenia or bipolar disorder: continuity and discontinuity between the major psychoses.

OBJECTIVE: This study aimed to answer the following questions: 1) Can we reliably measure the psychopathologic dimensions of schizophrenia by using a lifetime frame and by rating acute and interepisode periods separately? 2) Can we reproduce in subjects with familial schizophrenia the characteristic three-factor structure of schizophrenic symptoms that has been found previously in general groups of schizophrenic patients? 3) Is the factor structure also present in familial bipolar disorder? METHOD: Lifetime measures of psychotic symptoms were taken through a slightly modified version of the Comprehensive Assessment of Symptoms and History for 138 patients with highly familial DSM-III-R schizophrenia (N = 51), bipolar disorder (N = 44), or spectrum disorders (N = 43). Symptoms were rated separately in the acute episodes and in the stabilized interepisode intervals across the patients' lives. RESULTS: A satisfactory level of reliability was obtained. In this highly familial study group, the positive/negative factorial distinction was replicated, as was a three-factor model similar to that observed in prior general groups of schizophrenic patients. These factors were also present in bipolar affective disorder. The negative, psychoticism, and disorganized factor model applied more to the acute phase of illness than to the stabilized state. CONCLUSIONS: These findings offer an empirical basis for testing biological or genetic variables in relation to negative/positive symptom dimensions, rather than diagnoses. Observations of a shared structure for schizophrenia and bipolar disorder suggest some continuity in the causes of these disorders.

Reliability of best-estimate diagnosis in genetic linkage studies of major psychoses: results from the Quebec pedigree studies.

OBJECTIVE: Diagnostic classification and reliability are critical in genetic linkage studies of schizophrenia and bipolar disorder. To establish an optimal diagnostic procedure, the authors drew 13 methodological elements from 38 major linkage studies and workshop reports. They determined reliability for a consensus best-estimate diagnostic method based on these 13 features. METHOD: Each of 59 subjects from several large multiplex pedigrees, densely affected by either schizophrenia or bipolar disorder, received a best-estimate diagnosis from unblind diagnosticians in the field and also from a panel of four research psychiatrists who were blind to the proband's and relatives' clinical status. The best estimate was based on personal diagnostic interviews, all available medical records, and family history data. RESULTS: The diagnostic concordance between the field team and the blind psychiatric board yielded 78% to 90% agreement for the whole sample (kappa = 0.83-0.88) and 71% to 87% agreement for the subjects given field diagnoses (kappa = 0.76-0.83). The diagnoses made by the unblind field diagnosticians were biased toward a greater severity (or certainty) level in the diagnostic hierarchy (schizophrenic or bipolar) and more consistency with the most prevalent diagnosis affecting the pedigree. CONCLUSION: Since several previous linkage studies used diagnoses made by diagnosticians who were not blind to the status of the probands and the relatives or did not use a consensus best-estimate diagnosis, further reliability studies of different aspects of the best-estimate method and of its effect on linkage studies are needed. Such research is imperative given the serious impact of diagnostic misclassifications on genetic linkage results.

[Complete neuroleptic withdrawal in patients with schizophrenia with intense symptoms and resistant to treatment]. / Sevrage neuroleptique complet chez des patients schizophrènes présentant une symptomatologie intense et résistant au traitement.

We report 2 studies evaluating the effects of a complete and progressive neuroleptic withdrawal on the symptomatology of 2 groups of 10 young chronically ill schizophrenic inpatients. In a preliminary open study, we compare the psychiatric symptomatology during a 4-week-period before the beginning of withdrawal and during a similar period following the end of withdrawal. We observe the significative improvement of the blunted affect, the deterioration of an aspecific psychiatric symptomatology (including irritability, excitement, hostility) and the non-modification of the specific schizophrenic symptomatology (in its 3 main components: positive signs, negative signs, disorganization). The second study (a double blind one) reports the effects of a complete neuroleptic withdrawal maintained during a longer period (8 weeks): 1. The improvement of the blunted affect is transiently observed during the 2 first weeks after the end of withdrawal but not after this time. 2. The deterioration of the aspecific psychiatric symptomatology by opposition to the non-significative modification of the specific schizophrenic symptomatology is a fact confirmed by this second study. Even if we can not exclude that the influence of neuroleptic withdrawal on the specific psychotic symptoms may require a longer time frame than 8 weeks to detect, this dichotomic evolution raises the problem of the specific action of neuroleptics in this particular category of patients.(ABSTRACT TRUNCATED AT 250 WORDS)

[The law of informed consent and its impasses in psychiatry]. / La règle du consentement éclairé et ses impasses en psychiatrie.

Every medical intervention is submitted to the rule of informed consent. Over the years, criteria of consent validity and exception situations have been defined. After a discussion of the difficult application of the informed consent rule in psychiatry, this article suggests an analysis of the motivations of a refusal of neuroleptic medication in 20 psychotic patients of a psychiatric hospital. The irrational motivations of refusal (particularly, denial and delusional ideation) have been evoked much more often then rational motivations (therapeutic inefficiency, secondary effects). The authors question the denial as a sufficient reason to declare a psychotic patient incompetent to consent. The consequences of the refusal of the neuroleptic treatment in some patients, mainly the risk of criminalization, are discussed.

[Importance of medical information for the institutionalized patient]. / Intérêt de l'information médicale au patient institutionnalisé.

Medical information given to patients, notably to psychiatric patients, is guided by laws. Before starting any treatment the patient's informed consent is needed. One of the criteria of validity for such a consent is adequate information of the subject. This study shows that certain factors interfere with the institutionalized patient's initial knowledge about medication, hospitalization and illness. It points out that learning is diminished by two factors: the diagnostic of schizophrenia and the length of stay in the hospital. However learning is not changed by severity of symptoms. On the other hand the initial knowledge level is diagnosis independent but altered in case of intense psychiatric symptomatology. Possible explanations of these data are discussed. In conclusion, the importance of the variable of learning capacity is shown in the practice of the informed consent for psychiatric patients. The learning capacity must be taken into account when the patient is informed. Finally, additional research on that subject is indicated particularly concerning the persons disabled by schizophrenia.

[Medicolegal aspects of tardive dyskinesia in the United States]. / Aspects médico-légaux des dyskinésies tardives aux Etats-Unis.

Tardive dyskinesia is by definition a neurological complication resulting from neuroleptic treatment. The exact role of neuroleptic drugs in the etiopathogenicity of this syndrome is discussed. The manifestation of dyskinesia in a patient who is under neuroleptics may involve the responsibility of a physician. The evolution of jurisprudence in the United States is analysed.