Formal thought disorder is a major feature of schizophrenia and other psychotic disorders. It is heritable, found in healthy relatives of patients with schizophrenia and other mental disorders but knowledge of specific genetic factors is lacking. The aim of this study was to search for biologically relevant high-risk variants. Formal thought disorder was assessed in participants in the Copenhagen Schizophrenia Linkage Study (N=236), a unique high-risk family study comprised of six large pedigrees. Microsatellite linkage analysis of formal thought disorder was performed and subsequent haplotype analysis of the implicated region using phased microsatellite and SNP genotypes. Whole genome sequencing (N=3) was used in the attempt to identify causative variants in the linkage region. Linkage analysis of formal thought disorder resulted in a single peak at chromosome 6(q26-q27) centred on marker D6S1277, with a maximum LOD score of 4.0. Phasing and fine mapping of the linkage peak identified a 5.5Mb haplotype (chr6:162242322-167753547, hg18) in 31 individuals, all belonging to the same pedigree sharing the haplotype from a common ancestor. The haplotype segregated with increased total thought disorder index score (P=4.9 × 10(-5)) and qualitatively severe forms of thought disturbances. Whole genome sequencing identified a novel nucleotide deletion (chr6:164377205 AG>A, hg18) predicted to disrupt the potential binding of the transcription factor MEF2A. The MEF2A binding site is located between two genes previously reported to associate with schizophrenia, QKI (HGNC:21100) and PDE10A (HGNC:8772). The findings are consistent with MEF2A deregulation conferring risk of formal thought disorder.
Establishing the genetics of physiological traits associated with schizophrenia may be an important first step in building a neurobiological bridge between the disease phenotype and its genetic underpinnings. One of the best known of the traits associated with schizophrenia is a disorder of smooth pursuit eye tracking (ETD), which is present in 50-80% of schizophrenia patients. ETD is more than three times more prevalent in the families of a schizophrenia patient than is schizophrenia itself. Arolt et al.  estimated LOD scores for ETD of 2.85 for D6S282 and 3.70 for D6S271, two markers on 6p21.1, as well as obtaining an indication of possible linkage for schizophrenia. Our sample comprised two large families in Denmark. Markers in the region that was implicated by the study of Arolt et al. [1996, 1999] were analyzed as part of a genome scan using the "latent trait (L.T.) model" for the co-transmission of schizophrenia and ETD that we had previously fitted to segregation analysis data from Norway. We obtained a LOD score of 2.05 for D6S1017, a marker within 3 cM of the positive markers obtained by Arolt et al. [1996, 1999]. We regard our results as independent evidence supporting the findings of Arolt et al. [1996, 1999] and also as support for the L.T. model as a way of combining the traits ETD and schizophrenia.
Registry-based studies have found no or weak associations between premorbid intelligence and the broad entity of affective spectrum disorder, but none of the studies compared bipolar/unipolar subgroups.
IQ and educational level were assessed at the draft board, and hospital diagnoses were followed up to the ages 43-54 years for 294 individuals hospitalized with bipolar disorder and 1434 with unipolar or depressive disorder. Controls comprised 20,531 individuals without psychiatric registration.
Mean IQs of 98.32 and 96.71 were observed for patients with bipolar and depressive disorder respectively. For both patient groups a unimodal, slightly negatively skewed distribution was observed. The difference between the two patient samples was not statistically significant (p=0.10), but both obtained lower mean scores than the controls (p
Concern has been expressed as to the reliability of clinical ICD-10 diagnosis of schizophrenia. This study was designed to assess the diagnostic reliability of the clinical ICD-10 diagnosis of schizophrenia in a random sample of Danish in- and outpatients with a history of psychosis. A sample of 100 subjects was assessed using the operational criteria OPCRIT checklist for psychotic and affective illness. The most recent principal and clinical ICD-10 diagnosis was compared with diagnoses generated by the OPCRIT instrument. Data documented very high sensitivity (93%) and positive predictive value (87%) of ICD-10 schizophrenia and an overall good agreement between clinical and OPCRIT-derived diagnoses (kappa=0.60). An even higher positive predictive value was obtained when diagnoses were amalgamated into a diagnostic entity of schizophrenia-spectrum disorders (98%). Near perfect agreement was seen between OPCRIT-derived ICD-10 and DSM-IV diagnoses (kappa=0.87). Thus, this study demonstrates high reliability of the clinical diagnosis of schizophrenia and even more so of the diagnosis of schizophrenia-spectrum disorder.
The identification of individuals carrying unexpressed genetic liability to schizophrenia is crucial for both etiological research and clinical risk stratification. Subclinical psychopathological features detectable in the nonpsychotic part of the schizophrenia spectrum could improve the delineation of informative vulnerability phenotypes. Inspired by Meehl's schizotaxia-schizotypy heuristic model, we tested anomalous subjective experiences (self-disorders, SDs) as a candidate vulnerability phenotype in a sample of nonpsychotic, genetically high-risk subjects. A total of 218 unaffected members of 6 extended multiplex families (assessed between 1989 and 1999 during the Copenhagen Schizophrenia Linkage Study) were stratified into 4 groups of increasing psychopathological expressivity: no mental illness (NMI), no mental illness with schizotypal traits (NMI-ST), personality disorders not fulfilling other personality disorders (OPDs), and schizotypal personality disorder (SPD). We tested the distribution of SDs among the subgroups, the effect of SDs on the risk of belonging to the different subgroups, and the effect of experimental grouping and concomitant psychopathology (ie, negative symptoms (NSs) and subpsychotic formal thought disorder [FTD]) on the chances of experiencing SDs. SDs distribution followed an incremental pattern from NMI to SPD. SDs were associated with a markedly increased risk of NMI-ST, OPDs, or SPD. The odds of SDs increased as a function of the diagnostic category assignment, independently of sociodemographics and concomitant subclinical psychopathology (NSs and FTD). The results support SDs as an expression of schizotaxic vulnerability and indicate a multidimensional model of schizotypy--characterized by SDs, NSs, FTD--as a promising heuristic construct to address liability phenotypes in genetically high-risk studies.
Cites: Am J Psychiatry. 1993 Nov;150(11):1661-78214174
Cites: Arch Gen Psychiatry. 1993 Sep;50(9):707-148357296
Cites: Schizophr Bull. 1994;20(3):481-937973465
Cites: Arch Gen Psychiatry. 1995 Apr;52(4):296-3037702446
Cites: Am J Psychiatry. 1995 May;152(5):749-547726315
Formal thought disorder (FTD), a major symptom of schizophrenia, is known to aggregate in families. Our aim was to examine the specificity of FTD in the schizophrenia spectrum disorders and the hypothesized linear aggregation of FTD within pedigrees. Six individuals with a diagnosis of schizophrenia were identified in the Copenhagen High-Risk study and each pedigree was centered on one of the six original schizophrenic probands' nuclear families. The 329 pedigree members in the study were considered at risk for schizophrenia spectrum disorders because most were genetically related to the originating schizophrenic probands. The participants were administered the Copenhagen Interview of Functional Illness to determine diagnoses and the Thought Disorder Index (TDI) was used to assess FTD. Individuals with a schizophrenia diagnosis had higher global levels of FTD, exhibited more severe types of FTD, and had a qualitatively different type of FTD than did participants with other diagnoses or no mental illness. Individuals with Cluster A diagnoses exhibited more FTD and FTD similar in quality to participants with schizophrenia. These results support the construct of a spectrum of schizophrenia conditions. There was a generally high level of FTD in the pedigrees, in part due to assortative mating in this sample. However, there was no apparent pattern of linear aggregation of FTD within the families.
To explore whether the diagnostic homogeneity in a daily, routine clinical activity changed visibly over two historical periods (the ICD-8 and the ICD-10 era) across and within five psychiatric in-patient clinics.
In this register study, we analyzed the discharge diagnoses from five university-affiliated departments of psychiatry in Denmark in two time periods: 1980-1985 (ICD-8) and 2001-2010 (ICD-10).
The synchronic inter-departmental diagnostic differences did not decrease in the ICD-10 era compared with ICD-8 era. Nor did the diachronic stability within each department become more homogeneous.
The diagnostic variability reflected by the diagnostic differences between the departments and by the diagnostic homogeneity within each department remained similar in the two historical periods with no evidence of an increased homogeneity of diagnostic habits after the introduction of the ICD-10.
There is a myriad of variables that affects the diagnostic variability over time that we were not able to control.