A longitudinal twin study of cluster A personality disorders.

BACKGROUND: While cluster A personality disorders (PDs) have been shown to be moderately heritable, we know little about the temporal stability of these genetic risk factors. METHOD: Paranoid PD (PPD) and schizotypal PD (STPD) were assessed using the Structured Interview for DSM-IV Personality in 2793 young adult twins from the Norwegian Institute of Public Health Twin Panel at wave 1 and 2282 twins on average 10 years later at wave 2. Using the program Mx, we fitted a longitudinal latent factor model using the number of endorsed criteria for PPD and STPD. RESULTS: The stability over time of the criteria counts for PPD and STPD, estimated as polychoric correlations, were +0.34 and +0.40, respectively. The best-fit longitudinal model included only additive genetic and individual-specific environmental factors with parameter estimates constrained to equality across the two waves. The cross-wave genetic and individual-specific environmental correlations for a latent cluster A factor were estimated to equal +1.00 and +0.13, respectively. The cross-time correlations for genetic and environmental effects specific to the individual PDs were estimated at +1.00 and +0.16-0.20, respectively. We found that 68% and 71% of the temporal stability of PPD and STPD derived, respectively, from the effect of genetic factors. CONCLUSION: Shared genetic risk factors for two of the cluster A PDs are highly stable in adults over a 10-year period while environmental risk factors are relatively transient. Over two-thirds of the long-term stability of the common cluster A PD liability can be attributed to genetic influences.

The interaction between TMEM161B (rs768705) and paranoid personality traits in relation to the risk of major depressive disorder: Results form a longitudinal study of 7642 Chinese freshmen.

BACKGROUND: Rs768705 (TMEM161B) is one of the identified single nucleotide polymorphisms related to major depressive disorder (MDD). Paranoid personality traits are independently associated with the risk of MDD. This study aimed to investigate the interaction effect between rs768705 (TMEM161B) and paranoid personality traits on the new-onset risk of MDD in Chinese freshmen. METHODS: A longitudinal study was conducted among 7642 Chinese freshmen without lifetime MDD at baseline in 2018. 158 new-onset MDD cases were ascertained in 2019. DNA samples were extracted to detect the genotype of rs768705. The diagnostic and statistical manual of mental disorders-IV criteria were used to determine MDD and personality disorder traits. Multiplicative interaction was assessed by logistic regression models. Tomas Andersson's method for calculating biological interactions was used to estimate the additive interaction. RESULTS: Rs768705(AG) (OR = 1.88, 95 % CI: 1.24-2.83) and paranoid personality traits (OR = 3.68, 95 % CI: 2.57-5.26) were significantly associated with the risk of MDD. The multiplicative interaction model with the product term of rs768705 and paranoid personality trait traits had a significant interaction effect (OR = 4.20, 95 % CI:1.62-10.91). There was also a significant additive interaction effect (RR = 7.08, 95 % CI:4.31-11.65) for the incidence of MDD. Seventy seven percent patients among new MDD cases were attributed to the additive interaction effect between rs768705 and paranoid personality traits. CONCLUSIONS: Rs768705 (AG) may interact with paranoid personality traits to increase the incidence of MDD among Chinese college students. Schools and psychosocial health organizations should pay more attention to individuals with paranoid personality traits for MDD intervention and prevention.

Effects of interaction of NOS1AP gene polymorphisms and childhood abuse on paranoid personality disorder features among male violent offenders in China.

BACKGROUND: Paranoid Personality Disorder (PPD) results from a complex synergy between genetic and environmental factors. Childhood abuse is one of risk factors. Nitric Oxide Synthase 1 Adaptor Protein (NOS1AP) is a candidate gene of schizophrenia, which has similar pathophysiology to PPD. This study investigated the role of NOS1AP gene polymorphisms and a history of childhood abuse in predicting PPD features among male violent offenders in the Chinese Han population. METHOD: Four NOS1AP Single Nucleotide Polymorphisms (SNPs), rs4145621, rs3751284, rs348624 and rs6680461 were genotyped in a sample of 423 male prisoners. Participant evaluations included demographic information, measures of childhood abuse (Child Trauma Questionnaire, CTQ), and PPD features (Personality Diagnostic Questionnaire-4, PDQ-4). Participants were divided into a PPD group and non-PPD group assessed by PDQ-4. RESULTS: Regression analysis revealed that emotional abuse, NOS1AP SNPs rs348624 and rs4145621 predicted PPD features (P < 0.05) among prison samples. Significant interactions between childhood abuse history and NOS1AP SNPs rs3751284 and rs6680461 were also observed. Individuals carrying the C allele of rs3751284 were susceptible to PPD features when exposed to higher levels of emotional neglect (P < 0.05); Individuals with the G allele of rs6680461 were susceptible to PPD features when exposed to higher levels of emotional, physical and sexual abuse (P < 0.01). CONCLUSIONS: These results suggest that the interaction between childhood abuse and NOS1AP gene polymorphisms may have an influence on PPD features, at least in male violent offenders.

Schizotypal traits, neurocognition, and paternal age in unaffected first degree relatives of patients with familial or sporadic schizophrenia.

Studies comparing cognitive processes between familial and sporadic schizophrenia have yielded inconsistent findings. In this study we examined differences in neurocognition and schizotypal traits in unaffected relatives of schizophrenia-spectrum patients with either the familial (multiplex) or the sporadic (simplex) subtype of the disorder, taking paternal age at birth into consideration. Simplex (n = 65; SR), multiplex (n = 35; MR) relatives and controls (n = 114) were compared on several cognitive functions and schizotypal traits; between-group differences were evaluated with and without including paternal age in the analyses. SR and MR had higher negative and paranoid traits compared with controls, but paternal age abolished the differences between the SR and control groups. When taking into account schizotypal traits and participants' age, controls outperformed MR in strategy formation and set-shifting and SR in psychomotor speed, set-shifting and executive working memory. After including paternal age in the analyses, controls outperformed MR in strategy formation, working memory and executive working memory and both groups in psychomotor speed and set-shifting. These findings suggest that multiplex relatives present with a "riskier" personality and cognitive profile when considering the effects of paternal age. Nevertheless, simplex relatives are impaired in fundamental cognitive processes, thus highlighting the detrimental effects of paternal age on neurocognition.

A descriptive case-register study of delusional disorder.

OBJECTIVE: A few empirically based studies' data on delusional disorder (DD) exist. We aim to describe sociodemographic and clinical correlates of DD and to identify clinical profiles associated to DD and its subtypes. METHODS: This is a case-register study based on all those subjects attending community mental health services within a geographically well-defined area. Four hundred and sixty-seven patients had been diagnosed as DD cases at psychiatric services serving a catchment area of some 607,494 inhabitants living in South Barcelona (Spain) during a three-year period (2001-2003). A thorough systematic review of computerised medical records was used to establish DSM-IV diagnosis, rendering a valid sample of 370 patients who fulfilled DSM-IV criteria for DD. Independent variables gathered include sociodemographic data, family and personal psychiatric history, and comorbid diagnoses on all DSM-IV axes (including GAF). We used descriptive and univariate statistical methods to explore sample frequencies and correlates across DD types. RESULTS: The mean age of the patients was 55 years and the sample had a mean GAF score of 51 suggesting a poor functionality; 56.5% of the patients were female. The most frequent DD types were persecutory (48%), jealous (11%), mixed (11%) and somatic (5%), whilst 23% qualified for the NOS type. Most frequent symptoms identified were self-reference (40%), irritability (30%), depressive mood (20%) and aggressiveness (15%). Hallucinations were present in 16% of the patients (6% tactile; 4% olfactory). Nearly 9% had a family history of schizophrenia (higher among those with the jealous subtype) and 42% had a comorbid axis II diagnosis (mostly paranoid personality disorder). Depression was significantly more frequent among the persecutory and jealous types. Finally, global functioning was significantly better among jealous and mixed types and worse amongst erotomanic and grandiose cases (p=0.008). CONCLUSIONS: In the absence of other similar empirical data, this modest study provides unique empirical evidence of some clinical and risk correlates of DD and its subtypes.

Gene expression study of mitochondrial complex I in schizophrenia and paranoid personality disorder.

OBJECTIVES: The aetiology and molecular mechanisms of schizophrenia (SCZ) and paranoid personality disorder (PPD) are not yet clarified. The present study aimed to assess the role of mitochondrial complex I and cell bioenergetic pathways in the aetiology and characteristics of SCZ and PPD. METHODS: mRNA levels of all genomic and mitochondrial genes which encode mitochondrial complex I subunits (44 genes) were assessed in blood in 634 SCZ, 340 PPD patients and 528 non-psychiatric subjects using quantitative real-time PCR, and associated comprehensive psychiatric, neurological and biochemical assessments. RESULTS: Significant expression changes of 18 genes in SCZ patients and 11 genes in PPD patients were detected in mitochondrial complex I. Most of these genes were novel candidate genes for SCZ and PPD. Several correlations between mRNA levels and severity of symptoms, drug response, deficits in attention, working memory, executive functions and brain activities were found. CONCLUSIONS: Deregulations of both core and supernumerary subunits of complex I are involved in the aetiology of SCZ and PPD. These deregulations have effects on brain activity as well as disorder characteristics.

[The concept of schizoidia in psychiatry : From schizoidia to schizotypy and cluster A personality disorders]. / Das Schizoidie-Konzept in der Psychiatrie : Von der Schizoidie über die Schizotypie zu den Cluster­A­Persönlichkeitsstörungen.

From a perspective of conceptual evolution schizoidia was initially considered to describe features both of the premorbid personality of schizophrenic patients and of the personalities of non-psychotic family members (Bleuler, Kahlbaum, Kraepelin). On a psychopatholocial level a close link to the complex basic symptom of autism was stressed. From the very beginnings of modern psychiatry schizoidia was discussed within a conceptual frame of schizophrenia spectrum disorders (Kretschmer, Hoch, Polatin). Approaches to operationalize these conceptual works laid the basis for the cluster A personalities in DSM-III. Due to the prominent concept of schizotypy (Kety, Rado, Meehl) three split up diagnostic categories of schizotypal, schizoid and paranoid personality disorders resulted. Cluster A personality disorders are frequent in community-based epidemiological studies. Health-care seeking behaviour due to primary personality-related problems, however, seems to be less paramount compared to cluster B and C personality disorders. Many family- and twin-based genetic studies convincingly stress a close link between schizotypal personality disorder and schizophrenia. This link is less pronounced for paranoid personality disorder, and even vanishingly low for schizoid personality disorder. From a perspective of schizophrenia spectrum disorders a vast amount of data from molecular genetic, neurobiological, neuropsychological and psychosocial research has impressingly confirmed this link for schizotypal personality disorder. Major research deficits, however, have to be noticed for paranoid and schizoid personality disorder.

The relationship between anxiety disorders and dimensional representations of DSM-IV personality disorders: A co-twin control study.

BACKGROUND: There is substantial comorbidity between personality disorders (PDs) and anxiety disorders (ADs). Sharing of familial risk factors possibly explains the co-occurrence, but direct causal relationships between the disorders may also exist. METHODS: 2801 persons from 1391 twin pairs from the Norwegian Institute of Public Health Twin Panel were assessed for all DSM-IV PDs and ADs. Bivariate Poisson-regression analyses were performed to assess whether PDs predicted ADs at three different levels: All PDs combined, PDs combined within DSM-IV-clusters and each individual PD separately. Next, bivariate co-twin control analyses were executed within monozygotic (MZ) and dizygotic (DZ) twin pairs. A similar analytic strategy was employed in multivariate models including PDs as independent variables. RESULTS: PDs predicted ADs at all levels of analysis in bivariate regression models. Bivariate co-twin control analyses demonstrated an increased risk of ADs in all PDs combined, all PD-clusters and in schizotypal, paranoid, borderline, antisocial, avoidant and dependent PD. In the multivariate regression model, all PD-clusters and schizotypal, borderline, avoidant and obsessive-compulsive PD predicted ADs. Only borderline and avoidant PD predicted ADs in the multivariate co-twin control analysis. LIMITATIONS: Over-adjustment may explain the results from the multivariate analyses. The cross-sectional study design hampers causal inference. CONCLUSIONS: Comorbidity between ADs and PDs can be largely accounted for by shared familial risk factors. However, the results are also consistent with a direct causal relationship partly explaining the co-occurrence. Our results indicate specific environmental factors for comorbidity of ADs and borderline and avoidant PDs that are not shared with other PDs.

Familial aggregation of schizophrenia and schizophrenia spectrum disorders. Evaluation of conflicting results.

In this issue, Coryell and Zimmerman report no significant increase in the risk of schizophrenia or "schizophrenia spectrum" personality disorders in relatives of schizophrenics vs never-ill controls. This article attempts to evaluate critically and interpret their findings. Given the modest number of relatives studied, their negative findings regarding schizophrenia could easily be the result of sampling variation. Relatives were assessed using a general personality disorder instrument, and over two thirds were interviewed by telephone; this method may have a low sensitivity to detect key features of the schizophrenia spectrum such as inadequate rapport and suspiciousness. True population differences may, however, exist in the pattern of familial aggregation for schizophrenia and related disorders. The convincing demonstration of this would be of considerable interest and should lead to a constructive search for the source of the interpopulation differences.

The heritability of schizophrenia and schizoaffective disorder. A family study.

Ninety-one consecutively admitted patients with schizophrenia (n = 21), schizoaffective depression (n = 43), or psychotic depression (n = 27) entered a blind family study along with 36 never-ill controls. Though schizophrenia spectrum disorders clustered within families, they were not significantly more prevalent in the families of schizophrenic probands. In contrast, morbid risks for affective disorder clearly separated the families of psychotically depressed probands from the families of both schizophrenics and controls. Family study data for schizoaffective probands indicated links to both affective disorder and schizophrenia and suggested, as well, that a small number of patients with schizoaffective disorder may carry a genetic liability to both conditions.

An independent analysis of the Danish Adoption Study of Schizophrenia. VI. The relationship between psychiatric disorders as defined by DSM-III in the relatives and adoptees.

In this report, modified DSM-III criteria were applied to all the available interviews with adoptees from the greater Copenhagen sample of the Danish Adoption Study of Schizophrenia. In the adoptees, reasonable agreement was found between our DSM-III diagnoses and the original diagnoses using global DSM-II-based criteria by Kety et al for their categories of chronic and acute, but not borderline, schizophrenia. Comparing DSM-III-based diagnoses in adoptees and relatives, schizophrenia, schizotypal personality disorder, and paranoid personality disorder were all significantly more common in the biologic relatives of schizophrenic v screened control adoptees. These three diagnoses, which together form a tentative "schizophrenia spectrum," were also significantly concentrated in the biologic relatives of adoptees with schizoaffective disorder, mainly schizophrenic subtype, and schizotypal personality disorder, but not in biologic relatives of adoptees with schizophreniform disorder or atypical psychosis.

Increased morbid risk for schizophrenia-related disorders in relatives of schizotypal personality disordered patients.

To evaluate whether probands from a clinical sample diagnosed as having DSM-III schizotypal and/or paranoid personality disorder have a familial relationship to the schizophrenia-related disorders, the morbid risk for schizophrenia-related disorders and other psychiatric disorders were evaluated in the first-degree relatives of patients with schizotypal and/or paranoid personality disorder and compared with the corresponding risk for these disorders in the first-degree relatives of patients with other non-schizophrenia-related personality disorders. The morbid risk for all schizophrenia-related disorders, and specifically for schizophrenia-related personality disorders, was significantly greater among the relatives of the probands with schizotypal and/or paranoid personality disorder than among the relatives of probands with other personality disorder. The morbid risk for other psychiatric disorders did not differ significantly between the first-degree relatives of the schizotypal/paranoid personality disorder and the other personality disorder control proband samples. These results suggest a specific familial association between schizophrenia-related disorders, particularly schizophrenia-related personality disorders, and clinically diagnosed schizotypal patients.

Independent diagnoses of adoptees and relatives as defined by DSM-III in the provincial and national samples of the Danish Adoption Study of Schizophrenia.

BACKGROUND: This report describes the independent application of DSM-III criteria to the adoptees and relatives in the Provincial sample of the Danish Adoption Study of Schizophrenia of Kety and colleagues. We report these results and combine them with those reported previously for the Copenhagen sample to form the National sample. METHODS: Personal interviews and institutional record summaries of adoptees and biological and adoptive relatives were "blindly" diagnosed using DSM-III criteria. "Schizophrenia spectrum" was a priori defined as schizophrenia; schizoaffective disorder, mainly schizophrenic subtype; and schizotypal and paranoid personality disorders. RESULTS AND CONCLUSION: In the Provincial sample, the prevalence of "spectrum" disorders was significantly greater in biological relatives of schizophrenia spectrum vs control adoptees. The results were also consistent with the genetic transmission of individual diagnoses within the spectrum. When combined into the National sample, the results provided strong evidence for (1) the genetic transmission of DSM-III schizophrenia; (2) a genetic relationship between DSM-III schizophrenia, mainly schizophrenic schizoaffective disorder, and schizotypal personality disorder; and (3) the absence of a significant genetic relationship between the schizophrenia spectrum and either psychotic nonspectrum disorders, major depression, or anxiety disorders. We found no evidence for the familial environment transmission of schizophrenia spectrum disorders. These results are consistent with the findings reported by Kety and coworkers from their diagnostic review.

Schizophrenia and schizophrenia-spectrum personality disorders in the first-degree relatives of children with schizophrenia: the UCLA family study.

BACKGROUND: This study tested the hypothesis that childhood-onset schizophrenia (COS) is a variant of adult-onset schizophrenia (AOS) by determining if first-degree relatives of COS probands have an increased risk for schizophrenia and schizotypal and paranoid personality disorders. METHODS: Relatives of COS probands (n = 148) were compared with relatives of attention-deficit/hyperactivity disorder (ADHD) (n = 368) and community control (n = 206) probands. Age-appropriate structured diagnostic interviews were used to assign DSM-III-R diagnoses to probands and their relatives. Family psychiatric history was elicited from multiple informants. Diagnoses of relatives were made blind to information about probands' diagnoses. Final consensus diagnoses, which integrated family history, direct interview information, and medical records, are reported in this article. RESULTS: There was an increased lifetime morbid risk for schizophrenia (4.95% +/- 2.16%) and schizotypal personality disorder (4.20% +/- 2.06%) in the parents of COS probands compared with parents of ADHD (0.45% +/- 0.45%, 0.91% +/- 0.63%) and community control (0%) probands. The parents of COS probands diagnosed as having schizophrenia had an early age of first onset of schizophrenia. Risk for avoidant personality disorder (9.41% +/- 3.17%) was increased in the parents of COS probands compared with parents of community controls (1.67% +/- 1.17%). CONCLUSIONS: The psychiatric disorders that do and do not aggregate in the parents of COS probands are remarkably similar to the disorders that do and do not aggregate in the parents of adults with schizophrenia in modern family studies. These findings provide compelling support for the hypothesis of etiological continuity between COS and AOS.

Personality disorder in the families of depressed, schizophrenic, and never-ill probands.

In a blind family study of 176 probands with nonpsychotic major depression, psychotic major depression, schizophrenia, or no history of DSM-III disorders, only the relatives of depressed probands with mood-incongruent psychotic features had a risk for personality disorders higher than that for the relatives of never-ill probands. The authors did not find a high rate of borderline personality in relatives of depressed probands or of schizotypal personality disorder in relatives of probands with schizophrenia or any psychosis. However, depressed probands with normal dexamethasone test results had a significantly higher familial loading for the DSM-III cluster of histrionic, antisocial, borderline, and narcissistic personality disorders.

A family history study of schizophrenia-related personality disorders.

This study examined whether the family history method can be used to detect cases of schizophrenia-related personality disorder in the families of schizophrenic patients. After proposing specific family history criteria for this diagnosis, the authors applied these criteria in a blind family history study and found that schizophrenia-related personality disorders were significantly more common in the first-degree relatives of schizophrenic patients than in the relatives of medically ill controls.

Diagnostic accuracy and linkage analysis: how useful are schizophrenia spectrum phenotypes?

OBJECTIVE: Numerous studies suggest that the nonschizophrenic relatives of schizophrenic patients exhibit psychiatric and other features that discriminate them from normal comparison subjects. These features have been put forth as "spectrum" phenotypes that may be variant manifestations of the schizophrenia genotype. However, most of these studies do not address a key measurement question: does the diagnostic accuracy of these spectrum classifications warrant their use in genetic linkage studies of schizophrenia? METHOD: The authors reviewed 30 studies of putative indicators of the schizophrenic genotype: schizotypal personality disorder, eye tracking dysfunction, attentional impairment, auditory evoked potentials, neurological signs, neuropsychological impairment, and allusive thinking. RESULTS: Although each of 42 measures of these indicators discriminated the relatives of schizophrenic patients from the normal comparison subjects, a diagnostic accuracy analysis suggested that only six of these would improve the informativeness of genetic linkage data. CONCLUSIONS: Many proposed spectrum phenotypes for schizophrenia may not be useful for linkage analysis because of high false positive rates (poor specificity). Future work aimed at describing and developing phenotypes for linkage analysis should assess the diagnostic accuracy of proposed measures.

A family study of schizophrenic and normal control probands: implications for the spectrum concept of schizophrenia.

Morbidity risks for mental illness were determined in 750 first-degree relatives of chronic schizophrenic and normal control probands. Psychiatric disorders that were more frequent in relatives of schizophrenic probands than in relatives of normal control probands were chronic schizophrenia (5.8% versus 0.6%), schizotypal personality disorder (definite, 14.6% versus 2.1%; probable, 12.1% versus 6.5%), and paranoid personality disorder (7.3% versus 2.3%). The data suggest that schizotypal and paranoid personality disorders are genetically related to schizophrenia. The implications for schizophrenia research are discussed.

Modern research criteria and the genetics of schizophrenia.

The authors assessed the relevance of narrowly defined diagnostic criteria to genetic research in schizophrenia in the nuclear families of 84 chronic schizophrenic probands compared with families of 90 normal control probands. The morbidity risk for narrowly defined schizophrenia in first-degree relatives of patients with the narrow diagnosis was significantly higher than the control rate (3.8% versus 0.3%). The rate of chronic schizophrenia in the relatives of all schizophrenic patients was also significantly higher than the control rate (7.1% versus 0.6%), as was the rate of "spectrum" disorders (33.4% versus 11.3%). The data support the case for familial transmission of narrowly defined schizophrenia.

Genetic boundaries of the schizophrenia spectrum: evidence from the Finnish Adoptive Family Study of Schizophrenia.

OBJECTIVE: Identification of the genetically related disorders in the putative schizophrenia spectrum is an unresolved problem. Data from the Finnish Adoptive Family Study of Schizophrenia, which was designed to disentangle genetic and environmental factors influencing risk for schizophrenia, were used to examine clinical phenotypes of schizophrenia spectrum disorders in adopted-away offspring of mothers with schizophrenia spectrum disorders. METHOD: Subjects were 190 adoptees at broadly defined genetic high risk who had biological mothers with schizophrenia spectrum disorders, including a subgroup of 137 adoptees at narrowly defined high risk whose mothers had DSM-III-R schizophrenia. These high-risk groups, followed to a median age of 44 years, were compared diagnostically with 192 low-risk adoptees whose biological mothers had either a non-schizophrenia-spectrum diagnosis or no lifetime psychiatric diagnosis. RESULTS: In adoptees whose mothers had schizophrenia, the mean lifetime, age-corrected morbid risk for narrowly defined schizophrenia was 5.34% (SE=1.97%), compared to 1.74% (SE=1.00%) for low-risk adoptees, a marginally nonsignificant difference. In adoptees whose mothers had schizophrenia spectrum disorders, the mean age-corrected morbid risk for a schizophrenia spectrum disorder was 22.46% (SE=3.56%), compared with 4.36% (SE=1.51%) for low-risk adoptees, a significant difference. Within the comprehensive array of schizophrenia spectrum disorders, schizotypal personality disorder was found significantly more often in high-risk than in low-risk adoptees. The frequency of the group of nonschizophrenic nonaffective psychoses collectively differentiated high-risk and low-risk adoptees, but the frequencies of the separate disorders within this category did not. The two groups were not differentiated by the prevalence of paranoid personality disorder and of affective disorders with psychotic features. CONCLUSIONS: In adopted-away offspring of mothers with schizophrenia spectrum disorders, the genetic liability for schizophrenia-related illness (with the rearing contributions of the biological mothers disentangled) is broadly dispersed. Genetically oriented studies of schizophrenia-related disorders and studies of genotype-environment interaction should consider not only narrowly defined, typical schizophrenia but also schizotypal and schizoid personality disorders and nonschizophrenic nonaffective psychoses.