Correlates of hallucinations in schizophrenia: A cross-cultural evaluation.

INTRODUCTION: Demographic, clinical and familial factors may plausibly influence the manifestation of hallucinations. It is unclear if the pattern of the effects is similar in different environmental/cultural settings. AIMS: To evaluate factors associated with hallucination from a demographic, clinical and familial perspective in two distinct cultural settings. METHODS: Patients with a clinical diagnosis of schizophrenia (SZ) or schizoaffective disorder (SZA) were diagnosed systematically using DSM IV criteria. Two independent samples were recruited in India and USA using identical inclusion/exclusion criteria and assessment procedures (n=1287 patients total; 807 Indian and 480 US participants). The association of key demographic and clinical factors with hallucinations of different modalities was examined. To evaluate the impact of familial factors, we separately analyzed correlations among affected sibling pairs (ASPs, n=136, Indian; n=77, US). RESULTS: The prevalence of different modalities of hallucinations differed in the Indian and US samples, though the rank order of frequency was similar. The pattern of associations between selected variables and the risk of hallucinations was different across cultures, except for some correlations with indices of severity. No significant concordance was observed among the ASPs after correcting for multiple comparisons. CONCLUSIONS: The factors associated with hallucinations vary across environments. Our results are consistent with a multi-factorial etiology of psychopathology, but re-direct attention to endophenotypic features in the causal chain that precede the symptoms themselves.

Mice lacking the chromodomain helicase DNA-binding 5 chromatin remodeler display autism-like characteristics.

Although autism spectrum disorders (ASDs) share a core set of nosological features, they exhibit substantial genetic heterogeneity. A parsimonious hypothesis posits that dysregulated epigenetic mechanisms represent common pathways in the etiology of ASDs. To investigate this hypothesis, we generated a novel mouse model resulting from brain-specific deletion of chromodomain helicase DNA-binding 5 (Chd5), a chromatin remodeling protein known to regulate neuronal differentiation and a member of a gene family strongly implicated in ASDs. RNA sequencing of Chd5-/- mouse forebrain tissue revealed a preponderance of changes in expression of genes important in cellular development and signaling, sociocommunicative behavior and ASDs. Pyramidal neurons cultured from Chd5-/- cortex displayed alterations in dendritic morphology. Paralleling ASD nosology, Chd5-/- mice exhibited abnormal sociocommunicative behavior and a strong preference for familiarity. Chd5-/- mice further showed deficits in responding to the distress of a conspecific, a mouse homolog of empathy. Thus, dysregulated chromatin remodeling produces a pattern of transcriptional, neuronal and behavioral effects consistent with the presentation of ASDs.

Animal models to improve our understanding and treatment of suicidal behavior.

Worldwide, suicide is a leading cause of death. Although a sizable proportion of deaths by suicide may be preventable, it is well documented that despite major governmental and international investments in research, education and clinical practice suicide rates have not diminished and are even increasing among several at-risk populations. Although nonhuman animals do not engage in suicidal behavior amenable to translational studies, we argue that animal model systems are necessary to investigate candidate endophenotypes of suicidal behavior and the neurobiology underlying these endophenotypes. Animal models are similarly a critical resource to help delineate treatment targets and pharmacological means to improve our ability to manage the risk of suicide. In particular, certain pathophysiological pathways to suicidal behavior, including stress and hypothalamic-pituitary-adrenal axis dysfunction, neurotransmitter system abnormalities, endocrine and neuroimmune changes, aggression, impulsivity and decision-making deficits, as well as the role of critical interactions between genetic and epigenetic factors, development and environmental risk factors can be modeled in laboratory animals. We broadly describe human biological findings, as well as protective effects of medications such as lithium, clozapine, and ketamine associated with modifying risk of engaging in suicidal behavior that are readily translatable to animal models. Endophenotypes of suicidal behavior, studied in animal models, are further useful for moving observed associations with harmful environmental factors (for example, childhood adversity, mechanical trauma aeroallergens, pathogens, inflammation triggers) from association to causation, and developing preventative strategies. Further study in animals will contribute to a more informed, comprehensive, accelerated and ultimately impactful suicide research portfolio.

Psychiatric endophenotypes and the development of valid animal models.

Endophenotypes are quantifiable components in the genes-to-behaviors pathways, distinct from psychiatric symptoms, which make genetic and biological studies of etiologies for disease categories more manageable. The endophenotype concept has emerged as a strategic tool in neuropsychiatric research. This emergence is due to many factors, including the modest reproducibility of results from studies directed toward etiologies and appreciation for the complex relationships between genes and behavior. Disease heterogeneity is often guaranteed, rather than simplified, through the current diagnostic system; inherent benefits of endophenotypes include more specific disease concepts and process definitions. Endophenotypes can be neurophysiological, biochemical, endocrine, neuroanatomical, cognitive or neuropsychological. Heritability and stability (state independence) represent key components of any useful endophenotype. Importantly, they characterize an approach that reduces the complexity of symptoms and multifaceted behaviors, resulting in units of analysis that are more amenable to being modeled in animals. We discuss the benefits of more direct interpretation of clinical endophenotypes by basic behavioral scientists. With the advent of important findings regarding the genes that predispose to psychiatric illness, we are at an important crossroads where, without anthropomorphizing, animal models may provide homologous components of psychiatric illness, rather than simply equating to similar (loosely analogized) behaviors, validators of the efficacy of current medications or models of symptoms. We conclude that there exists a need for increased collaboration between clinicians and basic scientists, the result of which should be to improve diagnosis, classification and treatment on one end and to increase the construct relevance of model organisms on the other.

Reliability and validity in binary ratings: areas of common misunderstanding in diagnosis and symptom ratings.

Confusion may exist between the reliability of a binary rating (for example, schizophrenia versus not-schizophrenia) and its implications for validity. High reliability does not guarantee validity, but paradoxically, low reliability does not imply poor validity in all contexts. Changes in the base rate or in experimental design may indicate high validity even when the reliability was thought to be low. Attempts to improve the psychiatric nomenclature by increasing only reliability run the risk of the "attenuation paradox" where further increases in reliability will make the ratings less valid. Finally, the assumption of random error in making diagnoses does not always hold, so that statistical analyses must be adjusted accordingly. New statistical methods are needed to index only false-positive or false-negative rates in order to quantify the error that will reduce some validity coefficients.

Confirming unexpressed genotypes for schizophrenia. Risks in the offspring of Fischer's Danish identical and fraternal discordant twins.

Margit Fischer reported in 1971 that the risk of schizophrenia in the offspring of her Danish schizophrenic monozygotic twins and their normal cotwins was equal and not different from the risks in the children of schizophrenics in the literature. All of her identical and fraternal twins who had children and all of their offspring have been followed up through the Danish National Psychiatric Register as of 1985, some 18 years after study by Fischer. The morbid risk (age-corrected) for schizophrenia and schizophrenia-related disorders in the offspring of schizophrenic identical twins is 16.8%; it is 17.4% in their normal cotwins' offspring. The risks in the offspring of schizophrenic fraternal twins and their normal cotwins are 17.4% and 2.1%, respectively. The results suggest that discordance in identical twins may primarily be explained by the capacity of a schizophrenic genotype or diathesis to be unexpressed unless it is released by some kinds of environmental, including nonfamilial, stressors. Sporadic cases and phenocopies caused by cerebral abnormalities, diseases, or viruses would thus be deemphasized as necessary or sufficient explanatory causes for schizophrenia in our study but could account for some of the remaining discordance, infrequent phenocopies should encourage linkage researchers, but unexpression of genotypes will frustrate them.

Twin concordance for DSM-III schizophrenia. Scrutinizing the validity of the definition.

DSM-III diagnoses were applied to 26 monozygotic (MZ) and 34 dizygotic (DZ) probands and their co-twins from the Maudsley Hospital (1948 to 1965) schizophrenic series of Gottesman and Shields. DSM-III criteria for schizophrenia were found to be highly reliable and valid, and to have a broad heritability of 0.85, which is comparable with the Research Diagnostic Criteria and Feighner criteria from which they were derived. When the full range of DSM-III diagnoses were considered, both affective disorder and schizophrenia were found in genetically identical individuals. The effect of DSM-III nosology on the twin series was also explored by adding other diagnoses to that of schizophrenia and observing the effect on the MZ/DZ concordance ratio. The addition of affective disorder with mood-incongruent delusions to the schizophrenia spectrum produced the largest increase in the ratio and, by implication, a "more genetic" combination than schizophrenia alone. The maximum MZ/DZ concordance ratio (7.68) was produced by schizophrenia, plus affective disorder with mood-incongruent delusions, plus schizotypal personality disorder, plus atypical psychosis. The effect of adding paranoid disorder (paranoia) and all other affective categories was a reduction in the ratio.

Implications of sex differences in the prevalences of antisocial personality, alcoholism, and criminality for familial transmission.

We describe three multifactorial models of disease transmission in which the prevalences of a disease differ in men and women. These models demonstrate explicitly how such sex differences may be caused by genetic factors, home environment, sociocultural, or other nonfamilial factors. Independent sets of family data about antisocial personality and alcoholism in the United States and criminality in Danish twins are analyzed according to these quantitative models. Relevant clinical and adoption data about these disorders are reviewed. The sex differences observed in the development of antisocial personality and of crime appear to be due to familial factors whereas the differences between male and female alcoholics are due to nonfamilial factors. The models and results are discussed in terms of their general implications for testing hypotheses about gender-related differences.

Psychiatric vulnerability, monoamine oxidase, and the average evoked potential.

College students in two separate studies had platelet monoamine oxidase (MAO) activity determinations and average evoked potential (AEP) measurements taken. On the basis of Minnesota Muliphasic Personality Inventory (MMPI) or Research Diagnostic Criteria (RDC) evaluations, psychopathology, particularly affective disorder, was found to be more prevalent among both persons with the combination of low MAO activity and AEP augmenting and those with high MAO activity and AEP reducing. The same pattern is apparent whether students were selected for extremely high or low MAO activity (study 1) or for elevated or normal MMPI scores (study 2). Some psychiatric patient groups also show this pattern. An interactive model of sensation-seeking and sensory inhibition is presented.

Twin concordance for operationally defined schizophrenia. Confirmation of familiality and heritability.

Six sets of operational criteria for diagnosing schizophrenia were applied to a systematically ascertained twin series by raters who were blind to zygosity and to the psychiatric status of the co-twin. Assuming a multifactorial/threshold model of transmission, twin correlations in liability and, where possible, approximate broad heritabilities were calculated for each criterion. All definitions resulted in significant monozygotic twin correlations. The highest heritabilities (of approximately 0.8) were given by the Research Diagnostic Criteria and by the categories "probable" plus "definite" schizophrenia according to the criteria of Feighner et al. In contrast, Schneider's first-rank symptoms defined a form of schizophrenia with a heritability of 0 and, together with the criteria of Carpenter et al and Taylor et al, proved to be excessively restrictive, identifying fewer than half of the probands as schizophrenic.

The New York High-Risk Project. Psychoses and cluster A personality disorders in offspring of schizophrenic parents at 23 years of follow-up.

BACKGROUND: We herein present lifetime prevalence rates of psychoses and DSM-III-R cluster A personality disorders in sample A of the New York High-Risk Project, a prospective study following offspring of parents with schizophrenia (HRSz subjects) and affective illness (HRAff subjects) and of psychiatrically normal parents (NC subjects) from midchildhood to adulthood. METHODS: We interviewed the offspring in adulthood with the Schedule for Affective Disorders and Schizophrenia, Lifetime Version, for Axis I disorders and the Personality Disorder Examination for Axis II disorders. RESULTS: Lifetime prevalence rates (+/- SE) of schizophrenia and unspecified psychosis were 11.1% +/- 4.3% and 5.6% +/- 3.1%, respectively, in the HRSz group and 0% in the HRAff and NC groups. Rates of schizoaffective disorder subclassified as mainly schizophrenic, however, were highest in the HRAff group. Rates of psychotic affective disorders did not differ between the HRSz and other groups. Age-corrected morbidity risks were similar to lifetime prevalence rates. Rates of the three cluster A personality disorders did not differ among the groups, but the combined rate was greater in the HRSz and HRAff groups than in the NC group. CONCLUSIONS: Our data strongly support a specific familial liability to narrowly defined schizophrenia that is not shared by families of probands with affective disorder. Schizoaffective disorder and cluster A personality disorders, however, occur in families of both schizophrenic probands and probands with affective disorder. Psychotic affective disorders, which are not increased in HRSz subjects, do not appear to be an expression of the liability to schizophrenia.

The New York High-Risk Project. Prevalence and comorbidity of axis I disorders in offspring of schizophrenic parents at 25-year follow-up.

BACKGROUND: The New York High-Risk Project is a study of offspring of patients with schizophrenia (HRSz group) or affective illness (HRAff group) and psychiatrically normal parents (NC group) observed prospectively from childhood to adulthood. We herein present lifetime prevalence and comorbidity rates of Axis I disorders in subjects and their siblings from sample A of the project. METHODS: Schedule for Affective Disorders and Schizophrenia-Lifetime Version interviews conducted with the offspring in adulthood were used to obtain diagnoses of Axis I disorders. RESULTS: Schizophrenia and unspecified psychoses occurred only in the HRSz group. However, schizoaffective and psychotic affective disorders occurred equally in the HRSz and HRAff groups. Total rates of psychosis in these groups were significantly higher than in the NC group. All groups had similar rates of nonpsychotic affective and substance abuse disorders. The HRAff group, however, had significantly more total affective illness than the NC group and tended to have more anxiety disorders than the other groups. Comorbidity rates in the HRSz and HRAff groups were nearly twice those of the NC group. CONCLUSIONS: The familial liabilities to schizophrenia and affective disorders show specificities and commonalities, differing markedly from each other in their expression of some disorders and sharing others. Patterns of comorbidity are generally, although not entirely, similar to these liabilities.

Heritability estimates for psychotic disorders: the Maudsley twin psychosis series.

BACKGROUND: Previous twin studies have supported a genetic contribution to the major categories of psychotic disorders, but few of these have employed operational diagnostic criteria, and no such study has been based on a sample that included the full range of functional psychotic disorders. METHODS: A total of 224 twin probands (106 monozygotic, 118 dizygotic) with a same-sex co-twin and a lifetime history of psychosis was ascertained from the service-based Maudsley Twin Register in London, England. Research Diagnostic Criteria psychotic diagnoses were made on a lifetime-ever basis. Main-lifetime diagnoses of DSM-III-R and International Statistical Classification of Diseases, 10th Revision schizophrenia were also made. Probandwise concordance rates and correlations in liability were calculated, and biometrical model fitting applied. RESULTS: A substantial genetic contribution to variance in liability was confirmed for the major diagnostic categories except Research Diagnostic Criteria depressive psychosis and unspecified functional psychosis, where familial transmission was confirmed, but the relative contribution of genetic and common environmental factors was unclear. Heritability estimates for Research Diagnostic Criteria schizophrenia, schizoaffective disorder, mania, DSM-III-R schizophrenia, and International Statistical Classification of Diseases, 10th Revision schizophrenia were all between 82% and 85%. None of the estimates differed significantly from any other. CONCLUSIONS: Heritability estimates for schizophrenia, schizoaffective disorder, and mania were substantial and similar. Population morbid risk estimates were inferred rather than directly measured, but the results were very similar to those from studies where morbid risks were directly estimated.

Replicated psychometric correlates of schizophrenia.

OBJECTIVE: The authors' goals are to use scales from the MMPI hypothesized in their previous research to be correlates of liability to schizophrenia to differentiate DSM-III schizophrenia from bipolar and unipolar affective illness and to cross-validate these correlates in an independently ascertained sample of patients with Research Diagnostic Criteria (RDC) schizophrenia or affective disorder. METHOD: The criterion sample consisted of 83 patients consecutively admitted to a state-operated community mental health center. Diagnosis of schizophrenia; bipolar disorder, manic; and major depression were assigned by using DSM-III. The replication sample consisted of 60 adults with RDC diagnoses of schizophrenia, schizoaffective disorder, bipolar disorder, and unipolar disorder who were parents of children in two samples collected for a study of offspring at high risk for schizophrenia and other psychopathology. After the patients in the criterion sample were classified by logistic regression analysis, the results were used to classify patients in the replication sample. RESULTS: The MMPI indicators had adequate sensitivity, specificity, and predictive power for classifying schizophrenia, and there was a moderately high rate of diagnostic agreement between the MMPI and DSM-III. Cross-validation in the replication sample was successful. Overall, the MMPI index was an adequate inclusion and exclusion criterion not only for DSM-III-defined but also for RDC-defined schizophrenia. CONCLUSIONS: A psychometric index composed of the paranoid schizophrenia, psychoticism, and manifest hostility scales from the MMPI would be a cost-effective measure to increase diagnostic efficacy in future schizophrenia research and clinical practice.

Second-trimester markers of fetal size in schizophrenia: a study of monozygotic twins.

OBJECTIVE: Since the second prenatal trimester is the critical period of massive neural cell migration to the cortex, and fingertip dermal cells migrate to form ridges during this same period, the authors sought to determine whether there are differences in fingertip ridge count in pairs of monozygotic twins discordant for schizophrenia, possibly indicating that a prenatal anatomical insult affected the twins differently. METHOD: The fingertip dermal ridges of 30 pairs of monozygotic twins (23 pairs in which the twins were discordant for schizophrenia and seven pairs in which both twins were normal) were counted by two persons trained in anthropometric research. Intrapair differences in the counts were then measured, and the differences among the pairs of normal twins were compared with the differences among the pairs discordant for schizophrenia. RESULTS: The twins discordant for schizophrenia had significantly greater absolute intrapair differences in total finger ridge count and significantly greater percent intrapair differences than the normal twins; i.e., their fingerprints were significantly less "twin-like." CONCLUSIONS: The study suggests that various second-trimester prenatal disturbances in the epigenesis of one twin in a pair discordant for schizophrenia may be related to the fact that only one of the twins expresses his or her genetic predisposition toward schizophrenia. This is consistent with a "two-strike" etiology of schizophrenia: a genetic diathesis plus a second-trimester environmental stressor.

Attention, memory, and motor skills as childhood predictors of schizophrenia-related psychoses: the New York High-Risk Project.

OBJECTIVE: Childhood neurobehavioral deficits in offspring of schizophrenic, affectively ill, and psychiatrically normal parents were evaluated as predictors of schizophrenia-related psychoses in adulthood. METHOD: The offspring were tested with neurobehavioral measures at 7-12 years of age and assessed in mid-adulthood for axis I diagnoses. The relationships of childhood deficits in attention, verbal memory, and gross motor skills to adulthood schizophrenia-related psychoses were examined in separate path analyses by using logistic regression equations. Sensitivity and specificity were determined for each of the childhood dysfunctions. RESULTS: For the offspring of schizophrenic parents, childhood deficits in verbal memory, gross motor skills, and attention identified 83%, 75%, and 58%, respectively, of the subjects with schizophrenia-related psychoses; 50% were identified by all three variables combined. False positive rates in subjects who did not develop schizophrenia-related psychoses ranged from 18% for those with deficits in attention during childhood to 28% for those with deficits in memory. The three variables had low deficit rates in the offspring of the other two parental groups and were not associated with other psychiatric disorders in any group. CONCLUSIONS: Schizophrenia-related psychoses in adulthood are distinguished in subjects at risk for schizophrenia by childhood deficits in verbal memory, gross motor skills, and attention. The findings suggest that deficits in these variables are relatively specific to schizophrenia risk and may be indicators of the genetic liability to schizophrenia.

High polymorphism level of genomic sequences flanking insertion sites of human endogenous retroviral long terminal repeats.

The polymorphism at the multitude of loci adjacent to human endogenous retrovirus long terminal repeats (LTRs) was analyzed by a technique for whole genome differential display based on the PCR suppression effect that provides selective amplification and display of genomic sequences flanking interspersed repeated elements. This strategy is simple, target-specific, requires a small amount of DNA and provides reproducible and highly informative data. The average frequency of polymorphism observed in the vicinity of the LTR insertion sites was found to be about 12%. The high incidence of polymorphism within the LTR flanks together with the frequent location of LTRs near genes makes the LTR loci a useful source of polymorphic markers for gene mapping.

Biological and genetic contributors to violence--Widom's untold tale.

In her review of the literature on the intergenerational transmission of violent behaviors, Widom (1989a) addressed the social issues but omitted all references to the relevant biological and genetic literature. This addition to her review introduces studies of criminality, delinquency, and violence from a behavioral genetic standpoint. There is clear evidence for a genetic role in criminality and for a physiological basis for violent behavior. The inclusion of such genetic and biological evidence is necessary for a more complete understanding of the transmission of violence from one generation to another.

Twin studies of schizophrenia: from bow-and-arrow concordances to star wars Mx and functional genomics.

Twin studies have been vital for establishing an important genetic contribution to the etiology of schizophrenia. The five newest studies since 1995 from Europe and Japan have confirmed earlier findings. They yielded probandwise concordance rates of 41-65% in monozygotic (MZ) pairs and 0-28% in dizygotic (DZ) pairs, and heritability estimates of approximately 80-85%. Twin studies are also valuable for investigating the etiological relationships between schizophrenia and other disorders, and the genetic basis of clinical heterogeneity within schizophrenia. Studies of discordant MZ pairs provide further insights into non-inherited factors that contribute to the multifactorial etiology of this disorder. More recently, twin studies have begun to be used to directly investigate molecular genetic and epigenetic processes underlying schizophrenia.

Schizoaffective psychoses: genetical clues to classification.

The diagnostic classification of schizoaffective psychoses has varied much since Kasanin introduced the concept in 1933. The various classifications have agreed that schizoaffective psychoses present a combination of schizophreniform and affective symptoms, but the diagnostic criteria differ as to the number, quality, and time sequence of the symptoms even in recent classifications like RDC, DSM-III-R, and ICD-10. The classifications are syndromatical, and the etiology of the schizoaffective psychoses is still undetermined apart from evidence for a strong genetic factor. Results from family, twin, and adoption studies are divergent, but all the same, support a separate classification of broadly defined schizoaffective psychoses as possibly being phenotypical variations or expressions of genetic interforms between schizophrenia and affective psychoses.