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C R Cloninger

Publications and source records attributed to C R Cloninger.

At least 55 records · Page 3Linked to original sources
PubMed1997

No evidence for a schizophrenia susceptibility gene in the vicinity of IL2RB on chromosome 22.

Pulver et al. [1994a] reported modest linkage evidence for a dominantly (D) inherited "schizophrenia gene" in the vicinity of IL2RB on chromosome 22q12, and Coon et al. [1994] adduced moderate evidence under a recessive (R) model. We report here a replication study to test the hypothesis that one of these two models (or a third, intermediate (I) model) adequately describes the co-segregation of schizophrenia and chromosome 22q12 markers in an independent sample of 23 multiplex families. Altogether nine transmission models were evaluated. The models differed depending on whether the 15 family members with a diagnosis of schizophrenia spectrum disorders were considered unaffected (a "narrow" (N) definition), affected (a "wide" (W) definition), or declared "unknown" (U). The entire region between D22S268 and D22S307 is excluded (i.e., lod <-2) for models RN, RW, RU, and IW. Lod scores for the remaining models are uniformly negative; albeit, equivocal with respect to the dominant hypothesis over a small region between D22S268 and IL2RB. Nonparametric analysis under both diagnostic criteria also failed to yield any evidence for a susceptibility locus in this region of chromosome 22.

Chromosomes, Human, Pair 22↗
PubMed1997

Anticipation in schizophrenia: biology or bias?

Anticipation is a genetic phenomenon wherein age of disease onset decreases and/ or severity increases in successive generations. Anticipation has been demonstrated for several neuropsychiatric disorders with expanding trinucleotide repeats recently identified as the underlying molecular mechanism. We report here the results of an analysis of anticipation performed with multiplex families segregating schizophrenia. Thirty-three families were identified through the NIMH Genetics Initiative that met the following criteria: had at least two affected members in successive generations and were not bilineal. Affectation diagnoses included schizophrenia, schizoaffective disorder-depressed, and psychosis NOS. Additional analyses included the Cluster A personality disorders. Three indices of age of onset were used. Disease severity was measured by several different indices. Four sampling schemes as suggested by McInnis et al. were tested, as well as additional analysis using pairs ascertained through the parental generation. Anticipation was demonstrated for age of onset, regardless of the index or sampling scheme used (P<0.05). Anticipation was not supported for disease severity. Analyses that took into account drug use and diminished fecundity did not affect the results. While the data strongly support intergenerational differences in disease onset consistent with anticipation, they must be viewed cautiously given unavoidable biases attending these analyses.

Age of Onset↗
PubMed1997

No association between polymorphisms in the human dopamine D3 and D4 receptors genes and alcoholism.

The human dopamine D2 receptor gene (DRD2) has received considerable attention for the past several years as a potential candidate that may affect susceptibility to alcoholism. The association studies that compared the frequencies of alleles of DRD2 gene between alcoholics and control groups have produced equivocal results. Dopamine D3 and D4 receptor genes (DRD3 and DRD4) are in the same class as DRD2 but with different pharmacological properties. We have used relative risk and haplotype relative risk approaches to test associations between alleles of DRD3 and DRD4 genes and alcoholism. For relative risk studies 162 probands from multiple incidence alcoholic families have been compared to 89 psychiatrically normal controls. Haplotype relative risk approaches have used 29 alcoholic probands in which both parents were available for genotyping. The Bal I restriction enzyme site in DRD3 and tandem repeat (VNTR) in DRD4 genes polymorphisms were used to genotype the above samples. The results of relative risk approaches for both DRD3 and DRD4 genes were negative for comparisons of alcoholics and subtypes of alcoholics with normal controls. Haplotype relative risk approaches also were negative for both genes. These results suggest that any role played by these receptors may account for only part of the variation in susceptibility to alcoholism.

Alcoholism↗
PubMed1997

Serotonergic autoreceptor blockade in the reduction of antidepressant latency: personality variables and response to paroxetine and pindolol.

No antidepressant currently in use exerts a significant antidepressant effect for at least two to three weeks after the patient starts taking it. Open studies suggest that, for selective serotonergic re-uptake inhibitor (SSRI) antidepressants, this latency may be reduced when the drug is taken with the 5HT1A receptor blocker pindolol. We have undertaken a randomised, placebo controlled, double blind trial of augmentation of the selective SSRI antidepressant paroxetine in combination with pindolol. All our patients (n = 54; mean age 36 [range 19-65]) met criteria for major depression and received a standard dose (20 mg o.d.) of paroxetine plus, randomly, either pindolol (2.5 mg t.d.s.) or placebo for six weeks. We examined personality variables in 48 consecutive subjects according to a short version (TCI-125) of Cloninger et al's self-rated Temperament and Character Inventory (Cloninger et al., 1994) and correlated the results with clinical responses in the trial. The results suggest that personality can influence clinical outcome. After the double blind period patients were offered paroxetine 20 mg or 40 mg for up to 6 months. Twenty-six patients took this up. The results suggest that high scores in the temperament dimension of Reward Dependence and low scores in the temperament dimension of Harm Avoidance had a better outcome at 6 weeks. Patients who had received paroxetine and pindolol during the trial and who reported high Novelty Seeking and low Harm Avoidance scores had a better outcome at 6 weeks and 6 months. We suggest that temperament factors may influence outcome of antidepressant treatment.

Adrenergic beta-Agonists↗
PubMed1997

Exploring the TPQ as a possible predictor of antidepressant response to nefazodone in a large multi-site study.

Subjects in the midst of a major depressive episode completed the Tridimensional Personality Questionnaire (TPQ) prior to beginning an open trial of nefazodone. A multiple regression analysis was used to further examine the finding of Joyce et al. (1994; Temperament predicts clomipramine and desipramine response in major depression, J. Affect. Disord. 30 (1994) 35-46) that a model involving TPQ Reward Dependence and Harm Avoidance scores, and their interaction, significantly predicted treatment response. The model was found to have significant predictive value (R2 = 0.011, P = 0.0053), but to account for a trivial 1.1% of the variance. Individuals with high Reward Dependence scores had a significantly lower response rate when response was defined as a 60% reduction from baseline HAM-D score. Although the clinical utility of the present findings is uncertain, this line of investigation attempting to link temperament to pharmacological response represents a potentially useful future strategy.

Antidepressive Agents↗
PubMed1997

Role of personality self-organization in development of mental order and disorder.

Normal and abnormal personality development can be quantified in terms of 15 specific steps in the self-organization of character as a complex adaptive system. Character is measured as three dimensions of Self-directedness, Cooperativeness, and Self-transcendence, each with five components corresponding to steps in personality development. Each of these steps is differentially influenced by heritable temperament dimensions, antecedent steps in character development, and life experiences. Predictions about the nonlinear dynamics of personality development, such as equifinality and multifinality, are confirmed in longitudinal data about individuals representative of the general population. The stepwise development of character determines large differences between individuals in their risk of psychopathology, as well as varying degrees of maturity and health.

Child↗
PubMed1997

Integrative psychobiological approach to psychiatric assessment and treatment.

A Developmental approach to integrative psychobiology provides a flexible framework for both clinical assessment and treatment planning. Assessment of seven dimensions of personality using the Temperament and Character Inventory (TCI) allows for comprehensive description of individual differences in feelings, thoughts, and actions. Four temperament factors that are stable throughout life can be decomposed in terms of their underlying genetic structure. Character factors that mature in response to social learning can be decomposed in terms of the components that unfold in a stepwise fashion from infancy through adulthood. Pharmacotherapy and psychotherapy can be systematically matched to the personality structure and stage of character development of each individual. This provides comprehensive paradigm that integrates psychodynamic, cognitive-behavioral, interpersonal, and neurobiological insights into case formulation. Use of the TCI in clinical assessment and treatment planning was illustrated by a case independently assessed by Mardi Horowitz using another approach.

Adult↗
PubMed1997

Human GABAA receptor alpha 1 and alpha 3 subunits genes and alcoholism.

gamma-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the brain. GABA effects are largely mediated by binding to the postsynaptic GABAA receptor, causing the opening of an integral chloride-ion channel. The GABAA antagonists picrotoxin and bicuculline reduce some ethanol-induced behaviors, such as motor impairment, sedation, and hypnosis. The role of this receptor in alcoholism is further supported by effective alleviation of alcohol withdrawal symptoms by GABAA agonists. To determine the role of the GABAA receptor (GABR) genes in the development of alcoholism, we have used alpha 1 and alpha 3 simple sequence repeat polymorphisms in a sample of unrelated alcoholics, alcoholic probands with both parents, and psychiatrically normal controls. For the GABR alpha 1 gene, the differences between allele frequencies, when all alleles were compared together, were not significant between total alcoholics, subtypes of alcoholics, and normal controls. However, for GABR alpha 3, the differences between total alcoholics and normal controls were significant when all alleles were compared together. The differences between subtypes of alcoholics and normal controls were not significant. The results of haplotype relative risk analysis for both genes, GABR alpha 1 and GABR alpha 3, were also negative. It is possible that the sample size in the haplotype relative risk is too small to have power to detect the differences in transmitted versus nontransmitted alleles. There is a need for a replication study in a large family sample that will allow haplotype relative risk or affected sib-pair analysis.

Adult↗
PubMed1996

Platelet serotonergic markers and Tridimensional Personality Questionnaire measures in a clinical sample.

A group of patients with major depressive disorder, with and without comorbid obsessive-compulsive disorder, completed the Tridimensional Personality Questionnaire (TPQ). Harm Avoidance scores were found to be high compared to published age-matched norms and to display a significant positive correlation with Hamilton Depression Rating Scale scores. Platelet 125I-lysergic acid diethylamide (125I-LSD) and 3H-paroxetine binding Bmax values were measured to test Cloninger's hypothesis that Harm Avoidance scores would correlate significantly with measures of serotonergic function. A significant inverse correlation was found between Harm Avoidance scores and 125I-LSD Bmax values. Correlations between 3H-paroxetine Bmax values and TPQ scale scores were not significant. These results suggest an alternative view of the literature relating platelet 5-hydroxytryptamine-2a receptors and mood disorders in that the temperament dimension, Harm Avoidance, may explain prior inconsistencies involving links with depression and suicidality.

Adult↗
PubMed1996

Replication of the Stockholm Adoption Study of alcoholism. Confirmatory cross-fostering analysis.

BACKGROUND: Two forms of alcoholism with distinct clinical features and mode of inheritance were first distinguished in the Stockholm Adoption Study. This involved a large sample of children born in Stockholm, Sweden, who were adopted at an early age and reared by nonrelatives. Type 1 alcoholism had adult onset and rapid progression of dependence without criminality, whereas type 2 had teenage onset of recurrent social and legal problems from alcohol abuse. METHODS: A replication study was carried out with 577 men and 660 women born in Gothenburg, Sweden, and adopted at an early age/by nonrelatives. The genetic and environmental backgrounds of the adoptees were classified by the exact procedures calibrated by discriminant analysis in the original study. RESULTS: Both type 2 and severe type 1 alcoholism were confirmed as independently heritable forms of alcoholism in male adoptees. The lifetime risk of severe alcoholism was increased 4-fold in adopted men with both genetic and environmental risk factors characteristic of type 1 alcoholism compared with the others (11.4% vs 3.0%). Neither genetic nor environmental risk factors for type 1 alcoholism by themselves were sufficient to cause alcoholism. In contrast, the risk of type 2 alcoholism was increased 6-fold in adopted sons with a type 2 genetic background compared with others; regardless of their postnatal environment (10.7% vs 2.0%). The sons with a type 2 genetic background in the replication sample had no excess of type 1 alcoholism, and vice versa. There was no increased risk of mild abuse in adopted men regardless of their genetic or environmental background. CONCLUSION: Type 1 and type 2 alcoholism are clinically distinct forms of alcoholism with causes that are independent but not mutually exclusive.

Adoption↗
PubMed1996

Diagnostic accuracy and confusability analyses: an application to the Diagnostic Interview for Genetic Studies.

The dominant, contemporary paradigm for developing and refining diagnoses relies heavily on assessing reliability with kappa coefficients and virtually ignores a core component of psychometric practice: the theory of latent structures. This article describes a psychometric approach to psychiatric nosology that emphasizes the diagnostic accuracy and confusability of diagnostic categories. We apply these methods to the Diagnostic Interview for Genetic Studies (DIGS), a structured psychiatric interview designed by the NIMH Genetics Initiative for genetic studies of schizophrenia and bipolar disorder. Our results show that sensitivity and specificity were excellent for both DSM-III-R and RDC diagnoses of major depression, bipolar disorder, and schizophrenia. In contrast, diagnostic accuracy was substantially lower for subtypes of schizoaffective disorder-especially for the DSM-III-R definitions. Both the bipolar and depressed subtypes of DSM-III-R schizoaffective disorder had excellent specificity but poor sensitivity. The RDC definitions also had excellent specificity but were more sensitive than the DSM-III-R schizoaffective diagnoses. The source of low sensitivity for schizoaffective subtypes differed for the two diagnostic systems. For RDC criteria, the schizoaffective subtypes were frequently confused with one another; they were less frequently confused with other diagnoses. In contrast, the DSM-III-R subtypes were often confused with schizophrenia, but not with each other.

Bipolar Disorder↗
PubMed1996

Genetic and environmental structure of the Tridimensional Personality Questionnaire: three or four temperament dimensions?

Previous phenotypic factor analyses suggest that C. R. Cloninger's Tridimensional Personality Questionnaire (TPQ; 1987c) assesses 4 rather than 3 temperament dimensions. The purpose of this study was to determine whether Cloninger's revised 4-factor model showed incremental validity over his original model and to investigate the convergent and discriminant validity of Cloninger's dimensions in comparison to the personality dimensions proposed by H. J. Eysenck (1981) and J. A. Gray (1970). The sample included 2,420 women and 870 men (aged 50-96) from a volunteer population-based sample of twins. Joint phenotypic factor analyses supported Cloninger's 4-dimensional temperament model. A 4-dimensional genetical factor structure was also confirmed in genetic analyses of the TPQ higher order dimensions in women. For men only 3 genetic factors were necessary to explain the genetic variance among the TPQ dimensions.

Aged↗
PubMed1996

Platelet adenylyl cyclase activity in alcoholics and subtypes of alcoholics. WHO/ISBRA Study Clinical Centers.

Adenylyl cyclase (AC) activity was measured in membrane preparations of platelets from control and alcoholic subjects. The sample consisted of 51 alcoholics who were categorized as type I or type II using the criteria of Gilligan et al. (Genet. Epidemiol. 4:395-414, 1987) and 54 normal controls. Alcoholic males exhibited significantly lower values than controls in basal and fluoride-stimulated platelet AC activity. When male alcoholics were segregated into type I and type II categories, the platelet AC activity did not differ between subtypes, and both subtypes had AC activity that was below control values. Western blot analysis of the quantity of Gs alpha and Gi alpha proteins in a subset of male controls and alcoholic subjects demonstrated no significant relationship between quantity of G proteins and AC activity. The results confirm lower platelet AC activity in male alcoholics, compared with controls. Given the lack of quantitative relations between Gs alpha and Gi alpha proteins and AC activity, the results support the contention that individual differences in platelet AC activity in the alcoholic subjects may reflect quantitative or qualitative differences in the AC catalytic units.

Adenylyl Cyclases↗
PubMed1996

Towards an understanding of defense style in terms of temperament and character.

The aim was to investigate the relationships between a model of personality based on the concept of defense mechanisms, as articulated by Vaillant, with the psychobiological model of personality, as developed by Cloninger. A total of 128 adults from 11 family pedigrees with at least two alcohol-dependent members completed the self-report Defense Style Questionnaire and the Temperament and Character Inventory. Immature defenses were largely explained by low character scores, while neurotic defenses were part temperament and part character. Cluster A, B and C defenses were related to low reward dependence, high novelty-seeking and high harm avoidance respectively. In a regression analysis, cluster B and C defenses were more related to low character scores than to temperament but, for cluster A defenses, temperament and character both contributed. The results suggest that it is possible to integrate an ego defense model of personality with a psychobiological model of personality, thereby enriching both approaches.

Adolescent↗
PubMed1995

Monoamine oxidases and alcoholism. I. Studies in unrelated alcoholics and normal controls.

Low platelet MAO activity has been associated with alcoholism. In order to evaluate the role of MAO genes in susceptibility to alcoholism, we have taken a biochemical and molecular genetic approach. The sample consisted of 133 alcoholic probands who were classified by subtypes of alcoholism and 92 normal controls. For those subjects typed for platelet MAO activity, alcoholics (N = 74) were found not to differ from the non-alcoholics controls (N = 34). Neither was there a significant difference between type I and type II alcoholics or between either subtype and normal controls. However, we do find significant differences between male and female alcoholics, but not between male and female controls. The allele frequency distribution for the MAO-A and MAO-B dinucleotide repeats is different between the alcoholic sample (N = 133) and the normal control sample (N = 92). In a two-way analysis of variance of MAO-B activity as a function of the allelic variation of each marker locus and diagnosis, there is no evidence for mean differences in activity levels for the different alleles. Our findings do not rule out a role for the MAO-B gene in controlling the enzyme activity because the dinucleotide repeats are located in introns.

Adult↗
PubMed1995

Monoamine oxidases and alcoholism. II. Studies in alcoholic families.

Thirty-five alcoholic families have been studied to investigate the relationship between DNA markers at the monoamine oxidase (MAO) loci and 1) platelet activity levels and 2) alcoholism. A quantitative linkage analysis failed to reveal any evidence that the variation in activity levels cosegregates with the DNA markers. A sib-pair analysis did not reveal a significant excess of MAO haplotype sharing among alcoholic sibs, although the deviation from random sharing was in the direction consistent with an X-linked component. A reanalysis of platelet MAO activity levels in a subset of these families revealed that the lower levels previously found in alcoholics is more likely due to the differences between males and females. Only among males and only when a "broad" definition of alcoholism is used (and MAO activity levels are transformed to normality) does it appear that alcoholics have depressed activities compared to nonalcoholics. Finally, when the confounding due to gender difference is removed, no differences between type I and type II alcoholics are found in these families.

Alcoholism↗