Evolution of genetic networks for human creativity.

The genetic basis for the emergence of creativity in modern humans remains a mystery despite sequencing the genomes of chimpanzees and Neanderthals, our closest hominid relatives. Data-driven methods allowed us to uncover networks of genes distinguishing the three major systems of modern human personality and adaptability: emotional reactivity, self-control, and self-awareness. Now we have identified which of these genes are present in chimpanzees and Neanderthals. We replicated our findings in separate analyses of three high-coverage genomes of Neanderthals. We found that Neanderthals had nearly the same genes for emotional reactivity as chimpanzees, and they were intermediate between modern humans and chimpanzees in their numbers of genes for both self-control and self-awareness. 95% of the 267 genes we found only in modern humans were not protein-coding, including many long-non-coding RNAs in the self-awareness network. These genes may have arisen by positive selection for the characteristics of human well-being and behavioral modernity, including creativity, prosocial behavior, and healthy longevity. The genes that cluster in association with those found only in modern humans are over-expressed in brain regions involved in human self-awareness and creativity, including late-myelinating and phylogenetically recent regions of neocortex for autobiographical memory in frontal, parietal, and temporal regions, as well as related components of cortico-thalamo-ponto-cerebellar-cortical and cortico-striato-cortical loops. We conclude that modern humans have more than 200 unique non-protein-coding genes regulating co-expression of many more protein-coding genes in coordinated networks that underlie their capacities for self-awareness, creativity, prosocial behavior, and healthy longevity, which are not found in chimpanzees or Neanderthals.

Promoting healthy lives and well-being for all: The contribution of the International College of Person-Centered Medicine (ICPCM).

This article defines the scope of Person-Centered Medicine, traces its roots in ancient conceptions, explains the reasons for the revival of this perspective in our times, and highlights the contribution of the International College of Person-Centered Medicine (ICPCM) in the promotion of the personcentered perspective in health and disease. The value of communication is underlined with reference to both diagnosis and treatment. The concept of Health is considered historically and the inclusiveness, holistic vista and positive health orientation of the WHO definition of Health (1948) is underlined. It is emphasized that Mental Health Promotion is differentiated conceptually from Disease Prevention in that promotion deals with health and prevention deals with illness, the relationship of Health Promotion with Salutogenesis (Antonovsky 1996) is noted and it is pointed out that among the targets of health promotion, preservation of peace is also included (WHO, 2004). In line with this, the ICPCM has supported and co-signed the Athens Anti-War Declaration (2016). Evaluating the impact of Health Promotion efforts is a necessary but difficult task as it requires targeted research and there are many inherent confounding factors. The social or environmental contexts of health behaviors should be taken into account as well as the subjective indicators of health. In an attempt to resolve the difficulties arising from this issue, the ICPCM has developed a prototype "Person-centered Care Index" (Kirisci et al 2016). With reference to Education it is pointed out that it is necessary for the educators to speak with the students rather than speak to them. Concerning research, the ICPCM in its 2013 Geneva Declaration has identified the main research areas in the person-centered field. The importance of assuring healthy lives and well-being for ALL is underlined and the difficulties associated with the achievement of this goal are noted. Lastly, the need to apply the principles of Person-centered Medicine to victims of natural, human-made and economic disasters (Christodoulou et al 2016) is underlined, especially in view of the frequent occurrence of these disasters in our times. In conclusion, the contribution of the ICPCM during the ten years of its existence, with reference to the sensitization of health professionals in the Person-centered approach is noted. This contribution has been carried out in line with the principles of the ICPCM and with its Geneva Declarations.

Who attracts whom to rural general practice? Variation in temperament and character profiles of GP registrars across different vocational training pathways.

INTRODUCTION: The ongoing rural doctor workforce shortage continues to stimulate interest in new strategies to alleviate the situation. Alongside increasingly promising approaches is the notion that attracting and nurturing the 'right' individuals may be paramount to achieving long-term success in recruitment and retention. This study compares the patterns of demographic and temperament and character trait profiles of general practice registrars in training across three Australian vocational training pathways: the Australian College of Rural and Remote Medicine independent rural pathway, and the rural and general pathways of Australian general practice training. The aim is to describe the predominant personalities of existing trainees. At its foundation, this study strives to obtain more information about those individuals choosing rural practice, which may inform ways to enhance future recruitment and training into rural medicine. This rationale has been explored with medical students using intention as the dependent variable, but registrars are that much closer to their final career choice, and therefore may provide more practical and reliable indicators of the notion of who attracts whom into rural practice. METHODS: A cross-sectional design sampled four registrar training groups: one from the Australian College of Rural and Remote Medicine, one Australian general practice training rural only, and two Australian general practice training rural and general pathway regional training providers. Registrars (451) completed a questionnaire that gathered basic demographics and a personality trait profile using the Temperament and Character Inventory plus a measure of resilience. Statistical analysis explored the relationships between variables (multivariate analyses of variance) and compared levels of traits between registrar groups (analyses of variance). RESULTS: Registrars training via the Australian College of Rural and Remote Medicine pathway were more likely to be male, older, have a definite interest in or already practising in a rural area and were significantly (with moderate effect sizes) lower in levels of harm avoidance and higher in persistence, self-directedness and resilience compared to the other training pathways. CONCLUSIONS: The implications of the data to the recruitment and training of general practice registrars goes further than identifying groups of individuals with similar temperament and character trait patterns. This sample is portrayed as relatively homogenous in light of their overall trait levels as compared to population norms. However, it is the combination of the levels of individual traits that suggests a profile that differs between registrars on a rural or general training path. Importantly the combination of trait levels that tend to differentiate registrars (low harm avoidance, high self-directedness and persistence) correlates strongly with high levels of resilience. Doctors and medical students benefit from a high level of resilience to cope with and manage the challenges of the profession and arguably more so in rural practice. Along with certain demographic characteristics, the combination and levels of temperament (stable) and character (developmental) traits support the notion of a mixture of personal traits that may be indicative of individuals best suited to rural and remote medicine. Further investigation is needed to determine whether individuals with a certain pattern of personal traits are attracted to rural practice training or whether the training itself, in part by exposure to rural life and rural medical practice, selects for those who are most suited to and will eventually choose to practice in a rural location.

Temperament, character and serotonin activity in the human brain: a positron emission tomography study based on a general population cohort.

BACKGROUND: The psychobiological model of personality by Cloninger and colleagues originally hypothesized that interindividual variability in the temperament dimension 'harm avoidance' (HA) is explained by differences in the activity of the brain serotonin system. We assessed brain serotonin transporter (5-HTT) density in vivo with positron emission tomography (PET) in healthy individuals with high or low HA scores using an 'oversampling' study design. Method Subjects consistently in either upper or lower quartiles for the HA trait were selected from a population-based cohort in Finland (n = 2075) with pre-existing Temperament and Character Inventory (TCI) scores. A total of 22 subjects free of psychiatric and somatic disorders were included in the matched high- and low-HA groups. The main outcome measure was regional 5-HTT binding potential (BPND) in high- and low-HA groups estimated with PET and [11C]N,N-dimethyl-2-(2-amino-4-methylphenylthio)benzylamine ([11C]MADAM). In secondary analyses, 5-HTT BPND was correlated with other TCI dimensions. RESULTS: 5-HTT BPND did not differ between high- and low-HA groups in the midbrain or any other brain region. This result remained the same even after adjusting for other relevant TCI dimensions. Higher 5-HTT BPND in the raphe nucleus predicted higher scores in 'self-directedness'. CONCLUSIONS: This study does not support an association between the temperament dimension HA and serotonin transporter density in healthy subjects. However, we found a link between high serotonin transporter density and high 'self-directedness' (ability to adapt and control one's behaviour to fit situations in accord with chosen goals and values). We suggest that biological factors are more important in explaining variability in character than previously thought.

Temperament and character inventory dimensions and anhedonia in detoxified substance-dependent subjects.

In this study we aimed to investigate the relationship between anhedonia, craving and temperament and character dimensions in a sample of 50 patients with alcohol and opiate dependence recruited after a period of detoxification. The following scales were applied: Snaith-Hamilton Pleasure Scale (SHAPS), Bech-Rafaelsen Melancholia Scale (BRMS), Scale for the Assessment of Negative Symptoms (SANS), Visual Analogue Scales (VAS) for craving, and Temperament and Character Inventory (TCI). The temperament dimension of Novelty Seeking was positively correlated to craving and anhedonia (p < .01), with a higher score of Novelty Seeking in the subsample of anhedonic subjects with respect to both non-anhedonic and control subjects. In our study, the possibility that difficulty in experiencing pleasure in psychiatric disorders can lead to the use of psychoactive substances in an attempt to decrease anhedonia, is extended to subjects without psychiatric disorders who may try substances to counterbalance a tonic state of anhedonia.

Personality characteristics in obesity and relationship with successful weight loss.

OBJECTIVE: Personality influences lifestyle behaviors. Therefore, certain personality traits could contribute to obesity and the response to behaviorally based weight loss therapy. PURPOSE: The aims of this study were to test the hypothesis that personality characteristics differ between lean and obese persons in the community, obese persons in the community and obese persons seeking weight loss therapy by enrolling in a comprehensive weight loss program, and in obese persons who were successful and unsuccessful in achieving behavioral therapy-induced weight loss. METHODS: The Temperament and Character Inventory was administered to 264 lean (body mass index (BMI) <25 kg/m(2)) and 56 obese (BMI> or =35 kg/m(2)) subjects from the St Louis community and 183 obese patients (BMI=44+/-10 kg/m(2)) enrolled in the Washington University Weight Management Program (WUWMP), which involved weekly group behavioral therapy and diet education sessions for 22 weeks. RESULTS: Compared with lean subjects, obese subjects in the community scored higher in novelty seeking (19.7+/-5.9 vs 16.2+/-6.0, P<0.05), lower in Persistence (4.1+/-1.8 vs 4.8+/-1.7, P<0.05) and lower in self-directedness (32.1+/-7.6 vs 34.3+/-6.6, P<0.05.) Patients enrolled in the WUWMP scored higher than obese persons in the general population in both Reward Dependence (17.1+/-4.2 vs 15.7+/-4.3, P<0.05) and cooperativeness (36.9+/-5.4 vs 34.5+/-6.2, P<0.05). Patients who were successful in losing weight (>10% weight loss) after 22 weeks of behavioral therapy scored lower in novelty seeking than those who were unsuccessful in losing weight (<5% weight loss) (17.6+/-5.9 vs 20.2+/-5.9, P<0.05). DISCUSSION: These results suggest that personality traits differ between lean and obese persons, and between obese persons who enroll and who do not enroll in a comprehensive weight management program. Moreover, high scores in novelty seeking are associated with decreased success in achieving behavioral therapy-induced weight loss.

The Temperament and Character Inventory-Revised (TCI-R): psychometric characteristics of the French version.

OBJECTIVE: To explore the psychometric characteristics of a modified version of the Cloninger's personality questionnaire, the Temperament and Character Inventory-Revised (TCI-R). METHOD: A 482-subject sample, including clinical and non-clinical subjects, completed the TCI-R. We performed principal component analyses and explored the factorial structure of the questionnaire, and the internal consistency of each dimension. RESULTS: The factorial structure of the TCI-R was well defined as expected and similar to those shown with the TCI. Robust factors were obtained for Reward Dependence and Persistence in the TCI-R, even more clearly than in the original TCI. All dimensions obtained higher alpha Cronbach coefficients with the TCI-R than with the TCI. We obtained highly satisfying reliability coefficients in test-retest and TCI/TCI-R comparisons. CONCLUSION: The TCI-R seems to have similar psychometric and feasibility characteristics as those of the initial version, but with significant improvements in terms of factorial structure and internal consistency of most dimensions.

[Temperament and Character Inventory Revised (TCI-R). Standardization and normative data in a general population sample]. / Inventario del Temperamento y el Carácter-Revisado (TCI-R). Baremación y datos normativos en una muestra de población general.

INTRODUCTION: The revised version of the Temperament and Character Inventory (TCI-R), a tool designed by C. R. Cloninger for the evaluation of the seven dimensions defined in his psychobiological model of personality, was translated and adapted to Spanish. The aim of the study was to obtain normative data and scales with T-scores in a incidental sample of the general Spanish population. METHODS: After adaptation to Spanish, the tool was administered to 400 subjects from several areas of Spain. The sample is stratified according to age and gender according to the year 2001 Spanish population census. We have studied the differences between men and women and the association between age and dimensions. We have checked the normal distribution of the traits, and proceeded with the standardization and normalization of the scores. RESULTS: We present the mean and standard deviation according to sex for each of the main dimensions and subscales. The scores of the main dimensions obtained for general population according to gender show a normal distribution that has allowed us to standardize them into T-scores. The reliability of the dimensions is high. There are differences in the means depending on gender: women scored higher in Harm Avoidance, Reward Dependence and Cooperativeness. Men scored higher in Persistence. There were no high correlations between age and the dimensions. CONCLUSIONS: The Spanish version of the new TCI-R is an adequate tool for the study of personality dimensions of normal population.

Inventario del Temperamento y el Carácter-Revisado (TCI-R). Baremación y datos normativos en una muestra de población general / Temperament and Character Inventory Revised (TCI-R). Standardization and normative data in a general population sample

Introducción. Se ha traducido y adaptado al castellano la versión revisada del Inventario del Temperamento y el Carácter (TCTR), instrumento diseñado por C. R. Cloninger para evaluar las siete dimensiones de personalidad definidas en su modelo psicobiológico de personalidad. El objetivo es la obtención de datos normativos y baremos tipificados en una muestra incidental de población general española. Métodos. Tras la adaptación al castellano del instrumento se administra a 400 sujetos de varias áreas geográficas del estado español. La muestra se estratifica por edades y sexo según el censo español del año 2001.Se estudian las diferencias para hombre y mujer y la asociación entre edad y las dimensiones. Se verifica la distribución normal de los rasgos, y se procede a la estandarización y normalización de las puntuaciones. Resultados. Se presenta la media y desviación estándar por género para cada una de las dimensiones principales y las subescalas. Las puntuaciones de las dimensiones principales, obtenidas en la población general por sexo, muestran una distribución normal que ha permitido estandarizarlas en puntuaciones tipificadas. La fiabilidad de las dimensiones es elevada. Existen diferencias en las medias según el género puntuando las mujeres más alto en evitación del daño, dependencia de la recompensa y cooperación. Los hombres puntuaron más alto en persistencia. No existen correlaciones elevadas entre la edad y las dimensiones. Conclusiones. La versión española de la nueva versión del TCTR constituye un instrumento adecuado para el estudio de las dimensiones de la personalidad en población normal (AU)

Temperament, character, and personality disorders: etiologic, diagnostic, treatment issues.

OBJECTIVE: In this paper, we explore the underlying dimensional structure of personality disorder, propose a novel approach to its diagnosis, and outline our concepts of its etiology and treatment based on the seven factor psychobiological model of temperament and character. METHOD: Temperament and character traits were evaluated in a consecutive series of 109 psychiatric out-patients, with or without personality disorder and varying mood and anxiety states. RESULTS: Low scores on character dimensions consistently correlated with high symptom counts for personality disorder. Each subtype of personality disorder created a unique combination of correlations with the four temperament traits. CONCLUSION: Temperament and Character Inventory (TCI) temperament and character traits efficiently diagnose personality disorder and differentiate its individual subtypes. Character traits are used to diagnose the presence and the severity of personality disorder, whereas temperament traits are used for differential diagnosis. The distinction between temperament and character provides an attractive theoretical basis for etiological postulates and treatment of personality disorder.

Serotonergic pathway genes and subtypes of alcoholism: association studies.

Disturbances of the serotonergic pathway have been implicated in many psychiatric disorders, including alcoholism, aggression, schizophrenia and depression. The personality dimension of harm avoidance is correlated positively with the activity of mesolimbic serotonergic neurons. The goal of this study was to determine the role of the genes in this pathway in the development of type II alcoholism. A sample of alcoholics and normal controls were screened with the variations in tryptophan hydroxylase (TPH), serotonin receptors (5-HT2A and 5-HT2C), serotonin transporter (5-HTT), and monoamine oxidase A (MAO-A) genes. The results of association studies for type II alcoholics were the most significant with 5-HTT (P = 0.011) and MAO-A (P = 0.029) genes. However, after correction for multiple comparisons, none of the results reached the significance level. These data indicate that the genes in the serotonergic pathway may be involved in the development of type II alcoholism but the gene effects are very small.

Linkage disequilibrium for schizophrenia at the chromosome 15q13-14 locus of the alpha7-nicotinic acetylcholine receptor subunit gene (CHRNA7).

The transmission/disequilibrium test was used for fine mapping of the linkage of schizophrenia to the chromosome 15q13-14 region, the site of a candidate gene, the alpha7 nicotinic acetylcholine receptor subunit gene (CHRNA7), in parent-child triads from the NIMH Schizophrenia Genetics Initiative families. This candidate gene was identified from neurobiological studies of deficits in schizophrenics of the inhibitory gating of the P50 auditory evoked potential. The neurobiological deficit was also used as a phenotype for subsequent linkage analysis. In the present study, significant genotype-wise disequilibrium (P < 0.007) was found at D15S165, a polymorphic simple sequence marker physically located within 1 megabase of both CHRNA7 and a partially duplicated, expressed sequence that includes exons 5-10 of CHRNA7. Replication of this result was found in an additional set of families. The results support this region as a chromosomal location involved in the genetic transmission of schizophrenia.

Visual P300 and the self-directedness scale of the Temperament and Character Inventory.

Reduced amplitude of the P300 event-related brain potential has been associated with several psychopathological conditions and is thought to represent brain dysfunction in such conditions. Predisposition to personality disorders and psychopathology in general is also associated with low scores on the self-directedness (SD) scale of the Temperament and Character Inventory. The present preliminary study investigated the relationship between amplitudes of P300 elicited by rare target stimuli in a visual oddball task and SD scores in 58 healthy participants. P300 was found to be significantly reduced in subjects with low SD, as supported by correlational analysis and by comparison of groups formed on the basis of SD scores. This finding may be relevant to prior findings indicating reduced P300 amplitudes in a variety of psychopathological conditions and suggests that a common vulnerability factor, reflected in the low SD personality scores, may contribute to the P300 reduction in psychiatric populations.

Traumatic brain injury and schizophrenia in members of schizophrenia and bipolar disorder pedigrees.

OBJECTIVE: Schizophrenia following a traumatic brain injury could be a phenocopy of genetic schizophrenia or the consequence of a gene-environment interaction. Alternatively, traumatic brain injury and schizophrenia could be spuriously associated if those who are predisposed to develop schizophrenia have greater amounts of trauma for other reasons. The authors investigated the relationship between traumatic brain injury and psychiatric diagnoses in a large group of subjects from families with at least two biologically related first-degree relatives with schizophrenia, schizoaffective disorder, or bipolar disorder. METHOD: The Diagnostic Interview for Genetic Studies was used to determine history of traumatic brain injury and diagnosis for 1,275 members of multiplex bipolar disorder pedigrees and 565 members of multiplex schizophrenia pedigrees. RESULTS: Rates of traumatic brain injury were significantly higher for those with a diagnosis of schizophrenia, bipolar disorder, and depression than for those with no mental illness. However, multivariate analysis of within-pedigree data showed that mental illness was related to traumatic brain injury only in the schizophrenia pedigrees. Independent of diagnoses, family members of those with schizophrenia were more likely to have had traumatic brain injury than were members of the bipolar disorder pedigrees. The members of the schizophrenia pedigrees also failed to show the gender difference for traumatic brain injury (more common in men than in women) that was expected and was present in the bipolar disorder pedigrees. Subjects with a schizophrenia diagnosis who were members of the bipolar disorder pedigrees (and thus had less genetic vulnerability to schizophrenia) were less likely to have had traumatic brain injury (4.5%) than were subjects with schizophrenia who were members of the schizophrenia pedigrees (and who had greater genetic vulnerability to schizophrenia) (19.6%). CONCLUSIONS: Members of the schizophrenia pedigrees, even those without a schizophrenia diagnosis, had greater exposure to traumatic brain injury compared to members of the bipolar disorder pedigrees. Within the schizophrenia pedigrees, traumatic brain injury was associated with a greater risk of schizophrenia, consistent with synergistic effects between genetic vulnerability for schizophrenia and traumatic brain injury. Posttraumatic-brain-injury schizophrenia in multiplex schizophrenia pedigrees does not appear to be a phenocopy of the genetic disorder.

Evidence for the multigenic inheritance of schizophrenia.

Schizophrenia is assumed to have complex inheritance because of its high prevalence and sporadic familial transmission. Findings of linkage on different chromosomes in various studies corroborate this assumption. It is not known whether these findings represent heterogeneous inheritance, in which various ethnic groups inherit illness through different major gene effects, or multigenic inheritance, in which affected individuals inherit several common genetic abnormalities. This study therefore examined inheritance of schizophrenia at different genetic loci in a nationally collected European American and African American sample. Seventy-seven families were previously genotyped at 458 markers for the NIMH Schizophrenia Genetics Initiative. Initial genetic analysis tested a dominant model, with schizophrenia and schizoaffective disorder, depressed type, as the affected phenotype. The families showed one genome-wide significant linkage (Z = 3.97) at chromosome 15q14, which maps within 1 cM of a previous linkage at the alpha 7-nicotinic receptor gene. Chromosome 10p13 showed suggestive linkage (Z = 2.40). Six others (6q21, 9q32, 13q32, 15q24, 17p12, 20q13) were positive, with few differences between the two ethnic groups. The probability of each family transmitting schizophrenia through two genes is greater than expected from the combination of the independent segregation of each gene. Two trait-locus linkage analysis supports a model in which genetic alleles associated with schizophrenia are relatively common in the general population and affected individuals inherit risk for illness through at least two different loci.

Relationships between Tridimensional Personality Questionnaire Dimensions and DSM-III-R personality traits in Italian adolescents.

The predictions of Cloninger's neurobiologic learning model on the relationships between novelty seeking (NS), harm avoidance (HA), reward dependence (RD), and persistence (P) and the traditional DSM-III-R personality disorders (PDs) were tested on a sample of 2,889 (1,475 males and 1,414 females) Italian high school students aged 16 to 18 years, using the Structured Clinical Interview for DSM-III-R Personality Disorders-self-report (SCID-II) and the Tridimensional Personality Questionnaire (TPQ). All relationships were in the predicted direction for antisocial, narcissistic, avoidant, and obsessive-compulsive PD alone, and at least two were in the predicted direction for schizoid, histrionic, borderline-explosive, dependent, and passive-aggressive PD. Eight of nine relationships were in the predicted direction for NS, but only seven of nine for HA and RD. This study provides substantial support for Cloninger's neurobiologic learning model as a useful tool to describe and classify personality variants and, because of the supposed neurochemical implications, to link personality traits to the underlying neurochemical and neuroanatomic substrate.

Diagnosis of posttraumatic stress disorder with the MMPI: PK scale scores in somatization disorder.

Clinic patients with diagnoses of either major depression or somatization disorder were given the MMPI. Women with somatization disorder had high scores on Keane's MMPI scale (PK) for posttraumatic stress disorder. Following the procedure for the MMPI-2 (46 of the 49 PK items and MMPI-2 norms), 59% of the women with somatization disorder and 21% of the women with major depression would have T scores > or = 65 on the MMPI-2 scale although none of them were known to have developed psychiatric disorder after exposure to a life threatening event. The PK scale has little use in the differential diagnosis of women patients with somatization disorder.

Ondansetron for reduction of drinking among biologically predisposed alcoholic patients: A randomized controlled trial.

CONTEXT: Early-onset alcoholism differs from late-onset alcoholism by its association with greater serotonergic abnormality and antisocial behaviors. Thus, individuals with early-onset alcoholism may be responsive to treatment with a selective serotonergic agent. OBJECTIVE: To test the hypothesis that drinking outcomes associated with early vs late-onset alcoholism are differentially improved by the selective 5-HT(3) (serotonin) antagonist ondansetron. DESIGN: Double-blind, randomized, placebo-controlled clinical trial. SETTINGS: University of Texas Health Science Center in Houston (April 1995-June 1998) and University of Texas Health Science Center in San Antonio (July 1998-December 1999). PARTICIPANTS: A total of 321 patients with diagnosed alcoholism (mean age, 40.6 years; 70.5% male; 78.6% white) were enrolled, 271 of whom proceeded to randomization. INTERVENTIONS: After 1 lead-in week of single-blind placebo, patients were randomly assigned to receive 11 weeks of treatment with ondansetron, 1 microg/kg (n = 67), 4 microg/kg (n = 77), or 16 microg/kg (n = 71) twice per day; or identical placebo (n = 56). All patients also participated in weekly standardized group cognitive behavioral therapy. MAIN OUTCOME MEASURES: Self-reported alcohol consumption (drinks per day, drinks per drinking day, percentage of days abstinent, and total days abstinent per study week); and plasma carbohydrate deficient transferrin (CDT) level, an objective and sensitive marker of transient alcohol consumption. RESULTS: Patients with early-onset alcoholism who received ondansetron (1, 4, and 16 microg/kg twice per day) compared with those who were administered placebo, had fewer drinks per day (1.89, 1.56, and 1.87 vs 3.30; P =.03, P =.01, and P =.02, respectively) and drinks per drinking day (4.75, 4.28, and 5.18 vs 6.90; P =.03, P =.004, and P =.03, respectively). Ondansetron, 4 microg/kg twice per day, was superior to placebo in increasing percentage of days abstinent (70.10 vs 50.20; P =.02) and total days abstinent per study week (6.74 vs 5.92; P =.03). Among patients with early-onset alcoholism, there was a significant difference in the mean log CDT ratio between those who received ondansetron (1 and 4 microg/kg twice per day) compared with those who received the placebo (-0.17 and -0.19 vs 0.12; P =.03 and P =.01, respectively). CONCLUSION: Our results suggest that ondansetron (particularly the 4 microg/kg twice per day dosage) is an effective treatment for patients with early-onset alcoholism, presumably by ameliorating an underlying serotonergic abnormality. JAMA. 2000;284:963-971

Age of onset as a discriminator between alcoholic subtypes in a treatment-seeking outpatient population.

Subtyping alcoholics may provide a more accurate guide as to the course and character of the disease. Classifications of different ages of onset of problem drinking have so far resulted in categorical inconsistencies. In the past, hospital-based alcoholics have over-represented those most severely ill, and comprehensive evaluations of psychopathology for discriminating between alcoholic subtypes have been infrequent. In a heterogeneous treatment-seeking, outpatient, alcoholic population, we tested the hypothesis that age of onset represents a continuum of disease, and that greater severity of psychopathology is associated with lower ages of onset. Using a standard questionnaire, 253 male and female treatment-seeking alcoholics were stratified according to specific ages of onset: a) < 20 years; b) 20-25 years, and c) > 25 years. These age of onset groups were compared on alcohol severity and craving, family history, childhood behavior, personality, hostility, overt aggression, mood, and social functioning. Symptom severity and age of onset were negatively correlated, and the 20-25-year onset group usually had intermediate scores. The < 20 year onset group was characterized by greater severity of alcohol-related problems, family history, childhood behavioral problems, craving, hostility, antisocial traits, mood disturbance, and poor social functioning. Alcoholics with an earlier age of onset have relatively greater psychopathology than those of later onset. While the preponderance of psychopathology among those in the < 20-year onset group could be conceptualized as a clinical "subtype," such a characterization would not define an entirely homogeneous category. Yet, this clinical characterization would be clinically important if specific age of onset levels were found to be differentially sensitive to pharmacological and/or psychological treatments.