Salivary cortisol in unaffected twins discordant for affective disorder

Dysfunction in the hypothalamic-pituitary-adrenal (HPA) axis has been proposed as a biological endophenotype for affective disorders. In the present study the hypothesis that a high genetic liability to affective disorder is associated with higher cortisol levels was tested in a cross-sectional high-risk study. Healthy monozygotic (MZ) and dizygotic (DZ) twins with (High-Risk twins) and without (Low-Risk twins) a co-twin history of affective disorder were identified through nationwide registers. Awakening and evening salivary cortisol levels were compared between the 190 High- and Low-Risk twins. The 109 High-Risk twins had significantly higher evening cortisol levels than the 81 Low-Risk MZ twins, also after adjustment for age, sex, and the level of subclinical depressive symptoms. No significant difference was found in awakening cortisol levels between High-Risk and Low-Risk twins. In conclusion, a high genetic liability to affective disorder was associated with a higher evening cortisol level, but not with awakening cortisol level. Future prospective family, high-risk and twin studies are needed to decide whether abnormalities in the HPA axis can be identified as an endophenotype of affective disorder.     

Personality traits in unaffected twins discordant for affective disorder

OBJECTIVE: To examine whether a high genetic liability to develop affective disorder is associated with specific personality traits. METHOD: A cross-sectional, high-risk, case-control study. Through nation-wide registers, healthy monozygotic (MZ) and dizygotic (DZ) twins with (high-risk twins) and without (the control group/low-risk twins) a co-twin history of affective disorder were identified. Personality traits were compared for a total of 211 high-risk and low-risk twins. RESULTS: In univariate analyses, the high-risk twins had a higher level of neuroticism than the control twins (P = 0.03). In multivariate analyses, a high genetic liability to affective disorder was not significantly associated with neuroticism but correlated to sex, minor psychopathology and recent life events. CONCLUSION: A high genetic liability to affective disorder showed an association with neuroticism, but the association interacts with other predictors of affective disorder such as female gender, minor psychopathology and recent adversity.     

Early onset psychiatric disorder in high risk children and increased familial morbidity

The relationship between child psychopathology and familial morbidity in second degree relatives was examined for children considered at risk on the basis of parental affective illness. Second degree relatives in high-risk families with no child psychopathology were no different from low-risk families in their rates of depression and anxiety. Second degree relatives in high-risk families positive for child psychopathology had significantly higher rates of depression and anxiety than relatives of low-risk children and relatives of high-risk children with no disorder. The implications of these findings are discussed with respect to risk status, prepubertal onset of psychopathology, and familial morbidity for specific psychiatric disorders.     

Hippocampal volume changes in healthy subjects at risk of unipolar depression

Unipolar depression is moderately heritable. It is unclear whether structural brain changes associated with unipolar depression are present in healthy persons at risk of the disorder. Here we investigated whether a genetic predisposition to unipolar depression is associated with structural brain changes. A priori, hippocampal volume reductions were hypothesized. Using a high-risk study design, magnetic resonance imaging brain scans were obtained from 59 healthy high-risk subjects having a co-twin with unipolar depression, and 53 healthy low-risk subjects without a first-degree family history of major psychiatric disorder. High-risk twins had smaller hippocampal volumes than low-risk twins (p < 0.04). The finding was most pronounced in DZ twins. Groups did not differ on global brain tissue volumes or regional tissue volumes assessed in exploratory voxel-wise whole cerebrum analyses. In conclusion, hippocampal volume reduction may index a predisposition to develop depression and thus may be predictive of future onset of the disorder. Further studies are needed to elucidate the role of (shared) environmental and genetic factors.     

Variations in 5-HTTLPR: Relation to familiar risk of affective disorder,life events,neuroticism and cortisol

Background

Variations in the serotonin transporter gene (5-HTTLPR) and stressful life events are associated with affective disorders.

Aim

To investigate whether the distribution of the alleles of the 5-HTTLPR is associated with a genetic predisposition to affective disorder and whether these variations interact with life events in relation to depressive symptoms, neuroticism and salivary cortisol.

Method

In a high-risk population study, healthy monozygotic and dizygotic twins with (high-risk twins) and without (low-risk twins) a co-twin history of affective disorder were identified through nationwide registers.

Results

When comparing the 81 individuals homozygote for the long allele with the 125 individuals hetero- and homozygote for the short allele no associations between the allele distribution and a genetic predisposition were found. The presence of the short allele of the 5-HTTLPR and the experience of SLE was associated with a higher neuroticism score, but not with depressive symptoms nor awakening or evening salivary cortisol.

Conclusion

A combination of variants in 5-HTTLPR and environmental stress seems to increase neuroticism in healthy individuals.     

Sex influences on shared risk factors for bulimia nervosa and other psychiatric disorders

BACKGROUND: The examination of opposite-sex and same-sex dizygotic twins allows us to explore the sex-specific comorbidity of psychiatric disorders. To date, this question has not been explored in eating disorders. OBJECTIVE: To determine whether sex influences shared risk factors between bulimia nervosa (BN) and other forms of psychopathology. DESIGN: The study examines associations between BN and other forms of psychopathology in twin pairs using interview and survey reports. SETTING: Twins from the Virginia population-based twin registry. PARTICIPANTS: Male-female dizygotic twins (N = 1192 pairs), mean (SD) age 36.6 (8.9) years, and female-female dizygotic twins (N = 467 pairs), mean (SD) age 36.0 (7.6) years. MAIN OUTCOME MEASURES: Lifetime psychiatric disorders as diagnosed by a structured psychiatric interview, including major depression, anxiety disorders, and substance abuse and dependence. Also, continuous measures of body mass index and personality, including neuroticism and novelty seeking. RESULTS: Significant within-person associations existed for women between BN and higher body mass index, neuroticism, novelty seeking, and all lifetime psychopathology. Results from this study suggest the presence of either familial or nonfamilial shared risk factors between BN and generalized anxiety disorder, neuroticism, psychoactive substance use, novelty seeking, major depression, and panic disorder. The shared risk factors between BN and generalized anxiety disorder and BN and novelty seeking were only present in men. CONCLUSION: Evidence supports the existence of a sex-specific manifestation of familial liability with respect to BN and generalized anxiety disorder and BN and novelty seeking.     

Psychometric deviance in offspring at risk for schizophrenia: I. Initial delineation of a distinct subgroup

Psychometric signs from the Minnesota Multiphasic Personality Inventory (MMPI), which measure substantive disturbances in thinking, social relatedness, volition, and affective expressivity, were evaluated as possible indicators of transmissible liability specific to schizophrenia. Children of three criterion groups in the New York High-Risk Project--offspring at high risk (HR) for schizophrenia, psychiatric comparison (PC) offspring at risk for affective disorders, and normal comparison (NC) offspring not at augmented risk for psychiatric morbidity--were tested before the expression of schizophrenic psychopathology, when the subjects ranged in age from 13 to 26 years. The rate of psychometric deviance in the HR group (23%) was significantly higher than that in either the PC (7%) or NC (2%) groups, and profile analyses showed that the HR subgroup could be delineated by qualitative distinctions in personality functioning. Our results support the utility of MMPI indicators in etiologic investigations of schizophrenia.     

Prevalence of psychopathology in bipolar high-risk offspring and siblings: a meta-analysis

This meta-analysis aimed to update existing data on the comparison of prevalence rates of psychopathology primarily among offspring with at least one parent with bipolar disorder (BD) and offspring of parents without psychiatric illness. Seventeen studies were derived from a systematic search of PsychInfo, Medline, Scopus and Embase. Inclusion criteria were use of a control offspring group, standardized diagnostic procedures and reporting of clear frequency data. Risk of psychopathology was estimated by aggregating frequency data from selected studies. Compared to control offspring, high-risk BD offspring are nine times more likely to have a bipolar-type disorder, almost two and a half times more likely to develop a non-BD affective disorder and over two times more likely to develop at least one anxiety disorder. High-risk offspring also showed a significant increased risk of other non-mood psychopathology such as attention deficit hyperactivity disorder (ADHD), any type of behavioral disorder and substance use disorder (SUDs). Risk of developing a broad range of affective and non-affective psychopathology is significantly higher in high-risk BD offspring. Identifying clinical presentations of this genetically high-risk cohort is important in establishing appropriate preventative treatment.     

The Munich vulnerability study on affective disorders: premorbid psychometric profile of affected individuals

OBJECTIVE: We conducted a longitudinal high-risk study to identify psychometric vulnerability markers for affective disorders. METHOD: We examined 82 healthy subjects [high-risk probands (HRPs)] with at least one first-degree relative suffering from an affective disorder. The premorbid psychometric profile of 20 HRPs who developed a psychiatric disorder during follow-up was compared with the profile of control subjects without personal and family history of psychiatric disorders matched for age and gender. RESULTS: Somatization, complaints (vegetative lability), and perception of strain are increased in HRPs who developed a psychiatric disorder. These alterations were not influenced by the time interval until the onset of the disorder. CONCLUSION: The premorbid psychometric profile in subjects at high risk for affective disorders is characterized by somatization, complaints, and elevated perception of strain. Together with previous findings our results suggest that these alterations can be regarded as potential vulnerability markers for affective disorders.     

Genetic and environmental effects on offspring alcoholism: new insights using an offspring-of-twins design

CONTEXT: Although there is now considerable evidence that genetic effects play a critical role in the development of alcohol dependence (AD), theoretical and methodological limitations of this literature require caution in describing the etiology and development of this disorder. OBJECTIVE: To disentangle genetic and environmental effects on AD by means of the infrequently used, yet potentially powerful, offspring-of-twins design. DESIGN: Offspring of twins. PARTICIPANTS: Male monozygotic and dizygotic twins concordant or discordant for AD and control pairs from the Vietnam Era Twin Registry were assessed, as were the offspring of these twins and the mothers of these offspring. INTERVENTIONS: Structured psychiatric interviews. MAIN OUTCOME MEASURES: Participants' psychiatric, alcohol abuse (AA), and AD histories (DSM-IV). RESULTS: Offspring of monozygotic and dizygotic twins with a history of AD were significantly more likely to exhibit AA or AD than were offspring of nonalcoholic fathers. Offspring of an alcohol-abusing monozygotic twin whose co-twin was AD were also more likely to exhibit AD than were offspring of nonalcoholic twins. In contrast, offspring of an unaffected (ie, no history of abuse or dependence) monozygotic twin whose co-twin was AD were no more likely to exhibit AA or AD than were offspring of nonalcoholic twins. CONCLUSIONS: These findings support the hypothesis that family environmental effects do make a difference in accounting for offspring outcomes, in particular, that a low-risk environment (ie, the absence of parental alcoholism) can moderate the impact of high genetic risk regarding offspring for the development of alcohol-use disorders.     

Psychiatric disorders after childhood stroke

OBJECTIVES: To determine the rate, types, and correlates of psychiatric disorder (PD) following stroke and orthopedic disorders in children and adolescents. METHOD: Children aged 5 to 19 were assessed. The study used a cross-sectional design that compared 29 stroke subjects with 29 congenital clubfoot or scoliosis subjects. Assessments of psychiatric status; cognitive, adaptive, academic, and family functioning; family psychiatric history; neuroimaging; and neurological status were conducted. The main outcome measure was a current PD not present before the stroke or orthopedic disorder. RESULTS: Poststroke PD occurred significantly more often than postorthopedic diagnosis PD (17/29 [59%] versus 4/29 [14%], p < or =.001). Subjects with ongoing poststroke PD had significantly more impaired intellectual and adaptive functioning, higher intensity family psychiatric history scores, and tended toward higher neurological severity index scores, but they were not different regarding lesion volume or family functioning compared with stroke subjects without PD. Regression analyses showed that neurological severity and family psychiatric history independently contributed significantly to predicting PD. CONCLUSIONS: The data suggest that there are significant biopsychosocial correlates of PD in children with focal neurological lesions. These include a relatively abnormal neurological exam, lower IQ, and increased family psychopathology.     

Socio-economic status and mental disorder--profile of a Nigerian psychiatric inpatient population

A study of the socio-economic and diagnostic profile of psychiatric patients treated at a mental hospital in Nigeria over a period of six months was conducted. Schizophrenia, organic psychosis, and mental sub-normality were found to have been diagnosed more often among under privileged persons from lower socio-economic classes; while affective disorder (manic depression) and neurotic illness were commoner among persons from economically more fortunate higher social classes. Males exceeded females in the cohort and the patients generally exhibited upward social mobility when compared with their parents. Possible socio-cultural factors contributing to the findings have been discussed. A suggestion is made for a more elaborate field work to study the relationship between socio-economic class and psychopathology in a developing country like Nigeria.     

Healthy co-twins of patients with affective disorders show reduced risk-related activation of the insula during a monetary gambling task

BackgroundHealthy first-degree relatives of patients with affective disorders are at increased risk for affective disorders and express discrete structural and functional abnormalities in the brain reward system. However, value-based decision making is not well understood in these at-risk individuals.MethodsWe investigated healthy monozygotic and dizygotic twins with or without a co-twin history of affective disorders (high-risk and low-risk groups, respectively) using functional MRI during a gambling task. We assessed group differences in activity related to gambling risk over the entire brain.ResultsWe included 30 monozygotic and 37 dizygotic twins in our analysis. Neural activity in the anterior insula and ventral striatum increased linearly with the amount of gambling risk in the entire cohort. Individual neuroticism scores were positively correlated with the neural response in the ventral striatum to increasing gambling risk and negatively correlated with individual risk-taking behaviour. Compared with low-risk twins, the high-risk twins showed a bilateral reduction of risk-related activity in the middle insula extending into the temporal cortex with increasing gambling risk. Post hoc analyses revealed that this effect was strongest in dizygotic twins.LimitationsThe relatively old average age of the mono- and dizygotic twin cohort (49.2 yr) may indicate an increased resilience to affective disorders. The size of the monozygotic high-risk group was relatively small (n = 13).ConclusionThe reduced processing of risk magnitude in the middle insula may indicate a deficient integration of exteroceptive information related to risk-related cues with interoceptive states in individuals at familial risk for affective disorders. Impaired risk processing might contribute to increased vulnerability to affective disorders.     

Psychometric deviance in offspring at risk for schizophrenia: II. Resolving heterogeneity through admixture analysis

The longitudinal and prospective study of offspring at risk for schizophrenia is complicated by within-group heterogeneity in liability, as only a subgroup of those at risk will ultimately become affected. Here, we attempt to resolve such heterogeneity in the New York High-Risk Project by conducting an admixture analysis of values on a psychometric index of liability to schizophrenia derived from the Minnesota Multiphasic Personality Inventory (MMPI). We fit mixtures of components to the overall distribution in 171 children from three criterion groups: offspring at risk (HR) for schizophrenia, psychiatric comparison (PC) offspring at risk for affective illness, and normal comparison (NC) offspring not at increased risk for psychiatric morbidity. The distribution of psychometric scores was bimodal, and separation of two latent classes showed that there is a valid and nonarbitrary distinction between a subgroup of MMPI-deviant (primarily HR) offspring and a larger homogeneous group of MMPI-nondeviant HR, PC, and NC subjects. While continued followup is required to demonstrate a correspondence between these two classes and an underlying taxonomy of liability to schizophrenia, our findings demonstrate the utility of objective psychometric measurement and admixture analysis for resolving within-group heterogeneity in high-risk research. The wider implications of including our MMPI indicators in other genetic investigations of schizophrenia are discussed.     

Suicide attempts in an adolescent female twin sample.

OBJECTIVE: To examine suicide attempts in an epidemiologically and genetically informative youth sample. METHOD: 3,416 Missouri female adolescent twins (85% participation rate) were interviewed from 1995 to 2000 with a telephone version of the Child Semi-Structured Assessment for the Genetics of Alcoholism, which includes a detailed suicidal behavior section. Mean age was 15.5 years at assessment. RESULTS: At least one suicide attempt was reported by 4.2% of the subjects. First suicide attempts were all made before age 18 (and at a mean age of 13.6). Major depressive disorder, alcohol dependence, childhood physical abuse, social phobia, conduct disorder, and African-American ethnicity were the factors most associated with a suicide attempt history. Suicide attempt liability was familial, with genetic and shared environmental influences together accounting for 35% to 75% of the variance in risk. The twin/cotwin suicide attempt odds ratio was 5.6 (95% confidence interval [CI] 1.75-17.8) for monozygotic twins and 4.0 (95% CI 1.1 -14.7) for dizygotic twins after controlling for other psychiatric risk factors. CONCLUSIONS: In women, the predisposition to attempt suicide seems usually to manifest itself first during adolescence. The data show that youth suicide attempts are familial and possibly influenced by genetic factors, even when controlling for other psychopathology.     

Clinical characteristics of major depression that predict risk of depression in relatives

BACKGROUND: Major depression (MD) is both clinically and etiologically heterogeneous. We attempt to relate clinical and etiologic heterogeneity by determining those features of MD that reflect a high familial liability to depressive illness. METHODS: Our sample, 3786 personally interviewed twin pairs from a population-based registry, contained 1765 people with a lifetime history of MD by DSM-III-R criteria, of whom 639 (36.2%) had affected co-twins. We examine, using Cox proportional hazard models, the clinical features of MD in affected twins that predicted the risk for MD in the co-twin. Control variables were zygosity, age at interview, and sex of the twin and co-twin. RESULTS: The best-fitting model contained 4 significant predictors: number of episodes, duration of longest episode, recurrent thoughts of death or suicide, and level of distress or impairment. These 4 clinical features were similarly predictive of the risk for MD in the co-twins of male and female twins and predicted risk of illness more strongly in monozygotic than in dizygotic twins. Variables that did not uniquely predict risk of MD in the co-twin included age at onset and number of depressive symptoms. For number of episodes, the best-fitting model indicated an inverted U-shaped function with greatest co-twin risk for MD with 7 to 9 lifetime episodes. CONCLUSIONS: The clinical features of MD in epidemiologic samples can be meaningfully related to the familial vulnerability to illness. Familial MD is best characterized by intermediate levels of recurrence, long duration of episodes, high levels of impairment, and recurrent thoughts of death or suicide. These clinical features probably reflect a high genetic liability to depressive illness.     

Sleep electroencephalographic coherence abnormalities in individuals at high risk for depression: a pilot study.

BACKGROUND: Sleep electroencephalographic (EEG) studies of individuals with major depressive disorder have identified several microarchitectural features associated with the illness. These abnormalities are also found in clinically remitted individuals, raising the question of whether they are vulnerability markers of depression. This study evaluated the sleep EEG in high-risk individuals to see if abnormalities are present in the sleep EEG prior to the onset of illness. METHODS: A total of 26 subjects (13 males and 13 females) were recruited for study on the basis of 1) having a parent or grandparent treated for major depressive or bipolar affective disorder and 2) having no history of personal psychiatric illness. Polysomnographic data were collected and compared with gender- and age-matched healthy control subjects with no personal or family history of psychiatric illness. The primary outcome measures were interhemispheric and intrahemispheric coherence. RESULTS: Period analysis of the sleep EEG showed that beta-delta coherence was lower bilaterally in male high-risk subjects. Right-hemispheric theta-delta coherence was also lower in male high-risk subjects, with female high-risk subjects evidencing lower beta coherence. CONCLUSIONS: Sleep-EEG abnormalities associated with major depressive disorder are present in never mentally ill individuals at high risk for the illness. These markers may be useful in the prediction of illness and in family genetic studies of mood disorders.     

PERSONALITY FEATURES AND DISORDER IN THE SUBJECTS IN THE NEW YORK HIGH-RISK PROJECT

One hundred and seventy-five offspring of parents in two psychiatrically ill groups and of normal controls in the New York High-Risk Project (NYHRP) were assessed for Axis II personality traits and disorders as defined by the Diagnostic and Statistical Manual of Mental Disorders, Third Edition, Revised (DSM-III-R). These offspring include: subjects at high risk for schizophrenia (HRSz, n = 48), all of whom have a parent with schizophrenic disorder; subjects at high risk for affective disorder (HRAff, n = 40), all of whom have a parent with affective disorder; and subjects at no increased risk for psychiatric illness (NC, n = 87), whose parents are psychiatrically normal. The trained interviewers, who administered a standardized direct interview, were blind to parental clinical status and to previous clinical status of the offspring.

The rates for any personality disorder (PD) ranged from 7% to 20%. Comorbidity between Axis I and Axis II disorders was high for all groups.     

The Munich vulnerability study on affective disorders: premorbid polysomnographic profile of affected high-risk probands.

BACKGROUND: The most characteristic alterations in the sleep electroencephalogram (EEG) during major depression are a shortened latency to rapid eye movement (REM) sleep and an elevated REM density. Because these changes persist in remission, they might represent vulnerability markers. To identify vulnerability markers, we investigated premorbid sleep EEG parameters in healthy high-risk probands (HRPs) with a positive family history of affective disorders. METHODS: We identified 136 depressed inpatients from referrals to our hospital who had first-degree relatives with an affective disorder as well as first-degree relatives with no current or lifetime history of psychiatric disorders. The latter (the HRP group) were investigated by polysomnography. During the follow-up period, 20 HRPs developed an affective disorder. Their premorbid sleep data were analyzed. RESULTS: Premorbid sleep EEG of affected HRPs showed an increased REM density (total night and first REM period) compared with the control group without personal or family history of a psychiatric disorder. CONCLUSIONS: Increased REM density can be observed not only in patients with depression, but also in their healthy relatives. Moreover, it is predictive for the onset of a psychiatric disorder. Therefore, it can be recommended as a possible endophenotype of these diseases.     

Family psychiatric history, cerebrospinal fluid monoamine metabolites, and temperament in infants.

BACKGROUND: Variations in cerebrospinal fluid (CSF) levels of the monoamine metabolites 5-hydroxyindoleacetic acid, 3-methoxy-4-hydroxyphenylglycol, and homovanillic acid have been associated with behavioral abnormalities in nonhuman primates, and with psychopathology in studies of children and adults. METHODS: We assayed monoamine metabolites in "left-over" spinal fluid from 167 neurologically normal newborn infants (0-3 months of age), and later (at age 18-21 months of age) obtained their family psychiatric histories and assessed their temperament using the Colorado Childhood Temperament Inventory (CCTI). RESULTS: Family history of antisocial personality disorder predicted significantly lower scores for soothability (p = .003) at 18-21 months. There were no statistically significant associations between newborn monoamine metabolite levels and any aspect of temperament on the CCTI. CONCLUSIONS: These findings suggest complex relationships between genetic liability for psychiatric disorders and CSF monoamine metabolite levels; those relationships do not seem to be mediated by infant temperament. It appears likely that interindividual differences in monoamine metabolite levels change over the course of development in humans.