Genetic influences on behavioral inhibition and anxiety in juvenile rhesus macaques

In humans and other animals, behavioral responses to threatening stimuli are an important component of temperament. Among children, extreme behavioral inhibition elicited by novel situations or strangers predicts the subsequent development of anxiety disorders and depression. Genetic differences among children are known to affect risk of developing behavioral inhibition and anxiety, but a more detailed understanding of genetic influences on susceptibility is needed. Nonhuman primates provide valuable models for studying the mechanisms underlying human behavior. Individual differences in threat-induced behavioral inhibition (freezing behavior) in young rhesus monkeys are stable over time and reflect individual levels of anxiety. This study used the well-established human intruder paradigm to elicit threat-induced freezing behavior and other behavioral responses in 285 young pedigreed rhesus monkeys. We examined the overall influence of quantitative genetic variation and tested the specific effect of the serotonin transporter promoter repeat polymorphism. Quantitative genetic analyses indicated that the residual heritability of freezing duration (behavioral inhibition) is h ² = 0.384 ( P  = 0.012) and of 'orienting to the intruder' (vigilance) is h ² = 0.908 ( P  = 0.00001). Duration of locomotion and hostility and frequency of cooing were not significantly heritable. The serotonin transporter polymorphism showed no significant effect on either freezing or orienting to the intruder. Our results suggest that this species could be used for detailed studies of genetic mechanisms influencing extreme behavioral inhibition, including the identification of specific genes that are involved in predisposing individuals to such behavior.     

Anxiety‐related behavioral inhibition in rats: a model to examine mechanisms underlying the risk to develop stress‐related psychopathology

Behavioral inhibition (BI) is an adaptive defensive response to threat; however, children who display extreme BI as a stable trait are at risk for development of anxiety disorders and depression. The present study validates a rodent model of BI based on an ethologically relevant predator exposure paradigm. We show that individual differences in rat BI are stable and trait‐like from adolescence into adulthood. Using in situ hybridization to quantify expression of the immediate early genes homer1a and fos as measures of neuronal activation, we show that individual differences in BI are correlated with the activation of various stress‐responsive brain regions that include the paraventricular nucleus of the hypothalamus and CA3 region of the hippocampus. Further supporting the concept that threat‐induced BI in rodents reflects levels of anxiety, we also show that BI is decreased by administration of the anxiolytic, diazepam. Finally, we developed criteria for identifying extreme BI animals that are stable in their expression of high levels of BI and also show that high BI (HBI) individuals exhibit maladaptive appetitive responses following stress exposure. These findings support the use of predator threat as a stimulus and HBI rats as a model to study mechanisms underlying extreme and stable BI in humans.     

Intensified Neuronal Investment in the Processing of Chemosensory Anxiety Signals in Non-Socially Anxious and Socially Anxious Individuals

Background

The ability to communicate anxiety through chemosensory signals has been documented in humans by behavioral, perceptual and brain imaging studies. Here, we investigate in a time-sensitive manner how chemosensory anxiety signals, donated by humans awaiting an academic examination, are processed by the human brain, by analyzing chemosensory event-related potentials (CSERPs, 64-channel recording with current source density analysis).

Methodology/Principal Findings

In the first study cerebral stimulus processing was recorded from 28 non-socially anxious participants and in the second study from 16 socially anxious individuals. Each individual participated in two sessions, smelling sweat samples donated from either female or male donors (88 sessions; balanced session order). Most of the participants of both studies were unable to detect the stimuli olfactorily. In non-socially anxious females, CSERPs demonstrate an increased magnitude of the P3 component in response to chemosensory anxiety signals. The source of this P3 activity was allocated to medial frontal brain areas. In socially anxious females chemosensory anxiety signals require more neuronal resources during early pre-attentive stimulus processing (N1). The neocortical sources of this activity were located within medial and lateral frontal brain areas. In general, the event-related neuronal brain activity in males was much weaker than in females. However, socially anxious males processed chemosensory anxiety signals earlier (N1 latency) than the control stimuli collected during an ergometer training.

Conclusions/Significance

It is concluded that the processing of chemosensory anxiety signals requires enhanced neuronal energy. Socially anxious individuals show an early processing bias towards social fear signals, resulting in a repression of late attentional stimulus processing.     

Mom—It Helps When You're Right Here! Attenuation of Neural Stress Markers in Anxious Youths Whose Caregivers Are Present during fMRI

Close proximity to an attachment figure, such as a caregiver, has been shown to attenuate threat-related activity in limbic regions such as the hypothalamus in healthy individuals. We hypothesized that such features might be similarly attenuated by proximity during a potentially stressful situation in a clinically anxious population of youths. Confirmation of this hypothesis could support the role of attachment figures in the management of anxiety among children and adolescents. Three groups were analyzed: anxious children and adolescents who requested that their caregiver accompany them in the scanner room, anxious children and adolescents without their caregiver in the scanner room and healthy controls (each of N = 10). The groups were matched for age and, among the two anxious groups, for diagnosis (mean age 9.5). The children and adolescents were exposed to physical threat words during an fMRI assessment. Results indicate that activity in the hypothalamus, ventromedial, and ventrolateral prefrontal cortex were significantly reduced in anxious children and adolescents who requested that their caregiver accompany them in the scanner room compared to those without their caregiver in the scanner room. Mean activity in these regions in anxious children and adolescents with their caregiver in the scanner room was comparable to that of healthy controls. These data suggest links between social contact and neural mechanisms of emotional reactivity; specifically, presence of caregivers moderates the increase in anxiety seen with stressful stimuli. Capitalizing on the ability of anxious youths to manifest low levels of anxiety-like information processing in the presence of a caregiver could help in modeling adaptive function in behavioral treatments.     

Netherlands twin family study of anxious depression (NETSAD).

In a longitudinal study of Dutch adolescent and young adult twins, their parents and their siblings, questionnaire data were collected on depression, anxiety and correlated personality traits, such as neuroticism. Data were collected by mailed surveys in 1991, 1993, 1995 and 1997. A total of 13,717 individuals from 3344 families were included in the study. To localise quantitative trait loci (QTLs) involved in anxiety and depression, the survey data were used to select the most informative families for a genome-wide search. For each individual a genetic factor score was computed, based on a genetic multivariate analysis of anxiety, depression, neuroticism and somatic anxiety. A family was selected if at least two siblings (or DZ twins) had extreme factor scores. Both discordant (high-low) and concordant (high-high and low-low) pairs were included in the selected sample. Once an extreme sibling pair was selected, all family members (parents and additional siblings of the selected pair) who had at least once returned a questionnaire booklet were asked to provide a DNA sample. In total, 2724 individuals from 563 families (1007 parents and 1717 offspring) were approached and 1975 individuals from 479 families (643 patients and 1332 offspring) complied by returning a buccal swab for DNA isolation. All offspring from selected families were asked to participate in a psychiatric interview and in a 24-hour ambulatory assessment of cardiovascular parameters and cortisol. The interview consisted of the WHO-Composite International Diagnostic Interview and was administered to 1253 offspring. In this paper we describe the genetic-epidemiological analyses of the survey data on anxiety, somatic anxiety, neuroticism and depression. We detail how these data were used to select families for the QTL study and discuss strategies that may help elucidate the molecular pathways leading from genes to anxious depression.     

Sex differences in vulnerability and maladjustment as a function of parental investment: an evolutionary approach.

Sex differences in aspects of mental health are examined as a function of uneven parental investment in children. Relative vulnerability is a new construct mediating the influence of parental investment on mental health. Couples (129) in three stages of the family life cycle are measured by scales for parental investment, relative vulnerability, anxiety, depression, and ten psychosomatic syndromes. Results show a path of positive correlations from the parent's sex to level of parental investment, to level of relative vulnerability, and to levels of anxiety and depression. Women invest more than men, and hence they are more vulnerable, anxious, and depressed. They reach the summit of their vulnerability while they have three young children. Relative vulnerability was found to have positive effects along with the negative ones and to affect women in different ways than it does men. Results are interpreted in terms of different parental strategies selected by evolution for each sex.     

The role of anxious and hyperthymic temperaments in mental disorders: a national epidemiologic study

Temperament has been demonstrated clinically to be linked to mental disorders. We aimed to determine the possible role of temperament in mental disorders in a national epidemiologic study. A nationally representative sample of adults (n=1320) was administered the Lebanese-Arabic version of the Temperament Evaluation of the Memphis, Pisa, Paris and San Diego Autoquestionnaire (TEMPS-A), and the Arabic CIDI 3.0, as part of the LEBANON study. The association among temperaments and DSM-IV mood, anxiety, and impulse control disorders was assessed. The anxious temperament was shown to be a robust predictor of most disorders, especially within the anxiety and depressive clusters. The hyperthymic temperament had a uniquely protective effect on most mental disorders, with the exception of separation anxiety, bipolar, substance abuse and impulse control disorders. These effects were moderated by age and education. Temperaments, previously largely neglected in epidemiologic studies, could play a major role in the origin of mental disorders.     

Anxiété et personnalité: études catégorielle et dimensionnelle de leur association et facteurs de vulnérabilité

Anxiety disorders often appear in patients with particular personality traits, and in some cases with actual personality disorders. This clinical observation may question the respective interactions between personality and anxiety disorders: Is it possible to evaluate the personality of patients with severe anxiety disorders reliably? What is the real co-morbidity between personality disorders and anxiety disorders? Are there psychopathological and etiological links between these two disorders? Studies relying on categorical approaches of personality suggest that about 40-60% of anxious patients fulfill the diagnostic criteria of at least one personality disorder. The most frequent diagnoses belong to the cluster C of the DSM-IV axis II classification, with a majority having avoidant and dependent personalities, but without any real specificity according to the types of anxiety disorders. On the other hand, dimensional studies have shown that anxiety disorders are often associated with avoidant personality traits, with very deviant scores in some cases, even after treatment of the anxiety disorder. These works support the existence of some temperament traits, underlined by psychobiological, stable, and inheritable dimensions, which may constitute early vulnerability factors for anxiety disorders in both children and adults.     

Analysis of interdependence of temperament,neuroendocrine control and psychophysiological state during dry immersion

Interdependence of temperament, hormonal and psychophysiological states was investigated in eight young volunteers during seven-day dry immersion (DI). The levels of insulin and sex, steroid, and thyroid hormones in the blood and the psychomotor parameters were determined on days 3 and 7 of DI and on day 7 of recovery. Before DI, the volunteers filled in the Cattell’s Personality Factor Questionnaire. During DI, anxious subjects spent less time to compare visual patterns, demonstrating a high and stable speed of reactions with a slight deterioration. Extraverts showed high speed of reactions and stability of psychomotor parameters without increase in the number of errors. Easy-tempered and introvert subjects preserved inherently high insulin concentrations in DI. Support deprivation was accompanied by the drop of triiodothyronine and cortisol levels and the increase in prolactin and thyroxin. The results of multiple correlation analysis lead to the conclusion that DI increased the role of original extra-introversion and decreased that of the original anxiety. Successful activity can be attained by adequate alteration of the levels of steroid and thyroid hormones with effectively balanced vagoinsular-sympathoadrenal neuroendocrine control and monoaminergic CNS activity.     

Cortisol and ACTH responses to the Dex/CRH test: influence of temperament

Temperament and personality traits such as neuroticism and behavioral inhibition are prospective predictors of the onset of depression and anxiety disorders. Exposure to stress is also linked to the development of these disorders, and neuroticism and inhibition may confer or reflect sensitivity to stressors. Several lines of research have documented hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis in some patients with major depression, as well as in children and non-human primates with inhibited temperaments. The present investigation tested the hypothesis that stress-reactive temperaments would be predictive of plasma adrenocorticotropin (ACTH) and cortisol concentrations in the dexamethasone/corticotropin-releasing hormone (Dex/CRH) test. Sixty adults completed diagnostic interviews and questionnaires assessing the temperament domains of novelty seeking and harm avoidance and symptoms of anxiety and depression. All subjects were free of any current or past Axis I psychiatric disorder. The Dex/CRH test was performed on a separate visit. A repeated-measures general linear model (GLM) showed a main effect of harm avoidance in predicting cortisol concentrations in the test (F(1, 58)=4.86, p<.05). The GLM for novelty seeking and cortisol response also showed a main effect (F(1, 58)=5.28, p<.05). Higher cortisol concentrations were associated with higher levels of harm avoidance and lower levels of novelty seeking. A significant interaction of time with harm avoidance and novelty seeking (F(4, 53)=3.37, p<.05) revealed that participants with both high levels of harm avoidance and low levels of novelty seeking had the highest cortisol responses to the Dex/CRH test. Plasma ACTH concentrations did not differ as a function of temperament. The results indicate that temperament traits linked to sensitivity to negative stimuli are associated with greater cortisol reactivity during the Dex/CRH test. Increased adrenocortical reactivity, which previously has been linked to major depression and anxiety disorders, may contribute to the association between temperament/personality traits and these disorders.     

fMRI Study of Social Anxiety during Social Ostracism with and without Emotional Support

Social anxiety is characterized by an excessive fear of being embarrassed in social interactions or social performance situations. Emotional support can help to decrease or diminish social distress. Such support may play an important role at different points of social interaction. However, it is unclear how the beneficial effects of social support are represented in the brains of socially anxious individuals. To explore this, we used the same paradigm previously used to examine the effects of emotional support on social pain caused by exclusion. Undergraduates (n = 46) showing a wide range of social anxiety scores underwent functional magnetic resonance imaging (fMRI) while participating in a Cyberball game. Participants were initially included and later excluded from the game. In the latter half of the session in which participants were excluded, they were provided with supportive messages. In line with our previous work, we found that social exclusion led to increased anterior cingulate cortex (ACC) activity, whereas emotional support led to increased left dorsolateral prefrontal cortex (DLPFC) activity. Despite validation of the paradigm, social anxiety was not associated with increased ACC activity during social exclusion, or during perceived emotional support. Instead, fear of negative evaluation as assessed by the Brief Fear of Negative Evaluation (BFNE) scale showed positive associations with left DLPFC activation while receiving emotional support, compared to while being socially excluded. The more socially anxious an individual was, the greater was the left DLPFC activity increased during receipt of messages. This suggests that highly socially anxious people still have the ability to perceive social support, but that they are nevertheless susceptible to negative evaluation by others.     

Neuroendocrine Response to School Load in Prepubertal Children: Focus on Trait Anxiety

At the time of school-age, the most frequent stress stimuli are related to school environment and educational process. Anxiety may play a big role in coping with stressful situations associated with school load. To approach this issue, we performed a real-life study at school during the classwork. The sample consisted of 36 healthy children aged 10 years, which were divided to low and high trait anxiety group based on the median value of the anxiety score. The investigations were carried out in the classroom during a stress condition (final exams) and non-stress condition (without any exam). In the whole sample, the condition with exam was associated with higher cortisol and lower testosterone concentrations in saliva compared to the condition without exam. The activity of salivary alpha-amylase increased at the end of the exam. Anxious children showed higher concentrations of aldosterone and lower activity of alpha-amylase compared to children with low trait anxiety. Cortisol levels were higher in anxious children in the first morning samples before starting the lessons. Children with high and low trait anxiety did not differ in extraversion, neuroticism, as well as non-verbal intelligence and school success. Thus, the anxious children at school showed a more rapid decrease of anticipatory stress-induced cortisol concentrations, higher aldosterone levels, and lower alpha-amylase activities compared to non-anxious children. These changes, particularly high concentrations of aldosterone in children with high trait anxiety, may have an impact on their psychophysiological development.     

High visual working memory capacity in trait social anxiety

Working memory capacity is one of the most important cognitive functions influencing individual traits, such as attentional control, fluid intelligence, and also psychopathological traits. Previous research suggests that anxiety is associated with impaired cognitive function, and studies have shown low verbal working memory capacity in individuals with high trait anxiety. However, the relationship between trait anxiety and visual working memory capacity is still unclear. Considering that people allocate visual attention more widely to detect danger under threat, visual working memory capacity might be higher in anxious people. In the present study, we show that visual working memory capacity increases as trait social anxiety increases by using a change detection task. When the demand to inhibit distractors increased, however, high visual working memory capacity diminished in individuals with social anxiety, and instead, impaired filtering of distractors was predicted by trait social anxiety. State anxiety was not correlated with visual working memory capacity. These results indicate that socially anxious people could potentially hold a large amount of information in working memory. However, because of an impaired cognitive function, they could not inhibit goal-irrelevant distractors and their performance decreased under highly demanding conditions.     

Game-based biofeedback for paediatric anxiety and depression

Twenty-four children and adolescents aged 9-17 who were referred for treatment for anxiety were assigned to either a game-based biofeedback group or a waiting list comparison group. The eight-session biofeedback intervention included psychoeducation, identification of triggers and signs of anxiety, and in vivo practice. The intervention used computer-based gaming technology to teach and practise relaxation. Analyses using ANCOVA revealed significant differences in post-test scores of anxiety and depression measures between the two groups. The intervention group reduced anxiety and depression scores on standardised tests. Findings suggest that biofeedback-assisted relaxation training can be useful in decreasing anxiety and depressive symptoms in anxious youths.     

Prevalence and correlations with depression, anxiety, and other features in outpatients with chronic obstructive pulmonary disease in China: a cross-sectional case control study

ABSTRACT: BACKGROUND: Patients with chronic obstructive pulmonary disease (COPD) often experience depression and anxiety, but little information is available regarding Chinese patients with these conditions. The present study assessed depression and anxiety in Chinese patients with COPD. METHODS: A case--controlled study was designed with 1100 patients with COPD enrolled in the case group and1100 residents without COPD and respiratory symptoms selected as the control group. Anxiety and depression in both groups were evaluated using the Hospital Anxiety and Depression Scale (HADS). The body mass index,degree of airflow obstruction, dyspnea, and exercise capacity (BODE ) index was used to assess COPD severity. Binary logistic regression models were used to test the association between anxiety and depression. RESULTS: The patients with COPD were more likely than controls to experience depression (cases, HADS 10.5 +/- 3.6, prevalence 35.7%; controls, HADS 8.7 +/- 2.7, prevalence 7.2%) and anxiety (cases, HADS 10.4 +/- 3.1, prevalence 18.3%; controls, HADS 8.6 +/- 2.1, prevalence 5.3%). Subjects with anxious and depressive symptoms had poorer health outcomes including a higher BODE index, a shorter 6-minute-walk distance (6MWD), more dyspnea, and a higher St George's respiratory questionnaire (SGRQ) score. The prevalence of anxious and depressive symptoms increased with increasing BODE scores. On the basis of binary logistic regression, the BODE index was significantly correlated with anxiety (OR = 1.47, p < 0.001) and depression (OR = 1.51, p < 0.001). Anxious and depressive symptoms were also associated with several factors including younger age, female sex, higher education level, lower household income and history of smoking. CONCLUSIONS: This study confirmed the high prevalence of anxiety and depression in Chinese outpatients with COPD. Patients with COPD who had anxiety and/or depression had a poorer health-related quality of life.Trial registrationChinese Clinical Trials Registration(ChiCTR-TRC-12001958).     

Psychophysiological indices in six-to eight-year-old children under information load depending on anxiety as a stable individual characteristic

The study of psychophysiological indices in children aged six to eight years under information loads of various complexity showed that anxious subjects were characterized by a high level of nonspecific activation at rest and a shift of the autonomic balance towards a relative domination of the tone of the sympathetic division of the autonomic nervous system (ANS). The information load in the “auto-rate” mode caused in children aged six to eight years an increase in the level of nonspecific activation and the activity of sympathetic regulation and an inhibition of parasympathetic regulation. An information load in the “maximum rate of work” mode caused a decrease in the quantitative and qualitative indices of mental activity in comparison with that under comfortable conditions and a subsequent increase in autonomic shifts and the level of situational anxiety. The decrease in the efficiency of intellectual work performed at a maximum rate against the background of a high level of nonspecific activation and an increase in situational anxiety in both groups apparently reflected an increase in the activity of the modulating cerebral system due to the domination of the nonproductive activation system related to defensive behavior. At the same time, in children with a high personal anxiety, autonomic manifestations of activation and situational anxiety in both modes of work were more distinct and the efficiency of work lower than in subjects with a low anxiety. This indicates that, in anxious children, due to the excess activation of the sympathetic division of the ANS, the information load has a higher physiological cost. Thus, children with a high level of personal anxiety under intense information loads are characterized by a larger increase in the activity of the sympathetic division of the ANS and the attenuation of the effect of the parasympathetic division; a considerable increase in situational anxiety; low efficiency of activity; and, hence, its high physiological cost.     

Diagnostic Criteria for Depression in Type 2 Diabetes: A Data-Driven Approach

BackgroundWhile depression is a frequent psychiatric comorbid condition in diabetes and has significant clinical impact, the syndromal profile of depression and anxiety symptoms has not been examined in detail.AimsTo determine the syndromal pattern of the depression and anxiety spectrum in a large series of patients with type 2 diabetes, as determined using a data-driven approach based on latent class analysis (LCA).MethodType 2 diabetes participants from the observational community-based Fremantle Diabetes Study Phase II underwent assessment of lifetime depression using the Brief Lifetime Depression Scale, the Patient Health Questionnaire 9-item version (PHQ-9) for current depression symptoms, and the Generalized Anxiety Disorder Scale that was specifically developed and validated for this study. The main outcome measure was classes of patients with a specific syndromal profile of depression and anxiety symptoms based on LCA.ResultsLCA identified four classes that were interpreted as “major anxious depression”, “minor anxious depression”, “subclinical anxiety”, and “no anxious depression”. All nine DSM-IV/5 diagnostic criteria for major depression identified a class with a high frequency of major depression. All symptoms of anxiety had similar high probabilities as symptoms of depression for the “major depression-anxiety” class. There were significant differences between classes in terms of history of depression and anxiety, use of psychoactive medication, and diabetes-related variables.ConclusionsPatients with type 2 diabetes show specific profiles of depression and anxiety. Anxiety symptoms are an integral part of major depression in type 2 diabetes. The different classes identified here provide empirically validated phenotypes for future research.     

Combined Healthy Lifestyle Is Inversely Associated with Psychological Disorders among Adults

Background and Aims

Joint association of lifestyle-related factors and mental health has been less studied in earlier studies, especially in Middle Eastern countries. This study aimed to examine how combinations of several lifestyle-related factors related to depression and anxiety in a large group of middle-age Iranian population.

Methods

In a cross-sectional study on 3363 Iranian adults, a healthy lifestyle score was constructed by the use of data from dietary intakes, physical activity, smoking status, psychological distress and obesity. A dish-based 106-item semi-quantitative validated food frequency questionnaire (FFQ), General Practice Physical Activity Questionnaire (GPPAQ), General Health Questionnaire (GHQ) and other pre-tested questionnaires were used to assess the components of healthy lifestyle score. The Hospital Anxiety and Depression Scale (HADS) was applied to screen for anxiety and depression.

Results

After adjustment for potential confounders, we found that individuals with the highest score of healthy lifestyle were 95% less likely to be anxious (OR: 0.05; 95% CI: 0.01–0.27) and 96% less likely to be depressed (OR: 0.04; 95% CI: 0.01–0.15), compared with those with the lowest score. In addition, non-smokers had lower odds of anxiety (OR: 0.64; 95% CI: 0.47–0.88) and depression (OR: 0.62; 95% CI: 0.48–0.81) compared with smokers. Individuals with low levels of psychological distress had expectedly lower odds of anxiety (OR: 0.13; 95% CI: 0.10–0.16) and depression (OR: 0.10; 95% CI: 0.08–0.12) than those with high levels. Individuals with a healthy diet had 29% lower odds of depression (OR: 0.71; 95% CI: 0.59–0.87) than those with a non-healthy diet.

Conclusion

We found evidence indicating that healthy lifestyle score was associated with lower odds of anxiety and depression in this group of Iranian adults. Healthy diet, psychological distress, and smoking status were independent predictors of mental disorders.     

Health status and anxiety in the elderly. A longitudinal perspective

The prognostic value of physical health for changes in anxiety symptoms in older people was investigated in a prospective longitudinal study design with data from the Longitudinal Aging Study Amsterdam (LASA). In a sample of 2165 older (> 55 yrs.) respondents anxiety symptoms were measured twice over a three year interval with the anxiety subscale of the Hospital Anxiety and Depression Scale (HADS-A). Utilizing a cut-off value of 4 on the HADS-A, subjects were considered as anxious or as non-anxious. Based on the first assessment two groups were formed: subjects with and subjects without anxiety symptoms. In the non-anxious cohort the effect of physical health on the development of anxiety symptoms was studied; in the anxious cohort the same factors were evaluated on their predictive value for chronicity of anxiety. Indices of physical health included the presence of chronic diseases, functional limitations, and self-perceived health at the first assessment and changes on these variables over time. Results revealed that poor self-perceived health was predictive of incidence (OR = 1.5; 95% CI = 1.3-1.8) and chronicity of anxiety (OR = 1.2; CI = 1.0-1.5). Regarding chronic diseases, the results showed that suffering from more than one chronic disease predicted becoming anxious and chronicity of anxiety (OR = 1.7; CI = 1.2-2.5 and OR = 2.2; CI = 1.3-3.6, respectively). Specific chronic diseases were not strongly related to a change in anxiety levels. Thus, somatic diseases not only lead to depression, a finding reported in numerous studies, but also increase the likelihood of anxiety symptoms at a later point in time.     

Variability in the Effect of 5-HTTLPR on Depression in a Large European Population: The Role of Age,Symptom Profile,Type and Intensity of Life Stressors

Background

Although 5-HTTLPR has been shown to influence the risk of life stress-induced depression in the majority of studies, others have produced contradictory results, possibly due to weak effects and/or sample heterogeneity.

Methods

In the present study we investigated how age, type and intensity of life-stressors modulate the effect of 5-HTTLPR on depression and anxiety in a European population cohort of over 2300 subjects. Recent negative life events (RLE), childhood adversity (CHA), lifetime depression, Brief Symptoms Inventory (BSI) depression and anxiety scores were determined in each subject. Besides traditional statistical analysis we calculated Bayesian effect strength and relevance of 5-HTTLPR genotypes in specified models.

Results

The short (s) low expressing allele showed association with increased risk of depression related phenotypes, but all nominally significant effects would turn to non-significant after correction for multiple testing in the traditional analysis. Bayesian effect strength and relevance analysis, however, confirmed the role of 5-HTTLPR. Regarding current (BSI) and lifetime depression 5-HTTLPR-by-RLE interactions were confirmed. Main effect, with other words direct association, was supported with BSI anxiety. With more frequent RLE the prevalence or symptoms of depression increased in ss carriers. Although CHA failed to show an interaction with 5-HTTLPR, in young subjects CHA sensitized towards the depression promoting effect of even mild RLE. Furthermore, the direct association of anxiety with the s allele was driven by young (≤30) individuals.

Limitations

Our study is cross-sectional and applies self-report questionnaires.

Conclusions

Albeit 5-HTTLPR has only weak/moderate effects, the s allele is directly associated with anxiety and modulates development of depression in homogeneous subgroups.