Juan Ángel Bellón

The risk for depression conferred by stressful life events is modified by variation at the serotonin transporter 5HTTLPR genotype: evidence from the Spanish PREDICT-Gene cohort

We report results from the PREDICT-Gene case-control study nested in a prospective cohort designed to identify predictors of the onset of depression among adult primary-care attendees. We tested the potential gene-by-environment interaction between 5HTTLPR genotype at the serotonin transporter gene and previous exposure to threatening life events (TLEs) in depression. A total of 737 consecutively recruited participants were genotyped. Additional information was gathered on exposure to TLEs over a 6-month period, socio-demographic data and family history of psychological problems among first-degree relatives. Diagnoses of depression were ascertained using the Composite International Diagnostic Interview (CIDI) by trained interviewers. Two different depressive outcomes were used (ICD-10 depressive episode and ICD-10 severe depressive episode). Both the s/s genotype and exposure to increasing number of TLEs were significantly associated with depression. Moreover, the 5HTTLPR s/s genotype significantly modified the risk conferred by TLEs for both depressive outcomes. Thus, s/s homozygous participants required minimal exposure to TLE (1 TLE) to acquire a level of risk for depression that was only found among l/s or l/l individuals after significantly higher exposure to TLEs (two or more TLEs). The interaction was more apparent when applied to the diagnosis of ICD-10 severe depressive episode and after adjusting for gender, age and family history of psychological problems. Likelihood ratios tests for the interaction were statistically significant for both depressive outcomes (ICD-10 depressive episode: LR X2=4.7, P=0.09 (crude), LR-X2=6.4, P=0.04 (adjusted); ICD-10 severe depressive episode: LR X2=6.9, P=0.032 (crude), LR-X2=8.1, P=0.017 (adjusted)).

The 5‐HTTLPR s/s genotype at the serotonin transporter gene (SLC6A4) increases the risk for depression in a large cohort of primary care attendees: The PREDICT‐gene study

Previous reports and meta‐analyses have yielded inconclusive results as to whether the s/s genotype at the 5‐HTTLPR serotonin transporter polymorphism confers increased risk for depression. We tested the association between s/s genotype and depression in a large cohort (n = 737) of Spanish primary care consecutive attendees participating in a European study on predictors for depression in primary care (PREDICT study). Participants were administered the Composite International Diagnostic Interview (CIDI) depression subscale allowing diagnoses using ICD‐10 criteria for depressive episodes. Participants were genotyped to establish 5HTTLPR genotype. Both univariable and multivariable associations between the s/s genotype and depression were tested twice using two different depressive outcomes (ICD‐10 depressive episode and ICD‐10 severe depressive episode). We found an association between the s/s genotype and both depressive outcomes that was independent of age, sex, family history of psychological problems among first degree relatives and presence of comorbid generalized anxiety disorder. When comparing s/s homozygous versus the rest, the adjusted odds ratio for any ICD‐10 depressive episode and for severe ICD‐10 depressive episode were 1.50 (95% CI: 1.0–2.2; P = 0.045) and 1.79 (95% CI: 1.1–2.8; P = 0.016), respectively. The association was significantly stronger with increasing severity of depression (χ2 for linear association=6.1; P = 0.013) suggesting a dose‐dependent relationship. Our results are consistent with previous reports suggesting a small but independent effect by the s/s 5‐HTTLPR genotype increasing the risk for depression.

Validity of self reported utilisation of primary health care services in an urban population in Spain

STUDY OBJECTIVE To assess the validity and factors related with the validity of self reported numbers of visits to a primary health care centre, in comparison with the recorded number. DESIGN Cross sectional study. SETTING The urban area served by the Zaidín-Sur Primary Health Care Centre (Granada, Spain). PARTICIPANTS Two population samples (236 high users and 420 normal users) who were seen at the centre from 1985 to 1991 were interviewed in 1993. MAIN RESULTS A net tendency to overreport the actual number of visits was observed. Absolute concordance between self reported and recorded utilisation decreased as time interval lengthened, although this mainly reflected the increase in maximum variability both with time interval length and with the number of recorded visits. Corrected Spearman ρ coefficients obtained between the number of self reported and recorded visits ranged from 0.602 for the two weeks before the interview to 0.678 for the year before. Regression slopes of self reported utilisation upon recorded utilisation did not change between periods. In multiple regression analyses the actual number of visits was the main factor associated with both underreporting and overreporting. Older age was also significantly associated with underreporting. Poor health status and high satisfaction with health care were significantly associated with overreporting. CONCLUSIONS There was a substantial degree of inaccuracy in self reported utilisation, with a net tendency to overreport the number of visits. In relative terms, however, accuracy of self reports did not seem to decrease appreciably as the recall time lengthened. To compare the accuracy of different measures, it is important to take into account the maximum variability of each one. Otherwise, contradictory results may be obtained.

Risk factors for the onset of panic and generalised anxiety disorders in the general adult population: A systematic review of cohort studies

BACKGROUND We aimed to assess available evidence on risk factors associated with the onset of panic disorder (PD) and/or generalised anxiety disorder (GAD) in cohort studies in the general adult population. METHODS Systematic review using MEDLINE, PsycINFO and Embase. Search terms included panic disorder, generalised anxiety disorder, cohort studies and risk factors. RESULTS We finally selected 21 studies, involving 163,366 persons with a median follow-up of 5 years. 1) Sociodemographic factors: PD was associated with age, female gender, and few economic resources. GAD was associated with age, non-Hispanics and Blacks, being divorced or widowed, and few economic resources. 2) Psychosocial factors: PD was associated with smoking and alcohol problems. GAD was associated with stressful life events in childhood and adulthood, and personality. 3) Physical and mental health factors: PD was associated with the number of physical diseases suffered and the joint hypermobility syndrome. PD was also associated with a parental history of mental disorders, as well as with other anxiety disorders and other mental health problems in the person affected. GAD was associated with a parental history of mental disorders, as well as with other anxiety disorders and other mental health problems in the person affected, plus already having received psychiatric care. LIMITATIONS Few studies examined the same risk factors. CONCLUSIONS Sociodemographic, psychosocial and mental-physical health risk factors were determinant for the onset of PD and GAD in the general adult population. These findings could be useful for developing preventive interventions in PD and GAD.

High-activity variants of the uMAOA polymorphism increase the risk for depression in a large primary care sample

Studies on the association between the functional uMAOA polymorphism and depression have yielded non‐conclusive results up till now. One thousand two hundred twenty eight consecutive Spanish primary care attendees, participating in the PREDICT study, agreed to take part in this genetic PREDICT‐Gene study. We explored the association between depression and either high‐activity uMAOA alleles or genotypes. Depression was diagnosed using the Composite International Diagnostic Interview (CIDI) to establish three different depressive outcomes (ICD‐10 Depressive Episode (DE), ICD‐10 Severe Depressive Episode (SDE) and DSM‐IV Major Depression (MD)). uMAOA genetic variation was determined by PCR amplification and subsequent electrophoresis. Crude and adjusted (gender and/or age) odds ratios, with 95% confidence intervals, were calculated for the associations between allele or genotype frequencies and all three depressive outcomes. We found associations between all three depressive phenotypes and either high‐activity alleles or high‐activity genotypes in both sexes. The associations were statistically significant for females but not for males. Testing the same associations on the entire sample (males and females) also yielded significant associations between depression and either high‐activity alleles or high‐activity genotype distribution that were independent of age and/or gender (ICD‐10 DE: OR = 1.98; 95% CI: 1.42–1.77; P = 0.00002; ICD‐10‐SDE: OR = 2.05; 95% CI: 1.38–3.05; P = 0.0002; DSM‐IV MD: OR = 1.91; 95% CI: (1.26–2.91); P = 0.0014). Our results provide fairly consistent evidence that high‐activity variants of the MAOA promoter polymorphism confer a modestly higher risk for depression.

Polymorphic variation at the serotonin 1-A receptor gene is associated with comorbid depression and generalized anxiety.

Background Serotonin 1-A receptors are key regulators of serotonin activity and their dysregulation might be implicated in the emergence of both major depression (MD) and generalized anxiety disorder (GAD). Previous studies have yielded inconclusive results as to whether the 5-HT1A receptor gene (HTR1A) has a role in the aetiology of MD and no study up to date has analysed this polymorphism on either pure MD or MD comorbid with GAD. Methods In this study, 1059 patients taking part in the PREDICT-Gene study were ascertained for Diagnostic and Statistical Manual of Mental Disorders-IV MD and GAD diagnoses using the Composite International Diagnostic Interview and the Primary Care Evaluation of Mental Disorders questionnaire, respectively. They were also genotyped for the C(-1019)G functional polymorphism at the promoter region of HTR1A gene. Results Genetic variability at HTR1A was significantly associated with MD [odds ratio (OR)=1.67; 95% confidence interval (CI)=1.14–2.44; P=0.008], although this effect disappeared after adjusting for GAD (OR=1.43; 95% CI=0.96–2.14; P=0.080). Similarly, a crude association between C(-1019)G polymorphism and GAD was found (OR=2.54; 95% CI=1.28–4.86; P=0.003), but these results became no longer significant after adjusting for MD (OR=1.97; 95% CI=0.99–3.91; P=0.050). However, a main effect of HTR1A G(-1019) allele on comorbid MD–GAD was found (OR=3.41; 95% CI=1.44–8.05; P=0.005) and it remained robust and statistically significant after adjusting by sex, age and family history of psychological problems (OR=2.82; 95% CI=1.18–6.77; P=0.020). Conclusion In our study, the HTR1A C(-1019)G polymorphism was found to be associated to the frequent clinical presentation of comorbid MD and GAD, suggesting a common genetic background for mixed depression and anxiety states. These findings should be considered as preliminary. Future replications in independent samples would be needed to confirm or discard such association.

Predicting the onset of major depression in primary care: international validation of a risk prediction algorithm from Spain

BACKGROUND The different incidence rates of, and risk factors for, depression in different countries argue for the need to have a specific risk algorithm for each country or a supranational risk algorithm. We aimed to develop and validate a predictD-Spain risk algorithm (PSRA) for the onset of major depression and to compare the performance of the PSRA with the predictD-Europe risk algorithm (PERA) in Spanish primary care. METHOD A prospective cohort study with evaluations at baseline, 6 and 12 months. We measured 39 known risk factors and used multi-level logistic regression and inverse probability weighting to build the PSRA. In Spain (4574), Chile (2133) and another five European countries (5184), 11 891 non-depressed adult primary care attendees formed our at-risk population. The main outcome was DSM-IV major depression (CIDI). RESULTS Six variables were patient characteristics or past events (sex, age, sex×age interaction, education, physical child abuse, and lifetime depression) and six were current status [Short Form 12 (SF-12) physical score, SF-12 mental score, dissatisfaction with unpaid work, number of serious problems in very close persons, dissatisfaction with living together at home, and taking medication for stress, anxiety or depression]. The C-index of the PSRA was 0.82 [95% confidence interval (CI) 0.79-0.84]. The Integrated Discrimination Improvement (IDI) was 0.0558 [standard error (s.e.)=0.0071, Zexp=7.88, p<0.0001] mainly due to the increase in sensitivity. Both the IDI and calibration plots showed that the PSRA functioned better than the PERA in Spain. CONCLUSIONS The PSRA included new variables and afforded an improved performance over the PERA for predicting the onset of major depression in Spain. However, the PERA is still the best option in other European countries.

Brain Changes in Long-Term Zen Meditators Using Proton Magnetic Resonance Spectroscopy and Diffusion Tensor Imaging: A Controlled Study

Introduction This work aimed to determine whether 1H magnetic resonance imaging (MRI), magnetic resonance spectroscopy (MRS), diffusion-weighted imaging (DWI) and diffusion tensor imaging (DTI) are correlated with years of meditation and psychological variables in long-term Zen meditators compared to healthy non-meditator controls. Materials and Methods Design. Controlled, cross-sectional study. Sample. Meditators were recruited from a Zen Buddhist monastery. The control group was recruited from hospital staff. Meditators were administered questionnaires on anxiety, depression, cognitive impairment and mindfulness. 1H-MRS (1.5 T) of the brain was carried out by exploring four areas: both thalami, both hippocampi, the posterior superior parietal lobule (PSPL) and posterior cingulate gyrus. Predefined areas of the brain were measured for diffusivity (ADC) and fractional anisotropy (FA) by MR-DTI. Results Myo-inositol (mI) was increased in the posterior cingulate gyrus and Glutamate (Glu), N-acetyl-aspartate (NAA) and N-acetyl-aspartate/Creatine (NAA/Cr) was reduced in the left thalamus in meditators. We found a significant positive correlation between mI in the posterior cingulate and years of meditation (r = 0.518; p = .019). We also found significant negative correlations between Glu (r = −0.452; p = .045), NAA (r = −0.617; p = .003) and NAA/Cr (r = −0.448; P = .047) in the left thalamus and years of meditation. Meditators showed a lower Apparent Diffusion Coefficient (ADC) in the left posterior parietal white matter than did controls, and the ADC was negatively correlated with years of meditation (r = −0.4850, p = .0066). Conclusions The results are consistent with the view that mI, Glu and NAA are the most important altered metabolites. This study provides evidence of subtle abnormalities in neuronal function in regions of the white matter in meditators.

Predicting the onset and persistence of episodes of depression in primary health care. The predictD-Spain study: Methodology

BackgroundThe effects of putative risk factors on the onset and/or persistence of depression remain unclear. We aim to develop comprehensive models to predict the onset and persistence of episodes of depression in primary care. Here we explain the general methodology of the predictD-Spain study and evaluate the reliability of the questionnaires used.MethodsThis is a prospective cohort study. A systematic random sample of general practice attendees aged 18 to 75 has been recruited in seven Spanish provinces. Depression is being measured with the CIDI at baseline, and at 6, 12, 24 and 36 months. A set of individual, environmental, genetic, professional and organizational risk factors are to be assessed at each follow-up point. In a separate reliability study, a proportional random sample of 401 participants completed the test-retest (251 researcher-administered and 150 self-administered) between October 2005 and February 2006. We have also checked 118,398 items for data entry from a random sample of 480 patients stratified by province.ResultsAll items and questionnaires had good test-retest reliability for both methods of administration, except for the use of recreational drugs over the previous six months. Cronbachs alphas were good and their factorial analyses coherent for the three scales evaluated (social support from family and friends, dissatisfaction with paid work, and dissatisfaction with unpaid work). There were 191 (0.16%) data entry errors.ConclusionThe items and questionnaires were reliable and data quality control was excellent. When we eventually obtain our risk index for the onset and persistence of depression, we will be able to determine the individual risk of each patient evaluated in primary health care.

Psychometric properties of the List of Threatening Experiences—LTE and its association with psychosocial factors and mental disorders according to different scoring methods

BACKGROUND The List of Threatening Experiences (LTE) questionnaire is frequently used to assess stressful events; however, studies of its psychometric properties are scarce. We examined the LTEs reliability, factorial structure, construct validity and explored the association between LTE scores and psychosocial variables and mental disorders. METHOD This study involved interviewing 5442 primary care attendees from Spain. Associations between four different methods of quantifying LTE scores, psychosocial factors, major depression (CIDI), anxiety disorders (PRIME-MD), alcohol misuse and dependence (AUDIT) were measured. RESULTS The LTE showed high test-retest reliability (Kappa range=0.61-0.87) and low internal consistency (α=0.44). Tetrachoric factorial analysis yielded four factors (spousal and relational problems; employment and financial problems; personal problems; illness and bereavement in close persons). Logistic multilevel regression found a strong association between greater social support and a lower occurrence of stressful events (OR range=0.36-0.79). The association between religious-spiritual beliefs and the LTE, was weaker. The association between mental disorders and LTE scores was greater for depression (OR range=1.64-2.57) than anxiety (OR range=1.35-1.97), though the highest ORs were obtained with alcohol dependence (OR range=2.86-4.80). The ordinal score (ordinal regression) was more sensitive to detect the strength of association with mental disorders. LIMITATIONS We are unable to distinguish the direction of the association between stressful events, psychosocial factors and mental disorders, due to our cross-sectional design of the study. CONCLUSIONS The LTE is a valid and reliable measure of stress in mental health, and the strength of association with mental disorders depends on the method of quantifying LTE scores.