Collaborative meta-analysis finds no evidence of a strong interaction between stress and 5-HTTLPR genotype contributing to the development of depression.

The hypothesis that the S allele of the 5-HTTLPR serotonin transporter promoter region is associated with increased risk of depression, but only in individuals exposed to stressful situations, has generated much interest, research and controversy since first proposed in 2003. Multiple meta-analyses combining results from heterogeneous analyses have not settled the issue. To determine the magnitude of the interaction and the conditions under which it might be observed, we performed new analyses on 31 data sets containing 38 802 European ancestry subjects genotyped for 5-HTTLPR and assessed for depression and childhood maltreatment or other stressful life events, and meta-analysed the results. Analyses targeted two stressors (narrow, broad) and two depression outcomes (current, lifetime). All groups that published on this topic prior to the initiation of our study and met the assessment and sample size criteria were invited to participate. Additional groups, identified by consortium members or self-identified in response to our protocol (published prior to the start of analysis) with qualifying unpublished data, were also invited to participate. A uniform data analysis script implementing the protocol was executed by each of the consortium members. Our findings do not support the interaction hypothesis. We found no subgroups or variable definitions for which an interaction between stress and 5-HTTLPR genotype was statistically significant. In contrast, our findings for the main effects of life stressors (strong risk factor) and 5-HTTLPR genotype (no impact on risk) are strikingly consistent across our contributing studies, the original study reporting the interaction and subsequent meta-analyses. Our conclusion is that if an interaction exists in which the S allele of 5-HTTLPR increases risk of depression only in stressed individuals, then it is not broadly generalisable, but must be of modest effect size and only observable in limited situations.

Predicting mental disorders from hypothalamic-pituitary-adrenal axis functioning: a 3-year follow-up in the TRAILS study.

BACKGROUND: Hypothalamic-pituitary-adrenal axis functioning, with cortisol as its major output hormone, has been presumed to play a key role in the development of psychopathology. Predicting affective disorders from diurnal cortisol levels has been inconclusive, whereas the predictive value of stress-induced cortisol concentrations has not been studied before. The aim of this study was to predict mental disorders over a 3-year follow-up from awakening and stress-induced cortisol concentrations. METHOD: Data were used from 561 TRAILS (TRacking Adolescents' Individual Lives Survey) participants, a prospective cohort study of Dutch adolescents. Saliva samples were collected at awakening and half an hour later and during a social stress test at age 16. Mental disorders were assessed 3 years later with the Composite International Diagnostic Interview (CIDI). RESULTS: A lower cortisol awakening response (CAR) marginally significantly predicted new disorders [odds ratio (OR) 0.77, p = 0.06]. A flat recovery slope predicted disorders with a first onset after the experimental session (OR 1.27, p = 0.04). Recovery revealed smaller, non-significant ORs when predicting new onset affective or anxiety disorders, major depressive disorder, or dependence disorders in three separate models, corrected for all other new onsets. CONCLUSIONS: Our results suggest that delayed recovery and possibly reduced CAR are indicators of a more general risk status and may be part of a common pathway to psychopathology. Delayed recovery suggests that individuals at risk for mental disorders perceived the social stress test as less controllable and less predictable.

Diagnosing overtraining in athletes using the two-bout exercise protocol.

OBJECTIVE: In this work, whether a two-bout exercise protocol can be used to make an objective, immediately available distinction between non-functional over reaching (NFO) and overtraining syndrome (OTS) was studied. DESIGN: Underperforming athletes who were diagnosed with the suspicion of NFO or OTS were included in the study. Recovery of the athletes was monitored by a sports physician to retrospectively distinguish NFO from OTS. SETTING: Sports medicine laboratory PARTICIPANTS: The protocol was started and completed by 10 underperforming athletes. NFO was retrospectively diagnosed in five athletes, and OTS was diagnosed in five athletes. INTERVENTIONS: A two-bout maximal exercise protocol was used to measure physical performance and stressinduced hormonal reactions. MAIN OUTCOME MEASUREMENTS: Exercise duration, heart rate and blood lactate concentration were measured at the end of both exercise tests. Venous concentrations cortisol, adrenocorticotrophic hormone (ACTH), prolactin and growth hormone were measured both before and after both exercise tests. RESULTS: Maximal blood lactate concentration was lower in OTS compared with NFO, while resting concentrations of cortisol, ACTH and prolactin concentrations were higher. However, sensitivity of these measures was low. The ACTH and prolactin reactions to the second exercise bout were much higher in NFO athletes compared with OTS and showed the highest sensitivity for making the distinction. CONCLUSIONS: NFO might be distinguished from OTS based on ACTH and prolactin reactions to a two-bout exercise protocol. This protocol could be a useful tool for diagnosing NFO and OTS; however, more data should be collected before this test can be used as the gold standard.

Plasticity genes do not modify associations between physical activity and depressive symptoms.

OBJECTIVE: Physical activity is inversely associated with depression in adolescents, but the overall associations are fairly weak, suggesting individual differences in the strength of the associations. The aim of this study was to investigate whether plasticity genes modify the reciprocal prospective associations between physical activity and depressive symptoms found previously. METHODS: In a prospective population-based study (N = 1,196), physical activity and depressive symptoms were assessed three times, around the ages of 11, 13.5, and 16. Structural Equation Modeling was used to examine reciprocal effects of physical activity and depressive symptoms over time. The plasticity genes examined were 5-HTTLPR, DRD2, DRD4, MAOA, TPH1, 5-HTR2A, COMT, and BDNF. A cumulative gene plasticity index consisting of three groups (low, intermediate, and high) according to the number of plasticity alleles carried by the adolescents was created. Using a multigroup approach, we examined whether the associations between physical activity and depressive symptoms differed between the three cumulative plasticity groups, as well as between the individual polymorphisms. RESULTS: We found significant cross-sectional and cross-lagged paths from physical activity to depressive symptoms and vice versa. Neither the cumulative plasticity index nor the individual polymorphisms modified the strengths of these associations. CONCLUSION: Associations between adolescents' physical activity and depressive symptoms are not modified by plasticity genes.

Differential susceptibility in youth: evidence that 5-HTTLPR x positive parenting is associated with positive affect 'for better and worse'.

Positive affect has been implicated in the phenomenological experience of various psychiatric disorders, vulnerability to develop psychopathology and overall socio-emotional functioning. However, developmental influences that may contribute to positive affect have been understudied. Here, we studied youths' 5-HTTLPR genotype and rearing environment (degree of positive and supportive parenting) to investigate the differential susceptibility hypothesis (DSH) that youth carrying short alleles of 5-HTTLPR would be more influenced and responsive to supportive and unsupportive parenting, and would exhibit higher and lower positive affect, respectively. Three independent studies tested this gene-environment interaction (GxE) in children and adolescents (age range 9-15 years; total N=1874). In study 1 (N=307; 54% girls), positive/supportive parenting was assessed via parent report, in study 2 (N=197; 58% girls) via coded observations of parent-child interactions in the laboratory and in study 3 (N=1370; 53% girls) via self report. Results from all the three studies showed that youth homozygous for the functional short allele of 5-HTTLPR were more responsive to parenting as environmental context in a 'for better and worse' manner. Specifically, the genetically susceptible youth (that is, S'S' group) who experienced unsupportive, non-positive parenting exhibited low levels of positive affect, whereas higher levels of positive affect were reported by genetically susceptible youth under supportive and positive parenting conditions. These GxE findings are consistent with the DSH and may inform etiological models and interventions in developmental psychopathology focused on positive emotion, parenting and genetic susceptibility.

Evidence for plasticity genotypes in a gene-gene-environment interaction: the TRAILS study.

The purpose was to study how functional polymorphisms in the brain derived neurotrophic factor gene (BDNF val66met) and the serotonin transporter gene linked promotor region (5-HTTLPR) interact with childhood adversities in predicting Effortful Control. Effortful Control refers to the ability to regulate behavior in a goal-directed manner and is an interesting endophenotype for psychopathology because of its heritability and the association of low Effortful Control with both internalizing and externalizing problems. In a longitudinal population-based study Effortful Control was assessed with the parent version of the Early Adolescent Temperament Questionnaire at age 11. Pregnancy and delivery adversities and childhood events were assessed in a parent interview at age 11. Long-term difficulties until age 11 were assessed with a parent questionnaire at age 13.5. Blood or buccal cells were collected at age 16 for genotyping the rs6265 and rs25531 SNPs and the 5-HTTLPR length polymorphism. The study included 1032 complete data sets. Effortful Control was significantly predicted by the interaction between BDNF val66met, 5-HTTLPR and childhood events. The BDNF val66met val/val-5-HTTLPR l'/l' genotype was unaffected by childhood events, while having either at least one BDNF val66met met or 5-HTTLPR s' allele (l'/l'-met-carrier; l'/s'-val/val; s'/s'-val/val) made children sensitive to childhood events. Predictions of Effortful Control by pregnancy and delivery adversities and long-term difficulties were largely independent of genotype. We concluded that the l'/l'-met-carrier, l'/s'-val/val and the s'/s'-val/val genotypes showed greatest plasticity while the l'/l'-val/val genotype was unaffected by childhood events.

Different diagnostic tools in nonfunctional overreaching.

The current diagnosis of overreaching and overtraining is based on exclusion. In the present paper, four possible confirmative tools have been examined in three female speed skaters between 16 and 19 years old. A nonfunctional overreached (NFO) athlete, an athlete who was recovering from NFO and a healthy athlete were examined. The NFO athlete showed high stress and low regeneration levels at the Recovery Stress Questionnaire for Athletes. The recovering athlete showed a more favorable profile, although she still showed higher stress and lower recovery than the control athlete. On the Profile of Mood States, the NFO athlete showed an unfavorable profile. The control athlete showed the typical iceberg profile. The recovering athlete showed a profile similar to sedentary individuals. Results on a reaction time task showed decreased performance under pressure for the NFO but not for the control and the recovering athlete. Hormonal reactions to two maximal exercise bouts also differed between the three subjects with an overreaction after the second exercise bout of the NFO athlete as the most remarkable finding. The Recovery Stress Questionnaire for Athletes, reaction times and hormonal reactions to exercise showed to be possible tools that can be used in the diagnostic procedure.

The effect of high load training on psychomotor speed.

The purpose of the present study was to investigate whether overreached athletes show psychomotor slowness after a period of high load training. Fourteen well-trained cyclists (10 male, 4 female, mean age 25.3 [SD = 4.1] years, mean maximal oxygen consumption 65.5 [SD = 8.1] ml/kg.min) performed a maximal graded exercise test on a cycle ergometer, filled out two questionnaires and performed two tests of psychomotor speed before and after high load training and after two weeks of recovery training. A control group performed the two tests of psychomotor speed on the same occasions without changing physical activity levels. Five cyclists were classified as functional overreached, seven cyclists were classified as well-trained and two cyclists were excluded from analysis. Results showed no significant differences in psychomotor speed between the control, well-trained and functional overreached groups on the three measurements. A trend towards psychomotor slowness was found for the functional overreached compared to the control group after high load training. Additional research with more subjects and a greater degree of overload training is necessary to more conclusively determine if psychomotor speed can be used as an early marker for overtraining.