5-HTTLPR与抑郁相关性的研究动态

摘 要 5-HTTLPR是5-羟色胺转运蛋白基因启动子区域上的多态性位点,对其转录效率具有调节作用。5-HTTLPR基因型与抑郁存在相关,但必须把二者的关系置于一个多基因与环境交互作用的框架下考察。一方面,环境因素的作用不容忽视：S等位基因携带者暴露于负性生活事件时,表现出更多情绪问题,更易发生抑郁。另一方面,CYP2C9、BDNF等基因与5-HTTLPR有交互作用,共同影响抑郁的发生。此外,年龄、性别等因素会对研究结果造成混淆。未来研究应侧重于对机制的探讨。     

Timing is everything: Anticipatory stress dynamics among cortisol and blood pressure reactivity and recovery in healthy adults

Psychological states of anticipation modulate biological stress responsivity. While researchers generally investigate how subjective distress corresponds to the magnitude of stress reactivity, physiological recovery after acute stressors must also be considered when investigating disease vulnerabilities. This study assessed whether anticipatory stress would correspond to stress reactivity and recovery of salivary cortisol and blood pressure levels in response to a well-validated psychosocial stressor. Thirty participants (63% female; mean?±?SEM age 45.4?±?2.12 years) were exposed to the Trier Social Stress Test (TSST) consisting of a public speech and mental arithmetic. Ten salivary cortisol samples and systolic and diastolic blood pressure recordings were collected at time points spanning 50?min before and up to 50?min after stress exposure. These data were transformed into parameters representing stress reactivity (area under the curve) and stress recovery (percent change). The Primary Appraisal Secondary Appraisal scale assessed anticipatory stress before exposure to the TSST. Our results revealed that increased anticipatory stress predicted increased stress reactivity for cortisol (p?=?0.009) but not blood pressure. For stress recovery, increased anticipatory stress predicted greater decrements of cortisol concentration (p?=?0.015) and blood pressure (p?=?0.039), even when controlling for total systemic "output" by incorporating baseline activity. This efficient shutdown of stress responses would have otherwise been ignored by solely investigating reactive increases. These findings underscore the importance of measuring multiple dynamic parameters such as recovery when investigating physiological stress response patterns as a function of psychosocial factors.     

Attentional bias to negative information and 5-HTTLPR genotype interactively predict students' emotional reactivity to first university semester

People strongly differ in their emotional reactions to potentially stressing and challenging environmental circumstances. Two classes of individual differences have independently been reported to contribute to such emotional vulnerability: an attentional bias to negative information and a variation in the serotonin transporter gene (5-HTTLPR). The present study was conducted to investigate the possibility that these cognitive and genetic markers interact in their prospective prediction of emotional reactivity to an extended and mild potential stressor. Changes in dysphoria and anxiety across their first university semester were measured in 120 students. Results indicate that attentional bias toward negative information on Week 1 of the semester significantly predicted cross-semester changes in both anxiety and dysphoria. For the latter, this predictive capacity depended on the 5-HTTLPR genotype. Specifically, only in homozygous carriers of the 5-HTTLPR short allele did attentional bias to negative information on Week 1 significantly predict cross-semester change in dysphoria. These results carry important theoretical and practical implications concerning the ability to identify individuals vulnerable to experiencing elevated emotional reactivity to potentially stressing life-events.     

Genetic Gating of Human Fear Learning and Extinction: Possible Implications for Gene-Environment Interaction in Anxiety Disorder

ABSTRACT— Pavlovian fear conditioning is a widely used model of the acquisition and extinction of fear. Neural findings suggest that the amygdala is the core structure for fear acquisition, whereas prefrontal cortical areas are given pivotal roles in fear extinction. Forty-eight volunteers participated in a fear-conditioning experiment, which used fear potentiation of the startle reflex as the primary measure to investigate the effect of two genetic polymorphisms (5-HTTLPR and COMTval158met) on conditioning and extinction of fear. The 5-HTTLPR polymorphism, located in the serotonin transporter gene, is associated with amygdala reactivity and neuroticism, whereas the COMTval158met polymorphism, which is located in the gene coding for catechol-O-methyltransferase (COMT), a dopamine-degrading enzyme, affects prefrontal executive functions. Our results show that only carriers of the 5-HTTLPR s allele exhibited conditioned startle potentiation, whereas carriers of the COMT met/met genotype failed to extinguish conditioned fear. These results may have interesting implications for understanding gene-environment interactions in the development and treatment of anxiety disorders.     

Associations between serotonin transporter gene promoter region (5-HTTLPR) polymorphism and gaze bias for emotional information

The serotonin transporter promoter region polymorphism (5-HTTLPR) is associated with neural response to negative images in brain regions involved in the experience of emotion. However, the behavioral implications of this sensitivity have been studied far less extensively. The current study used eye-tracking methodology to examine how individuals genotyped for the 5-HTTLPR, including the single nucleotide polymorphism (SNP) rs25531, allocated attention during prolonged (30-s) exposure to face stimuli depicting positive and negative emotion. Short 5-HTTLPR allele carriers and carriers of the long allele with guanine at the sixth nucleotide (S/LG) displayed a stronger gaze bias (total fixation time, number of fixations, mean fixation length) for positive than for sad, threat, or neutral stimuli. In contrast, those homozygous for the long 5-HTTLPR allele with adenine at the sixth nucleotide (LA) viewed the emotion stimuli in an unbiased fashion. Time course analyses indicated no initial 5-HTTLPR group differences; however, S/LG 5-HTTLPR allele carriers were more likely than LA 5-HTTLPR homozygotes to direct gaze toward happy than toward sad stimuli over time. This bias toward positive stimuli during the later stages of information processing likely reflects a strategic effort to downregulate heightened reactivity to negative stimuli among 5-HTTLPR S/LG allele carriers.     

Stress reactivity in social anxiety disorder with and without comorbid depression

Previous research on neuroendocrine responding to a psychological stressor in individuals with Social Anxiety Disorder (SAD) has provided inconsistent results. A recent meta-analysis concluded that Major Depressive Disorder (MDD), which is frequently comorbid with SAD, is associated with blunted stress reactivity. It is, thus, possible that comorbidity status contributes to the inconsistent findings in the SAD literature. In this study, salivary cortisol responses to a psychological stressor were examined in three groups: healthy controls (CTL), SAD, and SAD with comorbid MDD (COM). The SAD group differed from the other two groups in their cortisol stress reactivity. It is important to note that analyses combining participants with SAD with and without comorbid MDD obscured findings of cortisol reactivity. In addition, the differences in cortisol reactivity cannot be accounted for by participants' affective responses to the stressor. The current findings indicate that individuals with SAD exhibit distinct stress-related cortisol responses depending on their comorbidity statuses.     

Stressful life events, perceived stress, and 12-month course of geriatric depression: direct effects and moderation by the 5-HTTLPR and COMT Val158Met polymorphisms

Although the relation between stressful life events (SLEs) and risk of major depressive disorder is well established, important questions remain about the effects of stress on the course of geriatric depression. Our objectives were (1) to examine how baseline stress and change in stress is associated with course of geriatric depression and (2) to test whether polymorphisms of serotonin transporter (5-HTTLPR) and catechol-O-methyltransferase (COMT Val158Met) genes moderate this relation. Two-hundred and sixteen depressed subjects aged 60 years or older were categorized by remission status (Montgomery-Asberg depression rating scale≤6) at 6 and 12 months. At 6 months, greater baseline numbers of self-reported negative and total SLEs and greater baseline perceived stress severity were associated with lower odds of remission. At 12 months, only baseline perceived stress predicted remission. When we examined change in stress, 12-month decrease in negative SLEs and level of perceived stress were associated with improved odds of 12-month remission. When genotype data were included, COMT Val158Met genotype did not influence these relations. However, when compared with 5-HTTLPR L/L homozygotes, S allele carriers with greater baseline numbers of negative SLEs and with greater decrease in negative SLEs were more likely to remit at 12 months. This study demonstrates that baseline SLEs and perceived stress severity may influence the 12-month course of geriatric depression. Moreover, changes in these stress measures over time correlate with depression outcomes. 5-HTTLPR S carriers appear to be more susceptible to both the effects of enduring stress and the benefit of interval stress reduction.     

Negative affect as a predisposing factor for cortisol release after an acute stress--the impact of unpleasant priming

Glucocorticoids have a key role in stress responses. There are, however, substantial differences in cortisol reactivity among individuals. We investigated if affective trait and mood induction influence the reactivity to psychological stress in a group of 63 young adults, male (n=27) and female (n=36), aged ca. 21 years. On the experimental day the participants viewed either a block of pleasant or unpleasant pictures for 5 min to induce positive or negative mood, respectively. Then, they had 5 min to prepare a speech to be delivered in front of a video-camera. Saliva samples were collected to measure cortisol, and questionnaire-based affective scales were used to estimate emotional states and traits. Compared to basal levels, a cortisol response to the acute speech stressor was only seen for those who had first viewed unpleasant pictures and scored above the average on the negative affect scale. There were no sex differences. In conclusion, high negative affect associated with exposure to an unpleasant context increased sensitivity to an acute stressor, and was critical to stimulation of cortisol release by the speech stressor.     

Relational Security Moderates the Effect of Serotonin Transporter Gene Polymorphism (5-HTTLPR) on Stress Generation and Depression among Adolescents

Previous research demonstrates that carriers of the short allele of the serotonin transporter gene (5-HTTLPR) show both greater susceptibility to depression in response to stressful life events and higher rates of generation of stressful events in response to depression. The current study examines relational security (i.e., self-reported beliefs about attachment security) as a moderator of these effects, building on emerging research suggesting that the short allele acts as a marker of sensitivity to the social environment. Participants were 354 Caucasian adolescents oversampled for maternal depression (137 male, 217 female), assessed at ages 15 and 20. Results indicated that the short allele predicted increased stress generation at age 20 among those with low age 15 security but decreased stress generation among those with high security, and revealed a three-way interaction between age 15 depression, age 15 security, and genotype, where depression predicted stress generation only among short allele carriers with low security. Further, among boys only, security interacted with genotype to predict longitudinal changes in depression diagnosis, with the s-allele predicting relative increases in probability of depression among boys with low security but decreases among boys with high security. Results support the notion of the short allele as a marker of social reactivity, and suggest that attachment security may buffer against the genetic vulnerability introduced by the short allele, in line with predictions of the differential susceptibility theory.     

Post-traumatic stress symptoms of children and adolescents exposed to the 2008 Wenchuan Earthquake: A longitudinal study of 5-HTTLPR genotype main effects and gene–environment interactions

Experiencing disasters causes severe mental disorders, among which post-traumatic stress disorder (PTSD) is the most common. We conducted a longitudinal study to examine the effect of 5-hydroxyl tryptamine transporter gene-linked polymorphic region (5-HTTLPR) genotype on child and adolescent PTSD symptom course after the 2008 Wenchuan Earthquake. We genotyped 963 participants who personally experienced the earthquake. PTSD symptoms were measured by University of California, Los Angeles PTSD reaction index at 2.5, 3.5, 4.5 and 5.5 years after the earthquake, respectively. Latent growth model was utilised to examine the main effect and gene–environment interaction effect of 5-HTTLPR on PTSD's symptom course. 5-HTTLPR genotype predicted initial PTSD symptom severity (β = 0.108, p = .019) and rates of symptom recovery (β = −0.120, p = .031) between 2.5 and 5.5 years. Compared with L′ allele carriers, those with S′S′ genotype showed higher initial symptom severity but also faster recovery rate. 5-HTTLPR genotype only predicted symptom severity at 2.5 years after the earthquake, after controlling for sex, age, ethnicity and trauma severity (β = 0.108, p = .019). This is the first evidence of the effect of 5-HTTLPR genotype on child and adolescent PTSD symptoms longitudinally, offering a novel perspective on the effect of 5-HTTLPR on PTSD symptom development following trauma exposure.     

Effect of the 5-HTTLPR polymorphism on posttraumatic stress disorder,depression, anxiety,and quality of life among Iraq and Afghanistan veterans

Background and Objectives: Posttraumatic stress disorder (PTSD), depression, anxiety, and stress are significant problems among returning veterans and are associated with reduced quality of life. Design: A correlational design was used to examine the impact of a polymorphism (5-HTTLPR) in the serotonin transporter promoter gene on post-deployment adjustment among returning veterans. Methods: A total of 186 returning Iraq and Afghanistan veterans were genotyped for the 5-HTTLPR polymorphism. Symptoms of PTSD, depression, general stress, and anxiety were assessed along with quality of life. Results: After controlling for combat exposure, age, sex of the participant, and race, 5-HTTLPR had a significant multivariate effect on post-deployment adjustment, such that S′ carriers reported more post-deployment adjustment problems and worse quality of life than veterans homozygous for the L′ allele. This effect was larger when the analyses were restricted to veterans of European ancestry. Conclusions: Our findings suggest that veterans who carry the S′ allele of the 5-HTTLPR polymorphism may be at increased risk for adjustment problems and reduced quality of life following deployments to war zones.     

Altered stress responses in children exposed to early adversity: a systematic review of salivary cortisol studies

Pathological stress responses are implicated in numerous disorders. Hypothalamic-pituitary-adrenal axis function is influenced by gene-environment interaction, with early-life environmental adversity having long-lasting effects. We examine the evidence that, in humans, these effects are apparent from infancy. We systematically reviewed published findings on cortisol response to a stressor, in 0-5-year-olds already exposed to adversity. Adversity was defined as a negative environmental influence present post-conception. We searched Ovid MEDLINE (1950-May 2010), EMBASE (1980-May 2010) and PsychINFO (1806-May 2010). We included peer-reviewed, English language studies that analysed salivary cortisol before and after a standardised stressor. We identified 30 studies, of which 27 reported a significant effect of adversity on the cortisol response to stress. Six of these demonstrated an effect of prenatal substance exposure. Thirteen studies found that psychosocial adversity increased cortisol reactivity. Three studies reported that cortisol reactivity could be normalised by intervention programmes. The studies were heterogeneous, both in nature of adversity studied and in stressor used, precluding meta-analysis and assessment of publication bias. Our review presents evidence that adversity disrupts the stress response from an early age. Longitudinal studies are required to determine whether effects persist, alter with time, or are reversible with intervention.     

Effects of soy lecithin phosphatidic acid and phosphatidylserine complex (PAS) on the endocrine and psychological responses to mental stress

Phosphatidylserine, derived from cow brains, has been shown previously to dampen the ACTH and cortisol response to physical stress. Further research investigated the influence of soy lecithin phosphatidylserine supplementation on mood and heart rate when faced with an acute stressor. In this study, we investigated the effects of soy lecithin phosphatidic acid and phosphatidylserine complex (PAS) supplementation on pituitary adrenal reactivity (ACTH, cortisol) and on the psychological response (Spielberger State Anxiety Inventory stress subscale) to a mental and emotional stressor. Four groups of 20 subjects were treated for three weeks with daily dosages of either 400 mg PAS, 600 mg PAS, 800 mg PAS, or placebo before exposure to the Trier Social Stress Test (TSST). Treatment with 400 mg PAS resulted in a pronounced blunting of both serum ACTH and cortisol, and salivary cortisol responses to the TSST, but did not affect heart rate. The effect was not seen with larger doses of PAS. With regard to the psychological response, 400 mg PAS seemed to exert a specific positive effect on emotional responses to the TSST. While the placebo group showed the expected increase in distress after the test, the group treated with 400 mg PAS showed decreased distress. These data provide initial evidence for a selective stress dampening effect of PAS on the pituitary-adrenal axis, suggesting the potential of PAS in the treatment of stress related disorders.     

Genetics and personality affect visual perspective in autobiographical memory

Major depression is associated with a decrease of 1st person (versus 3rd person) visual perspective in autobiographical memory, even after full remission. This study aimed to examine visual perspective in healthy never-depressed subjects presenting with either genetic or psychological vulnerability for depression. Sixty healthy participants performed the Autobiographical Memory Test with an assessment of visual perspective. Genetic vulnerability was defined by the presence of at least one S or L_G allele of the polymorphism of the serotonin-transporter-linked promoter region (5-HTTLPR). Psychological vulnerability was defined by high scores of harm avoidance measured by the Temperament and Character Inventory. Life stress exposure, depressive mood, rumination, and familial history of depression were assessed through standardized procedures. Visual perspective for positive memories was independently predicted by both harm avoidance and a gene by environment interaction between the 5-HTTLPR polymorphism and life stress exposure. Visual perspective and vulnerability for depression may share some biological bases.     

Trait rumination and response to negative evaluative lab-induced stress: neuroendocrine,affective, and cognitive outcomes

Theoretical models of depression posit that, under stress, elevated trait rumination predicts more pronounced or prolonged negative affective and neuroendocrine responses, and that trait rumination hampers removing irrelevant negative information from working memory. We examined several gaps regarding these models in the context of lab-induced stress. Non-depressed undergraduates completed a rumination questionnaire and either a negative-evaluative Trier Social Stress Test (n?=?55) or a non-evaluative control condition (n?=?69), followed by a modified Sternberg affective working memory task assessing the extent to which irrelevant negative information can be emptied from working memory. We measured shame, negative and positive affect, and salivary cortisol four times. Multilevel growth curve models showed rumination and stress interactively predicted cortisol reactivity; however, opposite predictions, greater rumination was associated with blunted cortisol reactivity to stress. Elevated trait rumination interacted with stress to predict augmented shame reactivity. Rumination and stress did not significantly interact to predict working memory performance, but under control conditions, rumination predicted greater difficulty updating working memory. Results support a vulnerability-stress model of trait rumination with heightened shame reactivity and cortisol dysregulation rather than hyper-reactivity in non-depressed emerging adults, but we cannot provide evidence that working memory processes are critical immediately following acute stress.     

HPA-Axis Activation as a Key Moderator of Childhood Trauma Exposure and Adolescent Mental Health

Individual differences in a child’s sensitivity to stress may influence whether youth exposed to trauma develop symptoms of psychopathology. We examined the interaction between HPA-axis reactivity to an acute stressor and exposure to different types of childhood trauma as predictors of mental health symptoms in a sample of youth. Youth (n?=?121, ages 9–16; 47% female) completed a standardized stress task, including 5 post-stress salivary cortisol samples. Parents also completed the Child Behavior Checklist as a measure of child internalizing and externalizing symptoms in the past month, and completed the Early Trauma Inventory (ETI) as a measure of their child’s trauma exposure. More emotional abuse and non-intentional trauma were associated with greater internalizing symptoms. Youth exposed to physical abuse who demonstrated slower HPA-axis reactivity had elevated internalizing and externalizing symptoms. Youth exposed to emotional abuse or non-intentional traumatic events who demonstrated faster HPA-axis reactivity had elevated internalizing and externalizing symptoms. Profiles of exaggerated or attenuated HPA-axis reactivity to acute stress may be risk factors for psychopathology in children facing different stressful social environments.     

The impact of cortisol reactivity to acute stress on memory: sex differences in middle-aged people

Stress has been identified as a main factor involved in the cognitive changes that occur during the aging process. This study investigated sex differences in the relationship between the magnitude of the acute stress-induced salivary cortisol response and memory performance among middle-aged people. To this end, 16 men and 16 women (aged 54-72 years) were exposed to the Trier Social Stress Test and a control condition in a crossover design. Afterwards their memory performance was measured using a standardized memory test (Rey's Auditory Verbal Learning Test). Only among women, there was an acute impact of stress on memory performance and a significant relationship between a higher cortisol response to the stressor and poorer memory performance in both the stress and control conditions. Additionally, a poorer memory performance was related to earlier timing of sexual maturation (age at menarche), which was also marginally related to higher cortisol reactivity to stress. These results confirm that sex is a critical factor in the relationship between cortisol and poor memory performance. Furthermore, the findings emphasize a strong link between the individual cortisol response to stress and memory functioning among postmenopausal women.     

The effects of exposure to an acute naturalistic stressor on working memory, state anxiety and salivary cortisol concentrations

Exposure to an acute naturalistic stressor induces both psychological and physiological changes in humans. The two studies reported here explored the impact of exposure to an acute naturalistic stressor on state anxiety, working memory and HPA axis activation (salivary cortisol). In both experiments, ten healthy male participants were exposed to an acute naturalistic stressor, helicopter underwater evacuation training (HUET), and their physiological and behavioural responses before (first study) and after (second study) the stressor were compared to ten non-stressed controls. The results of both experiments showed that working memory performance was preserved during anticipation of an acute stressor, but impairments were observed immediately after stress exposure. Participants reported significantly higher state anxiety levels during anticipation and following stress exposure, whereas significant elevations in cortisol levels were only observed 25 min post exposure to stress, but not before or immediately after stress exposure. The results of both experiments demonstrated a dissociation between behavioural and biochemical measures and provided evidence for a dissociation of the effects of stress on cognitive and physiological measures depending on the time of testing, with cognitive impairments most evident following stress exposure.     

The Impact of Exercise on Hormones Is Related to Autonomic Reactivity to a Mental Task

This study examined the effects of an acute physical stressor on salivary testosterone (Tsal) and cortisol (Csal) and their relationship with the autonomic responsiveness to a mental task in fit young men (n = 30). Salivary testosterone (Tsal) and cortisol (Csal) levels were determined before and after a maximal bicycle exercise. Heart rate (HR) and skin conductance levels (SCL) were continuously recorded before, during, and after a Stroop task. Tsal and Csal levels diminished while HR and SCL increased in response to stressors in all the sample. When subjects were distributed in function of their endocrine response to the physical stressor, high Tsal responders showed higher HR reactivity than low responders, and high Csal responders showed higher SCL reactivity and lower reaction time in the Stroop task. These results show that the influence of an acute physical stressor on hormones is associated with the autonomic responses to a mental task.     

Stress-induced salivary cortisol secretion during hypobaric hypoxia challenge and in vivo urinary thromboxane production in healthy male subjects

Few studies have assessed the effects of stress on in vivo platelet activation. In the present study, hypobaric hypoxia induced by rapid decompression during high-altitude simulated flight in a hypobaric chamber was used to evaluate the effects of environmental stress on salivary cortisol and urinary thromboxane metabolite (TXM) excretion, a noninvasive marker of in vivo platelet function. Twenty-one male aviators (mean ± SD age = 36 ± 7 years) experiencing hypoxia by removing their oxygen mask for 4-5 min during a simulated flight to 25,000 ft (7,620 m; pO(2) = 59.17 mmHg) and a matched control group of thirteen flying instructors wearing oxygen masks during the challenge, were studied. Hypobaric hypoxia induced a transient significant increase (P < 0.001) in the aviators' salivary cortisol concentration; the overall pattern of diurnal cortisol fluctuation was maintained in both groups. Urinary TXM showed a significant ～30% reduction (P < 0.01) after the chamber session in aviators exposed to hypobaric hypoxia, but not in controls. A significant inverse correlation was found between salivary cortisol and urinary TXM in aviators (r = - 0.64, P = 0.0015). Salivary cortisol was a significant predictor (P < 0.001) for urinary TXM concentrations in aviators. In conclusion, here we observed that an acute stress-induced salivary cortisol increase was associated with reduced urinary thromboxane biosynthesis, providing the first indirect evidence for an inhibitory effect of acute stress on in vivo platelet function.