Striatin genotype-based, mineralocorticoid receptor antagonist-driven clinical trial: study rationale and design.

OBJECTIVES: In human studies and genetically altered mouse studies, variants in the striatin gene (STRN) are associated with increased blood pressure (BP) and aldosterone on a liberal salt diet. This clinical trial is based on the presumed mechanism for striatin-associated HTN - increased aldosterone. It is designed to determine if participants with the STRN risk alleles will have a greater BP reduction on a liberal salt diet with a specific, mechanism-based therapy - a mineralocorticoid receptor antagonist, eplerenone - as compared with a nonspecific anti-hypertensive therapy - amlodipine. METHODS: One hundred five hypertensive adults with the STRN risk alleles (SNP rs2540923 carriers or rs888083 homozygotes) will be enrolled in a 12-week, double-blind, dose-escalation, clinical trial. After a minimum 2-week washout period and baseline assessment of BP on a liberal salt diet, participants will be randomized to either daily eplerenone or amlodipine. Participants will take daily at-home BP recordings as a safety check. After 4 and 8 weeks of drug therapy, BP will be measured by the study team and medication will be increased, if needed, to achieve a participant goal BP of <140/90 mmHg.Anticipated results We anticipate that STRN risk allele carriers will demonstrate a greater reduction in BP with eplerenone and will require a lower dose of eplerenone to reach goal BP as compared with amlodipine. CONCLUSION: This is a proof-of-concept clinical trial. Positive results support the feasibility of performing genetically-defined, mechanistically-driven trials in HTN. Clinically, it would suggest that genetic biomarkers can identify individuals highly responsive to specific treatment.

A clinical trial to evaluate the effect of statin use on lowering aldosterone levels.

BACKGROUND: Statins are the first-line pharmaceutical agent in the management of hypercholesterolemia and cardiovascular (CV) risk reduction, and the most commonly prescribed class of drugs worldwide. Studies describing CV risk reduction independent of LDL-cholesterol lowering have evoked an interest in the pleiotropic mechanisms of statins' benefits. We recently demonstrated that administration of statins in animal models lowers aldosterone levels and observed an association between statin use and reduced aldosterone levels in two human cohorts, with lipophilic statins displaying a greater effect than hydrophilic statins. Therefore, we designed a randomized, placebo-controlled, double-blinded intervention study to assess whether statin treatment lowers aldosterone in a type-dependent manner in humans, with simvastatin (lipophilic) showing a greater effect than pravastatin (hydrophilic). METHODS/DESIGN: One hundred five healthy participants will be recruited from the general population to enroll in a 12-week, randomized, placebo-controlled, double-blinded, 3-arm clinical trial. Ninety participants are anticipated to complete the protocol. After baseline assessment of aldosterone levels, participants will be randomized to daily simvastatin, pravastatin, or placebo. Aldosterone levels will be assessed after 2 days on study drug and again after 6 weeks and 12 weeks on study drug. Prior to each aldosterone assessment, participants will consume an isocaloric sodium and potassium-controlled run-in diet for 5 days. Assessments will occur on an inpatient research unit to control for diurnal, fasting, and posture conditions. The primary outcome will compare 12-week angiotensin II-stimulated serum aldosterone by study drug. Secondary outcomes will compare baseline and 12-week 24-h urine aldosterone by study drug. DISCUSSION: Results from this rigorous study design should provide strong support that statins lower aldosterone levels in humans. These results may explain some of the beneficial effects of statins that are not attributed to the LDL-lowering effect of this important class of medications. Results would demonstrate that statin lipophilicity is an important attribute in lowering aldosterone levels. The outcomes of this program will have implications for the design of studies involving statin medications, as well as for the differential use of classes of statins. TRIAL REGISTRATION: ClinicalTrials.gov; NCT02871687 ; First Posted August 18, 2016.

Effects of childhood trauma on sleep quality and stress-related variables in adulthood: evidence from two multilevel studies.

Childhood trauma has been found to have serious negative consequences for mental and physical health. However, the precise mechanisms through which trauma influences health outcomes are unclear. Childhood trauma-related disruptions to sleep in adulthood represent an important potential mechanism. Two 7-day multilevel studies investigated the effects of childhood trauma on daily sleep outcomes and stress-related variables and whether the effects of trauma on sleep outcomes were mediated through these stress-related variables (or vice versa). Participants completed the Childhood Trauma Questionnaire before a 7-day online daily diary study. Measures of daily stress, perseverative cognition, and sleep were completed daily. Multi-level modelling found that higher levels of childhood neglect were associated with poorer daily sleep quality, shorter sleep duration, longer sleep onset latency, and higher daily stress and rumination levels. Higher childhood abuse was associated with shorter sleep duration, greater morning tiredness, and higher levels of daily stress, rumination, and worry. Childhood trauma was found also to have bidirectional, indirect effects on sleep quality and morning tiredness through daily stress-related variables. The current findings suggest that interventions aimed at mitigating the negative effects of childhood trauma should also incorporate components that target modifiable risk factors, such as sleep, stress, worry, and rumination.

Resilience and vulnerability factors influence the cortisol awakening response in individuals vulnerable to suicide.

Suicide is a global health issue. Dysregulated hypothalamic-pituitary-adrenal (HPA) axis activity, as measured by cortisol levels, has been identified as one potential risk factor. Evidence is emerging to suggest that different psychological factors may be associated with increased resilience and vulnerability in this context. The current study investigated whether trait resilience, social support, socially prescribed perfectionism, trait worry and trait impulsivity influenced the cortisol awakening response (CAR) over a 7-day study in individuals vulnerable to suicide. 142 participants with a history of suicidal attempt or ideation (suicide vulnerability group; n = 95) and with no suicide risk history (control group; n = 47) were recruited. Participants completed baseline questionnaires before commencing a 7-day study where they provided cortisol samples immediately upon waking, at 15 min, 30 min and 45 min on 7 consecutive days. Higher worry, socially prescribed perfectionism and impulsivity, lower resilience and social support were found in the suicide vulnerability group compared to the control group. Lower levels of resilience, higher levels of socially prescribed perfectionism, worry and impulsivity were associated with significantly lower total CAR. Suicide group membership was also found to have an indirect effect on total CAR via trait worry. The current findings show for the first time, that these well-known psychological risk factors for suicide are associated with smaller total cortisol awakening responses. Researchers ought to elucidate the precise causal mechanisms linking these traits, CAR and suicide risk in order to develop interventions to help build resilience in vulnerable populations.

Effects of childhood trauma, daily stress, and emotions on daily cortisol levels in individuals vulnerable to suicide.

Suicide is a leading cause of mortality worldwide. Dysregulated hypothalamic-pituitary-adrenal (HPA) axis activity, as measured by cortisol levels, has been identified as 1 potential risk factor. Evidence has indicated that childhood trauma is associated with dysregulated cortisol reactivity to stress in adulthood. The current study investigated for the first time whether childhood trauma and daily stressors and emotions were associated with diurnal cortisol levels over a 7-day study in individuals vulnerable to suicide. One hundred and forty-two participants were categorized according to their suicidal history into 3 groups: suicide attempt, suicidal ideation, or control group. Participants completed questionnaires before commencing a 7-day study. Cortisol samples were provided immediately upon waking, at 15 min, 30 min, 45 min, 3 hr, 6 hr, 9 hr, and 12 hr on 7 consecutive days. Measures of daily stressors, mood, defeat, and entrapment were completed at the end of each day. Participants in the suicide attempt and ideation groups released significantly lower cortisol upon awakening (CAR) and had a tendency toward flatter wake-peak to 12 hr (WP-12) cortisol slopes compared to controls. Childhood trauma was found to be associated with significantly lower CAR and a tendency toward flatter WP-12 cortisol slope. Childhood trauma also had an indirect effect on suicide vulnerability group membership via lower daily CAR levels. Lower CAR was associated with increased suicide ideation at 1 month but not 6 months. Daily stress and emotion measures were not associated with cortisol levels. This is the first 7-day daily diary investigation of naturally fluctuating cortisol levels in individuals vulnerable to suicide. The results indicate that dysregulated HPA axis activity is associated with suicidal ideation and behavior. Childhood trauma appears to be an important distal factor associated with HPA-axis dysregulation. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Distinguishing suicide ideation from suicide attempts: Further test of the Integrated Motivational-Volitional Model of Suicidal Behaviour.

Suicidal behaviour poses a significant public health concern. Research into the factors that distinguish between the emergence of suicide ideation and the enactment of a suicide attempt is crucial. This study tests central tenets of the Integrated Motivational-Volitional Model of suicidal behaviour (IMV, O'Connor and Kirtley, 2018) which posits that volitional phase factors govern the transition from thinking to attempting suicide. 299 adults completed a face-to-face interview and were allocated to groups based on their suicidal history: Suicide attempt group (N = 100), suicide ideation group (N = 105), and a control group (N = 94). Measures were taken at baseline, at 1-month and 6-months follow-up. As predicted, the attempt group differed from the ideation group on all volitional phase factors. Those who had attempted suicide reported higher capability for suicide, were more likely to have a family member or friend who had self-injured or attempted suicide, and were more impulsive. In keeping with the IMV model, the ideation and attempt groups had similar scores on the motivational factors. Defeat and entrapment were significant predictors of ideation at baseline, and mediation analyses indicated that defeat had an indirect effect on ideation through entrapment at baseline and at 1-month follow-up. The results support the IMV model and suggest that entrapment should be routinely included in suicide risk assessments. Further research to test predictors of the transition from suicide ideation to suicide attempts is crucial to inform future intervention development and health care delivery.

Effects of childhood trauma on cortisol levels in suicide attempters and ideators.

OBJECTIVES: Suicide is a global health issue. Dysregulated hypothalamic-pituitary-adrenal (HPA) axis activity, as measured by cortisol levels, has been identified as one potential risk factor for suicide. Recent evidence has indicated that blunted cortisol reactivity to stress is associated with suicidal behavior. The current study investigated whether childhood trauma was associated with blunted cortisol reactivity to a laboratory stressor and resting cortisol levels in suicide attempters and ideators. METHODS: 160 Participants were recruited and grouped according to history of previous suicidal attempt, suicidal ideation or as control participants. Participants completed background questionnaires, including the Childhood Trauma Questionnaire, before completing a laboratory stress task. Cortisol levels were assessed at rest and during the stress task. RESULTS: The highest levels of childhood trauma were reported in those who had attempted suicide (78.7%), followed by those who thought about suicide (37.7%) and then those with no suicidal history (17.8%). Moreover, regression analyses showed that childhood trauma was a significant predictor of blunted cortisol reactivity to stress and resting cortisol levels, such that higher levels of trauma were associated with lower cortisol levels in those with a suicidal history. Family history of suicide did not interact with the effects of childhood trauma on cortisol levels. CONCLUSIONS: These results indicate that childhood trauma is associated with blunted HPA axis activity in vulnerable populations in adulthood. The challenge for researchers is to elucidate the precise causal mechanisms linking trauma, cortisol and suicide risk and to investigate whether the effects of childhood trauma on cortisol levels are amendable to psychological intervention.

Cortisol reactivity and suicidal behavior: Investigating the role of hypothalamic-pituitary-adrenal axis responses to stress in suicide attempters and ideators.

Every 40s a person dies by suicide somewhere in the world. The causes of suicidal behavior are not fully understood. Dysregulated hypothalamic-pituitary-adrenal (HPA) axis activity, as measured by cortisol levels, is one potential risk factor. The current study aimed to investigate whether cortisol reactivity to a laboratory stress task differentiated individuals who had previously made a suicide attempt from those who had thought about suicide (suicide ideators) and control participants. One hundred and sixty participants were recruited to a previous attempt, a suicidal ideation or a control group. Participants completed background questionnaires before completing the Maastricht Acute Stress Test (MAST). Cortisol levels were assessed throughout the stress task. Measures of suicide behavior were measured at baseline, 1 month and 6 month follow-up. Participants who had made a previous suicide attempt exhibited significantly lower aggregate cortisol levels during the MAST compared to participants in the control group; suicide ideators were intermediate to both groups. This effect, however, was driven by participants who made an attempt within the past year, and to some degree by those with a family history of attempt. Participants who made a suicide attempt and had a family history of suicide exhibited the lowest levels of cortisol in response to stress. Finally, lower levels of cortisol in response to the MAST were associated with higher levels of suicidal ideation at 1-month follow-up in the suicide attempter group. These results are consistent with other findings indicating that blunted HPA axis activity is associated with some forms of suicidal behavior. The challenge for researchers is to elucidate the precise causal mechanisms linking stress, cortisol and suicide risk.

The Chernyshenko Conscientiousness Scales: A New Facet Measure of Conscientiousness.

The current research sought to validate the Chernyshenko Conscientiousness Scales (CCS), a novel measure designed to assess six facets of conscientiousness. Data from 7,569 U.S. participants and 649 U.K. participants were analyzed to assess the internal reliability and factorial structure of the scales. Test-retest reliability, convergent and divergent validity, and criterion-related validity were also evaluated using a separate U.K. sample (n = 118; n = 80 for test-retest). The results showed that those items designed to measure industriousness, order, self-control, traditionalism, and virtue were best represented by a five-factor structure, broadly consistent with the five scales. However, the content and structure of the responsibility scale requires further investigation. Overall, the CCS has the potential to be a useful alternative to the faceted measures of conscientiousness that are currently available. However, future research is required to refine a number of problematic items and to clarify which facets can be better described as interstitial dimensions between conscientiousness and other Big Five domains.

Cortisol levels and suicidal behavior: A meta-analysis.

Suicide is a major cause of death worldwide, responsible for 1.5% of all mortality. The causes of suicidal behavior are not fully understood. Dysregulated hypothalamic-pituitary-adrenal (HPA) axis activity, as measured by cortisol levels, is one potential risk factor. This meta-analytic review aimed (i) to estimate the strength and variability of the association between naturally fluctuating cortisol levels and suicidal behavior and (ii) to identify moderators of this relationship. A systematic literature search identified 27 studies (N=2226; 779 suicide attempters and 1447 non-attempters) that met the study eligibility criteria from a total of 417 unique records initially examined. Estimates of effect sizes (r) obtained from these studies were analysed using Comprehensive Meta-Analysis. In these analyses, we compared participants identified as having a past history of suicide attempt(s) to those with no such history. Study quality, mean age of sample and percentage of male participants were examined as potential moderators. Overall, there was no significant effect of suicide group on cortisol. However, significant associations between cortisol and suicide attempts were observed as a function of age. In studies where the mean age of the sample was below 40 years the association was positive (i.e., higher cortisol was associated with suicide attempts; r=.234, p<.001), and where the mean age was 40 or above the association was negative (i.e., lower cortisol was associated with suicide attempts; r=-.129, p<.001). These findings confirm that HPA axis activity, as indicated by age-dependent variations in cortisol levels, is associated with suicidal behavior. The challenge for theory and clinical practice is to explain the complete reversal of the association with age and to identify its clinical implications.