Christian Otte

Depression and cortisol responses to psychological stress: A meta-analysis

The purpose of this meta-analysis is to examine the association between depression and cortisol responses to psychological stressors. A total of seven studies comparing plasma or cortisol responses to psychological stressors in clinically depressed (MDD) and non-depressed (ND) individuals (N = 196: 98 MDD, 98 ND; 83 men, 113 women; mean age = 40 years) were included. Sample size-adjusted effect sizes (Cohens d statistic) were calculated and averaged across baseline (before stressor onset), stress (stressor onset up to 25 min after stressor offset), and recovery (more than 25 min after stressor offset) periods. Overall, MDD and ND individuals exhibited similar baseline and stress cortisol levels, but MDD patients had much higher cortisol levels during the recovery period than their ND counterparts. There was also a significant time of day effect in which afternoon studies were more likely to reveal higher baseline cortisol levels, blunted stress reactivity, and impaired recovery in MDD patients. This blunted reactivity-impaired recovery pattern observed among the afternoon studies was most pronounced in studies with older and more severely depressed patients.

Depressive Symptoms, Health Behaviors, and Risk of Cardiovascular Events in Patients With Coronary Heart Disease

CONTEXT Depressive symptoms predict adverse cardiovascular outcomes in patients with coronary heart disease, but the mechanisms responsible for this association are unknown. OBJECTIVE To determine why depressive symptoms are associated with an increased risk of cardiovascular events. DESIGN AND PARTICIPANTS The Heart and Soul Study is a prospective cohort study of 1017 outpatients with stable coronary heart disease followed up for a mean (SD) of 4.8 (1.4) years. SETTING Participants were recruited between September 11, 2000, and December 20, 2002, from 12 outpatient clinics in the San Francisco Bay Area and were followed up to January 12, 2008. MAIN OUTCOME MEASURES Baseline depressive symptoms were assessed using the Patient Health Questionnaire (PHQ). We used proportional hazards models to evaluate the extent to which the association of depressive symptoms with subsequent cardiovascular events (heart failure, myocardial infarction, stroke, transient ischemic attack, or death) was explained by baseline disease severity and potential biological or behavioral mediators. RESULTS A total of 341 cardiovascular events occurred during 4876 person-years of follow-up. The age-adjusted annual rate of cardiovascular events was 10.0% among the 199 participants with depressive symptoms (PHQ score > or = 10) and 6.7% among the 818 participants without depressive symptoms (hazard ratio [HR], 1.50; 95% confidence interval, [CI], 1.16-1.95; P = .002). After adjustment for comorbid conditions and disease severity, depressive symptoms were associated with a 31% higher rate of cardiovascular events (HR, 1.31; 95% CI, 1.00-1.71; P = .04). Additional adjustment for potential biological mediators attenuated this association (HR, 1.24; 95% CI, 0.94-1.63; P = .12). After further adjustment for potential behavioral mediators, including physical inactivity, there was no significant association (HR, 1.05; 95% CI, 0.79-1.40; P = .75). CONCLUSION In this sample of outpatients with coronary heart disease, the association between depressive symptoms and adverse cardiovascular events was largely explained by behavioral factors, particularly physical inactivity.

Predictors of Posttraumatic Stress in Police and Other First Responders

Abstract:  We provide an overview of previous research conducted by our group on risk and resilience factors for PTSD symptoms in police and other first responders. Based on our work, the findings of other investigators on individual differences in risk for PTSD, and drawing on preclinical studies fear conditioning and extinction, we propose a conceptual model for the development of PTSD symptoms emphasizing the role of vulnerability and resilience to peritraumatic panic reactions. We tested this conceptual model in a cross‐sectional sample of police officers (n= 715). Utilizing an hierarchical linear regression model we were able to explain 39.7% of the variance in PTSD symptoms. Five variables remained significant in the final model; greater peritraumatic distress (β= 0.240, P < .001), greater peritraumatic dissociation (β= 0.174, P < .001), greater problem‐solving coping (β= 0.103, P < .01), greater routine work environment stress (β= 0.182, P < .001), and lower levels of social support (β=−0.246, P < .001). These results were largely consistent with the proposed conceptual model. Next steps in this line of research will be to test this model prospectively in a sample of 400 police academy recruits assessed during training and currently being followed for the first 2 years of police service.

Cognitive Impairment in Major Depression: Association with Salivary Cortisol

BACKGROUND Cognitive deficits and elevated cortisol are hallmarks of depression. Cortisol acts via mineralocorticoid and glucocorticoid receptors, which have their highest density in the hippocampus, a brain area closely related to cognitive function. Several studies have separately examined cortisol secretion and cognitive deficits in depression. However, only few studies have assessed their association in the same patients producing inconclusive results. METHODS We examined 52 medication-free patients with major depression (37 women, 15 men; mean age 35 +/- 11 years; Hamilton Depression Scale mean score 27 +/- 5) and 50 healthy control subjects, matched for age, gender, and years of education. We applied several neuropsychological tests. Salivary cortisol levels were measured on the same day at 08:00, 12:00, 16:00, and 22:00 hours. RESULTS Compared with healthy subjects, patients had significantly higher cortisol levels and were impaired in verbal memory, visuospatial memory, working memory, and selective attention. In depressed patients, but not in healthy control subjects, we found a negative correlation between salivary cortisol levels (area under the curve) and hippocampus-related neuropsychological domains (verbal memory, visuospatial memory) and executive function. CONCLUSIONS Cognitive deficits, especially those closely related to hippocampus function, appear to be related to cortisol secretion in depressed patients. Elevated cortisol may downregulate mineralocorticoid and glucocorticoid receptors in the hippocampus, which could, in part, be responsible for cognitive deficits in depressed patients.

Depression and 24-hour urinary cortisol in medical outpatients with coronary heart disease: The Heart and Soul Study

BACKGROUND In patients with coronary heart disease (CHD), depression leads to worse cardiovascular outcomes. Depression has been associated with increased cortisol in medically healthy patients, suggesting that cortisol may act as a mediator in the pathway between depression and cardiovascular events. However, it is not known whether depression is associated with elevated cortisol levels in patients with CHD. METHODS We examined the association between depression (assessed by the Computerized Diagnostic Interview Schedule) and 24-hour urinary cortisol in 693 medical outpatients with known CHD. RESULTS Of 693 participants, 138 (20%) had current depression. Depressed participants had greater mean cortisol levels than those without depression (42 +/- 25 vs. 36 +/- 20 microg/day, p <.01). With each increasing quartile of cortisol concentration the frequency of depression increased (p <.01). Participants in the highest quartile of cortisol had a twofold increased odds of having depression, compared with those in the lowest quartile (odds ratio [OR] 2.1, 95% confidence interval [CR] 1.2-3.6, p =.01). This association remained strong after adjusting for potential confounding variables (OR 2.4, 95% CI 1.3-4.4, p <.01). In this cross-sectional analysis, elevated cortisol was not associated with worse cardiac function. CONCLUSIONS In patients with CHD,depression is associated with elevated cortisol levels.

Prospective Prediction of Posttraumatic Stress Disorder Symptoms Using Fear Potentiated Auditory Startle Responses

BACKGROUND Posttraumatic stress disorder (PTSD) has been most consistently associated with exaggerated physiologic reactivity to startling sounds when such sounds occur in threatening contexts. There is conflicting evidence about whether startle hyperreactivity is a preexisting vulnerability factor for PTSD or an acquired result of posttrauma neural sensitization. Until now, there have been no prospective studies of physiologic reactivity to startling sounds in threatening contexts as predictors of PTSD symptoms. METHODS One hundred and thirty-eight police academy cadets without current psychopathology were exposed to repeated 106-dB startling sounds under increasing (low, medium, or high) threat of mild electric shock while their eye-blink electromyogram, skin conductance, heart rate, and subjective fear responses were recorded. Measures of response habituation were also calculated. Following 1 year of exposure to police-related trauma, these participants were assessed for PTSD symptom severity. RESULTS After accounting for other baseline variables that were predictive of PTSD symptom severity (age and general psychiatric distress), more severe PTSD symptoms were prospectively and independently predicted by the following startle measures: greater subjective fear under low threat, greater skin conductance under high threat, and slower skin conductance habituation. CONCLUSIONS These results imply that hypersensitivity to contextual threat (indexed by greater fear under low threat), elevated sympathetic nervous system reactivity to explicit threat (indexed by larger responses under high threat), and failure to adapt to repeated aversive stimuli (evidenced by slower habituation) are all unique preexisting vulnerability factors for greater PTSD symptom severity following traumatic stress exposure. These measures may eventually prove useful for preventing PTSD.

Pharmacological Relapse Prevention of Alcoholism: Clinical Predictors of Outcome

Objective: The efficacy of pharmacological relapse prevention in alcoholism with acamprosate and naltrexone has been supported by several controlled trials. It remains uncertain whether any differential indication for treatment exists. Methods: We evaluated outcome data of a controlled trial on acamprosate and naltrexone in patients with low vs. high baseline somatic distress, depression and anxiety (Symptom Checklist-90, SCL-90), low vs. high baseline craving, and according to typological differentiation as proposed by Cloninger and Lesch. These variables have previously been suggested to be predictors of outcome. Results: Comparing the course of abstinence rates, acamprosate was mainly efficacious in patients with low baseline somatic distress, whereas naltrexone was effective especially in patients with high baseline depression. Baseline craving showed no predictive value. Pharmacological treatment was efficacious in type II alcoholics according to Cloninger. Applying Lesch’s typological differentiation, acamprosate was shown to be mainly effective in type I, whereas naltrexone revealed best treatment effects in type III and IV. Conclusion: The study supports the hypothesis that different subgroups of alcohol dependent subjects might benefit from a differential treatment with either naltrexone or acamprosate. Baseline psychopathology and especially typological differentiation might be useful in matching patients to distinct pharmacotherapeutic interventions.

Major Depressive Disorder

Major depressive disorder (MDD) is a debilitating disease that is characterized by depressed mood, diminished interests, impaired cognitive function and vegetative symptoms, such as disturbed sleep or appetite. MDD occurs about twice as often in women than it does in men and affects one in six adults in their lifetime. The aetiology of MDD is multifactorial and its heritability is estimated to be approximately 35%. In addition, environmental factors, such as sexual, physical or emotional abuse during childhood, are strongly associated with the risk of developing MDD. No established mechanism can explain all aspects of the disease. However, MDD is associated with alterations in regional brain volumes, particularly the hippocampus, and with functional changes in brain circuits, such as the cognitive control network and the affective–salience network. Furthermore, disturbances in the main neurobiological stress-responsive systems, including the hypothalamic–pituitary–adrenal axis and the immune system, occur in MDD. Management primarily comprises psychotherapy and pharmacological treatment. For treatment-resistant patients who have not responded to several augmentation or combination treatment attempts, electroconvulsive therapy is the treatment with the best empirical evidence. In this Primer, we provide an overview of the current evidence of MDD, including its epidemiology, aetiology, pathophysiology, diagnosis and treatment.

Introducing a novel method to assess cumulative steroid concentrations: Increased hair cortisol concentrations over 6 months in medicated patients with depression

Depression has been linked to increased cortisol concentrations using point measures taken from urine, blood, or saliva samples. However, with regard to hypercortisolism-induced consequences, long-term cumulative cortisol burden is of relevance. Our objective was to use hair analysis as a new method to assess cortisol exposure over 6 months in depressed patients and healthy controls. We examined 23 depressed patients (8 men and 15 women, mean age: 41.6 years ( ± standard deviation (SD), 13.1 years); mean duration of current depressive episode 9 months ( ± SD, 13 months)) and 64 healthy controls, matched for age and gender. Cortisol concentrations in two 3-cm hair segments from near to the scalp were analyzed, representing cortisol secretion during the 6 months prior to sampling. Compared with healthy individuals, depressed patients had higher hair cortisol concentrations in the first (mean ± SD: 26.7 ± 20.8 vs. 18.7 ± 11.5 pg/mg, p < 0.05) and second hair segment (mean ± SD: 21.9 ± 23.7 vs. 13.4 ± 9.6 pg/mg, p < 0.05). In conclusion, hair cortisol analysis confirmed enhanced cortisol secretion in depressed patients over a prolonged time period. Because of the retrospective and cumulative nature of cortisol in hair, the assessment of hair cortisol concentration may help in addressing unanswered questions regarding hypothalamic–pituitary–adrenal axis overactivity and associated health consequences in psychiatric disorders.

Blockade of the mineralocorticoid receptor in healthy men: effects on experimentally induced panic symptoms, stress hormones, and cognition.

Animal studies have shown that blockade of central mineralocorticoid receptors (MR) has anxiolytic effects and impairs several aspects of cognitive function. No study to date assessed the effects of MR blockade on anxiety and cognitive function in humans. In the present study, 16 healthy young men were treated either with placebo or with 300 mg spironolactone, a MR-antagonist, at 1100, 1330, and 1630 hours in a balanced cross-over design with the two study conditions being 1 week apart. At 1500 hours, the panic symptoms provoking compound cholecystokinin-tetrapeptide (CCK-4) was administered i.v. on both occasions and panic symptoms were assessed. We measured plasma ACTH and cortisol between 1300 and 1900 hours and assessed cognitive function between 1800 and 1900 hours. CCK-4 elicited panic symptoms and increased ACTH and cortisol secretion in both conditions. Intensity of panic symptoms after CCK-4 was not different between spironolactone and placebo. Spironolactone significantly impaired selective attention and delayed recall of visuospatial memory, and diminished set shifting/mental flexibility on a trend level. Pretreatment with spironolactone led to higher baseline cortisol levels compared to placebo whereas no differences in stimulated cortisol, baseline ACTH, and stimulated ACTH emerged. Blockade of MR with spironolactone increases baseline cortisol secretion and impairs cognitive function but has no effect on experimentally induced panic symptoms in humans, for the study design and dosage of spironolactone used. The domains of cognitive function that are impaired after blockade of MR in men, that is, selective attention, visuospatial memory, and mental flexibility/set shifting appear to be remarkably similar to those described in animal studies.