Faculty Bibliography

OBJECTIVE: Overgeneral autobiographical memory has become a well established phenomenon within major depressive disorder (MDD). Neuroendocrinologically, MDD is often characterized by a dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, i.e. hypercortisolemia and reduced feedback sensitivity. In healthy participants cortisol administration has been found to impair autobiographical memory retrieval. The purpose of this study was to compare the effects of acute cortisol administration on autobiographical memory in MDD patients with the effects observed in healthy controls. We hypothesized that in contrast to healthy control subjects acute cortisol administration would not affect autobiographical memory performance in MDD due to reduced central glucocorticoid sensitivity. METHODS: In a placebo-controlled, double-blind crossover study, 16 patients with MDD and 16 healthy control subjects received a placebo or 10mg of hydrocortisone orally before autobiographical memory testing (AMT). RESULTS: In the placebo condition depressed patients performed poorer than controls. After hydrocortisone intake, healthy subjects reported significantly fewer specific memories on the AMT compared to placebo treatment. In contrast, memory specificity of MDD patients was not affected by hydrocortisone treatment. CONCLUSIONS: The present findings replicate previous findings of impaired autobiographical memory retrieval after hydrocortisone treatment in healthy subjects and of impaired AMT performance in depressed patients. We speculate that the missing acute impairing effect of hydrocortisone on autobiographical memory in depressed patients might reflect reduced central glucocorticoid sensitivity. However alternative explanations cannot be ruled out

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

Alterations of glucocorticoid receptor sensitivity have been associated with depression. Thus, variation in the glucocorticoid receptor gene that determines glucocorticoid sensitivity may influence risk for depression. In a cross-sectional genetic association study of 526 white outpatients with chronic coronary heart disease, we examined whether haplotypes of the glucocorticoid receptor gene (NR3C1) are associated with depression. Participants were genotyped for four common glucocorticoid receptor gene polymorphisms (ER22/23EK, BclI C/G, N363S, and 9beta A/G) and haplotype analyses were conducted. Depression was assessed by an interview (Computerized Diagnostic Interview Schedule). Of the 526 participants, 355 (67.5%) were non-carriers, 153 (29.1%) had one copy, and 17 (3.2%) had 2 copies of the haplotype 3 allele, which includes the minor allele of the 9beta A/G polymorphism and which has been associated with reduced glucocorticoid sensitivity. The prevalence of depression ranged from 24.4% in the non-carriers to 34.4% in heterozygotes to 52.9% in participants homozygous for the haplotype 3 allele (p<0.01). In logistic regression analyses, carriers of one haplotype 3 allele had an odds ratio of 1.64 (95% CI 1.1-2.5, p=0.02) for depression, while the odds ratio of homozygous haplotype 3 carriers was 3.52 (95% CI 1.3-9.4, p=0.01). These associations persisted after adjusting for potentially confounding variables. A common GR haplotype was associated with depression in a gene-dosage dependent manner and might be a vulnerability factor for depression

We examined gender effects and the role of cortisol in the association between depressive symptoms and metabolic risk in the Stress, Atherosclerosis, and ECG Study (STRATEGY). In 215 healthy adults from the general population (n=107 men, n=108 women, distributed equally across four age groups, 30-70 years), we assessed depressive symptoms by the Patient Health Questionnaire (PHQ score >10) and measured variables of the metabolic syndrome: high-density lipoprotein (HDL), triglycerides, systolic and diastolic blood pressure, fasting blood glucose and waist circumference. Salivary cortisol was assessed at 08:00, 12:00, 16:00 and 22:00 h. Depressive symptoms were not associated with the metabolic syndrome as entity in the total sample or in men and women separately. However, women with depressive symptoms had larger waist circumferences, higher fasting blood glucose, lower HDL-cholesterol, higher diastolic blood pressure, and higher 16:00 and 22:00 h salivary cortisol compared to women without depressive symptoms. These results persisted after adjusting for age, education, smoking, and physical activity. In adjusted regression analyses, inclusion of cortisol attenuated the association between depressive symptoms and waist, fasting glucose, HDL and diastolic blood pressure in women. In men, we did not find an association between depressive symptoms and variables of the metabolic syndrome. In women, depressive symptoms are associated with several variables of the metabolic syndrome. Elevated afternoon and evening cortisol appear to partially mediate this association

OBJECTIVE: To evaluate whether depression is associated with whole blood serotonin in outpatients with stable coronary heart disease (CHD). Depression is associated with incident CHD and with adverse cardiovascular outcomes. Dysregulation of peripheral serotonin, common to both depression and CHD, may contribute to this association. METHODS: We performed a cross-sectional study of 791 participants with stable CHD enrolled in the Heart and Soul Study and not taking antidepressant medication. We assessed major depression using the Computerized Diagnostic Interview Schedule (CDIS-IV) and measured whole blood serotonin (WBS) from fasting venous samples. RESULTS: Of the 791 participants, 114 (14%) had current (past month) major depression, 186 (24%) had past (but not current) major depression, and 491 (62%) had no history of depression. Age-adjusted mean WBS was higher in participants with current major depression (139 +/- 6.5 ng/ml) than in those with past depression (120 +/- 5.0 ng/ml) or no history of depression (119 +/- 3.1 ng/ml) (p = .02). This association was unchanged after adjustment for demographic characteristics, medical comorbidities, medication use, and cardiac disease severity (p = .02). When serotonin was analyzed as a dichotomous variable, current depression was associated with a 70% greater odds of having WBS in the highest quartile (adjusted odds ratio = 1.71; 95% Confidence Interval = 1.03-2.83; p = .04). CONCLUSIONS: In this sample of patients with stable CHD, current major depression was independently associated with higher mean WBS levels. Future studies should examine whether elevated WBS may contribute to adverse outcomes in patients with depression and CHD

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

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

Since the 1980s a large body of empirical effort has been devoted to mood-congruent memory (MCM) biases in clinical depression. Whereas there is broad, albeit not unequivocal, evidence that depressive patients retain negative-valenced memory items better than neutral material, few studies have investigated false memories in depression. In a pilot study we gathered support for both enhanced true and false memory for emotional material in depression. The present study aimed to extend these preliminary findings. In view of investigations suggesting that arousing and meaningful stimuli have facilitated access to memory, personal salience was considered a moderator for MCM. In the present study 21 depressed and 22 healthy participants were presented six false memory lists dealing with neutral, negative, and positive themes. At recognition, each item had to be appraised for its degree of valence subsequent to an old-new judgement. Pre-categorised and subjective valence did not discriminate groups. However, relative to controls depressed patients showed both more veridical as well as false recognition for items that concurrently elicited higher salience ratings in patients. In contrast, group differences in recognition performance did not significantly affect salience ratings. Results indicate that salience modulates MCM and may account for discrepancies in the literature

Depression is one of the most pressing public health issues, because of its high lifetime prevalence and because it is associated with substantial disability. In depressed patients, psychiatric and medical comorbidity is the rule rather than the exception. About 60% to 70% of depressed patients have at least one, while 30% to 40% have two or more, concurrent psychiatric disorders, Among these, anxiety disorders and substance use disorders are the most common axis I comorbidities. Furthermore, two thirds of depressed patients have at least one comorbid medical illness. Among depressed patients, those with a current comorbid psychiatric condition (in particular an anxiety or substance use disorder) or medical illness seem to have an impaired response and remission rate during treatment compared with those patients without comorbidity. However, in depressed patients who all have the same comorbid condition, the relative benefit of an antidepressant compared with placebo appears to be equal to those effects achieved in depressed patients without comorbidity. These findings raise important research and treatment issues regarding the generalizability from randomized controlled trials that to exclude patients tend to exclude patients with comorbidity