Increased cortisol awakening response was associated with time to recurrence of major depressive disorder.

INTRODUCTION: Although HPA-axis activity has been studied extensively in relation to depression, there is no consensus whether HPA-axis parameters predicts major depressive disorder (MDD) recurrence. We investigated whether HPA-axis parameters (cortisol awakening response (CAR), the dexamethasone suppression test (DST) and evening cortisol) predict time to recurrence in remitted subjects with a history of MDD and whether childhood trauma and life events interact with HPA-axis parameters in increasing the risk for recurrence. METHOD: Data were derived from 549 subjects with a lifetime diagnosis of MDD in remission for at least six months preceding the baseline assessment of the Netherlands Study of Depression and Anxiety (NESDA). Subjects were followed up with two interviews over the course of four years to assess recurrence. DSM-IV based diagnostic interviews were used to assess time to recurrence of MDD. Seven salivary cortisol samples collected at baseline with information on CAR, evening cortisol and the DST. Hazard ratios were calculated using Cox regression analysis, adjusted for covariates. RESULTS: A higher CAR was associated with time to recurrence of MDD (HR=1.03, 95%CI 1.003-1.060, p=0.03) whereas evening cortisol and DST were not. No interactions between HPA-axis parameters and stress-related factors were found. CONCLUSIONS: Our data support previous studies reporting that subjects with a higher CAR are more vulnerable to recurrence of MDD.

Evening salivary alpha-amylase, major depressive disorder, and antidepressant use in the Netherlands Study of Depression and Anxiety (NESDA).

Salivary alpha-amylase (sAA) may be a suitable index for sympathetic activity and dysregulation of the autonomic nervous system. The relationship between antidepressants and depression with sAA levels was studied, since antidepressants were previously shown to have a profound impact on heart rate variability as an ANS indicator. Data are from 1692 participants of the Netherlands Study of Depression and Anxiety (NESDA) who were recruited from the community, general practice, and specialized mental health care. Differences in evening sAA levels were examined between patient groups (i.e., 752 current major depressive disorder [MDD], 611 remitted MDD, and 329 healthy controls) and between 46 tricyclic antidepressant (TCA) users, 307 selective serotonin reuptake inhibitor (SSRI) users, 97 users of another antidepressant, and 1242 non-users. Each participant sampled twice at 22.00h and 23.00h. In multivariable analysis, there was a trend over the three groups with increasing sAA levels from controls to remitted MDD to current MDD that approached significance. Furthermore, in comparison to non-users of antidepressants, TCA rather than SSRI users showed higher sAA levels, that persisted after multivariable adjustment. The present study shows that higher evening sAA levels in depressed patients, indicative of an increased sympathetic activity, may be induced by TCAs.

Salivary cortisol levels and the 2-year course of depressive and anxiety disorders.

INTRODUCTION: Depression and anxiety disorders have been associated with hyperactivity of the hypothalamic-pituitary adrenal (HPA) axis. However, lower cortisol levels have also been observed in depressed patients. Whether cortisol level predicts the course of these disorders has not been examined in detail. We examined whether salivary cortisol indicators predict the 2-year course of depression and anxiety disorders. METHODS: Longitudinal data are obtained from 837 participants of the Netherlands Study of Depression and Anxiety, with a DSM-IV based depressive and/or anxiety disorder at baseline. At baseline, seven saliva samples were obtained, including the 1-h cortisol awakening response, evening cortisol level and a 0.5mg dexamethasone suppression test. At follow-up, DSM-IV based diagnostic interviews and Life Chart Interview integrating diagnostic and symptom trajectories over 2 years were administered to determine an unfavorable course. RESULTS: 41.5% of the respondents had a 2-year unfavorable course trajectory without remission longer than 3 months. Adjusted analyses showed that a lower awakening response was associated with an unfavorable course (RR=0.83, p=0.03). No associations were found between evening cortisol or cortisol suppression after dexamethasone ingestion and an unfavorable course trajectory. CONCLUSIONS: Among patients with depressive or anxiety disorders, a lower cortisol awakening response - which may be indicative of underlying exhaustion of the HPA axis - predicted an unfavorable course trajectory.

The impact of stress systems and lifestyle on dyslipidemia and obesity in anxiety and depression.

BACKGROUND: Dyslipidemia and obesity have been observed in persons with severe anxiety or depression, and in tricyclic antidepressant (TCA) users. This likely contributes to the higher risk of cardiovascular disease (CVD) in anxiety and depressive disorders. We aimed to elucidate whether biological stress systems or lifestyle factors underlie these associations. If so, they may be useful targets for CVD prevention and intervention. METHODS: Within 2850 Netherlands Study of Depression and Anxiety (NESDA) participants, we evaluated the explaining impact of biological stress systems (i.e., the hypothalamic-pituitary-adrenal [HPA] axis, autonomic nervous system [ANS] and inflammation) and lifestyle factors (i.e., tobacco and alcohol use, and physical activity) on adverse associations of anxiety and depression severity and TCA use with high and low-density lipoprotein cholesterol, triglycerides, body mass index and waist circumference. Through linear regression analyses, percentual change (%Δ) in ß was determined and considered significant when %Δ>10. RESULTS: The inflammatory marker C-reactive protein had the most consistent impact (explaining 14-53% of the associations of anxiety and depression severity and TCA use with lipid and obesity levels), followed by tobacco use (explaining 34-43% of the associations with lipids). The ANS mediated all associations with TCA use (explaining 32-61%). The HPA axis measures did not explain any of the associations. CONCLUSIONS: Increased dyslipidemia and (abdominal) obesity risk in patients with more severe anxiety disorders and depression may be partly explained by chronic low-grade inflammation and smoking. TCAs may increase metabolic risk through enhanced sympathetic and decreased parasympathetic ANS activity. That the HPA axis had no impact in our sample may reflect the possibility that the HPA axis only plays a role in acute stress situations rather than under basal conditions.

Determinants of salivary evening α-amylase in a large sample free of psychopathology.

OBJECTIVE: Recently, salivary alpha-amylase (sAA) has been proposed as a suitable index for sympathetic activity and dysregulation of the autonomic nervous system (ANS). Although determinants of sAA have been described, they have not been studied within the same study with a large sample size without potential disturbances of psychopathology. In this paper, we report about correlates of evening sAA in saliva. METHODS: In 487 participants (mean age=42.9years, 59.8% female) without lifetime psychiatric disorders from the Netherlands Study of Depression and Anxiety (NESDA), sociodemographic, health and sampling determinants of sAA levels were examined using multivariable linear regression analysis. sAA was measured in two saliva samples that participants collected in the late evening, at 22:00h and 23:00h, after which these were averaged. RESULTS: In multivariate analysis, age (ß=0.20, p<0.001) and daily alcohol intake (ß=-0.13, p=0.01) were independent determinants of evening sAA levels. Gender, allergy or lung disease, and the use of oral contraceptives were univariate correlates, but no longer associated with sAA in the multivariate model. CONCLUSIONS: Age and alcohol use were identified as potential confounding factors that should be taken into account in epidemiologic studies that examine the ANS function using sAA.

The relationships of working conditions, recent stressors and childhood trauma with salivary cortisol levels.

BACKGROUND: An etiological model has been suggested where stress leads to high cortisol levels and hypothalamic-pituitary-adrenal (HPA) axis dysregulation, resulting in somatic diseases and psychopathology. To evaluate this model we examined the association of different stressors (working conditions, recent life events and childhood trauma) with various cortisol indicators in a large cohort study. METHODS: Data are from 1995 participants of the Netherlands Study of Depression and Anxiety (NESDA). Most of the selected participants had a current or remitted anxiety and/or depressive disorder. Working conditions were assessed with self-report questionnaires, life-events and childhood trauma were assessed with interview questionnaires. Cortisol levels were measured in seven saliva samples, determining the 1-h cortisol awakening response (CAR), evening cortisol levels and cortisol suppression after a 0.5mg dexamethasone suppression test (DST). RESULTS: Regression analyses--adjusted for covariates--showed two significant associations: low social support at work and high job strain were associated with more cortisol suppression after the DST. No other associations were found with any of the cortisol variables. CONCLUSIONS: Working conditions, recent stressors and childhood trauma were not convincingly associated with cortisol levels.

Co-occurring manic symptomatology influences HPA axis alterations in depression.

Although dysfunctioning of the HPA axis is considered to be a core pathophysiological process in mood disorders, the evidence with regard to depression remains conflicting. This could partly be due to the large heterogeneity within mood disorders, since HPA axis abnormalities may also be associated with the extent of co-occurring manic symptomatology as is seen in bipolar disorder. In this study, patients with depressive disorder and bipolar spectrum disorders were studied with regard to their HPA axis functioning. In 304 healthy controls, 1,134 patients with pure unipolar depressive disorder (UP), and 133 bipolar spectrum disorder patients (BD spectrum), cortisol was measured in 7 saliva samples to determine the 1 h cortisol awakening response (CAR), evening cortisol levels and cortisol suppression after a 0.5 mg dexamethasone suppression test. Both patient groups had overall higher CAR levels compared to controls, but only UP patients showed a higher increase over time in the CAR. A linear association was found between increasing bipolarity and cortisol diurnal slope: BD spectrum patients had a significantly higher diurnal slope than UP patients. Dexamethasone suppression did not differ between mood disorder diagnoses. The heterogeneity in HPA axis functioning in patients with depression can partially be explained by co-existing manic symptomatology, since an increase in the CAR appears to be more specific for pure depression whereas the presence of bipolarity is associated with an increase in the diurnal slope of cortisol.

Antidepressant use and salivary cortisol in depressive and anxiety disorders.

Antidepressants are an effective treatment for depressive and anxiety disorders. Those disorders are frequently accompanied by heightened cortisol levels. Antidepressants may affect hypothalamic-pituitary-adrenal axis functioning, the alteration of which could be partially responsible for treatment efficacy. The association between antidepressants and cortisol was investigated in 1526 subjects of the Netherlands Study of Depression and Anxiety who were grouped into 'serotonin reuptake inhibitor (SSRI) users' (n=309), 'tricyclic antidepressant (TCA) users' (n=49), 'other antidepressant users' (n=100), and 'non-users' (n=1068). All subjects had a current or past diagnosis of anxiety and/or depression. Subjects provided 7 saliva samples from which 3 cortisol indicators were calculated: cortisol awakening response (CAR), evening cortisol, and cortisol suppression after ingestion of 0.5mg dexamethasone. As compared to non-users, TCA users had a flattened CAR (effect size: Cohen's d=0.34); SSRI users had higher evening cortisol levels (d=0.04); and SSRI users showed decreased cortisol suppression after dexamethasone ingestion (d=0.03). These findings suggest that antidepressant subtypes are associated with distinct alterations of the HPA axis. TCA users, who showed a flattened CAR, displayed the strongest alterations of salivary cortisol.

Heavy alcohol use, rather than alcohol dependence, is associated with dysregulation of the hypothalamic-pituitary-adrenal axis and the autonomic nervous system.

BACKGROUND: Heavy alcohol use as well as alcohol dependence (AD) have been associated with dysregulation of the hypothalamic-pituitary-adrenal (HPA)-axis and the autonomic nervous system (ANS). However, the relative contribution of alcohol use and AD is unclear. METHODS: Baseline data were derived from 2947 persons of the Netherlands Study of Depression and Anxiety (NESDA), including non-drinkers (n=498), moderate drinkers (n=2112) and heavy drinkers (n=337). We also distinguished between persons with no lifetime DSM-IV AD (n=2496), remitted AD (> 1 year; n = 243), and current AD (≤ 1 year; n=208). ANS measures included ECG-based heart rate (HR), respiratory sinus arrhythmia (RSA, high RSA reflecting high cardiac parasympathetic control) and pre-ejection period (PEP, high PEP reflecting low cardiac sympathetic control). HPA-axis measures included the cortisol awakening response (area under the curve with respect to the ground [AUCg] and increase [AUCi]), evening cortisol and a 0.5mg dexamethasone suppression test, all measured in saliva. RESULTS: Heavy drinkers showed higher basal cortisol levels (AUCg: p=.02; evening cortisol: p=.006) and increased cardiac sympathetic control (higher HR: p=.04; lower PEP: p=.04) compared to moderate drinkers. Persons with current or remitted AD did not differ from persons without lifetime AD on any of the HPA-axis or ANS indicators (all p>.33). Similar patterns of HPA-axis and ANS activity across alcohol use groups were found in persons with and without lifetime AD. CONCLUSIONS: Our findings suggest that current heavy alcohol use, rather than current or remitted AD, is associated with hyperactivity of the HPA-axis and increased cardiac sympathetic control.

Common functional mineralocorticoid receptor polymorphisms modulate the cortisol awakening response: Interaction with SSRIs.

BACKGROUND: Cortisol controls the activity of the hypothalamic-pituitary-adrenal (HPA) axis during stress and during the circadian cycle through central mineralocorticoid (MR) and glucocorticoid receptors (GR). Changes in MR and GR functioning, therefore, may affect HPA axis activity. In this study we examined the effect of common functional MR gene variants on the cortisol awakening response (CAR), which is often disturbed in stress-related disorders like depression. METHODS: Common functional MR single nucleotide polymorphisms (SNPs; MR -2G/C and I180V) and haplotypes were tested for association with variability in the CAR in a large cohort (Netherlands Study of Depression and Anxiety, NESDA) of patients diagnosed with a lifetime major depressive disorder (MDD). Saliva cortisol measurements and genotypes could be obtained from a total of 1026 individuals, including 324 males and 702 females. RESULTS: The MR -2C/C genotype was associated with an attenuated CAR increase in women (p=.03) but not in men (p=.18; p=.01 for SNP-by-sex interaction). The MR I180V SNP had no significant effect on the CAR. Additional analysis revealed that effect of the -2G/C SNP on the CAR was due to an interaction with frequent use of selective serotonin reuptake inhibitors (SSRIs). Only in subjects using SSRIs (men and women) highest total morning cortisol levels were observed in -2G/G carriers, while the CAR was completely flattened in women with the -2C/C genotype (p<.05). The results were independent of multiple potential confounders and had an effect size of r=.14-.27. CONCLUSIONS: This study shows that the MR -2G/C SNP modulated the CAR only in the MDD patients using SSRIs, with a clear allele-dose effect in women. This suggests that effect of SSRIs on cortisol regulation depends in part on the MR genotype with possible implications for future treatment selection.

Dimensions of depression and anxiety and the hypothalamo-pituitary-adrenal axis.

BACKGROUND: Results on the association between depression and the hypothalamo-pituitary-adrenal (HPA) axis have been inconsistent, possibly due to heterogeneity of the DSM-IV category of depression. Specific symptom-dimensions could be used as a more homogenous phenotype in HPA-axis research. METHODS: Subjects (n = 1029) with a lifetime depression and/or anxiety disorder from the NESDA study (Netherlands Study of Depression and Anxiety) (mean age: 43.0 ± 12.7 years, 67.4% women) provided seven saliva samples to yield the cortisol awakening response (CAR), evening cortisol, and dexamethasone suppression data. The dimensions of the tripartite model (General Distress, Anhedonic Depression, and Anxious Arousal) were measured with the 30-item adapted Mood and Anxiety Symptoms Questionnaire (MASQ-D30) and analyzed in association with the cortisol measures with linear and nonlinear regression. RESULTS: Median (interquartile range) scores of General Distress, Anhedonic Depression, and Anxious Arousal were 20 (14-27), 36 (28-44), and 15 (12-19), respectively, indicating large variability. Nonlinear associations with the shape of an inverted U were found between General Distress, Anhedonic Depression, and Anxious Arousal on one hand and total morning secretion and the dynamic of the CAR by contrast. Both high and low severity levels were associated with a lower CAR, compared with intermediate levels of severity. Most of the associations remained significant when adjusted for covariates and the presence of DSM-IV diagnoses. CONCLUSIONS: Nonlinear associations were found between the CAR and the dimensions of the tripartite model. This could explain previous inconsistent findings regarding HPA-axis activity in depressed patients and illustrates the added value of symptom-dimensions for HPA-axis research.

Psychological traits and the cortisol awakening response: results from the Netherlands Study of Depression and Anxiety.

BACKGROUND: Hypothalamus-Pituitary-Adrenal (HPA) axis dysregulation is often seen in major depression, and is thought to represent a trait vulnerability - rather than merely an illness marker - for depressive disorder and possibly anxiety disorder. Vulnerability traits associated with stress-related disorders might reflect increased sensitivity for the development of psychopathology through an association with HPA axis activity. Few studies have examined the association between psychological trait factors and the cortisol awakening response, with inconsistent results. The present study examined the relationship between multiple psychological trait factors and the cortisol awakening curve, including both the dynamic of the CAR and overall cortisol awakening levels, in a sample of persons without psychopathology, hypothesizing that persons scoring high on vulnerability traits demonstrate an elevated cortisol awakening curve. METHODS: From 2981 participants of the Netherlands Study of Depression and Anxiety (NESDA), baseline data from 381 controls (aged 18-65) without previous, current and parental depression and anxiety disorders were analyzed. Psychological measures included the Big Five personality traits (neuroticism, extraversion, openness to experience, conscientiousness, and agreeableness) measured using the NEO-FFI, anxiety sensitivity assessed by the Anxiety Sensitivity Index, cognitive reactivity to sadness (hopelessness, acceptance/coping, aggression, control/perfectionism, risk aversion, and rumination) as measured by the LEIDS-R questionnaire, and mastery, assessed using the Pearlin and Schooler Mastery scale. Salivary cortisol levels were measured at awakening, and 30, 45, and 60 min afterwards. RESULTS: In adjusted analyses, high scores of hopelessness reactivity (ß=.13, p=.02) were consistently associated with a higher cortisol awakening response. In addition, although inconsistent across analyses, persons scoring higher on extraversion, control/perfectionism reactivity, and mastery tended to show a slightly flatter CAR. No significant associations were found for neuroticism, openness to experience, agreeableness, conscientiousness, anxiety sensitivity, and acceptance/coping, aggression, or risk aversion reactivity. CONCLUSION: Of various psychological traits, only hopelessness reactivity, a trait that has been associated with depression and suicidality, is consistently associated with HPA axis dysregulation. Hopelessness reactivity may represent a predisposing vulnerability for the development of a depressive or anxiety disorder, possibly in part mediated by HPA axis activity.

Parental history of depression or anxiety and the cortisol awakening response.

BACKGROUND: It is unclear whether altered hypothalamic-pituitary-adrenal (HPA) axis regulation, which frequently accompanies depression and anxiety disorders, represents a trait rather than a state factor. AIMS: To examine whether HPA axis dysregulation represents a biological vulnerability for these disorders, we compared cortisol levels in unaffected people with and without a parental history of depressive or anxiety disorders. We additionally examined whether possible HPA axis dysregulations resemble those observed in participants with depression or anxiety disorders. METHOD: Data were from the Netherlands Study of Depression and Anxiety. Within the participants without a lifetime diagnoses of depression or anxiety disorders, three groups were distinguished: 180 people without parental history, 114 with self-reported parental history and 74 with CIDI-diagnosed parental history. These groups were additionally compared with people with major depressive disorder or panic disorder with agoraphobia (n = 1262). Salivary cortisol samples were obtained upon awakening, and 30, 45 and 60 min later. RESULTS: As compared with unaffected participants without parental history, unaffected individuals with diagnosed parental history of depression or anxiety showed a significantly higher cortisol awakening curve (effect size (d) = 0.50), which was similar to that observed in the participants with depression or anxiety disorders. Unaffected people with self-reported parental history did not differ in awakening cortisol levels from unaffected people without parental history. CONCLUSIONS: Unaffected individuals with parental history of depression or anxiety showed a higher cortisol awakening curve, similar to that of the participants with depression or anxiety disorders. This suggests that a higher cortisol awakening curve reflects a trait marker, indicating an underlying biological vulnerability for the development of depressive and anxiety disorders.

Long-term benzodiazepine use and salivary cortisol: the Netherlands Study of Depression and Anxiety (NESDA).

BACKGROUND: As benzodiazepines (BZDs) have anxiolytic effects, it is expected that they influence the stress system. During short-term treatment, BZD use was found to suppress cortisol levels. However, little research has been done on the effects of long-term BZD administration on the hypothalamic-pituitary-adrenal (HPA) axis. METHODS: The association between long-term BZD use and cortisol levels was investigated in subjects of the Netherlands Study of Depression and Anxiety with a lifetime diagnosis of anxiety or depression (n = 1531). The subjects were categorized as "daily BZD users" (n = 96), "infrequent BZD users" (n = 172), and "nonusers" (n = 1263). Possible associations between characteristics of BZD use (dose, duration, and dependence) and salivary cortisol levels were analyzed. MAIN OUTCOME MEASURE: Subjects provided 7 saliva samples, from which 4 cortisol indicators were calculated: the cortisol awakening response, diurnal slope, evening cortisol, and cortisol suppression after ingestion of 0.5 mg of dexamethasone. RESULTS: Daily users used BZDs for a median duration of 26.5 months and had a median daily dosage of 6.0 mg as measured in diazepam equivalents. Evening cortisol levels were significantly lower in daily users (P = 0.004; effect size: d = 0.24) and infrequent users (P = 0.04; effect size: d = 0.12) compared to nonusers. We did not find significant differences in the cortisol awakening response, diurnal slope, or in the dexamethasone suppression test. CONCLUSIONS: Despite the finding of slightly lower evening cortisol levels in daily and infrequent BZD users compared to nonusers, results indicate that long-term BZD use is not convincingly associated with HPA axis alterations.

Increased sympathetic and decreased parasympathetic activity rather than changes in hypothalamic-pituitary-adrenal axis activity is associated with metabolic abnormalities.

CONTEXT: Stress is suggested to lead to metabolic dysregulations as clustered in the metabolic syndrome, but the underlying biological mechanisms are not yet well understood. OBJECTIVE: We examined the relationship between two main str systems, the autonomic nervous system and the hypothalamic-pituitary-adrenal (HPA) axis, with the metabolic syndrome and its components. DESIGN: The design was baseline data (yr 2004-2007) of a prospective cohort: the Netherlands Study of Depression and Anxiety (NESDA). SETTING: The study comprised general community, primary care, and specialized mental health care. PARTICIPANTS: This study included 1883 participants aged 18-65 yr. MAIN OUTCOME MEASURES: Autonomic nervous system measures included heart rate, respiratory sinus arrhythmia (RSA; high RSA reflecting high parasympathetic activity), and preejection period (PEP; high PEP reflecting low sympathetic activity). HPA axis measures included the cortisol awakening response, evening cortisol, and a 0.5 mg dexamethasone suppression test as measured in saliva. Metabolic syndrome was based on the updated Adult Treatment Panel III criteria and included high waist circumference, serum triglycerides, blood pressure, serum glucose, and low high-density lipoprotein cholesterol. RESULTS: RSA and PEP were both independently negatively associated with the presence of the metabolic syndrome, the number of metabolic dysregulations as well as all individual components except high-density lipoprotein cholesterol (all P < 0.02). Heart rate was positively related to the metabolic syndrome, the number of metabolic dysregulations, and all individual components (all P < 0.001). HPA axis measures were not related to metabolic syndrome or its components. CONCLUSION: Our findings suggest that increased sympathetic and decreased parasympathetic nervous system activity is associated with metabolic syndrome, whereas HPA axis activity is not.

Salivary cortisol levels in persons with and without different anxiety disorders.

OBJECTIVE: To examine the association between several subtypes of anxiety disorders and various cortisol indicators in a large cohort study. Anxiety disorders have been suggested to be linked to hypothalamic-pituitary-adrenal (HPA) axis activity, although results are scarce and inconsistent. No earlier studies have examined consistency of HPA axis findings across several anxiety subtypes and whether associations are state or trait dependent. METHODS: Data are derived from 1427 participants of the Netherlands Study of Depression and Anxiety. Three groups were compared: 342 control participants without psychiatric disorders; 311 persons with a remitted (no current) anxiety disorder (social phobia, generalized anxiety disorder, panic disorder); and 774 persons with a current anxiety disorder, as diagnosed using the Composite International Diagnostic Interview psychiatric interview. Cortisol levels were measured in seven saliva samples, determining the 1-hour cortisol awakening response, evening cortisol, and cortisol response after 0.5 mg of dexamethasone ingestion. RESULTS: Current anxiety disorder was associated with higher awakening cortisol levels (p = .002). These findings were mainly present for patients with panic disorder with agoraphobia and anxious patients with comorbid depressive disorder. Remitted anxiety only showed a trend toward higher morning cortisol (p = .08). No associations were observed for anxiety status and evening cortisol level or cortisol suppression after dexamethasone. CONCLUSIONS: This study showed a modest but significantly higher 1-hour cortisol awakening response among anxiety patients, which was driven by those with panic disorder with agoraphobia and those with comorbid depression.

Major depressive disorder and hypothalamic-pituitary-adrenal axis activity: results from a large cohort study.

CONTEXT: There is a central belief that depression is associated with hyperactivity of the hypothalamic-pituitary-adrenal axis, resulting in higher cortisol levels. However, results are inconsistent. OBJECTIVE: To examine whether there is an association between depression and various cortisol indicators in a large cohort study. DESIGN, SETTING, AND PARTICIPANTS: Data are from 1588 participants of the Netherlands Study of Depression and Anxiety who were recruited from the community, general practice care, and specialized mental health care. Three groups were compared: 308 control subjects without psychiatric disorders, 579 persons with remitted (no current) major depressive disorder (MDD), and 701 persons with a current MDD diagnosis, as assessed using the DSM-IV Composite International Diagnostic Interview. MAIN OUTCOME MEASURES: Cortisol levels were measured in 7 saliva samples to determine the 1-hour cortisol awakening response, evening cortisol levels, and cortisol suppression after a 0.5-mg dexamethasone suppression test. RESULTS: Both the remitted and current MDD groups showed a significantly higher cortisol awakening response compared with control subjects (effect size [Cohen d] range, 0.15-0.25). Evening cortisol levels were higher among the current MDD group at 10 pm but not at 11 pm. The postdexamethasone cortisol level did not differ between the MDD groups. Most depression characteristics (severity, chronicity, symptom profile, prior childhood trauma) were not associated with hypothalamic-pituitary-adrenal axis activity except for comorbid anxiety, which tended to be associated with a higher cortisol awakening response. The use of psychoactive medication was generally associated with lower cortisol levels and less cortisol suppression after dexamethasone ingestion. CONCLUSIONS: This large cohort study shows significant, although modest, associations between MDD and specific hypothalamic-pituitary-adrenal axis indicators. Because a higher cortisol awakening response was observed among both subjects with current MDD and subjects with remitted MDD, this may be indicative of an increased biological vulnerability for depression.

Associations between sociodemographic, sampling and health factors and various salivary cortisol indicators in a large sample without psychopathology.

BACKGROUND: Cortisol levels are increasingly often assessed in large-scale psychosomatic research. Although determinants of different salivary cortisol indicators have been described, they have not yet been systematically studied within the same study with a large sample size. Sociodemographic, health and sampling-related determinants of salivary cortisol levels were examined in a sample without potential disturbances because of psychopathology. METHODS: Using 491 respondents (mean age=43.0 years, 59.5% female) without lifetime psychiatric disorders from the Netherlands Study of Depression and Anxiety (NESDA), sociodemographic, sampling and health determinants of salivary cortisol levels were examined. Respondents collected seven salivary cortisol samples providing information about 1-h awakening cortisol, diurnal slope, evening cortisol and a dexamethasone (0.5mg) suppression test (DST). RESULTS: Higher overall morning cortisol values were found for smokers, physically active persons, persons without cardiovascular disease, sampling on a working day or in a month with less daylight. In addition, the cortisol awakening response was significantly flattened for males, persons with cardiovascular disease, those with late awakening times and those with longer sleep duration. Diurnal slope was steeper in men, physically active persons, late awakeners, working persons, and season with less daylight. A higher evening cortisol level was associated with older age, smoking and season with more daylight. Cortisol suppression after dexamethasone ingestion was found to be less pronounced in smokers, less active persons and sampling on a weekday. CONCLUSION: Sociodemographic variables (sex, age), sampling factors (awakening time, working day, sampling month, sleep duration) and health indicators (smoking, physical activity, cardiovascular disease) were shown to influence different features of salivary cortisol levels. Smoking had the most consistent effect on all cortisol variables. These factors should be considered in psychoneuroendocrinology research.

Hypertension during pregnancy in South Australia, part 1: pregnancy outcomes.

BACKGROUND: There have been conflicting reports about pregnancy outcome in the hypertensive disorders of pregnancy. The present study was undertaken to examine outcomes using a population database. AIMS: To examine for differences in a range of pregnancy outcomes between three different groups of hypertensive women and normotensive women in South Australia. METHODS: Nine pregnancy outcomes were compared for 70,386 singleton pregnancies in the South Australian perinatal data collection in 1998-2001, consisting of 639 women with pre-existing hypertension, 5356 women with pregnancy hypertension, 448 women with superimposed pre-eclampsia and 63 943 normotensive women. Means for the four groups were calculated for birthweight, gestational age, the baby's and mother's length of stay. The groups were also compared for perinatal deaths with an earlier period, 1991-1997. RESULTS: While all three hypertensive groups had high incidences of induction of labour and emergency Caesarean, only pre-existing hypertension and superimposed pre-eclampsia were significantly associated with elective Caesarean section. All hypertensive groups had increased risks for low birthweight and preterm birth and special and neonatal intensive care. Uncomplicated pre-existing hypertension was not associated with small for gestational age infants, but with preterm delivery between 32 and 36 weeks' gestation. Superimposed pre-eclampsia had the worst prognosis for perinatal and maternal morbidity. While pregnancy hypertension held the intermediate position, it was not associated with an increase in perinatal mortality. The perinatal mortality rate for women with hypertensive disorders in 1998-2001 was significantly lower than that of an earlier period and equivalent to that for normotensive women. CONCLUSIONS: Superimposed pre-eclampsia occurs in approximately 40% of pregnancies of women with pre-existing hypertension and has the most severe outcomes. The hypertensive disorders are associated with high levels of morbidity and intervention, but the high perinatal mortality associated with these disorders has fallen significantly.

Hypertension during pregnancy in South Australia, part 2: risk factors for adverse maternal and/or perinatal outcome - results of multivariable analysis.

OBJECTIVE: To identify factors associated with adverse pregnancy outcomes among women with hypertension during pregnancy. DESIGN: A population-based retrospective multivariable analysis using the South Australian perinatal data collection. METHODS: Perinatal data on 70,386 singleton births in 1998-2001 were used in multivariable analyses on three groups: all women combined, all hypertensive women and women with pregnancy hypertension only, in order to identify independent risk factors for requirement for level II/III care, preterm birth, small for gestational age (SGA) birth and maternal length of stay greater than 7 days. RESULTS: The risks for the four morbidities were all increased among women with hypertension compared with normotensive women. Those with pre-existing hypertension had the lowest risk (with odds ratios (OR) 1.26-2.90). Pregnancy hypertension held the intermediate position (OR 1.52-5.70), while superimposed pre-eclampsia was associated with the highest risk (OR 2.00-8.75). Among women with hypertension, Aboriginality, older maternal age, nulliparity and pre-existing or gestational diabetes increased the risk for level II/III nursery care, preterm birth and prolonged hospital stay. Smokers had shorter stays, which may be related to their decreased risk of having a Caesarean section or operative vaginal delivery. Asian women, Aboriginal women, smokers and unemployed women had an increased risk for having an SGA baby, while women with pre-existing or gestational diabetes had a reduced risk. CONCLUSIONS: Among hypertensive pregnant women, nulliparity, older maternal age, Aboriginality, unemployment and diabetes are independent risk factors for one or more major adverse pregnancy outcomes. Smoking does not always worsen the outcome for hypertensive women except for SGA births.