Tineke van Veen

Biomarkers in burnout: A systematic review

BACKGROUND Burnout is a stress state characterized by symptoms of mental exhaustion and physical fatigue, detachment from work, and feelings of diminished competence. Several biomarkers have been tested for association with burnout, but the results are conflicting. AIM The objective of this review was to identify potential biomarkers for burnout. METHODS We carried out a systematic review of studies comparing biomarkers in individuals with burnout and healthy controls, or individuals with low scores and those with high scores on burnout questionnaires. Literature searches in MEDLINE and EMBASE were performed. We describe biomarkers on which at least three studies were available. Where appropriate, a meta-analysis was carried out. RESULTS We identified 31 studies on 38 biomarkers involved in the hypothalamus-pituitary-adrenal axis, autonomic nervous system, immune system, metabolic processes, antioxidant defense, hormones, and sleep. At least 3 studies were available for cortisol in saliva and blood, blood pressure, heart rate, cholesterol, dehydroepiandrosterone sulfate, (numbers or activity of) natural killer cells, C-reactive protein, and prolactin. The comparability of studies was limited, due to differences in the methods used to characterize patients and controls, to assess biomarkers, and to control for confounders. Furthermore, burnout was operationalized in different ways. Meta-analyses showed no differences for cortisol awakening response and cortisol awakening response after administration of dexamethasone, cortisol in blood, and blood pressure. CONCLUSIONS No potential biomarkers for burnout were found, largely due to the incomparability of studies. We emphasize the need for a dimensional and longitudinal approach in future research to account for the heterogeneity of burnout.

Adulthood trauma and HPA-axis functioning in healthy subjects and PTSD patients: a meta-analysis.

BACKGROUND Hypothalamic-pituitary-adrenal (HPA)-axis dysregulation has inconsistently been associated with posttraumatic stress disorder (PTSD). Yet, trauma exposure rather than PTSD may be responsible for HPA-axis dysregulation. In two meta-analyses, we assessed the association of adulthood trauma exposure and HPA-axis functioning in healthy subjects with and without PTSD. METHOD A literature search in Pubmed and PsychInfo, using keywords and MeSH terms such as cortisol, emotional trauma, and PTSD, was performed. Only studies that included mentally healthy trauma-exposed (TE) individuals as well as non-exposed (NE) healthy individuals and/or PTSD patients (PTSD) were selected. This resulted in 1511 studies of which ultimately, 37 studies (21 TE versus NE and 34 TE versus PTSD, N=2468) were included. Methodological quality of all studies was assessed according to specific quality criteria. Pooled effect sizes (Hedgess g) on cortisol levels were compared. For all analyses, random effect models were used. RESULTS Cortisol levels were neither significantly different between TE versus NE subjects (-0.029; 95%CI: -0.145; 0.088) nor between TE subjects versus PTSD patients (0.175; 95%CI: -0.012; -0.362). Subgroup analyses showed an increased cortisol suppression after the low dose dexamethasone suppression test (DST) in TE versus NE subjects (-0.509; 95%CI: -0.871; -0.148). This meta-analysis was limited by the fact that lifetime psychiatric illness and childhood trauma were not an exclusion criterion in all 37 studies. CONCLUSION Neither adulthood trauma exposure nor PTSD were associated with differences in HPA-axis functioning, although adulthood trauma may augment cortisol suppression after the DST. More evidence on other dynamic tests of HPA-axis functioning in PTSD and adulthood trauma exposure is needed.

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.

Effects of childhood trauma on HPA-axis reactivity in women free of lifetime psychopathology.

Exposure to childhood trauma may induce persistent changes in Hypothalamic-Pituitary-Adrenal (HPA)-axis functioning even in the absence of current psychopathology. Because previous studies did not systematically exclude subjects with lifetime psychiatric morbidity, prevalent psychopathology may have confounded the association. In this study we investigated whether women exposed to childhood trauma, but without a history of psychiatric disorders, show alterations in HPA-axis functioning. We included 10 women exposed to significant childhood trauma and 12 non-exposed women. All women were between 29 and 64 years old,mentally and physically healthy, and without current or lifetime psychopathology. HPA-axis functioning was assessed as 1) basal activity with salivary cortisol patterns over 8 time points on two consecutive sampling days and 2) plasma cortisol and adrenocorticotropic hormone (ACTH) reactivity over 7 time points after the combined dexamethasone/corticotropin-releasing hormone (dex/CRH) challenge test. Basal salivary cortisol output did not differ between trauma-exposed compared to non-exposed women. Significantly blunted plasma cortisol and ACTH responses in response to dex/CRH administration were found in the trauma exposed compared to the non-exposed women (F(1,20)=5.08, p=0.04 and F(1,20)=5.23, p=0.03 respectively). Adjusting for age, body mass index (BMI), oral contraceptive use, and menopausal status,somewhat weakened the associations for cortisol as well as ACTH (F(1,16)=3.30, p=0.09) and F(1,16)=2.17, p=0.16 respectively), but for cortisol absolute differences in point estimates were largely unaffected.Although basal cortisol patterns were similar in the two groups, exposure to childhood trauma seemed to be related to a blunted HPA-axis reactivity in women who were free of current or lifetime psychopathology.

Associations Between Serum Lipids and Major Depressive Disorder: Results From the Netherlands Study of Depression and Anxiety (NESDA)

BACKGROUND Several studies have suggested an association between lipids or lipoproteins and depression, but findings are contradictory. However, previous studies did not always take into consideration potentially mediating factors or heterogeneity of symptoms, which may clarify contradicting findings. METHOD We compared levels of serum total, low-density lipoprotein (LDL), and high-density lipoprotein (HDL) cholesterol and triglyceride between 761 subjects with current major depressive disorder (MDD) (Composite International Diagnostic Interview, based on the DSM-IV), 1,071 subjects with remitted MDD, and 629 controls, aged 18 to 65 years. Subjects participated in the baseline assessment of the Netherlands Study of Depression and Anxiety, which lasted from September 2004 to February 2007. We studied the impact of adjustment for sociodemographics, lifestyle-related covariates, and antidepressant use and examined the association between specific psychopathological characteristics and lipid/lipoprotein levels. RESULTS HDL cholesterol level was lower (P = .007) and triglyceride level was higher (P = .001) in current MDD versus remitted MDD and controls. After adjustment for level of education, body mass index (BMI), smoking status, and alcohol use, dissimilarities lost statistical significance. Depression severity, comorbid dysthymia, and melancholic and atypical features were all associated with lipids/lipoproteins, but most associations attenuated after adjustment for covariates, especially BMI. The association between melancholic features and lower HDL cholesterol (P = .038) and between atypical depression and higher total and LDL cholesterol (P = .004 and P = .002, respectively) persisted after full adjustment. CONCLUSIONS Adverse lipoprotein patterns were found in patients with MDD. The fact that these associations diminished after adjustment for lifestyle-related factors, especially BMI, suggests that the unfavorable lipid/lipoprotein pattern among depressed subjects is mainly secondary to lifestyle-related factors. However, melancholic features were independently associated with lower HDL cholesterol, and atypical depression was independently associated with higher total and LDL cholesterol.

Development and validation of a 30-item short adaptation of the Mood and Anxiety Symptoms Questionnaire (MASQ)

The original Mood and Anxiety Symptoms Questionnaire (MASQ) is a 90-item self-report, designed to measure the dimensions of Clark and Watsons tripartite model. We developed and validated a 30-item short adaptation of the MASQ: the MASQ-D30, which is more suitable for large-scale psychopathology research and has a clearer factor structure. The MASQ-D30 was developed through a process of item reduction and grouping of the appropriate subscales in a sample of 489 psychiatric outpatients, using a validated Dutch translation, based on the original English MASQ, as a starting point. Validation was done in two other large samples of 1461 and 2471 subjects, respectively, with an anxiety, somatoform and/or depression diagnosis or no psychiatric diagnosis. Psychometric properties were investigated and compared between the MASQ-D30 and the full (adapted) MASQ. A three-dimensional model (negative affect, positive affect and somatic arousal) was found to represent the data well, indicating good construct validity. The scales of the MASQ-D30 showed good internal consistency (all alphas>0.87) in patient samples. Correlations of the subscales with other instruments indicated acceptable convergent validity. Psychometric properties were similar for the MASQ-D30 and the full questionnaire. In conclusion, the MASQ-D30 is a valid instrument to assess dimensional aspects of depression and anxiety and can easily be implemented in psychopathology studies.

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 β 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.

Correlates of (inappropriate) benzodiazepine use: the Netherlands Study of Depression and Anxiety (NESDA)

AIM Results on determinants of benzodiazepine (BZD) use in general and inappropriate use were inconsistent and mostly univariate. The relative importance of sociodemographic, psychological and physical determinants has never been investigated in a comprehensive, multivariate model. METHODS We included 429 BZD users and 2423 non-users from the Netherlands Study of Depression and Anxiety (NESDA) in order to investigate sociodemographic, psychological and physical determinants of BZD use and inappropriate use by logistic and linear regression analyses. RESULTS BZDs were used by a considerable proportion of the 2852 NESDA participants (15.0%). BZD use was independently associated with older age, singleness, unemployment, treatment in secondary care, higher medical consumption (more severe) anxiety, depression (OR [95% CI]=1.95 [1.29, 2.93]), comorbidity, insomnia, SSRI (OR [95% CI]=2.05 [1.55, 2.70]), TCA and other antidepressant (OR [95% CI]=2.44 [1.64, 3.62]) use. Overall, BZD use was rarely in accordance with all guidelines, mainly because most users (82.5%) exceeded the recommended duration of safe use. Inappropriate use was independently associated with older age (β=0.130) and chronic illnesses (β=0.120). Higher scores on agreeableness were associated with less inappropriate use. CONCLUSIONS Mentally or physically vulnerable subjects were most likely to use BZDs. The most vulnerable (i.e. the old and physically ill) BZD users were at highest risk of inappropriate BZD use. Without further evidence of the effectiveness of BZDs in long-term use, caution in initiating BZD prescriptions is recommended, particularly when patients are chronically ill and old, as those are most likely to display inappropriate use.

Longitudinal Relationship of Depressive and Anxiety Symptoms With Dyslipidemia and Abdominal Obesity

Objective Previous research indicates that patients with severe symptoms of depression or anxiety are prone toward the development of dyslipidemia and abdominal obesity. We sought to study these associations longitudinally. Methods Among 2126 Netherlands Study of Depression and Anxiety participants, we studied whether severity of depressive (Inventory of Depressive Symptoms) or anxiety (Beck Anxiety Inventory) symptoms at baseline was associated with changes in lipids (i.e., total, high-density lipoprotein [HDL] or low-density lipoprotein cholesterol, and triglycerides) or waist circumference during a 2-year follow-up period. We also examined whether changes in severity of symptoms were associated with changes in lipid or waist circumference levels over these 2 years. Multivariate linear regression analyses were adjusted for age, sex, education, and tobacco consumption. Results Baseline symptoms of depression or anxiety predicted a decrease in HDL cholesterol (adjusted &bgr; = −.062 [p = .003] and &bgr; = −.050 [p = .02], respectively) and an increase in waist circumference (adjusted &bgr; = .060 [p = .01] and &bgr; = .053 [p = .02], respectively) for 2 years. Reduction of symptoms of depression or anxiety over time did not coincide with an amelioration of lipid or waist circumference values. Conclusions People with initially severe symptoms of depression or anxiety showed a subsequent decrease in HDL cholesterol levels and an increase in abdominal obesity over time, independent of a potential reduction in symptom severity in this period. Therefore, such people are at elongated and increasing risk for dyslipidemia and obesity, predisposing them to cardiovascular disease.

Efficacy versus Effectiveness: A Direct Comparison of the Outcome of Treatment for Mild to Moderate Depression in Randomized Controlled Trials and Daily Practice

Background: Results from randomized controlled trials (RCTs) are considered to give the most reliable information on treatment outcome (efficacy). Yet, the generalizability of efficacy results to daily practice (effectiveness) might be diminished by the design of RCTs. The STAR*D trial approached daily practice as much as possible, but still has some properties of an RCT. In this study, we compare results from treatment of major depressive disorder (MDD) in routine clinical practice to those of RCTs and STAR*D. Methods: Effectiveness in routine clinical practice was compared with efficacy results from 15 meta-analyses on antidepressant, psychotherapeutic and combination treatment and results from STAR*D. Data on daily practice patients and treatments were derived from a routine outcome monitoring (ROM) system. Treatment outcome was defined as proportion of remitters (MADRS ≤10) and within-group effect size. Results: From ROM, 598 patients suffering from a MDD episode according to the MINI-plus were included. Remission percentages were lower in routine practice than in meta-analyses for all treatment modalities (32 vs.40–74%). Differences were less explicit for antidepressants (21 vs. 34–47%) than for individual psychotherapy (27 vs. 34–58%; effect size 0.85 vs. 1.71) and combination therapy (21 vs. 45–63%), since only 60% of the meta-analyses for antidepressants showed significant differences with ROM, while for psychotherapy and combination treatment almost all meta-analyses showed significant differences. No differences in effectiveness were found between routine practice and STAR*D (antidepressants 27 vs. 28%; individual psychotherapy 27 vs. 25%; combination treatment 21 vs. 23%, respectively). Conclusions: Effectiveness of treatment for mild-to-moderate MDD in daily practice is similar to STAR*D and significantly lower than efficacy results from RCTs.