Characteristics of suicidal outpatients with mood, anxiety and somatoform disorders: The role of childhood abuse and neglect.

BACKGROUND: The most prevalent psychiatric disorders are mood, anxiety and somatoform (MAS) disorders which show high mutual comorbidity, childhood trauma and elevated risk of suicidality. So far, no studies have compared suicide risk in a secondary care population with comorbid MAS disorders. This gap was taken as starting point for the study. AIMS: In comparing suicidal and non-suicidal MAS patients, the following was examined: suicide risk in the three disorder groups, socio-demographic and clinical characteristics, occurrence of childhood trauma types and contribution of childhood trauma to suicidality. METHODS: This cross-sectional study compared suicidal (n = 316) versus non-suicidal comorbid MAS outpatients (n = 929) by means of the Mini-International Neuropsychiatric Interview Plus (MINI-Plus), Brief Symptom Inventory (BSI), Short Form Health Survey 36 (SF-36), Dimensional Assessment of Personality Pathology-Short Form (DAPP-SF) and Childhood Trauma Questionnaire (CTQ). RESULTS: Compared to non-suicidal MAS patients, suicidal MAS patients mostly had mood disorders (single/comorbid), multiple diagnoses, worse functioning, more personality pathology (self-harm) and more childhood neglect and abuse. CONCLUSION: Especially (comorbid) depressed patients are at risk for suicide, and routine screening and monitoring of childhood trauma and suicidality in them are recommended, along with the timely deployment of appropriate trauma-focused psychotherapy.

A comparative analysis of personality pathology profiles among patients with pure depressive-, pure anxiety-, and pure somatoform disorders.

BACKGROUND: Depressive-, anxiety-, and somatoform disorders are among the most common psychiatric disorders. The assessment of comorbid personality pathology or traits in these disorders is relevant, because it can lead to the exacerbation of them or to poorer remission rates. To date, no research findings have been published on the comparison of these three prevalent patient groups with regard to comorbid dimensional personality pathology. METHODS: Data of participants (18-60 years) came from a web-based Routine Outcome Monitoring (ROM) programme. The present study used baseline data and was designed to compare personality pathology profiles between three separate outpatient groups: pure anxiety disorders (n=1633), pure depressive disorders (n=1794), and pure somatoform disorders (n=479). Personality pathology was measured with the Dimensional Assessment of Personality Pathology-Short Form (DAPP-SF). RESULTS: The pure depressive disorder group, in comparison to the other two disorder groups, exhibited the worst psychopathological and functional health image and most personality pathology. In the pure anxiety disorder group, the highest mean was found for the personality trait Anxiousness; and in the pure depressive disorder group for the traits Identity problems, Affective lability, Anxiousness, and Restricted expression. LIMITATIONS: The cross-sectional nature of the study limits the conclusions that can be drawn. CONCLUSIONS: The assessment of comorbid personality pathology in depressive-, anxiety-, somatoform disorders is clinically relevant, whether a patient has a personality disorder or not. This way, treatment could partly be focused on specific personality traits that may be counterproductive for treatment outcome, especially in depressive disorders.

The use of symptom dimensions to investigate the longitudinal effects of life events on depressive and anxiety symptomatology.

BACKGROUND: Findings on the association between life events and depression have been quite inconsistent. This could be due to the heterogeneity of traditionally used depression outcomes. The aim of this study was to investigate whether specific symptom dimensions can be used as an alternative to detect more specific life event effects. METHODS: Participants with/without psychiatric diagnoses were included (n=2252). Dimensions of the tripartite model (General Distress [GD], Anhedonic Depression [AD] and Anxious Arousal [AA]) were assessed at baseline, 1-year and 2-year follow-up. Life events occurring between measurements were assessed retrospectively. Longitudinal associations between life events and dimensional scores were analysed with Linear Mixed Models. RESULTS: Occurrence of negative life events was associated with increasing GD and AA, and less with AD. Positive life events were associated with decreasing GD and AD, but not with AA. The association between negative life events and AD was larger in the absence of previous psychiatric problems, lending support to a dimension-specific 'kindling' effect. Also, the negative association between negative life events and GD was stronger in those with high neuroticism. Multivariable analyses with individual life events showed that a few strong independent effects remained for each dimension. LIMITATIONS: Life event reports were retrospective; only three outcome dimensions were used. CONCLUSIONS: These results show that the effects of life events and modifying factors depend, to an extent, on the symptom domain that is considered as outcome, illustrating the need to account for symptom heterogeneity in etiological life event research.

High dose benzodiazepines prolong reaction times in chronic users who have major depressive and/or anxiety disorders.

AIM: Short term administration of benzodiazepines (BZD) was found to prolong reaction time (RT) in experimental studies. However, studies on long term BZD use did not always adjust for important confounders and showed inconsistent results. We aimed to identify a possible relationship between long term BZD use and RT in BZD users in this large cross-sectional, observational study. METHODS: The RTs of non-users (n = 2404) were compared with low (n = 288), intermediate (n = 74), and high dose BZD users (n = 57) in the Netherlands Study of Depression and Anxiety (NESDA). RTs were obtained from the Implicit Association Test. Analyses were adjusted for sociodemographic characteristics, health indicators, severity of psychopathology and antidepressant use. RESULTS: Of the NESDA participants, 419 subjects (14.8%) used BZDs. A higher dose of BZDs was associated with prolonged RTs (P = 0.01). When comparing the different dose groups, the high dose group, but not the low and medium dose groups, had significantly longer RTs than the non-users. CONCLUSIONS: Tolerance for the RT prolonging effect of relatively high doses of BZDs does not seem to develop. As prolonged RTs can have adverse consequences in daily life, BZDs should be prescribed conservatively at the lowest possible dose.

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.

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 ß = -.062 [p = .003] and ß = -.050 [p = .02], respectively) and an increase in waist circumference (adjusted ß = .060 [p = .01] and ß = .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.

The generalizability of psychotherapy efficacy trials in major depressive disorder: an analysis of the influence of patient selection in efficacy trials on symptom outcome in daily practice.

BACKGROUND: Treatment guidelines for major depressive disorder (MDD) are based on results from randomized clinical trials, among others in psychotherapy efficacy trials. However, patients in these trials differ from routine practice patients since trials use stringent criteria for patient selection. It is unknown whether the exclusion criteria used in psychotherapy efficacy trials (PETs) influence symptom outcome in clinical practice. We first explored which exclusion criteria are used in PETs. Second, we investigated the influence of commonly used exclusion criteria on symptom outcome in routine clinical practice. METHODS: We performed an extensive literature search in PubMed, PsycInfo and additional databases for PETs for MDD. From these, we identified commonly used exclusion criteria. We investigated the influence of exclusion criteria on symptom outcome by multivariate regression models in a sample of patients suffering from MDD according to the MINIplus from a routine clinical practice setting (n=598). Data on routine clinical practice patients were gathered through Routine Outcome Monitoring. RESULTS: We selected 20 PETs and identified the following commonly used exclusion criteria: 'a baseline severity threshold of HAM-D≤14', 'current or past abuse or dependence of alcohol and/or drugs' and 'previous use of medication or ECT'. In our routine clinical practice sample of patients suffering from MDD (n=598), presence of 'current or past abuse of or dependence on alcohol and/or drugs' had no significant influence on outcome.'Meeting a baseline severity threshold of HAM-D≤14' and 'previous use of medication or ECT' were associated with better outcome, but the explained variance of the models was very small (R2=2-11%). CONCLUSIONS: The most consistently used exclusion criteria are not a major threat to the generalizability of results found in PETs. However, PETs do somewhat improve their results by exclusion of patients with minor depression and patients who used antidepressants prior to psychotherapy.

Dimensions of the inventory of depressive symptomatology as predictors of the course of depressive and anxiety disorders.

For depressive and anxiety disorders general course characteristics are known. However, prognosis varies among patients with the same diagnosis. The current study investigated whether the more homogeneous symptom dimensions of mood/cognition and anxiety/arousal, could be used to predict more differentiated prognoses than with overall course-categories. One-thousand-and-fifty-three subjects with a depressive and/or anxiety disorder from the Netherlands Study of Depression and Anxiety (NESDA) were assessed at baseline and at 2-year follow-up. Dimensions of mood/cognition and anxiety/arousal were extracted from the Self Report Inventory of Depressive Symptomatology (IDS-SR). Diagnoses at baseline and follow-up were assessed with a standardized psychiatric interview. Course trajectories were assessed with a life chart interview. Increased mood/cognition scores predicted single depression (OR = 1.80) and comorbid depression-anxiety (OR = 2.00 [CI: 1.28-2.54]) at follow-up and unfavourable course trajectories of depressive symptomatology (OR = 1.94-2.08). Increased anxiety/arousal predicted single panic disorder at follow-up (OR = 2.21 [CI: 1.62-3.03]) and unfavourable course trajectories of anxiety symptomatology (OR = 1.38-1.42). All associations remained significant when adjusted for other prognostic factors, including baseline diagnosis. In conclusion, the widely used IDS-SR can be used to measure two dimensions that contribute prognostic value on top of other, previously known prognostic factors.

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.

Different gene sets contribute to different symptom dimensions of depression and anxiety.

Although many genetic association studies have been carried out, it remains unclear which genes contribute to depression. This may be due to heterogeneity of the DSM-IV category of depression. Specific symptom-dimensions provide a more homogenous phenotype. Furthermore, as effects of individual genes are small, analysis of genetic data at the pathway-level provides more power to detect associations and yield valuable biological insight. In 1,398 individuals with a Major Depressive Disorder, the symptom dimensions of the tripartite model of anxiety and depression, General Distress, Anhedonic Depression, and Anxious Arousal, were measured with the Mood and Anxiety Symptoms Questionnaire (30-item Dutch adaptation; MASQ-D30). Association of these symptom dimensions with candidate gene sets and gene sets from two public pathway databases was tested using the Global test. One pathway was associated with General Distress, and concerned molecules expressed in the endoplasmatic reticulum lumen. Seven pathways were associated with Anhedonic Depression. Important themes were neurodevelopment, neurodegeneration, and cytoskeleton. Furthermore, three gene sets associated with Anxious Arousal regarded development, morphology, and genetic recombination. The individual pathways explained up to 1.7% of the variance. These data demonstrate mechanisms that influence the specific dimensions. Moreover, they show the value of using dimensional phenotypes on one hand and gene sets on the other hand.

Personality traits and childhood trauma as correlates of metabolic risk factors: the Netherlands Study of Depression and Anxiety (NESDA).

OBJECTIVE: Personality and childhood trauma may affect cardiovascular disease (CVD) risk. However, evidence for an association with metabolic risk factors for CVD is limited and ambiguous. Moreover, despite their interrelatedness, personality and childhood trauma were not yet studied simultaneously. Therefore, we aimed to explore whether personality and childhood trauma are correlates of metabolic risk factors. METHODS: Among 2755 participants of the Netherlands Study of Depression and Anxiety (NESDA), we investigated through linear regression models whether Big Five personality traits (i.e., extraversion, openness, agreeableness, neuroticism and conscientiousness) and childhood trauma type (i.e., emotional neglect, and psychological, physical and sexual abuse) were correlates of metabolic risk factors (i.e., lipids, waist circumference (WC), glucose and blood pressure). Basic covariates (i.e., age, sex and income level), lifestyle, severity of depressive symptoms and years of education were taken into account. RESULTS: Openness was the most robust favorable correlate, and sexual abuse was the most robust unfavorable correlate of lipids and WC, and of overall metabolic risk (ß=-.070; p<.001 and ß=.035; p=.04, respectively). CONCLUSIONS: People with a low openness trait and those who experienced childhood sexual abuse are at higher risk of dyslipidemia and abdominal obesity.

Reliability and validity of the Global Assessment of Functioning Scale in clinical outpatients with depressive disorders.

RATIONALE, AIMS AND OBJECTIVES: The Global Assessment of Functioning Scale (GAF) is widely used to assess psychological, social and occupational functioning. The validity and reliability of the GAF in clinical practice have only scarcely been studied in naturalistic samples. METHODS: A total of 432 outpatients with a current major depressive disorder (MDD) were evaluated with routine outcome monitoring (ROM). At baseline the GAF score was assessed by the treating clinician and at ROM baseline and follow-up sessions also by a trained test nurse. Sociodemographic data, the Mini International Neuropsychiatric Interview Plus and scores on the Montgomery-Äsberg Depression Rating Scale, Beck Depression Inventory-revised, Brief Symptom Inventory and Short Form-36 were assessed. RESULTS: At baseline, the mean GAF score by the clinician was 54.8 (range 35-85), and this was systematically lower than the mean GAF score by the test nurse of 57.5 (range 31-88). GAF scores by the clinician and test nurse correlated weakly (r = 0.26). The GAF scores of the clinicians correlated strongly with disease severity, and social and physical functioning. CONCLUSION: The GAF showed rather poor inter-rater reliability as well as poor discriminant validity with disease severity and physical limitations in a large naturalistic sample of outpatients with MDD.

Symptom dimensions as predictors of the two-year course of depressive and anxiety disorders.

BACKGROUND: Because of the heterogeneity of known predictive factors, course-predictions for depression and anxiety are often unspecific. Therefore, it was investigated whether symptom-dimensions could be used as more specific course-predictors, on top of already known predictors, such as diagnosis and overall severity. METHODS: A sample of 992 subjects with depressive and/or anxiety disorders was followed in a 2-year prospective cohort study. Dimensions of the tripartite model (general distress, anhedonic depression and anxious arousal) were assessed at baseline. Diagnostic and course information were assessed at baseline and 2-year follow-up. RESULTS: Dimensional scores at baseline predicted diagnosis after two years and course-trajectories during follow-up. Increased general distress at baseline was associated with comorbid depression-anxiety at follow-up, increased anhedonic depression was associated with single depression and anxious arousal was associated with (comorbid) panic disorders at follow-up. Baseline general distress was associated with an unfavorable course in all patients. All associations were independent and added prognostic information on top of diagnosis and other predictive factors at baseline. LIMITATIONS: Only prevalent patients were included at baseline and only three dimensions were measured CONCLUSIONS: Symptom dimensions predict the future 2-year course of depression and anxiety. Importantly, the dimensions yield predictive information on top of diagnosis and other prognostic factors at baseline.

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 (Hedges's 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.

Determinants of initiated and continued benzodiazepine use in the Netherlands study of depression and anxiety.

BACKGROUND: Longitudinal research on determinants of initiated and continued benzodiazepine (BZD) use is inconsistent and has identified many possible determinants. It is unclear which of those are most important in the prediction of BZD use. We aimed to identify the most important predictors of initiated and continued BZD use. Therefore, we analyzed the most consistently identified determinants from previous research plus some new determinants. METHODS: We identified baseline and 2-year longitudinal predictors of initiated BZD use (vs nonuse) among 2205 baseline BZD nonusers and of continued use (vs discontinued use) among 369 baseline BZD users in the Netherlands Study of Depression and Anxiety using logistic regression analyses. RESULTS: During follow-up, BZD use was initiated by 4.9% of BZD nonusers at baseline. Initiated use was predicted by insomnia (odds ratio [OR], 1.60), enduring anxiety symptoms (OR, 2.02), entering secondary care during follow-up (OR, 2.85), and past BZD use (OR, 3.57). Positive life events during follow-up reduced the likelihood of BZD initiation (OR, 0.76). Of BZD users at baseline, 54.2% continued use during the entire follow-up period. Continuation of BZD use was predicted by higher age (OR, 1.03), severe anxiety (OR, 1.85), and a long duration of BZD use (OR, 1.54). Leaving secondary care was associated with less continued BZD use (OR, 0.29). CONCLUSION: Insomnia and anxiety were the main risk factors of initiated use, whereas advanced age and anxiety severity were the main risk factors of continued use. Sex, education, pain, and physical health seemed to be less important.

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.

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.

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 (ß=0.130) and chronic illnesses (ß=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.

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.

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.