Treatment Course Comparison Between Anxiety-Related Disorders in Adult Outpatients: A Leiden Routine Outcome Monitoring Study.

ABSTRACT: Anxiety-related disorders constitute the leading prevalent mental disorders, with major burden on patients, their relatives, and society. Moreover, there is considerable treatment nonadherence/nonresponse. We used routine outcome monitoring (ROM) data from outpatients covering four anxiety-related disorders ( DSM-IV-R , N = 470) to examine their 6-month treatment course and its predictors: generalized anxiety disorder, panic disorder with agoraphobia, obsessive-compulsive disorder, and posttraumatic stress disorder. Measures included Mini-International Neuropsychiatric Interview Plus, Brief Symptom Inventory (BSI), Montgomery-Åsberg Depression Rating Scale (MADRS), Brief Anxiety Scale (BAS), and Short Form Health Survey 36 (SF-36). On the clinician-rated instruments (MADRS/BAS), all anxiety-related disorder groups showed a significant albeit modest improvement after treatment. On the BSI self-rating, only generalized anxiety disorder and posttraumatic stress disorder showed a significant modest improvement. No anxiety-related disorder groups improved significantly regarding SF-36 physical functioning. For BSI symptom course, significant predictors were comorbid somatoform/total disorders, SF-36 physical functioning/general health, and MADRS score. Clinical implications and future research recommendations are discussed.

Development and psychometric evaluation of the Decision Tool Anxiety Disorders, OCD and PTSD (DTAOP): Facilitating the early detection of patients in need of highly specialized care.

BACKGROUND: Early identification of patients with an anxiety disorder, obsessive-compulsive disorder (OCD), or post-traumatic stress disorder (PTSD) in need of highly specialized care could facilitate the selection of the optimal initial treatment in these patients. This paper describes the development and psychometric evaluation of the Decision Tool Anxiety Disorders, OCD and PTSD (DTAOP), which aims to aid clinicians in the early identification of patients with an anxiety disorder, OCD, or PTSD in need of highly specialized mental healthcare. METHODS: A systematic literature review and a concept mapping procedure were carried out to inform the development of the DTAOP. To evaluate the psychometric properties of the DTAOP, a cross-sectional study in 454 patients with a DSM-IV-TR anxiety disorder was carried out. Feasibility was evaluated by the completion time and the content clarity of the DTAOP. Inter-rater reliability was assessed in a subsample of 87 patients. Spearman's rank correlation coefficients between the DTAOP and EuroQol five-dimensional questionnaire (EQ-5D-5L) scores were computed to examine the convergent validity. Criterion validity was assessed against independent clinical judgments made by clinicians. RESULTS: The average time required to complete the eight-item DTAOP was 4.6 min and the total DTAOP was evaluated as clear in the majority (93%) of the evaluations. Krippendorff's alpha estimates ranged from 0.427 to 0.839. Based on the qualitative feedback, item wording and instructions were improved. As hypothesized, the DTAOP correlated negatively with EQ-5D-5L scores. The area under the curve was 0.826 and the cut-off score of ≥4 optimized sensitivity (70%) and specificity (71%). CONCLUSIONS: The DTAOP demonstrated excellent feasibility and good validity, but weak inter-rater reliability. Based on the qualitative feedback and reliability estimates, revisions and refinements of the wording and instructions were made, resulting in the final version of the DTAOP.

Dynamic time warp analysis of individual symptom trajectories in depressed patients treated with electroconvulsive therapy.

BACKGROUND: Although electroconvulsive therapy (ECT) effectively improves severity scores of depression, its effects on its individual symptoms has scarcely been studied. We aimed to study which depressive symptom trajectories dynamically cluster together in individuals as well as groups of patients during ECT using Dynamic Time Warp (DTW) analysis. METHODS: We analysed the standardized weekly scores on the 25-item abbreviated version of the Comprehensive Psychopathological Rating Scale (CPRS) in depressed patients before and during their first six weeks of ECT treatment. DTW analysis was used to analyse the (dis)similarity of time series of items scores at the patient level (300 'DTW distances' per patient) as well as on the group level. Hierarchical cluster, network, and Distatis analyses yielded symptom dimensions. RESULTS: We included 133 patients, 64.7% female, with an average age of 60.4 years (SD 15.1). Individual DTW distance matrices and networks revealed marked differences in hierarchical and network clusters among patients. Based on cluster analyses of the aggregated matrices, four symptom clusters emerged. In patients who reached remission, the average DTW distance between their symptoms was significantly smaller than non-remitters, reflecting denser symptom networks in remitters than non-remitters (p=0.04). LIMITATIONS: The assessments were done only weekly during the first six weeks of ECT treatment. The use of individual items of the abbreviated CPRS may have led to measurement error as well as floor and ceiling effects. CONCLUSION: DTW offers an efficient new approach to analyse symptom trajectories within individuals as well as groups of patients, aiding personalized medicine of psychopathology.

The Leiden Family Lab study on Social Anxiety Disorder: A multiplex, multigenerational family study on neurocognitive endophenotypes.

OBJECTIVES: Social anxiety disorder (SAD) is a serious and prevalent psychiatric condition, with a heritable component. However, little is known about the characteristics that are associated with the genetic component of SAD, the so-called "endophenotypes". These endophenotypes could advance our insight in the genetic susceptibility to SAD, as they are on the pathway from genotype to phenotype. The Leiden Family Lab study on Social Anxiety Disorder (LFLSAD) is the first multiplex, multigenerational study aimed to identify neurocognitive endophenotypes of social anxiety. METHODS: The LFLSAD is characterized by a multidisciplinary approach and encompasses a variety of measurements, including a clinical interview, functional and structural magnetic resonance imaging and an electroencephalography experiment. Participants are family members from 2 generations, from families genetically enriched for SAD. RESULTS: The sample (n = 132 participants, from 9 families) was characterized by a high prevalence of SAD, in both generations (prevalence (sub)clinical SAD: 38.3%). Furthermore, (sub)clinical SAD was positively related to self-reported social anxiety, fear of negative evaluation, trait anxiety, behavioral inhibition, negative affect, and the level of depressive symptoms. CONCLUSIONS: By the multidimensional character of the measurements and thorough characterization of the sample, the LFLSAD offers unique opportunities to investigate candidate neurocognitive endophenotypes of SAD.

Behavioral and EEG responses to social evaluation: A two-generation family study on social anxiety.

Social anxiety disorder is an invalidating psychiatric disorder characterized by extreme fear and avoidance of one or more social situations in which patients might experience scrutiny by others. The goal of this two-generation family study was to delineate behavioral and electrocortical endophenotypes of social anxiety disorder related to social evaluation. Nine families of patients with social anxiety disorder (their spouse and children, and siblings of these patients with spouse and children) performed a social judgment paradigm in which they believed to be evaluated by peers. For each peer, participants indicated their expectation about the evaluative outcome, after which they received social acceptance or rejection feedback. Task behavior, as well as the feedback-related EEG brain potentials (N1, FRN, P3) and theta power were tested as candidate endophenotypes based on two criteria: co-segregation with social anxiety disorder within families and heritability. Results indicated that reaction time for indicating acceptance-expectations might be a candidate behavioral endophenotype of social anxiety disorder, possibly reflecting increased uncertainty or self-focused attention and vigilance during the social judgment paradigm. N1 in response to expected rejection feedback and P3 in response to acceptance feedback might be candidate electrocortical endophenotypes of social anxiety disorder, although the heritability analyses did not remain significant after correcting for multiple tests. Increased N1 possibly reflects hypervigilance to socially threatening stimuli, and increased P3 might reflect that positive feedback is more important for, and/or less expected by, participants with social anxiety disorder. Finally, increased feedback-related negativity and theta power in response to unexpected rejection feedback compared to the other conditions co-segregated with social anxiety disorder, but these EEG measures were not heritable. The candidate endophenotypes might play a new and promising role in future research on genetic mechanisms, early detection and/or prevention of social anxiety disorder.

Delta-beta correlation as a candidate endophenotype of social anxiety: A two-generation family study.

BACKGROUND: Social anxiety disorder (SAD) is characterized by an extreme and intense fear and avoidance of social situations. In this two-generation family study we examined delta-beta correlation during a social performance task as candidate endophenotype of SAD. METHODS: Nine families with a target participant (diagnosed with SAD), their spouse and children, as well as target's siblings with spouse and children performed a social performance task in which they gave a speech in front of a camera. EEG was measured during resting state, anticipation, and recovery. Our analyses focused on two criteria for endophenotypes: co-segregation within families and heritability. RESULTS: Co-segregation analyses revealed increased negative delta-low beta correlation during anticipation in participants with (sub)clinical SAD compared to participants without (sub)clinical SAD. Heritability analyses revealed that delta-low beta and delta-high beta correlation during anticipation were heritable. Delta-beta correlation did not differ between participants with and without (sub)clinical SAD during resting state or recovery, nor between participants with and without SAD during all phases of the task. LIMITATIONS: It should be noted that participants were seen only once, they all performed the EEG tasks in the same order, and some participants were too anxious to give a speech. CONCLUSIONS: Delta-low beta correlation during anticipation of giving a speech might be a candidate endophenotype of SAD, possibly reflecting increased crosstalk between cortical and subcortical regions. If validated as endophenotype, delta-beta correlation during anticipation could be useful in studying the genetic basis, as well as improving treatment and early detection of persons at risk for developing SAD.

A Validation Study of the Web Screening Questionnaire (WSQ) Compared With the Mini-International Neuropsychiatric Interview-Plus (MINI-Plus).

BACKGROUND: There is a need for brief screening methods for psychiatric disorders in clinical practice. This study assesses the validity and accuracy of a brief self-report screening questionnaire, the Web Screening Questionnaire (WSQ), in detecting psychiatric disorders in a study group comprising the general population and psychiatric outpatients aged 18 years and older. OBJECTIVE: The aim of this study was to investigate whether the WSQ is an adequate test to screen for the presence of depressive and anxiety disorders in clinical practice. METHODS: Participants were 1292 adults (1117 subjects from the general population and 175 psychiatric outpatients), aged 18 to 65 years. The discriminant characteristics of the WSQ were examined in relation to the ("gold standard") Mini-International Neuropsychiatric Interview-Plus (MINI-Plus) disorders, by means of sensitivity, specificity, area under the curve (AUC), and positive and negative predictive values (PPVs, NPVs). RESULTS: The specificity of the WSQ to individually detect depressive disorders, anxiety disorders, and alcohol abuse or dependence ranged from 0.89 to 0.97 for most disorders, with the exception of post-traumatic stress disorder (0.52) and specific phobia (0.73). The sensitivity values ranged from 0.67 to 1.00, with the exception of depressive disorder (0.56) and alcohol abuse or dependence (0.56). Given the low prevalence of separate disorders in the general population sample, NPVs were extremely high across disorders (≥0.97), whereas PPVs were of poor strength (range 0.02-0.33). CONCLUSIONS: In this study group, the WSQ was a relatively good screening tool to identify individuals without a depressive or anxiety disorder, as it accurately identified those unlikely to suffer from these disorders (except for post-traumatic stress disorders and specific phobias). However, in case of a positive WSQ screening result, further diagnostic procedures are required.

Long-term follow-up of psychogenic pseudosyncope.

OBJECTIVE: To determine the outcome of patients with psychogenic pseudosyncope (PPS) after communication of the diagnosis. METHODS: This was a retrospective cohort study of patients with PPS referred in 2007 to 2015 to a tertiary referral center for syncope. We reviewed patient records and studied attack frequency, factors affecting attack frequency, health care use, and quality of life using a questionnaire. We explored influences on attack freedom and attack frequency in the 6 months before follow-up for age, sex, education level, duration until diagnosis, probability of diagnosis, additional syncope, and acceptance of diagnosis. RESULTS: Forty-seven of 57 patients with PPS could be traced, of whom 35 (74%) participated. Twelve (34%) were attack-free for at least 6 months. The median time from diagnosis to follow-up was 50 months (range 6-103 months). Communicating and explaining the diagnosis resulted in immediate reduction of attack frequency (p = 0.007) from the month before diagnosis (median one attack, range 0-156) to the month after (median one attack, range 0-16). In the 6 months before follow-up, the number of admissions decreased from 19 of 35 to 0 of 35 (p = 0.002). The use of somatic and mental health care shifted toward the latter (p < 0.0001). Quality of life at follow-up (Short Form Health Survey 36) showed lower scores for 7 of 8 domains compared to matched Dutch control values; quality of life was not influenced by attack freedom. CONCLUSIONS: After communication of the diagnosis in PPS, attack frequency decreased and health care use shifted toward mental care. Low quality of life underlines that PPS is a serious condition.

Electroconvulsive therapy in the intensive care unit for the treatment of catatonia: a case series and review of the literature.

OBJECTIVE: Catatonia is an underdiagnosed syndrome that may occur in severely ill patients. The malignant subtype, consisting of motor symptoms, autonomic instability and fever, is associated with high mortality rates, though exact current mortality rates are unknown. This subtype requires a fast detection and treatment with high doses of a benzodiazepine or electroconvulsive therapy (ECT), preferably in an intensive care unit (ICU) setting. METHOD: Case series and qualitative literature review. RESULTS: This paper presents four patients admitted to the ICU of an academic hospital diagnosed with malignant catatonia. All patients received ECT after an ineffective trial of high-dose intravenous benzodiazepine treatment. The duration of ECT ranged from 6 to 23 treatments after which the catatonic features partially or fully remitted. In addition, we have reviewed the diagnostic challenges, neurobiology, possible causes, differential diagnosis and treatment options of catatonia, focusing on the treatment with ECT and the importance of detection and multidisciplinary collaboration. CONCLUSION: Malignant catatonia is an underdiagnosed, potentially life-threatening syndrome that requires fast recognition and prompt treatment, preferably in an ICU setting.

Dutch Translation and Psychometric Testing of the 9-Item Shared Decision Making Questionnaire (SDM-Q-9) and Shared Decision Making Questionnaire-Physician Version (SDM-Q-Doc) in Primary and Secondary Care.

PURPOSE: The SDM-Q-9 and SDM-Q-Doc measure patient and physician perception of the extent of shared decision making (SDM) during a physician-patient consultation. So far, no self-report instrument for SDM was available in Dutch, and validation of the scales in other languages has been limited. The aim of this study was to translate both scales into Dutch and assess their psychometric characteristics. METHODS: Participants were patients and their treating physicians (general practitioners and medical specialists). Patients (N = 182) rated their consultation using the SDM-Q-9, 43 physicians rated their consultations using the SDM-Q-Doc (N = 201). Acceptability, reliability (internal consistency), and the factorial structure of the instruments were determined. For convergent validity the CPSpost was used. RESULTS: Reliabilities of both scales were high (alpha SDM-Q-9 0.88; SDM-Q-Doc 0.87). The SDM-Q-9 and SDM-Q-Doc total scores correlated as expected with the CPSpost (SDM-Q-9: r = 0.29; SDM-Q-Doc: r = 0.48) and were significantly different between the CPSpost categories, with lowest mean scores when the physician made the decision alone. Principal Component Analyses showed a two-component model for each scale. A confirmatory factor analysis yielded a mediocre, but acceptable, one-factor model, if Item 1 was excluded; for both scales the best indices of fit were obtained for a one-factor solution, if both Items 1 and 9 were excluded. CONCLUSION: The Dutch SDM-Q-9 and SDM-Q-Doc demonstrate good acceptance and reliability; they correlated as expected with the CPSpost and are suitable for use in Dutch primary and specialised care. Although the best model fit was found when excluding Items 1 and 9, we believe these items address important aspects of SDM. Therefore, also based on the coherence with theory and comparability with other studies, we suggest keeping all nine items of the scale. Further research on the SDM-concept in patients and physicians, in different clinical settings and different countries, is necessary to gain a better understanding of the SDM-construct and its measurement.

Short-term effects of electroconvulsive therapy on subjective and actigraphy-assessed sleep parameters in severely depressed inpatients.

Background. Sleep disturbances are a key feature of major depression. Electroconvulsive treatment (ECT) may improve polysomnography-assessed sleep characteristics, but its short-term effects on actigraphy-assessed and subjective sleep characteristics are unknown. We therefore aimed to assess the effects of ECT on subjective and objective sleep parameters in a proof-of-principle study. Methods. We assessed subjective and objective sleep parameters in 12 severely depressed patients up to 5 consecutive days during their ECT course, corresponding to a total of 43 nights (including 19 ECT sessions). The 12 patients were 83% female and on average 62 (standard deviation (SD) 14) years old and had an average MADRS score of 40 at baseline (SD 21). Results. Subjective and objective sleep parameters were not directly affected by ECT. The subjective sleep efficiency parameter was similar on the day after ECT and other days. ECT did not affect the number of errors in the Sustained Attention to Response Task. Patients subjectively underestimated their total sleep time by 1.4 hours (P < 0.001) compared to actigraphy-assessed sleep duration. Conclusion. ECT did not affect subjective and actigraphy-assessed sleep in the short term. Depressed patients profoundly underestimated their sleep duration.

Economic Evaluation of Concise Cognitive Behavioural Therapy and/or Pharmacotherapy for Depressive and Anxiety Disorders.

BACKGROUND: Depressive and anxiety disorders cause great suffering and disability and are associated with high health care costs. In a previous conducted pragmatic randomised controlled trial, we have shown that a concise format of cognitive behavioural- and/or pharmacotherapy is as effective as standard care in reducing depressive and anxiety symptoms and in improving subdomains of general health and quality of life in secondary care psychiatric outpatients. AIMS OF THE STUDY: In this economic evaluation, we examined whether a favourable cost-utility of concise care compared to standard care was attained. METHODS: The economic evaluation was performed alongside a pragmatic randomised controlled trial. Health-related quality of life was measured using the Short-Form (SF-36) questionnaire. Cost of healthcare utilization and productivity loss (absenteeism and presenteeism) were assessed using the Trimbos/iMTA questionnaire for Costs associated with Psychiatric Illness (TiC-P). A cost-utility analysis, using cost-effectiveness acceptability curves, comparing differences in societal costs and Quality-Adjusted Life Years (QALYs) at 1 year was performed. RESULTS: One year after study entry, the difference in mean cost per patient of the two primary treatments was not significant between both groups. No significant differences in other healthcare and non- healthcare costs could be detected between patients receiving concise care and standard care. Also, QALYs were not statistically different between the groups during the study period. From both the societal and healthcare perspective, the probability that concise care is more cost-effective compared to standard care remains below the turning point of 0.5 for all acceptable values of the willingness to pay for a QALY. The economic evaluation suggests that concise care is unlikely to be cost-effective compared to standard care in the treatment for depressive- and anxiety disorders in secondary mental health care during a one year follow up period. DISCUSSION: Total costs and QALYs were not significantly different between standard and concise care, with no evidence for cost-effectiveness of concise care in the first year. The longer impact of concise care for patients with mild to moderate symptoms of depressive and/or anxiety disorders compared to standard care in secondary care needs to be further studied. IMPLICATIONS: This economic evaluation failed to find significant differences in cost between concise and standard care over the study period of one year. Replication of our economic evaluation might benefit from an extended follow-up period and strict adherence to the study protocol. If concise care will be found to be cost-effective in the long term, this would have major implications for recommendations how to optimize secondary mental health care in the treatment of depressive -- and anxiety disorders.

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.

A randomized controlled trial of the efficacy and cost-effectiveness of a brief intensified cognitive behavioral therapy and/or pharmacotherapy for mood and anxiety disorders: design and methods.

BACKGROUND: Anxiety and mood disorders involve a high disease burden and are associated with high economic costs. A stepped-care approach intervention and abbreviated diagnostic method are assumed to increase effectiveness and efficiency of the mental healthcare and are expected to reduce economic costs. METHODS: Presented are the rationale, design, and methods of a two-armed randomized controlled trial comparing 'treatment as usual' (TAU) with a brief intensified cognitive behavioral therapy (CBT) and/or pharmacotherapy. Eligible participants (N=500) of five Dutch outpatient Mental Healthcare Centers are randomly assigned to either TAU or to the experimental condition (brief CBT and/or pharmacotherapy). Data on patients' progress and clinical effectiveness of treatment are assessed at baseline, post-treatment (3 months after baseline), and at 6 and 12 months post-treatment by Routine Outcome Monitoring (ROM). Cost analysis is performed on the obtained data. DISCUSSION: Since few studies have investigated both the clinical and cost effectiveness of a stepped-care approach intervention and a shortened diagnostic ROM method in both anxiety and/or mood disorders within secondary mental health care, the results of this study might contribute to the improvement of (cost)-effective treatment options and diagnostic methods for these disorders.

Routine outcome monitoring and feedback on physical or mental health status: evidence and theory.

OBJECTIVES: Routine Outcome Monitoring (ROM) is an important quality tool for measuring outcome of treatment in health care. The objective of this article is to summarize the evidence base that supports the provision of feedback on ROM results to (mental) health care professionals and patients. Also, some relevant theoretical aspects are considered. METHODS: Literature study (Pubmed, Medline, PsychINFO, Embase Psychiatry, 1975-2009) concerning randomized controlled trials (RTC's) of ROM and feedback on physical or mental health status of patients of all ages. Main search terms were routine outcome monitoring/measurement, feedback, health status measurement, patient reported outcome measures. RESULTS: Included were 52 RCT's concerning ROM and feedback with adult or older patients: of these seven RCT's were exclusively focused on physical health and 45 RCT's (also) on the mental health of the patient, although not always in a mental health care setting or as primary outcome measure. There appears to be a positive impact of ROM on diagnosis and monitoring of treatment, and on communication between patient and therapist. Other results were less clear. There were no published RCT's on this topic with children or adolescents. CONCLUSIONS: ROM appears especially effective for the monitoring of patients who are not doing well in therapy. Further research into this topic and the clinical-and cost-effectiveness of ROM is recommended, especially in mental health care for both adults and children. Also, more theory-driven research is needed with relevant conceptualizations such as Feedback Intervention Theory, Therapeutic Assessment.

Basal cortisol levels in relation to dimensions and DSM-IV categories of depression and anxiety.

The Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV classification may fail to adequately distinguish neuroendocrine factors involved in the etiology of depressive and anxiety disorders. Continuous phenotypic dimensions may correlate better with underlying neuroendocrine dysregulations. We compared the categorical DSM-IV diagnoses with a dimensional approach in the same group of outpatients with depressive (n=36), anxiety (n=18), and comorbid depressive and anxiety (n=19) disorders, who were free of psychotropic medication, and in 36 healthy controls. The Mood and Anxiety Symptom Questionnaire (MASQ) was used to measure the three dimensions of the tripartite model, i.e., anhedonic depression, anxious arousal, and general distress. The salivary cortisol awakening response (CAR) (0, 30, 45, and 60 min after awakening), and diurnal cortisol decline (11:00 h, 15:00 h, 19:00 h, and 23:00 h) were analyzed for linear and nonlinear associations. The CAR showed statistically significant nonlinear relationships with two MASQ dimensions, i.e., anhedonic depression and general distress, but no differences between DSM-IV categories. The diurnal cortisol decline was linearly related to the MASQ dimensions anhedonic depression and general distress and significantly higher AUC(diurnal) levels and a steeper slope were found in depressive patients compared to controls using DSM-IV categories. The present study shows that linear and nonlinear associations with salivary cortisol are detected when using phenotypic dimensions and may be complementary to phenotypic DSM-IV categories when doing neuroendocrine research.

C-reactive protein polymorphisms are associated with the cortisol awakening response in basal conditions in human subjects.

Cortisol affects the acute-phase response, but it is unknown whether C-reactive protein (CRP), an acute-phase reactant, also affects hypothalamus?pituitary?adrenal axis activity. In the present study, associations were explored between CRP haplotypes with plasma CRP concentrations and basal salivary cortisol level. We included 266 physically healthy Caucasian subjects (103 females and 163 males) aged between 18 and 65 years of whom 94 had a psychiatric disorder in a genetic association study. Six tag single-nucleotide polymorphisms capturing the common genetic variation of the CRP gene were genotyped (i.e. rs2808628, rs2808630, rs1205, rs1800947, rs1417938, and rs3091244) to yield common CRP haplotypes. Plasma CRP concentrations, the salivary cortisol awakening response (CAR) (0, 30, 45, and 60?min after awakening), and the diurnal cortisol decline (11:00, 15:00, 19:00, and 23:00 h) were assessed for 2 days. rs2808628, rs1205, rs1417938, and rs3091244 showed expected associations not only with CRP concentrations, but also with salivary cortisol levels during the CAR. Five well-characterized CRP haplotypes were arranged in ascending order according to increasing CRP levels. There was an inverse linear association between CRP haplotypes and cortisol levels during the CAR, but no association with the diurnal cortisol decline. Hence, genetic variants in the CRP gene that are associated with lifetime plasma CRP levels were also associated with salivary cortisol levels after awakening, in basal, non-inflammatory conditions.

The effects of female reproductive hormones in generalized social anxiety disorder.

OBJECTIVE: Although generalized social anxiety disorder (gSAD) is more prevalent in women, the role of female reproductive hormones in gSAD has never been investigated. Therefore, our aim was to make a first inventory of the influence of female reproductive hormones on gSAD symptoms. METHOD: Female patients with gSAD who had previously participated in our research projects in the University Medical Center Utrecht and the Leiden University Medical Center were recruited. A self-report survey with questions on the influence of menarche, the periods of the menstrual cycle, oral contraceptive use, pregnancy, lactation, postpartum period, and menopause on gSAD symptoms was returned by 46% of 140 women suffering form gSAD. Non-parametric statistical tests were used to analyze the data. RESULTS: A subgroup of patients reported an influence of female hormonal cycle on gSAD symptoms. In this subgroup, statistical differences were found for the menstrual cycle and pregnancy. In the premenstrual period, patients reported more severe gSAD symptoms. During pregnancy symptoms decreased, but postpartum symptom severity returned to the same levels as before pregnancy. CONCLUSIONS: A subgroup of women with gSAD seemed vulnerable for the influences of gonadal hormones. Prospective research in women with gSAD, in which the gonadal hormones are assessed, is warranted.

Tryptophan depletion affects the autonomic stress response in generalized social anxiety disorder.

In generalized social anxiety disorder (gSAD), serotonergic dysfunctions are found, as well as abnormalities of the autonomic nervous system (ANS) in basal conditions and of the hypothalamic pituitary adrenal (HPA) axis in response to psychological challenges. These findings raise the question whether these phenomena are interrelated. Therefore we designed a study in which two groups with nine pair wise age and gender matched gSAD patients (total of 10 men and 8 women), who were successfully treated with a selective serotonin reuptake inhibitor (SSRI), underwent a tryptophan depletion challenge (TD) or a placebo condition. A TD procedure temporarily decreases serotonergic neurotransmission. In order to activate the stress system the TD/placebo challenge was combined with a public speaking task. We assessed ANS responses, as measured with the promising new marker salivary alpha-amylase (sAA), and HPA-axis responses, as measured with salivary cortisol. The most important result was that the TD group showed a significant larger sAA response to the public speaking task as compared to the placebo group, reflecting hyperresponsivity of the ANS in this group, whereas no differences were seen in cortisol responses. This suggests that in gSAD there is a vulnerability of the ANS more than the HPA-axis.

Salivary cortisol, serum lipids, and adiposity in patients with depressive and anxiety disorders.

Depressive and anxiety disorders are associated with an increased risk of cardiovascular disease. Chronic stress induces hypothalamus-pituitary-adrenal (HPA)-axis perturbations, which might subsequently induce atherogenic lipoprotein profiles and adiposity. The aim of the present study was to investigate the relationship between basal saliva cortisol levels and serum lipids and adiposity in psychiatric patients. Eight salivary cortisol samples (awakening; 30, 45, and 60 minutes after awakening; 11:00 AM, 3:00 PM, 7:00 PM, and 11:00 PM) on 2 consecutive days in medication-free outpatients with depressive and/or anxiety disorders (n = 72) and in healthy controls (n = 42) were used to derive 2 measures of HPA-axis function: basal cortisol concentrations (ie, area under the curve [AUC(cortisol)]) and circadian cortisol variability (variability(cortisol)). Index z scores were calculated for dyslipidemia (from serum triglycerides, inverse high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol) and adiposity (from body mass index and waist-to-hip ratio). Regression analyses were conducted to determine the contribution of AUC(cortisol) and variability(cortisol) in explaining the variance of, respectively, the lipid and adiposity index. Patients showed a higher mean AUC(cortisol) compared with healthy controls (t = 2.7, P = .01). Both cortisol parameters were independently associated with dyslipidemia in patients after adjustment for age, alcohol use, and smoking habits (beta = .31, P = .02 and beta = -.29, P = .02, respectively), but not in controls. Cortisol measures were not associated with adiposity in either group. We conclude that elevated basal cortisol concentrations and lower circadian cortisol variability were independently associated with a less favorable lipoprotein profile in patients with depressive and/or anxiety disorders. These data lend support to the hypothesis that the relationship between affective disorders and cardiovascular disease is partly mediated by HPA-axis perturbations.