Long-term disability in anxiety disorders.

BACKGROUND: This longitudinal study aims to investigate differences in long-term disability between social anxiety disorder (SAD), panic disorder with agoraphobia (PDA), panic disorder without agoraphobia (PD), generalized anxiety disorder (GAD) and multiple anxiety disorders (multiple AD), focusing on the effects of different course trajectories (remission, recurrence and chronic course) and specific symptom dimensions (anxiety arousal and avoidance behaviour). METHODS: Data were used from participants with no psychiatric diagnosis (healthy controls, n = 647) or with a current anxiety disorder (SAD, n = 191; PDA, n = 90; PD, n = 84; GAD, n = 110; multiple AD, n = 480). Severity of anxiety arousal and avoidance behaviour symptoms was measured using the Beck Anxiety Inventory and the Fear Questionnaire. The World Health Organization Disability Assessment Schedule II was used to measure disability. RESULTS: Long-term disability was most prevalent in participants with SAD and multiple AD, and lowest in PDA and PD. GAD had an intermediate position. Anxiety arousal and avoidance behaviour were associated with more long-term disability in anxiety disorders than course trajectories. CONCLUSIONS: Various anxiety disorders have different disability levels over 4 years of time, therefore diagnostic distinction is important for treatment focus. Anxiety arousal and avoidance behaviour are major predictors for long-term disability in anxiety disorders.

The association between depressive disorder and cardiac autonomic control in adults 60 years and older.

BACKGROUND: Altered cardiac autonomic control has often been reported in depressed persons and might play an important role in the increased risk for cardiovascular disease (CVD). A negative association between cardiac autonomic control and depression might become specifically clinically relevant in persons 60 years or older as CVD risk increases with age. METHODS: This study included data of 321 persons with a depressive disorder and 115 controls participating in the Netherlands Study of Depression in Older Persons (mean age = 70.3 years, 65.7% female). Respiratory sinus arrhythmia (RSA), heart rate (HR), and preejection period (PEP) were measured and compared between depressed persons and controls. In addition, the role of antidepressants and clinical characteristics (e.g., age of depression onset and comorbid anxiety) was examined. RESULTS: Compared with controls, depressed persons had lower RSA (mean [standard error of the mean] = 23.5 [1.2] milliseconds versus 18.6 [0.7] milliseconds, p = .001, d = 0.373) and marginally higher HR (73.1 [1.1] beats/min versus 75.6 [0.6] beats/min, p = .065, d = 0.212), but comparable PEP (113.9 [2.1] milliseconds versus 112.0 [1.2] milliseconds, p = .45, d = 0.087), fully adjusted. Antidepressants strongly attenuated the associations between depression and HR and RSA. Antidepressant-naïve depressed persons had similar HR and RSA to controls, whereas users of antidepressants showed significantly lower RSA. In addition, tricyclic antidepressant users had higher HR (p < .001, d = 0.768) and shorter PEP (p = .014, d = 0.395) than did controls. CONCLUSIONS: Depression was not associated with cardiac autonomic control, but antidepressants were in this sample. All antidepressants were associated with low cardiac parasympathetic control and specifically tricyclic antidepressants with high cardiac sympathetic control.

Disorder-specific cognitive profiles in major depressive disorder and generalized anxiety disorder.

BACKGROUND: This investigation examines differences in cognitive profiles in subjects with major depressive disorder (MDD) and generalized anxiety disorder (GAD). METHODS: Data were used from subjects with current MDD (n = 655), GAD (n = 107) and comorbid MDD/GAD (n = 266) diagnosis from the Netherlands Study of Depression and Anxiety (NESDA). The Composite Interview Diagnostic Instrument was used to diagnose MDD and GAD. Cognitive profiles were measured using the Leiden Index of Depression Sensitivity, the Anxiety Sensitivity Index, and the Penn State Worry Questionnaire. RESULTS: Results showed that differences in cognitive profiles between single MDD and single GAD subjects were present: scores on hopelessness/suicidality and rumination were significantly higher in MDD than GAD, whereas anxiety sensitivity for physical concerns and pathological worry were higher in GAD than MDD. The cognitive profile of comorbid MDD/GAD showed more extreme depression cognitions compared to single disorders, and a similar anxiety profile compared to single GAD subjects. CONCLUSIONS: Despite the commonalities in cognitive profiles in MDD and GAD, there are differences suggesting that MDD and GAD have disorder-specific cognitive profiles. Findings of this investigation give support for models like the cognitive content-specificity model and the tripartite model and could provide useful handles for treatment focus.

Two-year course of anxiety disorders: different across disorders or dimensions?

OBJECTIVE: This study compares diagnostic and symptom course trajectories across different anxiety disorders, and examines the role of anxiety arousal vs. avoidance behaviour symptoms in course prediction. METHOD: Data were from 834 subjects with a current anxiety disorder from the Netherlands Study of Depression and Anxiety (NESDA) who were re-interviewed after 2 years. DSM-IV-based diagnostic interviews and Life Chart Interviews (LCI) were used to assess the diagnostic and symptom course trajectory over 2 years. Anxiety arousal and avoidance behaviour symptoms were measured with LCI, Beck Anxiety Inventory and Fear Questionnaire. RESULTS: Prognosis varied across disorders, with favourable remittance rates of 72.5% for panic disorder without agoraphobia and 69.7% for generalized anxiety disorder; gradually declining to 53.5% for social phobia and 52.7% for panic disorder with agoraphobia. Only 42.9% of those with multiple anxiety disorder remitted, and this group showed a more chronic course than pure anxiety disorders. Both baseline duration and severity were course predictors. Avoidance behaviour symptoms predicted the outcome better than anxiety arousal symptoms. CONCLUSIONS: These data suggest that the specific anxiety disorders such as recognized by DSM-IV are useful in predicting the outcome and that this may be determined largely by the relative severity of avoidance behaviour that patients have developed.

Association between anxiety disorders and heart rate variability in The Netherlands Study of Depression and Anxiety (NESDA).

OBJECTIVE: To determine whether patients with different types of anxiety disorder (panic disorder, social phobia, generalized anxiety disorder) have higher heart rate and lower heart rate variability compared with healthy controls in a sample that was sufficiently powered to examine the confounding effects of lifestyle and antidepressants. METHODS: The standard deviation of the normal-to-normal intervals (SDNN), heart rate (HR), and respiratory sinus arrhythmia (RSA) were measured in 2059 subjects (mean age = 41.7 years, 66.8% female) participating in The Netherlands Study of Depression and Anxiety (NESDA). Based on the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV) and Composite International Diagnostic Interview (CIDI), NESDA participants were classified as healthy controls (n = 616), subjects with an anxiety diagnosis earlier in life (n = 420), and subjects with current anxiety diagnosis (n = 1059). RESULTS: Current anxious subjects had a significantly lower SDNN and RSA compared with controls. RSA was also significantly lower in remitted anxious subjects compared with controls. These associations were similar across the three different types of anxiety disorders. Adjustment for lifestyle had little impact. However, additional adjustment for antidepressant use reduced all significant associations between anxiety and HRV to nonsignificant. Anxious subjects who used a tricyclic antidepressant, a selective serotonin reuptake inhibitor, or another antidepressant showed significantly lower mean SDNN and RSA compared with controls (effect sizes = 0.20-0.80 for SDNN and 0.42-0.79 for RSA). Nonmedicated anxious subjects did not differ from controls in mean SDNN and RSA. CONCLUSION: This study shows that anxiety disorders are associated with significantly lower HR variability, but the association seems to be driven by the effects of antidepressants.

Long-term work disability and absenteeism in anxiety and depressive disorders.

BACKGROUND: This longitudinal study aims to compare long-term work disability and absenteeism between anxiety and depressive disorders focusing on the effects of different course trajectories (remission, recurrence and chronic course) and specific symptom dimensions (anxiety arousal, avoidance behaviour and depressive mood). METHODS: We included healthy controls, subjects with a history of - and current anxiety and/or depressive disorders with a paid job (n=1632). The Composite International Diagnostic Interview was used to diagnose anxiety and depressive disorders and to assess course trajectories at baseline, over 2 and 4 years. The World Health Organization Disability Assessment Schedule II and the Health and Labour Questionnaire Short Form were used to measure work disability and absenteeism. Symptom dimensions were measured using the Beck Anxiety Inventory, the Fear Questionnaire and the Inventory for Depressive Symptomatology. RESULTS: A history of - and current anxiety and/or depressive disorders were associated with increasing work disability and absenteeism over 4 years, compared to healthy controls. Long-term work disability and absenteeism were most prominent in comorbid anxiety-depressive disorder, followed by depressive disorders, and lowest in anxiety disorders. A chronic course, anxiety arousal and depressive mood were strong predictors for long-term work disability while baseline psychiatric status, a chronic course and depressive mood were strong predictors for long-term work absenteeism. LIMITATIONS: Results cannot be generalized to other anxiety disorders, such as obsessive compulsive disorder, posttraumatic stress disorder and specific phobias. Self-reported measures of work disability and absenteeism were used. CONCLUSIONS: Our results demonstrate that depressive syndromes and symptoms have more impact on future work disability and absenteeism than anxiety, implying that prevention of depression is of major importance.

The Association between IGF-1 Polymorphisms, IGF-1 Serum Levels, and Cognitive Functions in Healthy Adults: The Amsterdam Growth and Health Longitudinal Study.

Several studies have demonstrated an association between polymorphisms in the insulin-like growth factor-1 (IGF-1) gene and IGF-1 serum levels. IGF-1 levels have been associated with cognitive functioning in older persons and growth hormone deficient patients. The present study investigates whether IGF-1 polymorphisms, IGF-1 levels, and cognition are interconnected in healthy adults. Data of 277 participants (mean age: 42.4 years) of the Amsterdam Growth and Health Longitudinal Study on IGF-1 promoter polymorphisms, IGF-1 serum level, spatial working memory (SWM), paired associate learning (PAL), and IQ tests were analyzed. (M)ANOVAs were applied to confirm the associations between IGF-1 polymorphisms and IGF-1 levels and between IGF-1 levels and cognition. Three groups were distinguished based on specific IGF-1 polymorphism alleles: a homozygote 192 bp/192 bp genotype, a heterozygote 192 bp/x genotype, and a noncarrier x/x genotype. Although different IGF-1 levels were found for the three genotypes, performance on all cognitive tasks and IQ measures was similar. Despite the associations between IGF-1 polymorphisms and IGF-1 levels, no association was found between cognition and IGF-1 levels. It seems that IGF-1 does not play a role in the cognitive performance of healthy middle-aged adults. Possible, IGF-1 fulfills a more developmental and protective role in cognition which becomes apparent during childhood, old-age, or disease.

Disability in anxiety disorders.

BACKGROUND: This study compares disability levels between different anxiety disorders and healthy controls. We further investigate the role of anxiety arousal and avoidance behaviour in disability, and whether differences in these symptom patterns contribute to disability differences between anxiety disorders. METHODS: Data were from 1826 subjects from the Netherlands Study of Depression and Anxiety (NESDA). The Composite Interview Diagnostic Instrument was used to diagnose anxiety disorders. The World Health Organization Disability Assessment Schedule II was used to measure disability in six domains (cognition, mobility, selfcare, social interaction, life activities, participation). Severity of anxiety arousal and avoidance behaviour symptoms was measured using the Beck Anxiety Inventory and the Fear Questionnaire. RESULTS: All anxiety disorders were associated with higher disability. Disability was generally highest in multiple anxiety disorder (e.g. mean disability in cognition=33.7) and social anxiety disorder (mean=32.7), followed by generalized anxiety disorder (mean=27.2) and panic disorder with agoraphobia (mean=26.3), and lowest in panic disorder without agoraphobia (mean=22.1). Anxiety arousal was more associated with disability in life activities (B=8.5, p<0.001) and participation (B=9.9, p<0.001) whereas avoidance behaviour was more associated with disability in cognition (B=7.4, p<0.001) and social interaction (B=8.6, p<0.001). Different disability patterns between anxiety disorders were not completely explained by anxiety arousal and avoidance behaviour. LIMITATIONS: The cross-sectional study design precludes any causal interpretations. In order to examine the full range of comorbidity among anxiety, a greater range of anxiety disorders would have been preferable. CONCLUSIONS: Disability is highest in social anxiety disorder and multiple anxiety disorder. Both anxiety arousal and avoidance behaviour are associated with higher disability levels but do not fully explain the differences across anxiety disorders.

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.

Identifying genetic variants for heart rate variability in the acetylcholine pathway.

Heart rate variability is an important risk factor for cardiovascular disease and all-cause mortality. The acetylcholine pathway plays a key role in explaining heart rate variability in humans. We assessed whether 443 genotyped and imputed common genetic variants in eight key genes (CHAT, SLC18A3, SLC5A7, CHRNB4, CHRNA3, CHRNA, CHRM2 and ACHE) of the acetylcholine pathway were associated with variation in an established measure of heart rate variability reflecting parasympathetic control of the heart rhythm, the root mean square of successive differences (RMSSD) of normal RR intervals. The association was studied in a two stage design in individuals of European descent. First, analyses were performed in a discovery sample of four cohorts (n = 3429, discovery stage). Second, findings were replicated in three independent cohorts (n = 3311, replication stage), and finally the two stages were combined in a meta-analysis (n = 6740). RMSSD data were obtained under resting conditions. After correction for multiple testing, none of the SNPs showed an association with RMSSD. In conclusion, no common genetic variants for heart rate variability were identified in the largest and most comprehensive candidate gene study on the acetylcholine pathway to date. Future gene finding efforts for RMSSD may want to focus on hypothesis free approaches such as the genome-wide association study.

Dysregulation of the autonomic nervous system predicts the development of the metabolic syndrome.

CONTEXT: Stress is suggested to lead to metabolic dysregulations as clustered in the metabolic syndrome. Although dysregulation of the autonomic nervous system is found to associate with the metabolic syndrome and its dysregulations, no longitudinal study has been performed to date to examine the predictive value of this stress system in the development of the metabolic syndrome. OBJECTIVE: We examined whether autonomic nervous system functioning predicts 2-year development of metabolic abnormalities that constitute the metabolic syndrome. DESIGN: Data of the baseline and 2-year follow-up assessment of a prospective cohort: the Netherlands Study of Depression and Anxiety was used. SETTING: Participants were recruited in the general community, primary care, and specialized mental health care organizations. PARTICIPANTS: A group of 1933 participants aged 18-65 years. MAIN OUTCOME MEASURES: The autonomic nervous system measures included heart rate (HR), respiratory sinus arrhythmia (RSA; high RSA reflecting high parasympathetic activity), pre-ejection period (PEP; high PEP reflecting low sympathetic activity), cardiac autonomic balance (CAB), and cardiac autonomic regulation (CAR). 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 (HDL) cholesterol. RESULTS: Baseline short PEP, low CAB, high HR, and CAR were predictors of an increase in the number of components of the metabolic syndrome during follow-up. High HR and low CAB were predictors of a 2-year decrease in HDL cholesterol, and 2-year increase in diastolic and systolic blood pressure. Short PEP and high CAR also predicted a 2-year increase in systolic blood pressure, and short PEP additionally predicted 2-year increase in diastolic blood pressure. Finally, a low baseline RSA was predictive for subsequent decreases in HDL cholesterol. CONCLUSION: Increased sympathetic activity predicts an increase in metabolic abnormalities over time. These findings suggest that a dysregulation of the autonomic nervous system is an important predictor of cardiovascular diseases and diabetes through dysregulating lipid metabolism and blood pressure over time.

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.

Recurrence of major depressive disorder across different treatment settings: results from the NESDA study.

OBJECTIVE: Examine time to recurrence of major depressive disorder (MDD) across different treatment settings and assess predictors of time to recurrence of MDD. METHODS: Data were from 375 subjects with a MDD diagnosis from the Netherlands Study of Depression and Anxiety (NESDA). The study sample was restricted to subjects with a remission of at least three months. These subjects were followed until recurrence or the end of the two year follow-up. DSM-IV based diagnostic interviews and Life Chart Interviews were used to assess time to recurrence of MDD across treatment settings. Predictors of time to recurrence were determined using Cox's proportional hazards analyses. RESULTS: Although trends indicated a slightly higher rate of and shorter time to recurrence in specialized mental health care, no significant difference in recurrence rate (26.8% versus 33.5%, p=0.23) or in time to recurrence (controlled for covariates) of MDD was found between respondents in specialized mental health care and respondents treated in primary care (average 6.6 versus 5.5 months, p=0.09). In multivariable analyses, a family history of MDD and previous major depressive episodes were associated with a shorter time to recurrence. Predictors did not differ across treatment settings. LIMITATIONS: The study sample may not be representative of the entire population treated for MDD in specialized mental health care. CONCLUSIONS: Health care professionals in both settings should be aware of the same risk factors since the recurrence risk and its predictors appeared to be similar across settings.

Recurrent suicide attempts in patients with depressive and anxiety disorders: the role of borderline personality traits.

BACKGROUND: The presence of a comorbid borderline personality disorder (BPD) may be associated with an increase of suicidal behaviors in patients with depressive and anxiety disorders. The aim of this study is to examine the role of borderline personality traits on recurrent suicide attempts. METHODS: The Netherlands Study on Depression and Anxiety included 1838 respondents with lifetime depressive and/or anxiety disorders, of whom 309 reported at least one previous suicide attempt. A univariable negative binomial regression analysis was performed to examine the association between comorbid borderline personality traits and suicide attempts. Univariable and multivariable negative binomial regression analyses were performed to identify risk factors for the number of recurrent suicide attempts in four clusters (type and severity of axis-I disorders, BPD traits, determinants of suicide attempts and socio-demographics). RESULTS: In the total sample the suicide attempt rate ratio increased with 33% for every unit increase in BPD traits. A lifetime diagnosis of dysthymia and comorbid BPD traits, especially the symptoms anger and fights, were independently and significantly associated with recurrent suicide attempts in the final model (n=309). LIMITATIONS: The screening of personality disorders was added to the NESDA assessments at the 4-year follow-up for the first time. Therefore we were not able to examine the influence of comorbid BPD traits on suicide attempts over time. CONCLUSIONS: Persons with a lifetime diagnosis of dysthymia combined with borderline personality traits especially difficulties in coping with anger seemed to be at high risk for recurrent suicide attempts. For clinical practice, it is recommended to screen for comorbid borderline personality traits and to strengthen the patient's coping skills with regard to anger.

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.

Effects of antidepressants, but not psychopathology, on cardiac sympathetic control: a longitudinal study.

Increased sympathetic activity has been hypothesized to have a role in the elevated somatic disease risk in persons with depressive or anxiety disorders. However, it remains unclear whether increased sympathetic activity reflects a direct effect of anxiety or depression or an indirect effect of antidepressant medication. The aim of this study was to test longitudinally whether cardiac sympathetic control, measured by pre-ejection period (PEP), was increased by depression/anxiety status and by antidepressant use. Cross-sectional and longitudinal data were from a depression and anxiety cohort: the Netherlands Study of Depression and Anxiety (NESDA). Baseline data of 2838 NESDA subjects (mean age 41.7 years, 66.7% female) and 2-year follow-up data of 2226 subjects were available for analyses. Included were subjects with and without depressive/anxiety disorders, using or not using different antidepressants at baseline or follow-up. The PEP was measured non-invasively by 1.5 h of ambulatory impedance cardiography. Cross-sectional analyses compared PEP across psychopathology and antidepressant groups. Longitudinal analyses compared 2-year changes in PEP in relation to changes in psychopathology and antidepressant use. Cross-sectional analyses showed that antidepressant-naïve depressive/anxious subjects had comparable PEP as controls, whereas subjects using tricyclic (TCA) or combined serotonergic/noradrenergic antidepressants (SNRI) had significantly shorter PEP compared with controls. In contrast, subjects using selective serotonin re-uptake inhibitors (SSRIs) had longer PEP than controls. Longitudinal results confirmed these findings: compared with 2-year change in PEP in continuous non-users (+2 ms), subjects who started TCA or SNRI treatment showed significantly shortened PEP (-11 ms, p=0.005 and p<0.001), whereas subjects who started SSRI treatment showed significant prolongation of PEP (+9 ms, p=0.002). Reversed findings were observed among those who stopped antidepressant use. These findings suggest that depressive and anxiety disorders are not associated with increased cardiac sympathetic control. However, results pose that TCA and SNRI use increases sympathetic control, whereas SSRI use decreases sympathetic control.

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.

Dysregulation of the autonomic nervous system and its association with the presence and intensity of chronic widespread pain.

OBJECTIVE: To test the hypotheses that dysregulation of the autonomic nervous system (ANS) is associated with the presence of chronic widespread pain (CWP), and that dysregulation of the ANS is associated with higher pain intensity in CWP. METHODS: Cross-sectional data were obtained from 1,574 subjects (healthy controls as well as persons with depressive and anxiety disorders) participating in The Netherlands Study of Depression and Anxiety. The Chronic Pain Grade was used to assess pain intensity and pain-related disability. Heart rate (HR), SD of the normal-to-normal interval (SDNN), the preejection period (PEP), and respiratory sinus arrhythmia (RSA) were used to assess the ANS. Logistic regression analyses and linear regression analyses were conducted with adjustment for potential confounders. RESULTS: No differences in HR, PEP, SDNN, or RSA values were found between CWP subjects and controls after adjustment for confounders. However, lower SDNN and lower RSA were associated with higher pain intensity in subjects with CWP. CONCLUSION: Lower parasympathetic activity, as assessed with SDNN and RSA, is associated with higher pain intensity in subjects with CWP. This large and well-controlled study does not provide evidence for an association between dysregulation of the ANS and the presence of CWP.

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.

Longitudinal evidence for unfavorable effects of antidepressants on heart rate variability.

BACKGROUND: It was previously shown that antidepressants are associated with diminished vagal control over the heart. Longitudinal studies are needed to test the causality of this association further. METHODS: Longitudinal data were obtained in the Netherlands Study of Depression and Anxiety. At baseline and at 2-year follow-up, heart rate and cardiac vagal control as indexed by respiratory sinus arrhythmia were measured in 2114 subjects (mean age = 42.0 years; 66.2% female), who either used antidepressants at one or two time points (n = 603) or did not use antidepressants at any time point (n = 1511). Linear mixed-model analyses were conducted to compare changes in respiratory sinus arrhythmia and heart rate over time across antidepressant-naive subjects, subjects who started using an antidepressant during follow-up, subjects who stopped using an antidepressant, and persistent antidepressant users. Analyses were adjusted for demographics, health, and lifestyle factors. RESULTS: Compared with continuous nonusers, subjects who started the use of a tricyclic antidepressant or a serotonergic and noradrenergic antidepressant showed a significantly greater increase in heart rate and a decrease of respiratory sinus arrhythmia at 2 years. Subjects who started the use of selective serotonin reuptake inhibitors also showed a decrease in respiratory sinus arrhythmia, but their heart rate did not increase. Discontinuing antidepressants systematically caused opposite effects; levels returned in the direction of those observed among nonusers. CONCLUSIONS: These 2-year longitudinal results indicate that all antidepressants cause a decrease in cardiac vagal control. After discontinuing antidepressants, autonomic function recovers, suggesting that the unfavorable effects are (partly) reversible.