Femke Lamers

Evidence for a differential role of HPA-axis function, inflammation and metabolic syndrome in melancholic versus atypical depression

The hypothalamic–pituitary–adrenal (HPA) axis and the inflammatory response system have been suggested as pathophysiological mechanisms implicated in the etiology of major depressive disorder (MDD). Although meta-analyses do confirm associations between depression and these biological systems, effect sizes vary greatly among individual studies. A potentially important factor explaining variability is heterogeneity of MDD. Aim of this study was to evaluate the association between depressive subtypes (based on latent class analysis) and biological measures. Data from 776 persons from the Netherlands Study of Depression and Anxiety, including 111 chronic depressed persons with melancholic depression, 122 with atypical depression and 543 controls were analyzed. Inflammatory markers (C-reactive protein, interleukin-6, tumor necrosis factor-α), metabolic syndrome components, body mass index (BMI), saliva cortisol awakening curves (area under the curve with respect to the ground (AUCg) and with respect to the increase (AUCi)), and diurnal cortisol slope were compared among groups. Persons with melancholic depression had a higher AUCg and higher diurnal slope compared with persons with atypical depression and with controls. Persons with atypical depression had significantly higher levels of inflammatory markers, BMI, waist circumference and triglycerides, and lower high-density lipid cholesterol than persons with melancholic depression and controls. This study confirms that chronic forms of the two major subtypes of depression are associated with different biological correlates with inflammatory and metabolic dysregulation in atypical depression and HPA-axis hyperactivity in melancholic depression. The data provide further evidence that chronic forms of depressive subtypes differ not only in their symptom presentation, but also in their biological correlates. These findings have important implications for future research on pathophysiological pathways of depression and treatment.

Understanding the somatic consequences of depression: biological mechanisms and the role of depression symptom profile

Depression is the most common psychiatric disorder worldwide. The burden of disease for depression goes beyond functioning and quality of life and extends to somatic health. Depression has been shown to subsequently increase the risk of, for example, cardiovascular, stroke, diabetes and obesity morbidity. These somatic consequences could partly be due to metabolic, immuno-inflammatory, autonomic and hypothalamic-pituitary-adrenal (HPA)-axis dysregulations which have been suggested to be more often present among depressed patients. Evidence linking depression to metabolic syndrome abnormalities indicates that depression is especially associated with its obesity-related components (for example, abdominal obesity and dyslipidemia). In addition, systemic inflammation and hyperactivity of the HPA-axis have been consistently observed among depressed patients. Slightly less consistent observations are for autonomic dysregulation among depressed patients. The heterogeneity of the depression concept seems to play a differentiating role: metabolic syndrome and inflammation up-regulations appear more specific to the atypical depression subtype, whereas hypercortisolemia appears more specific for melancholic depression. This review finishes with potential treatment implications for the downward spiral in which different depressive symptom profiles and biological dysregulations may impact on each other and interact with somatic health decline.

Comorbidity Patterns of Anxiety and Depressive Disorders in a Large Cohort Study: the Netherlands Study of Depression and Anxiety (NESDA)

BACKGROUND Comorbidity of depressive and anxiety disorders is common and has been shown to be a consistent predictor of chronicity. Comorbidity patterns among specific depressive and anxiety disorders have not been extensively reported. This study examines comorbidity patterns and temporal sequencing of separate depressive and anxiety disorders using data from a large psychiatric cohort. METHOD Baseline data (N = 1,783) of the Netherlands Study of Depression and Anxiety, collected between September 2004 and February 2007, were used. Current and lifetime comorbidity rates for depressive and anxiety disorders (DSM-IV-TR criteria) were calculated. Associations of comorbidity with sociodemographic, vulnerability, and clinical characteristics, and temporal sequencing of disorders were examined. RESULTS Of those with a depressive disorder, 67% had a current and 75% had a lifetime comorbid anxiety disorder. Of persons with a current anxiety disorder, 63% had a current and 81% had a lifetime depressive disorder. Comorbidity of depressive and anxiety disorders was associated with more childhood trauma (OR = 1.19; 95% CI, 1.06-1.33), higher neuroticism (OR = 1.05; 95% CI, 1.02-1.08), earlier age at onset of first disorder (OR = 1.59; 95% CI, 1.22-2.07), longer duration of depressive and/or anxiety symptoms (OR = 1.01; 95% CI, 1.01-1.01), and higher symptom severity (ORs ranging from 1.01 to 1.03; all P values < .05). In 57% of comorbid cases, anxiety preceded depression, and in 18%, depression preceded anxiety. Comorbidity with preceding depression compared to preceding anxiety was associated with a shorter duration of symptoms of depressive and/or anxiety symptoms (OR = 0.99; 95% CI, 0.98-0.99), earlier age at first onset (OR = 0.46; 95% CI, 0.31-0.68), and fewer fear symptoms (OR = 0.98; 95% CI, 0.97-0.99). CONCLUSIONS Comorbidity rates in anxiety and depressive disorders were very high, indicating that it is advisable to assess both disorders routinely regardless of the primary reason for consultation. This is especially important since comorbid patients showed a specific vulnerability pattern, with more childhood trauma, neuroticism, and higher severity and duration of symptoms.

Two-year course of depressive and anxiety disorders: Results from the Netherlands Study of Depression and Anxiety (NESDA).

BACKGROUND Whether course trajectories of depressive and anxiety disorders are different, remains an important question for clinical practice and informs future psychiatric nosology. This longitudinal study compares depressive and anxiety disorders in terms of diagnostic and symptom course trajectories, and examines clinical prognostic factors. METHODS Data are from 1209 depressive and/or anxiety patients residing in primary and specialized care settings, participating in the Netherlands Study of Depression and Anxiety. Diagnostic and Life Chart Interviews provided 2-year course information. RESULTS Course was more favorable for pure depression (n=267, median episode duration = 6 months, 24.5% chronic) than for pure anxiety (n=487, median duration = 16 months, 41.9% chronic). Worst course was observed in the comorbid depression-anxiety group (n=455, median duration > 24 months, 56.8% chronic). Independent predictors of poor diagnostic and symptom trajectory outcomes were severity and duration of index episode, comorbid depression-anxiety, earlier onset age and older age. With only these factors a reasonable discriminative ability (C-statistic 0.72-0.77) was reached in predicting 2-year prognosis. LIMITATION Depression and anxiety cases concern prevalent - not incident - cases. This, however, reflects the actual patient population in primary and specialized care settings. CONCLUSIONS Their differential course trajectory justifies separate consideration of pure depression, pure anxiety and comorbid anxiety-depression in clinical practice and psychiatric nosology.

Identifying Depressive Subtypes in a Large Cohort Study: Results From the Netherlands Study of Depression and Anxiety (NESDA)

OBJECTIVE The heterogeneity of depression in the current classification system remains a point of discussion in the psychiatric field, despite previous efforts to subclassify depressive disorders. Data-driven techniques may help to come to a more empirically based classification. This study aimed to identify depressive subtypes within a large cohort of subjects with depression. METHOD Baseline data from 818 persons with a DSM-IV diagnosis of current major depressive disorder or minor depression who participated in the Netherlands Study of Depression and Anxiety were used. Respondents were recruited in the community, in primary care, and in specialized mental health care from September 2004 through February 2007. Latent classes were derived from latent class analysis using 16 depressive symptoms from the Composite International Diagnostic Interview and the Inventory of Depressive Symptomatology. Classes were characterized using demographic, clinical psychiatric, psychosocial, and physical health descriptors. RESULTS Three classes were identified: a severe melancholic class (prevalence, 46.3%), a severe atypical class (prevalence, 24.6%), and a class of moderate severity (prevalence, 29.1%). Both severe classes were characterized by more neuroticism (melancholic OR = 1.05 [95% CI, 1.01-1.10]; atypical OR = 1.07 [95% CI, 1.03-1.12]), more disability (melancholic OR = 1.07 [95% CI, 1.05-1.09]; atypical OR = 1.06 [95% CI, 1.04-1.07]), and less extraversion (melancholic OR = 0.95 [95% CI, 0.92-0.99]; atypical OR = 0.95 [95% CI, 0.92-0.99]) than the moderate class. Comparing the melancholic class with the atypical class revealed that the melancholic class had more smokers (atypical OR = 0.57 [95% CI, 0.39-0.84]) and more childhood trauma (atypical OR = 0.86 [95% CI, 0.74-1.00]), whereas the atypical class had more women (atypical OR = 1.52 [95% CI, 0.99-2.32]), a higher body mass index (atypical OR = 1.13 [95% CI, 1.09-1.17]), and more metabolic syndrome (atypical OR = 2.17 [95% CI, 1.38-3.42]). CONCLUSIONS Both depression severity (moderate vs severe) and the nature of depressive symptoms (melancholic vs atypical) were found to be important differentiators between subtypes. Higher endorsement rates of somatic symptoms and more metabolic syndrome in the atypical class suggest the involvement of a metabolic component.

Summed score of the Patient Health Questionnaire-9 was a reliable and valid method for depression screening in chronically ill elderly patients

OBJECTIVE To assess the psychometric properties of the Patient Health Questionnaire-9 (PHQ-9) as a screening instrument for depression in elderly patients with diabetes mellitus (DM) and chronic obstructive pulmonary disease (COPD) without known depression. STUDY DESIGN AND SETTING DM and COPD patients aged >59 years were selected from general practices. A test-retest was conducted in 105 patients. Criterion validity, using the Mini International Neuropsychiatric Interview psychiatric interview to diagnose major depressive disorder (MDD) and any depressive disorder (ADD) as diagnostic standard, was evaluated for both summed and algorithm-based PHQ-9 score in 713 patients. Correlations with quality of life and severity of illness were calculated to assess construct validity. RESULTS Cohens kappa for the algorithm-based score was 0.71 for MDD and 0.69 for ADD. Correlation for test-retest assessment of the summed score was 0.91. The algorithm-based score had low sensitivity and high specificity, but both sensitivity and specificity were high for the optimal cut-off point of 6 on the summed score for ADD (Se 95.6%, Sp 81.0%). Correlations between summed score and quality of life and severity of illness were acceptable. CONCLUSION The summed PHQ-9 score seems a valid and reliable screening instrument for depression in elderly primary care patients with DM and COPD.

Sociodemographic and psychiatric determinants of attrition in the Netherlands Study of Depression and Anxiety (NESDA)

BACKGROUND Although attrition is inevitable in longitudinal epidemiological studies, psychiatric studies are thought to be especially sensitive to attrition. This study aimed to evaluate the sociodemographic and psychiatric determinants of attrition at 2-year follow-up in the Netherlands Study of Depression and Anxiety. METHODS Logistic regression was used to examine sociodemographic and psychiatric determinants of attrition and the influence of clinical psychiatric characteristics on attrition. In addition, differences in determinants between 3 types of attrition (refusal, noncontact, and not able to participate) were evaluated. RESULTS The attrition rate at the 2-year follow-up assessment was 12.9% (385/2981), representing 6 deceased persons, 250 refusers, 51 noncontacts, and 78 persons unable to participate because of health reasons. Determinants of attrition were younger age, less years of education, not being of North European descent, being recruited in Amsterdam, no previous participation in research, and having major depressive disorder. Only the effects of age, sampling site, and previous participation in research differed between types of attrition. Furthermore, comorbid depressive and anxiety disorders and higher symptom severity were associated with attrition. CONCLUSIONS In contrast to the view that psychiatric epidemiological research is more prone to high attrition rates, this study revealed a relatively low attrition rate. Furthermore, both sociodemographic and psychiatric variables were independent determinants of attrition. Oversampling of subgroups that are at higher risk of dropout may be advisable for future psychiatric cohort studies.

DEPRESSIVE AND ANXIETY DISORDERS AND THE ASSOCIATION WITH OBESITY, PHYSICAL, AND SOCIAL ACTIVITIES

Objective: There is evidence of more obesity among persons with depressive and depressive and anxiety disorders. However, the nature and the underlying mechanisms of the association are still unclear. This study examines the association between depressive and anxiety disorders and obesity, physical activity, and social activity, and examines whether social and physical activity are potential influencing factors in the association between depressive and anxiety disorders and obesity. Method: Cross‐sectional data were used from the Netherlands Study of Depression and Anxiety. A total of 1,854 women and 955 men aged 18–65 years were recruited from the community, general practices, and specialized mental health care. Depressive and anxiety disorders were determined with the Composite International Diagnostic Interview. Body mass index (BMI<30 kg/m2) was used to determine obesity. Physical and social activities were measured by self‐report. Results: The odds of obesity adjusted for covariates was significantly higher among those with a current pure Major Depressive Disorder (MDD;odds ratio [OR] OR:1.43; 95% CI:1.07–1.92) compared to controls. Physical activity and social activities were lower among persons with depressive and anxiety disorders compared to controls. The association between MDD and obesity was influenced by social and physical activities. Conclusion: This study confirmed a link between depressive disorders and obesity that was influenced by lower social and physical activities among the depressed. Depression and Anxiety, 2010.  © 2010 Wiley‐Liss, Inc.

Are sedentary television watching and computer use behaviors associated with anxiety and depressive disorders

Sedentary behaviors may be more common among persons with mental disorders and thereby result in poorer health outcomes. This study examined whether independently of general physical activity level, mental disorders are linked to two important examples of sedentary behavior: computer use and watching television. We used cross-sectional data from The Netherlands Study of Depression and Anxiety (NESDA). Our study sample consisted of 2353 participants (age 18-65) of whom 1701 had a current anxiety and/or depressive diagnosis and 652 were healthy controls. Anxiety and depression diagnoses were conducted using the DSM-IV based Composite International Diagnostic Interview. Controlling for sociodemographics and physical activity level we found that persons with a major depressive disorder (MDD) spend significantly more leisure time using the computer. We found that persons with dysthymia, panic disorder and agoraphobia spend significantly more daily hours watching television compared to controls. This study illustrates that sedentary behaviors occur more frequently among persons with a mental disorder, independent of general physical activity level.

Polygenic dissection of major depression clinical heterogeneity

The molecular mechanisms underlying major depressive disorder (MDD) are largely unknown. Limited success of previous genetics studies may be attributable to heterogeneity of MDD, aggregating biologically different subtypes. We examined the polygenic features of MDD and two common clinical subtypes (typical and atypical) defined by symptom profiles in a large sample of adults with established diagnoses. Data were from 1530 patients of the Netherlands Study of Depression and Anxiety (NESDA) and 1700 controls mainly from the Netherlands Twin Register (NTR). Diagnoses of MDD and its subtypes were based on DSM-IV symptoms. Genetic overlap of MDD and subtypes with psychiatric (MDD, bipolar disorder, schizophrenia) and metabolic (body mass index (BMI), C-reactive protein, triglycerides) traits was evaluated via genomic profile risk scores (GPRS) generated from meta-analysis results of large international consortia. Single nucleotide polymorphism (SNP)-heritability of MDD and subtypes was also estimated. MDD was associated with psychiatric GPRS, while no association was found for GPRS of metabolic traits. MDD subtypes had differential polygenic signatures: typical was strongly associated with schizophrenia GPRS (odds ratio (OR)=1.54, P=7.8e-9), while atypical was additionally associated with BMI (OR=1.29, P=2.7e-4) and triglycerides (OR=1.21, P=0.006) GPRS. Similar results were found when only the highly discriminatory symptoms of appetite/weight were used to define subtypes. SNP-heritability was 32% for MDD, 38% and 43% for subtypes with, respectively, decreased (typical) and increased (atypical) appetite/weight. In conclusion, MDD subtypes are characterized by partially distinct polygenic liabilities and may represent more homogeneous phenotypes. Disentangling MDD heterogeneity may help the psychiatric field moving forward in the search for molecular roots of depression.