Innovations In Clinical Neuroscience

ISCTM Supplement 2015

A peer-reviewed, evidence-based journal for clinicians in the field of neuroscience

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[ V O L U M E 1 2 , N U M B E R 3 – 4 , S U P P L E M E N T A , M A R C H – A P R I L 2 0 1 5 ] Innovations in CLINICAL NEUROSCIENCE 31S reasonable consensus in the field in support of the alternative conceptualization. Furthermore, it is useful to note that robust findings in s tudies using the alternative approach that show convincing clinical benefits have a way of overcoming initial regulatory reluctance. BIOLOGICAL DIFFERENTIATION OF DEPRESSION SUBTYPES: CORTISOL, INFLAMMATORY MARKERS, AND COURSE (F. Lamers) Heterogeneity MDD. The known heterogeneity of MDD is hindering research, at the basic, clinical and therapeutic levels. The current classification systems based on descriptive phenomenology, not on etiology and pathophysiology, largely due to our lack of understanding of the latter. Though en face it would seem intuitively obvious that phenomenological heterogeneity should be the direct result of etiological heterogeneity, at this juncture this link has not been established empirically. Not taking into account heterogeneity of MDD could partially explain inconsistent findings as well as small effect sizes in clinical trials. In the literature there are several starting points for the subtyping of MDD. 10 The first starting point is symptom-based, comprising the categories melancholic, psychotic (delusional), atypical, and anxious depression. Another approach is etiology-based, including adjustment disorder with depressed mood, early trauma, reproductive depression, perinatal depression, organic depression, and drug-induced depression. Finally there are the time- of-onset based categories (e.g., early vs. late onset, seasonal affective disorder). To identify subtypes from a symptom-based perspective, a data- driven analysis (latent class analysis) was conducted within the Netherlands Study of Depression and Anxiety (NESDA). NESDA is a longitudinal naturalistic cohort study on the course and consequences of depression and anxiety, 11 and consists of 2,981 subjects (1,979 female and 1,002 male), aged 18 to 65 years, recruited in community, primary, and s pecialized care settings. The population comprises healthy controls, persons with depressive disorders (e.g., MDD, dysthymia), and persons with anxiety disorders (e.g., panic disorder, social phobia, agoraphobia, GAD). For the LCA, 818 persons with a diagnosis of MDD or minor depression were included. The best fitting model was a three- class model. Based on symptom probabilities, the first group was labeled "severe melancholic" (prevalence 46.3%) and was characterized mainly by decreased appetite and weight loss, but also had the highest probabilities on suicidal thought, psychomotor changes, and lack of responsiveness. The second class was labeled "severe atypical" (24.6%) characterized mainly by overeating and weight gain, and with the highest probabilities of leaden paralysis and interpersonal sensitivity, and the third class was labeled "moderate" (29.1%) and was characterized by lower symptom probabilities and overall lower severity. 1 2 Clinical characteristics only significantly differed between the moderate and the severe groups, with the moderate group having less comorbidity, less often had a positive family history and a shorter duration of the depression. 12 While the severe atypical and severe melancholic group did not differ in clinical characteristics, the melancholic group was significantly more likely to smoke than severe atypicals. Atypicals, on the other hand had significantly more metabolic disturbances than the severe melancholic class, as indicated by higher body mass index (BMI) and higher prevalence of metabolic syndrome. 12 Neuroendocrine and inflammatory markers in depression. It has long been known that changes in the hypothalamic- pituitary-adrenal (HPA) axis may occur in major depression. 13 Adrenocorticotropic hormone (ACTH) alpha 1-24 infusion has been shown to cause significantly higher cortisol c oncentrations, with earlier peak responses, in patients with endogenous depression than in normal subjects. 14 At one point, the ACTH stimulation test was even proposed as a diagnostic for depression. 15 More recently the concentrations of certain inflammatory markers have been found to be altered in depression. 16–18 The NESDA data collection also included biological measures such as salivary cortisol (cortisol awakening curve), and inflammatory markers (C-reactive protein [CRP]), interleukin-6 (IL-6), and tumor necrotic factor-alpha (TNF- a)), and these were evaluated in MDD groups. Some differences in biomarker profiles were observed between patients with melancholic depression and patients with atypical depression. Vreeburg et al 19 had previously demonstrated within the NESDA sample that, as compared to controls, both patients in a current episode of MDD and those who had remitted had similarly elevated areas under the curves (AUC) for cortisol during the first hour after awakening. When Lamers et al 20 examined a group of NESDA participants divided into stable melancholic vs. stable atypical subtypes, they found that patients with stable melancholic depression had higher cortisol AUCs than either controls or patients with stable atypical depression, in line with the finding of a larger effect size for melancholic depression by Stetler et al. 13 Moreover, there was no difference between stable atypicals and controls. 20 In NESDA participants with current MDD and remitted MDD as compared to healthy controls, CRP, TNF-a, and IL-6 levels were not significantly different. 21 However, when Lamers et al 20 compared these same three markers among melancholic depression, atypical depression and controls a very different picture emerged. Patients with atypical depression had elevated levels of CRP, TNF-a, and IL-6 compared to either

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