Short-term effects of etifoxine on human gut microbiome in healthy men.

Background: Neurosteroids have recently gained in interest as a treatment strategy for affective disorders. Etifoxine is known for its dual mode of action, one of which is to stimulate endogenous neurosteroid synthesis. The gut microbiome has been studied in affective disorders, but it has not been investigated in the context of human etifoxine or neurosteroid interventions. Methods: We performed a crossover study with 36 healthy male volunteers who received etifoxine versus alprazolam and placebo in a balanced Williams design. Participants were randomized into six sequences and went through three 5-day treatments followed by wash-out phases of 9 days. Bacterial compositions in stool samples were determined by high-throughput 16S rRNA amplicon sequencing. Results: Gut microbiome analyses revealed no relevant effects between treatments with respect to alpha and beta diversity. Differential abundance analyses yielded etifoxine treatment as the only effect related to changes in microbial features with reductions of Faecalibacterium duncaniae, Roseburia hominis and Lactobacillus rogosae (i.e., Bacteroides galacturonicus). Conclusion: Here we report on the first human investigation of the gut microbiome with short-term etifoxine intervention. Differences in diversity and compositional structure of the microbiome were more likely due to between- subject effects rather than medication. However, five-day treatment with etifoxine reduced the abundance of a few bacterial species. These species are currently seen as beneficial components of a healthy intestinal microbiome. This reduction in abundances may be related to elevated endogenous neurosteroids.

[Depressive Disorders in Adolescence: Current State of Studies Concerning the Microbiota-Gut-Brain Axis]. / Depressive Störungen in der Adoleszenz: Aktuelle Studienlage zur Mikrobiota-Darm-Hirn-Achse.

Depressive Disorders in Adolescence: Current State of Studies Concerning the Microbiota-Gut-Brain Axis Abstract. Depressive disorders increase during adolescence and often lead to significant impairment in affected individuals - despite treatment. Current research efforts aim to further investigate the pathophysiology of depression, considering the influence of gut microbiota on the gut-brain axis. The present narrative review outlines the current state of studies of the microbiota-gut-brain axis in depressive disorders as well as the direct and indirect interactions in adolescence. Besides providing promising results from animal studies, studies on the microbiota-gut-brain axis in adults suffering from depressive disorders are growing steadily. In depressed adolescents, however, the study situation is still marginal, making a recommendation for the supplementation of probiotics and prebiotics in depressed children and adolescents impossible according to the current state of research. Against the background of a very limited number of studies involving adolescents with depressive disorders, the interactive role of the microbiota-gut-brain axis in adolescent development should receive special attention in future research projects.

Effect of Minocycline on Depressive Symptoms in Patients With Treatment-Resistant Depression: A Randomized Clinical Trial.

Importance: Insufficient treatment response and resulting chronicity constitute a major problem in depressive disorders. Remission rates range as low as 15% to 40% and treatment-resistant depression (TRD) is associated with low-grade inflammation, suggesting anti-inflammatory interventions as a rational treatment strategy. Minocycline, which inhibits microglial activation, represents a promising repurposing candidate in the treatment of TRD. Objective: To determine whether 6 weeks of minocycline as add-on to antidepressant treatment as usual can significantly reduce depressive symptoms in patients with TRD. Design, Setting, and Participants: The study was conducted in Germany and designed as a multicenter double-blind randomized clinical trial (RCT) of 200 mg/d minocycline treatment over a course of 6 weeks with a 6-month follow-up. Participants were recruited from January 2016 to August 2020 at 9 university hospitals that served as study sites. Key inclusion criteria were a diagnosis of major depressive disorder (according to Diagnostic and Statistical Manual of Mental Disorders [Fifth Edition] criteria), severity of depressive symptoms on the Hamilton Depression Rating Scale (HAMD-17) greater than or equal to 16 points, aged 18 to 75 years, body mass index 18 to 40, Clinical Global Impression Scale (CGI-S) greater than or equal to 4, failure to adequately respond to an initial antidepressant standard medication as per Massachusetts General Hospital Antidepressant Treatment History Questionnaire, and stable medication for at least 2 weeks. A total of 258 patients were screened, of whom 173 were randomized and 168 were included into the intention-to-treat population. Statistical analysis was performed from April to November 2020. Interventions: Participants were randomized (1:1) to receive adjunct minocycline (200 mg/d) or placebo for 6 weeks. Main Outcomes and Measures: Primary outcome measure was the change in Montgomery-Åsberg Depression Rating Scale (MADRS) score from baseline to week 6 analyzed by intention-to-treat mixed model repeated measures. Secondary outcome measures were response, remission, and various other clinical rating scales. Results: Of 173 eligible and randomized participants (84 randomized to minocycline and 89 randomized to placebo), 168 formed the intention-to-treat sample (79 [47.0%] were women, 89 [53.0%] were men, 159 [94.6%] were White, 9 [6.4%] were of other race and ethnicity, including Asian and unknown ethnicity), with 81 in the minocycline group and 87 in the placebo group. The mean (SD) age was 46.1 (13.1) years, and the mean (SD) MADRS score at baseline was 26.5 (5.0). There was no difference in rates of completion between the minocycline (83.3% [70 of 81]) and the placebo group (83.1% [74 of 87]). Minocycline treatment did not alter the course of depression severity compared with placebo as assessed by a decrease in MADRS scores over 6 weeks of treatment (1.46 [-1.04 to 3.96], P = .25). Minocycline treatment also exhibited no statistically significant effect on secondary outcomes. Conclusions and Relevance: In this large randomized clinical trial with minocycline at a dose of 200 mg/d added to antidepressant treatment as usual for 6 weeks, minocycline was well tolerated but not superior to placebo in reducing depressive symptoms in patients with TRD. The results of this RCT emphasize the unmet need for therapeutic approaches and predictive biomarkers in TRD. Trial Registration: EU Clinical Trials Register Number: EudraCT 2015-001456-29.

Induced neural progenitor cells and iPS-neurons from major depressive disorder patients show altered bioenergetics and electrophysiological properties.

The molecular pathomechanisms of major depressive disorder (MDD) are still not completely understood. Here, we follow the hypothesis, that mitochondria dysfunction which is inevitably associated with bioenergetic disbalance is a risk factor that contributes to the susceptibility of an individual to develop MDD. Thus, we investigated molecular mechanisms related to mitochondrial function in induced neuronal progenitor cells (NPCs) which were reprogrammed from fibroblasts of eight MDD patients and eight non-depressed controls. We found significantly lower maximal respiration rates, altered cytosolic basal calcium levels, and smaller soma size in NPCs derived from MDD patients. These findings are partially consistent with our earlier observations in MDD patient-derived fibroblasts. Furthermore, we differentiated MDD and control NPCs into iPS-neurons and analyzed their passive biophysical and active electrophysiological properties to investigate whether neuronal function can be related to altered mitochondrial activity and bioenergetics. Interestingly, MDD patient-derived iPS-neurons showed significantly lower membrane capacitance, a less hyperpolarized membrane potential, increased Na+ current density and increased spontaneous electrical activity. Our findings indicate that functional differences evident in fibroblasts derived from MDD patients are partially present after reprogramming to induced-NPCs, could relate to altered function of iPS-neurons and thus might be associated with the aetiology of major depressive disorder.

Mental health-related risk factors and interventions in patients with heart failure: a position paper endorsed by the European Association of Preventive Cardiology (EAPC).

The prevalence and public health burden of chronic heart failure (CHF) in Europe is steadily increasing mainly caused by the ageing population and prolonged survival of patients with CHF. Frequent hospitalizations, high morbidity and mortality rates, and enormous healthcare costs contribute to the health-related burden. However, multidisciplinary frameworks that emphasize effective long-term management and the psychological needs of the patients are sparse. The present position paper endorsed by the European Association of Preventive Cardiology (EAPC) provides a comprehensive overview on the scientific evidence of psychosocial aspects of heart failure (HF). In order to synthesize newly available information and reinforce best medical practice, information was gathered via literature reviews and consultations of experts. It covers the evidence for aetiological and prospective psychosocial risk factors and major underlying psycho-biological mechanisms. The paper elucidates the need to include psychosocial aspects in self-care concepts and critically reviews the current shortcomings of psychotherapeutic and psycho-pharmacological interventions. It also highlights the need for involvement of psychological support in device therapy for patients with HF and finally calls for better palliative care in the final stage of HF progression.

The cytokine IL-17A as a marker of treatment resistance in major depressive disorder?

Major depression is a complex disease and-among others, inflammation appears to play an important role in its pathophysiology. In this study, we investigated a broad range of cytokines in depressed patients. Plasma levels of interleukin (IL)-12/ IL-23p40, IL-15, IL-16, IL-17A, IL-1α, IL-7, tumor necrosis factorß and vascular endothelial growth factor were compared in 48 patients suffering from major depression before, after one and after six weeks of antidepressive treatment in relation to therapy response. Interestingly, the level of IL-17A turned out to rise significantly in the non-responder group compared to responder during antidepressive treatment. IL-17A is a pro-inflammatory cytokine that initiates the production of other cytokines, thereby inducing and mediating immune response. It is also involved in allergic and autoimmune-related diseases. The database investigating the role of IL-17A in major depressive disorder has grown within the last few years comparing levels of this cytokine in depressed patients versus healthy subjects. However, little is known about the expression of IL-17A during the course of antidepressive treatment. In summary, our study provides valuable evidence that this cytokine might serve as a marker of therapy resistance to antidepressants.

SARS-CoV-2 Risk Management in Clinical Psychiatry: A Few Considerations on How to Deal With an Unrivaled Threat.

The pandemic spread of the corona virus SARS-CoV-2 has even-handedly shattered national and international health systems and economies almost in an instant. As numbers of infections and COVID-19-related deaths rise from day to day, fears and uncertainties on how to deal with this unknown threat are extremely present both for individuals and societies as a whole. In this manuscript, we aim to exemplarily describe the bullet points concerning (a) the internal risk management, (b) the organizational and structural changes, and (c) the communicational strategies applied in a Psychiatric University Hospital in the Southern part of Germany. The authors are well aware about the fact that almost none of these considerations may be considered as evidence-based at the moment. However, the authors trust that these reflections and experiences may be useful as an orientation for similar risk constellations in other afflicted countries due to the temporal delay of the pandemic course.

Major Depressive Disorder is Associated with Impaired Mitochondrial Function in Skin Fibroblasts.

Mitochondrial malfunction is supposed to be involved in the etiology and pathology of major depressive disorder (MDD). Here, we aimed to identify and characterize the molecular pathomechanisms related to mitochondrial dysfunction in adult human skin fibroblasts, which were derived from MDD patients or non-depressive control subjects. We found that MDD fibroblasts showed significantly impaired mitochondrial functioning: basal and maximal respiration, spare respiratory capacity, non-mitochondrial respiration and adenosine triphosphate (ATP)-related oxygen consumption was lower. Moreover, MDD fibroblasts harbor lower ATP levels and showed hyperpolarized mitochondrial membrane potential. To investigate cellular resilience, we challenged both groups of fibroblasts with hormonal (dexamethasone) or metabolic (galactose) stress for one week, and found that both stressors increased oxygen consumption but lowered ATP content in MDD as well as in non-depressive control fibroblasts. Interestingly, the bioenergetic differences between fibroblasts from MDD or non-depressed subjects, which were observed under non-treated conditions, could not be detected after stress. Our findings support the hypothesis that altered mitochondrial function causes a bioenergetic imbalance, which is associated with the molecular pathophysiology of MDD. The observed alterations in the oxidative phosphorylation system (OXPHOS) and other mitochondria-related properties represent a basis for further investigations of pathophysiological mechanisms and might open new ways to gain insight into antidepressant signaling pathways.

Minocycline alters behavior, microglia and the gut microbiome in a trait-anxiety-dependent manner.

Major depressive disorder is the main cause of disability worldwide with imperfect treatment options. However, novel therapeutic approaches are currently discussed, from augmentation strategies to novel treatments targeting the immune system or the microbiome-gut-brain axis. Therefore, we examined the potential beneficial effects of minocycline, a tetracycline antibiotic with pleiotropic, immunomodulatory action, alone or as augmentation of escitalopram on behavior, prefrontal microglial density, and the gut microbiome in rats selectively bred for high anxiety-like behavior (HAB). We show that concomitant with their high innate anxiety and depression, HABs have lower microglial numbers in the infralimbic and prelimbic prefrontal cortex and an altered gut microbiota composition compared with controls. Three weeks of minocycline treatment alleviated the depressive-like phenotype, further reduced microglial density, exclusively in male HAB rats, and reduced plasma concentrations of pro-inflammatory cytokines. However, coadministration of escitalopram, which had no effect alone, prevented these minocycline-induced effects. Moreover, minocycline led to a robust shift in cecal microbial composition in both HABs and rats non-selected for anxiety-like behavior. Minocycline markedly increased relative abundance of Lachnospiraceae and Clostridiales Family XIII, families known for their butyrate production, with a corresponding increase and positive correlation in plasma 3-OH-butyrate levels in a trait-dependent manner. Thus, our data suggest that the antidepressant effect of minocycline is sex- and trait-dependent, associated with a reduced microglial number in the prefrontal cortex, and with changes in microbial composition and their metabolites. These results further support the microbiome-gut-brain axis as potential target in the treatment of depression.

Classical Risk Factors and Inflammatory Biomarkers: One of the Missing Biological Links between Cardiovascular Disease and Major Depressive Disorder.

BACKGROUND: Cardiovascular disorders (CVD) and major depressive disorder (MDD) are the most frequent diseases worldwide responsible for premature death and disability. Behavioral and immunological variables influence the pathophysiology of both disorders. We therefore determined frequency and severity of MDD in CVD and studied whether MDD without CVD or other somatic diseases influences classical and inflammatory biomarkers of cardiovascular risk. In addition, we investigated the influence of proinflammatory cytokines on antidepressant treatment outcome. METHODS: In a case-control design, 310 adults (MDD patients without CVD, CVD patients, and cardiologically and psychiatrically healthy matched controls) were investigated. MDD patients were recruited after admission in a psychiatric university hospital. Primary outcome criteria were clinical depression ratings (HAM-D scale), vital signs, classical cardiovascular risk factors and inflammatory biomarkers which were compared between MDD patients and healthy controls. RESULTS: We detected an enhanced cardiovascular risk in MDD. Untreated prehypertension and signs directing to a metabolic syndrome were detected in MDD. Significantly higher inflammatory biomarkers such as the high sensitivity C-reaktive protein (hsCRP) and proinflammatory acute phase cytokines interleukine-1ß (IL-1ß) and interleukine-6 (IL-6) underlined the higher cardiovascular risk in physically healthy MDD patients. Surprisingly, high inflammation markers before treatment were associated with better clinical outcome and faster remission. The rate of MDD in CVD patients was high. CONCLUSIONS: Patients suffering from MDD are at specific risk for CVD. Precise detection of cardiovascular risks in MDD beyond classical risk factors is warranted to allow effective prophylaxis and treatment of both conditions. Future studies of prophylactic interventions may help to provide a basis for prophylactic treatment of both MDD and CVD. In addition, the high risk for MDD in CVD patients was confirmed and underlines the requirement for clinical attention.

Neurobiology of depression: A neurodevelopmental approach.

OBJECTIVES: The main aims of this paper are to review and evaluate the neurobiology of the depressive syndrome from a neurodevelopmental perspective. METHODS: An English language literature search was performed using PubMed. RESULTS: Depression is a complex syndrome that involves anatomical and functional changes that have an early origin in brain development. In subjects with genetic risk for depression, early stress factors are able to mediate not only the genetic risk but also gene expression. There is evidence that endocrine and immune interactions have an important impact on monoamine function and that the altered monoamine signalling observed in the depressive syndrome has a neuro-endocrino-immunological origin early in the development. CONCLUSIONS: Neurodevelopment is a key aspect to understand the whole neurobiology of depression.

A standardized stepwise drug treatment algorithm for depression reduces direct treatment costs in depressed inpatients - Results from the German Algorithm Project (GAP3).

BACKGROUND: In a previous single center study we found that a standardized drug treatment algorithm (ALGO) was more cost effective than treatment as usual (TAU) for inpatients with major depression. This report aimed to determine whether this promising initial finding could be replicated in a multicenter study. METHODS: Treatment costs were calculated for two time periods: the study period (from enrolment to exit from study) and time in hospital (from enrolment to hospital discharge) based on daily hospital charges. Cost per remitted patient during the study period was considered as primary outcome. RESULTS: 266 patients received ALGO and 84 received TAU. For the study period, ALGO costs were significantly lower than TAU (ALGO: 7 848 ± 6 065 €; TAU: 10 033 ± 7 696 €; p = 0.04). For time in hospital, costs were not different (ALGO: 14 734 ± 8 329 €; TAU: 14 244 ± 8 419 €; p = 0.617). Remission rates did not differ for the study period (ALGO: 57.9%, TAU: 50.0%; p=0.201). Remission rates were greater in ALGO (83.3%) than TAU (66.2%) for time in hospital (p = 0.002). Cost per remission was lower in ALGO (13 554 ± 10 476 €) than TAU (20 066 ± 15 391 €) for the study period (p < 0.001) and for time in hospital (ALGO: 17 582 ± 9 939 €; TAU: 21 516 ± 12 718 €; p = 0.036). LIMITATIONS: Indirect costs were not assessed. Different dropout rates in TAU and ALGO complicated interpretation. CONCLUSIONS: Treatment algorithms enhance the cost effectiveness of the care of depressed inpatients, which replicates our prior results in an independent sample.

"I Am I and My Bacterial Circumstances": Linking Gut Microbiome, Neurodevelopment, and Depression.

Recently, there has been renewed interest in the role played by microbiome in both human health and human disease. A correct equilibrium between the human host and their microorganisms is important for an appropriate physiological function. Extensive research has shown that microbes that inhabit the gastrointestinal tract-or gut microbiota-are involved not only in both nutritive and digestive activities but also in immunological processes. Moreover, the gut microbiome influences both central nervous system and energy homeostasis. An altered gut microbiome has been associated with the pathophysiology of different diseases, including neuropsychiatric disorders. Apparently, both environmental-diet, exposition to antibiotics, and infections-and host-genetic factors have a strong influence on gut microbiome, modulating the risk for neuropsychiatric illness. Also, early life disruption of the microbiome-gut-brain (MGB) axis has been associated with an increased risk of developing depression later in life, suggesting a link between gut microbiome, neurodevelopment, and depression. This review aims to contribute to this growing area of research by exploring the role played by the gut microbiome in neurodevelopment and in the etiology of the depressive syndrome, including nutritional, immunological, and energy homeostasis approaches.

Macrophage-Derived Chemokine: A Putative Marker of Pharmacological Therapy Response in Major Depression?

INTRODUCTION: Inflammatory processes play an important and complex role in the pathophysiology of major depressive disorder (MDD), but, so far, no specific investigation of chemokines exists. METHODS: In this study, we investigated the changes of plasma chemokine levels (eotaxin-1, eotaxin-3, IP-10, MCP-1, MCP-4, MDC, MIP-1α, MIP-1ß, and TARC) in 47 MDD patients before (PRE) and after 1 and 6 weeks of pharmacological treatment (POST1 and POST6) in relation to the response to antidepressive therapy. We hypothesized that the direction of alterations in levels of chemokines would significantly differ between the 2 groups, responders and nonresponders. RESULTS: Among the investigated chemokines, only the level of macrophage-derived chemokine (MDC) changed significantly in relation to therapy response. MDC levels were significantly elevated in the responder group at POST6. DISCUSSION: MDC is a constitutively expressed chemokine involved in the pathophysiology of infectious and neoplastic diseases. This is the first study providing valuable hints that MDC might serve as a marker of pharmacological therapy response in MDD.

How Effective Is Algorithm-Guided Treatment for Depressed Inpatients? Results from the Randomized Controlled Multicenter German Algorithm Project 3 Trial.

Background: Treatment algorithms are considered as key to improve outcomes by enhancing the quality of care. This is the first randomized controlled study to evaluate the clinical effect of algorithm-guided treatment in inpatients with major depressive disorder. Methods: Inpatients, aged 18 to 70 years with major depressive disorder from 10 German psychiatric departments were randomized to 5 different treatment arms (from 2000 to 2005), 3 of which were standardized stepwise drug treatment algorithms (ALGO). The fourth arm proposed medications and provided less specific recommendations based on a computerized documentation and expert system (CDES), the fifth arm received treatment as usual (TAU). ALGO included 3 different second-step strategies: lithium augmentation (ALGO LA), antidepressant dose-escalation (ALGO DE), and switch to a different antidepressant (ALGO SW). Time to remission (21-item Hamilton Depression Rating Scale ≤9) was the primary outcome. Results: Time to remission was significantly shorter for ALGO DE (n=91) compared with both TAU (n=84) (HR=1.67; P=.014) and CDES (n=79) (HR=1.59; P=.031) and ALGO SW (n=89) compared with both TAU (HR=1.64; P=.018) and CDES (HR=1.56; P=.038). For both ALGO LA (n=86) and ALGO DE, fewer antidepressant medications were needed to achieve remission than for CDES or TAU (P<.001). Remission rates at discharge differed across groups; ALGO DE had the highest (89.2%) and TAU the lowest rates (66.2%). Conclusions: A highly structured algorithm-guided treatment is associated with shorter times and fewer medication changes to achieve remission with depressed inpatients than treatment as usual or computerized medication choice guidance.

The sex-dependent role of the glucocorticoid receptor in depression: variations in the NR3C1 gene are associated with major depressive disorder in women but not in men.

Genetic variations in the glucocorticoid receptor (GR) and the mineralocorticoid receptor (MR) have been associated with maladaptive stress responses and major depressive disorder (MDD). In a case-control study design, we examined whether single nucleotide polymorphisms (SNPs) and haploid genotype (haplotype) associations of MR gene NR3C2, GR gene NR3C1 and genes of GR chaperone molecules FK506 binding protein 5 (FKBP5) and corticotrophin-releasing hormone receptor 1 (CRHR1) differed between healthy subjects (n = 634) and inpatients with major depressive disorder (n = 412). All analyses were conducted for women and men separately. After conservative correction of Type-I-error to obtain reliable p values, one SNP in the NR3C1 gene, namely rs6195, showed a significant association with the presence of a major depression (p = 0.048) in females. In contrast, NR3C2, FKBP5 and CRHR1 polymorphisms were not significantly associated with MDD. No haplotype effects could be identified. Our results support the notion of an association between variants of GR-related genes in women and the pathophysiology of depression: females suffering from MDD showed a more than three times higher frequency of the T/C polymorphism compared to controls, which thus seems to increase the vulnerability to depression in females.

Report of the WPA section of pharmacopsychiatry on the relationship of antiepileptic drugs with suicidality in epilepsy.

INTRODUCTION: This report from the World Psychiatric Association Section on Pharmacopsychiatry examines the possible relationship of antiepileptic drugs with suicide-related clinical features and behaviors in patients with epilepsy. MATERIALS AND METHODS: A systematic review of the MEDLINE search returned 1039 papers, of which only 8 were considered relevant. A critical analysis of the Food and Drug Administration (FDA) report on the increase risk for patients under antiepileptics to manifest suicidality is also included in this report. RESULTS: The analysis of these studies revealed that the data are not supportive of the presence of a "class effect" on suicide-related behavior; on the contrary, there are some data suggesting such an effect concerning treatment with topiramate, lamotrigine, and levetiracetam for which further research is needed. DISCUSSION: For the majority of people with epilepsy, anticonvulsant treatment is necessary and its failure for any reason is expected to have deleterious consequences. Therefore, clinicians should inform patients and their families of this increased risk of suicidal ideation and behavior, but should not overemphasize the issue. Specific subgroups of patients with epilepsy might be at a higher risk, and deserve closer monitoring and follow-up. Future research with antiepileptics should specifically focus on depression and suicidal thoughts.

Characteristics and differences in treatment outcome of inpatients with chronic vs. episodic major depressive disorders.

BACKGROUND: Approximately 20-30% of patients with Major depressive disorder (MDD) develop a chronic course of their disease. Chronic depression is associated with increased health care utilisation, hospitalisation and a higher disease burden. We identified clinical correlates and differences in treatment response of chronic MDD (cMDD) patients compared with non-chronic episodic depression in a huge sample of depressive inpatients. METHODS: Data were collected from 412 inpatients who had been diagnosed with a major depressive episode (MDE; according to ICD-10) and scored 15 or higher on the 21-item Hamilton Depression Rating Scale (HRSD-21). All subjects were participants in the German Algorithm Project, phase 3 (GAP3). Patients who were diagnosed with a MDE within the last two years or longer (herein referred to as CD) were compared with non-chronic depressive patients (herein referred to as non-CD). CD and non-CD patients were assessed for the following: psychosocial characteristics, symptom reduction from hospital admission to discharge, symptom severity at discharge, remission and response rates, and pharmacological treatment during inpatient treatment. The primary outcome measure was the HRSD-21. RESULTS: 13.6% (n=56) of patients met the criteria for chronic depression. Compared with non-CD patients, patients with CD showed increased axis I comorbidities (74% vs. 52%, χ(2) (1)=7.31, p=.02), a higher level of depressive symptoms at baseline and discharge, increased duration of inpatient treatment (64.8 vs. 53.3 days; t=2.86, p=.03) and lower response (HRSD: 60.0% vs. 72.0%; χ(2) (1)=3.61, p<.04; BDI: 40.5% vs. 54.2%; χ(2) (1)=3.56, p=.04) and remission rates (BDI 17.9.% vs. 29.7%; χ(2) (1)=3.42, p=.05. However, both groups achieved a comparable symptom reduction during inpatient treatment. The prescribed pharmacological strategy had no significant influence on treatment outcome in patients with CD. CONCLUSION: Inpatients with CD show higher symptom severity, lower response and remission rates and a longer duration of inpatient treatment, although they achieve comparable symptom reduction during treatment. These findings support the need to recognise CD and its defining characteristics as a distinct subclass of depression.

The influence of Hatha yoga as an add-on treatment in major depression on hypothalamic-pituitary-adrenal-axis activity: a randomized trial.

OBJECTIVES: The impact of Hatha yoga as add-on treatment to quetiapine fumarate extended release (QXR) or escitalopram (ESC) in depressed patients on hypothalamic-pituitary-adrenal (HPA) axis activity was assessed. METHODS: 60 inpatients suffering from major depressive disorder (MDD) according to DSM-IV were randomized for a 5 week treatment with Yoga or not (control group) and with either QXR (300 mg/day) or ESC (10 mg/day). Serial dexamethasone/corticotropin releasing hormone (DEX/CRH) tests were performed to assess HPA axis function. The Hamilton Depression Rating Scale (21-HAMD) was used weekly. RESULTS: A more pronounced down regulation of the HPA axis activity due to yoga could not be detected. The stepwise long term cortisol reduction was seen in both medication groups, irrespectively of yoga add-on treatment. In addition, cortisol improvers in week 1 of therapy (reduction in cortisol peak value within the DEX/CRH test) reached significant greater amelioration of depressive symptoms after 5 weeks. CONCLUSIONS: Our results suggest that antidepressant agents down regulate HPA axis function to a greater extent than additional Hatha yoga treatment. Moreover, an early reduction of HPA system hyperactivity after one week of pharmacological treatment seems to raise the possibility of a favorable treatment response.

Effects of escitalopram/quetiapine combination therapy versus escitalopram monotherapy on hypothalamic-pituitary-adrenal-axis activity in relation to antidepressant effectiveness.

The hypothalamic-pituitary-adrenocortical (HPA) system is believed to play an important role in the pathophysiology of major depressive disorder. In this context, the atypical antipsychotic quetiapine (QUE) has been shown to inhibit HPA system activity in healthy subjects. In this study we investigated whether the putative inhibitory effects of QUE on HPA system activity may contribute to its antidepressant efficacy. We analyzed the effects of QUE as an augmentation to the selective serotonin reuptake inhibitor (SSRI) escitalopram (ESC) on HPA system activity in comparison to a monotherapy with ESC in relation to the antidepressant effectiveness. HPA axis activity (cortisol and ACTH) was measured by means of the dexamethasone/corticotropin-releasing hormone (DEX/CRH) test which was performed before (week 0) and during (week 1, week 5) antidepressant psychopharmacotherapy. The combination therapy, but not the ESC monotherapy showed significantly inhibiting effects on HPA system activity leading to stepwise down-regulation. ACTH concentrations were reduced in the ESC/QUE group during five weeks of treatment. The inhibitory effect of QUE maybe involved in its antidepressant effects as an augmentation strategy.