Acute and Chronic Macrophage Differentiation Modulates TREM2 in a Personalized Alzheimer's Patient-Derived Assay.

Neuroinflammation plays a pivotal role in the pathogenesis of Alzheimer`s disease (AD). Brain macrophage populations differentially modulate the immune response to AD pathology according to the disease stage. Triggering receptor expressed on myeloid cells 2 (TREM2) is known to play a protective role in AD and has been postulated as a putative therapeutic target. Whether, and to which extent TREM2 expression can be modulated in the aged macrophage population of the brain is unknown, emphasizing the need for a human, patient-specific model. Using cells from AD patients and matched controls (CO) we designed an assay based on monocyte-derived macrophages to mimic brain-infiltrating macrophages and to assess the individualized TREM2 synthesis in vitro. We systematically assessed the effects of short-term (acute-2 days) and long-term (chronic-10 days) M1- (LPS), M2- (IL-10, IL-4, TGF-ß), and M0- (vehicle) macrophage differentiation on TREM2 synthesis. Moreover, the effects of retinoic acid (RA), a putative TREM2 modulator, on individualized TREM2 synthesis were assessed. We report increased TREM2 synthesis after acute M2- compared to M1-differentiation in CO- but not AD-derived cells. Chronic M2- and M0-differentiation however resulted in an increase of TREM2 synthesis in both AD- and CO-derived cells while chronic M1-differentiation increased TREM2 in AD-derived cells only. Moreover, chronic M2- and M0-differentiation improved the amyloid-ß (Aß) uptake of the CO-derived whereas M1-differentiation of the AD-derived cells. Interestingly, RA-treatment did not modulate TREM2. In the age of personalized medicine, our individualized model could be used to screen for potential drug-mediated treatment responses in vitro. Triggering receptor expressed on myeloid cells 2 (TREM2) has been postulated as a putative therapeutic target in Alzheimer's disease (AD). Using cells from AD patients and matched controls (CO), we designed a monocyte-derived macrophages (Mo-MФs) assay to assess the individualized TREM2 synthesis in vitro. We report increased TREM2 synthesis after acute M2- compared to M1- macrophage differentiation in CO- but not AD-derived cells. Chronic M2- and M0- differentiation however resulted in an increase of TREM2 synthesis in both AD- and CO-derived cells while chronic M1-differentiation increased TREM2 in AD-cells only.

The impact of emotional dysregulation and comorbid depressive symptoms on clinical features, brain arousal, and treatment response in adults with ADHD.

Introduction: The role of emotional dysregulation (ED) in attention-deficit/hyperactivity disorder (ADHD) has become an important issue. This study, in which we analyzed data from a predictive pharmaco-EEG-trial, aimed to examine whether symptoms of ED in adult ADHD affect ADHD symptom severity, brain arousal regulation as measured by resting EEG, and the response to stimulant medication. Methods: ED is defined as having a sex- and age-corrected T-score of >70 on the emotional lability subscale of the German version of Conners' Adult ADHD Rating Scale. A total of 115 participants were included in the study, 56 of whom had ED. Participants with ED were more impaired in terms of the severity of core ADHD symptoms, especially inattentive symptoms, comorbid depressive symptoms, interpersonal relationships, and quality of life. In addition, participants with ED were more likely to report a total score above 13 on the Beck Depression Inventory-II, which was considered to be the cutoff for mild depression. Results: No differences were found between the ED and non-ED groups in response to stimulant medication or in brain arousal regulation. In addition, there was no significant effect of ED with comorbid depressive symptoms on treatment response. There was a trend for subgroups that showed a change in brain arousal regulation associated with symptom improvement. Discussion: Our findings may support the assumption that ED may be an important feature of ADHD. The use of EEG-based brain arousal regulation as a diagnostic and predictive tool in ADHD in the presence of ED and comorbid depressive symptoms should be further investigated.

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.

The role of comorbid depressive symptoms on long-range temporal correlations in resting EEG in adults with ADHD.

Attention deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder, characterized by core symptoms of inattention, hyperactivity and impulsivity. Comorbid depression is commonly observed in ADHD-patients. Psychostimulants are recommended as first-line treatment for ADHD. Aberrant long-range temporal correlations (LRTCs) of neuronal activities in resting-state are known to be associated with disorganized thinking and concentrating difficulties (typical in ADHD) and with maladaptive thinking (typical in depression). It has yet to be examined whether (1) LRTC occur in ADHD-patients, and if so, (2) whether LRTC might be a competent biomarker in ADHD comorbid with current depression and (3) how depression affects psychostimulant therapy of ADHD symptoms. The present study registered and compared LRTCs in different EEG frequency bands in 85 adults with ADHD between groups with (n = 28) and without (n = 57) additional depressive symptoms at baseline. Treatment-related changes in ADHD, depressive symptoms and LRTC were investigated in the whole population and within each group. Our results revealed significant LRTCs existed in all investigated frequency bands. There were, however, no significant LRTC-differences between ADHD-patients with and without depressive symptoms at baseline and no LRTC-changes following treatment. However, depressed ADHD patients did seem to benefit more from the therapy with psychostimulant based on self-report.

Gradient of electro-convulsive therapy's antidepressant effects along the longitudinal hippocampal axis.

Despite decades of successful treatment of therapy-resistant depression and major scientific advances in the field, our knowledge about electro-convulsive therapy's (ECT) mechanisms of action is still scarce. Building on strong empirical evidence for ECT-induced hippocampus anatomy changes, we sought to test the hypothesis that ECT has a differential impact along the hippocampus longitudinal axis. We acquired behavioural and brain anatomy magnetic resonance imaging (MRI) data in patients with depressive episode undergoing ECT (n = 9) or pharmacotherapy (n = 24) and healthy controls (n = 30) at two time points 3 months apart. Using whole-brain voxel-based statistical parametric mapping and topographic analysis focused on the hippocampus, we observed ECT-induced gradient of grey matter volume increase along the hippocampal longitudinal axis with predominant impact on its anterior portion. Clinical outcome measures showed strong correlations with both baseline volume and rate of ECT-induced change exclusively for the anterior, but not posterior hippocampus. We interpret our findings confined to the anterior hippocampus and amygdala as additional evidence of the regional specific impact of ECT that unfolds its beneficial effect on depression via the "limbic" system. Main limitations of the study are patients' polypharmacy, heterogeneity of psychiatric diagnosis, and long-time interval between scans.

M1/M2 polarization in major depressive disorder: Disentangling state from trait effects in an individualized cell-culture-based approach.

Accumulating evidence indicates the specific involvement of inflammatory processes in major depressive disorder (MDD), particularly affecting innate immunity. Most immune alterations have so far been determined based on plasma or cerebrospinal fluid cytokine levels. To precisely characterize putative innate immune-mediated mechanisms in MDD pathogenesis, we sought to disentangle "state" from "trait" effects in a patient-specific cell model by quantifying the impact of patient-derived autologous sera (AS) on patient-specific monocyte-derived macrophages (Mo-MФs) polarization in vitro. Mo-MФs were generated from 28 patients with moderate to severe MDD and 28 age-, sex-, smoking status- and BMI-matched healthy controls (HC). Cells were treated either with AS or fetal calf serum (FCS) and polarized into M1 (LPS), M2 (IL-10, IL-4, TGF-ß) or M0 (unstimulated) macrophages. Polarization capacity was quantified by means of specific M1 (CCR7, CD86, CXCL10, IL-12p70, TNF-α, IL-6, IL-1ß, IL-12p40, IL-23, IP-10) and M2 (CD206, IL-10, TARC, IL-1RA) markers. Compared to HC, significantly increased M1-polarization was observed for MDD patients in the presence of FCS, however, polarization in AS enriched media determined an increased M2-polarization in patients. Moreover, female MDD patients exhibited increased M1- and decreased M2-polarization in both conditions compared to male MDD patients. Our data suggests that Mo-MФs derived from patients with MDD exhibit facilitated M1-polarization under traditional cell culture conditions and an increased potential for M2-polarization when cultured in AS. Striking inter-individual variation and pronounced gender effects highlight the potential utility of our personalized cell model-based approach to aid diagnostic and therapeutic decisions.

A Central Clearing Clinic to Provide Mental Health Services for Refugees in Germany.

Objective: To determine migration related distress pattern in refugees and feasibility of a de novo established, central low-threshold outpatient clinic serving more than 80,000 newly arrived refugees in the metropole of Berlin. Methods: In an observational cohort study the relative prevalence of major psychiatric disorders by age, place of living within berlin, language and region of origin were assessed in a refugee cohort from 63 nationalities speaking 36 languages. Findings: Within 18 months, a total of 3,096 cases with a mean age of 29.7 years (11.7) have been referred from all 12 districts and 165 of 182 subdistricts of Berlin to the CCC. 33.7% of the patients were female. The three most frequent diagnoses were unipolar depression (40.4%), posttraumatic stress disorder (24.3%), and adjustment disorder (19.6%). Conclusion: The present data gives insight into the distribution of mental disorders in a large sample of refugees and provides evidence that a CCC is an effective service to quickly and broadly provide psychiatric consultations and thus to overcome classical barriers refugees usually experience in the host communities. In Berlin, Germany, and Europe treatment resources for this population should focus on stress and trauma related disorders.

The "VIP-ADHD trial": Does brain arousal have prognostic value for predicting response to psychostimulants in adult ADHD patients?

EEG studies have shown that adult ADHD patients have less stable brain arousal regulation than age and gender matched controls. Psychostimulants have brain arousal stabilising properties evident in EEG patterns. The aim of this study was to investigate whether the stability of brain arousal regulation has prognostic value in predicting response to methylphenidate therapy in adult ADHD patients. In an open-label, single-arm, multi-centre, confirmatory trial, 121 adult ADHD patients were recruited and 112 qualified for the full analysis set. All participants received an initial dose of 20 mg extended release methylphenidate at baseline. After a titration phase of up to 4 weeks, patients remained on a weight-based target dose of extended release methylphenidate for 4 weeks. Using the Vigilance Algorithm Leipzig (VIGALL 2.1), we assessed brain arousal regulation before the treatment with methylphenidate, based on a 15-min EEG at quiet rest recorded at baseline. Using automatic stage-classification of 1 s segments, we computed the mean EEG-vigilance (indexing arousal level) and an arousal stability score (indexing arousal regulation). The primary endpoint was the association between successful therapy, defined by a 30% reduction in CAARS, and stable/unstable brain arousal. 52 patients (46%) showed an unstable brain arousal regulation of which 23% had therapy success. In the stable group, 35% had therapy success, implying an absolute difference of 12 percentage points (95% CI -5 to 29, p = 0.17) in the direction opposite to the hypothesized one. There were no new findings regarding the tolerability and safety of extended release methylphenidate therapy.

Clozapine modulates retinoid homeostasis in human brain and normalizes serum retinoic acid deficit in patients with schizophrenia.

The atypical antipsychotic clozapine is one of the most potent drugs of its class, yet its precise mechanisms of action remain insufficiently understood. Recent evidence points toward the involvement of endogenous retinoic acid (RA) signaling in the pathophysiology of schizophrenia. Here we investigated whether clozapine may modulate RA-signaling. Effects of clozapine on the catabolism of all-trans RA (at-RA), the biologically most active metabolite of Vitamin A, were assessed in murine and human brain tissue and peripheral blood-derived mononuclear cells (PBMC). In patients with schizophrenia with and without clozapine treatment and matched healthy controls, at-RA serum levels and blood mRNA expression of retinoid-related genes in PBMCs were quantified. Clozapine and its metabolites potently inhibited RA catabolism at clinically relevant concentrations. In PBMC-derived microsomes, we found a large interindividual variability of the sensitivity toward the effects of clozapine. Furthermore, at-RA and retinol serum levels were significantly lower in patients with schizophrenia compared with matched healthy controls. Patients treated with clozapine exhibited significantly higher at-RA serum levels compared with patients treated with other antipsychotics, while retinol levels did not differ between treatment groups. Similarly, in patients without clozapine treatment, mRNA expression of RA-inducible targets CYP26A and STRA6, as well as at-RA/retinol ratio, were significantly reduced. In contrast, clozapine-treated patients did not differ from healthy controls in this regard. Our findings provide the first evidence for altered peripheral retinoid homeostasis in schizophrenia and suggest modulation of RA catabolism as a novel mechanism of action of clozapine, which may be useful in future antipsychotic drug development.

Using routine MRI data of depressed patients to predict individual responses to electroconvulsive therapy.

Electroconvulsive therapy (ECT) is one of the most effective treatments in cases of severe and treatment resistant major depression. 60-80% of patients respond to ECT, but the procedure is demanding and robust prediction of ECT responses would be of great clinical value. Predictions based on neuroimaging data have recently come into focus, but still face methodological and practical limitations that are hampering the translation into clinical practice. In this retrospective study, we investigated the feasibility of ECT response prediction using structural magnetic resonance imaging (sMRI) data that was collected during ECT routine examinations. We applied machine learning techniques to predict individual treatment outcomes in a cohort of N = 71 ECT patients, N = 39 of which responded to the treatment. SMRI-based classification of ECT responders and non-responders reached an accuracy of 69% (sensitivity: 67%; specificity: 72%). Classification on additionally investigated clinical variables had no predictive power. Since dichotomisation of patients into ECT responders and non-responders is debatable due to many patients only showing a partial response, we additionally performed a post-hoc regression-based prediction analysis on continuous symptom improvements. This analysis yielded a significant relationship between true and predicted treatment outcomes and might be a promising alternative to dichotomization of patients. Based on our results, we argue that the prediction of individual ECT responses based on routine sMRI holds promise to overcome important limitations that are currently hampering the translation of such treatment biomarkers into everyday clinical practice. Finally, we discuss how the results of such predictive data analysis could best support the clinician's decision on whether a patient should be treated with ECT.

No Words for Feelings? Not Only for My Own: Diminished Emotional Empathic Ability in Alexithymia.

The present study has been designed to disentangle cognitive and emotional dimensions of empathy in a group of mentally healthy and highly alexithymic individuals (ALEX, n = 24) and well-matched controls (n = 26) through questionnaire Interpersonal Reactivity Index (IRI) and Multifaceted Empathy Task (MET) used during the fMRI and after the fMRI. Simultaneously, Skin Conductance Response (SCR) has been acquired as an implicit measure of emotional reaction. Results show an impaired emotional empathic ability in alexithymic individuals, with lower levels of SCR and higher activation in prefrontal brain regions such as the ventrolateral prefrontal cortex (VLPFC) and inferior frontal gyrus (IFG). Cognitive empathy was not impaired in the alexithymic group and the results were accompanied by a higher activation left IFG. The study leads to the conclusion that alexithymia does not only involve a diminished ability to identify and describe one's own emotions. Furthermore, it is related to a deeper disability of emotion regulation, which becomes visible through impaired emotional concern for others and higher levels of personal distress.

A simple approach to optimum pool size for pooled SARS-CoV-2 testing.

Systematic, large-scale testing of asymptomatic subjects is an important strategy in the management of the SARS-CoV-2 pandemic. In order to increase the capacity of laboratory-based molecular SARS-CoV-2 testing, it has been suggested to combine several samples and jointly measure them in a sample pool. While saving cost and labour at first sight, pooling efficiency depends on the pool size and the presently experienced prevalence of positive samples. Here we address the question of the optimum pool size at a given prevalence. We demonstrate the relation between analytical effort and pool size and delineate the effects of the target prevalence on the optimum pool size. Finally, we derive a simple-to-use formula and table that allow laboratories performing sample pooling to assess the optimum pool size at the currently experienced target prevalence rate.

Inhibition of monoamine oxidase activity by repetitive transcranial magnetic stimulation: implications for inter-train interval and frequency.

Repetitive transcranial magnetic stimulation (rTMS) is a neuromodulation technique that stimulates cortical regions via time-varying electromagnetic fields; in several countries this technique has been approved as a treatment for major depressive disorder. One empirically established target in antidepressant pharmacotherapy is the flavin-containing monoamine oxidoreductase (MAO). The function of MAO enzymes is based on oxidation processes that may be sensitive towards strong electromagnetic fields. Therefore, we hypothesized that rTMS-induced electromagnetic fields impact the activity of this enzyme. Using crude synaptosomal cell preparations from human SH-SY5Y neuroblastoma cells and rat cortex as well as viable cells, we assessed the effects of rTMS on MAO-A and -B activity in a well-controlled in vitro set up. In short, samples were stimulated at maximal intensity with an equal number of total stimuli at frequencies of 5, 20, and 100 Hz. Sham stimulation was performed in parallel. Treatment at frequencies of 5 and 20 Hz significantly decreased mainly MAO-B activity in all tissue preparations and species, whereas 100 Hz stimulation remained without effect on any MAO activity. Our results support the hypothesis, that rTMS-induced electromagnetic fields affect MAO activity and provide further evidence for intracellular effects possibly contributing to therapeutic effects of this neuromodulatory method. On a cautionary note, however, our findings are solely based on in vitro evidence.

What happens with schizophrenia patients after their discharge from hospital? Results on outcome and treatment from a "real-world" 2-year follow-up trial.

Aim of the study was to examine the course of schizophrenia patients within 2 years after discharge. Within a multicenter study of the German Competence Network on Schizophrenia, patients suffering from a schizophrenia spectrum disorder were examined regarding their psychopathological improvement, tolerability, and the treatment regime applied during hospitalization and a 2-year follow-up period. Response, remission, the level of everyday functioning, and relapse were furthermore evaluated during the follow-up period using established definitions for these outcome domains. The psychopharmacological treatment was specifically evaluated in terms of a potential association with relapse. 149 patients were available for analysis, with 65% of the patients being in response, 52% in symptomatic remission, and 64% having a satisfiable everyday functioning 2 years after their discharge from hospital. Despite these favorable outcome rates, 63% of the patients suffered from a relapse within the 2-year follow-up period with 86% of these patients being rehospitalized. Discharge non-responder and non-remitter were twice as likely to relapse during follow-up. A significant decrease of side-effects was observed with negligible rates of extrapyramidal side-effects, sedation, and weight gain during follow-up. Patients receiving treatment with atypical antipsychotics were found to have the lowest risk to relapse (p < 0.0001). The results highlight the natural and unsteady course of schizophrenia in most patients underlining the need to develop more specific treatment strategies ensuring ongoing stability and preventing relapse.

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.

Remission in schizophrenia - What are we measuring? Comparing the consensus remission criteria to a CGI-based definition of remission and to remission in major depression.

BACKGROUND: Despite being recommended for use in clinical trials, the consensus remission criteria were found to leave patients with persisting symptoms, relevant areas of functional impairment and a decreased sense of wellbeing. Therefore, to evaluate the appropriateness of the schizophrenia consensus criteria, a definition of remission based on the Clinical Global Impression Scale (CGI) was developed and remitter subgroups were compared. METHODS: 239 patients with a schizophrenia spectrum disorder were evaluated regarding their remission status after inpatient treatment. Remission in schizophrenia was defined according to the symptom-severity component of the consensus criteria by Andreasen et al. and a CGI based definition was calculated using sensitivity and specificity using receiver operating curves (asymptomatic remitter). Both remitter groups (schizophrenia consensus versus asymptomatic remitters) were compared regarding different clinical variables at discharge as well as the likelihood to relapse within a 1-year follow-up period. Both schizophrenia remitter subgroups were compared to remitters in major depression as a reference value. RESULTS: Following the consensus criteria, 63% of the schizophrenia patients were in remission compared to only 18% following the asymptomatic criterion. The schizophrenia consensus remitters were less likely to be concurrent treatment responders (p < 0.0001), had a significantly greater illness severity (p < 0.0001) and less functioning (p = 0.0358) as well as a significantly greater risk to relapse (p = 0.0174) compared to the schizophrenia asymptomatic remitters as well as the depressed remitters. CONCLUSION: It should be critically re-evaluated if the currently proposed consensus criteria are adequate to measure what is traditionally understood to be remission.

Anti-inflammatory effects of minocycline are mediated by retinoid signaling.

BACKGROUND: Minocycline is a lipophilic tetracycline of increasing appeal in neuroscience as it inhibits microglial activation, a mechanism involved in numerous neuropsychiatric disorders. Own data point towards retinoid-mediated effects of minocycline in murine brain and skin, and towards a vicious cycle of neuroinflammation which is driven by microglial activation-induced breakdown of local retinoids such as retinoic acid (RA). We therefore sought to study minocycline's anti-inflammatory effects on human microglial-like monocyte-derived cells in the context of retinoid signaling. RESULTS: As hypothesized, minocycline exposure resulted in a substantial increase of RA levels in the human monocytic cell line THP-1. While pro-inflammatory stimulation with lipopolysaccharides resulted in increased tryptophane-degrading indoleamine-2,3-dioxygenase IDO-expression and TNF-α levels in primary human monocyte-derived microglial-like cells, this effect was attenuated by minocycline only in the presence of retinoids. The anti-inflammatory effects of minocycline on TNF-α expression were completely abolished by a pharmacological blockage of retinoic acid receptors (RARs) using BMS-493 and unaffected by selectively blocking retinoid-X-receptors using UVI-3003. CONCLUSIONS: Our data indicate for the first time a RA-dependent, anti-inflammatory effect for minocycline in human microglial-like cells via inhibition of local RA turnover. The RA-dependent mode of action for minocycline appears to be predominantly mediated through RAR-signaling.

Subtypes of depression and their overlap in a naturalistic inpatient sample of major depressive disorder.

Subtyping depression is important in order to further delineate biological causes of depressive syndromes. The aim of this study was to evaluate clinical and outcome characteristics of distinct subtypes of depression and to assess proportion and features of patients fulfilling criteria for more than one subtype. Melancholic, atypical and anxious subtypes of depression were assessed in a naturalistic sample of 833 inpatients using DSM-IV specifiers based on operationalized criteria. Baseline characteristics and outcome criteria at discharge were compared between distinct subtypes and their overlap. A substantial proportion of patients (16%) were classified with more than one subtype of depression, 28% were of the distinct anxious, 7% of the distinct atypical and 5% of the distinct melancholic subtype. Distinct melancholic patients had shortest duration of episode, highest baseline depression severity, but were more often early improvers; distinct anxious patients had higher NEO-Five Factor Inventory (NEO-FFI) neuroticism scores compared with patients with unspecific subtype. Melancholic patients with overlap of anxious features had worse treatment outcome compared to distinct melancholic and distinct anxious subtype. Distinct subtypes differed in only few variables and patients with overlap of depression subtypes may have independent clinical and outcome characteristics. Studies investigating biological causes of subtypes of depression should take influence of features of other subtypes into account.

Retinoic Acid Enhances Apolipoprotein E Synthesis in Human Macrophages.

Apolipoprotein E (ApoE) represents a pivotal target in Alzheimer's disease (AD) and is modulated through retinoic acid (RA), an endogenous neuroprotective and anti-inflammatory compound. A major source of ApoE are microglia, which are pathologically activated in AD. Activated microglia are known to block RA signaling. This suggests a vicious cycle between inflammation, RA signaling, and ApoE homeostasis in AD pathogenesis. To test this hypothesis, we investigated effects of RA and proinflammatory activation on ApoE synthesis in primary human macrophage-derived microglial-like cells. Our results indicate that proinflammatory activation attenuates ApoE synthesis, an effect blocked by RA.