Who is at risk for weight gain after weight-gain associated treatment with antipsychotics, antidepressants, and mood stabilizers: A machine learning approach.

BACKGROUND: Weight gain is a common side effect in psychopharmacology; however, targeted therapeutic interventions and prevention strategies are currently absent in day-to-day clinical practice. To promote the development of such strategies, the identification of factors indicative of patients at risk is essential. METHODS: In this study, we developed a transdiagnostic model using and comparing decision tree classifiers, logistic regression, XGboost, and a support vector machine to predict weight gain of ≥5% of body weight during the first 4 weeks of treatment with psychotropic drugs associated with weight gain in 103 psychiatric inpatients. We included established variables from the literature as well as an extended set with additional clinical variables and questionnaires. RESULTS: Baseline BMI, premorbid BMI, and age are known risk factors and were confirmed by our models. Additionally, waist circumference has emerged as a new and significant risk factor. Eating behavior next to blood glucose were found as additional potential predictor that may underlie therapeutic interventions and could be used for preventive strategies in a cohort at risk for psychotropics induced weight gain (PIWG). CONCLUSION: Our models validate existing findings and further uncover previously unknown modifiable factors, such as eating behavior and blood glucose, which can be used as targets for preventive strategies. These findings underscore the imperative for continued research in this domain to establish effective preventive measures for individuals undergoing psychotropic drug treatments.

Higher T central and lower effector memory cells in bipolar disorder: A differentiation abnormality?

The aim of this study was to elucidate the nature of T cell abnormalities in bipolar disorder (BD). With the use of multicolor flow cytometry, we first quantified the composition of the different memory and pro-inflammatory immune subpopulations in samples of 58 patients with BD and compared them to 113 healthy controls. Second, to assess if cytomegalovirus infection was related to the resulted immune subpopulation compositions in the two groups, we measured cytomegalovirus-specific antibodies in serum. Thirdly, we assessed differences between the two groups in the serum levels of the immune cell differentiation factor interleukin-7. Compared to healthy controls, patients showed significantly higher T helper-17, T regulatory and T central memory cells (CD4+ and CD8+). Besides, patients showed significantly lower CD4+ T effector memory and CD4+ T effector memory re-expressing RA cells. Cytomegalovirus infection was not related to the observed abnormalities, with the exception of T helper-17 cells. This immune subpopulation was significantly higher only in patients seropositive to cytomegalovirus infection. Finally, interleukin-7 levels were significantly lower in BD compared to healthy controls. In conclusion, the aberrant levels of T memory cell populations in BD may suggest a T cell differentiation abnormality. The role of interleukin-7 in this putative abnormality should be further investigated.

Association of clinical parameters and polygenic risk scores for body mass index, schizophrenia, and diabetes with antipsychotic-induced weight gain.

Antipsychotic-induced weight gain (AIWG) is a common adverse event in schizophrenia. Genome-wide association studies (GWAS) and polygenic risk scores (PRS) for other diseases or traits are recent approaches to disentangling the genetic architecture of AIWG. 200 patients with schizophrenia treated monotherapeutically with antipsychotics were included in this study. A multiple linear regression analysis with ten-fold crossvalidation was performed to predict the percentage weight change after five weeks of treatment. Independent variables were sex, age, body mass index (BMI) at baseline, medication-associated risk, and PRSs (BMI, schizophrenia, diabetes, and metabolic syndrome). An explorative GWAS analysis was performed on the same subjects and traits. PRSs for BMI (ß = 3.78; p = 0.0041), schizophrenia (ß = 5.38; p = 0.021) and diabetes type 2 (ß = 13.4; p = 0.046) were significantly associated with AIWG. Other significant factors were sex, baseline BMI and medication. Compared to the model without genetic factors, the addition of PRSs for BMI, schizophrenia, and diabetes type 2 increased the goodness of fit by 6.5 %. The GWAS identified the association of three variants (rs10668573, rs10249381 and rs1988834) with AIWG at a genome-wide level of p < 1 · 10-6. Using PRS for schizophrenia, BMI, and diabetes type 2 increased the explained variation of predicted weight gain, compared to a model without PRSs. For more precise results, PRSs derived from other traits (ideally AIWG) should be investigated. Potential risk variants identified in our GWAS need to be further investigated and replicated in independent samples.

Deconstructing depression by machine learning: the POKAL-PSY study.

Unipolar depression is a prevalent and disabling condition, often left untreated. In the outpatient setting, general practitioners fail to recognize depression in about 50% of cases mainly due to somatic comorbidities. Given the significant economic, social, and interpersonal impact of depression and its increasing prevalence, there is a need to improve its diagnosis and treatment in outpatient care. Various efforts have been made to isolate individual biological markers for depression to streamline diagnostic and therapeutic approaches. However, the intricate and dynamic interplay between neuroinflammation, metabolic abnormalities, and relevant neurobiological correlates of depression is not yet fully understood. To address this issue, we propose a naturalistic prospective study involving outpatients with unipolar depression, individuals without depression or comorbidities, and healthy controls. In addition to clinical assessments, cardiovascular parameters, metabolic factors, and inflammatory parameters are collected. For analysis we will use conventional statistics as well as machine learning algorithms. We aim to detect relevant participant subgroups by data-driven cluster algorithms and their impact on the subjects' long-term prognosis. The POKAL-PSY study is a subproject of the research network POKAL (Predictors and Clinical Outcomes in Depressive Disorders; GRK 2621).

Premature T cell aging in major depression: A double hit by the state of disease and cytomegalovirus infection.

Introduction: Previous research indicates that premature T cell senescence is a characteristic of major depressive disorder (MDD). However, known senescence inducing factors like cytomegalovirus (CMV) infection or, probably, childhood adversity (CA) have not been taken into consideration so far. Objective: Differentiation and senescent characteristics of T cells of MDD patients were investigated in relation to healthy controls (HC), taking the CMV seropositivity and CA into account. Methods: 127 MDD and 113 HC of the EU-MOODSTRATIFICATION cohort were analyzed. Fluorescence activated cell sorting (FACS) analysis was performed to determine B, NK, and T cell frequencies. In a second FACS analysis, naïve, effector memory (Tem), central memory (Tcm), effector memory cells re-expressing RA (TEMRA), as well as CD28+ and CD27+ memory populations, were determined of the CD4+ and CD8+ T cell populations in a subsample (N = 35 MDD and N = 36 HC). CMV-antibody state was measured by IgG ELISA and CA by the Childhood Trauma Questionnaire. Results: We detected a CMV-antibody positivity in 40% of MDD patients (35% HC, n. s.) with seropositive MDD cases showing a higher total childhood trauma score. Second, a higher inflation of memory CD4+ T helper cells in CMV seronegative patients as compared to seronegative HC and reduced numbers of naïve CD4+ T helper cells in CMV seropositive patients (not in CMV seropositive HC) were found. Third, a higher inflation of memory CD8+ T cytotoxic cells in CMV seropositive cases as compared to CMV seropositive HC, particularly of the TEMRA cells, became apparent. Higher percentages of CD4+ TEMRA and late stage CD27-CD28- TEMRA cells were similar in both HC and MDD with CMV seropositivity. Overall, apportioning of T cell subpopulations did not differ between CA positive vs negative cases. Conclusions: MDD patients show several signs of a CMV independent "MDD specific" premature T cell aging, such as a CMV independent increase in CD4+ T memory cells and a latent naïve CD4 T-cell reduction and a latent CD8+ T-cell increase. However, these two latent T cell senescence abnormalities only become evident with CMV infection (double hit).

Anti-Inflammatory Treatment Efficacy in Major Depressive Disorder: A Systematic Review of Meta-Analyses.

Purpose: Immune imbalances in major depressive disorder (MDD) have been targeted by anti-inflammatory treatment approaches in clinical trials to increase responsiveness to therapy. However, even after several meta-analyses, no translation of evidence into clinical practice has taken place. We performed a systematic review to evaluate meta-analytic evidence of randomized controlled trials on the use of anti-inflammatory agents for MDD to summarize efficacy estimates and elucidate shortcomings. Methods: Pooled effect estimates and heterogeneity indices were primary outcomes. Characteristics of the included meta-analyses were extracted. Scientific quality of meta-analyses was assessed using the Revised Assessment of Multiple Systematic Reviews (R-AMSTAR). Results: N=20 meta-analyses met the eligibility criteria. Study characteristics like outcome scales, composition of patient populations, and add-on or monotherapy regimen varied very little for celecoxib studies, varied little for minocycline studies, and were rather variable for omega 3 fatty acids studies. R-AMSTAR scores ranged from 26 to 39 out of 44 points indicating variable quality, where a comprehensive literature search was the strongest and the consideration of scientific quality in the conclusions was the weakest domain across all meta-analyses. For minocycline and celecoxib, superiority was demonstrated with medium to large effect size with substantial heterogeneity and with large to very large effect size with negligible heterogeneity, respectively. For omega 3 fatty acids, superiority was also demonstrated with mainly small and medium effect sizes with substantial heterogeneity. However, for minocycline and omega 3 fatty acids, non-significant meta-analyses were found also. Conclusion: Even in our synthesized approach, no clear recommendations could be derived on the use of anti-inflammatory treatment for MDD due to several critical aspects like heterogeneity, diversity of patient populations, treatment regimen, and outcomes, and limited scientific quality. However, we observed clear inter-substance differences with meta-analytic evidence being strongest for celecoxib and weakest for omega 3 fatty acids.

Lifestyle behaviors, metabolic disturbances, and weight gain in psychiatric inpatients treated with weight gain-associated medication.

Many psychiatric patients suffer from overweight/obesity and subsequent metabolic disturbances, where psychotropic medication is one of the main contributors. However, the magnitude of weight gain ranges individually, which leads to questioning the role of other contributors like lifestyle factors. The present study investigated several lifestyle factors among psychiatric inpatients, their relation to biological factors, and their predictive capability for weight gain during treatment. Using a naturalistic observational study design, psychiatric inpatients of all diagnoses were followed for 4 weeks from the start of treatment with weight gain-associated medication. N = 163 participants entered the study. Lifestyle factors were assessed by patient self-report questionnaires. Body weight change over time was calculated relative to baseline body weight. Our study provides three main findings: (1) Obesity and/or metabolic syndrome (metSy) were associated with emotional eating (disinhibition), craving for fast food and sweets, and weight cycling. (2) Patients without metSy and normal BMI experienced increased sweets craving (also for women), a more positive attitude towards drugs, and an improvement of affect (also for men). (3) Sex, presence of metSy and/or drug dosage interacted with disinhibition change, sweets craving change (trend), and fast food craving change to predict weight change over time. Furthermore, drug attitude change interacted with BMI, drug dosage, and presence of metSy to predict weight change. Lifestyle factors, especially eating behaviors, are related to metabolic disturbances and predict weight gain in interaction with clinical parameters.

A comprehensive approach to predicting weight gain and therapy response in psychopharmacologically treated major depressed patients: A cohort study protocol.

BACKGROUND: A subgroup of patients with Major Depressive Disorder shows signs of low-grade inflammation and metabolic abberances, while antidepressants can induce weight gain and subsequent metabolic disorders, and lacking antidepressant response is associated with inflammation. OBJECTIVES: A comprehensive investigation of patient phenotypes and their predictive capability for weight gain and treatment response after psychotropic treatment will be performed. The following factors will be analyzed: inflammatory and metabolic markers, gut microbiome composition, lifestyle indicators (eating behavior, physical activity, chronotype, patient characteristics (childhood adversity among others), and polygenic risk scores. METHODS: Psychiatric inpatients with at least moderate Major Depressive Disorder will be enrolled in a prospective, observational, naturalistic, monocentric study using stratified sampling. Ethical approval was obtained. Primary outcomes at 4 weeks will be percent weight change and symptom score change on the Montgomery Asberg Depression Rating Scale. Both outcomes will also be binarized into clinically relevant outcomes at 5% weight gain and 50% symptom score reduction. Predictors for weight gain and treatment response will be tested using multiple hierachical regression for continuous outcomes, and multiple binary logistic regression for binarized outcomes. Psychotropic premedication, current medication, eating behavior, baseline BMI, age, and sex will be included as covariates. Further, a comprehensive analysis will be carried out using machine learning. Polygenic risk scores will be added in a second step to estimate the additional variance explained by genetic markers. Sample size calculation yielded a total amount of N = 171 subjects. DISCUSSION: Patient and physician expectancies regarding the primary outcomes and non-random sampling may affect internal validity and external validity, respectively. Through the prospective and naturalistic design, results will gain relevance to clinical practice. Examining the predictive value of patient profiles for weight gain and treatment response during pharmacotherapy will allow for targeted adjustments before and concomitantly to the start of treatment.

Efficacy of Sertraline Plus Placebo or Add-On Celecoxib in Major Depressive Disorder: Macrophage Migration Inhibitory Factor as a Promising Biomarker for Remission After Sertraline-Results From a Randomized Controlled Clinical Trial.

Introduction: Previous research delivers strong indications that inflammatory activation leads to treatment resistance in a subgroup of patients with Major Depressive Disorder (MDD). Thus, tailored interventions are needed. The present study aimed to find potential biomarkers that may enable patients to be stratified according to immune activation. Methods: A phase IIa randomized placebo-controlled trial was performed to assess levels of inflammatory compounds in responders/remitters and non-responders/non-remitters to sertraline plus celecoxib (n = 20) and sertraline plus placebo (n = 23). Levels of macrophage migration inhibitory factor, neopterin, and tumor necrosis factor alpha were determined by enzyme-linked immunosorbent assay; response and remission were measured by reduction of the Montgomery Åsberg Depression Rating Scale score. Results: Both treatment groups showed a significant decline in depression symptoms, but no difference was found between groups. A clear pattern emerged only for macrophage migration inhibitory factor: placebo remitters showed significantly lower baseline levels than non-remitters (a similar trend was seen in responders and non-responders) while celecoxib responders showed a trend for higher baseline levels than non-responders. Conclusion: Small subsample sizes are a notable limitation, wherefore results are preliminary. However, the present study provides novel insights by suggesting macrophage migration inhibitory factor as a promising biomarker for treatment choice. The trial was registered in EU Clinical Trials Register (EU-CTR): https://www.clinicaltrialsregister.eu/ctr-search/trial/2009-011990-34/DE, EudraCT-No.: 2009-011990-34.

Monocyte mitochondrial dysfunction, inflammaging, and inflammatory pyroptosis in major depression.

BACKGROUND: The macrophage theory of depression states that macrophages play an important role in Major Depressive Disorder (MDD). METHODS: MDD patients (N = 140) and healthy controls (N = 120) participated in a cross-sectional study investigating the expression of apoptosis/growth and lipid/cholesterol pathway genes (BAX, BCL10, EGR1, EGR2, HB-EGF, NR1H3, ABCA1, ABCG1, MVK, CD163, HMOX1) in monocytes (macrophage/microglia precursors). Gene expressions were correlated to a set of previously determined and reported inflammation-regulating genes and analyzed with respect to various clinical parameters. RESULTS: MDD monocytes showed an overexpression of the apoptosis/growth/cholesterol and the TNF genes forming an inter-correlating gene cluster (cluster 3) separate from the previously described inflammation-related gene clusters (containing IL1 and IL6). While upregulation of monocyte gene cluster 3 was a hallmark of monocytes of all MDD patients, upregulation of the inflammation-related clusters was confirmed to be found only in the monocytes of patients with childhood adversity. The latter group also showed a downregulation of the cholesterol metabolism gene MVK, which is known to play an important role in trained immunity and proneness to inflammation. CONCLUSIONS: The upregulation of cluster 3 genes in monocytes of all MDD patients suggests a premature aging of the cells, i.e. mitochondrial apoptotic dysfunction and TNF "inflammaging", as a general feature of MDD. The overexpression of the IL-1/IL-6 containing inflammation clusters and the downregulation of MVK in monocytes of patients with childhood adversity indicates a shift in this condition to a more severe inflammation form (pyroptosis) of the cells, additional to the signs of premature aging and inflammaging.

Assessing the links between childhood trauma, C-reactive protein and response to antidepressant treatment in patients with affective disorders.

Adverse Childhood Experiences (ACE) are a well-known risk-factor for depression. Additionally, (high-sensitive) C-reactive Protein (hsCRP) is elevated in subgroups of depressed patients and high following ACE. In this context the literature considers hsCRP and ACE to be associated with treatment resistant depression. With the data being heterogenous, this study aimed to explore the associations of ACE, hsCRP levels and response to antidepressant treatment in uni- and bipolar depression. N = 76 patients diagnosed with uni- or bipolar depression and N = 53 healthy controls were included. Treatment was over 6 weeks in an inpatient psychiatric setting within an observatory study design. Depressive symptoms were assessed by the Montgomery-Asberg Depression Rating Scale (MADRS), ACE were assessed by the Childhood Trauma Questionnaire (CTQ); the body-mass-index (BMI) and hsCRP were measured. HsCRP levels did not differ between the study population and the healthy controls. While the depressive symptoms decreased, the hsCRP levels increased. Sexual abuse was associated with significant higher and emotional abuse with lower levels of hsCRP after 6 weeks. The baseline hsCRP levels and the ACE subgroups did not show significant associations with the treatment response in unipolar depressed patients. The long-lasting effects of specific forms of ACE may have relevant impact on inflammation, supporting hsCRP to be a suitable biomarker. With ACE and hsCRP not showing any significant associations with treatment response in the unipolar depressed subgroup, a more differentiate research concerning biomarkers and treatment regimens is needed when talking about treatment response.

Low-Grade Inflammation as a Predictor of Antidepressant and Anti-Inflammatory Therapy Response in MDD Patients: A Systematic Review of the Literature in Combination With an Analysis of Experimental Data Collected in the EU-MOODINFLAME Consortium.

Low-grade inflammation plays a role not only in the pathogenesis of major depressive disorder (MDD) but probably also in the poor responsiveness to regular antidepressants. There are also indications that anti-inflammatory agents improve the outcomes of antidepressants. Aim: To study whether the presence of low-grade inflammation predicts the outcome of antidepressants, anti-inflammatory agents, or combinations thereof. Methods: We carried out a systematic review of the literature on the prediction capability of the serum levels of inflammatory compounds and/or the inflammatory state of circulating leukocytes for the outcome of antidepressant/anti-inflammatory treatment in MDD. We compared outcomes of the review with original data (collected in two limited trials carried out in the EU project MOODINFLAME) on the prediction capability of the inflammatory state of monocytes (as measured by inflammatory gene expression) for the outcome of venlafaxine, imipramine, or sertraline treatment, the latter with and without celecoxib added. Results: Collectively, the literature and original data showed that: 1) raised serum levels of pro-inflammatory compounds (in particular of CRP/IL-6) characterize an inflammatory form of MDD with poor responsiveness to predominately serotonergic agents, but a better responsiveness to antidepressant regimens with a) (add-on) noradrenergic, dopaminergic, or glutamatergic action or b) (add-on) anti-inflammatory agents such as infliximab, minocycline, or eicosapentaenoic acid, showing-next to anti-inflammatory-dopaminergic or lipid corrective action; 2) these successful anti-inflammatory (add-on) agents, when used in patients with low serum levels of CRP/IL-6, decreased response rates in comparison to placebo. Add-on aspirin, in contrast, improved responsiveness in such "non-inflammatory" patients; 3) patients with increased inflammatory gene expression in circulating leukocytes had a poor responsiveness to serotonergic/noradrenergic agents. Conclusions: The presence of inflammation in patients with MDD heralds a poor outcome of first-line antidepressant therapies. Immediate step-ups to dopaminergic or glutamatergic regimens or to (add-on) anti-inflammatory agents are most likely indicated. However, at present, insufficient data exist to design protocols with reliable inflammation parameter cutoff points to guide such therapies, the more since detrimental outcomes are possible of anti-inflammatory agents in "non-inflamed" patients.