Combined Pharmacological Treatment Research Articles

Exploring the Comorbidity, Pathophysiology, and Integrated Treatment Strategies of Hypertension and Depression

Hypertension and depression are widely prevalent conditions with substantial comorbidity. Hypertension, characterized by persistently elevated arterial pressure, is associated with significant cardiovascular morbidity and mortality. Depression, a multifactorial mood disorder, adversely affects mental and physical health through mechanisms involving neuroinflammation, neurotransmitter imbalances, and hormonal dysregulation. The association between these disorders has been recognized since the mid-20th century.Historical medical literature from ancient Chinese and Indian systems identified symptoms indicative of hypertension, later classified as a distinct disease entity by Fredrick Akbar Mahomed in the 19th century. Notable epidemiological studies have elucidated the significant relationship between hypertension and depression, particularly among medical students and other high-risk populations.Research indicates that common pathophysiological mechanisms, including sympathetic nervous system overactivity, chronic inflammation, and endothelial dysfunction, underlie the comorbidity of hypertension and depression. Elevated levels of norepinephrine, proinflammatory cytokines, and oxidative stress contribute to the expression or worsening of both conditions. Shared genetic and environmental factors further compound this relationship, highlighting the need for integrated treatment strategies.Pharmacological interventions, including angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, have shown potential to improve mental health outcomes in patients with comorbid hypertension and depression. However, inconsistent findings regarding the impact of antihypertensive medications on depression necessitate further investigation. The comorbidity of these conditions complicates treatment adherence, leading to poorer health outcomes and increased healthcare costs.The clinical implications of this unidirectional or bidirectional comorbidity are considerable, affecting quality of life, treatment adherence, and overall health outcomes. Integrated care approaches, incorporating lifestyle modifications and combined pharmacological treatments, have shown promise in improving compliance and outcomes.Despite extensive research, limitations persist, including difficulties in establishing causality, inconsistent diagnostic criteria, and the influence of confounding variables. Future research should focus on clarifying the bidirectional relationship between these conditions, the impact of social determinants, and the efficacy of various treatment modalities. Identifying high-risk populations and refining intervention strategies are crucial for improving clinical outcomes in patients with comorbid hypertension and depression.This paper aims to review the current literature regarding the association and comorbidity of hypertension and depression.Abbreviations: ACE: Angiotensin-Converting Enzyme; ARBs: Angiotensin Receptor Blockers; DBP: Diastolic Blood Pressure; mm Hg: Millimeters of Mercury; QoL: Quality of Life; SBP: Systolic Blood Pressure

Autologous Slings in Female Stress Urinary Incontinence Treatment: Systematic Review and Meta-Analysis of Randomized Controlled Trials.

The aim of this study is to evaluate the efficacy and safety of autologous fascial slings (AFS) compared with other surgical methods for female stress urinary incontinence (SUI) treatment. The search was performed on studies published before September 2023 to identify articles assessing the effectiveness and safety of AFS compared with other surgical methods in female SUI. Inclusion criteria were randomized controlled trials (RCTs) and adult women with SUI. Exclusion criteria were other urinary incontinence types, combined pharmacological treatment, pregnancy, and lactation. This systematic review was conducted according to the Population, Intervention, Comparison, and Outcome framework, Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 checklist, and was registered in the Prospective Register of Systematic Reviews. Twenty RCTs were included in the systematic review and 10 RCTs in the meta-analysis. Comparison between AFS and synthetic midurethral slings (SMUS) did not show any statistically significant differences in the cure rate, frequency of urinary retention, or self-catheterization. SMUS showed more long-term postoperative complications (RR = 0.12, 95% CI: 0.03 to 0.50, p = 0.004), AFS had more in de novo urgency cases: (RR = 2.84, 95% CI: 1.13 to 7.10, p = 0.03). Operation time of SMUS was lower: (RR = 2.87, 95% CI: 2.56 to 3.19, p < 0.00001, I2 = 97%). SMUS showed significantly lower hospital stay duration: (RR = 1.92, 95% CI: 1.44 to 2.41, p < 0.00001). In this systematic review and meta-analysis, autologous slings demonstrated the same efficacy in comparison with SMUS in the management of SUI in women. AFS showed lower incidence of long-term postoperative complications. SMUS demonstrated lower operation time, hospital stay and de novo urgency.

Modern approaches to rational combination pharmacotherapy of allergic rhinitis

Allergic rhinitis (AR) can significantly reduce the quality of life of patients leading to increased fatigue, mood changes, cognitive impairment, and depression. In clinical practice, insufficient effectiveness of initial AR monotherapy is often noted, and a significant proportion of patients referring for medical care have moderate-severe AR. In this regard, the issues of optimization of combined pharmacological treatment of AR are becoming more and more urgent. This paper provides analysis of the opportunities of combined pharmacotherapy within the framework of current management strategy of AR. Based on the results of some studies and known pharmacological properties of medications it is being discussed the advantages of combined use of intranasal corticosteroids and leukotriene receptor antagonists, in particular mometasone furoate and montelukast, in the therapy of AR, including such comorbidities as bronchial asthma, chronic polyposis rhinosinusitis and pharyngeal tonsil hyperplasia. Some aspects of combination therapy with montelukast and second-generation systemic antihistamines as an alternative approach in case of inability to take intranasal corticosteroids, including the reasonability of using a fixed combination of montelukast and levocetirizine, are analyzed from the perspective of rational pharmacotherapy. The problem of interchangeability of brand-name and generic drugs for the treatment of AR is discussed, considering the almost complete absence of studies of their therapeutic equivalence.

USE OF COMBINATION TREATMENT IN HYPERTENSION MANAGEMENT AND ITS ASSOCIATION WITH HYPERTENSION CONTROL

Objective: Achievement of blood pressure (BP) targets in hypertension is crucial for cardiovascular prevention and, in most cases, requires combined pharmacological treatment. Current ESC/ESH Guidelines for hypertension management recommend initiating treatment with combination therapy in most hypertensives, except low-risk individuals with mildly elevated BP. Our aim was to assess how this recommendation is applied in practice and whether it is associated with differences in hypertension control. Design and method: In the setting of an ongoing cardiovascular prevention trial (CV-PREVITAL) we prospectively recruited 278 hypertensive patients with no history of cardiovascular disease, among individuals who responded to the advertisement campaign in outpatient facilities of Istituto Auxologico Italiano. Physical examination, standard routine blood tests, office blood pressure recording and standard 24h ABPM has been performed at baseline. We analyzed the office and ambulatory BP control in relationship to the number of antihypertensive drugs and cardiovascular risk assessed by SCORE for low risk countries. Results: Median age of our sample was 61 years, with balanced gender distribution. Ninety-nine (36%) participants were not receiving any pharmacological treatment, 106 (41%) were on monotherapy and 73 (23%) on combined treatment. Comparison of principal characteristics among the three groups is shown in Table 1. Among study participants 44 (16%) had low to moderate CV risk and 227 (84%) had high or very high estimated risk. The percentage of participants receiving combined treatment in these groups was 4.1% and 22.5%, respectively, and the percentage of patients with well controlled office/ambulatory BP was 50%/41% in low to moderate risk and 35%/65% in high to very high risk participants, respectively. Conclusions: In this sample of patients with known hypertension, a considerable proportion received substandard treatment (no treatment or monotherapy), even among those at high risk. This was associated with worse BP control in these individuals. Implementation of current hypertension guidelines in practice remains largely suboptimal.

Two case studies of the treatment of simple onycholysis with disappearing nail bed caused by trauma by combined pharmacological, orthonyxia and taping methods.

Simple onycholysis is a common complaint after trauma and consists in separation of the nail plate from the nail bed. If untreated, prolonged onycholysis may cause a disappearing nail bed (DNB) that leads to the shortening or narrowing of the nail plate. This study is aimed at discussing possible treatment of chronic simple onycholysis with DNB by combined conservative methods. Simple onycholysis and DNB treatment consists of Onygen® cream application, nail bed massages, bracing procedures and nail folds taping with kinesio tape. Long-lasting simple onycholysis with DNB may be fully eliminated by applying the combined pharmacological, orthonyxia and taping treatment. Advanced simple onycholysis, which leads to the DNB and, in consequence, to the shortening or narrowing of the nail plate, causes cosmetic discomfort for patients. A damaged nail apparatus is also more susceptible to new traumas. Even long-standing onycholysis with DNB can be successfully treated with easy-to-apply conservative methods. The key point of therapy is the use of several methods of treatment with different effects on the nail apparatus. The effects of described therapy are highly satisfactory, the only drawback being its long term, which is caused by slow growth of the nails.

PPAR-Gamma Orchestrates EMT, AGE, and Cellular Senescence Pathways in Colonic Epithelium and Restrains the Progression of IBDs.

Intestinal fibrosis, the most common complication of inflammatory bowel disease (IBD), is characterized by an uncontrolled deposition of extracellular matrix proteins leading to complications resolvable only with surgery. Transforming growth factor is the key player in the epithelial-mesenchymal transition (EMT) and fibrogenesis process, and some molecules modulating its activity, including peroxisome proliferator-activated receptor (PPAR)-γ and its agonists, exert a promising antifibrotic action. The purpose of this study is to evaluate the contribution of signaling other than EMT, such as the AGE/RAGE (advanced glycation end products/receptor of AGEs) and the senescence pathways, in the etiopathogenesis of IBD. We used human biopsies from control and IBD patients, and we used a mouse model of colitis induced by dextran-sodium-sulfate (DSS), without/with treatments with GED (PPAR-gamma-agonist), or 5-aminosalicylic acid (5-ASA), a reference drug for IBD treatment. In patients, we found an increase in EMT markers, AGE/RAGE, and senescence signaling activation compared to controls. Consistently, we found the overexpression of the same pathways in DSS-treated mice. Surprisingly, the GED reduced all the pro-fibrotic pathways, in some circumstances more efficiently than 5-ASA. Results suggest that IBD patients could benefit from a combined pharmacological treatment targeting simultaneously different pathways involved in pro-fibrotic signals. In this scenario, PPAR-gamma activation could be a suitable strategy to alleviate the signs and symptoms of IBD and also its progression.

Enhancing Psychological Interventions for Post-Traumatic Stress Disorder (PTSD) Treatment with Memory Influencing Drugs.

Post-traumatic stress disorder (PTSD) is a chronic psychiatric disease resulting from the experience or witnessing of traumatic events. Persistent PTSD symptoms impair patients' daily quality of life, jeopardizing sleep, mood, sociability, and arousal. Recommended psychological or pharmacological interventions are effective only in a small portion of patients and often lead to relapse. Thus, there is a critical need to address a lack of advancement in the treatment of PTSD. The combination of psychological interventions, aimed at facilitating the extinction of the traumatic memory, and pharmacological medications, represents a promising tool for PTSD treatment. Timely use of psychotherapy in conjunction with pharmacological treatments, rather than monotherapy, could thus determine a synergistic effect by potentiating the effects of psychological interventions. In such a scenario, drugs that modulate cognitive processes involved in the development and/or persistence of post-traumatic symptomatology could be of great help to improve the outcome of psychotherapies and patients' prognosis. The purpose of the present article is to review the current data available from clinical trials on combined pharmacological treatments with psychological interventions in PTSD therapy. An overview of findings from animal studies that prompted clinical research is also discussed.

The Evaluation Of Smoking Cessation Treatment Success and Related Factors in Adults Age 65 Years and Older

ABSTRACT Objectives The aim was to evaluate smoking cessation treatment success and factors associated in older adults. Methods In the retrospective cohort study, the patients’ sociodemographic data, smoking history, Fagerström Test for Nicotine Dependence scores (FTND), type of treatments (Pharmacological treatments, behavioral counseling, and/or both) and the number of follow-up sessions in the Smoking Cessation Outpatient Clinic were taken from hospital files of the patients. Treatment success was evaluated as one year of abstinence from smoking. Results Participants’ reported with 53% classified as high-very high nicotine dependence. Overall, 36% reported abstinence from smoking for one year or more. Treatment success was associated with higher attendance at follow-up sessions. Using pharmacologic treatments and behavioral counseling together was proved to be more effective than behavioral counseling alone. Conclusions One-year smoking cessation was achieved in one-third of older adults attending a smoking cessation clinic. In older adults in this sample low FTND scores, use of combined pharmacologic and behavioral treatment, and attendance at follow up sessions were associated with one year smoking abstinence. Clinical Implications Older adults should be referred for smoking cessation treatment. Use of combined pharmacological and behavioral counseling is recommended. Efforts to enhance attendance at follow-up sessions should be considered.

Landscape of Druggable Molecular Pathways Downstream of Genomic CDH1/Cadherin-1 Alterations in Gastric Cancer.

Loss of CDH1/Cadherin-1 is a common step towards the acquisition of an abnormal epithelial phenotype. In gastric cancer (GC), mutation and/or downregulation of CDH1/Cadherin-1 is recurrent in sporadic and hereditary diffuse GC type. To approach the molecular events downstream of CDH1/Cadherin-1 alterations and their relevance in gastric carcinogenesis, we queried public databases for genetic and DNA methylation data in search of molecular signatures with a still-uncertain role in the pathological mechanism of GC. In all GC subtypes, modulated genes correlating with CDH1/Cadherin-1 aberrations are associated with stem cell and epithelial-to-mesenchymal transition pathways. A higher level of genes upregulated in CDH1-mutated GC cases is associated with reduced overall survival. In the diffuse GC (DGC) subtype, genes downregulated in CDH1-mutated compared to cases with wild type CDH1/Cadherin-1 resulted in being strongly intertwined with the DREAM complex. The inverse correlation between hypermethylated CpGs and CDH1/Cadherin-1 transcription in diverse subtypes implies a common epigenetic program. We identified nonredundant protein-encoding isoforms of 22 genes among those differentially expressed in GC compared to normal stomach. These unique proteins represent potential agents involved in cell transformation and candidate therapeutic targets. Meanwhile, drug-induced and CDH1/Cadherin-1 mutation-related gene expression comparison predicts FIT, GR-127935 hydrochloride, amiodarone hydrochloride in GC and BRD-K55722623, BRD-K13169950, and AY 9944 in DGC as the most effective treatments, providing cues for the design of combined pharmacological treatments. By integrating genetic and epigenetic aspects with their expected functional outcome, we unveiled promising targets for combinatorial pharmacological treatments of GC.

Prognostic significance of germline BRCA mutations in patients with HER2-POSITIVE breast cancer

BackgroundHER2-positive breast cancers are rare amongst BRCA mutation carriers. No data exist regarding clinicopathological characteristics and prognosis of this subgroup of patients. Materials and methodsUsing a retrospective matched cohort design, we collected data from 700 women who were diagnosed with operable invasive breast cancer from January 2006 to December 2016 and were screened for germline BRCA mutations. Clinicopathological features and survival rates were analyzed by BRCA and HER2 status. ResultsOne hundred and fifteen HER2-positive/BRCA mutated cases were evaluated in comparison to the three control groups: HER2-positive/BRCA wild type (n = 129), HER2-negative/BRCA mutated (n = 222), HER2-negative/BRCA wild type (n = 234). HER2-positive breast cancers were more likely to have high histologic grade and high proliferation rate than HER2-negative neoplasms, regardless of BRCA mutation status. An interaction between BRCA mutations and HER2-positive status was found to correlate with worse survival after adjusting for prognostic variables (HR = 3.4; 95% CI: 1.3–16.7). ConclusionsCo-occurrence of BRCA mutations and HER2-positive status is a poor prognostic factor in patients with early or locally advanced breast cancer. This finding may be a proof of concept that a combined pharmacological intervention directed to these targets could be synergistic.

Statins, Fibrates and Myopathy: pathophysiological mechanism, risk factors and laboratory markers / Estatinas, Fibratos e Miopatia: mecanismos fisiopatológicos, fatores de risco e marcadores laboratoriais

With the increasing life expectancy of the world population, the elderly experiences the occurrence of multiple chronic diseases, a phenomenon called multimorbidity. Such condition induces the need for the elderly to engage in combined pharmacological treatments, giving rise to polypharmacy, leading to the often unnecessary and inadequate consumption of some drugs. Among these, we can mention fibrates and statins, widely used in the control and treatment of dyslipidemia. Both classes of drugs present as the main adverse effect of concern the genesis of myalgias and myositis, with evolution to rhabdomyolysis. In view of the above, this study aimed to understand the mechanism responsible for inducing muscle damage in the administration of these drugs, also considering the factors that favor their appearance and the laboratory markers used for diagnostic purposes. This work was carried out from a bibliographic review using scientific articles published in English, Portuguese and Spanish, available in the PubMed, Scielo, LILACS and Google academic databases.

Systematic Review and Meta-analysis: Pharmacological and Nonpharmacological Interventions for Persistent Nonepisodic Irritability

This meta-analysis examined the efficacy of available pharmacological and nonpharmacological interventions for irritability among youth with autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), disruptive behavior disorders (DBD), disruptive mood dysregulation disorder (DMDD), and/or severe mood dysregulation (SMD). Literature searches were conducted in October 2020, resulting in 564 abstracts being reviewed to identify relevant papers, with 387 articles being reviewed in full. A random effects model was used for the meta-analysis, with subgroup meta-regressions run to assess effects of study design, intervention type, medication class, and clinical population. A total of 101 studies were included (80 pharmacological, 13 nonpharmacological, 8 combined). Despite high heterogeneity in effects (I2= 94.3%), pooled posttreatment effect size for decreasing irritability was large (Hedges' g= 1.62). Large effects were found for pharmacological (g=1.85) and nonpharmacological (g= 1.11) interventions; moderate effects were found for combined interventions relative to monotherapy interventions (g= 0.69). Antipsychotic medications provided the largest effect for reducing irritability relative to all other medication classes and nonpharmacological interventions. A large effect was found for youth with ASD (g= 1.89), whereas a medium effect was found for youth with ADHD/DMDD/DBD/SMD (g= 0.64). This meta-analysis provides a comprehensive review of interventions targeting persistent nonepisodic irritability among youth with various psychiatric disorders. Strong evidence was found for medium-to-large effects across study design, intervention type, and clinical populations, with the largest effects for pharmacological interventions, particularly antipsychotic medications and combined pharmacological interventions, and interventions for youth with ASD.

Perceived Criticism and Family Attitudes as Predictors of Recurrence in Bipolar Disorder.

Bipolar disorder (BD) is a highly recurrent psychiatric condition. While combined pharmacological and psychosocial treatments improve outcomes, not much is known about potential moderators that could affect these treatments. One potential moderator might be the quality of interpersonal relations in families, for example, familial attitudes and perceived criticism. To explore this question we conducted a post-hoc analysis that used an existing data set from a previous study by our group that compared cognitive behavioral therapy (CBT) and supporting therapy (ST) in remitted BD. In the present study, we used Cox proportional hazard models. We found that the relatives' ratings of criticism predicted the likelihood of depressive recurrences, especially in the ST condition. The patients' ratings of negative familial attitudes predicted the risk of recurrences in general, irrespective of the therapy condition. These results suggest that it might be important to assess perceived criticism and familial attitudes as potential moderators of treatment outcome in BD.

Inhibition of CK2 mitigates Alzheimer\u2019s tau pathology by preventing NR2B synaptic mislocalization

Alzheimer’s disease (AD) is a neurodegenerative disorder that exhibits pathological changes in both tau and synaptic function. AD patients display increases in hyperphosphorylated tau and synaptic activity. Previous studies have individually identified the role of NR2B subunit-containing NMDA receptors in AD related synaptic dysfunction and aggregated tau without reconciling the conflicting differences and implications of NR2B expression. Inhibition of extrasynaptically located NR2B mitigates tau pathology in AD models, whereas the inhibition of synaptic NR2B replicates tau-associated hyperactivity. This suggests that a simultaneous increase in extrasynaptic NR2B and decrease in synaptic NR2B may be responsible for tau pathology and synaptic dysfunction, respectively. The synaptic location of NR2B is regulated by casein kinase 2 (CK2), which is highly expressed in AD patients. Here, we used patient brains diagnosed with AD, corticobasal degeneration, progressive supranuclear palsy or Pick’s disease to characterize CK2 expression across these diverse tauopathies. Human derived material was also utilized in conjunction with cultured hippocampal neurons in order to investigate AD-induced changes in NR2B location. We further assessed the therapeutic effect of CK2 inhibition on NR2B synaptic distribution and tau pathology. We found that aberrant expression of CK2, and synaptically translocated NR2B, is unique to AD patients compared to other tauopathies. Increased CK2 was also observed in AD-tau treated neurons in addition to the mislocalization of NR2B receptors. Tau burden was alleviated in vitro by correcting synaptic:extrasynaptic NR2B function. Restoring NR2B physiological expression patterns with CK2 inhibition and inhibiting the function of excessive extrasynaptic NR2B with Memantine both mitigated tau accumulation in vitro. However, the combined pharmacological treatment promoted the aggregation of tau. Our data suggests that the synaptic:extrasynaptic balance of NR2B function regulates AD-tau pathogenesis, and that the inhibition of CK2, and concomitant prevention of NR2B mislocalization, may be a useful therapeutic tool for AD patients.

Impact of Repeated Lidocaine Injections, Exercise, and Mindfulness on Fibromyalgia Symptoms in a Clinical Population

Fibromyalgia (FM) patients usually are resistant to conventional single mode therapy. Therefore, the efficacy of combined pharmacological and nonpharmacological treatments for the management of FM symptoms in a clinical population was assessed. Participants were injected with 4x5 mL 1% lidocaine HCl solution and given education materials and support on increasing their daily steps walked and to engage in mindfulness techniques to reduce their overall pain and accompanying symptoms of their condition. Participants self-reported pain intensity, unpleasantness, anxiety, fatigue, and depression three days prior to and after each injection. Overall ratings of pain intensity and unpleasantness showed statistically significant reductions of 34.7 and 47.2 percent respectively with the combined use of treatments. Additionally, fatigue levels had a significant decrease but depression and anxiety ratings were not significantly modified by this treatment modality. Patients who had a greater adherence to their protocol had an improved pain relief when compared to others. These results suggest that the use of a combination treatment method for FM in a clinical setting and when used in combination is effective. This pilot study can be used as a model for future randomized controlled studies on comprehensive treatments for FM.

Interventions to improve adherence to pharmacological therapy for chronic obstructive pulmonary disease (COPD).

Interventions to improve adherence to pharmacological therapy for chronic obstructive pulmonary disease (COPD).

Association of plasma and CSF cytochrome P450, soluble epoxide hydrolase, and ethanolamide metabolism with Alzheimer\u2019s disease

BackgroundAlzheimer’s disease, cardiovascular disease, and other cardiometabolic disorders may share inflammatory origins. Lipid mediators, including oxylipins, endocannabinoids, bile acids, and steroids, regulate inflammation, energy metabolism, and cell proliferation with well-established involvement in cardiometabolic diseases. However, their role in Alzheimer’s disease is poorly understood. Here, we describe the analysis of plasma and cerebrospinal fluid lipid mediators in a case–control comparison of ~150 individuals with Alzheimer’s disease and ~135 healthy controls, to investigate this knowledge gap.MethodsLipid mediators were measured using targeted quantitative mass spectrometry. Data were analyzed using the analysis of covariates, adjusting for sex, age, and ethnicity. Partial least square discriminant analysis identified plasma and cerebrospinal fluid lipid mediator discriminates of Alzheimer’s disease. Alzheimer’s disease predictive models were constructed using machine learning combined with stepwise logistic regression.ResultsIn both plasma and cerebrospinal fluid, individuals with Alzheimer’s disease had elevated cytochrome P450/soluble epoxide hydrolase pathway components and decreased fatty acid ethanolamides compared to healthy controls. Circulating metabolites of soluble epoxide hydrolase and ethanolamides provide Alzheimer’s disease predictors with areas under receiver operator characteristic curves ranging from 0.82 to 0.92 for cerebrospinal fluid and plasma metabolites, respectively.ConclusionsPrevious studies report Alzheimer’s disease-associated soluble epoxide hydrolase upregulation in the brain and that endocannabinoid metabolism provides an adaptive response to neuroinflammation. This study supports the involvement of P450-dependent and endocannabinoid metabolism in Alzheimer’s disease. The results further suggest that combined pharmacological intervention targeting both metabolic pathways may have therapeutic benefits for Alzheimer’s disease.

New Incretin Combination Treatments under Investigation in Obesity and Metabolism: A Systematic Review.

The worldwide upward trend in obesity in adults and the increased incidence of overweight children suggests that the future risk of obesity-related illnesses will be increased. The existing anti-obesity drugs act either in the central nervous system (CNS) or in the peripheral tissues, controlling the appetite and metabolism. However, weight regain is a common homeostatic response; current anti-obesity medications show limited effectiveness in achieving long-term weight loss maintenance; in addition to being linked to various side effects. Combined anti-obesity medications (per os or injectable) target more than one of the molecular pathways involved in weight regulation, as well as structures in the CNS. In this systematic review, we conducted a search of PubMed and The ClinicalTrials.gov up to February 2021. We summarized the Food and Drug Administration (FDA)-approved medications, and we focused on the combined pharmacological treatments, related to the incretin hormones, currently in a clinical trial phase. We also assessed the mechanism of action and therapeutic utility of these novel hybrid peptides and potential interactions with other regulatory hormones that may have beneficial effects on obesity. As we improve our understanding of the pathophysiology of obesity, we hope to identify more novel treatment strategies.

Evaluating treatments for posttraumatic stress disorder, alcohol and other drug use disorders using meta-analysis of individual patient data: Design and methodology of a virtual clinical trial

This paper describes Project Harmony, a Virtual Clinical Trial (VCT) funded by the National Institute on Alcohol Abuse and Alcoholism (NIAAA) to harmonize and analyze data from over 40 independent psychological, pharmacologic and/or combined pharmacological treatment studies for posttraumatic stress disorder and comorbid alcohol and other drug use disorders (PTSD/AOD). The study attends to three distinct analysis challenges: (1) variation in measurement of PTSD/AOD across studies, time, populations and reporters, (2) cross-study variation in treatment effect sizes and (3) non-randomized, cross-study variation in the classification of treatments (despite within-study randomization of treatment arms). To address these challenges, the study combines meta-analysis of individual patient data (MIPD), integrative data analysis (IDA) and propensity score weighting (PSW) to integrate raw data from these clinical trials. This protocol shows how this VCT analytic framework was used to (1) develop commensurate scale scores of PTSD and AOD severity when measures vary across studies, (2) compare the efficacy of evidence-based treatment models for PTSD/AOD, (3) test for potential mediators of treatment effects on AOD and PTSD across treatment models, and (4) explore individual- and study-level moderators to inform for whom each of the treatment models works best. The advantages of the general VCT approach are juxtaposed against the limitations of single randomized controlled trials and conventional meta-analysis.

Impact of Tai Chi on global connectivity in geriatric depression

<h3>Introduction</h3> Depression is generally associated with dysconnectivity among brain regions. Mind-body interventions such as Tai Chi can improve stress, and thus, comprise a promising adjunct treatment to antidepressants. We tested the effect of twelve weekly Tai Chi lessons on global connectivity in older depressed adults (aged >60 years). <h3>Methods</h3> Forty older adults with major depressive disorder under concurrent antidepressant treatment were randomized to receive Tai Chi training (N=21; 17 women; age, 67.1±7.4 years) or health education (N=19; 15 women; age, 68.2±5.6 years), and completed baseline and 12-week follow-up resting state magnetic resonance imaging scans. Fine-grained parcellation of the brain into 718 cortical and subcortical parcels, with each parcel assigned to one of 12 major networks, was performed using the CAB-NP atlas. Pairwise correlations between parcel timeseries were computed, and the change in connectivity (post–pre) was submitted to general linear modeling, with correction for multiple comparisons (1000 permutations; false discovery rate) and adjustment for sex and age. <h3>Results</h3> There were few significant increases with health education (∼0.03% of ∼257K pairwise connections; post vs pre). In the Tai Chi group, connectivity changes mainly reflected increased connectivity (∼0.3% of all pairwise connections; post vs pre), with the increase in connectivity reaching significance in the comparison between groups (Tai Chi post-pre vs control post-pre) for 194 connections, which were highly concentrated (48/194; 25%) within the default mode network (DMN; Figure 1), followed by connections between DMN and frontoparietal network regions (12/194; 6%). Within-DMN connections that significantly increased with Tai Chi and showed a significant group difference in the increase in connectivity are shown in Figure 1. The 718 nodes of the CAB-NP atlas are shown in the figure, with regions assigned to the DMN in purple and regions assigned to other networks in blue. <h3>Conclusions</h3> Tai Chi as an adjunct to antidepressants is effective in reorganizing the brain toward greater global connectivity, especially affecting DMN connectivity, in older depressed adults. DMN within-network connectivity has been implicated in depression, mainly in terms of dysconnectivity, and connectivity between the DMN and a subsystem of the frontoparietal control network is thought to be involved in the regulation of introspective processes. Our previous study suggested that symptom improvement with combined pharmacological treatment is associated with increased connectivity of core DMN nodes. The present study further supports the importance of the DMN in depression, and suggests that non-pharmacological adjuncts can also enhance DMN functional reorganization in geriatric depression. <h3>Funding</h3> Sponsored by NIH grant AT008383 and National Center for Advancing Translational Science (NCATS) UCLA CTSI Grant Number UL1TR001881.