Cognitive remission: a novel objective for the treatment of major depression?

BACKGROUND: Cognitive dysfunction in major depressive disorder (MDD) encompasses several domains, including but not limited to executive function, verbal memory, and attention. Furthermore, cognitive dysfunction is a frequent residual manifestation in depression and may persist during the remitted phase. Cognitive deficits may also impede functional recovery, including workforce performance, in patients with MDD. The overarching aims of this opinion article are to critically evaluate the effects of available antidepressants as well as novel therapeutic targets on neurocognitive dysfunction in MDD. DISCUSSION: Conventional antidepressant drugs mitigate cognitive dysfunction in some people with MDD. However, a significant proportion of MDD patients continue to experience significant cognitive impairment. Two multicenter randomized controlled trials (RCTs) reported that vortioxetine, a multimodal antidepressant, has significant precognitive effects in MDD unrelated to mood improvement. Lisdexamfetamine dimesylate was shown to alleviate executive dysfunction in an RCT of adults after full or partial remission of MDD. Preliminary evidence also indicates that erythropoietin may alleviate cognitive dysfunction in MDD. Several other novel agents may be repurposed as cognitive enhancers for MDD treatment, including minocycline, insulin, antidiabetic agents, angiotensin-converting enzyme inhibitors, S-adenosyl methionine, acetyl-L-carnitine, alpha lipoic acid, omega-3 fatty acids, melatonin, modafinil, galantamine, scopolamine, N-acetylcysteine, curcumin, statins, and coenzyme Q10. The management of cognitive dysfunction remains an unmet need in the treatment of MDD. However, it is hoped that the development of novel therapeutic targets will contribute to \u27cognitive remission\u27, which may aid functional recovery in MDD

Investigating the bidirectional association between cardiovascular diseases and depression

Background: Cardiovascular diseases (CVDs) are the leading cause of disability and mortality globally. Although there has been substantial medical advancement in treating and managing CVDs, surviving CVD patients are at a greater risk of mortality and morbidity. Thus, preventative approaches aiming to identify, manage and control CVD risk factors remain the highest priority. Depression is a leading cause of disability worldwide, and it has been considered a relevant emergent, non-classical risk factor for the onset and poor prognosis of CVDs. Several systematic reviews have been published on this subject, providing evidence that depression is associated with an increased risk of CVD incidence. However, these reviews were limited by incorporating poor study designs and by focusing predominantly on a single CVD outcome. This previously fragmented investigation masked the overall picture of how strongly depression impacts each CVD subtype. At the same time, hypertension is one of the biggest risk factors for CVD; hence, the management and control of hypertension is of the utmost importance. Hypertensive patients mainly rely on antihypertensive treatment with a high dosage regimen and/or a combination of several antihypertensive drugs for the long term to control blood pressure and to consequently prevent the development or complication of CVD. Emerging evidence has investigated the effect of antihypertensive drugs in relation to depression onset, though the exact relationship remains unclear. Given that both hypertension and depression are risk factors for CVD, it becomes important that therapeutic agents to control blood pressure not have deleterious effects toward triggering depressive disorders, as both conditions will have a relevant big impact on patient’s health particularly those at high CVD risk. Objectives: This thesis has two main objectives: (1) updating the evidence of the association between depression and the risk of major subtypes of CVDs and (2) to investigate the association between exposure to antihypertensive drugs and risk of depression incident. Method: For the first objective, I conducted a systematic review and meta-analyses. Depression in the review referred to depressive symptoms or clinical depression and main outcomes of interest were incidence of fatal/non-fatal coronary heart diseases (CHD), heart failure (HF) and stroke, each measured as a single endpoint and reported as hazard ratio (HR) and 95% confidence interval (CI). The results for the systematic review were divided into three main results chapters based on the main outcomes (4-6). For the second objective, a secondary analysis of existing data held in the Glasgow Blood Pressure Clinic (GBPC) was conducted. Exposure was antihypertensive drugs which involves the five major classes including calcium channel blocker (CCB), beta-blocker (BB), angiotensin converting enzyme inhibitor (ACEI), angiotensin receptor blocker (ARB) and thiazide diuretic (TZD). The primary outcome was depression as indicated by the first prescription of antidepressants drug. Main findings of this analysis are presented in chapter 7. Results: Chapter 4 evaluated the relation between depression and risk of stroke. The meta-analysis included 19 studies enrolling 3,154,290 participants, with an average follow-up of 11.2 years. The pooled estimated risk revealed that baseline depression is associated with a 22% (HR = 1.22, 95% CI, 1.11-1.33) increased risk of developing first-ever stroke, with evidence of substantial statistical heterogeneity between studies (I2 = 67%). The magnitude of risk presented in this study is more modest than that previously reported in past systematic reviews for stroke outcomes. Sensitivity analyses were carried out to assess for a possible reverse causality (i.e. depression manifested as an acute sickness response to a subclinical stroke). This was achieved by restricting the analysis to four studies that considered a lag period, excluding stroke events occurring during the first years of follow-up. The results showed that depression remains a statistically strong predictor of stroke incidents with a more pronounced effect, and a wider 95% CI was obtained, which might indicate uncertainty (HR = 1.39, 95% CI, 1.11, 1.74). The statistical positive association remained significant after further restricting the analysis to five studies that measured depression over multiple instants over the follow-up period and modelled depression as a time-varying exposure (HR = 1.33, 95% CI, 1.10, 1.59). This finding suggests that elevated lifetime depressive symptoms among adults can be used as a reliable measure to predict future risk of stroke; however, due to the limited number of studies included to derive these findings, the result should be considered with caution and more work is required to confirm this finding. Subgroup analysis was also performed, and the findings showed that depressed elderly participants aged 65 years or above were at a lower risk of developing stroke than depressed participants at a younger age (< 65 years). However, the group difference showed only a borderline significance (p = .5). The results of this analysis may indicate that depression occurring at an early age might have a more devastating effect than late-life depression, though this finding should be considered with caution given the good heart health condition of elderly patients at baseline. Future epidemiological studies should be carried out on a large-scale to identify the clinical characteristics of participants that make them more prone to developing depression at an early age. Chapter 5 examined the association between depression and incident CHD. The meta-analysis incorporated 23 studies with 33,786299 participants and an average follow-up of 12.4 years. The pooled summary effect showed that the risk of CHD incident increased with depression by 22% (HR= 1.22, 95% CI, 1.13-1.32, p < .000) with evidence of substantial statistical heterogeneity between studies (I2 = 77%). The estimated risk presented in this study is almost identical to the latest review. This study also found that depression is associated with a 24% higher risk of developing myocardial infarction (HR = 1.24, 95% CI, 1.19, 1.29) with no evidence of statistical heterogeneity between studies (I2 = 0%). Sensitivity analyses comprising five cohort studies that considered a lag period provided similar risk estimates (HR = 1.22, 95% CI, 1.01, 1.48). Five studies modelled depression as a time varying exposure; a meta-analysis of these studies revealed an increased risk of incident CHD for depression, though a slightly lower magnitude was observed (HR = 1.17, 95% CI, 1.07, 1.28). Subgroup analysis by type of depression measures showed that the effect of clinical depression is more pronounced (HR = 1.26, 95% CI, 1.20, 1.32; I2 = 0%) than depressive symptoms (HR = 1.17, 95% CI, 1.10, 1.25; I2 = 0%) on risk of CHD incidence. In Chapter 6, I investigated the association between depression and incident HF in a CVD-free population. The meta-analysis was based on only four cohort studies with 2,200,308 participants and an average follow-up of 10.13 years. The main finding revealed that depression was associated with a 17% (HR = 1.17, 95% CI, 1.08, 1.38) increased risk of HF in the absence of CVD events at baseline, with no statistically significant amount of heterogeneity (I2 = 0%). The hypothesis of a dose-response relation was also assessed. Overall, this review identified 12 cohort studies that assessed a dose-response relation between depression and CVD outcomes. For stroke outcomes, four studies suggested a dose-response relation, and two did not confirm this finding (chapter 4). For CHD events, four studies showed no evidence of a dose-response relation and four found that depression increased the risk of CHD incident in a dose-response manner (chapter 5). Importantly, there was substantial heterogeneity in terms of how the studies defined ‘a dose of depression’, which seriously hampered the meta-analysis and drawing of conclusions. Future studies should establish guidance for researchers on the optimal measures of ‘a dose of depression’ to investigate such a relation. Chapter 7 covered the investigation of the association between antihypertensive drugs and the risk of incident depression. This was a retrospective cohort study in which I analysed data of hypertensive patients attending the GBPC, providing secondary and tertiary care service, between January 2005 and March 2013. All patients aged between 18 and 80 years who were newly commenced on antihypertensive drugs were included in this cohort. Exposure to ACEI, ARB, BB, CCB, and diuretics was assessed. Patients were prospectively followed up to the outcome, death, or end of the study. Depression as an outcome in this cohort was defined as patients who filled at least two prescriptions of antidepressants during the study period. Two analyses were performed. The first analysis was on patients who were on antihypertensive monotherapy. Eligible patients had no known history of depression and were on an antihypertensive monotherapy of the same drug class within a 12-month window defined as the exposure period. Patients who died or developed the outcome during the exposure period were excluded. The association between antihypertensive drug classes and depression incidence was investigated using Cox proportional hazards models to estimate HR, and patients who received ACEI therapy were set as the reference group. In this analysis, a dose-response relationship was also investigated, whereby the cumulative defined daily dose (cDDD) of antihypertensives during the exposure period was stratified into tertiles and the lowest tertile was set as the reference group. The second analysis was on patients who were either on antihypertensive monotherapy or polytherapy. In this analysis, eligible patients had an exposure period of 6 months preceded by 6 months of no antihypertensive or antidepressant prescription records. Patients who developed the outcome or died within the six months of the exposure period were excluded. Studied antihypertensive drug classes were additionally included alpha-blocker and centrally acting antihypertensive drugs. CCB and diuretic classes were divided into dihydropyridine CCB and non-dihydropyridine CCB, diuretics, and mineralocorticoids diuretic, correspondingly. Both Cox proportional hazards models and the generalised estimating equation (GEE) were used to investigate the association between antihypertensive drugs and incident depression. The reference group in this analysis was also patients on ACEI therapy. Findings of the monotherapy analysis showed that, among the five major classes of antihypertensive drugs, CCB had the highest risk of developing depression after adjusting for covariates, compared to the ACEI group (HR = 1.39; 95% CI: 1.07, 1.82). Consistence results derived from the polytherapy analysis showed that dihydropyridine CCB was associated with a significantly increased risk of incident depression in comparison to ACEI (HR = 1.38; 95% CI: 1.03, 1.86). The GEE analysis further confirmed this finding (OR = 1.32 95% CI: 1.06, 1.64). The dose-response analysis demonstrated that higher cDDD of ARB was associated with a greater risk of depression, although the association was marginally significant (p = 0.055). Conclusion: This thesis provided evidence that depression imposes a similar level of risk across different CVD subtypes. Future epidemiological studies should examine the dynamic aspects of depressive symptoms in relation to CVD and subclinical CVD, whether the risk of CVD is related to a specific subtype of depression, and the role of antidepressant drugs in this association. The present thesis showed that among population with complicated hypertension, CCB is associated with an increased risk of depression incidence compared to ACEI, supporting findings of previous studies. The risk of developing depression is also linked to ARB, although it might be dose dependent. A well-designed randomised control trial is the optimal study design to validate these findings, and up to that time when a clear association is established, these medications should continue to be used as recommended by the current guidelines for hypertension treatment and CVD prevention

Core evidence elements for generating medicine safety evidence for pregnancy using population-based data: Recommendations from IMI-ConcePTION

Background: The risks and benefits of medicine use during pregnancy are typically established through post-approval population-based observational studies. Currently, there is heterogeneity in the identification, selection and the definitions of key pregnancy and maternal outcomes of interest, exposures, risk factors, and confounders. There is also a large range of different study designs and statistical tools available for these studies. Objectives: IMI-ConcePTION (https://www.imi-conception.eu/) identified the need to create recommendations for standardized key concepts and research methods. Methods: The core evidence elements guide for population-based observational studies was compiled using expertise in pharmacovigilance, pharmacoepidemiology, perinatal epidemiology, statistics, perinatal clinical pharmacology, and health services research, both internal and external to IMI-ConcePTION. It also included reviews of the literature, best practices, and regulatory guidance documents. Results: The recommendations cover core evidence elements including gestational age, exposures (dose/duration of medicine and etiological window); relevant confounders; pregnancy outcomes (live and non-live births), congenital anomalies, infant/childhood outcomes (including long-term outcomes), and maternal outcomes; research design considerations; analytical methods; statistical power/sample size considerations and study limitations. A list of “default” core evidence elements is also proposed as a minimal set of elements that should be considered in all pregnancy medicine safety surveillance studies. The recommendations also include guidance when assessing the quality of data sources. Conclusions: This core evidence elements recommendations will facilitate setting standards with regards to the definitions used in medicine and pregnancy studies, the quality of the data and the suitability of data sources used for this work. It can also be tailored to address studies with specific research questions, particular medicines/disease areas or specific outcomes. It will promote the conduct of more standardized, high quality and clinically meaningful population-based studies among pregnant women. It will also help with alignment across different studies to improve evidence synthesis

Evaluation of the efficacy, safety and tolerability of herbal medicine for management of the behavioural and psychological symptoms of dementia

Dementia involves a gradual loss of memory and cognitive skills. Over 50% of people with dementia also suffer from the behavioural and psychological symptoms of dementia (BPSD). BPSD refer to disturbed perception, thought content and mood associated with dementia, and include psychosis, agitation, aggression, irritability, depression, anxiety and abnormal motor activity. BPSD can have a negative impact on the progression of Alzheimer’s disease and related disorders and are associated with a greater level of caregiver distress. Currently recommended pharmacological treatments for dementia, including acetylcholinesterase inhibitors and memantine, focus on relieving cognitive symptoms, while BPSD are managed according to the presenting symptoms. Guidelines recommend non-pharmacological approaches for BPSD but selective serotonin reuptake inhibitors, analgesics and second generation antipsychotics may be used when other approaches fail. Pharmacological treatments for BPSD have limited benefit and safe prescribing is difficult as some may produce severe adverse effects and may worsen cognitive symptoms. Consequently, there is a pressing need for new approaches to BPSD management. Multiple clinical studies have reported that herbal medicines (HMs), such as Ginkgo biloba leaf extract, can alleviate BPSD as well as improve cognition in dementia. The present project aimed to determine the current state of evidence for HMs and propose future directions for the development of plant-based therapeutics for managing BPSD. Both historical use and contemporary clinical trials provide evidence for the use of herbs for management of memory impairment, cognitive symptoms of dementia and BPSD. Based on these findings, there is potential for identifying effective herbal interventions that could be fast-tracked into clinical use for this unmet need. Identification of useful compounds and their possible mechanisms of action may contribute to development of new therapeutic approaches and/or drug discovery. Notably, the acetylcholinesterase inhibitors galantamine and rivastigmine were discovered from plant-derived compounds. The objectives of this project were to assess the current state of evidence and its limitations regarding the efficacy, safety and tolerability of HMs for BPSD by systematically reviewing and analysing the results of clinical trials and the classical Chinese medicine literature on BPSD; identify any HMs that show potential benefit for BPSD; based on the best available evidence, select a herbal intervention suitable for further clinical investigation; and design a rigorous randomised controlled trial (RCT) to test the intervention that addresses the limitations of previous clinical studies. The comprehensive systematic review and meta-analysis included 31 controlled clinical trials testing 19 different HMs. Meta-analysis of well-designed, placebo-controlled studies indicated that the G. biloba leaf extract EGb 761® was safe and well-tolerated. Significant and clinically meaningful improvements in BPSD and cognition were detected at 24 weeks. However, independently funded studies of G. biloba leaf extract are needed to confirm these findings. Meta-analysis of randomised, comparative effectiveness studies of the Japanese multi-herb formula Yokukansan (Chinese: Yi gan san) showed no significant differences on BPSD outcomes when compared to standard pharmacotherapies used in Japan for BPSD management and superiority to no treatment. However, the only placebo-controlled study of Yokukansan for BPSD did not find any difference in BPSD outcomes at the end of four weeks treatment. Important limitations were identified in this trial which could have resulted in a false negative. These included its short duration, relatively small sample size, large improvement in the placebo group, and the use of a simplified outcome measure which could be less likely to detect changes in symptoms. Overall, the clinical evidence for Yokukansan suggested improvements in BPSD, notably in the clinically important symptoms of irritability/lability and agitation/aggression. An issue identified with Yokukansan was the increased risk of liquorice-induced hypokalaemia, which requires monitoring. Lack of replication and methodological issues in the studies testing other HMs precluded any conclusions for these other interventions. The classical Chinese medical literature was evaluated using the Zhong Hua Yi Dian database, using similar methods to a previous study which evaluated the herbs used for treatment of the cognitive symptoms of dementia. No specific term in the literature corresponded with BPSD, although terms for specific symptoms such as anxiety, depression and agitation were frequently mentioned in conjunction with terms for memory impairment. Some of the HMs described in the classical Chinese medical literature for treatment of memory impairments with mood and behavioural symptoms had also been tested in the clinical trial literature, including Glycyrrhiza uralensis, Poria cocos and Angelica species, which are ingredients of Yokukansan, but the most frequently cited herbs in the classical literature were generally not the same as the frequently tested HMs in clinical trials. The in vitro and in vivo literature showed evidence of relevance to treatment of BPSD for G. biloba, Yokukansan and their constituent compounds. For both these HMs, animal studies have reported anti-aggression-like, antidepressant-like, anxiolytic-like effects as well as benefits on abnormal motor activities and reduction in cognitive impairments and mental stress. Important activities of G. biloba leaf and Yokukansan of relevance to BPSD include modulation of neurotransmission, neuroendocrine regulation and antioxidant effects. The issue of wide variation in placebo effect sizes in BPSD studies was explored through meta-analysis of placebo data. Results showed that placebo effect sizes for BPSD have increased over time. Proposed new studies may therefore require larger sample sizes in order to be adequately powered. Based on the available evidence, it appears that EGb 761® provides small improvements in cognitive symptoms and reduces BPSD while Yokukansan can improve BPSD but not cognition, although it does not appear to have any negative effect on cognition. Both HMs are available commercially, are well characterised and are in widespread use but their combination has not been tested in a clinical trial. Notably, most studies of EGb 761® were conducted in Europe or Russia while Yokukansan was tested in Japan. Therefore, it was proposed that the combination of EGb 761® and Yokukansan at conservative dosages should be tested through an adequately powered, randomised, placebo-controlled clinical trial. A clinical trial protocol was designed which utilised validated diagnostic criteria and assessments relevant to an older population with BPSD, including assessments of caregiver distress associated with BPSD. Issues relating to informed consent from participants and their caregivers were addressed. Safety was an important consideration and was addressed through inclusion and exclusion criteria, careful monitoring of adverse events and strategies to reduce the risk of liquorice-induced hypokalaemia. The results of the RCT would provide useful data on the safety, tolerability and efficacy of this combined intervention in an Australian population with BPSD. The results would assist with clinical decision-making in the management of BPSD

Gastrointestinal Tract Disorders

Gastrointestinal tract disorders are a wide group of diseases involving both the gastrointestinal tube (esophagus, stomach, small and large intestine) and related organs (liver, pancreas, and gallbladder). These dysfunctions may differ by site, etiology, and severity, going from simple malfunctions to mere diseases. Because of their variety and heterogeneity, gastrointestinal disorders can affect many people and are widespread throughout the population. Therefore, scientific research in this area is facing a great challenge. Better knowledge of gastrointestinal disorders in terms of their pathophysiology, clinical features, and possible complications is necessary for the development of new diagnostic methods and therapeutic strategies. During the last several decades, some scientific developments have already been made, giving more opportunities to these patients. However, much remains to be discovered and to be done to help physicians in their everyday work and to give patients a better prognosis. The present Special Issue aims to highlight recent advances in gastrointestinal tract disorders, focusing on their diagnostic and therapeutic path, evolution, and complications

Medical-Data-Models.org:A collection of freely available forms (September 2016)

MDM-Portal (Medical Data-Models) is a meta-data repository for creating, analysing, sharing and reusing medical forms, developed by the Institute of Medical Informatics, University of Muenster in Germany. Electronic forms for documentation of patient data are an integral part within the workflow of physicians. A huge amount of data is collected either through routine documentation forms (EHRs) for electronic health records or as case report forms (CRFs) for clinical trials. This raises major scientific challenges for health care, since different health information systems are not necessarily compatible with each other and thus information exchange of structured data is hampered. Software vendors provide a variety of individual documentation forms according to their standard contracts, which function as isolated applications. Furthermore, free availability of those forms is rarely the case. Currently less than 5 % of medical forms are freely accessible. Based on this lack of transparency harmonization of data models in health care is extremely cumbersome, thus work and know-how of completed clinical trials and routine documentation in hospitals are hard to be re-used. The MDM-Portal serves as an infrastructure for academic (non-commercial) medical research to contribute a solution to this problem. It already contains more than 4,000 system-independent forms (CDISC ODM Format, www.cdisc.org, Operational Data Model) with more than 380,000 dataelements. This enables researchers to view, discuss, download and export forms in most common technical formats such as PDF, CSV, Excel, SQL, SPSS, R, etc. A growing user community will lead to a growing database of medical forms. In this matter, we would like to encourage all medical researchers to register and add forms and discuss existing forms