Drugs For Major Depressive Disorder Research Articles

BDNF-related mutations in major depressive disorder: a systematic review.

A better understanding of the genetic, molecular and cellular mechanisms of brain-derived neurotrophic factor (BDNF) and its association with neuroplasticity could play a pivotal role in finding future therapeutic targets for novel drugs in major depressive disorder (MDD). Because there are conflicting results regarding the exact role of BDNF polymorphisms in MDD still, we set out to systematically review the current evidence regarding BDNF-related mutations in MDD. We conducted a keyword-guided search of the PubMed and Embase databases, using 'BDNF' or 'brain-derived neurotrophic factor' and 'major depressive disorder' and 'single-nucleotide polymorphism'. We included all publications in line with our exclusion and inclusion criteria that focused on BDNF-related mutations in the context of MDD. Our search yielded 427 records in total. After screening and application of our eligibility criteria, 71 studies were included in final analysis. According to present overall scientific data, there is a possibly major pathophysiological role for BDNF neurotrophic systems to play in MDD. However, on the one hand, the synthesis of evidence makes clear that likely no overall association of BDNF-related mutations with MDD exists. On the other hand, it can be appreciated that solidifying evidence emerged on specific significant sub-conditions and stratifications based on various demographic, clinico-phenotypical and neuromorphological variables. Further research should elucidate specific BDNF-MDD associations based on demographic, clinico-phenotypical and neuromorphological variables. Furthermore, biomarker approaches, specifically combinatory ones, involving BDNF should be further investigated.

Adiponectin predicts poor response to antidepressant drugs in major depressive disorder.

Produced by adipocytes, adiponectin crosses the blood-brain barrier to bind with specific receptors in the hypothalamus, brainstem, hippocampus, and cortex. In patients with major depressive disorder (MDD), circulating levels of adiponectin inversely related with antidepressant response to ketamine, and predicted a better response to multi-target drug combinations than to escitalopram. We investigated the effect of adiponectin on response to antidepressants in a naturalistic setting. We assessed baseline plasma levels of adiponectin in 121 MDD inpatients, treated with antidepressant drug monotherapy based on clinical need (selective serotonin reuptake inhibitors, venlafaxine, duloxetine) in a specialized hospital setting. Severity of depression was weekly assessed with Hamilton scale ratings. Adiponectin plasma levels were higher in patients with MDD compared with healthy controls, and negatively influenced the pattern of antidepressant response (higher baseline levels, worse response) independent of the drug class and of the baseline severity of depression, and of age, sex, and body mass index. The identification of adiponectin as a predictor of antidepressant response to drugs of different mechanism of action, such as ketamine, SSRIs, and SNRIs, and both in experimental and in clinical settings, warrants interest for further study of its pathways to search for novel biomarkers and therapeutic targets.

P.445 Dose-response relationships of antipsychotic drugs for major depressive disorder: a systematic review and meta-analysis

New projects being implemented or planned at CERN, such as the LHC Injectors Upgrade (LIU), the High-Luminosity LHC (HL-LHC) or the Future Circular Collider (FCC), motivate the change of several architectural paradigms in the Low Level RF systems (LLRF). In the upgraded Super Proton Synchrotron (SPS) LLRF, the distribution of RF, the revolution frequency, settings and synchronization timings will rely on a deterministic link, the White Rabbit (WR), exploiting a distributed topology. The digital electronics (FPGA) will now use a fixed frequency clock extracted locally in each node from this data stream. The paper presents a new solution for algorithms that treat beam-induced perturbations as they must solve the challenge to tune their processing to the instantaneous revolution frequency, Beam Synchronous Processing (BSP). We use dynamic resampling of uniform sampled data as tuning element between a sweeping spectrum and the static processing implemented with fixed frequency clocks. The paper applies the novel Beam Synchronous Processing method to transient beam loading compensation. It presents a One Turn delay FeedBack (OTFB) for the SPS based on a cascade of two variable ratio resamplers.

Impact of demographic factors on the antidepressant effect: A patient-level data analysis from depression trials submitted to the Pharmaceuticals and Medical Devices Agency in Japan

A substantial and variable placebo response can cause unreliable findings in clinical trials designed to demonstrate the efficacy of antidepressants, and the high rate of failed trials represents a major obstacle in the development of new drugs for major depressive disorder (MDD). However, the influence of demographic and symptom factors on the antidepressant effect remains to be established. The purpose of this study was to estimate the magnitude of this influence. A patient-level meta-analysis of data from double-blind, randomized, placebo-controlled trials involving the use of antidepressants for adults with MDD was performed. Data from five confirmatory trials evaluating the efficacy of four antidepressants that were submitted to the Pharmaceuticals and Medical Devices Agency (PMDA) to support new drug applications were pooled (n = 1898). The change in the total score of 17-item Hamilton Depression Rating Scale (HDRS17) was the primary outcome of interest in our analysis. The changes in the total HDRS17 score in both the antidepressant medication group (ADM) and the placebo group (PBO) increased in relation to baseline symptom severity. Among older patients and those with a history of prior treatment with antidepressants, the changes in the total HDRS17 score decreased in ADM and remained static in PBO. There were no notable clinical symptoms that influenced the change in the total HDRS17 score. Baseline symptom severity, participant age and a history of previous treatment with antidepressants were suggested as moderators of the antidepressant effect. The drug-placebo difference in the estimated changes as a function of baseline symptom severity varied depending on the regression models used, and further studies are required to investigate appropriate models.

Prescribing patterns of psychiatric drugs in major depressive disorder – Findings from a large European multicenter, cross-sectional study

IntroductionThe multicenter, cross-sectional survey summarizes the current prescription patterns of psychopharmacological medications in patients with major depressive disorder (MDD) treated in European university psychiatric centers.MethodsThe study included a total of 1181 MDD patients who were recruited in 9 academic sites across 8 European countries. Socio-demographic, clinical, and psychopharmacological characteristics were collected within a detailed clinical interview and the current depressive symptom severity was measured by the Montgomery and Åsberg Depression Rating Scale (MADRS). Symptom reduction during the present MDD episode was analyzed by calculating retrospective MADRS scores. Descriptive statistics, analyses of variance (ANOVAs), and Spearman correlation analyses were performed to examine the impact of various features on the applied pharmacological strategies.ResultsRegarding first-line antidepressant medication, the most frequently prescribed drug classes were selective serotonin reuptake inhibitors (SSRIs) (53.4%), serotonin-norepinephrine reuptake inhibitors (SNRIs) (23.6%), noradrenergic and specific serotonergic antidepressants (NaSSAs) (8.2%), tricyclic antidepressants (TCA) (5.1%), and the melatonergic antidepressant agomelatine (5.0%). The most commonly used individual antidepressants were escitalopram (18.4%), venlafaxine (15.2%), sertraline (12.9%), paroxetine (9.1%), mirtazapine (8.2%), duloxetine (7.0%), and fluoxetine (6.5%). Among the patients, 59.4% were treated with polypsychopharmaceutical medications (mean: 2 drugs) and for the number of individual drugs, we found a significant correlation with the present MADRS total score and the MADRS total score change during the current depressive episode.ConclusionConsistent with surveys investigating primarily municipal psychiatric treatment centers, we could replicate the observation that SSRIs are the most commonly used antidepressants in MDD for the first time for European university centers.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Geriatric characteristics in randomised controlled trials on antidepressant drugs for older adults: a systematic review.

Meta-analyses of antidepressant drug treatment trials have found that increasing age is associated with a less favourable outcome. Because the prevalence of geriatric characteristics, like disability, medical co-morbidity, malnutrition, cognitive (dys)function and frailty increase with age and are associated with depression, these characteristics are likely to modify the treatment outcome of antidepressant drugs in late-life depression. This review examines how these five characteristics are taken into account in randomised controlled trials (RCTs) with antidepressant drugs for major depressive disorder in patients aged 60 years or above. A systematic search in PubMED, PsychInfo and EMBASE, from the year 2000 onwards, yielded 27 RCTs, with a total of 6356 subjects with a median age of 71 years. Two reviewers independently assessed whether each characteristic was considered as inclusion or exclusion criterion, descriptive variable, stratification variable, co-variable, outcome measure, or in adverse effect monitoring. Malnutrition and frailty were not taken into account in any study. Disability was used as an outcome measure in five studies. Two studies explicitly included a population with possibly serious medical co-morbidity. Cognitive status was the only condition taken into account as co-variable (n = 3) or stratifying variable (n = 1) and was used as outcome measure in seven studies. We conclude that geriatric characteristics are rarely taken into account in RCTs on antidepressant drugs in late-life depression, and studies including the oldest adults are underrepresented. This warrants recruitment of the oldest adults and adjustment of treatment strategies in future studies. Copyright © 2016 John Wiley & Sons, Ltd.

SLC17A7 gene may be the indicator of selective serotonin reuptake inhibitor treatment response in the Chinese Han population.

Selective serotonin reuptake inhibitors (SSRIs) are widely used drugs for major depressive disorder (MDD), although the treatment outcomes vary in different people. The vesicular glutamate transporter 1 coded by SLC17A7 gene has been reported associated with MDD. According to its role in glutamate transmission, it is reasonable to consider it as a potential pharmacogenetic candidate in SSRI treatment. A total of 290 MDD patients who had been taking SSRIs for 6 weeks were recruited. Their genotypes were assessed for the presence of 4 single-nucleotide polymorphisms, which were selected from either the HapMap Chinese ethnic group or the literature report. Treatment effects were evaluated by the change rate of Hamilton Rating Scale for Depression. After the adjustment for the false discovery rate, 1 single-nucleotide polymorphism (rs74174284, false discovery rate; P = 0.032) demonstrated significant association with SSRI treatment response at week 6. Our results suggest that genetic variants in the SLC17A7 gene may be indicators of treatment response in MDD patients treated by SSRIs.

Bioenergetics for Depression: Something Different for Depression

Back to table of contents Previous article Next article PerspectivesFull AccessBioenergetics for Depression: Something Different for DepressionStephen M. Strakowski, M.D.Stephen M. StrakowskiSearch for more papers by this author, M.D.Published Online:1 Sep 2012https://doi.org/10.1176/appi.ajp.2012.12050720AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail The approach of translating neuroscience advances into clinical research represents the best strategy toward innovative interventions, as opposed to the more typical “me too” approach to drug development.At those times when I slow down enough to reflect on the current state of psychiatry and my own clinical experiences since I completed residency 20 years ago, I am struck by how much we have learned yet how relatively little we have advanced. Although we have a number of new medications and therapies, most of these are from the same general drug classes or psychotherapy models that I used in residency, e.g., dopamine antagonists for psychosis or cognitive-behavioral therapy for anxiety. Most of these were based on serendipitous discoveries. Consequently, the management of major depression remains little changed over the last two decades (1); the general approach is still to increase the concentration of monoamines serotonin and norepinephrine in the synapse, generally through reuptake inhibition (even though the initial increases seem to have little to do with the eventual antidepressant response), and then add some cognitive-behavioral or other evidenced-based therapy to try to improve outcome. The drugs are a bit different now from those in use when I was in training, e.g., fluoxetine is more specific than nortriptyline and perhaps better tolerated, but the general mechanisms of action are largely the same. This state of affairs would be fine if our depressed patients were robustly improving, but only one-half to two-thirds of patients respond to a specific intervention, often only after multiple treatment trials (2); response tends to be slow, on the order of 6–12 weeks; and many individuals develop side effects. Additionally, if a patient does not respond to the first intervention, subsequent interventions are mostly “more of the same” and do not promise robust outcomes (2). Clearly, we need a paradigm shift in treatment development in order to make meaningful advances in how we care for depressed patients.Lyoo et al. (3) in this issue provide just such an example of an innovative approach to developing new treatments for major depression. In this study, the investigators relied on a growing database that demonstrates that bioenergetic abnormalities in the brain may underlie aspects of the development of depression. Moreover, they note that brain bioenergetics can be influenced; for example, increases in brain creatine reserves are thought to shift brain creatine kinase activity, thereby increasing ATP production, perhaps improving brain bioenergetics in depression (2). A previously studied rodent model suggested that creatine may have antidepressant effects, at least in female animals (4). On the basis of these hypothetical considerations and preclinical findings, the investigators initiated a double-blind, placebo-controlled clinical trial of creatine augmentation of escitalopram in depressed women. Creatine augmentation was well tolerated and significantly improved escitalopram response by as early as the second week of the 8-week trial. Augmentation with creatine appeared to accelerate treatment response by approximately 2 weeks and may also have contributed to an overall greater response rate, although a longer follow-up would be needed to determine if that was true. Regardless, this study is unusual in that it translated preclinical neuroscience into a potentially novel antidepressant strategy, very different from the standard emphasis on monoamine uptake inhibition or serendipity.Limitations in the study must be considered before everyone starts prescribing creatine to their patients. The study group was limited to Korean women who were mostly first-episode, treatment-naive patients. This group is obviously very narrow. First-episode patients may be particularly treatment responsive and are not representative of individuals with recurrent affective episodes or treatment-resistant depression, who constitute the bulk of most psychiatric practices. Also, the animal model of creatine treatment was successful in females but not males, which suggests that this treatment may be useful only for women. Although of heuristic interest for how we think about sex differences in the mechanisms of depression and psychiatric illness, unfortunately, in the absence of men in the study, this interest cannot be examined. A next step is to determine whether creatine alone might also be an antidepressant or whether it works only in conjunction with a selective serotonin reuptake inhibitor (SSRI); if the latter, the neurobiological underpinnings are different from those of effective creatine monotherapy. Clearly, more work is needed to determine the role of creatine in the treatment of depression. Nonetheless, the approach of translating neuroscience advances into clinical research represents the best strategy toward innovative interventions, as opposed to the more typical “me too” approach to drug development that has been rife in psychiatry during the last 20 years.During the same 20 years that antidepressant therapy has minimally advanced, our understanding of the brain has exploded, especially because of increasing knowledge of the functional neuroanatomic, molecular, and genetic control of emotional network function and the neural basis of affective illness (see, for example, references 5–7). What has lagged is applying this new information in order to identify novel interventions for depression. One alternative goal has been to try to personalize treatment by identifying subpopulations of depressed patients who respond differently to different treatments; however, attempts to meet this goal are limited by a collection of medications that essentially share the same mechanism of action (i.e., SSRIs). Recent innovations using neuromodulatory therapies (e.g., repetitive transcranial magnetic stimulation [8], ketamine administration [9], or circadian rhythm regulation [10]) are beginning to challenge standard models of depression, partly on the basis of advances in neuroscience, thereby providing alternatives to permit personalization and, in the process, refine different neurophysiological models for depressive disorders. A paradigm shift in the treatment of depression is overdue, and translational neuroscience, like that presented in this issue (3), presents a step toward that end. Perhaps this study will inspire others to use a similar translational approach leading to a significant advance in how we manage folks with major depression.From the Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati College of Medicine.Address correspondence to Dr. Strakowski (stephen.[email protected]edu).Dr. Strakowski reports that from 2010 to May 2012 he received research grants (through the University of Cincinnati academic medical center) from AstraZeneca, Eli Lilly, Janssen, Martek, Nutrition 21, Pfizer, Repligen, Sumatomo, NARSAD, the National Institute on Drug Abuse, NIMH, and the National Institute on Alcohol Abuse and Alcoholism; he also reports being a consultant to the University of Utah and the University of Nebraska and receiving speaking fees from the American Academy of Child and Adolescent Psychiatry, CME Outfitters, and Adamed; he has also received fees from WebMD, Consensus Medical Communications, and APA. Dr. Freedman has reviewed this editorial and found no evidence of influence from these relationships.References1 Kupfer DJ, Frank E, Phillips ML: Major depressive disorder: new clinical, neurobiological, and treatment perspectives. Lancet 2012; 379:1045–1055Crossref, Medline, Google Scholar2 Rush AJ, Trivedi MH, Wisniewski SR, Nierenberg AA, Stewart JW, Warden D, Niederehe G, Thase ME, Lavori PW, Lebowitz BD, McGrath PJ, Rosenbaum JF, Sackeim HA, Kupfer DJ, Luther J, Fava M: Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry 2006; 163:1905–1917Link, Google Scholar3 Lyoo IK, Yoon S, Kim T-S, Hwang J, Kim JE, Won W, Bae S, Renshaw PF: A randomized, double-blind placebo-controlled trial of oral creatine monohydrate augmentation for enhanced response to a selective serotonin reuptake inhibitor in women with major depressive disorder. Am J Psychiatry 2012; 169:937–945Link, Google Scholar4 Allen PJ, D’Anci KE, Kanarek RB, Renshaw PF: Chronic creatine supplementation alters depression-like behavior in rodents in a sex-dependent manner. Neuropsychopharmacology 2010; 35:534–546Crossref, Medline, Google Scholar5 Strakowski SM, Adler CM, Almeida J, Altshuler LL, Blumberg HP, Chang KD, Delbello MP, Frangou S, McIntosh A, Phillips ML, Sussman JE, Townsend JD: The functional neuroanatomy of bipolar disorder: a consensus model. Bipolar Disord 2012; 14:313–325Crossref, Medline, Google Scholar6 Renshaw PF, Parow AM, Hirashima F, Ke Y, Moore CM, Frederick BdeB, Fava M, Hennen J, Cohen BM: Multinuclear magnetic resonance spectroscopy studies of brain purines in major depression. Am J Psychiatry 2001; 158:2048–2055Link, Google Scholar7 Keers R, Uher R: Gene-environment interaction in major depression and antidepressant treatment response. Curr Psychiatry Rep 2012; 14:129–137Crossref, Medline, Google Scholar8 Dell’osso B, Camuri G, Castellano F, Vecchi V, Benedetti M, Bortolussi S, Altamura AC: Meta-review of metanalytic studies with repetitive transcranial magnetic stimulation (rTMS) for the treatment of major depression. Clin Pract Epidemiol Ment Health 2011; 7:167–177Crossref, Medline, Google Scholar9 Connolly KR, Thase ME: Emerging drugs for major depressive disorder. Expert Opin Emerg Drugs 2012; 17:105–126Crossref, Medline, Google Scholar10 Carney RM, Shelton RC: Agomelatine for the treatment of major depressive disorder. Expert Opin Pharmacother 2011; 12:2411–2419Crossref, Medline, Google Scholar FiguresReferencesCited byDetailsCited ByA life course view on depression: Social determinants of depressive symptom trajectories over 25 Years of Americans’ Changing LivesSSM - Population Health, Vol. 18Elevating the level of hypoxia inducible factor may be a new potential target for the treatment of depressionMedical Hypotheses, Vol. 146Psychotropic Effects of a New Pyrazolo[C]Pyridine Derivate GIZh-72 are Related to Functional Activity of Atp-Sensitive Potassium Channels7 March 2020 | Bulletin of Experimental Biology and Medicine, Vol. 168, No. 4Journal of Psychiatric Research, Vol. 104Brain Structure and Function, Vol. 221, No. 6Biological Psychiatry, Vol. 80, No. 6Purinergic Signalling, Vol. 11, No. 2Pharmacological Reports, Vol. 66, No. 4 Volume 169Issue 9 September 2012Pages 891-893 Metrics PDF download History Accepted 1 May 2012 Published online 1 September 2012 Published in print 1 September 2012

Emerging drugs for major depressive disorder

Most current pharmacologic antidepressant treatments target either or both serotonin and norepinephrine systems in the brain to alleviate depressive symptoms. However, ≥ 30% of patients with major depressive disorder fail to respond to these antidepressants, inciting a need for alternative treatment strategies. In the past decade, there has been extensive research into improving the mechanism of action for monoamine agents as well as identifying novel treatment targets for depression. For monoamines, drugs that increase serotonin, norepinephrine, melatonin or dopamine have been explored as putative antidepressants and in some cases approved (agomelatine and desvenlafaxine). Novel drugs that act on amino acid receptors, neurotrophic factors, cytokines, neuropeptides and acetylcholine are also in development. This review will discuss the scientific rationale for these targets, as well as highlight the current status of drugs in development.