Current Neuropharmacology - Volume 13, Issue 5, 2015

Major depressive disorder is a highly prevalent, chronic and recurring disorder, associated with substantial impairment in cognitive and interpersonal functions. Accumulating evidence suggests that inflammatory processes play an important role in the etio-pathogenesis, phenomenology, comorbidity and treatment of MDD. Suboptimal remission rates and the persistence of cognitive deficits contribute to functional impairment in MDD inviting the need for the development of mechanistically novel and domain specific treatment approaches. The MEDLINE/ Pubmed database was searched from inception to February, 9th, 2014 with combinations of the following search terms: ‘TNF-alpha’, ‘depression’, ‘infliximab’, ‘etanercept’, ‘adalimumab’, ‘golimumab’ and ‘certolizumab’. Preclinical and clinical evidence linking TNF-α to MDD pathophysiology were reviewed as well as the current status of TNF-α modulators as novel agents for the treatment of MDD. Experimental models and clinical studies provide encouraging preliminary evidence for the efficacy of TNF- α antagonists in mitigating depressive symptoms and improving cognitive deficits. Further studies are warranted to confirm these data in larger randomized controlled trials in primary psychiatric populations. Translational research provides a promising perspective that may aid the development and/or repurposing of mechanism-based treatments for depressive symptoms and cognitive impairment in MDD.

The current Review article provides a narrative review about the neurobiological underpinnings and treatment of treatment resistant late-life depression (TRLLD). The manuscript focuses on therapeutic targets of late-life depression, which include pharmacological, psychological, biophysical and exercise treatment approaches. Therefore, we summarize available evidences on that kind of therapies for patients suffering from late-life depression. The search for evidences of therapeutic options of late-life depression were done using searching websites as “pubmed”, and using the searching terms “depression”, “late-life depression”, “treatment”, “biophysical therapy”, “exercise therapy”, “pharmacological therapy” and “psychological therapy”. To the end, we summarize and discuss current data, providing some directions for further research. Treatment recommendations for elderly depressive patients favour a multimodal approach, containing psychological, pharmacological and secondary biophysical therapeutic options. Particularly, a combination of psychotherapy and antidepressant medication reflects the best therapeutic option. However, mostly accepted and used is the pharmacological treatment although evidence suggests that the drug therapy is not as effective as it is in younger depressive patients. Further studies employing larger samples and longer follow-up periods are necessary and may focus on comparability of study designs and involve novel approaches to establish the validity and reliability of multimodal treatment programs.

Bipolar disorder is prevalent, with high risks of disability, substance abuse and premature mortality. Treatment responses typically are incomplete, especially for depressive components, so that many cases can be considered “treatment resistant.” We reviewed reports on experimental treatments for such patients: there is a striking paucity of such research, mainly involving small incompletely controlled trials of add-on treatment, and findings remain preliminary. Encouraging results have been reported by adding aripiprazole, bupropion, clozapine, ketamine, memantine, pramipexole, pregabalin, and perhaps tri-iodothyronine in resistant manic or depressive phases. The urgency of incomplete responses in such a severe illness underscores the need for more systematic, simpler, and better controlled studies in more homogeneous samples of patients.

During the last decade, several meta-analytic studies employing different methodological approaches have had inconsistent conclusions regarding antidepressant efficacy. Herein, we aim to comment on methodological aspects that may have contributed to disparate findings. We initially discuss methodological inconsistencies and limitations related to the conduct of individual antidepressant randomized controlled trials (RCTs), including differences in allocated samples, limitations of psychometric scales, possible explanations for the heightened placebo response rates in antidepressant RCTs across the past two decades as well as the reporting of conflicts of interest. In the second part of this article, we briefly describe the various meta-analyses techniques (e.g., simple random effects meta-analysis and network meta-analysis) and the application of these methods to synthesize evidence related to antidepressant efficacy. Recently published antidepressant metaanalyses often provide discrepant results and similar results often lead to different interpretations. Finally, we propose strategies to improve methodology considering real-world clinical scenarios.

Major depressive disorder (MDD) is associated with a significant burden and costs to the society. As remission of depressive symptoms is achieved in only one-third of the MDD patients after the first antidepressant trial, unsuccessful treatments contribute largely to the observed suffering and social costs of MDD. The present article provides a summary of the therapeutic strategies that have been tested for treatment-resistant depression (TRD). A computerized search on MedLine/PubMed database from 1975 to September 2014 was performed, using the keywords “treatment-resistant depression”, “major depressive disorder”, “adjunctive”, “refractory” and “augmentation”. From the 581 articles retrieved, two authors selected 79 papers. A manual searching further considered relevant articles of the reference lists. The evidence found supports adding or switching to another antidepressant from a different class is an effective strategy in more severe MDD after failure to an initial antidepressant trial. Also, in subjects resistant to two or more classes of antidepressants, some augmentation strategies and antidepressant combinations should be considered, although the overall response and remission rates are relatively low, except for fast acting glutamatergic modulators. The wide range of available treatments for TRD reflects the complexity of MDD, which does not underlie diverse key features of the disorder. Larger and well-designed studies applying dimensional approaches to measure efficacy and effectiveness are warranted.

Major depressive disorder (MDD) is a leading cause of disability worldwide. Current first line therapies target modulation of the monoamine system. A large variety of agents are currently available that effectively alter monoamine levels; however, approximately one third of MDD patients remain treatment refractory after adequate trials of multiple monoamine based therapies. Therefore, patients with treatment-resistant depression (TRD) may require modulation of pathways outside of the classic monoamine system. The purpose of this review was thus to discuss novel targets for TRD, to describe their potential mechanisms of action, the available clinical evidence for these targets, the limitations of available evidence as well as future research directions. Several alternate pathways involved in the patho-etiology of TRD have been uncovered including the following: inflammatory pathways, the oxidative stress pathway, the hypothalamic-pituitary-adrenal (HPA) axis, the metabolic and bioenergetics system, neurotrophic pathways, the glutamate system, the opioid system and the cholinergic system. For each of these systems, several targets have been assessed in preclinical and clinical models. Preclinical models strongly implicate these pathways in the patho-etiology of MDD. Clinical trials for TRD have been conducted for several novel targets; however, most of the trials discussed are small and several are uncontrolled. Therefore, further clinical trials are required to assess the true efficacy of these targets for TRD. As well, several promising novel agents have been clinically tested in MDD populations, but have yet to be assessed specifically for TRD. Thus, their applicability to TRD remains unknown.

Current pharmacological treatments for bipolar disorder (BD) are limited and efficacy has historically been discovered through serendipity. There is now scope for new drug development, focused on the underlying biology of BD that is not targeted by current therapies. The need for novel treatments is urgent when considering treatment resistant BD, where current therapies have failed. While established drugs targeting the monoamine systems continue to be worthwhile, new biological targets including inflammatory and oxidative an nitrosative pathways, apoptotic and neurotrophic pathways, mitochondrial pathways, the N-methyl-Daspartate (NMDA)–receptor complex, the purinergic system, neuropeptide system, cholinergic system and melatonin pathways are all being identified as potential anchors for the discovery of new agents. Many agents are experimental and efficacy data is limited, however further investigation may provide a new line for drug discovery, previously stalled by lack of corporate interest.

An increasing body of evidences from preclinical as well as epidemiological and clinical studies suggest a potential beneficial role of dietary intake of omega-3 fatty acids for cognitive functioning. In this narrative review, we will summarize and discuss recent findings from epidemiological, interventional and experimental studies linking dietary consumption of omega-3 fatty acids to cognitive function in healthy adults. Furthermore, affective disorders and schizophrenia (SZ) are characterized by cognitive dysfunction encompassing several domains. Cognitive dysfunction is closely related to impaired functioning and quality of life across these conditions. Therefore, the current review focues on the potential influence of omega-3 fatty acids on cognition in SZ and affective disorders. In sum, current data predominantly from mechanistic models and animal studies suggest that adjunctive omega-3 fatty acid supplementation could lead to improved cognitive functioning in SZ and affective disorders. However, besides its translational promise, evidence for clinical benefits in humans has been mixed. Notwithstanding evidences indicate that adjunctive omega-3 fatty acids may have benefit for affective symptoms in both unipolar and bipolar depression, to date no randomized controlled trial had evaluated omega-3 as cognitive enhancer for mood disorders, while a single published controlled trial suggested no therapeutic benefit for cognitive improvement in SZ. Considering the pleiotropic mechanisms of action of omega-3 fatty acids, the design of well-designed controlled trials of omega-3 supplementation as a novel, domain-specific, target for cognitive impairment in SZ and affective disorders is warranted.

Akathisia is a troubling side effect that leads to non-adherence with antipsychotic regimens. Second generation antipsychotics (SGAs) tend to cause less akathisia than older agents but the risk still exists and rates vary between agents. Little is known about the incidence of akathisia among the newer SGAs. The purpose of this study was to conduct a meta-analysis of akathisia incidence rates for three of the newer SGAs: aripiprazole, asenapine, and lurasidone. Data were drawn from published and unpublished clinical trials comparing the drug of interest to either placebo or another SGA in adults with schizophrenia. Twenty-four studies (11 aripiprazole, 5 asenapine, and 8 lurasidone) provided incidence rates for akathisia and related nervous system events. Data showed that the relative risk (RR) of akathisia was double that of controls, with lurasidone having the highest individual RR at 2.7 [CI: 2-3.6]. Sensitivity analysis changed the RR of akathisia to less than 10%. The RR of akathisia was still elevated (1.75 [1.4-2.1]) when these drugs were compared only to actives (older SGAs). Agitation and anxiety RRs were also higher with the newer SGAs as compared to the older SGAs. Previous theory suggests antagonism of serotonin (5-HT)2A receptors may decrease akathisia risk. Expectations were that aripiprazole, asenapine and lurasidone would have a low incidence of akathisia, as all display strong antagonism at 5-HT2A. However, in this study all three had a significantly higher risk of akathisia compared to placebo or other SGAs. This suggests the pathophysiology of akathisia involves other receptors and is multifactorial.

Tinnitus, a phantom sensation experienced by people around the world, currently is endured without a known cure. Some find the condition tolerable, while others are tortured on a daily basis from the incessant phantom noises. For those who seek treatment, oftentimes, they have a comorbid condition (e.g., depression, anxiety, insomnia), which is treated pharmaceutically. These products aim to reduce the comorbities associated with tinnitus thereby minimizing the overall burden present. Because of the phantom nature of tinnitus, it is often compared to neurologic pain. Since pain can be managed with pharmaceutical options, it is reasonable to assume that similar agents might work to alleviate tinnitus. The effects of antidepressants, benzodiazepines, anticonvulsants, and glutamate antagonists are reviewed in this paper. Table 1 summarizes the pharmaceutical products discussed. Due to the variety of comorbid factors and potential causes of tinnitus, there may not be one pharmaceutical treatment that will combat every type of tinnitus. Nevertheless, a product that finally addresses the true cause of tinnitus, and not just its comorbidities, will benefit millions of people worldwide.

Myalgic Encephalomyelitis (ME) continues to cause significant morbidity worldwide with an estimated one million cases in the United States. Hurdles to establishing consensus to achieve accurate evaluation of patients with ME continue, fueled by poor agreement about case definitions, slow progress in development of standardized diagnostic approaches, and issues surrounding research priorities. Because there are other medical problems, such as early MS and Parkinson’s Disease, which have some similar clinical presentations, it is critical to accurately diagnose ME to make a differential diagnosis. In this article, we explore and summarize advances in the physiological and neurological approaches to understanding, diagnosing, and treating ME. We identify key areas and approaches to elucidate the core and secondary symptom clusters in ME so as to provide some practical suggestions in evaluation of ME for clinicians and researchers. This review, therefore, represents a synthesis of key discussions in the literature, and has important implications for a better understanding of ME, its biological markers, and diagnostic criteria. There is a clear need for more longitudinal studies in this area with larger data sets, which correct for multiple testing.