CNS & Neurological Disorders - Drug Targets (Formerly Current Drug Targets - CNS & Neurological Disorders) - Volume 16, Issue 8, 2017

Background: Treatments for depression in bipolar disorder (BD) are far less well developed than for unipolar major depressive disorder. Several innovative and experimental approaches have been emerging recently, including use of the dissociative anesthetic ketamine and other antagonists of central NMDA glutamate receptors, as well as unsaturated fatty acids, anti-inflammatory agents, and possibly probiotic methods. Method: We reviewed relevant reports from the past decade. Findings: Ketamine, a phencyclidine-like NMDA-glutamate receptor antagonist, has emerged as a highly innovative, experimental treatment for treatment-resistant unipolar major depression, possibly in bipolar depression, and with brief antisuicidal effects. Its limitations include poor bioavailability, rapid but short-lived effects, and little information about long-term benefits and safety of repeated administration. Polyunsaturated fatty acids critical for the structure and functioning of neuronal and other cell membranes have some evidence of benefit as experimental treatments for depression including in BD. There also is evidence of altered expression of peptides associated with inflammation in mood disorder patients, encouraging experimental treatment with anti-inflammatory agents; of these, the COX-II inhibitor celecoxib has shown some evidence of benefit. The concept of altering intestinal flora with probiotic treatments to treat mood disorders remains speculative. Conclusion: Ketamine represents an innovative, rapidly acting, experimental treatment for bipolar depression with practical limitations. Unsaturated fatty acids and anti-inflammatory agents have inconsistent support; probiotic treatments lack evidence. These innovative approaches require much more clinical investigation.

Background: Schizophrenia is a complex psychiatric disorder that represents a challenge for all clinicians. Although treatment must address both positive and negative symptoms, several authors have reported the importance of managing unmet needs among patients with schizophrenia. Unmet needs in schizophrenia include difficulties at various clinical, psychosocial, relational, economic, and occupational levels. An important unmet need is represented by insight into the illness that is associated with treatment adherence and compliance with medical prescriptions. Conclusion: In order to improve our understanding and management of schizophrenia, it is critically important to address the complexity of needs among patients with schizophrenia.

Background: The management of acute agitation in patients with bipolar disorder or schizophrenia is a multifaceted and dynamic task, which presents unique and complex challenges to healthcare providers. Objective: To ascertain and describe which medications are best to use in patients with agitation, affected by bipolar disorder or schizophrenia. Method: Selective review of current literature and guidelines referred to the treatment of agitation in individuals affected with bipolar disorder or schizophrenia. Results: When possible, the pharmacologic management of agitation should be preceded by a in-depth evaluation of the possible causes of the agitation. The use for of first and second-generation antipsychotic medications, of benzodiazepines and of the newer inhaled antipsychotic loxapine, is reviewed and commented. Conclusion: The mainstay of medication treatment of acute agitation should be based on a thotough assessment cause. If agitation is due to delirium or to another physial condition, an attempt to address the underlying causes should be always considered. When agitation is primarily due to schizophrenia or bipolar disorder, antipsychotics and/or benzodiazepines are usually the mainstay of treatment. Newer inhaled formulation of loxapine has shown ability to rapidly reduce the agitation in mild to moderate patients with schizophrenia or bipolar disorder, with a decrease in agitation that was evident since the first assessment, 10 minutes after the first dose.

Background: Cognitive dysfunction is a core transdiagnostic domain of Major Depressive Disorder (MDD) and is a principal determinant of functional recovery. However, it has been insufficiently targeted within the current therapeutic framework for MDD. Objective: To highlight these unmet cognitive needs in MDD. Method: An article search was conducted using PubMed from inception to November 2016: Major Depressive Disorder (and/or variant) was cross-referenced with the following terms: antidepressants, augmentation, cognition, cognitive deficits, cognitive dysfunction, functional outcomes, mechanism of action, and treatment. Articles informed by observational studies, clinical trials, and review articles relevant to the discussion of cognition and cognitive impairment in MDD were included for review. Additional terms and citations previously not identified in the initial search were obtained from a manual review of article reference lists. Results: Cognitive deficits in MDD are replicable, non-specific, and clinically significant. Abnormalities in the domains of learning/memory, executive function, attention, concentration, and processing speed are consistently reported. Only two antidepressants (i.e., duloxetine and vortioxetine) have established procognitive effects utilizing rigorous methodology in MDD. Most antidepressants improve cognitive function(s), but the extent to which they directly exert pro-cognitive effects is not yet understood. Conclusion: Cognitive dysfunction in MDD is a principal determinant of patient-reported outcomes (e.g., psychosocial function). Healthcare providers are encouraged to screen for cognitive dysfunction in MDD and familiarize themselves with the efficacy profiles of antidepressants on disparate cognitive domains.

Objectives: This article are to describe current trends in the treatment of schizophrenia and the most interesting new approaches to optimizing outcome and fostering the development of new schizophrenia treatments. Results: Increasing utilization of diverse types of atypical antipsychotic drugs (AAPDs), e.g. clozapine-type serotonin (5-HT)2A and weak dopamine (DA) D2 antagonist, amisulpride, a D2/D3/5-HT7 antagonist, and cariprazine, a D3 partial agonist with additional neurotransmitter targets, is occurring as their advantages in efficacy, especially for cognitive impairment and mood symptoms, and side effects are becoming appreciated. Typical APDs, e.g. haloperidol, are diminishing in favor because of their EPS, especially, tardive dyskinesia (T D) and appreciation that reducing D2 receptor stimulation is not the only means to treat psychosis. Some of the mechanisms inherent in various AAPDs, e.g. 5-HT2A inverse agonism, and D3 receptor partial agonism, are now recognized as effective treatments for psychosis. A new focus on treating the cognitive impairment associated with schizophrenia (CIAS) has emerged via mechanisms such as stimulation of acetyldraline receptor with muscarinic and nicotinic receptor agonists, but demonstrating their efficacy in trials is proving elusive. Pharmacogenetic strategies which may lead to personalized treatment of schizophrenia are emerging but have not yet succeeded in being widely reimbursable. Transcranial stimulation and cognitive enhancement therapy are more common but more evidence for their efficacy is needed. Conclusion: The heterogeneity of the pathophysiology of the various domains of schizophrenia requires a diversity of treatments that are best met by the expert use of AAPDs at the current time. Pharmacogenetic efforts are consistent with new evidence that multiple genes are involved in the risk for schizophrenia and the effectiveness of AAPDs.

Background & Objective: Brain areas of functional activation during emotional stimuli and their correlations with affective temperaments evaluated using Temperament Evaluation of Memphis, Pisa, Paris and San Diego (TEMPS-A) and hopelessness levels assessed with the Beck Hopelessness Scale (BHS) have been investigated. Method: Brain activity in response to emotional stimuli was examined by Nuclear Magnetic Resonance Blood Oxygen Level Dependent (NMR BOLD) signal. Seventeen subjects (mean age ± SD = 57 ± 12), diagnosed with major affective disorders and eighteen healthy controls (HC) (mean age ± SD = 50±11) participated in this study. Higher functional activation of the left amygdala and cingulated gyrus was found in subjects with affective disorders; whereas, the right amygdala was mostly activated in the HC group. Higher BHS scores were associated with reduced BOLD activation throughout the primary somatosensorial cortex and left post-central gyrus. Conclusion: Conversely, increased BOLD activation throughout the parietal superior lobule and right anterior intraperietal sulcus, occipital cortex, and left optical radiation, right insular cortex, right frontal superior gyrus was correlated with higher BHS total scores. Future studies should investigate the nature of the associations among brain activation, suicide risk, and affective temperaments in larger samples.

Background & Objective: Despite the great effort spent over recent decades to unravel the pathological mechanisms underpinning the development of central nervous system disorders, most of them still remain unclear. In particular, the study of rare CNS diseases is hampered by the lack of postmortem samples and of reliable epidemiological studies, thus the setting of in vitro modeling systems appears essential to dissect the puzzle of genetic and environmental alterations affecting neural cells viability and functionality. The isolation and expansion in vitro of embryonic (ESC) and fetal neural stem cells (NSC) from human tissue have allowed the modeling of several neurological diseases “in a dish” and have also provided a novel platform to test potential therapeutic strategies in a pre-clinical setting. In recent years, the development of induced pluripotent stem cell (iPS) technology has added enormous value to the aforementioned approach, thanks to their capability for generating diseaserelevant cell phenotypes in vitro and to their perspective use in autologous transplantation. However, while the potentiality of ESC, NSC and iPS has been widely sponsored, the pitfalls related to the available protocols for differentiation and the heterogeneity of lines deriving from different individuals have been poorly discussed. Here we present pro and contra of using ESC, NSC or iPS for modeling rare diseases like Lysosomal Storage disorders and Motor Neuron Diseases. Conclusion: In this view, the advent of gene editing technologies is a unique opportunity to standardize the data analysis in preclinical studies and to tailor clinical protocols for stem cell-mediated therapy.

Background & Objective: Leber's hereditary optic neuropathy is an inherited form of optic neuropathy, genetically and pathophysiologically based on mitochondrial insufficiency causing bilateral loss of central vision mostly amongst young adults. Despite being one of the most common mitochondrial diseases, the explanation for its pathophysiological background and effective clinical solutions remain elusive. Widening the scope in the search for pathological findings beyond the optic system has yielded several non-ophthalmologic findings, which might imply that Leber's hereditary optic neuropathy is in fact a multi-systemic disease. Conclusion: The aim of this review is to provide an overview of literature regarding the epidemiology, etiology, pathogenesis, clinical features, diagnostics and possible treatment options and drug targets, as well as presenting challenges related to the disease and proposing a diagnostic algorithm based on current clinical experience.

Background & Objective: Huntington's disease (HD) is an autosomal-dominant, progressive neurodegenerative disease characterized by selective loss of neurons in the striatum and cortex, which leads to progressive motor dysfunction, cognitive decline and behavioral symptoms. HD is caused by a trinucleotide (CAG) repeat expansion in the gene encoding the protein huntingtin. Despite the fact that the HD gene was identified over 20 years ago, there is no effective disease-modifying therapy for HD and only symptomatic therapies are available to date. Recently, new agents and procedures have been investigated for HD and many of them have focused on immunomodulatory and/or anti- inflammatory strategies. Conclusion: The objective of the current review is to summarize data on the therapeutic strategies to treat HD that are based on immunomodulatory effects.

Background & Objective: Advances in the knowledge of the microbiota and concepts related to it have triggered a wake-up call in biomedicine. The development in various scientific areas has enabled a better and broader approach to everything concerning the set of families of microorganisms that coexist with an individual and are able to function as one or more organs in its body. Among the aforementioned scientific areas, those worth mentioning are the advances/progress in biotechnological resources and, in particular, molecular biology and related areas. This has given rise to the era of “omics”, marking a turning point in the understanding of numerous physiologic and pathophysiologic processes of the organism. The current theory is that the microbiota and the host maintain an intimate relationship that is of a markedly bilateral nature. This continuous feedback has different connotations between one individual and another, but also within the same individual throughout its life span, which is determined by its own conditioning factors (such as its genetic profile), and environmental ones (mainly diet and lifestyles). Both elements (microbiota and host) coexist harmoniously, maintaining a balance, which can be altered and give rise to different morbid entities. Among these is its relation to chronic processes, and especially those of an autoimmune origin. Such may be neurological diseases situations and, specifically, those of a neurodegenerative nature. In disorders such as multiple sclerosis, amyotrophic lateral sclerosis, Huntington's chorea and Alzheimer's disease, among others, it has been found that a disharmonic coexistence between microbiota and host may have implications in their etiology and pathogenesis. A better understanding of those implications has led to the development of actions on the gut microbiota as a target to slow down the advancement or establishment of neurodegeneration. Conclusion: In this scenario, several treatment strategies have emerged, such as probiotic food intake and stool transplantation. Their real potentialities remain to be elucidated, although current scientific evidence infers that the development of those therapeutic approaches could offer a ray of hope in the prospects of tackling neurodegenerative diseases.