Current Neuropharmacology - Volume 16, Issue 8, 2018

Heterogeneity, frequent diagnostic fluctuation across presentations, and global concerns with the absence of effective treatments all encourage science that moves the field toward individualized or precision medicine in eating disorders. We review recent advances in psychiatric genetics focusing on genome-wide association studies (GWAS) in eating disorders. Given that the only eating disorder to be the subject of GWAS to date is anorexia nervosa, we review anorexia GWAS and enumerate the prospects and challenges of a genomics-driven approach towards personalized intervention in eating disorders.

Background: The hypothalamic neuropeptide oxytocin regulates reproductive behavior and mother-infant interaction, and conclusive studies in humans indicate that oxytocin is also a potent modulator of psychosocial function. Pilot experiments have yielded first evidence that this neuropeptide moreover influences eating behavior. Methods: We briefly summarize currently available studies on the involvement of the oxytocin system in the pathophysiology of eating disorders, as well as on the effects of oxytocin administration in patients with these disorders. Results: Brain administration of oxytocin in animals with normal weight, but also with diet-induced or genetically induced obesity, attenuates food intake and reduces body weight. In normal-weight and obese individuals, acute intranasal oxytocin delivery curbs calorie intake from main dishes and snacks. Such effects might converge with the poignant social and cognitive impact of oxytocin to also improve dysfunctional eating behavior in the therapeutic context. This assumption has received support in first studies showing that oxytocin might play a role in the disease process of anorexia nervosa. In contrast, respective experiments in patients with bulimia nervosa and binge eating disorder are still scarce. Conclusions: We propose a framework of oxytocin's role and its therapeutic potential in eating disorders that aims at integrating social and metabolic aspects of its pharmacological profile, and ponder perspectives and limitations of oxytocin use in the clinical setting.

Background: Social difficulties in eating disorders can manifest as predisposing traits and premorbid difficulties, and/or as consequences of the illness. Objective: The aim of this paper is to briefly review the evidence of social problems in people with eating disorders and to consider the literature on treatments that target these features. Method: A narrative review of the literature was conducted. Results: People with eating disorders often manifest traits, such as shyness, increased tendency to submissiveness and social comparison, and problems with peer relationships before illness onset. Further social difficulties occur as the illness develops, including impaired social cognition and increased threat sensitivity. All relationships with family, peers and therapists are compromised by these effects. Thus, social difficulties are both risk and maintaining factors of eating disorders and are suitable targets for interventions. Several forms of generic treatments (e.g. interpersonal psychotherapy, cognitive analytic therapy, focal psychodynamic therapy) have an interpersonal focus and show some efficacy. Guided self-management based on the cognitive interpersonal model of the illness directed to both individuals and support persons has been found to improve outcomes for all parties. Adjunctive treatments that focus on specific social difficulties, such as cognitive remediation and emotion skills training and cognitive bias modification have been shown to have a promising role. Conclusion: More work is needed to establish whether these approaches can improve on the rather disappointing outcomes that are attained by currently used treatments for eating disorders.

Background: The role of the gut microbiota in Anorexia Nervosa (AN) has long been neglected by researchers, although the fact that the former is known to play an important role in health, disease and weight regulation. Cycles of overweight and underweight due to natural states of starvation and refeeding are normal in many vertebrates in their ecological niches. Objective: The aim of this review was to compare the similarities and differences of the gut microbiota in eating disorders with conditions of fasting and refeeding in other vertebrates. Method: A systematic literature search was conducted in Pubmed and Web of Science to find all relevant studies examining the gut microbiota in eating disorders and different states of fasting in vertebrates for this narrative review. Results: Gut microbiota appears to differ in AN versus normal-weight individuals. Induced fasting conditions in other vertebrates resulted in heterogeneous effects on gut microbiota with respect to their richness, diversity and community structures. The findings for hibernating animals were generally consistent. A decrease in microbial richness and diversity was observed in the hibernating animal compared to the active animal, and the community structures were linked to these conditions. Some similarities and differences between AN and different states of fasting in other vertebrates were found. Conclusion: The complexity of the relationship between fasting and gut microbiota is difficult to interprete. A deeper biological understanding is necessary to identify promising approaches for the modulation of the AN gut microbiota to support established psychotherapies.

Background: Functional magnetic resonance imaging (fMRI) has provided insight on how neural abnormalities are related to the symptomatology of the eating disorders (EDs): anorexia nervosa (AN), bulimia nervosa (BN), and binge eating disorder (BED). More specifically, an increasingly growing number of brain imaging studies has shed light on how functionally connected brain networks contribute not only to disturbed eating behavior, but also to transdiagnostic alterations in body/interoceptive perception, reward processing and executive functioning. Methods: This narrative review aims to summarize recent advances in fMRI studies of patients with EDs by highlighting studies investigating network alterations that are shared across EDs. Results and Conclusion: Findings on reward processing in both AN and BN patients point to the presence of altered sensitivity to salient food stimuli in striatal regions and to the possibility of hypothalamic inputs being overridden by top-down emotional-cognitive control regions. Additionally, innovative new lines of research suggest that increased activations in fronto-striatal circuits are strongly associated with the maintenance of restrictive eating habits in AN patients. Although significantly fewer studies have been carried out in patients with BN and BED, aberrant neural responses to both food cues and anticipated food receipt appear to occur in these populations. These altered responses, coupled with diminished recruitment of prefrontal cognitive control circuitry, are believed to contribute to the binge eating of palatable foods. Results from functional network connectivity studies are diverse, but findings tend to converge on indicating disrupted resting-state connectivity in executive networks, the default-mode network and the salience network across EDs.

Introduction: Brain volume deficits of grey matter (GM) and white matter (WM) are often found in patients with anorexia nervosa (AN). However, until recently, little was known about the influencing factors of these brain volume alterations, nor their exact quantification and rehabilitation. Methods: This review addresses these open questions and further explores what is now known about the underlying pathobiology and the clinical consequences including human studies as well as animal studies mimicking anorexia nervosa in rodents. Results: GM was reduced by 3.7% in adults and 7.6% in adolescents with AN. WM was reduced on average 2.2% in adult patients and 3.2% in adolescents. Most volume deficits in adults are reversible after long-term recovery; for adolescents, data are less clear. The main influencing factors for GM were absolute lowest weight at admission and illness duration. Cerebellar and WM reductions at admission predicted clinical outcome at one year follow-up. New studies found GABA receptor changes in GM and astrocyte loss in both GM and WM, as well as a possible role for oestrogen deficit. All three could partly explain clinical symptoms of anxiety, rigidity and learning impairments in patients with AN. Conclusion: Brain volume deficits in AN seem to play a causal role in the course and the prognosis of AN. A better understanding of these brain changes could lead to more targeted therapies for patients with AN, including astrocyte-directed approaches.

Introduction: Whilst psychological therapies are the main approach to treatment of eating disorders (EDs), advances in aetiological research suggest the need for the development of more targeted, brain-focused treatments. A range of neurostimulation approaches, most prominently repetitive transcranial magnetic stimulation (rTMS), transcranial direct current stimulation (tDCS) and deep brain stimulation (DBS), are rapidly emerging as potential novel interventions. We have previously reviewed these techniques as potential treatments of EDs. Aim: To provide an update of the literature examining the effects of DBS, rTMS and tDCS on eating behaviours, body weight and associated symptoms in people with EDs and relevant analogue populations. Methods: Using PRISMA guidelines, we reviewed articles in PubMed, Web of Science, and PsycINFO from 1st January 2013 until 14th August 2017, to update our earlier search. Studies assessing the effects of neurostimulation techniques on eating and weight-related outcomes in people with EDs and relevant analogue populations were included. Data from both searches were combined. Results: We included a total of 32 studies (526 participants); of these, 18 were newly identified by our update search. Whilst findings are somewhat mixed for bulimia nervosa, neurostimulation techniques have shown potential in the treatment of other EDs, in terms of reduction of ED and associated symptoms. Studies exploring cognitive, neural, and hormonal correlates of these techniques are also beginning to appear. Conclusions: Neurostimulation approaches show promise as treatments for EDs. As yet, large wellconducted randomised controlled trials are lacking. More information is needed about treatment targets, stimulation parameters and mechanisms of action.

Background: Neuropathic pain (NP) is an important public health problem and despite recent progress in the understanding, diagnosis, pathophysiological mechanisms and the treatment of NP, many patients remain refractory to pharmacotherapy. Objective: Currently used drugs have limited efficacy and dose-limiting adverse effects, and thus there is a substantial need for further development of novel medications for its treatment. Alternatively, drugs approved for use in diseases other than NP can be applied as experimental for NP conditions. This paper covers advances in the field of NP treatment. Results: The prime focus of this paper is on drugs with well-established pharmacological activity whose current therapeutic applications are distinct from NP. These drugs could be a potential novel treatment of NP. Data from preclinical studies and clinical trials on these experimental drugs are presented. The development of advanced methods of genomics enabled to propose new targets for drugs which could be effective in the NP treatment. Conclusion: Experimental drugs for NP can be a treatment option which should be tailor-made for each individual on the basis of pain features, previous therapies, associated clinical conditions, recurrence of pain, adverse effects, contraindications and patients' preferences. At present, there are only some agents which may have potential as novel treatments. Increasing knowledge about mechanisms underlying NP, mechanisms of drug action, as well as available data from preclinical and clinical studies make botulinum toxin A, minocycline, ambroxol, statins and PPAR agonists (ATx086001) promising potential future treatment options.

Background: Antipsychotic-induced metabolic side effects are major concerns in psychopharmacology and clinical psychiatry. Their pathogenetic mechanisms are still not elucidated. Methods: Herein, we review the impact of neurotransmitters on metabolic regulation, providing insights into antipsychotic-induced metabolic side effects. Results: Antipsychotic drugs seem to interfere with feeding behaviors and energy balance, processes that control metabolic regulation. Reward and energy balance centers in central nervous system constitute the central level of metabolic regulation. The peripheral level consists of skeletal muscles, the liver, the pancreas, the adipose tissue and neuroendocrine connections. Neurotransmitter receptors have crucial roles in metabolic regulation and they are also targets of antipsychotic drugs. Interaction of antipsychotics with neurotransmitters could have both protective and harmful effects on metabolism. Conclusion: Emerging evidence suggests that antipsychotics have different liabilities to induce obesity, diabetes and dyslipidemia. However this diversity cannot be explained merely by drugs'pharmacodynamic profiles, highlighting the need for further research.

Background: Traumatic brain injury (TBI) constitutes the primary reason for mortality and morbidity in persons worldwide below 45 years of age. 1.7 million Traumatic events occur yearly in the United States alone, considering for 50,000 deaths. In severe traumatic brain injury sufferers, a considerable achievement attained in treating short-term consequences; but till date, huge failures are occurring in researcher's capability to render severe traumatic brain injury sufferers to an elevated degree of performing. Methods: Initial damage force results in Primary brain injury, causing tissue destruction and distortion in the early post-injury period. These secondary injuries from TBI cause changes in cell performance and dissemination of trauma via activities like free-radical generation, depolarization, and formation of edema, excitotoxicity, and disruption of blood brain barrier, calcium homeostasis, and intracranial hematoma. The expectation for developing effect in TBI sufferers is the best knowledge of these activities and enhancement of remedies that restrict secondary brain damage. Results: The focal point of this study is on knowing the complex outburst of secondary impairments and studying the pathophysiology of TBI which provides alternative treatment benefits. Conclusion: While injured persons demonstrate dissimilar levels of harm and every case is novel with specific recovery profiles, this article strengthens the recent pathophysiological sight of TBI mainly attention on oxidative stress, excitotoxicity, cerebral oxygenation and cerebral blood flow (CBF), development of edema, and inflammatory activities. For initial research acknowledgment of these recurring factors could permit clarification of possible beneficial targets.

Background: Ever since the pioneering reports in the 60s, L-3,4-Dioxyphenylalanine (levodopa) has represented the gold standard for the treatment of Parkinson's Disease (PD). However, long-term levodopa (LD) treatment is frequently associated with fluctuations in motor response with serious impact on patient quality of life. The pharmacokinetic and pharmacodynamic properties of LD are pivotal to such motor fluctuations: discontinuous drug delivery, short half-life, poor bioavailability, and narrow therapeutic window are all crucial for such fluctuations. During the last 60 years, several attempts have been made to improve LD treatment and avoid long-term complications. Methods: Research and trials to improve the LD pharmacokinetic since 1960s are reviewed, summarizing the progressive improvements of LD treatment. Results: Inhibitors of peripheral amino acid decarboxylase (AADC) have been introduced to achieve proper LD concentration in the central nervous system reducing systemic adverse events. Inhibitors of catechol-O-methyltransferase (COMT) increased LD half-life and bioavailability. Efforts are still being made to achieve a continuous dopaminergic stimulation, with the combination of oral LD with an AADC inhibitor and a COMT inhibitor, or the intra-duodenal water-based LD/ carbidopa gel. Further approaches to enhance LD efficacy are focused on new non-oral administration routes, including nasal, intra-duodenal, intrapulmonary (CVT-301) and subcutaneous (ND0612), as well as on novel ER formulations, including IPX066, which recently concluded phase III trial. Conclusion: New LD formulations, oral compounds as well as routes have been tested in the last years, with two main targets: achieve continuous dopaminergic stimulation and find an instant deliver route for LD.