Dulaglutide reduces oxidative DNA damage and hypermethylation in the somatic cells of mice fed a high-energy diet by restoring redox balance, inflammatory responses, and DNA repair gene expressions.

Obesity is an established risk factor for numerous malignancies, although it remains uncertain whether the disease itself or weight-loss drugs are responsible for a greater predisposition to cancer. The objective of the current study was to determine the impact of dulaglutide on genetic and epigenetic DNA damage caused by obesity, which is a crucial factor in the development of cancer. Mice were administered a low-fat or high-fat diet for 12 weeks, followed by a 5-week treatment with dulaglutide. Following that, modifications of the DNA bases were examined using the comet assay. To clarify the underlying molecular mechanisms, oxidized and methylated DNA bases, changes in the redox status, levels of inflammatory cytokines, and the expression levels of some DNA repair genes were evaluated. Animals fed a high-fat diet exhibited increased body weights, elevated DNA damage, oxidation of DNA bases, and DNA hypermethylation. In addition, obese mice showed altered inflammatory responses, redox imbalances, and repair gene expressions. The findings demonstrated that dulaglutide does not exhibit genotoxicity in the investigated conditions. Following dulaglutide administration, animals fed a high-fat diet demonstrated low DNA damage, less oxidation and methylation of DNA bases, restored redox balance, and improved inflammatory responses. In addition, dulaglutide treatment restored the upregulated DNMT1, Ogg1, and p53 gene expression. Overall, dulaglutide effectively maintains DNA integrity in obese animals. It reduces oxidative DNA damage and hypermethylation by restoring redox balance, modulating inflammatory responses, and recovering altered gene expressions. These findings demonstrate dulaglutide's expediency in treating obesity and its associated complications.

Contemporary Management of Obesity: A Comparison of Bariatric Metabolic Surgery and Novel Incretin Mimetic Drugs.

The global prevalence of obesity has risen sharply during the past half-century, reaching pandemic proportions and creating a public health crisis. Obesity is a recognized risk factor for the development of diabetes, atherosclerosis, hypertension, hepatic steatosis, and many other cardiometabolic disorders with significant resultant morbidity and mortality. Though treatment of obesity can prevent or slow the progression of the aforementioned illnesses, efforts to help patients achieve reliable and sustainable weight loss have had limited success. Improving nutrition and increasing physical activity results in a host of health benefits; however, the weight loss achieved with lifestyle interventions alone is modest and difficult to sustain. Early attempts at medical and surgical treatment of obesity were plagued with adverse effects and complications. Moreover, these approaches failed to demonstrate long-term health benefits, even when weight loss was achieved. Recently, novel incretin-based therapies targeting glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptors have gained popularity because of their effectiveness in achieving substantial weight loss in patients both with and without diabetes. Following many successful clinical trials, there are now multiple GLP-1 receptor agonists and one dual GLP-1-GIP receptor agonist approved by the Food and Drug Administration for chronic weight management. Advancements in laparoscopic surgical technique and refinements in procedure selection have similarly improved the safety and efficacy of bariatric metabolic surgery for patients with obesity. In this review, we discuss the advantages and disadvantages of contemporary pharmacologic and surgical weight management strategies. We review the data regarding expected weight loss, glycemic control, cardiometabolic benefits, and potential adverse effects of various treatment approaches. As obesity rates continue to rise worldwide, it is imperative that clinicians keep these considerations in mind in order to better care for patients.

Antiobesity Drug Discovery Research: In vitro Models for Shortening the Drug Discovery Pipeline.

Obesity is a growing global health problem, leading to various chronic diseases. Despite standard treatment options, the prevalence of obesity continues to rise, emphasizing the need for new drugs. in vitro methods of drug discovery research provide a time and cost-saving platform to identify new antiobesity drugs. The review covers various aspects of obesity and drug discovery research using in vitro models. Besides discussing causes, diagnosis, prevention, and treatment, the review focuses on the advantages and limitations of in vitro studies and exhaustively covers models based on enzymes and cell lines from different animal species and humans. In contrast to conventional in vivo animal investigations, in vitro preclinical tests using enzyme- and cell line-based assays provide several advantages in development of antiobesity drugs. These methods are quick, affordable, and provide high-throughput screening. They can also yield insightful information about drug-target interactions, modes of action, and toxicity profiles. By shedding light on the factors that lead to obesity, in vitro tests can also present a chance for personalized therapy. Technology will continue to evolve, leading to the creation of more precise and trustworthy in vitro assays, which will become more and more crucial in the search for novel antiobesity medications.

Obesity pharmacotherapy - update 2023.

The increasing prevalence of obesity and its associated complications leads to the need to intensify its prevention and treatment. The treatment of obesity is currently based on lifestyle modification, which often fails in the long term. For the next decade, the long-term administration of anti-obesity drugs, i.e. drugs that have a positive effect not only on the reduction of excess weight but also on the health risks associated with obesity, seems to be a necessary part of obesity treatment, along with surgical approaches. This text provides an overview of the current options for the pharmacotherapy of obesity, including their indications, appropriate patient selection and adverse effects of treatment. It also provides an overview of studies that demonstrate the long-term efficacy and safety of these treatments. Although effective and safe anti-obesity drugs are currently available, it is not even partially covered by general health insurance. However, the cost of treatment is unaffordable in the long term for a large proportion of the obese. The virtual unavailability of effective antiobesity drugs for indicated patients has serious health-economic consequences. Failure to take advantage of effective therapeutic options, confirmed by evidence-based medicine, results in a high prevalence of obesity-related diseases, which are even more costly to treat economically and, in the case of type 2 diabetes, even less effective. We consider at least partial reimbursement of antiobesity drugs from general health insurance for cooperating patients under clearly defined conditions to be a necessary step towards improving the situation, and clearly cost-effective in its consequences.

5-HT2C Receptor Stimulation in Obesity Treatment: Orthosteric Agonists vs. Allosteric Modulators.

Obesity is a substantial health and economic issue, and serotonin (5-hydroxytryptamine, 5-HT) is an important neurotransmitter system involved in the regulation of body weight. The 5-HT2C receptors (5-HT2CRs), one of 16 of the 5-HT receptor (5-HTRs) subtypes, play a significant role in food intake and body weight control. In this review, we focused on the 5-HTR agonists, such as fenfluramines, sibutramine, and lorcaserin, which act directly or indirectly at 5-HT2CRs and have been introduced into the clinic as antiobesity medications. Due to their unwanted effects, they were withdrawn from the market. The 5-HT2CR positive allosteric modulators (PAMs) can be potentially safer active drugs than 5-HT2CR agonists. However, more in vivo validation of PAMs is required to fully determine if these drugs will be effective in obesity prevention and antiobesity pharmacology treatment. Methodology strategy: This review focuses on the role of 5-HT2CR agonism in obesity treatment, such as food intake regulation and weight gain. The literature was reviewed according to the review topic. We searched the PubMed and Scopus databases and Multidisciplinary Digital Publishing Institute open-access scientific journals using the following keyword search strategy depending on the chapter phrases: (1) "5-HT2C receptor" AND "food intake", and (2) "5-HT2C receptor" AND "obesity" AND "respective agonists", and (3) "5-HT2C receptor" AND "PAM". We included preclinical studies (only present the weight loss effects) and double-blind, placebo-controlled, randomized clinical trials published since the 1975s (mostly related to antiobesity treatment), and excluded the pay-walled articles. After the search process, the authors selected, carefully screened, and reviewed appropriate papers. In total, 136 articles were included in this review.

Evaluation of honokiol, magnolol and of a library of new nitrogenated neolignans as pancreatic lipase inhibitors.

Obesity is a complex disease defined as an excessive amount of body fat. It is considered a risk factor for several pathologies; therefore, there is an increasing interest in its treatment. Pancreatic lipase (PL) plays a key role in fat digestion, and its inhibition is a preliminary step in the search for anti-obesity agents. For this reason, many natural compounds and their derivatives are studied as new PL inhibitors. This study reports the synthesis of a library of new compounds inspired by two natural neolignans, honokiol (1) and magnolol (2) and bearing amino or nitro groups linked to a biphenyl core. The synthesis of unsymmetrically substituted biphenyls was achieved through an optimisation of the Suzuki-Miyaura cross-coupling reaction followed by the insertion of allyl chains, thus furnishing the O- and/or N-allyl derivatives, and finally, a sigmatropic rearrangement yielding in some cases, the C-allyl analogues. Magnolol, honokiol and the twenty-one synthesised biphenyls were evaluated for their in vitro inhibitory activity toward PL. Three compounds (15b, 16 and 17b) were more effective inhibitors than the natural neolignans (magnolol IC50 = 158.7 µM and honokiol IC50 = 115.5 µM) with IC50 of 41-44 µM. Detailed studies through kinetics suggested better inhibitory activity of the synthetic analogues compared with the natural 1 and 2. Magnolol (Ki = 614.3 µM; K'i of 140.9 µM) and the synthetic biphenyls 15b (Ki = 286.4 µM; K'i = 36.6 µM) and 16 (Ki = 176.2 µM; K'i = 6.4 µM) are mixed-type inhibitors, whereas honokiol (Ki = 674.8 µM) and 17b (Ki = 249 µM) are competitive inhibitors. Docking studies corroborated these findings, showing the best fitting for intermolecular interaction between biphenyl neolignans and PL. The above outcomes highlighted how the proposed structures could be considered interesting candidates for future studies for the development of more effective PL inhibitors.

Weight Regain After Bariatric Surgery: Scope of the Problem, Causes, Prevention, and Treatment.

PURPOSE OF REVIEW: Although bariatric surgery is the most effective treatment of severe obesity, a proportion of patients experience clinically significant weight regain (WR) with further out from surgery. The purpose of this review is to summarize the prevalence, predictors, and causes of weight regain. RECENT FINDINGS: Estimating the prevalence of WR is limited by a lack of consensus on its definition. While anatomic failures such as dilated gastric fundus after sleeve gastrectomy and gastro-gastric fistula after Roux-en-Y gastric bypass can lead to WR, the most common causes appear to be dysregulated/maladaptive eating behaviors, lifestyle factors, and physiological compensatory mechanisms. To date, dietary, supportive, behavioral, and exercise interventions have not demonstrated a clinically meaningful impact on WR, and there is limited evidence for pharmacotherapy. Future studies should be aimed at better defining WR to begin to understand the etiologies. Additionally, there is a need for non-surgical interventions with demonstrated efficacy in rigorous randomized controlled trials for the prevention and reversal of WR after bariatric surgery.

Prescribing trends and clinical characteristics of patients starting antiobesity drugs in the United States.

AIM: To assess the trends in the prescribing of antiobesity medications and the characteristics of patients recently initiating antiobesity drugs. MATERIALS AND METHODS: We conducted a population-based cohort study using claims data from commercial health insurances in the United States. Patients initiating an antiobesity drug between January 2004 and December 2018 were included. Trends in the utilization of antiobesity medications were plotted by year, as a proportion of any antiobesity treatment, and as initiation rates per 100 000. Descriptive statistics were used to summarize the characteristics of antiobesity initiators. RESULTS: From 2004 to 2018, 626 216 patients started an antiobesity medication (two per 100 000). Phentermine was the most frequently prescribed (50% in 2018). In recent years (2015-2018), among 227 692 patients who initiated an antiobesity drug, 51% started phentermine, 19% naltrexone-bupropion, and 13% liraglutide 3.0 mg. Compared to other agents, the use of liraglutide 3.0 mg increased between 2015 and 2018. The average age of initiators was 45 years, 81% of initiators were female, 32% had hypertension, 25% had dyslipidaemia, and 6% had type 2 diabetes. Time on treatment was generally short (mean 81 days). CONCLUSION: The overall use of antiobesity medications remained low over the past 15 years and phentermine was the preferred antiobesity agent. Although the use of potentially safer antiobesity agents, for example, liraglutide 3.0 mg, has increased in recent years, phentermine remained the most frequently prescribed agent among middle-aged adults with a moderate burden of comorbidities.

Obesity and cardiovascular disease.

Obesity with no comorbidities probably carries no cardiovascular risk, and the so-called obesity paradox even comes into play, wherein obesity may improve the prognosis of cardiovascular disease. Cardiovascular complications primarily occur indirectly due to metabolic comorbidities of obesity. However, a thrombogenic potential of obesity has also been established. A very important question in contemporary obesitology is whether antidiabetics currently administered in obese non-diabetic individuals will have a positive cardiovascular effect similar to that in diabetics. Myokines, muscle tissue hormones, certainly have a protective effect on the cardiovascular system. Also of importance is the research into epicardial and pericardial fat. Its investigation and management will aid in finding additional options of diagnosing and treating cardiovascular disease.

The limits and challenges of antiobesity pharmacotherapy.

INTRODUCTION: Pharmacotherapy is a useful adjunct when patients with obesity are unable to achieve adequate benefit from lifestyle interventions. AREAS COVERED: This review covers the history of antiobesity drugs, efficacy, and risks of currently approved drugs, limits of their usefulness in clinical practice, gaps in knowledge, methodological limitations of clinical trials, and reasons for underutilization. EXPERT OPINION: In randomized controlled trials, currently approved antiobesity drugs have yielded an average weight loss ranging from approximately 3% to 9% relative to placebo at 1 year. Inadequate inclusion of racial and ethnic minorities and men, and high dropout rates in clinical trials limit generalizability of these findings to clinical practice. Weight loss achieved with antiobesity drugs is generally associated with lowered glycemia, but improvements in blood pressure and lipid measures tend to be marginal. There is limited evidence for sustained weight loss beyond 1 year and for safety and efficacy of antiobesity drugs in children and adolescents, and in post-bariatric surgery patients. None have demonstrated reduction in major adverse cardiovascular events or other significant disease outcomes. Limited health insurance coverage and negative perceptions of physicians have hindered the utilization of antiobesity drugs.

Hypertension in Obesity: Novel Insights.

BACKGROUND: The relationship between obesity and hypertension has been established in both adults and children. The combination of obesity, hypertension and other cardiovascular risk factors significantly increases the likelihood of adverse cardiovascular effects and raises concerns about aggressive treatment strategies. OBJECTIVE: Despite the impressive elements which indicate an important role for excessive weight gain in increasing blood pressure, not all obese patients are hypertensive. A subgroup of obese people may not develop hypertension. Furthermore, masked hypertension occurs more common among obese patients, and body fat distribution has a major role in the development of hypertension. METHOD: We conducted a research of the relevant literature regarding obesity-induced hypertension and possible treatment strategies. RESULTS: Successful weight loss is correlated with blood pressure reduction and requires a multidisciplinary approach that includes personalized dietary interventions combined with regular exercise and cognitive behavioral therapy. CONCLUSION: Pharmacological therapy may be considered as part of a comprehensive obesity management strategy. More research and new treatment therapies are required in this field.

Contemporary state and perspectives of obesity pharmacotherapy.

The history of obesity pharmacotherapy is controversial. Many drugs are not used more due to severe side effects. Today we have four effective antiobesity drugs. The effect of some of them is comparable with bariatric sugary. Weight loss induced by bariatric surgery is culminating in the first year. The effect of incretine analogues is progressive in several years and culminating later. There are many antiobesity drugs in development. Both centrally or peripherally acting new drugs will be available soon. Even targeted therapy using antibodies will be used in obesitology soon.

The Triple Combination Phentermine Plus 5-HTP/Carbidopa Leads to Greater Weight Loss, With Fewer Psychomotor Side Effects Than Each Drug Alone.

Obesity has become a serious public health problem. Although diet, surgery, and exercise are the primary treatments for obesity, these activities are often supplemented using appetite suppressants. A previous study reported that obesity specialists frequently prescribed a new drug combination for its treatment that includes phentermine (Phen; dopaminergic appetite suppressant), a serotonin (5-HT) precursor 5-hydroxytryptophan (5-HTP; an appetite suppressant that increases the 5-HT concentration), and carbidopa (CB; peripheral blocker of conversion of 5-HTP to 5-HT). Despite its widespread use, there is neither a preclinical study confirming the drug efficacy nor studies of its effects on the brain. To fill this gap, in rats for seven consecutive days, we administered Phen intraperitoneally at different doses either alone or in combination with a fixed dose of 5-HTP/CB. In a different group, we infused drugs via an intraperitoneal catheter while extracellular-recordings were performed in the nucleus accumbens shell (NAcSh), a brain region with dopamine-releasing effects that is involved in the action of appetite suppressants. We found that the triple-drug combination leads to greater weight-loss than each drug alone. Moreover, and as the treatment progresses, the triple drug combination partially reversed psychomotor side-effects induced by Phen. Electrophysiological results revealed that Phen alone evoked a net inhibitory imbalance in NAcSh population activity that correlated with the onset of psychomotor effects. In addition, and unlike the greater weight loss, the addition of 5-HTP/CB did not alter the Phen-evoked inhibitory imbalance in NAcSh responses. Subsequent experiments shed light on the underlying mechanism. That is the majority of NAcSh neurons modulated by 5-HTP/CB were suppressed by Phen. Notably, and despite acting via a different mechanism of action (DA for Phen vs. 5-HT for 5-HTP/CB), both drugs recruited largely overlapping NAcSh neuronal ensembles. These data suggest that the neural correlates of the greater weight loss could be located outside the NAcSh, in other brain circuits. Furthermore, we conclude that Phen + 5-HTP/CB is a potential treatment for overweight and obesity.

Review of multimodal treatment for type 2 diabetes: combining metabolic surgery and pharmacotherapy.

Treating type 2 diabetes mellitus (T2DM) in patients with obesity remains a challenge for physicians, endocrinologists and surgeons, a fact supported by uncontroverted evidence from studies looking at mortality and associated morbidity. Metabolic surgery remains the most effective treatment for obesity and T2DM with evidence demonstrating an improvement or resolution of symptoms of T2DM and a reduction in a mortality and rates of cardiovascular events compared with pharmacotherapy alone. While these results are promising, two important limitations must be recognized and addressed. With regards to long-term remission of T2DM, the metabolic benefits of bariatric surgery appear to fatigue with time and a proportion of patients will not maintain normoglycaemia without pharmacotherapy. Second, there has been noteworthy progress in the development of several classes of medications for the treatment of T2DM which were unavailable when the original studies comparing the effects of bariatric surgery with pharmacotherapy were conducted. Recognizing the need for further treatment following metabolic surgery for long-term disease control in conjunction with the availability of newer medications offering more effective, nonsurgical treatment presents a critical turning point in treatment treating obesity. While the traditional approach would be to determine the superiority (or non-inferiority) of these agents compared with surgery, clinicians and surgeons must acknowledge the limitations of this attitude towards treatment given evidence from fields such as cancer, where a combinational approach is the gold standard. Recent advances in pharmacotherapy, present not only a novel approach to medical therapy but a renewed impetus to investigate what can be achieved through multimodal care.

Obesity and type 2 diabetes: Also linked in therapeutic options. / Obesidad y diabetes mellitus tipo 2: también unidas en opciones terapéuticas.

The prevalence of obesity has increased worldwide over the past decades. Obesity is associated with multiple comorbidities, such as type 2 diabetes, that generates a great impact on health and economy. Weight loss in these patients leads to glycemic control so it is a target to achieve. Lifestyle changes are not effective enough and recently other treatments have been developed such as bariatric/metabolic surgery, as well as drugs for type 2 diabetes and antiobesity drugs. The aim of this review is to compare the results in weight reduction and glycemic control of the different kinds of drugs with bariatric / metabolic surgery's results in type 2 diabetes.

Actualidades en el tratamiento farmacológico a largo plazo de la obesidad. ¿Una opción terapéutica? / Up-to-date in the long-term pharmacological treatment of obesity. A therapeutic option?

Resumen La obesidad es una enfermedad crónica, con afección sistémica y de carácter multifactorial que constituye un grave problema de salud pública, considerada por la Organización Mundial de la Salud una epidemia global. La obesidad es resultado del equilibrio energético positivo por tiempo prolongado, donde la energía derivada de los alimentos excede la energía gastada en la vida cotidiana. En vía de poner fin a este problema de salud pública se han buscado opciones de tratamiento, si bien las modificaciones al estilo de vida, incluida la dieta y el ejercicio, siguen siendo la piedra angular del tratamiento de la obesidad, estas modificaciones no han permitido mantener resultados a largo plazo, por esta razón los medicamentos contra la obesidad se vuelven una opción viable. Son cinco los medicamentos aprobados por la Dirección de Alimentos y Fármacos de Estados Unidos para el tratamiento a largo plazo de la obesidad: orlistat, fentarmina/topiramato de liberación prolongada, lorcarserina, naltrexona/bupropión de liberación prolongada y liraglutida, mismos que han demostrado eficacia y seguridad necesaria para tomarse en cuenta como una opción terapéutica. En este artículo revisaremos la eficacia y seguridad de cada uno los medicamentos aprobados contra la obesidad que se encuentran disponibles.

Abstract Obesity is a chronic disease, with systemic affection and of multifactorial character that constitutes a serious problem of public health, being considered by the World Health Organization a global epidemic. Obesity is the result of a positive energy balance by a long time, where the energy derived from food exceeds the energy expended in everyday life. In order to put an end to this public health problem, treatment options have been sought, although the modifications to the lifestyle included diet and exercise are still the cornerstone of the treatment for obesity, these modifications have not allowed to maintain long-term results; for this reason anti-obesity drugs become a viable option. There are five drugs approved by the FDA nowadays for the long-term treatment of obesity: orlistat, phentermine/topiramate prolonged release, lorcarserin, naltrexone/bupropion prolonged release, and liraglutide, which have shown efficacy and the necessary safety to be taken into account as a therapeutic option. In this article we will review the effectiveness and safety of each of the approved anti-obesity drugs that are available.

Obesity: Pathophysiology and Management.

Obesity continues to be among the top health concerns across the globe. Despite our failure to contain the high prevalence of obesity, we now have a better understanding of its pathophysiology, and how excess adiposity leads to type 2 diabetes, hypertension, and cardiovascular disease. Lifestyle modification is recommended as the cornerstone of obesity management, but many patients do not achieve long-lasting benefits due to difficulty with adherence as well as physiological and neurohormonal adaptation of the body in response to weight loss. Fortunately, 5 drug therapies-orlistat, lorcaserin, liraglutide, phentermine/topiramate, and naltrexone/bupropion-are available for long-term weight management. Additionally, several medical devices are available for short-term and long-term use. Bariatric surgery yields substantial and sustained weight loss with resolution of type 2 diabetes, although due to the high cost and a small risk of serious complications, it is generally recommended for patients with severe obesity. Benefit-to-risk balance should guide treatment decisions.

Pharmacotherapy of Obesity: Clinical Trials to Clinical Practice.

PURPOSE OF REVIEW: This review provides an overview of the current state of drug therapy for obesity, with a focus on four new drug therapies-lorcaserin, phentermine/topiramate, naltrexone/bupropion, and liraglutide 3.0 mg-which have been approved by the US Food and Drug Administration (FDA) for long-term management of obesity since 2012. Topics discussed in this paper include rationale for pharmacotherapy, history of antiobesity drugs, and efficacy and safety data from randomized controlled trials with implications for clinical practice. RECENT FINDINGS: Weight loss achieved by currently approved drugs ranges from approximately 3 to 9%, above and beyond weight loss with lifestyle counseling alone, after a year. Response and attrition rates in clinical trials indicate that the benefits of pharmacotherapy range from substantial for some patients, modest for others, and no benefits for others still. Decisions regarding selection of a suitable drug from the available pharmacotherapy options and duration of treatment should be based on the expected and observed benefit-to-risk balance and tailored to the needs of each individual patient using the principles of shared decision-making.

Emerging drugs for the treatment of obesity.

INTRODUCTION: The increasing prevalence of obesity represents a huge threat to public health and the current pharmacological treatment options are limited. Bariatric surgery is by far the most effective treatment for severe obesity, highlighting the urgent need for new and improved drug therapies. Areas covered: Based on the physiological regulation of energy homeostasis, pharmacological strategies to treat obesity are evaluated with focus on drugs in phase 2 and 3 clinical development. The potential impact of these drugs on current treatment standards and the barriers for development are discussed and set in a historical perspective of previous antiobesity medications. Expert opinion: The radical effects of bariatric surgery have extended our understanding of the mechanisms controlling appetite and boosted the search for new drug targets in obesity treatment. Accordingly, several compounds targeting the central nervous system and/or periphery are in pipeline for obesity. These drugs should be evaluated over a wide array of end-points; in particular, long-term safety monitoring is necessary as serious adverse events may appear. Combination therapy targeting more than one pathway controlling energy balance might be necessary to achieve substantial weight loss while minimising side effects.

Psychopathological Behaviour and Cognition in Morbid Obesity.

BACKGROUND: Obesity is a chronic condition with high prevalence and multifaceted aetiology, accompanied by an increased risk of morbidity and mortality. Obesity has several negative effects on the psychological status, and the severity of psychological disorders correlates with the degree of obesity. OBJECTIVE: Aim of this review is to provide an overview of the literature concerning the psychological distress associated with severe obesity, which contributes to deterioration of the quality of life of affected patients. METHODS: Dysfunctional eating behaviours and eating disorders, psychiatric comorbidity, cognition and quality of life will be discussed together with the most common drugs that can be employed to treat the various disorders in this peculiar clinical setting. The effects of bariatric surgery will be also reviewed. RESULTS: Obesity is often the result of pathological behaviours implemented in an eating disorder. Inconsistent results have been reported with regard to the effect of severe obesity on cognition, which recognize a multifaceted aetiology. Serotonergic agents play an important role in the management of patients with obesity and binge episodes, fluoxetine being currently a drug approved for this disorder. The efficacy of lorcaserin, a combination of bupropion and naltrexone, or antiepileptic medications (topiramate and zonisamide) has also been proposed. A neuroprotective role of leptin and oestrogen has been hypothesized. Bariatric surgery is a helpful treatment of morbid obese patients, with long-term favourable results on the psychopathological profile. CONCLUSION: Psychological, psychoeducational and psychopharmacological treatment can facilitate weight loss in morbid obese subjects with psychopathological comorbidities. A precise definition of the mechanisms affecting appetite, satiety and energy balance is expected to foster the development of new effective antiobesity drugs.