Lorcaserin: Worthy of Further Insights? Results from Recent Research.

Lorcaserin is a 3-benzazepine that binds 5-HT2C serotonin receptors in the hypothalamus, where it mediates lack of hunger and/or satiety, and in the ventral tegmental area, the site of origin of the mesolimbic and mesocortical dopaminergic projections, which mediate pleasure and reward. The drug has been first developed for the treatment of obesity, where it has shown efficacy, and subsequently trialed to counter substance use (mostly cocaine, cannabis, opioids, and nicotine) and craving, but showed inconsistent effects. Since 2020, the US Food and Drug Administration obtained that the drug was voluntarily withdrawn from the US market on the grounds that its long-term use was found to be associated with a greater incidence of some types of cancer. Provided it can show to be free from cancerogenic effects, ongoing research suggests that lorcaserin may have therapeutic potential for a variety of disorders and conditions beyond obesity. Since 5-HT2C receptors are involved in many diversified physiological functions (mood, feeding, reproductive behavior, neuronal processes related to impulsiveness, and modulating reward-related mechanisms) this drug has the potential to treat different central nervous system conditions, such as depression and schizophrenia.

Possible psychedelic therapeutic mechanism.

Psychedelics act on intracellular serotonin receptors that are not accessible by serotonin alone.

"Selective" serotonin 5-HT2A receptor antagonists.

Blockade of the serotonin 5-HT2A G protein-coupled receptor (5-HT2AR) is a fundamental pharmacological characteristic of numerous antipsychotic medications, which are FDA-approved to treat schizophrenia, bipolar disorder, and as adjunctive therapies in major depressive disorder. Meanwhile, activation of the 5-HT2AR by serotonergic psychedelics may be useful in treating neuropsychiatric indications, including major depressive and substance use disorders. Serotonergic psychedelics and other 5-HT2AR agonists, however, often bind other receptors, and standard 5-HT2AR antagonists lack sufficient selectivity to make well-founded mechanistic conclusions about the 5-HT2AR-dependent effects of these compounds and the general neurobiological function of 5-HT2ARs. This review discusses the limitations and strengths of currently available "selective" 5-HT2AR antagonists, the molecular determinants of antagonist selectivity at 5-HT2ARs, and the utility of molecular pharmacology and computational methods in guiding the discovery of novel unambiguously selective 5-HT2AR antagonists.

Improving the treatment of Parkinson's disease: Structure-based development of novel 5-HT2A receptor antagonists/inverse agonists.

Pimavanserin is a selective 5-HT2A receptor antagonist and inverse agonist approved by the FDA in 2016, which is used to treat patients with Parkinson's disease psychosis (PDP). But pimavanserin has potential risk with increasing mortality in elderly patients and also increasing the risk of QT interval prolongation in patients. Therefore, searching for new drugs with high efficacy and low toxicity is urgently needed. Based on the docking study of pimavanserin, a series of novel pimavanserin derivatives (7-1∼7-37) were designed and synthesized. The biological activities were evaluated by cell assays and compound 7-16 exhibited 50-fold higher 5-HT2A receptor antagonist activity (IC50 = 0.54 vs 27.3 nM) and 23-fold higher inverse agonist activity (IC50 = 2.1 vs 50 nM) than pimavanserin. Moreover, 7-16 showed increased potency window between the 5-HT2A and hERG activities than pimavanserin. Furthermore, compound 7-16 demonstrated excellent in vitro and in vivo pharmacokinetics, 4-fold more improvement in functional activity in vivo, and good safety profile. Therefore, compound 7-16 represents a potentially promising candidate as a novel anti-PDP agent that warrants further investigation.

Lorcaserin for Dravet Syndrome: A Potential Advance Over Fenfluramine?

Lorcaserin, a selective serotonin 5-HT2C receptor agonist, was developed as an appetite suppressant with the rationale of minimizing the risk of cardiovascular toxicity associated with non-selective serotoninergic agents such as fenfluramine. Eight years after FDA approval, however, it was withdrawn from the market, when a large safety study suggested a potential cancer risk. Following in the fenfluramine footsteps and utilizing the repurposing approach coupled with the regulatory orphan drug designation, lorcaserin is currently in clinical development for the treatment of epilepsy. This potential novel indication builds on the evidence that 5-HT2C receptor stimulation can protect against seizures, and accounts at least in part for fenfluramine's antiseizure effects in Dravet syndrome models. In animal models, lorcaserin shows a narrower range of antiseizure activity than fenfluramine. In particular, lorcaserin is inactive in classical acute seizure tests such as maximal electroshock and subcutaneous pentylenetetrazole in mice and rats, and the 6-Hz stimulation model in mice. However, it is active in the GAERS absence seizure model, and in mutant zebrafish models of Dravet syndrome. Preliminary uncontrolled studies in patients with Dravet syndrome have yielded promising results, and a phase III, double-blind, placebo-controlled, parallel group trial is currently ongoing to assess its efficacy and safety in children and adults with Dravet syndrome.

The 5-HT2C receptor as a therapeutic target for alcohol and methamphetamine use disorders: A pilot study in treatment-seeking individuals.

Alcohol use disorder (AUD) and methamphetamine use disorder (MUD) are prevalent and have high adverse impacts on both the individual and society. Current treatment strategies for these disorders are ineffective at a population level. Lorcaserin, a 5-HT2C receptor agonist, has shown potential at reducing the symptoms of substance use disorder. This pilot study (initiated prior to market withdrawal) examined feasibility and safety of lorcaserin treatment in people undergoing residential detoxification and treatment for AUD and MUD. This was an open label pilot study of lorcaserin where participants (n = 10 AUD; n = 8 MUD) received 10-mg lorcaserin daily for 4 days then twice daily for 1 month. Primary outcome measures included recruitment and retention rate, incidence of treatment-emergent events, incidence of methamphetamine or alcohol withdrawal-related events, heart rate, and blood pressure. Secondary measures included pharmacokinetic data and self-reported alcohol or methamphetamine use, craving, and psychological distress. AUD participants were recruited faster and had a greater retention rate compared with MUD participants. Lorcaserin did not alter vital signs, was well tolerated, and had a similar pharmacokinetic profile to individuals with obesity. Lorcaserin reduced self-reported alcohol and amphetamine-type substance use and craving in AUD and MUD participants, respectively. Self-reported psychological health also improved over the treatment period for all participants. Despite the pilot nature of this study, our data support the notion of 5-HT2C receptors as a therapeutic target for drug and alcohol abuse.

Overcoming Depression with 5-HT2A Receptor Ligands.

Depression is a multifactorial disorder that affects millions of people worldwide, and none of the currently available therapeutics can completely cure it. Thus, there is a need for developing novel, potent, and safer agents. Recent medicinal chemistry findings on the structure and function of the serotonin 2A (5-HT2A) receptor facilitated design and discovery of novel compounds with antidepressant action. Eligible papers highlighting the importance of 5-HT2A receptors in the pathomechanism of the disorder were identified in the content-screening performed on the popular databases (PubMed, Google Scholar). Articles were critically assessed based on their titles and abstracts. The most accurate papers were chosen to be read and presented in the manuscript. The review summarizes current knowledge on the applicability of 5-HT2A receptor signaling modulators in the treatment of depression. It provides an insight into the structural and physiological features of this receptor. Moreover, it presents an overview of recently conducted virtual screening campaigns aiming to identify novel, potent 5-HT2A receptor ligands and additional data on currently synthesized ligands acting through this protein.

Pimavanserin, a 5HT2A receptor inverse agonist, rapidly suppresses Aß production and related pathology in a mouse model of Alzheimer's disease.

Amyloid-ß (Aß) peptide aggregation into soluble oligomers and insoluble plaques is a precipitating event in the pathogenesis of Alzheimer's disease (AD). Given that synaptic activity can regulate Aß generation, we postulated that 5HT2A -Rs may regulate Aß as well. We treated APP/PS1 transgenic mice with the selective 5HT2A inverse agonists M100907 or Pimavanserin systemically and measured brain interstitial fluid (ISF) Aß levels in real-time using in vivo microdialysis. Both compounds reduced ISF Aß levels by almost 50% within hours, but had no effect on Aß levels in 5HT2A -R knock-out mice. The Aß-lowering effects of Pimavanserin were blocked by extracellular-regulated kinase (ERK) and NMDA receptor inhibitors. Chronic administration of Pimavanserin by subcutaneous osmotic pump to aged APP/PS1 mice significantly reduced CSF Aß levels and Aß pathology and improved cognitive function in these mice. Pimavanserin is FDA-approved to treat Parkinson's disease psychosis, and also has been shown to reduce psychosis in a variety of other dementia subtypes including Alzheimer's disease. These data demonstrate that Pimavanserin may have disease-modifying benefits in addition to its efficacy against neuropsychiatric symptoms of Alzheimer's disease. Read the Editorial Highlight for this article on page 560.

Psychedelics as an emerging novel intervention in the treatment of substance use disorder: a review.

Classical psychedelics are a group of drugs characterized by their activation of the serotonin-2A (5-hydroxytryptamine-2A; 5-HT2A) receptor and the unique hallucinogenic and mystical-type experiences that result. After a substantial period of restrictions limiting investigations into the therapeutic potential of psychedelics, a relatively recent recommencement of interest has sparked the burgeoning possibility for these drugs to play a part in the treatment of a wide array of psychopathologies. One of the most promising is in the study of addiction. Evidence has emerged that psychedelic agents may provide a novel avenue for the clinical treatment of patients dealing with substance use disorders (SUD). These serotonergic hallucinogens have displayed remarkable and enduring positive outcomes in this area, even when administered as one or two doses. The neural targets for these psychedelics are varied and underlie a complex mechanism of action-modulating multiple neural networks. It is believed that these agents allow for the reorganization of disordered neural pathways in the default mode network and attenuate maladaptive signaling in mesolimbic reward circuitry. The aim of this review is to examine the current standing of evidence regarding psychedelic psychopharmacology and to provide an overview of the use and effectiveness of these drugs in the treatment of SUD, alcohol use disorder, and for smoking cessation.

Psychedelic Psychiatry's Brave New World.

After a legally mandated, decades-long global arrest of research on psychedelic drugs, investigation of psychedelics in the context of psychiatric disorders is yielding exciting results. Outcomes of neuroscience and clinical research into 5-Hydroxytryptamine 2A (5-HT2A) receptor agonists, such as psilocybin, show promise for addressing a range of serious disorders, including depression and addiction.

Effects of 5-HT2C receptor modulation and the NA reuptake inhibitor atomoxetine in tests of compulsive and impulsive behaviour.

Drug repositioning has gained strategic value as a reaction to high attrition rates of new drugs as they pass through the clinical development process. The 5-HT2C receptor agonist lorcaserin (Belviq®), and the selective NA reuptake inhibitor atomoxetine (Strattera®) represent two drugs FDA approved for obesity and ADHD respectively. Although both drugs are of differing pharmacological class, each share a property of regulating impulsive behaviours in preclinical studies, and thus represent candidates for consideration in clinical conditions labelled as 'impulsive-compulsive disorders'. The present studies investigated both drugs, as well as the highly selective 5-HT2C agonist CP-809101 in two tests of compulsive action: schedule-induced polydipsia (SIP) and increased perseverative [PSV] (and premature [PREM]) responses emitted during an extended ITI 5-choice task. While lorcaserin (0.06-0.6 mg/kg), CP-809101 (0.1-1 mg/kg) and atomoxetine (0.1-1 mg/kg) each reduced both PREM and PSV measures in the 5-choice task, at equivalent doses only lorcaserin and CP-809101 affected excessive water intake in the SIP task, atomoxetine (0.1-2 mg/kg) was essentially ineffective. Further evidence supporting a role of the 5-HT2C receptor as an important regulator of impulsive-compulsive behaviours, the selective antagonist SB-242084 produced the opposing effects to lorcaserin, i.e promoting both impulsive and compulsive behaviours. The profile of atomoxetine may suggest differences in the nature of compulsive action measured either as non-regulatory drinking in the SIP task, and PSV responses made in a 5-choice task. These studies support the consideration of 5-HT2C receptor agonists, typified by lorcaserin, and atomoxetine as potential treatments for clinical conditions categorised as 'impulsive-compulsive disorders'. This article is part of the special issue entitled 'Serotonin Research: Crossing Scales and Boundaries'.

Chemistry, Analysis, Pharmacokinetics and Pharmacodynamics Aspects of Lorcaserin, a Selective Serotonin 5-HT2C Receptor Agonist: An Update.

This review refers to the all-inclusive details of Lorcaserin Hydrochloride on comprehensive information about the synthesis, analytical methods, pharmacodynamics, pharmacokinetics, drug interactions and adverse effects. Lorcaserin Hydrochloride is chemically (R)-8-Chloro-1-methyl-2,3,4,5- tetrahydro-1H-3-benzazepine hydrochloride. Lorcaserin HCl is a novel, synthetic, centrally-acting selective serotonin C (5-HT2c) receptor, l agonist, which results in increased satiety and decreased food consumption in patients. Headache, dizziness and nausea are the most common side effects associated with this drug. Lorcaserin HCl has two major metabolites, one conjugated with glucuronide called N-carbamoyl glucuronide which is excreted in urine and the second Lorcaserin N-sulfamate, which is circulated in the blood. Lorcaserin HCl is synthesized using four different schemes of which a six-step method that resulted in 92.3% yield with 99.8% of purity is employed for scale-up production. It is analyzed quantitatively in the plasma and brain tissue matrix of rats by Ultra Performance Liquid chromatographic (UPLC) method using MS-MS (Mass Spectrometric) detection.

Changing the treatment paradigm for Parkinson's disease psychosis with pimavanserin.

Introduction: Parkinson's disease psychosis (PDP) may affect up to 60% of patients with Parkinson's disease over the course of their disease, and is associated with poor prognosis, including increased risks of mortality and nursing home placement. PDP treatments have been limited to off-label use of atypical antipsychotics, most of which pose risks of worsened motor symptoms and other potential adverse events (AEs) due to their dopamine receptor blockade and additional off-target receptor affinities. Pimavanserin is a highly selective 5-HT2A inverse agonist and poses no known risks for worsening of parkinsonism or other off-target receptor AEs. Pimavanserin is the first and only medication approved for PDP treatment. Areas covered: This review covers estimated prevalence, clinical characteristics, diagnostic criteria, and risk factors for PDP; the hypothetical progression of PDP; management of PDP including use of antipsychotics; pharmacology and clinical trial data on pimavanserin; and expert opinion on PDP treatment. The NLM/PubMed database was searched for papers using the search terms of "PDP" AND "treatment" AND "pimavanserin" for the last 10 years. Expert opinion: The recent insights into PDP pathophysiology and approval of the only medication specifically to treat PDP are key advances that should improve the recognition, diagnosis, and management of PDP.

Effect of a 5-HT2c receptor agonist on urethral closure mechanism in healthy women.

AIMS: To evaluate the effect of ASP2205, a selective serotonin 5-HT2c receptor agonist, and Duloxetine on the urethral pressure in healthy female subjects. METHODS: Healthy females aged 18 to 55 years were recruited for this phase 1, single site, placebo-controlled, randomized, four-period, cross-over study. The interventions were single oral doses of 10 and 60 mg ASP2205, 80 mg duloxetine, and placebo. As a pharmacodynamics endpoint, opening urethral pressure (OUP), corrected for placebo, was measured using urethral pressure reflectometry under both resting and squeezing condition of the pelvic floor at predose and 3, 6, 12, and 24 hours after dosing. Safety and tolerability of ASP2205 were also compared with duloxetine and placebo. RESULTS: Eighteen healthy women signed informed consent, however, one dropped out before dosing and one dropped out after the first period, therefore, 16 subjects completed the study. Duloxetine significantly increased the OUP during both resting and squeezing condition (maximal increase 18.1 and 16.8 cmH2 O, respectively). Both doses of ASP2205 did not increase OUP at any time point. During squeezing OUP decreased significantly in the ASP2205 60 mg group from 6 to 24 hours after dosing. All subjects experienced predominantly central nervous system-related side effects (eg, dizziness and nausea) during ASP2205 treatment, which was most pronounced at 60 mg. CONCLUSIONS: ASP2205, a serotonin 5-HT2c receptor agonist, does not increase the urethral pressure and it is therefore unlikely that 5-HT 2c receptor agonists can be used as a treatment for stress urinary incontinence. ASP2205 was less well tolerated than the high dose of duloxetine.

Evaluation of Selective 5-HT2C Agonists in Acute Seizure Models.

The 5-HT releaser/reuptake inhibitor fenfluramine has been recently reported to provide benefit as an adjunctive treatment for Dravet and Lennox-Gastaut syndromes, two types of severe childhood epilepsy. Despite its enhancement of 5-HT function, many effects of fenfluramine have been demonstrated to be dependent on 5-HT2C receptor activation, suggesting that 5-HT2C receptor activation may have an anticonvulsant property. The present study was designed to evaluate fenfluramine and 5-HT agonists of varying 5-HT2C agonist selectivity, the relatively nonselective mCPP and Ro 60-0175, and the selective 5-HT2C agonists lorcaserin and CP-809101 across a variety of acute seizure tests conducted in adult rats and mice, which have been instrumental in identifying the majority of clinically efficacious antiepileptic drugs. Tests included the maximal electroshock seizure (MES), MES threshold, and 6 Hz electrical convulsive seizure models and the chemoconvulsant pentylenetetrazole test. The effect of mCPP, lorcaserin, and CP-809101 against electrically evoked seizures in amygdala kindled rats was also investigated. Overall, at doses known to interact with 5-HT2CR, there was no clear class-related effect of these agonists in any test. The only notable antiseizure effect of fenfluramine was inhibition of MES-induced tonic seizures in the rat. The current preclinical studies using the classical acute seizure tests and an amygdala kindling model do not identify a reliable antiseizure effect of fenfluramine, an agent now used in the treatment of human epilepsies, including Dravet syndrome and Lennox-Gastaut syndrome. Given the nature of these epilepsies, early life and/or genetic models may have better construct validity and be more appropriate for further study.

Effect of ASP2205 fumarate, a novel 5-HT2C receptor agonist, on urethral closure function in rats.

The pharmacological profile of ASP2205 fumarate (ASP2205), a novel 5-HT2C receptor agonist, was evaluated in vitro and in vivo. ASP2205 showed potent and selective agonistic activity for the human 5-HT2C receptor, with an EC50 of 0.85 nM in the intracellular Ca2+ mobilization assay. Rat 5-HT2C receptor was also activated by ASP2205 with an EC50 of 2.5 nM. Intraduodenal administration (i.d.) of ASP2205 (0.1-1 mg/kg) significantly elevated the leak point pressure (LPP) in anesthetized rats in a dose-dependent manner. This ASP2205 (0.3 mg/kg i.d.)-induced LPP elevation was inhibited by SB242084 (0.3 mg/kg i.v.), a selective 5-HT2C receptor antagonist. Urethral closure responses induced by intravesical pressure loading in rats were enhanced by ASP2205 (0.3 mg/kg i.v.), which was abolished by pretreatment with SB242084 (0.3 mg/kg i.v.) and bilateral transection of the pudendal nerve. In contrast, ASP2205 (0.3 mg/kg i.v.) did not change the resting urethral pressure in rats. These results indicate that ASP2205 can enhance the pudendal nerve-mediated urethral closure reflex via the 5-HT2C receptor, resulting in the prevention of involuntary urine loss.

The serotonin 2C receptor agonist WAY-163909 attenuates ketamine-induced hypothermia in mice.

Anesthesia-Induced Hypothermia (AIH) has been reported to be the cause of many postoperative adverse effects, including increased mortality, decreased immune responses, cardiac events, and a greater prevalence of postoperative surgical wound infections. AIH can in some cases be minimized with pre-warming fluids and gases and forced-air heating systems, but such techniques are not always effective and can result in patient burns or other adverse effects. Stimulation of 5-HT2 receptors has been reported to increase body temperature through a variety of mechanisms, and as such, may be a viable target for pharmacologically minimizing AIH. In the present study, we examined the effects of 5-HT2 receptor stimulation on hypothermia induced by the injectable anesthetic ketamine in Swiss-Webster mice using rectal thermometry. We report that ketamine dose-dependently induced hypothermia, and mice did not become tolerant to this effect of ketamine over the course of three injections spaced at once per week. Ketamine-induced hypothermia was significantly attenuated by pretreatment with the selective 5-HT2C receptor agonist WAY-163909 but not by pretreatment with the mixed 5-HT2A/2C receptor agonist 2,5-dimethoxy-4-iodoamphetamine (DOI). Moreover, the blockade of ketamine-induced hypothermia by WAY-163909 was reversed by pretreatment with the selective 5-HT2C receptor antagonist SB-242084. These findings demonstrate that stimulation of 5-HT2C receptors can reduce AIH, at least for ketamine-induced hypothermia. They warrant further study of the pharmacological and neurobiological mechanisms underlying this interaction and its extension to other anesthetics. Furthermore, these findings suggest that the maintenance of body temperature during surgery may be a new clinical use for 5-HT2C receptor agonists.

Persistent attenuation of nicotine self-administration in rats by co-administration of chronic nicotine infusion with the dopamine D1 receptor antagonist SCH-23390 or the serotonin 5-HT2C agonist lorcaserin.

Tobacco addiction each year causes millions of deaths worldwide. Brain nicotinic acetylcholine receptors have been shown to be central to tobacco addiction. Nicotine replacement therapy aids tobacco cessation, but the success rate is still far too low. This may in part be due to the fact that neurons with nicotinic receptors are not the only neural systems involved in tobacco addiction. Interacting neural systems also play important roles in tobacco addiction. Nicotine increases the release of a variety of neurotransmitters, including dopamine and serotonin. Dopamine, in particular dopamine D1 receptors, has been shown to be involved in the reinforcing action of nicotine. Serotonin through its actions on 5-HT2C receptors has been shown to play a key role in modulating the reinforcement of addictive drugs, including nicotine and alcohol. Combination of treatments could provide greater treatment efficacy. These studies were conducted to evaluate combination therapies utilizing nicotine replacement therapy in conjunction with either a dopamine D1 receptor antagonist SCH-23390 or a serotonin 5-HT2C receptor agonist, lorcaserin. Female Sprague-Dawley rats were given access to self-administer nicotine via IV infusions. Osmotic pumps were implanted to reproduce the kinetic of chronic nicotine patch therapy. SCH-23390 (0.02 mg/kg) or lorcaserin (0.6 mg/kg) were administered prior to nicotine self-administration sessions. Reproducing earlier findings SCH-23390, lorcaserin and nicotine replacement therapy were effective at reducing IV nicotine self-administration. 5HT2C agonist treatment had additive effects with chronic nicotine infusion for significantly lowering nicotine self-administration. This study demonstrates the feasibility of combination of chronic nicotine with therapies targeting non-nicotinic receptors as treatment options for tobacco addiction.

Lorcaserin and Renal Outcomes in Obese and Overweight Patients in the CAMELLIA-TIMI 61 Trial.

BACKGROUND: Obesity is thought to increase renal hyperfiltration, thereby increasing albuminuria and the progression of renal disease. The effect of pharmacologically mediated weight loss on renal outcomes is not well-described. Lorcaserin, a selective serotonin 2C receptor agonist that promotes appetite suppression, led to sustained weight loss without any increased risk for major adverse cardiovascular (CV) events in the CAMELLIA-TIMI 61 trial (Cardiovascular and Metabolic Effects of Lorcaserin in Overweight and Obese Patients-Thrombolysis in Myocardial Infarction 61). METHODS: CAMELLIA-TIMI 61 randomly assigned 12 000 overweight or obese patients with or at high risk for atherosclerotic CV disease to lorcaserin or placebo on a background of lifestyle modification. The primary renal outcome was a composite of new or worsening persistent micro- or macroalbuminuria, new or worsening chronic kidney disease, doubling of serum creatinine, end-stage renal disease, renal transplant, or renal death. RESULTS: At baseline, 23.8% of patients had an estimated glomerular filtration rate (eGFR) <60 mL·min-1·1.73 m-2 and 19.0% had albuminuria (urinary albumin:creatinine ratio ≥30 mg/g). Lorcaserin reduced the risk of the primary renal composite outcome (4.2% per year versus 4.9% per year; hazard ratio [HR], 0.87; 95% confidence interval [CI], 0.79-0.96; P=0.0064). The benefit was consistent across subpopulations at increased baseline CV and renal risk. Lorcaserin improved both eGFR and urinary albumin:creatinune ratio within the first year after randomization. The effect of lorcaserin on weight, hemoglobin A1c, and systolic blood pressure was consistent regardless of baseline renal function. Likewise, there was no excess in cardiovascular events in patients assigned to lorcaserin in comparison with placebo, regardless of renal function. After adjustment for baseline characteristics, those with evidence of kidney disease were at increased risk of major CV events. Compared with patients with an eGFR ≥90 mL·min-1·1.73 m-2, those with an eGFR 60-90 and those <60 mL·min-1·1.73 m-2 had HRs of 1.25 (95% CI, 1.01, 1.56) and 1.51 (95% CI, 1.17, 1.95), respectively ( P for trend 0.0015). Likewise, compared with patients with no albuminuria (<30 mg/g), those microalbuminuria and those with macroalbuminuria had HRs of 1.46 (95% CI, 1.22, 1.74) and 2.10 (95% CI, 1.58, 2.80), respectively ( P for trend <0.0001). CONCLUSIONS: Renal dysfunction was associated with increased CV risk in overweight and obese patients. When added to diet and lifestyle, lorcaserin reduced the rate of new-onset or progressive renal impairment in comparison with placebo. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT02019264.

Nucleus of the Solitary Tract Serotonin 5-HT2C Receptors Modulate Food Intake.

To meet the challenge to human health posed by obesity, a better understanding of the regulation of feeding is essential. Medications targeting 5-hydroxytryptamine (5-HT; serotonin) 2C receptors (htr2c; 5-HT2CR) improve obesity. Here we probed the functional significance of 5-HT2CRs specifically within the brainstem nucleus of the solitary tract (5-HT2CRNTS) in feeding behavior. Selective activation of 5-HT2CRNTS decreased feeding and was sufficient to mediate acute food intake reductions elicited by the 5-HT2CR agonist obesity medication lorcaserin. Similar to pro-opiomelanocortin neurons expressed within the hypothalamic arcuate nucleus (POMCARC), a subset of POMCNTS neurons co-expressed 5-HT2CRs and were activated by 5-HT2CR agonists. Knockdown of POMCNTS prevented the acute appetite-suppressive effect of lorcaserin, whereas POMCARC knockdown prevented the full anorectic effect. These data identify 5-HT2CRNTS as a sufficient subpopulation of 5-HT2CRs in reducing food intake when activated and reveal that 5-HT2CR agonist obesity medications require POMC within the NTS and ARC to reduce food intake.