The psychiatric side-effects of rimonabant

Moreira, Fabrício A.; Crippa, José Alexandre de Souza

doi:10.1590/s1516-44462009000200012

Cited by 192 publications

(143 citation statements)

References 59 publications

(66 reference statements)

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“…Most of the drugs in development to treat obesity target the G protein-coupled receptor class and are associated with side effects ranging from nausea to depression (51,52). Drugs acting through the G protein-coupled receptor class control appetite through central nervous system intervention, eventually leading to various neurological and psychological problems (53), as recently exemplified by the discontinuation of a cannabinoid antagonist due to severe psychological problems leading to suicide (54).…”

Section: Discussionmentioning

confidence: 99%

Estrogen Receptor-β-selective Ligands Alleviate High-fat Diet- and Ovariectomy-induced Obesity in Mice

Yepuru

Eswaraka

Kearbey

et al. 2010

Journal of Biological Chemistry

114

112

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Obesity is an epidemic problem affecting millions of people in the Western hemisphere and costs the United States economy more than $200 billion annually. Currently, there are no effective treatments to combat obesity. Recent studies have implicated the constitutive activity of estrogen receptor (ER) ␤ as an important regulator of metabolic diseases. However, the potential of ER-␤-selective ligands to offset obesity is not clear. We evaluated the pharmacological effect of ER-␤-selective ligands (␤-LGNDs) in animal models of high-fat diet-and ovariectomyinduced obesity. Ligand binding, transactivation, and uterotrophic studies with ␤-LGNDs demonstrated selectivity for ER-␤ over ER-␣. Animals fed a high-fat diet showed a significant increase in body weight, and this weight gain was attenuated by ␤-LGNDs. High-fat diet-mediated increases in serum cholesterol, leptin, glucose, and fat accumulation in organs were also reduced by ␤-LGNDs. In addition, MRI scanning indicated that ␤-LGNDs altered body composition by reducing fat mass and increasing lean body mass. Organ weights and gene expression analyses demonstrated that adipose tissue is the center of action for ␤-LGNDs, and the reduction in body weight is likely due to increased energy expenditure. In vitro and in vivo mechanistic studies indicated that the anti-obesity effects of ␤-LGNDs were due to indirect peroxisome proliferator-activated receptor ␥ antagonistic actions requiring the ligand binding domain of ER-␤ and through abrogation of the ability of PGC-1 to coactivate peroxisome proliferator-activated receptor ␥. In conclusion, these studies indicate that ligand-activated ER-␤ is a potential therapeutic target to combat obesity and obesity-related metabolic diseases.Obesity is an epidemic disease affecting over 400 million people globally (1). Two-thirds of adults and children in the United States are either overweight or obese, making it a serious health risk and economic burden to society (2). Obesity is not a standalone disease, as its emergence leads to various complications, including type 2 diabetes mellitus (T2DM), 3 hypertension, atherosclerosis, and other cardiovascular diseases, osteoporosis, and clinical depression (3, 4). The United States Food and Drug Administration required an anti-obesity drug to reduce the body weight by 5% and/or better results than placebo in 12 months, indicating that even a marginal reduction in body weight will cause a significant improvement in the welfare of these patients (5). Despite the exponentially growing global obesity pharmaceutical market, only two Food and Drug Administration-approved drugs are available for this indication: 1) amphetamines and sibutramine that act on the hypothalamus to control appetite stimulation in the central nervous system, and 2) Orlistat, which is a lipase inhibitor that blocks gastrointestinal absorption of fat and decreases energy uptake (6). Despite mediocre performance, these drugs are commonly associated with side effects such as tachycardia, hypertension, fecal incontinence, ...

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Section: Discussionmentioning

confidence: 99%

Estrogen Receptor-β-selective Ligands Alleviate High-fat Diet- and Ovariectomy-induced Obesity in Mice

Yepuru

Eswaraka

Kearbey

et al. 2010

Journal of Biological Chemistry

114

112

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“…However, the increasing interest concerning ECS dysfunction in depressive disorders was engendered after the clinical use of the CB1 receptor antagonist rimonabant for the treatment of obesity was interrupted. In line with the theory that a deficiency in CB1 receptor signaling could be involved in depression, rimonabant was withdrawn from the market because of undesirable psychiatric side effects such as anxiety, depression and suicidal ideations [80]. Although no controlled clinical trials concerning endocannabinoid signaling in depression are available, opposite changes in endocannabinoid activity could underlie the different forms of depressive illness.…”

Section: Cannabis Endocannabinoid System and Depression: Clinical Anmentioning

confidence: 99%

Role of the Endocannabinoid System in Depression: from Preclinical to Clinical Evidence

Micale

Tabiová

Kučerová

et al. 2015

Cannabinoid Modulation of Emotion, Memory, and Motivation

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The endogenous cannabinoid system (ECS) works as pro-homeostatic and pleiotropic signaling system activated in a time-and tissue-specific way during physiological conditions, which include cognitive, emotional and motivational processes. It is composed of two G protein-coupled receptors (the cannabinoid receptors types 1 and 2 [CB1 and CB2] for marijuana's psychoactive ingredient Δ9-tetrahydrocannabinol [Δ9-THC]), their endogenous small lipid ligands (anandamide [AEA] and 2-arachidonoylglycerol [2-AG], also known as endocannabinoids), and the proteins for endocannabinoid biosynthesis and deactivation. Data from preclinical and clinical studies have reported that a hypofunction of the endocannabinoid signaling could induce a depressive-like phenotype; consequently, enhancement of endocannabinoid signaling could be a novel therapeutic avenue for the treatment of depression. To this aim there have been proposed cannabinoid receptor agonists or synthetic molecules that inhibit endocannabinoid degradation. The latter ones do not induce the psychotropic side effects by direct CB1 receptor activation, but rather elicit antidepressant-like effects by enhancing the monoaminergic neurotransmission, promoting hippocampal neurogenesis and normalizing the hyperactivity of hypothalamic-pituitary-adrenal axis, similarly as the standard antidepressants. The dysfunction of elements belonging to the ECS and the possible therapeutic use of endocannabinoid deactivation inhibitors and phytocannabinoids in depression is discussed in this chapter.

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“…More specifically, these drugs act through CB1 receptor inverse agonism. Unfortunately, marketing of the first drug, rimonabant, was discontinued for psychiatric sideeffects, namely inducing depressive states and suicidal ideas 103,104 . However, newer cannabinoid compounds are emerging and a strong influence on appetite, metabolism and energy homeostasis is consistently reported [105][106][107] .…”

Section: Resultsmentioning

confidence: 99%

The common pathophysiology underlying the metabolic syndrome, schizophrenia and depression. A review

et al. 2015

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Background. There is a growing interest in metabolic alterations in patients with psychiatric disorders due to their increased risk for metabolic syndrome (MetS) development. Inflammation is known to underlie the pathophysiology of schizophrenia and depression as well as MetS. Vulnerability factors for schizophrenia/depression and MetS hence appear to be shared. Methods and Results. Based on a Web of Science search, this review examines current evidence for MetS pathophysiology involving dysregulation of adipose tissue signaling -adipokines and pro-inflammatory cytokine, both also known to be aberrant in schizophrenia/depression. Further, gender differences in the incidence and course of schizophrenia/ depression were reported. The disturbances linked to the MetS are also described. Therefore, this review further maps the gender differences in the psychiatric-metabolic comorbidities. Conclusion. There is evidence supporting a pathological predisposition to MetS in both schizophrenia and depression in both humans and animal models. This predisposition is dramatically enhanced by antipsychotic medication. Further, there are gender differences from clinical findings suggesting women with schizophrenia/depression are more vulnerable to MetS development. This has not yet been assessed in animal studies. We suggest further validation of existing schizophrenia and depression animal models for the assessment of metabolic disturbances to provide tools for developing new antipsychotics and antidepressants with "metabolically inert" profile or improving the metabolic status in schizophrenic/depressed patients.

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The psychiatric side-effects of rimonabant

Cited by 192 publications

References 59 publications

Estrogen Receptor-β-selective Ligands Alleviate High-fat Diet- and Ovariectomy-induced Obesity in Mice

Estrogen Receptor-β-selective Ligands Alleviate High-fat Diet- and Ovariectomy-induced Obesity in Mice

Role of the Endocannabinoid System in Depression: from Preclinical to Clinical Evidence

The common pathophysiology underlying the metabolic syndrome, schizophrenia and depression. A review

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