A Clinical Trial of the Efficacy and Acceptability of d-Fenfluramine in the Treatment of Neuroleptic-induced Obesity

Goodall, Edwin; Oxtoby, Christopher; Richards, R.; Watkinson, G.; Brown, Deirdre A.; Silverstone, Trevor

doi:10.1192/bjp.153.2.208

Cited by 62 publications

(35 citation statements)

References 9 publications

(2 reference statements)

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“…Indeed, the anorectic properties of the appetite suppressant drug d-fenfluramine are substantially due to activation of 5-HT 2C receptors in the rat Vickers et al 2001). Treatment of patients receiving typical neuroleptics with d-fenfluramine resulted in weight loss (Goodall et al 1988); however, this has not become a widespread treatment due to the adverse side-effects associated with fenfluramine usage. However, human weight gain associated with antipsychotic treatment correlates more closely with H 1 than 5-HT 2C receptor binding affinities (Wirshing et al 1999) and although there is some evidence of a role of H 1 receptors in satiety (Rossi et al 1999), clearly more work is required to separate the relative contribution of 5-HT 2C and H 1 receptors to weight gain associated with atypical antipsychotic drugs.…”

Section: Discussionmentioning

confidence: 99%

Effects of clozapine, olanzapine and haloperidol on the microstructure of ingestive behaviour in the rat

2003

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Clozapine and olanzapine increased fat intake whereas haloperidol did not, and this resembles the greater weight gain liability of atypical antipsychotics in humans. A delay or reduction of the post-ingestive satiety signal combined with preserved palatability appears to be the mechanism responsible for fat hyperphagia in rats treated with clozapine and olanzapine. Conversely, haloperidol leaves satiety unaffected but reduces the palatability of the fat emulsion resulting in reduced intake.

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Section: Discussionmentioning

confidence: 99%

Effects of clozapine, olanzapine and haloperidol on the microstructure of ingestive behaviour in the rat

2003

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“…2,3 Weight gain is distressing to most patients with schizophrenia who experience it, and it may affect their response to treatment. Weight gain is also associated with treatment noncompliance 4,5 and with several medical conditions, including hypertension, diabetes, arthritis, cerebral vascular disease, cardiovascular disease, pulmonary disease with sleep apnea, and cancer. Generally, a behavioral or pharmacologic approach is taken in the treatment of weight gain in schizophrenic patients.…”

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confidence: 99%

“…Therefore, for reasons of safety and efficacy, these agents are not recommended for the clinical treatment of obesity in individuals with schizophrenia. 5,[10][11][12] In recent clinical trials, metformin or reboxetine was used as an adjuvant treatment of drug-induced weight gain in schizophrenic patients, and positive results were reported. 13,14 Topiramate is a novel anticonvulsant that has been used in a wide variety of disorders, including bipolar affective disorder, migraine, and neuropathic pain.…”

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confidence: 99%

Topiramate as an Adjuvant Treatment With Atypical Antipsychotics in Schizophrenic Patients Experiencing Weight Gain

Joe

Jung

et al. 2005

Clinical Neuropharmacology

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Schizophrenic patients commonly suffer weight gain, which is often associated with widely prescribed antipsychotic medicines. It is distressing to most patients who experience it and may affect their response to treatment of schizophrenia. Weight gain is also associated with treatment noncompliance and several medical conditions. This study explored the efficacy and tolerability of topiramate as an adjuvant treatment of patients with schizophrenia who were carrying excess weight. In this 12-week, randomized, placebo-controlled prospective study, 66 hospitalized patients with schizophrenia who were carrying excess weight were given topiramate at doses of 100 mg/day or 200 mg/day, or a placebo. The primary measures made were body weight, body mass index, waist measurement, hip measurement, and waist-to-hip ratio. Safety measures included physical examinations and the monitoring of adverse effects, clinical laboratory data, and vital signs. The Clinical Global Impression-Severity of Illness scale (CGI-S) and the Brief Psychiatric Rating Scale (BPRS) were used to quantify changes in schizophrenic symptoms and signs. In the 200-mg/day topiramate group, body weight, body mass index, waist measurement, and hip measurement decreased significantly compared with the 100-mg/day topiramate and placebo groups over 12 weeks. However, the waist-to-hip ratio did not change in any group. Scores on the CGI-S and BPRS decreased significantly over the 12-week period in both topiramate groups, but the decrease was not clinically meaningful. These results suggest that a higher dose of topiramate is efficacious as an adjuvant treatment of patients with schizophrenia experiencing excess weight gain. Further clinical research is required to establish guidelines for the use of topiramate as an antiobesity agent in schizophrenic patients.

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“…Among the multiple receptor binding profiles of atypical antipsychotics, 5-HT 2C R has been implicated as mediating an orexigenic effect and diabetogenic side effect. The agonists of 5-HT 2C R, such as fenfluramine and mCPP, have been shown to be anorexigenic (60,61). There is a correlation between the drug affinity for 5-HT 2C R and the morbidity rate of type 2 diabetes mellitus (62).…”

Section: Discussionmentioning

confidence: 99%

Hypothalamic Ahi1 Mediates Feeding Behavior through Interaction with 5-HT2C Receptor

Wang

Huang

et al. 2012

Journal of Biological Chemistry

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It is indicated that there are important molecules interacting with brain nervous systems to regulate feeding and energy balance by influencing the signaling pathways of these systems, but relatively few of the critical players have been identified. In the present study, we provide the evidence for the role of Abelson helper integration site 1 (Ahi1) protein as a mediator of feeding behavior through interaction with serotonin receptor 2C (5-HT 2C R), known for its critical role in feeding and appetite control. First, we demonstrated the co-localization and interaction between hypothalamic Ahi1 and 5-HT 2C R. Ahi1 promoted the degradation of 5-HT 2C R through the lysosomal pathway. Then, we investigated the effects of fasting on the expression of hypothalamic Ahi1 and 5-HT 2C R. Fasting resulted in an increased Ahi1 expression and a concomitant decreased expression of 5-HT 2C R. Knockdown of hypothalamic Ahi1 led to a concomitant increased expression of 5-HT 2C R and a decrease of food intake and body weight. Last, we found that Ahi1 could regulate the expression of neuropeptide Y and proopiomelanocortin. Taken together, our results indicate that Ahi1 mediates feeding behavior by interacting with 5-HT 2C R to modulate the serotonin signaling pathway.Obesity and its associated ailments such as diabetes have become a worldwide epidemic carrying with them a heavy toll of morbidity and mortality. Over the past decades, it has become evident that neural circuits in the central nervous system play a direct and crucial role in controlling feeding and energy homeostasis (1, 2). Disruptions in the mechanisms of central nervous system energy sensing are able to alter the standard homeostatic responses and are factors that contribute to the pathophysiology of obesity and diabetes. The brain serotonin system has long been implicated in the neural regulation of food intake and energy metabolism, as highlighted by the clinical use of serotonin releasers and reuptake inhibitors as appetite suppressant and weight loss medication (3-5). Depletion of central serotonin using selective neurotoxins has been shown to result in hyperphagia and obesity, whereas the release of serotonin and the inhibition of reuptake by D-fenfluramine potently reduce feeding and body weight (6). More recently, several lines of evidence show that serotonin receptor agonists can significantly improve glucose tolerance and reduce plasma insulin in mouse models of obesity and type 2 diabetes (7-9).Numerous serotonin receptor subtypes have been identified in which serotonin receptor 2C (5-HT 2C R) 4 is recognized specifically as a mediator of serotonin-induced appetite and glucose regulation (10 -13). During the past few years, both pharmacological and genetic evidence has indicated that neuropeptide Y (NPY) and melanocortin systems are the necessary mechanisms by which 5-HT 2C R agonists reduce appetite and improve diabetic conditions (14 -16). Although significant progress has been made in the study of serotonin-mediated regulation of energy metabolism, we ...

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A Clinical Trial of the Efficacy and Acceptability of d-Fenfluramine in the Treatment of Neuroleptic-induced Obesity

Cited by 62 publications

References 9 publications

Effects of clozapine, olanzapine and haloperidol on the microstructure of ingestive behaviour in the rat

Effects of clozapine, olanzapine and haloperidol on the microstructure of ingestive behaviour in the rat

Topiramate as an Adjuvant Treatment With Atypical Antipsychotics in Schizophrenic Patients Experiencing Weight Gain

Hypothalamic Ahi1 Mediates Feeding Behavior through Interaction with 5-HT2C Receptor

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