P.3.c.052 Long-term efficacy and safety of bifeprunox in stable patients with schizophrenia: findings from a 6-month study

Bourin, Michel; Debelle, M.; Heisterberg, Jens; Østergaard, J. Buch; Sands, Earl; Yeung, Paul

doi:10.1016/s0924-977x(07)70689-2

Cited by 6 publications

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“…Both doses of bifeprunox were safe and well tolerated with a beneficial side-effect profile. Patients on bifeprunox also showed improved individual records on metabolic parameters -in particular regarding weight and lipids [79].…”

Section: Clinical Efficacy: Completed and Ongoing Clinical Trialsmentioning

confidence: 87%

Bifeprunox: A Novel Antipsychotic Agent with Partial Agonist Properties at Dopamine D2 and Serotonin 5-HT _1A Receptors

Wadenberg¹

2007

Future Neurol.

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Most second-generation, atypical, dopamine (DA) D2/5-HT2 blocking antipsychotics still induce extrapyramidal side effects (EPS) in higher doses. Weight gain and metabolic disturbances are also a problem, and negative and cognitive symptoms have not been sufficiently addressed. The current brain DA mesolimbic hyperactive/mesocortical hypoactive hypothesis of schizophrenia suggests that DA D2/5-HT 1A receptor partial agonist properties may be more efficacious with less side effects. DA D2 receptor partial agonists may stabilize a hyperactive/hypoactive DA condition. Additional 5-HT 1A stimulation may enhance therapeutic efficacy and also improve EPS liability profile. In clinical trials in schizophrenic patients, the novel DA D2/5-HT 1A partial agonist bifeprunox indeed demonstrates therapeutic efficacy, a safe EPS profile and appears beneficial regarding weight gain, prolactin, blood lipid and glucose levels and cardiac rhythm. The data on bifeprunox are promising and suggest that combined DA D2/5-HT 1A partial agonism may well be important properties for future-generation antipsychotics.Bifeprunox, a novel antipsychotic agent with a so-called third-generation atypical pharmacological profile, is currently in clinical trials and expected to launch as a schizophrenia therapy in the American market sometime in 2007, and in Europe in 2008. It is also being considered for treatment of bipolar disorder [101]. BackgroundSchizophrenia affects around 1% of the general population worldwide. The symptomatology includes positive symptoms (e.g., hallucinations, delusions and paranoia), negative symptoms (e.g., social withdrawal, poverty of speech, flat affect), as well as features of cognitive impairment. The main pharmacological property and therapeutic mechanism of action of traditional antipsychotic drugs (APDs), such as haloperidol (Haldol ® ), is dopamine (DA) D2 receptor blockade. However, owing to high DA D2 receptor occupancy in therapeutic doses, treatment with these drugs is frequently accompanied by disturbing extrapyramidal side effects (EPS), such as acute dystonia and parkinsonism, as well as endocrine effects such as increased prolactin levels. While effective against positive symptoms, these drugs have, over time, proven to be less efficacious against negative symptoms and cognitive impairment, and may even worsen these symptoms.The antipsychotic clozapine (Leponex ® , Clozaril ® ), a dibenzodiazepine that was introduced in 1967 [1], on the other hand, is pharmacologically different, with a multireceptor affinity profile (DA D1, D2, D4, 5-HT 2A /C, 5-HT 1A , histamine H1, α 1 , α 2 , cholinergic muscarinic receptor affinity) and comparatively lower affinity for the DA D2 receptor than traditional APDs. Clozapine produces good antipsychotic effect with virtually no EPS in therapeutic doses, and was therefore labeled atypical. Compared with traditional APDs, clozapine also shows superior therapeutic efficacy in treatment-resistant patients [2,3], beneficial effects against some aspects of cognitive impairment [...

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Section: Clinical Efficacy: Completed and Ongoing Clinical Trialsmentioning

confidence: 87%

Bifeprunox: A Novel Antipsychotic Agent with Partial Agonist Properties at Dopamine D2 and Serotonin 5-HT _1A Receptors

Wadenberg¹

2007

Future Neurol.

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“…Thus, switching to antipsychotics with a reduced propensity to cause weight gain may be a useful strategy for patients with schizophrenia who have gained excessive weight on other agents. 3,47 Emerging data suggest that bifeprunox, an investigational atypical antipsychotic, may be associated with weight decreases at least comparable to those of placebo, [48][49][50][51] a feature that may be related to this agent's receptor-binding profile and/or partial agonist activity at D 2 and 5-HT 1A receptors. While further confirmation is needed, this finding represents an example of an atypical antipsychotic that may result in weight decrease versus placebo.…”

Section: Weight Gainmentioning

confidence: 99%

“…71 Moreover, diabetes is frequently undiagnosed and undertreated in patients with schizophrenia, and screening methods vary significantly among different clinical studies. 71,72 Consequently, it is difficult to gauge the extent to which diabetes and other abnormalities in glucose metabolism result from Serotonin 5-HT 1A Weight gain 55 Histamine H 1 antagonism Weight gain, diabetes, sedation [51][52][53][54][55]59 Dopamine D 2 antagonism EPS, weight gain, endocrine effects [59][60][61] Muscarinic M 1 antagonism Anticholinergic (dry mouth, blurred vision, constipation) [12][13][14] Muscarinic M 3 antagonism…”

Section: Glucose Dysregulationmentioning

confidence: 99%

“…91 In both shortand longer-term studies, patients treated with bifeprunox experienced mean reductions of up to 24% in fasting triglyceride levels and 8% in fasting total cholesterol levels. 34,[48][49][50][51] The receptor-binding profiles that most closely correlate with antipsychotic-associated dyslipidemia are unclear, although peroxisome proliferator-activated receptors (PPARs), transcriptional regulators of lipid and carbohydrate metabolism, may play a role. 92 A number of reports have suggested a link between the PPARs and diabetes, obesity, dyslipidemia and inflammation.…”

Section: Dyslipidemiamentioning

confidence: 99%

“…11 a Associated with weight gain. 51,52 b Associated with increased risk of diabetes. 52,82 exhaustive investigation of the receptor-binding profiles of all currently marketed atypical agents.…”

Section: Introductionmentioning

confidence: 99%

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Atypical antipsychotic-induced metabolic side effects: insights from receptor-binding profiles

2007

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Atypical antipsychotic drugs offer several notable benefits over typical antipsychotics, including greater improvement in negative symptoms, cognitive function, prevention of deterioration, and quality of life, and fewer extrapyramidal symptoms (EPS). However, concerns about EPS have been replaced by concerns about other side effects, such as weight gain, glucose dysregulation and dyslipidemia. These side effects are associated with potential long-term cardiovascular health risks, decreased medication adherence, and may eventually lead to clinical deterioration. Despite a greater understanding of the biochemical effects of these drugs in recent years, the pharmacological mechanisms underlying their various therapeutic properties and related side effects remain unclear. Besides dopamine D 2 receptor antagonism, a characteristic feature of all atypical antipsychotic drugs, these agents also bind to a range of non-dopaminergic targets, including serotonin, glutamate, histamine, a-adrenergic and muscarinic receptors. This review examines the potential contribution of different receptors to metabolic side effects associated with atypical antipsychotic treatment for all seven agents currently marketed in the United States (risperidone, olanzapine, quetiapine, ziprasidone, aripiprazole, paliperidone and clozapine) and another agent (bifeprunox) in clinical development at the time of this publication.

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Bifeprunox versus placebo for schizophrenia

Chattopadhyay

Frey

Green

2016

Cochrane Database of Systematic Reviews

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Our results showed some positive effects and a favourable adverse effect profile for bifeprunox, although there were few data overall and none were of high quality. It would seem that these data alone would not have been enough for the FDA to decide to halt progress of the drug to market. We can only assume that we are missing important data. Both the FDA and the relevant pharmaceutical companies have not made all relevant data accessible. As some of these trials also involved an additional haloperidol, olanzapine, quetiapine, or risperidone arm, these data are not only relevant to evaluation of bifeprunox. In not making all data accessible, it is hard to see how the FDA and the drug companies have fulfilled their full obligations to people with schizophrenia or their clinicians.

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P.3.c.052 Long-term efficacy and safety of bifeprunox in stable patients with schizophrenia: findings from a 6-month study

Cited by 6 publications

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Bifeprunox: A Novel Antipsychotic Agent with Partial Agonist Properties at Dopamine D2 and Serotonin 5-HT _1A Receptors

Bifeprunox: A Novel Antipsychotic Agent with Partial Agonist Properties at Dopamine D2 and Serotonin 5-HT _1A Receptors

Atypical antipsychotic-induced metabolic side effects: insights from receptor-binding profiles

Bifeprunox versus placebo for schizophrenia

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P.3.c.052 Long-term efficacy and safety of bifeprunox in stable patients with schizophrenia: findings from a 6-month study

Cited by 6 publications

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Bifeprunox: A Novel Antipsychotic Agent with Partial Agonist Properties at Dopamine D2 and Serotonin 5-HT 1A Receptors

Bifeprunox: A Novel Antipsychotic Agent with Partial Agonist Properties at Dopamine D2 and Serotonin 5-HT 1A Receptors

Atypical antipsychotic-induced metabolic side effects: insights from receptor-binding profiles

Bifeprunox versus placebo for schizophrenia

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Bifeprunox: A Novel Antipsychotic Agent with Partial Agonist Properties at Dopamine D2 and Serotonin 5-HT _1A Receptors

Bifeprunox: A Novel Antipsychotic Agent with Partial Agonist Properties at Dopamine D2 and Serotonin 5-HT _1A Receptors