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 [...
