Bifeprunox: a Novel Antipsychotic Agent with Partial Agonist Properties at Dopamine D2 and Serotonin 5-HT1A Receptors
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DRUG EVALUATION Bifeprunox: a novel antipsychotic agent with partial agonist properties at dopamine D2 and serotonin 5-HT1A receptors Marie-Louise G Most second-generation, atypical, dopamine (DA) D2/5-HT2 blocking antipsychotics still Wadenberg induce extrapyramidal side effects (EPS) in higher doses. Weight gain and metabolic University of Kalmar, disturbances are also a problem, and negative and cognitive symptoms have not been Department of Natural Sciences, Norra Vagen 49, sufficiently addressed. The current brain DA mesolimbic hyperactive/mesocortical SE-391 82 Kalmar, Sweden hypoactive hypothesis of schizophrenia suggests that DA D2/5-HT1A receptor partial agonist Tel.: +46 480 446 277; properties may be more efficacious with less side effects. DA D2 receptor partial agonists Fax: +46 480 446 244; may stabilize a hyperactive/hypoactive DA condition. Additional 5-HT stimulation may marie-louise.wadenberg@ 1A hik.se enhance therapeutic efficacy and also improve EPS liability profile. In clinical trials in schizophrenic patients, the novel DA D2/5-HT1A 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-HT1A partial agonism may well be important properties for future-generation antipsychotics. Bifeprunox, a novel antipsychotic agent with a (DA D1, D2, D4, 5-HT2A/C, 5-HT1A, hista- so-called third-generation atypical pharmacolog- mine H1, α1, α2, cholinergic muscarinic recep- ical profile, is currently in clinical trials and tor affinity) and comparatively lower affinity for expected to launch as a schizophrenia therapy in the DA D2 receptor than traditional APDs. the American market sometime in 2007, and in Clozapine produces good antipsychotic effect Europe in 2008. It is also being considered for with virtually no EPS in therapeutic doses, and treatment of bipolar disorder [101]. was therefore labeled atypical. Compared with traditional APDs, clozapine also shows superior Background therapeutic efficacy in treatment-resistant Schizophrenia affects around 1% of the general patients [2,3], beneficial effects against some population worldwide. The symptomatology aspects of cognitive impairment [4], and is supe- includes positive symptoms (e.g., hallucinations, rior to newer, atypical (second-generation) delusions and paranoia), negative symptoms APDs, such as olanzapine, for preventing suicide (e.g., social withdrawal, poverty of speech, flat amongst patients with schizophrenia and affect), as well as features of cognitive impair- schizoaffective disorders [5]. This has created ment. The main pharmacological property and speculations in the drug development industry as therapeutic mechanism of action of traditional to which pharmacological properties may prima- antipsychotic drugs (APDs), such as haloperidol rily be responsible for its unique efficacy and (Haldol®), is dopamine (DA) D2 receptor atypicality profile. Clozapine is, however, associ- Authorblockade. However, owing to high DAProof D2 ated with an increased risk for agranulocytosis, receptor occupancy in therapeutic doses, treat- and was even temporarily withdrawn from the ment with these drugs is frequently accompanied market due to a number of cases with fatal out- by disturbing extrapyramidal side effects (EPS), comes [6]. such as acute dystonia and parkinsonism, as well as endocrine effects such as increased prolactin Pathophysiology of schizophrenia levels. While effective against positive symptoms, The therapeutic efficacy of DA D2 receptor Keywords: bifeprunox, these drugs have, over time, proven to be less blocking traditional APDs suggested an overac- dopamine D2, partial efficacious against negative symptoms and cog- tivity of brain DA neural transmission in schizo- agonism, schizophrenia, nitive impairment, and may even worsen these phrenia (the dopamine hypothesis of serotonin (5-HT)1A, third-generation atypical symptoms. schizophrenia). However, while recent data antipsychotics The antipsychotic clozapine (Leponex®, Cloz- more directly point to a specific mesolim- aril®), a dibenzodiazepine that was introduced in bic/subcortical dopaminergic over-reactivity as part of 1967 [1], on the other hand, is pharmacologically responsible for the positive symptoms in schizo- different, with a multireceptor affinity profile phrenia [7], other data suggest that negative 10.2217/14796708.2.2.xxx © 2007 Future Medicine Ltd ISSN 1479-6708 Future Neurol. (2007) 2(2), xxx–xxx 1 DRUG EVALUATION – Wadenberg symptoms and cognitive disturbances may AstraZeneca’s atypical APD quetiapine (ICI instead be due to a possibly parallel hypo- 204,636; Seroquel®), a dibenzothiazepine intro- dopaminergic state in prefrontal brain areas [8]. duced in the mid-1990s, is also on the market. This latter hypothesis is further supported by Quetiapine has a clozapine-like pharmacological findings suggesting a dysregulation of the profile, including low DA D2 receptor affinity and dopamine D1 receptor [9], known to be impor- high 5-HT2, α1 and histamine H1 receptor affin- tant for normal cognitive functions [10], and by ity. Its therapeutic profile is similar to clozapine, findings indicating a hypofunction of the gluta- with less EPS and prolactin elevation, but rela- matergic N-methyl-D-aspartate receptor [11] in tively high liability regarding weight gain, dyslipi- schizophrenic individuals as assessed postmor- demia, as well as a propensity to induce sedation, tem. Thus, current knowledge would suggest hypotension and, in some cases, syncope. that it might be more appropriate to think of Recently, focus has been on agonism/partial schizophrenia as a dual pathology disease. agonism at the 5-HT1A receptor [22]. Experimen- tally, 5-HT1A receptor stimulation produces a Antipsychotic drug development: preferential increase in prefrontal cortex DA overview of the market release [23], an effect that is expected to be benefi- Based on the hypothesis of a combined low DA cial against negative and cognitive symptoms in D2 and high 5-HT receptor affinity ratio as an schizophrenia. It is also possible that 5-HT 2 1A important mechanism of action of clozapine receptor agonism may contribute both to a gen- [12], the second-generation, so-called atypical eral antipsychotic effect as well as a reduced EPS ® APDs such as risperidone (Risperdal ) [13] and liability [24–26]. Indeed, 5-HT1A receptors have olanzapine (Zyprexa®) [14] were developed. been reported by some to be upregulated in fron- These drugs are an improvement in schizophre- tal cortex of schizophrenic individuals as deter- nia therapy, and EPS liability is often reduced. mined postmortem [27]. Some clinical This is most likely because additional 5-HT2 augmentation studies have reported ameliora- receptor blockage may allow for sufficient thera- tion of negative symptoms, and reduced inci- peutic efficacy at lower doses with subsequent dence of EPS with adjunctive treatment, with lower DA D2 receptor occupancy. Patients the 5-HT1A partial agonists buspirone or tandos- needing higher doses still show emerging EPS, pirone to haloperidol-treated schizophrenic indi- presumably because of a subsequent increase in viduals [28,29]. The fact that clozapine shows DA D2 receptor occupancy. Experimental data agonist properties at the 5-HT1A receptor may also support this notion [15–18]. thus contribute to some aspects of its superior 5-HT2 receptor blockade, in combination therapeutic profile [30,31]. with selective DA D2 receptor antagonists, has The novel APDs ziprasidone (Zeldox®, Geo- also been shown to increase prefrontal DA out- don®) [32] and aripiprazole (Abilify®) [33] include put as measured experimentally by in vivo 5-HT1A agonist, or partial agonist, properties. microdialysis in rats [19]. Nevertheless, treat- Ziprasidone was approved by the US FDA in ment-resistant patients, patients demonstrating 2001 for the treatment of schizophrenia, and is suicidal behavior, or pronounced negative available in intramuscular (for acute agita- and/or cognitive symptoms still do not always tion/aggression in schizophrenia) and oral respondAuthor optimally to treatment with the atypi- Proofforms. Ziprasidone is an antagonist at DA D2 cal APDs. Another serious concern with the and 5-HT2A receptors, the affinity for the atypicals, including clozapine, is their propen- 5-HT2 receptor being an order of magnitude sity to induce weight gain, as well as metabolic greater than that for the DA D2 receptor. In disturbances such as Type 2 diabetes, insulin addition, ziprasidone is an agonist at the resistance and dyslipidemia [20]. Both clozapine 5-HT1A receptor [34], and has less affinity than, and olanzapine show high liability in this for example, clozapine and olanzapine, for his- respect, while risperidone has a more beneficial tamine H1 receptors. Specific improvement of profile. Affinity for the histamine H1 receptor cognitive functions in clinically nonresponsive has been shown to be significantly correlated to patients [35], as well as efficacy against negative weight gain [21], but affinity for the 5-HT2C symptoms [36,37], by ziprasidone treatment have receptor subtype may also be a factor. Thus, in been reported. In a head-to-head comparison order to avoid such side effects, future APDs study with olanzapine, ziprasidone also showed should preferably be devoid of histamine H1 less propensity for weight gain, as well as a more receptor