Building a Better Antipsychotic: Receptor Targets for the Treatment of Multiple Symptom Dimensions of Schizophrenia

Abstract

Summary: Attempts to develop selective ("magic bullet") drugs for the treatment of schizophrenia have been frustrated by the complex etiology of the disease. The symptomatology of schizophrenia does not appear to arise from a single neurobiological entity, but rather may be derived from pathology at one or more receptor types. This has prompted multifactorial approaches to the development of new therapeutics, as embodied by polypharmacy and an alternative (or augmentative) strategy known as "intramolecular polypharmacy," in which a single drug possesses the capacity to affect multiple receptor types.Atypical antipsychotics are a well-known example of this approach; each atypical possesses a unique portfolio of activities at receptors that may contribute to therapeutic effects (as well as side effects). In this article we present a discussion of some of the receptor targets that are currently thought to mediate symptoms of schizophrenia, as well as their possible implications for the design of future multifunctional antipsychotics.

Trace Amines and Their Receptors

“…These drugs act as antagonists at D2Rs, and they act on serotonergic (e.g., 5-HT 2A ), cholinergic (e.g., muscarinic M1), and histaminergic (e.g., H1) receptors as well (Kim et al, 2009). These include first-generation drugs such as the phenothiazines and butyrophenones, which are associated with frequent and severe extrapyramidal symptoms such as drug-induced parkinsonism and the neuroleptic malignant syndrome despite having great potency as antipsychotics.…”

“…Second-generation (atypical) antipsychotics are currently the mainstay of therapy for both disorders and include compounds such as clozapine, olanzapine, quetiapine, risperidone, and aripiprazole. These second-generation compounds are associated with less severe extrapyramidal symptoms but are associated with a metabolic syndrome (dyslipidemia, insulin resistance, pronounced weight gain, and elevations in blood pressure), which can unfavorably alter the benefit-risk ratio (Gründer et al, 2009;Kim et al, 2009;Meyer and Stahl, 2009;Thomas et al, 2009). The metabolic syndrome and obesity are estimated to occur in 33% of patients with schizophrenia and bipolar disorders.…”

Effect of Antipsychotic Drugs on Body Composition in Patients Attending Psychiatry Clinic, Jimma, Ethiopia

“…Several factors explain weight gain due to antipsychotics and the impact of duration of antipsychotics use on bodyweight. Antipsychotics medication induces changes in appetite and food intake, most likely because of the interaction with serotonergic, histaminergic and dopaminergic neurotransmitter systems inducing increase in appetite and food intake [23,24]. Therefore, their effects on weight and Body Mass Index (BMI) likely will progress with time.…”

Clinical and Cost Consequences of Metabolic Effects of Lurasidone Versus Other Atypical Antipsychotics in Schizophrenia

“…This drug has a lack of affinity for histamine H 1 and muscarinic M 1 receptors, which have been implicated in weight gain-related adverse events; accordingly, it is not expected to have a substantial adverse impact on metabolic parameters [14,15]. In keeping with this, clinical studies published to date indicate that lurasidone has efficacy comparable with that of other atypical antipsychotics and a near-neutral effect on weight gain and other metabolic parameters [16,17].…”