Serotonergic approaches in the development of novel antipsychotics

Caitlin A. Jones and Andrew C. McCreary

Institute of Neuroscience, School of Biomedical Sciences, Queen's Medical Centre, University of Nottingham, Nottingham NG7 2UH, UK Solvay Pharmaceuticals Research Laboratories, van Houtenlaan 36, 1381 CP Weesp, the Netherlands

Received 25 April 2008; 

revised 24 May 2008; 

accepted 27 May 2008. 

Available online 3 June 2008.

 

Abstract

Schizophrenia is a chronic, debilitating neuropsychological disease characterised by positive, negative, and cognitive deficits. In recent years, new pharmacological treatment strategies have been developed to treat the sequalae of schizophrenia based upon more selective receptor activity profiles in the hope that treatment efficacy can be increased without inducing the side-effect profiles seen with current available therapies. One such strategy involves the development of combined (partial) 5-HT_1A agonists and D₂ receptor (partial) antagonists such as bifeprunox, SLV313, F15063 and SSR-181507 in an attempt to increase therapeutic efficacy of all symptom domains whilst alleviating adverse side effects. Other novel drugs including SLV310 and SLV314 combine selective serotonin reuptake inhibition (SSRI) functionality with D₂ receptor antagonism in an attempt to not only improve schizophrenic symptoms, but to also relieve other affective disorders intricately linked with the disorder. The main scope of this review will evaluate the major preclinical and clinical pharmacological findings concerning the aforementioned strategies and pharmacological agents, and compare their therapeutic potential with currently available antipsychotics; however, recent developments at other emerging serotonergic targets such as 5-HT_2C, 5-HT₆ and 5-HT₇ receptors will also be considered.

Keywords: Schizophrenia; Serotonin; 5-HT_1A; 5-HT_2C; 5-HT₆; 5-HT₇; SSRI; Antipsychotic; D₂

Abbreviations: 8-OH-DPAT, 8-hydroxy-2-(di-N-propylamino)-tetralin; 5-HT, 5-hydroxytryptamine, serotonin; 5-HTP, 5-hydroxytryptophan; ACh, acetylcholine; CAR, conditioned avoidance response; DA, dopamine; EPS, extrapyramidal symptoms; MK801, (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate; (m)PFC, (medial) prefrontal cortex; PCP, phencyclidine; NOR, novel object recognition; PPI, prepulse inhibition; SSRI, selective serotonin reuptake inhibitor; SNC, substantia nigra pars compacta; USV, ultrasonic vocalisation; VTA, ventral tegmental area; WAY100635, N-[2-[4-(2-methoxyphenyl)-1-piperazinyl] ethyl]-N-(2-pyridinyl)cyclohexanecarboxamide)