CHAPTER 6: Treating the Cognitive Deficits of Schizophrenia

The cognitive deficits in schizophrenia (CDS) are recognized as a discrete cluster of impairments that can emerge before the onset of frank psychoses. Untreated CDS results in poor work, social and independent living outcomes. Although existing antipsychotic drugs effectively treat positive symptoms, they provide inadequate improvement in CDS in most schizophrenia patients. To address this medical need, significant efforts have been made to develop agents that treat the cognitive aspects of this disease specifically. This chapter provides a brief biological rationale for treatment and describes the most advanced clinical landscape and medicinal chemistry challenges within the main areas of drug discovery for CDS treatment. The main focus is on the α7 nicotinic acetylcholine receptor and the dopamine D₁ receptor, two key research areas identified through the Measurement and Treatment Research to Improve Cognition in Schizophrenia initiative as having the highest probability of yielding effective treatments. This chapter also provides a brief synopsis of targets in other areas such as M₁ muscarinic acetylcholine receptor, serotonin subtype 6 receptor (5-HT₆), histamine H3 and catechol-O-methyl transferase inhibitors.