Chemical Biology: Approaches to Drug Discovery and Development to Targeting Disease

Chapter 18: Schizophrenia

Ferenc Martenyi

Lilly Research Laboratories, Indianapolis, Indiana

Since the discovery of chlorpromazine in 1953, the number of antipsychotic medications has increased tremendously. Most of these drugs affect the dopaminergic neurotransmission (primarily blocking dopamine D₂ receptors). Antipsychotics registered until 2008 could be classified into 3 groups based on receptor occupancy profile rather than using their chemical structure. Conventional (or first-generation antipsychotics, like haloperidol and fluphenazine) with a predominant D₂ receptor affinity have benefits in the treatment of delusions and hallucinations (positive symptoms of schizophrenia), which are parallel with a characteristic side-effect profile of extrapyramidal symptoms (EPS) and prolactin elevation. Atypical antipsychotics—which are characterized by a higher antagonist affinity to serotonin (5-hydroxytryptamine, 5HT) 5HT₂ receptors than to dopamine D₂ receptors—are generally thought to be effective in alleviation of negative symptoms (such as anhedonia, and lack of motivation) beyond the positive symptoms domain of schizophrenia, with a reduced EPS burden (such as clozapine, olanzapine, risperidone). A third group of novel antipsychotics has a partial dopamine agonist profile (aripiprazole), with a lack of or minimal EPS. The nondopaminergic N-methyl-D-aspartate (NMDA) antagonist model of schizophrenia raised new gulatamatergic targets for treatment. NMDA antagonists ketamine and ...