Schizophrenia in the 21st century: new insights and translation into improved therapies

Over 100 years have elapsed since schizophrenia was first described and over 50 years since chlorpromazine was utilised to alleviate hallucinations and delusions characteristic of the disorder. With the introduction of a swathe of antipsychotic drugs from the 1970s to date, there have been waves of optimism for improvements in the clinical efficacy of these drugs. Unfortunately, these treatments have not fulfilled expectations. As with chlorpromazine, current medications provide relief for the positive symptoms through dopamine D2 receptor antagonism, but have limited impact on the negative symptoms and cognitive deficits. Moreover, potential drug-induced side effects such as motor dysfunction and weight gain are highly undesirable. Lack of understanding of the causes of schizophrenia together with the continued use of dopamine-based preclinical models in drug discovery, with read-outs of limited translational relevance, are arguably key factors in the lack of major breakthroughs for improved treatments.