The second half of the 20th century also saw the development of biochemical hypotheses for schizophrenia. The most prominent was the dopamine hypothesis that Carlsson and Lindqvist originally put forth in 1963; it was based on the biochemical effects of treatment with the first antipsychotic drugs, which had been introduced only in 1952. Animal studies lent support to what became a building block of antipsychotic drug discovery - the search for dopamine receptor blockers - and treatment, and Carlsson shared a Nobel Prize for this and other research in 2002.
At this time multiple classes of dopamine receptors are known. Genetic mutations in dopamine receptors have also been discovered and have been applied to comparisons of patients and controls for decades. At first there appeared to be no association between these genetic changes and susceptibility to schizophrenia, but as evidence accumulated from studies of thousands of normal controls and patients with schizophrenia, a pattern emerged. Examination and reanalysis of meta-analyses has implicated three dopamine receptors that have genetic variants consistently associated with schizophrenia: DRD1, DRD2, and DRD4 (dopamine receptors 1, 2, and 4). Other evidence also implicates DRD3. Other specific genes, based on biochemical hypotheses, also have strong evidence for association with schizophrenia.
The overall picture for schizophrenia is now quite promising. The genes associated with schizophrenia vulnerability are also related to treatment in the case of dopamine receptors. This suggests that treatments might be tailored to the susceptibility variants, and that the tailored treatments would be more effective in patients who had the specific variants. It also suggests that new treatment approaches might be developed from translational research based on the more recently developed gene-disease associations. Finally, it invites research on prevention based on precautionary care of women through deterrence of viral infections during pregnancy, and improvements in obstetric delivery.
Elliot S. Gershon is Foundations Fund Professor of Psychiatry and Human Genetics at the University of Chicago.
Table 1. Environmental traumas associated with schizophrenia
|Event||Age at event|
|Influenza infection||In utero second trimester of pregnancy|
|Starvation||In utero second trimester of pregnancy|
|Traumatic brain injury||Throughout life|
|DRD4||Dopamine D4 receptor||11|
|DRD2||dopamine receptor D2||11|
|DRD1||dopamine receptor D1||5|
|IL1B||interleukin 1, beta proprotein||2|
|TPH1||Tryptophan hydroxylase 1||11|
|TP53||Tumor protein p53||17|
|DTNBP1||Dystrophin binding protein 1 (Dystrobrevin)||6|