Bridging pharmacology and neurodevelopment in schizophrenia.

At the beginning of the 20th century, when neuropathologists had long searched without success for the neural basis of schizophrenia, this field was called a ‘graveyard for neuropathologists ’. This disappointment opened the door for psychiatrists to focus on psychopathology. The discovery of antipsychotic agents in the 1950s provided a clue to understanding the pathology of this difficult disease. The anti-dopaminergic effect of antipsychotics, together with the induction of psychotic symptoms by psychostimulants, supported the dopamine hypothesis. On the other hand, phencyclidine (PCP) was found to cause symptoms resembling both positive and negative symptoms of schizophrenia. Since PCP inhibits the NMDA-type glutamate receptor, a glutamatergic hypothesis for schizophrenia was proposed. Starting in the 1970s, neuroimaging studies showed that patients with schizophrenia have ventricular enlargement and reduced hippocampal volume (Suddath et al., 1990). These studies revived the research focus on neuropathology; reduced hippocampal volume without gliosis was thought to reflect a neurodevelopmental abnormality that leads to schizophrenia. Genetic factors are well-established risk factors for schizophrenia. Initial genetic association studies focused on pharmacology-related candidate genes, such as the dopamine D2 receptor gene (Arinami et al., 1994). However, recent candidate genes derived from whole genome linkage analysis, such as DTNBP1 (Straub et al., 2002) and NRG1 (Stefansson et al., 2002), do not seem to have a direct relationship to dopaminergic or glutamatergic neurotransmission. Now, researchers are trying to combine these genetic findings into a pharmacological hypothesis. One of the most established genetic factor for schizophrenia, DISC1 (Millar et al., 2000), is thought to be directly related to neurodevelopment (Ozeki et al., 2003), but its relevance to a pharmacological hypothesis awaits further elucidation. Thus, a neurodevelopmental hypothesis is now emerging from the integration of genetic, neuroimaging and post-mortem brain findings in schizophrenia. However, it is not well understood how a pharmacological hypothesis of schizophrenia can be integrated with a neurodevelopmental hypothesis.