Non-dopaminergic hypotheses of schizophrenia

Recent research suggests that dopaminergic D2 hyperstimulation is relevant to the treatment of positive symptoms in most but not all patients with schizophrenia, and is probably irrelevant to negative symptoms. This suggests that other neurobiological alterations may be implicated in schizophrenia and may contribute to the symptoms and their treatment, either by contributing to the dopaminergic alterations, or by creating a different pathway to pathology. We will focus here on the evidence implicating other transmitter systems described in schizophrenia and their interactions. A deficient glutamate NMDA system in schizophrenia has been strongly suggested by clinical observations of behavioural effects of NMDA antagonists, the new findings of small genes effects that may affect the glutamate intrasynaptic machinery and imaging studies conducted in our laboratory showing that NMDA antagonists can lead to dopaminergic dysregulation, both in the striatum (Kegeles et al. 2000) and in the cortex (Narendran et al. 2005). On the other hand, strong evidence for GABA system alterations in prefrontal cortex of patients with schizophrenia has emerged mostly from post mortem studies (Lewis et al. 2005). Recently a convergence between NMDA and GABA hypofunction has been suggested by the studies of effects of NMDA antagonists on GABA-related cellular components in PFC in rodents (for review see Lewis and Gonzalez-Burgos (2006)). We also review the data implicating other systems such as serotonin, cannabinoids and the cholinergic systems in the pathophysiology of schizophrenia with the multiple new potential therapeutic targets that may derive from these systems. An overall hypothetical model of interactive neurochemical alterations along the circuitry implicated in schizophrenia will be presented as a way of generating a possible integrative approach to the neurobiology of schizophrenia. The complexity of these interactions also lends itself to thinking about comorbidity, as differential circuitry or neurochemical alterations may lead to different clinical profiles.