Mechanisms of schizophrenia

The underlying mechanisms of schizophrenia, a mental disorder characterized by a disintegration of the processes of thinking and of emotional responsiveness, are complex. A number of theories attempt to explain the link between altered brain function and schizophrenia, including the dopamine hypothesis and the glutamate hypothesis. These theories are separate from the causes of schizophrenia, which deal with the factors that lead to schizophrenia. The current theories attempt to explain how changes in brain functioning can contribute to symptoms of the disease. The underlying mechanisms of schizophrenia, a mental disorder characterized by a disintegration of the processes of thinking and of emotional responsiveness, are complex. A number of theories attempt to explain the link between altered brain function and schizophrenia, including the dopamine hypothesis and the glutamate hypothesis. These theories are separate from the causes of schizophrenia, which deal with the factors that lead to schizophrenia. The current theories attempt to explain how changes in brain functioning can contribute to symptoms of the disease. The exact pathophysiology of schizophrenia remains poorly understood. The most commonly supported theories are the dopamine hypothesis and the glutamate hypothesis. More recent theories center around specific dysfunction of interneurons, abnormalities in the immune system, abnormalities in myelination, and oxidative stress. The first formulations of the dopamine hypothesis of schizophrenia came from post-mortem studies finding increased striatal availability of D2/D3 receptors in the striatum, as well as studies finding elevated CSF levels of dopamine metabolites. Subsequently, most antipsychotics were found to have affinity for D2 receptors. More modern investigations of the hypothesis suggest a link between striatal dopamine synthesis and positive symptoms, as well as increased and decreased dopamine transmission in subcortical and cortical regions respectively. A meta analysis of molecular imaging studies observed increased presynaptic indicators of dopamine function, but no difference in the availability of dopamine transporters or dopamine D2/D3 receptors. Both studies using radio labeled L-DOPA, an indicator of dopamine synthesis, and studies using amphetamine release challenges observed significant differences between schizophrenics and control. These findings were interpreted as increased synthesis of dopamine, and increased release of dopamine respectively. These findings were localized to the striatum, and were noted to be limited by the quality of studies used. A large degree of inconsistency has been observed in D2/D3 receptor binding, although a small but nonsignificant reduction in thalamic availability has been found. The inconsistent findings with respect to receptor expression has been emphasized as not precluding dysfunction in dopamine receptors, as many factors such as regional heterogeneity and medication status may lead to variable findings. When combined with findings in presynaptic dopamine function, most evidence suggests dysregulation of dopamine in schizophrenia. Exactly how dopamine dysregulation can contribute to schizophrenia symptoms remains unclear. Some studies have suggested that disruption of the auditory thalamocortical projections give rise to hallucinations, while dysregulated corticostriatal circuitry and reward circuitry in the form of aberrant salience can give rise to delusions. Decreased inhibitory dopamine signals in the thalamus have been hypothesized to result in reduced sensory gating, and excessive activity in excitatory inputs into the cortex. One hypothesis linking delusions in schizophrenia to dopamine suggests that unstable representation of expectations in prefrontal neurons occurs in psychotic states due to insufficient D1 and NMDA receptor stimulation. This, when combined with hyperactivity of expectations to modification by salient stimuli is thought to lead to improper formation of beliefs. Beside the dopamine hypothesis, interest has also focused on the neurotransmitter glutamate and the reduced function of the NMDA glutamate receptor in the pathophysiology of schizophrenia. This has largely been suggested by lower levels of glutamate receptors found in postmortem brains of people previously diagnosed with schizophrenia and the discovery that glutamate blocking drugs such as phencyclidine and ketamine can mimic the symptoms and cognitive problems associated with the condition. The fact that reduced glutamate function is linked to poor performance on tests requiring frontal lobe and hippocampal function and that glutamate can affect dopamine function, all of which have been implicated in schizophrenia, have suggested an important mediating (and possibly causal) role of glutamate pathways in schizophrenia. Positive symptoms fail however to respond to glutamatergic medication. Reduced mRNA and protein expression of several NMDA receptor subunits has also been reported in postmortem brains from patients with schizophrenia. In particular, the expression of mRNA for the NR1 receptor subunit, as well as the protein itself is reduced in the prefrontal cortex of schizophrenic subjects post-mortem. Fewer studies have examined other subunits, and results have been equivocal, except for a reduction in prefrontal NRC2.