19.02.2 Neurochemistry of Psychosis and the Dopamine Theory

The history of dopamine’s involvement in psychosis and schizophrenia is long, and only the most recent theories will be considered here, since the early dopamine theories of schizophrenia did not withstand testing. The discovery that all early antipsychotics were antagonists of dopamine D₂ receptors pointed to a role for dopamine in psychosis. It was further shown that clinical efficacy of antipsychotics is consistently achieved when D₂ receptor occupancy reaches at least 60% (40-80%), and is correlated linearly with their D₂ receptor affinity.

Davis and colleagues (1991) theorised that reduced dopamine release in prefrontal cortex causes negative symptoms of schizophrenia and leads to increased dopamine release in subcortical regions (specifically the ventral striatum containing the nucleus accumbens) which causes positive symptoms. While this theory accounted for available data and integrated knowledge of brain regions and dopamine receptor distributions, clinical evidence is still limited, most of the evidence comes from animal studies. Howes and Kapur (2009) modified the theory to suggest that increased presynaptic dopamine function in the ventral striatum is the ‘final common pathway’ for psychosis. This theory is supported by clinical evidence of elevated presynaptic dopamine, dopamine release, and dopamine receptor density in the ventral striatum during psychosis, and animal models showing genetic and environmental factors contribute to this. It is thought that elevated dopamine transmission in the ventral striatum influences aberrant motivational salience to otherwise innocuous stimuli (people, objects and actions), and psychosis arises from an effort to construct plausible explanations.

While the role of dopamine is necessary in schizophrenia, it is not sufficient. Dopamine dysregulation no doubt accounts for psychosis, but it is thought multiple transmitter systems, including GABA and glutamate, underlie the negative and cognitive symptoms. Researchers have suggested dopamine forms the converging pathway in schizophrenia, not the primary abnormality, and that deficiencies in one or more other neurotransmitter systems which modulate domapine leads to the dopaminergic overactivity.