Fig. 3. Psychosis: a consequence of severe circuit specific cognitive impairment.

This schematic representation highlights the potential for cognitive symptoms to feed into psychosis networks and create positive feedback loops that spiral to psychosis. Non-specific and heterogeneous deficits in auxiliary neurocircuitry (in the context of psychosis) lead to broad cognitive impairments unique to each individual. These systems feed into the primary psychosis networks leading to destabilisation of associative striatal dysfunction and further cognitive impairment. In most individuals with schizophrenia, excessive dopamine signalling in the associative striatum leads to positive symptoms. Antipsychotics antagonise downstream D2 receptor signalling to blunt the expression of symptoms. In treatment-refractory patients (those who do not respond to first-line antipsychotics) blocking D2 receptors is insufficient to blunt positive symptoms suggesting further upstream dysfunction in the associative striatum or psychosis networks. Clozapine may lead to improvement in some of these individuals by stabilising function throughout these networks in addition to D2 receptor antagonism. Positive symptoms in treatment-refractory patients who fail to respond to clozapine may be the result of severe impairment throughout psychosis networks (and the associative striatum) that are independent of dopamine dysfunction. Thus, our current treatments for positive symptoms act downstream of the source of cognitive impairments, hence their ineffectiveness in treating cognitive symptoms. While the expression of psychotic symptoms may be a discrete outcome, separate to impairments in cognitive function, the upstream cause of these symptoms may share common neuropathology