Persistent psychosis after reduction in pre- and post-synaptic dopaminergic function

Abstract

The purpose of this study was to evaluate the hypothesis that neuroleptic non-response in the face of "adequate" DA post-synaptic receptor blockade reflects failure of regulatory mechanisms to decrease DA pre-synaptic activity. Eight chronic schizophrenics, meeting rigorous criteria for neuroleptic non-response, were treated for four weeks with alpha-methylparatyrosine as an adjunct to their previously stable neuroleptic dose. Treatment with AMPT produced a prompt decrease in plasma HVA that was, on average, 72% lower at the end of the study. While there was also strong clinical evidence of reduction in central dopaminergic activity (both a significant reduction in dyskinetic movements and increase in extrapyramidal symptoms), there was virtually no change in severity of psychotic symptoms. Thus, in this group of non-responders, psychotic symptoms persisted despite both extensive dopamine post-synaptic receptor blockade and marked reduction of presynaptic activity. These symptoms may not be directly DA dependent.

Treatment-Resistant Schizophrenia Patients Show Elevated Anterior Cingulate Cortex Glutamate Compared to Treatment-Responsive

“…10 Further support for the idea that treatment resistance is nondopaminergic comes from studies using drugs to deplete presynaptic dopamine stores. [11][12][13] These studies have found no benefit from dopamine depletion in treatment-resistant patients, in contrast to the reduction in psychotic symptoms that is seen in most patients.…”

Neuroimaging glutamatergic mechanisms differentiating antipsychotic treatment-response

“…However, approximately 30% show few or no gains from currently available treatments 4 . Data from dopamine depletion and positron emission tomography (PET) studies show that some individuals with refractory illness can have normal dopaminergic functioning 5 – 8 , which may explain their medication failure. Rather, a primarily glutamatergic dysfunction may be underpinning symptomatology, as evidenced by recent proton magnetic resonance spectroscopy (1H-MRS) studies that report elevated anterior cingulate cortex (ACC) glutamate levels in both first-episode and chronic illness individuals.…”