Dopamine blockade and clinical response: evidence for two biological subgroups of schizophrenia

Abstract

Because CNS neuroleptic concentration cannot be directly measured in patients, the relation between clinical response and extent of dopamine receptor blockade is unknown. This relationship is critical in ascertaining whether nonresponse to neuroleptics is the result merely of inadequate CNS drug levels or of more basic biological differences in pathophysiology. Using [18F]N-methylspiroperidol and positron emission tomography, the authors assessed dopamine receptor occupancy in 10 schizophrenic patients before and after treatment with haloperidol. Responders and nonresponders had virtually identical indices of [18F]N-methylspiroperidol uptake after treatment, indicating that failure to respond clinically was not a function of neuroleptic uptake or binding in the CNS.

Is treatment-resistant schizophrenia categorically distinct from treatment-responsive schizophrenia? a systematic review

“…If these findings reflect that treatment-resistant patients lack the striatal dopaminergic elevations typically detected in schizophrenia, this could explain why treatment-resistant patients show little response to D2 dopamine receptor blockade with conventional antipsychotic treatment [14]. This would implicate categorical differences between the two patient groups – one displaying normal dopamine function and one displaying abnormalities – rather than a difference of severity, and this is also the conclusion of another systematic review [48].…”

“…While clinical response to antipsychotics is strongly correlated with dopamine receptor D2 occupancy for most patients, treatment-resistant patients show no clinical response even when their D2 receptor occupancy is above the therapeutic threshold [14]. Furthermore, clozapine is found to be highly effective in treatment-resistant patients [6], despite relatively low levels of D2 receptor occupancy [15].…”

Mechanisms of Action of Antipsychotic Drugs of Different Classes, Refractoriness to Therapeutic Effects of Classical Neuroleptics, and Individual Variation in Sensitivity to their Actions: PART I

“…Admittedly, if it is assumed that therapeutic effects depend directly on action at their target receptor, it is difficult to account for the wide (>ten-fold) range of individual sensitivities, and, in some cases, total non-responsiveness. Many studies compare D2 receptor numbers between normal subjects and those with schizophrenia, but only one [155] documents the relationship between receptor numbers and neuroleptic responsiveness, the mean number being 25-30% lower in the non-responsive than in the responsive cases. “Receptor number” is however a dynamic variable, subject to compensatory change, unless receptor loss is a consequence of cell loss; and there are few precedents for a disorder caused primarily by lasting excess or deficit of any receptor type, independent of cell loss.…”

“…Nevertheless, the inter-strain variation in sensitivity seen in mice is similar to that seen between individuals in humans. A prediction for human patients, with some empirical support [155], is that lower striatal D2 receptor numbers are associated with relative or absolute neuroleptic non-responsiveness for therapy of psychotic states.…”

Mechanisms of Action of Antipsychotic Drugs of Different Classes, Refractoriness to Therapeutic Effects of Classical Neuroleptics, and Individual Variation in Sensitivity to their Actions: PART II

“…The difference is used to calculate binding in patients by the antipsychotic drug. However, if the foregoing theory is correct, the total number of receptors in the striatum will be reduced in patients refractory to, or with low sensitivity to neuroleptic drugs [131]. As a result total available receptors are overestimated, and the fraction of available receptors binding to a ligand is underestimated in such patients.…”