Striatal dopamine receptor occupancy during and following withdrawal from neuroleptic treatment: correlative evaluation by positron emission tomography and plasma prolactin levels

Abstract

The percentage occupation of striatal dopamine D2 receptors has been evaluated in 25 patients using 76Br-bromospiperone positron emission tomography (PET) and prolactin plasma levels (PRL) during oral neuroleptic treatment (11 studies), 1-90 days following discontinuation of such treatment (16 studies), and 1-120 days after last intramuscular administration of depot neuroleptics (nine studies). The PET-estimated occupation was highly significantly correlated in a sigmoid-like fashion to the logarithm of the chlorpromazine-equivalent dose of oral neuroleptics (suggesting a strict dose-occupation relationship during oral neuroleptic treatment and supporting the D2-mediated hypothesis of neuroleptic action), while PRL was weakly related to daily dosage. Following withdrawal, return to normal receptor availability, as estimated by PET, occurred within 5-15 days (suggesting that protracted effects of neuroleptics after withdrawal are not due to sustained D2 receptor occupation), but PRL values fell even more rapidly. Efficient treatment with depot neuroleptics resulted in marked PET-estimated D2 receptor occupation, stable over the whole 4-week drug-administration interval, suggesting that longer intervals could be appropriate; PRL values bore no relationship to PET-estimated occupation, indicating variable intersubject tolerance to neuro-endocrine dopamine blockade. Overall, PET was much more sensitive than PRL to estimate striatal D2 receptor occupation in vivo.

Receptor crosstalk: haloperidol treatment enhances A2A adenosine receptor functioning in a transfected cell model

“…Indeed, a crucial point that distinguishes antipsychotics is the degree of dopamine D 2 DR occupancy and the kinetics of drug-receptor dissociation, on which the drug response and some unpleasant side effects depend. Classical antipsychotics, such as haloper- idol, have high D 2 DR occupancy and slow dissociation rates compared to atypical antipsychotics [33]; occupancy increases above 80% and is connected with increased extrapyramidal side effects, elevation of prolactin levels [34,35] and dyskinesias. Clozapine, an atypical drug, shows a much lower occupancy (16%-68%) and a fast dissociation rate; this may explain its lack of extrapyramidal side effects and prolactin elevation [36,37].…”

Antipsychotic drugs which elicit little or no Parkinsonism bind more loosely than dopamine to brain D2 receptors, yet occupy high levels of these receptors

“…In fact, both R Conley 86 and Pickar et al 88 observed that the D2 occupancy by clozapine readily decreased upon clozapine withdrawal, in contrast to the 2 weeks or more of residual occupancy of D2 by traditional neuroleptics. 89 Any sudden surge of impulse-triggered release of endogenous dopamine will quickly displace any residual clozapine and may lead to a sudden clinical relapse. Table 2 summarizes this point that the relatively more rapid offset of drugs such as clozapine could result in a higher risk of earlier relapse when compared to the more traditional haloperidol and chlorpromazine drugs which are more tightly bound to the D2 receptor.…”

Effects of the Antipsychotic Risperidone on Dopamine Synthesis in Human Brain Measured by Positron Emission Tomography with l-[β-11C]DOPA: A Stabilizing Effect for Dopaminergic Neurotransmission?

“…This hypothesis has been supported by positron emission tomography (PET) studies to determine the occupancy of dopamine D 2 receptors in schizophrenia patients treated with firstgeneration antipsychotics, e.g., haloperidol (Farde et al, 1988;Baron et al, 1989) and second-generation antipsychotics, e.g., risperidone (Nyberg et al, 1993).…”