Pet Schizophrenia D2 Occupancy

Healthy volunteer

High D2 receptor availability : no occupancy

Clozapine treated patient with schizophrenia

Medium D2 receptor availability : medium (~60%) occupancy

Typical antipsychotic-treated patient with schizophrenia

Low D2 receptor availability = high (80%+) occupancy

Figure 4.2 Three single photon emission tomography (SPET), scans of striatal D2 and D2-like receptor availability at the level of the basal ganglia. In the scan on the left from a healthy volunteer there is no receptor occupancy and therefore 100% receptor availability for the binding of the D2 receptor tracer [123I]IBZM. The scan on the right is from a patient with schizophrenia receiving a typical antipsychotic. The bright areas from the left hand scan indicating high receptor density are not evident on the right-hand scan as the antipsychotic is occupying the majority of the receptors and preventing the tracer from binding. Unfortunately despite this high level of occupancy this patient has failed to respond to treatment. The central scan is from a patient receiving clozapine, although the striatum are not as 'bright' as in the healthy volunteer they are visible. This scan indicates intermediate occupancy of the receptors by clozapine. Importantly the patient with the intermediate occupancy has responded to treatment. Studies such as this one, when performed in larger groups, indicate that the simple dopamine hypothesis suggested by the data in Figure 4.1 needed refining. Figure reproduced with permission from Pilowsky LS, Costa DC, Ell PJ, et al. Clozapine, single photon emission tomography, and the D2 dopamine receptor blockade hypothesis of schizophrenia. Lancet 1992;340:199-202

another showing no change5. Although the majority of subsequent studies with PET or SPET have found no significant difference in striatal D2 receptor density between controls and patients with schizophrenia, in a recent meta-analysis of studies carried out between 1986 and 1997, a small but significant elevation of D2 receptors was noted in patients with schizophrenia5. However, the variability of D2 receptor density is high both in controls and patients with schizophrenia, and it has been argued that the small magnitude of the effect (approximately a 12% increase), and the possibility that any change reflects alteration in the baseline synaptic dopamine, means that there are no real functional differences in the density of striatal D2 receptors in schizophrenia (reviewed in reference 5).

Despite these equivocal findings in drug-naive patients, emission tomography has reinforced the accepted theory that antipsychotic efficacy is related to D2, with 65% blockade a putative threshold for antipsychotic response6. Nonetheless, the situation appears very complex in that non-responders to antipsychotics still show high levels of striatal D2 blockade7,8. Furthermore, the highly effective atypical antipsychotic clozapine produces far less striatal D2 blockade than typical antipsychotics7-9, often below the putative 65% threshold (Figure 4.2). These findings have yet to be fully explained.

Extrapyramidal side-effects (EPS) have also been studied and a threshold of 80% D2 occupancy has been repeatedly shown to be necessary to produce EPS6 (Figure 4.3). It may be that high levels of 5-HT2A receptor blockade, as seen with

Pet Scan Antipsychotic

Figure 4.3 Illustration of the relationship between clinical effectiveness, extrapyramidal side-effects (EPS) and D2 receptor occupancy. With the exception of clozapine-induced D2 occupancy, below 60% striatal D2 occupancy produced by an antipsychotic medication is likely to be associated with treatment non-response, whilst occupancies above 80% are likely to be associated with a high risk of EPS. Once a patient is receiving a dose of an antipsychotic likely to be producing an occupancy between 60% and 80% there is little to be gained, in terms of treatment response, by increasing the dose of the antipsychotic further as the patient will almost certainly develop EPS. Figure after references 6, 7 and 51

Figure 4.3 Illustration of the relationship between clinical effectiveness, extrapyramidal side-effects (EPS) and D2 receptor occupancy. With the exception of clozapine-induced D2 occupancy, below 60% striatal D2 occupancy produced by an antipsychotic medication is likely to be associated with treatment non-response, whilst occupancies above 80% are likely to be associated with a high risk of EPS. Once a patient is receiving a dose of an antipsychotic likely to be producing an occupancy between 60% and 80% there is little to be gained, in terms of treatment response, by increasing the dose of the antipsychotic further as the patient will almost certainly develop EPS. Figure after references 6, 7 and 51

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