FGA and SGA Drugs and D2/D3 Occupancy
FGAs (n = 28) produced significantly higher striatal (74 ± SD = 12%) occupancy than SGAs (n = 115, 49 ± 21%; t = 8.8, df = 73.7, P < 4 × 10−13). Both FGAs and SGAs produced 70%–80% D2/D3 occupancy in the temporal cortex, though FGAs had slightly higher cortical occupancy (77 ± 12%) than SGAs (67 ± 19%) (unpaired t test, t = 3.5, df = 62.3, P = .001) ().
Fig. 1. A: Dopamine D2/D3 Receptor Occupancy (Error Bars = SD) by First-Generation Antipsychotics (FGAs) (n = 28) and Second-Generation Antipsychotics (SGAs) (n = 111) in Striatum and Temporal Cortex. FGAs (n = 28) produced significantly higher striatal (74 ± (more ...)
FGAs showed a significantly greater occupancy of striatal dopamine D2/D3 receptors (S/T ratio = 96%, SD = 24%) than SGAs (S/T ratio = 74%, SD = 35%; t = 3.7, df = 41, P < .001). All SGAs showed greater differentiation between cortical and striatal D2/D3 binding within each subject than FGAs (amisulpride, 36 ± 15%; clozapine, 17 ± 16%; olanzapine, 40 ± 16%; quetiapine, 20 ± 12; risperidone, 26 ± 7%; sertindole, 16 ± 10%, FGAs, 5 ± 17%).
Correlation of Clinically Effective Dose With Receptor Occupancy
There was a high correlation of ED95eff with temporal cortex dopamine D2/D3 receptor ED95occ (r = .95, n = 7, P < .001; see ). A less strong correlation was also found between ED95eff and actual striatal dopamine D2/D3 receptor ED95occ (r = .76, n = 7, P = .046; see ; significance of difference between r = .95 and r = .76: t = 1.7, df = 4, P = .08). Substituting the FGA ED95occ with the dose required to achieve the same striatal occupancy as SGAs had no significant effect on the correlation (r = .76, n = 7, P = .046). Interestingly, the correlation between the natural log of the antipsychotic doses was highly significant for both striatum and temporal cortex D2/D3 ED95occ vs ED95eff, although temporal cortex still showed a slightly higher correlation (temporal cortex: r = .99, n = 7, P < .0001; striatum: high FGA occupancy, r = .94, n = 7, P < .005; striatum: same FGA occupancy as SGA, r = .86, n = 7, P < .05; significance of difference between r = .99 and r = .86: t = 3.1, df = 4, P = .02). The correlation between ED95eff and 5HT2A receptor ED95occ was not statistically significant (r = .29, n = 5, nonsignificant [ns]), partly because amisulpride produced no 5HT2 blockade and also because clozapine led to very high 5HT2A receptor occupancy at subtherapeutic doses (see ).
The mean correlation (r) between ED95eff and temporal or the actual striatal D2/D3 receptor occupancy using 28 different dose schedules was r = .98 for temporal cortex and r = .69 for striatum. Thus, the sensitivity analyses were consistent with the primary analysis.
Antipsychotic Propensity for EPSE and Regional Dopamine Receptor Occupancy
Doses of FGAs were moderate. Of the 28 subjects, 18 received haloperidol with an average dose of 9 mg/day while most others received high-potency FGAs. Only 3 subjects received doses of haloperidol over 12 mg/day. The FGA dose (in haloperidol equivalents) for each individual was significantly correlated with striatal D2/D3 receptor occupancy (r = .59, df = 22, P = .004; P = 0.004), but for temporal cortex D2/D3 receptor occupancy, this correlation was not significant (r = .38, df = 22, P = ns).
Comparison of Results Using SRTM Vs Ratio Modeling
The mean temporal cortex D2/D3 occupancy estimated was 61% by the ratio method and 78% with SRTM, a difference of 14.6% (95% confidence interval [CI]: to 21, F = 21.3, F = 8.8: df = 1, 127: P = .004). However, the ratio and SRTM methods did not produce a significant difference in striatal occupancy. (F = 1.5, df = 1, 127: ns). Importantly, the SRTM or ratio method did not alter the difference between typical vs atypical occupancy. The interaction of the SRTM/ratio method and typical/atypical drug was essentially zero for both striatal (F = 0.0, df = 1, 127: ns) and temporal cortex (F = 0.1, df = 1, 127: ns).
Comparison of Results Using Single Vs Dual Ligands
The ANOVA showed a significant difference between the single- and the dual-ligand method used in both brain areas (striatal and temporal). The single-ligand studies reported 18% (95% CI = 10% to 25%) lower striatal D2/D3 receptor binding than the dual-ligand studies (F = 22; df = 1, 128; P = .000007). In the temporal cortex, the single-ligand studies found 13% (95% CI = 6% to 21%) higher D2/D3 receptor occupancy than the dual-ligand studies (F = 13; df = 1, 128; P = .0006). The interaction of FGA-SGA used with single- vs dual-ligand method was not significant for striatal (F = 1.5; df = 1, 128; ns) or temporal cortex (F = 0.7; df = 1, 128; ns). After adjustment by ANCOVA with single/dual ligand and SRTM/ratio as covariates, the striatal occupancy was 74% (95% CI = 66% to 82%) for typical antipsychotics and 47% for atypicals (95% CI = 44% to 54%), a difference of 27% (18% to 36%), and statistically significant (F = 37, df = 1, 127, P = .00000005).