We interpret this finding of increased [11C]raclopride BP as an increase in postsynaptic DA D2 receptor density. However, some limitations of our study must be considered. First, the signal of caudate [11C]raclopride binding may have a component of binding to D3 receptors, since [11C]raclopride binds to both D2 and D3 receptors with almost similar affinity.18- 19 Dopamine D3 receptors are located in the human brain mainly in the nucleus accumbens, ventral parts of putamen and caudate, and the islands of Calleja.20- 21 The D3 receptor density in the ventral striatum has been reported to be elevated in drug-free patients with schizophrenia,22 although the D3 receptor messenger RNA levels were found to be normal in another study.23 The caudate ROI in the present study consists mainly of dorsal caudate,24- 25 where D3 receptor binding constitutes about 10% of the D2-like (D2 and D3) receptor binding.21 Therefore, and in the absence of direct evidence of D3 receptor density abnormalities in relatives of patients with schizophrenia, increased density of caudate D3 receptors in unaffected co-twins is not likely to explain our findings. Second, partial volume effects in small structures like the head of caudate may affect the observed ROI-based BP estimates due to the limited spatial resolution of the PET scanner. Although caudate volume abnormalities have been suggested in schizophrenia26 and schizotypal personality disorder,27- 28 no such changes have been found in healthy siblings29- 30 or unaffected MZ co-twins31 of patients with schizophrenia. The volumes of the manually delineated caudate ROIs did not differ between the study groups. Moreover, we were able to confirm our finding with a voxel-based receptor mapping analysis, an independent and objective analysis method free of operator-derived error in defining brain regions. Thus, it seems unlikely that the present findings are explained by group differences in the caudate volume. Third, factors other than receptor density may affect the BP of [11C]raclopride, since it represents the product of receptor density and affinity (for discussion, see Slifstein and Laruelle12). In this setting, it is not possible to exclude group differences in levels of baseline caudate DA concentration. Interestingly, patients with schizophrenia have been shown to exhibit increased baseline striatal D2 receptor occupancy by endogenous DA.5 However, it is not known whether this result is related to vulnerability or to the outbreak of schizophrenia. In healthy volunteers, most of the interindividual variance in BP values is more reflective of variations in receptor density than affinity.32- 33 As alterations in endogenous DA levels would lead to a different interpretation of the data presented herein, future studies should consider using a DA depletion paradigm in subjects with high genetic risk for schizophrenia. Also, other phenomena related to receptor-ligand interaction, such as receptor internalization and synaptic vs extrasynaptic D2 receptors,34 can also be involved in these findings. Cigarette smoking and alcohol use are not likely confounders of our results, since there were no differences across groups in smoking habits or major alcohol use (Table 1). Fourth, the small sample size in the present study limits the interpretation of findings, and the present results must be considered preliminary in that sense. In addition, we failed to demonstrate differences in D2 BP between DZ co-twins and healthy controls, a finding that would fit in the model of greater degree of abnormality with increasing genetic loading for schizophrenia. In contrast, such a linear scaling has been observed for neuropsychological dysfunction.9 The number of DZ co-twins in the present study may have been too small to disclose subtle differences in D2 BP, as, according to the model described above, the DZ co-twins should exhibit endophenotypic abnormalities intermediate in magnitude between those of MZ co-twins and healthy controls (ie, D2 BP increase of 0%-9% in the present study). It is also possible that there is a threshold for this endophenotypic phenomenon, but the sample size is too small to make definitive inferences. Future studies with larger samples are warranted.