The interpretation of our results rests on the following methodological considerations: (1) The significance of theα-[11C]MTrp/PET method has been questioned, and, in particular, Shoaf et al96 have suggested that it might measure blood brain barrier transport of tryptophan rather than synthesis of 5-HT. However, subsequent autoradiography studies on rodents,97 along with analyses of tracer kinetics and the effects of manipulations that selectively increase44,98 vs decrease 5-HT synthesis,99,100 support the general consensus that brain regionalα-[11C]MTrp trapping provides an acceptable proxy for 5-HT synthesis.41,42,45,48,101- 104 (2) Medication-free patients with OCD did not differ significantly from healthy controls in total and free plasma tryptophan concentrations or in the free plasma tryptophan fraction, making it unlikely that increased normalized K* values reflect group differences in circulating tryptophan concentrations, which otherwise could affect brain 5-HT synthesis.45,105- 108 (3) As in other functional neuroimaging studies of psychiatric populations, the sample size is relatively small (21 patients with OCD vs 21 healthy controls), such that general conclusions cannot be drawn until there is an independent replication. A larger sample would also allow one to test whether specific abnormalities are associated with early- vs late-onset OCD or phenotypical subtypes, such as predominantly“checkers” or“washers,” or more recently proposed symptom subtypes such as“symmetry” or“hoarding.”109,110 Other potential confounders, such as body mass index or seasonal variations, could also be more appropriately controlled for in a larger sample. Nevertheless, the sample size is in the upper range of similar neuroimaging studies and is one of the largest in a PET study of patients with OCD reported to date that used a 5-HT system tracer. Healthy controls and patients with OCD were also enrolled and observed in a parallel manner over time. Moreover, precautions included rigorous matching for age and sex, a negative toxicological screen on the day of the scan, and patient selection restricted to medication-free individuals without current comorbid conditions. (4) As frequently seen, 6 of 21 patients had a past history of depression that had developed secondarily to OCD and was in remission at the time of scanning. This, of course, could potentially bias our results because depression is linked to state abnormalities, and perhaps trait 5-HT abnormalities, as well as morphological and structural changes, in particular in the hippocampus. The latter, however, seems to develop with recurrent chronic major depressive disorder,111 which does not correspond to our sample phenotype, in which only some individuals suffered at some point a minor form of depression. Moreover, complementary analyses using Beck Depression Inventory scores did not reveal any significant correlations with K*. In addition, an analysis contrasting OCD patients with and without a history of depression did not reveal any significant differences in regional K*, and removing patients with a history of depression from the analysis did not change the results. (5) In contrast to our results, previous functional neuroimaging studies of the 5-HT transporter have not identified consistent changes in patients with OCD vs controls, either in the midbrain or terminal regions. A recent study,112 though, has measured [18F] altanserin binding values and found evidence of increases in 5-HT2A densities specifically within the caudate nucleus. (6) Under certain pathological conditions, such as inflammatory neurological diseases,113 intractable epilepsy in childhood,114 or brain tumors,115 an increased tryptophan metabolism might reflect the activation of the initial and rate-limiting enzyme of the kynurenine pathway, indolamine 2,3 dioxygenase. Indeed, cases of pediatric autoimmune neuropsychiatric disorders,116 including a subgroup of childhood-onset OCD with or without tics, have been associated with streptococcal infections. Moreover, abnormally increased serotonin synthesis was recently reported in Tourette syndrome.117 Whether neuroinflammatory processes prompted activation of the kynurenine pathway in some OCD cases, thus resulting in the increased rate of uptake and clearance ofα-[11C]MTrp reported here, is unknown. (7) Finally, although volumetric differences in patients with OCD have been reported previously, these findings have been inconsistent; for example, the orbitofrontal cortex and striatal tissue volumes have been reported to be abnormally high,118,119 abnormally low,119,120 or to not differ from those in controls.121 Moreover, recent meta-analyses indicate possible structural alterations in parietofrontal areas, the anterior cingulate cortex, the thalamus, lenticular/caudate nuclei, and the putamen, but they do not support the presence of structural alterations in the hippocampus, where we found functional differences.122- 124 In our study, careful segmentation (blind to the study group) did not reveal volumetric differences between the OCD and control groups.