Positron Emission Tomography Imaging of ...

Original Paper Neuropsychobiology 2006;53:157–168 DOI: 10.1159/000093342

Received: June 9, 2005 Accepted after revision: March 2, 2006 Published online: May 16, 2006

Positron Emission Tomography Imaging of Risperidone Augmentation in Serotonin Reuptake Inhibitor-Refractory Patients Monte S. Buchsbaum Eric Hollander Stefano Pallanti Nicolò Baldini Rossi Jimcy Platholi Randall Newmark Rachel Bloom Erica Sood Mount Sinai School of Medicine, New York, N.Y., USA

Key Words Obsessive-compulsive disorder 18F-deoxyglucose Caudate Putamen Cingulate gyrus

Abstract We studied 15 nondepressed patients with obsessive-compulsive disorder (OCD) who were nonresponders to serotonin reuptake inhibitors with an additive trial of risperidone. Positron emission tomography with 18F-deoxyglucose and magnetic resonance imaging was obtained at baseline and following 8 weeks of either risperidone or placebo in a double-blind parallel group design. Risperidone treatment was associated with significant increases in relative metabolic rate in the striatum, cingulate gyrus, the prefrontal cortex, especially in the orbital region, and the thalamus. Four of 9 patients who received risperidone showed clinical improvement (CGI score of 1 or 2 at 8 weeks) while none of the 6 patients who received placebo showed improvement. Patients with low relative metabolic rates in the striatum and high relative metabolic rates in the anterior cingulate gyrus were more likely to show a clinical response. These metabolic predictors of clinical response are consistent with earlier PET studies showing similar prediction when either neuroleptics or serotonin reuptake inhibitor treatments are administered individually. Our results are consistent with a frontostriatal circuit change related to both dopaminergic and serotonergic systems and with the presence of psychopharmacological subtypes within OCD. Copyright © 2006 S. Karger AG, Basel

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Introduction

Functional neuroimaging of obsessive-compulsive disorder (OCD) has most often identified differences from normal controls in the orbital prefrontal cortex, striatum, and cingulate gyrus. Positron emission tomography with FDG showed increased metabolic rates in the orbitofrontal and cingulate gyrus region in patients with OCD [1–4]. SPECT studies have supported these patient hyperactivity findings in some [5, 6] but not all studies [7, 8]. The effect was more marked in more ventral areas than dorsal areas in one study that presented this dimension [9] and more marked in medial frontal cortex in one study [10]. Low metabolic rates assessed by positron emission tomography with 18F-deoxyglucose (FDG-PET) in the striatum or thalamus [2, 3, 11–13] may also characterize the disorder (although high values in cingulate, pallidum/putamen and thalamus have also been reported [14]). SPECT studies, consistent with FDG-PET studies, also found low flow in the caudate [15–17] as did some fMRI studies [18]. SPECT studies found both reduced [17] and high flow [6] in the thalamus, however. Lastly, event-related brain potential measures of components associated with the anterior cingulate [19] and frontostriatal systems [20, 21] have had enhanced amplitudes in OCD patients and subjects with obsessive-compulsive characteristics. A recent and useful meta-analysis confirmed orbitofrontal gyrus and caudate activation abnormalities in OCD [22]. These findings taken together have suggested a circuit alteration

Monte S. Buchsbaum Mount Sinai School of Medicine 1 Gustave Levy Place, Box 1505 New York, NY 10029 (USA) Tel. +1 212 241 5294, Fax +1 212 423 0819, E-Mail [email protected]

in OCD [e.g. 23, 24]. Such a circuit might involve both dopaminergic and serotonergic components and is compatible with recent interest in augmentation strategies where atypical neuroleptics are combined with serotonin reuptake inhibitors (SRI) [25], although exactly how these drugs either complement or oppose each other is still not completely known. These findings are also compatible with biological heterogeneity in OCD, and the possibility that functional imaging assessment of circuit components might make it possible to predict medication response. The cingulate gyrus, identified as important in OCD versus normal functional imaging studies, may be an especially salient site in understanding individual differences in response to serotonergic psychopharmacotherapy. Four studies of antidepressant medications also linked degree of clinical improvement in patients with depression to baseline metabolic rates in the anterior cingulate and orbitofrontal region [26–29]. Brain imaging studies from our group [30, 31] and others [32, 33] have suggested that patients with relatively high rates of metabolism [31] or perfusion in the anterior cingulate gyrus before sleep deprivation, possibly a serotonergic phenomena, are more likely to show a favorable clinical response than are patients with lower rates of baseline activity. Not only did activity in the anterior cingulate gyrus predict therapeutic response, but patients whose depressive symptoms were diminished after sleep deprivation showed a posttreatment decrement in metabolism in the medial prefrontal cortex and the frontal pole [34, 35]. As with antidepressant response in affective disorder, cingulate and frontal activity at baseline may predict clinical improvement with medication. In the earliest study Swedo et al. [4] found lower FDG-PET values in right anterior cingulate and right orbitofrontal cortex in nonresponders (n = 6) to clomipramine than responders (n = 11), the opposite of the findings discussed above in affective illness. Similar results were found with correlation analysis in a sample (n = 9) of patients with OCD for the left orbitofrontal cortex for fluoxetine [36] some of whom had a history of major affective illness and both left and right orbitofrontal cortex for paroxetine [37]. Activation during stress also implicated the anterior cingulate although low values predicted sertraline response indicating that subject state may be important [38]. Lower rCBF values in orbitofrontal cortex were associated with a better fluvoxamine response in a 9-patient study of patients with OCD [39]. A higher metabolic rate in the right posterior cingulate has been associated with clinical response to anterior cingulotomy for OCD [40, 41]. Lastly, in a compelling meta-analysis, cingulate and orbitofrontal cortex are 158

Neuropsychobiology 2006;53:157–168

identified as major predictors of an antidepressant response [42]. The striatum, the region of both structural and functional differences between normals and schizophrenics [reviewed elsewhere 43, 44], has also been reported to be a predictor of a clinical response to neuroleptics in schizophrenics, [45] although not confirmed in some studies [46]. Thus some combination of cingulate and striatal changes should be useful in predicting response to or need for selective SRI (SSRI) and/or SSRI/atypical neuroleptic augmentation therapy in OCD. In support of this, lower pretreatment metabolism in the orbitofrontal cortex predicted greater improvement in OCD following treatment with the SRI paroxetine [37]. However, this study did not find baseline caudate metabolism predictive of medication response, although the reduction in caudate metabolic rate was greater in treatment responders than nonresponders. Higher pretreatment glucose metabolism in the right caudate predicted improvement in OCD symptoms with paroxetine [29], not inconsistent with the opposite direction for neuroleptic response noted above. The studies reviewed above implicate the orbitofrontal and cingulate cortex in OCD and SSRI response but differ in comorbid diagnoses, antidepressant tested, definitions of anatomical regions and hemisphere of significant effect. We hypothesized that (1) both striatal and orbitofrontal increase in relative metabolic rate would be seen with the addition of an atypical neuroleptic, and (2) individuals unresponsive to SSPI alone might show both striatal and orbitofrontal/cingulate predictors of clinical response to the addition of an atypical neuroleptic to their treatment.

Methods Subjects Sixteen outpatients with refractory OCD, who were free of medical illness and major comorbid psychiatric disorders, were enrolled in this randomized, double-blind parallel group design study. Diagnostic assessment was made by clinical interview using DSM-IV criteria and confirmed with the SCID. All subjects had been suffering from OCD, according to DSM-IV criteria, for at least 2 years but did not meet criteria for major depression. Baseline severity of obsessive-compulsive symptoms was assessed by the YBOCS [47, 48]. Depressive severity was assessed by the Hamilton Depression Rating Scale (HDRS) [49]. Subjects were treatment-resistant, defined as nonresponse (CGI-Improvement score of 3, minimally improved, or worse) to at least two SRI trials (including venlafaxine) of adequate dose and duration. In order to be eligible for the present study, subjects were required to be taking SRI medication currently for at least 12 weeks at a minimum daily dose of 125 mg of clomipramine, 40 mg of

Buchsbaum et al.

fluoxetine, 150 mg of fluvoxamine, 100 mg of sertraline, 30 mg of paroxetine, 40 mg of citalopram, or 150 mg of venlafaxine. However, 14 of the 15 subjects were taking a daily dose greater than the minimum required. The actual minimum daily doses in the 15 subjects were 200 mg of clomipramine, 60 mg of fluoxetine, 150 mg of fluvoxamine, 150 mg of sertraline, 60 mg of citalopram, and 325 mg of venlafaxine. No subjects were taking paroxetine at the time of augmentation Ten subjects were randomized to risperidone augmentation for the 8-week trial: 6 males and 4 females; mean age of 36.8 years (810.4); mean OCD duration of OCD of 19.3 8 12.4 years; mean baseline CGI-Severity of 5.33 (80.87); mean baseline Global Assessment of Functioning (SCID) of 50.89 (88.37); mean baseline total Hamilton Depression 17-item score of 12.50 (89.59); mean baseline YBOCS total score of 29.20 (85.73), with a mean baseline YBOCS obsession score of 15.20 (82.57) and compulsion score of 14.00 (83.86). Eight of 10 patients had a family history of psychiatric illness as determined by the intake interview (3 OCD, 4 mood disorders, 1 psychotic disorder); 4 of 10 had lifetime (not current) alcohol abuse on SCID; the current health status of each patient was determined through a clinical medical and neurological visit, general blood examination comprehensive of red and white cell assessment, liver, kidney and thyroid parameters, and electrolytes; 6 of 10 had previously undergone cognitive behavioral therapy (CBT). No other drug or nondrug treatment was allowed during the trial. Six patients were randomized to placebo augmentation: 3 males and 3 females; mean age of 43.2 8 15.8 years; mean OCD duration of 26.0 8 21.1 years; mean baseline CGI-Severity of 5.50 (80.84); mean baseline Global Assessment of Functioning (SCID) of 48.25 (89.95); mean baseline total Hamilton Depression 17-item score of 20.33 (810.86); mean baseline YBOCS total score of 29.33 (82.80), with a mean baseline YBOCS obsession score of 15.17 (82.32) and compulsion score of 14.17 (81.17). Four of 6 patients had a positive family psychiatric history (2 OCD, 2 mood disorders); 2 of 6 had, respectively, lifetime (not current) alcohol and cannabis abuse; 4 of 6 had previously had CBT. Ten subjects were randomized to risperidone augmentation and 6 to placebo for the 8-week trial but 1 subject randomized to risperidone did not receive any brain imaging before withdrawing. The medication dosage began at 0.5 mg/day and was gradually increased by 0.5 mg every 7 days until patients either (1) reached the maximum dose of 3 mg/day or (2) experienced therapeutic effects or side effects. Titration was limited to the first 6 weeks. A psychiatrist specialized in the treatment of OCD rated the subjects, and visits were scheduled every 2 weeks over the course of the study. Subjects were rated as responders or nonresponders to risperidone augmentation based on a 25% reduction in the total YBOCS score and/or CGI-Improvement score of 1 (very much improved) or 2 (much improved). The project and informed consent document was approved by the Institutional Review Board (IRB) of Mt. Sinai School of Medicine. Imaging PET scans were carried out as described elsewhere [50] (GE 2048 head-dedicated scanner, resolution 4.5 mm in plane, 5.0 mm axially). FDG uptake was done in the eyes-closed resting condition. Fifteen slices at 6.5-mm intervals were obtained in two sets to cover the entire brain. Slice counts of 1.5–3 M counts are typical. Scans were reconstructed with a blank, a calculated attenuation correc-

FDG-PET in Risperidone Treatment of OCD

Table 1. Patient demographics

Age, years Sex (M/F) Duration of OCD Marital status (single/married) Handedness (R/L) Baseline YBOCS Total Mean endpoint dose

Risperidone (n = 9)

Placebo (n = 6)

36 (10) 6/3 21.0 (11.8) 6/3 8/1

43 (16) 3/3 26.0 (21.1) 5/1 6/0

28.5 (5.68) 38 (0.78)

29.3 (2.8) 2.75 (0.50)

Figures in parentheses represent SD.

tion, and using the Hanning filter (width 3.15 mm). The same individually molded thermoplastic face mask was used for each scan to keep the head stationary during image acquisition and assist in PET/MRI image coregistration. PET images were obtained in nanocuries per pixel and standardized as relative glucose metabolic rate by dividing each pixel by the mean value for the entire brain (defined on the PET scan by using the brain edge from coregistered MRI) thus correcting in differences in whole-brain global mean. While this limits interpretations of single structure absolute activity, this normalization method is widely used when evaluating hypotheses related to patterns of metabolic rate across brain areas and was used in two earlier imaging studies of OCD and OCD treatment [37, 51]. Within 1 month of their PET scan, participants underwent MRI examination as described previously [52] (GE Signa 5! system, acquisition parameters: TR = 24 ms, TE = 5 ms, flip angle = 40°, slice thickness = 1.2 mm, matrix = 256 ! 256, field of view = 23 cm). MRIs were resectioned to standard TalairachTournoux [53] position. PET-MRI coregistration used the algorithm of Woods et al. [54]. Brain edges were visually traced on all MRI axial slices. Intertracer reliability on 27 individuals is 0.99 for area. We used two statistical approaches, a priori selection of regions of interest and a confirmatory testing of previously reported coordinates. On the basis of earlier studies on OCD, we focused on the cingulate, orbitofrontal and medial frontal regions and the striatum [37, 39, 51]. In all cases the coordinates are given either in the text or in table 1. For the first set of analyses, we located regions in advance of any analysis (or specific inspection of Talairach and Tournoux coordinates in previously published reports) in the Talairach-Tournoux atlas and recorded their coordinates (see table 1). For the cingulate, we used x-coordinates 8 mm from midline; for Brodmann areas (BA), we chose the position of numerals or halfway between duplicate numerals, 5 mm from the cortical edge. The square region of interest (ROI; 3H3 pixels) was applied centered on that coordinate and at the proportion as the brain-bounding box in the TalairachTournoux atlas to each subject’s own MRI image at the appropriate z level and the relative metabolic rate on the coregistered PET assessed. An adjustment was made so that ROIs were moved closer to the centroid of the slice if the box fell partly outside the coregistered brain outline, as could happen in brains that were especially


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narrow in the x direction for boxes placed at 45 and 135!. Coordinates were mirrored about the y axis, so values in the right and left hemisphere were equal distances from the midline. For the second confirmatory approach, we used the previously published Talairach and Tournoux coordinates for a region in the thalamus giving differences between OCD and normals [51] and the orbitofrontal cortex for a region showing effects of paroxetine [37]. Thus all regions of interest were selected a priori. This method, the reverse Talairach hypothesis-driven strategy, was used for three reasons: (1) to minimize type I statistical errors in evaluating large numbers of ROIs in both hemispheres through the use of multiway repeated measures ANOVA and a single F ratio test indicating the hypothesized diagnostic group-region interaction, (2) to minimize type II errors resulting from assessing small individual, potentially noisy ROIs and failing to observe orbitofrontal system-wide response by combining ROIs, and (3) to provide standard and known brain atlas locations for replication. We also controlled for type I error by not discussing main effects or interactions that are not interpretable (e.g. main effect of slice level across structures measured at multiple axial slice levels) or peripheral to our interest (main effect of hemisphere across conditions). Our analysis is limited in power by the sample size (n = 15) and we therefore felt it was especially important to test coordinates either chosen in advance or for replication from published studies. Choosing the reported center xyz coordinate of a patch found on exploratory significance probability mapping and applying that coordinate to the present data is a more explicit and unequivocal replication at p ! 0.05 than repeating the significance probability mapping and observing whether a patch of contiguous pixels overlaps the area of the earlier publication. The complex problem of how successful a replication is that only partially overlaps the previously published region has not been fully solved. Statistical Design The PET data set consisted of relative metabolic rates in dorsal and ventral cingulate, prefrontal cortex, and similarly dorsal and ventral caudate and putamen. In order to avoid the problems of type I error associated with doing large numbers of t tests on every brain region for the right and left hemisphere and dorsoventral level, we chose to use multiway repeated measures ANOVA to assess effects across groups of regions of interest in both hemispheres. For medication effects, a three-way mixed repeated measures ANOVA design was applied to relative glucose metabolic rate data obtained for independent groups (8 weeks minus baseline scores for the placebo and drug group) and for repeated measures for brain level (e.g. Talairach z = 12, 4, –4) and hemisphere (left, right). For medication effects in the striatum, we used a four-way ANOVA, adding structure (caudate, putamen, globus pallidus) as the fourth repeated measures dimension. Other analyses followed this general strategy. For differences between responders and nonresponders at baseline or medication effects we added response group as an independent group factor to match the most common clinical drug response statistical strategy. For clarity and simplicity in graphic presentation, we report the amount of change in the medication group minus the placebo group, so a positive difference indicates an increase in relative metabolic rate with medication corrected for placebo trial changes. The use of difference scores halves the number of functions to be plotted, and yields numerically equal F ratios to those that would be obtained with a five-way ANOVA. It should be noted that typical relative metabolic rates in

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gray matter structures are in the range of 0.80–1.20 with standard deviations of 0.06–0.15. Thus a medication change score of 0.10 indicates a relative metabolic rate increase in the range of an effect size of 0.70–1.3. All statistical analyses involving repeated measures with more than two levels used Greenhouse-Geisser epsilon corrections to adjust probabilities for repeated measures F values where there were up to two-way interactions; our program yielded only Rao’s R for higher-order interactions. Uncorrected, corrected, and MANOVA degrees of freedom are reported. To detect the source of significant interactions between group and hypothesized BA, we carried out ANOVA on each BA separately. Interactions involving slice level (except for cingulate and striatum where differences have been previously reported) replicated or ROI adjacent in position were not followed up as they were not part of our hypothesis or were neuroanatomically not important.

Results

Prefrontal Cortex and BA 10 and 11 The relative metabolic rate of BA 10 assessed at three Talairach and Tournoux levels (z = 12, 4, –4) was increased in the risperidone-treated groups in comparison to the placebo group (drug minus placebo group difference, 0.135, F = 12.2, d.f. = 1,13, p = 0.0040). Prefrontal and striatal increases (see below) were notable on visual inspection of scans, and a typical example of the z = 12 level is shown in figure 1. The anteriormost BA 11 ROI in the right hemisphere chosen to assess the significant anterior orbitofrontal decrease previously observed in paroxetine treatment was significant [37], but showed an increase with risperidone (0.26, t = –2.78, d.f. = 13, p = 0.022; Levene’s test p = 0.56; xyz coordinates 5, 57, –12). Striatum An increase in relative metabolic rate of the caudate, putamen and globus pallidus was observed and this was confirmed for the caudate (F = 7.37, d.f. = 1,13, p = 0.018) and globus pallidus (F = 5.19, d.f. = 1,13, p = 0.040; F = 8.57, p = 0.011 for caudate and pallidum ) but not the putamen (F = 0.33, d.f. = 1,13, p = 0.57). Higher-order interactions were not significant. Cingulate Gyrus The relative metabolic rate in the cingulate gyrus (xyz: 8, 33,12; 8, –57, 12; 8, 12, –12; BA 24, 23, 25, respectively, see fig. 1 for typical FDG-PET; table 2) was increased by risperidone (main effect of group, F = 5.14, d.f. = 1,13, p = 0.041,) and this was more prominent in the right hemisphere (drug minus placebo 0.15) than in the left (drug minus placebo 0.04; group by hemisphere interacBuchsbaum et al.

Baseline

8 weeks Cingulate

Cingulate

PET value 1.60

1.30

1.00

0.70

0.40

Fig. 1. FDG-PET at baseline and following risperidone treatment for typical representative subject. Increase in cingulate is prominent but little change is seen in occipital cortex. Top row shows axial images at z = 12, bottom row shows sagittal images at x = +4. Color bar shows metabolic rate relative to whole brain (voxel value divided by mean voxel value for all voxels within brain). Table 2 gives stereotaxic coordinates.

tion, F = 5.13, d.f. = 1,13, p = 0.041) as shown in figure 2. An analysis adding the hippocampus (xyz: 30, –17, –12) and amygdala (xyz: 21, –6, 12) yielded a group by hemisphere interaction F = 5.50, d.f. = 1,13, p = 0.036 but no group by region interaction; the drug effect was primarily confined to the cingulate and other limbic structures showed little effect and little asymmetry. Thalamus The right thalamus ROI (xyz: 16, 18, 20) was selected from significance probability mapping as an area showing significantly higher relative glucose metabolism in subjects with an OCD than in normal controls [5, 51]. This FDG-PET in Risperidone Treatment of OCD

area was significantly lower on risperidone than placebo with a double difference in relative metabolic rate of 0.25 (t = 2.62, p = 0.021, d.f. = 13; variances not different in Levene’s test, p = 0.11). An area located on the left thalamus did not reach statistical significance in our sample (t = 0.61, p = 0.54). Treatment Response The baseline and clinical characteristics of the two treatment groups are summarized in table 1. There were no significant differences in treatment setting, age, sex distribution, duration of OCD, psychiatric familiarity, lifetime substance abuse, previous CBT, or baseline CGI, Neuropsychobiology 2006;53:157–168

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1.10 Nonresponders Responders

Relative metabolic rate

1.05 1.00 0.95 0.90 0.85 0.80 0.75 0.70 0.65 25 –12

a

24 –4

24 4

24 12

b

25 –12

24 –4

24 4

24 BA 12 Talairach

Fig. 2. Baseline metabolic rate and response to risperidone in cingulate gyrus in right (a) and left (b) hemispheres.

The BA location and the Talairach z level are given along the horizontal axis. Responder vs. nonresponder by cingulate region by hemisphere interaction (F = 3.21, d.f. = 4,21, p ! 0.0176). Panel has radiological orientation.

Table 2. Talairach and Tournoux coordinates in striatum

Caudate

Putamen

Cingulate

x

y

z

x

y

z

x

y

z

11 8 7

11 13 14

12 4 –4

23 22 20

0 16 10

12 4 –4

8 8 8 8

12 23 32 33

–12 –4 4 12

Coordinates are obtained in millimeters from atlas [53] for right side of brain with left as mirror image about midline. For example, the last row in the cingulate column gives the x, y, and z coordinates and corresponds to the location of the number ‘24’ on the 12-mm z plate (see fig. 2).

YBOCS and HDRS scores. There was no significant difference in dosage between patients randomized to risperidone (2.25 8 0.86 mg/day) and placebo (2.75 8 0.50 mg/ day). Four (40%) of 10 risperidone-treated patients responded according to the CGI global improvement item, while none of 6 placebo-treated patients were categorized as responders (likelihood ratio = 4.53; p = 0.033; 1 d.f.). According to the YBOCS response criteria (a reduction from baseline to endpoint greater than 25%), 4 patients were responders for the total and compulsion scores (likelihood ratio = 4.53; p = 0.033; 1 d.f.), and 3 for the obsession score in the risperidone group, while no patient 162


responded in the placebo group. There was no statistical difference for risperidone daily dosage between responders and nonresponders (2.25 8 0.96 and 2.25 8 0.88 mg/ day). Mean YBOCS total values decreased from 29.20 8 5.73 to 23.10 8 8.33 in the risperidone group and from 29.33 8 2.80 to 28.00 8 7.31 in the placebo group, with a mean percentage reduction of 19.04 8 29.07 and 4.62 8 9.97, respectively. Mean YBOCS obsession and compulsion values had a reduction of 22.37 8 29.32 and 10.93 8 43.51% in the risperidone group and 6.34 8 8.87 and 2.28 8 13.68% in the placebo group. Mean HDRS total scores increased by 3.83 8 71.96% in the risperidone group and by 50.08 8 172.67% in the placebo group, but 4 subjects had a 6125% reduction in the risperidone group and 2 in the placebo one. We had 2 dropouts from the study in the placebo group (week 6 and 7) and they were all due to unsatisfactory clinical response. PET scans were obtained at the time of dropout and the data was included. One additional tenth subject randomized to risperidone inadvertently was never scheduled for a PET scan and dropped out in week 3; he is not included in any analysis. The risperidone augmentation was generally well-tolerated, and during the study period 4 of 10 risperidonetreated patients experienced at least 1 side effect. These included sedation (n = 3), dizziness (n = 1) and dry mouth (n = 2). Two of 6 patients receiving placebo experienced side effects (dry mouth and sexual dysfunction). No clinBuchsbaum et al.

Responders Nonresponders

1.4 1.3 1.2 1.1 1.0 0.9 12

a

4 Dorsoventral level

Drug minus baseline difference

Baseline relative metabolic rate

1.5

–4

0.15 0.10 0.05 0 –0.05 –0.10 –0.15 12

b

4

–4

Dorsoventral level

Fig. 3. Striatal metabolic rate and medication response. a Baseline metabolism in dorsal striatum lower in individuals who go on to respond (medication group by dorsoventral level interaction, F = 4.58, d.f. = 2,14, p = 0.0296). b Responders increase metabolic rate in ventral striatum but decrease it in dorsal striatum (medication group by dorsoventral level interaction, F = 5.79, p = 0.0147).

ical changes in blood pressure and heart rate were recorded, nor were risperidone-related extrapyramidal symptoms. Medication Response and Baseline Frontostriatal and Cingulate Relative Metabolic Rate Striatum We examined only the 9 patients with PET scans in the medication group for analysis of medication response [4 responders, 5 nonresponders based on CGI scores of 1 or 2 at 8 weeks; responder group ! structure (caudate, putamen) ! level (Talairach 12, 4, –4) ! hemisphere (r, l)]. As predicted, patients with lower levels of relative metabolic rate in the striatum (1.16) were more likely to be responders to risperidone than those with high levels (1.44; main effect of responder group, F = 5.66, d.f. = 1,7, p = 0.048). This was more marked in the dorsal striatum (fig. 3) than the ventral striatum (responder group ! level interaction F = 4.58, d.f. = 2,14, p = 0.030; GreenhouseGeisser d.f. = 1.67, 11.6, p = 0.039). Cingulate Second, we examined the ventral cingulate (BA 25 or ‘subgenual’ cingulate), BA 11, and a control area in the dorsal cingulate, BA 24 (xyz: 8, 12, –12; 8, 45, –12, and 8, 33, 12, respectively). Subjects with higher relative metabolic rates in the right cingulate tended to be responders (fig. 2, responder group by region by hemisphere interaction, F = 5.17, d.f. = 2,14, p = 0.020; Rao’s R = 6.38, d.f. = FDG-PET in Risperidone Treatment of OCD

2,6, p = 0.037). Examination of cingulate gyrus only for the arch of the anterior cingulate (BA 25 at z = –12 and BA 24 for z = –4, 4, and 12) yielded a significant responder group by region by hemisphere interaction F = 4.21, d.f. = 3,21, p = 0.017 (but Rao’s R = 3.58, d.f. = 3,5, p = 0.101). Addition of posterior cingulate locations including BA 31 failed to meet statistical significance for either group or group interactions. Using the right and left ventral cingulate and the dorsal caudate in multiple regression to predict CGI (as a continuous variable) produced an adjusted R2 of 0.79, F = 8.30, d.f. = 4,4, p = 0.03. The left and right cingulate and caudate values were significantly correlated (r = 0.84, 0.55, respectively) but cingulate and caudate were not significantly correlated. Discriminant analysis with the same four variables classified all 9 subjects correctly. Metabolic Change with Medication and Clinical Response We examined medication minus baseline metabolic difference scores in these analyses for simplicity of presentation. In the cingulate/orbitofrontal region, responders increased metabolic rates in their right cingulate gyrus (BA 25) while reducing metabolic rates in their right BA 11 [responder group by structure (cingulate, BA 11) by hemisphere interaction, F = 14.70, d.f. = 1,7, p = 0.006]. When adding dorsal cingulate (BA 24 or non-‘subgenual’ cingulate) as a control area the regional effect remained specific and significant (responder group by structure F = Neuropsychobiology 2006;53:157–168

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6.93, d.f. = 2,14, p = 0.0081; Rao’s R = 6.93, d.f. = 2,6, p = 0.028). Since the right posterior cingulate metabolic rate (BA 31) has been associated with response to anterior cingulotomy [40, 41, 55] and correlated with symptom severity [8] we examined our a priori choice of area 31 at 8, –65, 12 and did not obtain a significant correlation between baseline relative metabolic rate and medication response or between baseline relative metabolic rate and YBOCS scores. However we obtained a correlation of r = 0.61 (d.f. = 9, p ! 0.05, 1-tailed in replication) between responder category (1 = responder, 0 = nonresponder) and relative metabolic rate change with medication. Correlations for other change scores (medication minus baseline) were similar; YBOCS total, compulsions, obsessions, and HDRS were –0.62, –0.75, –0.55, and –0.65, respectively (r ! 0.58, p ! 0.05 1-tailed; r ! 0.67, p ! 0.05 2-tailed). In the striatal region, responders decreased metabolic rates (fig. 3) in the dorsal striatum with risperidone augmentation while it was increased in the ventral striatum (drug minus baseline difference scores, –0.08, +0.06, +0.11 for z = 12, 4, –4, respectively, response group H level interaction, F = 5.79, d.f. = 2,14, p = 0.015; Rao’s R = 9.75, d.f. = 2,6, p = 0.013). This effect was greater for the dorsalmost right (–0.08) than left (–0.03) caudate, consistent with earlier findings [37] but still greater at this level (z = 10) in the right putamen (–0.14) than the left (–0.09), not previously reported; no interaction between response group and brain structure was significant however. Simple interaction ANOVA were significant, for the caudate (F = 7.37, d.f. = 1,13, p = 0.018) but not the putamen. An exploratory analysis on the pallidum was also significant (F = 5.19, d.f. = 1,13, p = 0.011).

Discussion

This study confirmed significant metabolic rate increases with risperidone administration in the orbitofrontal and cingulate cortex and in the striatum, two areas found to differ in metabolic rate between normal volunteers and patients with OCD. The baseline metabolic rate in these areas also predicted clinical response to the addition of risperidone to SRI treatment and replicated earlier prediction response studies in affective disorder for SRI treatment [26, 27], in schizophrenia for neuroleptic treatment [45], and in OCD for SRI treatment [28, 29, 37, 55]. Taken together, these data indicate that the effects of medications tend to more likely to be statistically confirmed in areas of the brain which differ between patients with 164


OCD and normal controls, and in patients who show significant clinical response. Further, baseline metabolic rate appears to predict symptomatic outcome across patient groups as diverse as affective disorder, schizophrenia and OCD when similar medications are given. Our experimental design provided three important limitations: sample size, the lack of a drug-free baseline, and possible clinical heterogeneity within the patient sample. A major limitation of the study is sample size, with a total of 15 subjects for evaluation of group effects of medication on metabolic rate and 9 subjects for evaluation of individual differences in drug response (the 6 subjects who received placebo were untested for clinical response to risperidone). The sizes of earlier open studies of risperidone augmentation are not dissimilar: n = 1 [56], n = 3 [57], n = 4 [58], n = 9 [59], n = 9 [60], n = 14 [61], n = 20 [62], and n = 21 [63]. Our total YBOCS effect size of 0.80 is somewhat smaller than that of a comparable [25] double-blind study effect size of 1.12, and with the same sample size as that study (33 completers) would have had 95% power to detect a significant clinical improvement with risperidone augmentation. Our sample size was also in the same range of the FDG response prediction studies of fluoxetine, n = 9 [36], fluvoxamine, n = 9 [39], cingulotomy, n = 11 [40], and paroxetine, n = 20 [37]. However, the range restriction associated with selection of only nonresponders to SRI also limited our power as well as generalizability of the results. Our lack of an SRI drug-free interval prevented contrasts with either normal controls or patients with schizophrenia, diminishing our ability to make direct inferences about whether patterns of metabolism were brought closer to normal in the risperidone augmentation trial. We obtained similar results with the responder/nonresponder group division ANOVA as with continuous variable multivariate correlation with the CGI, indicating sufficient statistical robustness of our methods. Lastly, despite the exclusion of patients with a diagnosis of affective disorder, patients unavoidably had differing levels of the symptoms of depression as assessed by the HDRS. Earlier studies of patients with major depressive disorder showed caudate increases with paroxetine, while patients with OCD showed caudate decreases on paroxetine [55]. A better characterization of the group of patients here termed ‘SRI resistant’ is desirable [64], including age of onset [65]. Our imaging approach was constrained by the use of stereotaxically placed atlas regions, errors in coregistration, and the strategy of limiting the number of areas assessed to control type I error. The Talairach and Tournoux atlas is based on a single brain and margins of the cortical Buchsbaum et al.

areas are not determined histologically, limiting the accuracy of our choice of coordinates. This is balanced by the advantages of using coordinates from a standard source and coordinates widely used in reporting significance probability maps. Tracing smaller structures such as the caudate or globus pallidus on each subject’s MRI ( about 70 cingulate, 15 globus pallidus, and 25 for caudate and putamen in each hemisphere for 15 subjects) and assessing coregistered PET for those pixels may be superior in accuracy, but the values are not comparable with other published values. The size of the caudate (12 mm wide at its widest point, 28 mm high) and globus pallidus (9 mm wide and 12 mm high) are within the range of the two to more than 4-fold larger than the full-width-half-maximum resolution of the scanner. While they depart somewhat from spheres, some noise reduction is obtained by combining left and right and multiple levels in the ANOVA main effects. The finding of risperidone effects in the right thalamus is noteworthy because two recent studies noted right flow [5] and bilateral metabolic [51] activation in OCD patients, and right but not left thalamus rCBF was found in fluvoxamine responders [66]. Inclusion of the thalamus in future analysis with specific identification of thalamic nuclei on coregistered MRI [67] will be useful to fully document the circuits in OCD. The appearance of BA 31, the posterior cingulate, as an area where change in metabolic rate is linked to clinical improvement in our data is of interest, because of the earlier reports that BA 31 was a predictor of response to cingulotomy [40] and a correlate of baseline YBOCS symptom severity [8]. However, a specific BA 31 replication of these earlier reports was not obtained. A detailed tracing of the cingulate on coregistered MRI and analysis of the entire arch in a larger sample would be useful to better define these interactions between symptoms and improvement. We found a ventral increase and dorsal decrease in relative metabolic rate in the striatum with risperidone treatment. Since neuroleptics typically increase striatal metabolic rate, the ventral increase is expected. One might argue that SSRIs such as paroxetine might have an opposite action and studies of OCD patients with paroxetine alone might show opposite effects. A ventral (10, 12, –2) but not dorsal caudate decrease in FDG-PET was indeed found following paroxetine treatment in OCD [68], the opposite of our current risperidone effect. A second recent study with paroxetine [55] similarly reported caudate relative metabolic rate decreases with medication for traced ROI analysis. However, this analysis of paroxetine data com-

bined metabolic rates across dorsoventral levels, and matching SPM analysis on these OCD patients [55] failed to confirm any striatal effects. There may be additional statistical power with the entry of multiple assessments of caudate relative metabolic rate (six measurements, right and left, three slice levels; theoretical noise reduction by a factor of the square root of 6) into MANOVA in comparison to t tests limited to a single slice and hemisphere. Our findings that the relatively low metabolic rates in the striatum predict risperidone augmentation efficacy are parallel to our findings of a similar prediction of haloperidol efficacy in patients with schizophrenia. It is of interest that a comorbid schizotypal personality disorder predicted the success of olanzapine augmentation of fluvoxamine therapy in OCD [69], suggesting that some overlap with the schizophrenia spectrum may be associated with augmentation therapy success. It has been hypothesized that OCD and the schizophrenia spectrum may be linked indirectly along a dimension of schizotypy [70]. On the other hand, it has been widely suggested that schizotypy is a multidimensional construct [71–76]. However, because of the different structures of schizotypy reported [76–83] the exact number and item content of each factor is not clear. It is possible that one of the pathophysiological mechanisms underlying the OCD clinical phenomenology (such as resistance to SSRI) might be common to schizotypy as well, perhaps as a potentiator factor [84]. The outer boundaries of psychotic disorder are not so clearly demarcated, and OCD and schizotypy or schizophrenia spectrum patients may overlap in symptoms [81, 85]. Axis II assessment of future samples would be helpful. While haloperidol has greater effects on functional activity in the striatum than risperidone, risperidone effects are apparent both in caudate and putamen in comparison studies [86]. D2 receptor occupancy with risperidone in the limbic area seems to be comparable to that of typical antipsychotics in patients with schizophrenia [87]. Unique interactions between specific SRIs and specific typical and atypical neuroleptics, effects of drug dosages [57], and length of time adequate to achieve full clinical effect all need to be considered in planning future experiments. Our findings in the cingulate gyrus emphasize differences in the most ventral region, area 25, rather than the more dorsal BA 24. Area 25 is adjacent to (and potentially overlapping with) the orbitofrontal cortex. High values in the right BA 25 at baseline were predictive of response, and area 25 increased with risperidone administration. While area 24 was higher in responders than nonresponders, there was little change in area 24 (z = –4 to z =



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+12) with the administration of medication. Area 24 baseline activity did not predict improvement on the HDRS, not unexpectedly since patients were already nonresponders to SRI and on SRI at baseline. The area of the anterior cingulate at the z = 10 level has been found to be a predictor of SSRI response in depressed patients [27] and in a patient group of 71 patients with major affective disorder, OCD and both [29]. A midline prefrontal area was a predictor of improvement in depression at z = 6 in major affective disorder patients with and without OCD. Specific statistical contrasts of dorsal and ventral levels of the cingulate and adjacent medial frontal lobe would be valuable in new unmedicated patients with major affective disorder only, OCD only, and both. This would provide detailed data on the actual clinical usefulness of PET in predicting drug response in new patients. It should be noted that the lateralization to the right hemisphere seen strongly in our data was also observed in the study of depressed patients [27]. Area 25, the visceral emotional area, is followed by area 24, the attentional center, as we ascend the arch of the anterior cingulate; since OCD patients are not characterized by attentional deficits [88], the pattern of response is not unexpected.

Activity decreases with reduction in glucose metabolism or blood flow have been found in orbitofrontal cortex, anterior cingulate, caudate and thalamus of patients with OCD in response to SRIs. However, in our study we had nonresponders to SRIs who were on these medications for their baseline and had an augmentation of risperidone. A full sample of OCD patients with an unmedicated baseline, a single SRI scan and the augmentation scan (and/or a risperidone first, SRI augmentation arm) is really needed to fully explore the drug-drug interaction. Nevertheless, it appeared that the prediction findings from other studies may partly replicate across groups with differing baseline treatment.

Acknowledgments The authors thank Dr. Tse-Chung Wei for software development of the stereotaxic box program and Dr. Cheuk Tang for instrumentation support. The work was supported in part by a grant from Janssen Pharmaceuticals. An earlier version of this work was presented at the American Psychiatric Association Meeting in Philadelphia, Pa., May 2002.

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