- Email: [email protected]
Caudate and putamen volumes in good and poor outcome patients with schizophrenia
Schizophrenia Research 64 (2003) 53 – 62 www.elsevier.com/locate/schres
Caudate and putamen volumes in good and poor outcome patients with schizophrenia Monte S. Buchsbaum a,*, Lina Shihabuddin b, Adam M. Brickman a, Ruben Miozzo a, Radovan Prikryl c, Robert Shaw a, Kenneth Davis a a
Department of Psychiatry, Mount Sinai School of Medicine, Box 1505, 1 Gustave L. Levy Place, New York, NY 10029-6574, USA b Bronx VA Medical Center, Bronx, NY, USA c Psychiatry Department of Faculty Hospital in Brno, Brno, Czech Republic Received 11 June 2002; received in revised form 11 November 2002; accepted 25 November 2002
Abstract Magnetic resonance images of 37 patients with schizophrenia and 37 age- and sex-matched volunteers were acquired. The caudate nucleus and putamen were traced on axial slices from the most superior extent of the caudate to the most inferior point where the caudate and putamen merge. Two subtypes of schizophrenia were compared, the Kraepelinian subtype (n = 13), characterized by an unremitting and severe course, and the non-Kraepelinian subtype (n = 24), characterized by a remitting course and some periods of self-care. Patients with good outcome schizophrenia had larger relative mean putamen size (0.0129) than poor outcome patients (0.0123) or normal controls (0.0121), but not caudate size. This enlargement was most marked for the dorsal putamen and right hemisphere. Striatal size was not related to whether patients were currently being treated with atypical or typical neuroleptics or whether they had been predominantly treated with typical or atypical neuroleptics over the past 3 years. This suggests the possibility that the expansion of putamen size may be a physiological correlate of neuroleptic responsiveness or that small putamen size at disease onset may be a predictor of outcome. D 2003 Elsevier Science B.V. All rights reserved. Keywords: Caudate; Putamen; Kraepelinian subtype
1. Introduction Striatal volume in schizophrenia has generally been found to be increased (Hokama et al., 1995), particularly in patients who have been chronically treated with neuroleptic medication, and decreased in * Corresponding author. Tel.: +1-212-241-5294; fax: +1-212423-0819. E-mail address: [email protected] (M.S. Buchsbaum).
never-medicated patients (McCarley et al., 1999; Shihabuddin et al., 1998). This volume increase has been hypothesized to reflect increased dopaminergic innervation, probably secondary to neuroleptic treatment or an interaction between neuroleptic treatment and the pathophysiology underlying schizophrenia, since two longitudinal MRI follow-up studies found progressive enlargement in striatal volume following neuroleptic treatment (Chakos et al., 1994; Keshavan et al., 1994). In our own recent study, reduced caudate volume was found in never-medicated schizophrenic
0920-9964/03/$ - see front matter D 2003 Elsevier Science B.V. All rights reserved. doi:10.1016/S0920-9964(02)00526-1
54
M.S. Buchsbaum et al. / Schizophrenia Research 64 (2003) 53–62
patients compared to controls, and increased (relative to normal control values) dorsal putamen volume was found in previously medicated patients (Shihabuddin et al., 1998). Similar findings were reported in other subsequent studies (Corson et al., 1999; Gur et al., 1998), including greater increases in putamen than caudate in previously medicated patients (Gur et al., 1998). Interestingly, patients with schizotypal personality disorder had smaller putamens than either previously medicated patients with schizophrenia or controls (Shihabuddin et al., 2001). Image analysis using deformation-based morphometry also revealed increased putamen but not caudate size (Volz et al., 2000), and a recent MRI study demonstrated functional deficits in putamen but not caudate (Menon et al., 2001). Relatives of patients with schizophrenia also had smaller putamens, although only when gender and brain size were treated as controlled factors (Seidman et al., 1999). We hypothesized that putamen, and possibly caudate size, would be larger in patients with better outcome schizophrenia who responded to neuroleptics than in poor outcome patients who failed to respond. To address dorsoventral gradients in volume, we used high-resolution MRI to assess caudate and putamen volumes at five standardized proportional levels.
2. Methods 2.1. Subjects Thirty-seven patients (27 men, 10 women; ages [years]: M = 43, S.D. = 11.9, range = 20 –66; education [years]: M = 12.6, S.D. = 1.9) were recruited from the Mount Sinai and Bronx VA hospitals as well as the Pilgrim Psychiatric Center. Thirty-six patients were right-handed and one was ambidextrous, based on the Edinburgh Handedness Inventory (Oldfield, 1971). The patients were evaluated with the Comprehensive Assessment of Symptoms and History (CASH) (Andreasen et al., 1992) and diagnosed as having schizophrenia (n = 36) or schizoaffective disorder (n = 1) according to the DSM-IV criteria. The mean age of onset for these 37 patients is 21 (S.D. = 6.9) and the mean age for beginning neuroleptics is 25.6 (S.D. = 10.9). The patients’ mean number of hospitalizations (in months) is 40.4 (S.D. = 65). The onset age,
age of beginning neuroleptics and number of hospitalizations were not available for one of the patients. A battery of rating scales was administered on the week of the scan, including the Positive and Negative Syndrome Scale (PANSS; Kay et al., 1987). The psychopathology subscale scores were as follows: Positive (M = 21, S.D. = 9.8); Negative (M = 18, S.D. = 7.2); General (M = 33.3, S.D. = 12). The PANSS scores were not obtainable for one of the patients. 2.2. Group divisions and normal volunteers In addition, the schizophrenic patients were subdivided into poor outcome or Kraepelinian (n = 13) and good outcome or non-Kraepelinian (n = 24), as described elsewhere (Keefe et al., 1987). The Kraepelinian subgroups were characterized by continuous hospitalization or complete dependence for basic needs, unemployment and no evidence of remission of symptoms (Davis et al., 1998). This sample did not overlap with samples reported earlier (Buchsbaum et al., 1999; Shihabuddin et al., 2001). The poor and good outcome groups did not differ in age (47, S.D. = 9.0 vs. 41, S.D. = 12.1, t = 1.50, respectively) and age at which neuroleptic treatments began (22.2, S.D. = 13.8 vs. 26.8, S.D. = 6.4, t = 1.36, p = ns). The poor outcome patients, in comparison to good outcome patients, had an earlier age of onset (17.8, S.D. = 6.2 vs. 22.9, S.D. = 6.7, t = 2.21, p = 0.033) and higher scores on the PANSS Positive, Negative and General scales (27.6 vs. 17.3, 21.5 vs. 15.9 and 39.5 vs. 29.6, respectively, all t>2.3, p < 0.02). Medication history was evaluated by review of charts for the past 3 years. Since the majority of patients had changed medication type and dosage at least once during the past 3 years and multiple neuroleptic dosage was also common, simple characterization of the patients’ treatment history in chlorpromazine equivalents was not feasible. Therefore, to evaluate drug effects, we coded patients for the time of the MRI scan and for the predominant pattern over the past 3 years as off medication, typical neuroleptics, atypical neuroleptics and both. Thirty-seven normal volunteers (23 men, 14 women; ages [years]: M = 44.1, S.D. = 13.7, range = 22 –85; education [years]: M = 16, S.D. = 3.2) were recruited by word of mouth or advertisement. Thirty-
M.S. Buchsbaum et al. / Schizophrenia Research 64 (2003) 53–62
55
four controls were right-handed and two were lefthanded, based on the Edinburgh Handedness Inventory (Oldfield, 1971). All of the 37 normal controls were given a CASH interview to exclude history of psychiatric illness in themselves or in their firstdegree relatives.
the caudate and putamen are entirely merged. This distance was divided by six to yield five equally spaced slices for the caudate and putamen separately (Fig. 2) for tracing (e.g., most dorsal slice = 20, most ventral slice = 38, difference = 18, 18/6 = 3, slices 23, 26, 29, 32 and 35 are traced).
2.3. Image acquisition
2.5. Statistics
MRI acquisition used the Signa 5 system (GE Medical Systems, Milwaukee, WI) with a 3D-SPGR sequence (TR = 24 ms, TE = 5 ms, flip angle = 40j and slice thickness = 1.2 mm, matrix size 256 256).
Repeated-measures ANOVA or MANOVA was used in diagnostic group comparisons. Groups were independent dimensions for the whole population (schizophrenia, normal volunteers) and for good/poor outcome subgroups. Repeated measures were region (caudate, putamen), hemisphere (right, left), and slice level (1– 5, corresponding to 20 to 4 mm; Talairach and Tournoux, 1988). Group region and higher order interactions were examined to establish regional differences. Follow-up simple interactions were performed to identify the strongest sources of group interactions. We computed absolute size in cubic millimeters and relative size as the ratio of area of ROI/area of slice.
2.4. Automated edge finding An automated boundary-finding method based on the Sobel gradient filter provides a reproducible structure edge, with little operator variability (Shihabuddin et al., 1998). The caudate and putamen were outlined on the MRI by depositing points by mouse on the magnified and enhanced white structure edge using a semiautomated 3 3 local pixel maximum search. This placed the point at the center of the edge, enhancing interoperator consistency (Fig. 1). A spline curve was fit to the points and the ROI edge stored. Two tracers’ independent tracing of 10 subjects yielded ICC of 0.92 for the caudate and 0.98 for the putamen area. We determined the top of the caudate and putamen as the most dorsal axial slice showing a visible gray patch and the bottom as the slice in which
3. Results 3.1. Relative caudate and putamen sizes Patients with good outcome schizophrenia had larger relative mean putamen size (0.0129) than poor
Fig. 1. Left: Gradient filter transformed axial SPGR MRI slice. Dots indicate enhanced outline of putamen. Dots are placed on computerenhanced edge visually and adjusted by algorithm to fall on local (3 3 search maximum), and spline curve is fit to produce outline. If there are minor breaks in the outline, points are placed on either side of the break but not within the break. Outline values contain the two x coordinates for every y value and the MRI intensity values for every pixel within the outline. Right: Original MRI with dots.
56
M.S. Buchsbaum et al. / Schizophrenia Research 64 (2003) 53–62
M.S. Buchsbaum et al. / Schizophrenia Research 64 (2003) 53–62
57
Fig. 3. Relative putamen size in controls, poor and good outcome patients.
outcome patients (0.0123) or normal controls (0.0121), but not caudate size (group structure interaction, F = 3.77, df = 2, 71, p = 0.028). This enlargement was most marked for the dorsal putamen and right hemisphere (group slice structure hemisphere, F = 2.17, df = 8, 284, p = 0.030; Rao’s R = 2.31, p < 0.023, df = 8, 126). The main effect of diagnostic group was not significant, indicating that the effect was not general across the entire striatum. Follow-up tests for the caudate and putamen (Fig. 3) separately indicated that the putamen differences between good and poor outcome patients were significant (Rao’s R = 2.07, df = 8, 136, p = 0.043). Patients with schizophrenia had larger putamens than normal controls, whereas caudate sizes were similar (group region ventrodorsal level, F = 3.07,
df = 4, 288, p = 0.017; but Rao’s R = 2.17, df = 4, 69, p = 0.08; Fig. 4). Across caudate and putamen considered together, patients had larger dorsal area than normals ( F = 7.33, df = 1, 72, p = 0.0085). Post hoc ttests identified the difference in putamen sizes between normals (0.009, S.D. = 0.0020) and patients with schizophrenia (0.11, S.D. = 0.0021) to be greatest for the right dorsalmost slice (0.011, S.D. = 0.0021, t = 3.36, p = 0.0012); other individual slice levels did not reach statistical significance. 3.2. Absolute caudate and putamen sizes Patients with schizophrenia had larger putamens than normals, while caudate differences were small (Fig. 4, group structure dorsoventral level inter-
Fig. 2. Cortical levels and striatal tracing. Slices that contain the dorsalmost and ventralmost slice containing the caudate and putamen on the right and the left side are identified. Dorsally, this is the highest slice on which the head of the caudate is visible, and ventrally, the last. The interval is divided by the number of desired levels (5) plus 1. This 1/6 step, correct to three decimal places, is then added to the initial slice level and the number truncated to yield the first traceable slice. Five steps are generated in this way. Only slice levels containing a selected striatal outline are shown in the illustration. Note that this sometimes results in the left and right sides not being traced on the same slice level but creates a systematic set of five outlines placed proportionately in the caudate and putamen and suitable for multiway repeated-measures ANOVA. Absolute size can be generated by multiplying each slice area by the actual slice spacing. A program allows quick inspection of all striatal edges on all slice levels with a distinctive color for each region to facilitate checking of tracing quality and accuracy of hemisphere and structure filenaming.
58
M.S. Buchsbaum et al. / Schizophrenia Research 64 (2003) 53–62
Fig. 4. Increased size of putamen but not caudate in schizophrenia.
action, F = 2.99, df = 4, 288, p = 0.019). Good outcome patients had the largest putamen size (group structure interaction, F = 3.95, df = 2, 71, p = 0.023) and this was more marked at dorsal levels and in the right hemisphere (Rao’s R = 2.08, df = 8, 136, p = 0.042, for group slice structure hemisphere interaction). Poor outcome patients had smaller (196) striatal size (main effect of group, F = 5.87, df = 1, 35, p = 0.021) than good outcome patients (217), but other higher order interactions were not significant. Post hoc t-tests showed four areas significant, two-tailed: the right putamen (slice 1, t = 2.80, df = 1, 35, p = 0.008), right caudate (slice 3, t = 2.57, p = 0.014), right putamen (slice 3, t = 3.02, p = 0.005), right caudate (slice 5, t = 2.51, p = 0.016). 3.3. Age and age at first treatment Older normal volunteers had a smaller size of the caudate than younger volunteers (mean relative right caudate size vs. age, r = 0.53, df = 36, p = 0.001; left caudate, r = 0.42, p = 0.009) as well as the size of the putamen (r = 0.40, p = 0.015 and r = 0.07, p = ns, respectively). In patients with
schizophrenia, the age correlation was found for the left putamen (r = 0.54, p = 0.001) and mean of right and left putamen (r = 0.47, p = 0.005). Both the right and left putamen sizes were correlated with the age at which neuroleptics were first received (right putamen, r = 0.48, df = 36, p = 0.004; left putamen, r = 0.46, p = 0.006; mean of right and left, r = 0.50), indicating that individuals with larger putamens were treated at an earlier age. Post hoc analysis of the dorsal right putamen, since this was our strongest area of size difference, also revealed a significant correlation (r = 0.39, p = 0.024). Multiple regression to predict good vs. poor outcome with age, age of first neuroleptic treatment and volumes of dorsal putamen for the dorsalmost three slices was also significant with a significant beta weight for the mid-putamen slice [multiple R = 0.68, F = 2.96, df = 8, 27, p = 0.016, partial r for outcome vs. right mid-putamen (removing effects of age and age of first neuroleptic treatment) = 0.45, p = 0.01; beta weights right putamen, 0.51; age, 0.51; neuroleptic age, 0.51; other putamen levels had similar but not independently significant beta weights].
M.S. Buchsbaum et al. / Schizophrenia Research 64 (2003) 53–62
3.4. Caudate and putamen sizes and medication history There were no significant differences in type of medication treatment between the good and poor outcome patients. Analysis of predominant medication over the past 3 years as typical, atypical or both revealed similar distributions for good outcome patients (52%, 38%, 9%) and poor outcome patients (30%, 38%, 30%; chi-square = 2.9, df = 2, p = 0.23); the same analysis for time of scan (none, typical, atypical, both) also yielded nonsignificant distribution differences for good outcome patients (5%, 43%, 52%, 0%) and poor outcome patients (0%, 15%, 69%, 15%; chi-square = 6.1, df = 3, p = 0.10). There was no significant correlation between the number of years between first medication and the MRI scan (an approximate estimate of lifetime duration of medication treatment but uncorrected for the unknown number of months patients were unmedicated between first treatment and scan) in months and the absolute or relative size of the caudate or putamen. We also found no significant difference between patients on typical or atypical antipsychotic agents or both, currently or as predominant treatments over the past 3 years.
4. Discussion Striatal abnormalities have been extensively studied in patients with schizophrenia using techniques ranging from postmortem studies to structural and functional imaging. Striatal volume in schizophrenia has generally been found to be increased in patients who have been chronically medicated with neuroleptic medications and decreased in previously unmedicated patients, as we have reviewed elsewhere (Shihabuddin et al., 1998). We also found the dorsal right putamen (our region of greatest difference in the current study) to be smaller than control values to an equal extent in both never-medicated patients with schizophrenia and unmedicated patients with schizotypal personality disorder (Shihabuddin et al., 2001). While whole putamen volumes for never-medicated schizophrenic patients were not found smaller than control values in another study, in medicated patients, a correlation between both caudate and putamen
59
volumes and neuroleptic dose was found (Gur et al., 1998). However, not all studies have shown changes in striatal size with neuroleptic administration (Tauscher-Wisniewski et al., 2002) even after treatment for a year (Lang et al., 2001). These last authors investigated first-episode patients who qualified if they had received up to 12 weeks of treatment, so it is possible that size differences that might have been apparent in the patients when never previously treated were obscured by the first 12 weeks of medication. Other nonmedication-related factors might also possibly be involved. One study found increased putamen size in patients with schizophrenia who have antibodies to Borna disease virus (Waltrip et al., 1995). Our Kraepelinian patients are the most chronic patients who are in need of frequent lengthy hospitalization and are dependent on others for care. They usually are not responsive to medications and remain psychotic despite pharmacological interventions. These make them a unique population in which to study effects of medications on brain morphological changes. One might have expected them to have larger putamens because of the potential for longer and higher dose conventional neuroleptic treatment in this unresponsive group. Instead, their putamens were smaller than those of more responsive patients or normal controls. This suggests an association between drug responsiveness and striatal enlargement and the possibility that the widely observed striatal enlargement in medicated patients is associated with therapeutic improvement rather than merely a nonspecific effect of dopamine blockade. We were unable to show any significant relationship between duration of neuroleptic treatment or history of typical/atypical pharmacotherapy and putamen size, although the age at which neuroleptic treatment began was associated with smaller putamen size. The only two patients whose first neuroleptic treatments began before age 13 were in the poor outcome group. Less accuracy may be associated with the determination of age of onset than age of first neuroleptic treatment, but shifting diagnoses and lack of collateral information in older individuals limit rigorous interpretation of these historical data. However, the data were collected at a transitional therapeutic era when patients were being shifted from treatment with one or more conventional neuroleptics to atypical neuroleptics, so
60
M.S. Buchsbaum et al. / Schizophrenia Research 64 (2003) 53–62
calculating unambiguous ‘‘lifetime chlorpromazine equivalents’’ as computed in earlier studies was not really feasible or interpretable. Prospective studies in never previously medicated patients are necessary to fully address this issue, but the current data suggest the value of such longitudinal data and its potential for understanding individual differences in medication choice and response. Because the poor outcome patients had smaller putamens, it is necessary to consider the hypothesis that they were noncompliant in taking medications and actually ingested smaller doses of conventional neuroleptics than the good outcome patients. Our Kraepelinian patients are usually chronically hospitalized or living in a supervised setting where medications are administered to them, suggesting that their compliance might be equal to or better than that of unsupervised schizophrenics living independently. While it could be argued that some of these patients have been able to trick the staff and not take their psychiatric medications for many years, it does not seem likely that lifetime doses of neuroleptics were less on the average than in outpatients who had periods of noncompliance leading to successful inpatient treatment and release. It should be noted that we only reviewed records over the 3 years before imaging so that records were available on every patient; Kraepelinian patients might have had poorer medication compliance than non-Kraepelinian patients earlier in their illness. The only rigorous way to ensure that our findings are really related to medication exposures is by obtaining drug blood levels in a controlled dose monotherapy prospective study. Our finding of smaller putamens in poor outcome Kraepelinian patients following years of illness in the current sample might be associated with much smaller putamens at the onset of the illness than in good outcome patients. Because Kraepelinian patients have more severe psychopathology (Keefe et al., 1987), they might begin with greater size abnormalities and this might also contribute to their lesser responsiveness to typical neuroleptics (Harvey et al., 1991). While one report did not find first-episode patients to have small putamens (Gunduz et al., 2002), they traced the MRI on coronal sections and were not able to analyze dorsoventral levels separately as we did and were not able to assess effects limited to the dorsal or ventral striatum.
Our finding of smaller putamens in Kraepelinian patients might be associated with progressive loss of putamen volume in poor outcome Kraepelinian patients than good outcome non-Kraepelinian patients. Ventricular size has been shown to progressively enlarge over time in the poor outcome patients when compared to the good outcome patients, as reviewed elsewhere (Davis et al., 1998), and progressive enlargement was found associated with poor neuroleptic response patients (Garver et al., 1999). First episode studies of patients with schizophrenia tend to show less prominent reductions in the size of structures such as the hippocampus and temporal lobe (Niemann et al., 2000) than studies of more chronic patients, while ventricular size tends to be enlarged even in prodromal patients (Kurokawa et al., 2000). While longitudinal studies of medicated patients have not tended to confirm striatal size change (DeLisi et al., 1997) and postmortem studies have failed to find caudate neurodegeneration or neural injury (Falke et al., 2000), systematic prospective volumetric MRI studies relating drug response to disease-onset striatal size are not currently available. The greater effect in dorsal than ventral putamen is not easy to interpret because most receptor imaging studies have not provided statistical contrasts on the dorsoventral dimension. Elkashef et al. (2000) found DOPA uptake reduced in schizophrenics in dorsal caudate and ventral striatum, suggesting that our areas of volume reduction were the more normal DOPA uptake regions, although differences in region of interest methods make these comparisons limited. Nonresponders had less activation to neuroleptic treatment than responders in SPECT cerebral blood flow (Rodriguez et al., 1997) but dorsoventral contrasts were not provided. Our own studies also showed clinical improvement scores associated with greater FDG uptake in the striatum, and the largest correlation was between dorsal putamen increase and BPRS improvement ( 0.867) consistent with the dorsal rather than ventral putamen being important in clinical response (Buchsbaum et al., 1992). The limitations of this study include the lack of a premedication baseline scan and the heterogeneous medication treatment already noted above. In addition, additional examination of the striatum on coronal slices would have allowed anteroposterior dimensions of the caudate and the putamen to be evaluated.
M.S. Buchsbaum et al. / Schizophrenia Research 64 (2003) 53–62
Acknowledgements This work was supported by grants from the National Institute of Mental Health to Dr. Buchsbaum, ‘‘Normal metabolism and anatomy of the basal forebrain in man’’ (MH56489) and ‘‘Anatomy and function of the thalamus in schizophrenia’’ (MH60023) and by a VA Merit Award to Dr. Shihabuddin.
References Andreasen, N., Flaum, M., Arndt, S., 1992. The Comprehensive Assessment of Symptoms and History (CASH): an instrument for assessing diagnosis and psychopathology. Arch. Gen. Psychiatry 49, 615 – 623. Buchsbaum, M.S., Potkin, S.G., Marshall, J.F., Lottenberg, S., Teng, C., Heh, C.W., Tafalla, R., Reynolds, C., Abel, L., Plon, L., et al., 1992. Effects of clozapine and thiothixene on glucose metabolic rate in schizophrenia. Neuropsychopharmacology 6, 155 – 163. Buchsbaum, M.S., Hazlett, E.A., Haznedar, M.M., Spiegel-Cohen, J., Wei, T.C., 1999. Visualizing fronto-striatal circuitry and neuroleptic effects in schizophrenia. Acta Psychiatr. Scand., Suppl. 395, 129 – 137. Chakos, M., Lieberman, J., Bilder, R., 1994. Increase in caudate nuclei volume of first episode schizophrenia patients taking antipsychotic drugs. Am. J. Psychiatry 151, 1430 – 1436. Corson, P., Nopoulos, P., Miller, D., Arndt, S., Andreasen, N., 1999. Changes in basal ganglia volume over 2 years in patients with schizophrenia. Am. J. Psychiatry, 1200 – 1204. Davis, K.L., Buchsbaum, M.S., Shihabuddin, L., Spiegel-Cohen, J., Metzger, M., Frecska, E., Keefe, R.S., Powchik, P., 1998. Ventricular enlargement in poor-outcome schizophrenia. Biol. Psychiatry 43, 783 – 793. DeLisi, L.E., Sakuma, M., Tew, W., Kushner, M., Hoff, A.L., Grimson, R., 1997. Schizophrenia as a chronic active brain process: a study of progressive brain structural change subsequent to the onset of schizophrenia. Psychiatry Res. 74, 129 – 140. Elkashef, A.M., Doudet, D., Bryant, T., Cohen, R.M., Li, S.H., Wyatt, R.J., 2000. 6-(18)F-DOPA PET study in patients with schizophrenia. Positron emission tomography. Psychiatry Res. 100, 1 – 11. Falke, E., Han, L.Y., Arnold, S.E., 2000. Absence of neurodegeneration in the thalamus and caudate of elderly patients with schizophrenia. Psychiatry Res. 93, 103 – 110. Garver, D.L., Nair, T.R., Christensen, J.D., Holcomb, J., Ramberg, J., Kingsbury, S., 1999. Atrophic and static (neurodevelopmental) schizophrenic psychoses: premorbid functioning, symptoms and neuroleptic response. Neuropsychopharmacology 21, 82 – 92. Gunduz, H., Wu, H., Ashtari, M., Bogerts, B., Crandall, D., Robinson, D.G., Alvir, J., Lieberman, J., Kane, J., Bilder, R., 2002.
61
Basal ganglia volumes in first-episode schizophrenia and healthy comparison subjects. Biol. Psychiatry 51, 801 – 808. Gur, R., Maany, V., Mozley, P., Swanson, C., Bilker, W., Gur, R., 1998. Subcortical MRI volumes in neuroleptic-naive and treated patients with schizophrenia. Am. J. Psychiatry 155, 1711 – 1717. Harvey, P.D., Putnam, K.M., Davidson, M., Kahn, R.S., Powchik, P., McQueeney, R., Keefe, R.S., Davis, K.L., 1991. Brief neuroleptic discontinuation and clinical symptoms in Kraepelinian and non-Kraepelinian chronic schizophrenic patients. Psychiatry Res. 38, 285 – 292. Hokama, H., Shenton, M., Nestor, P., Kikinis, R., Levitt, J., Metcalf, D., Wible, C., O’Donnell, B., Jolesz, F., McCarley, R., 1995. Caudate, putamen and globus pallidus volume in schizophrenia. Psychiatry Res. Neuroimaging 61, 209 – 229. Kay, S.R., Fiszbein, A., Opler, L.A., 1987. The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr. Bull. 13, 261 – 276. Keefe, R.S., Mohs, R.C., Losonczy, M.F., Davidson, M., Silverman, J.M., Kendler, K.S., Horvath, T.B., Nora, R., Davis, K.L., 1987. Characteristics of very poor outcome schizophrenia. Am. J. Psychiatry 144, 889 – 895. Keshavan, M., Bagwell, W., Haas, G., Sweeney, J., Schooler, N., Pettegrew, J., 1994. Changes in caudate volume with neuroleptic treatment. Lancet 344, 1434. Kurokawa, K., Nakamura, K., Sumiyoshi, T., Hagino, H., Yotsutsuji, T., Yamashita, I., Suzuki, M., Matsui, M., Kurachi, M., 2000. Ventricular enlargement in schizophrenia spectrum patients with prodromal symptoms of obsessive-compulsive disorder. Psychiatry Res. 99, 83 – 91. Lang, D.J., Kopala, L.C., Vandorpe, R.A., Rui, Q., Smith, G.N., Goghari, V.M., Honer, W.G., 2001. An MRI study of basal ganglia volumes in first-episode schizophrenia patients treated with risperidone. Am. J. Psychiatry 158, 625 – 631. McCarley, R.W., Wible, C.G., Frumin, M., Hirayasu, Y., Levitt, J.J., Fischer, I.A., Shenton, M.E., 1999. MRI anatomy of schizophrenia. Biol. Psychiatry 45, 1099 – 1119. Menon, V., Anagnoson, R.T., Glover, G.H., Pfefferbaum, A., 2001. Functional magnetic resonance imaging evidence for disrupted basal ganglia function in schizophrenia. Am. J. Psychiatry 158, 646 – 649. Niemann, K., Hammers, A., Coenen, V.A., Thron, A., Klosterkotter, J., 2000. Evidence of a smaller left hippocampus and left temporal horn in both patients with first episode schizophrenia and normal control subjects. Psychiatry Res. 99, 93 – 110. Oldfield, R.C., 1971. The assessment and analysis of handedness: the Edinburgh inventory. Neuropsychologia 9, 97 – 113. Rodriguez, V.M., Andree, R.M., Castejon, M.J., Zamora, M.L., Alvaro, P.C., Delgado, J.L., Vila, F.J., 1997. Fronto-striato-thalamic perfusion and clozapine response in treatment-refractory schizophrenic patients. A 99mTc-HMPAO study. Psychiatry Res. 76, 51 – 61. Seidman, L.J., Faraone, S.V., Goldstein, J.M., Goodman, J.M., Kremen, W.S., Toomey, R., Tourville, J., Kennedy, D., Makris, N., Caviness, V.S., Tsuang, M.T., 1999. Thalamic and amygdalahippocampal volume reductions in first-degree relatives of patients with schizophrenia: an MRI-based morphometric analysis. Biol. Psychiatry 46, 941 – 954.
62
M.S. Buchsbaum et al. / Schizophrenia Research 64 (2003) 53–62
Shihabuddin, L., Buchsbaum, M., Hazlett, E., Haznedar, M., Harvey, P., Newman, A., Schnur, D., Spiegel-Cohen, J., Wei, T., Machac, J., Knesaurek, K., Vallabhojosula, S., Biren, M., Ciaravolo, T., Luu-Hsia, C., 1998. Dorsal striatal size, shape, and metabolic rate in neuroleptic-naive and previously medicated schizophrenic patients performing a verbal learning task. Arch. Gen. Psychiatry 55, 235 – 243. Shihabuddin, L., Buchsbaum, M., Hazlett, E., Silverman, J., New, A., Brickman, A., Mitropoulou, V., Nunn, M., Fleischman, M., Tang, C., Siever, L., 2001. Striatal size and relative glucose metabolic rate in schizotypal personality disorder and schizophrenia. Arch. Gen. Psychiatry 58, 877 – 884. Talairach, J., Tournoux, P., 1988. Co-planar Stereotaxic Atlas of the Human Brain Thieme, Stuttgart.
Tauscher-Wisniewski, S., Tauscher, J., Logan, J., Christensen, B., Mikulis, D., Zipursky, R., 2002. Caudate volume changes in first episode psychosis parallel the effects of normal aging: a 5-year follow-up study. Schizophr. Res. 58, 185 – 188. Volz, H., Gaser, C., Sauer, H., 2000. Supporting evidence for the model of cognitive dysmetria in schizophrenia—a structural magnetic resonance imaging study using deformation-based morphometry. Schizophr. Res. 46, 45 – 56. Waltrip II, R.W., Buchanan, R.W., Summerfelt, A., Breier, A., Carpenter Jr., W.T., Bryant, N.L., Rubin, S.A., Carbone, K.M., 1995. Borna disease virus and schizophrenia. Psychiatry Res. 56, 33 – 44.
Caudate and putamen volumes in good and poor outcome patients with schizophrenia Monte S. Buchsbaum a,*, Lina Shihabuddin b, Adam M. Brickman a, Ruben Miozzo a, Radovan Prikryl c, Robert Shaw a, Kenneth Davis a a
Department of Psychiatry, Mount Sinai School of Medicine, Box 1505, 1 Gustave L. Levy Place, New York, NY 10029-6574, USA b Bronx VA Medical Center, Bronx, NY, USA c Psychiatry Department of Faculty Hospital in Brno, Brno, Czech Republic Received 11 June 2002; received in revised form 11 November 2002; accepted 25 November 2002
Abstract Magnetic resonance images of 37 patients with schizophrenia and 37 age- and sex-matched volunteers were acquired. The caudate nucleus and putamen were traced on axial slices from the most superior extent of the caudate to the most inferior point where the caudate and putamen merge. Two subtypes of schizophrenia were compared, the Kraepelinian subtype (n = 13), characterized by an unremitting and severe course, and the non-Kraepelinian subtype (n = 24), characterized by a remitting course and some periods of self-care. Patients with good outcome schizophrenia had larger relative mean putamen size (0.0129) than poor outcome patients (0.0123) or normal controls (0.0121), but not caudate size. This enlargement was most marked for the dorsal putamen and right hemisphere. Striatal size was not related to whether patients were currently being treated with atypical or typical neuroleptics or whether they had been predominantly treated with typical or atypical neuroleptics over the past 3 years. This suggests the possibility that the expansion of putamen size may be a physiological correlate of neuroleptic responsiveness or that small putamen size at disease onset may be a predictor of outcome. D 2003 Elsevier Science B.V. All rights reserved. Keywords: Caudate; Putamen; Kraepelinian subtype
1. Introduction Striatal volume in schizophrenia has generally been found to be increased (Hokama et al., 1995), particularly in patients who have been chronically treated with neuroleptic medication, and decreased in * Corresponding author. Tel.: +1-212-241-5294; fax: +1-212423-0819. E-mail address: [email protected] (M.S. Buchsbaum).
never-medicated patients (McCarley et al., 1999; Shihabuddin et al., 1998). This volume increase has been hypothesized to reflect increased dopaminergic innervation, probably secondary to neuroleptic treatment or an interaction between neuroleptic treatment and the pathophysiology underlying schizophrenia, since two longitudinal MRI follow-up studies found progressive enlargement in striatal volume following neuroleptic treatment (Chakos et al., 1994; Keshavan et al., 1994). In our own recent study, reduced caudate volume was found in never-medicated schizophrenic
0920-9964/03/$ - see front matter D 2003 Elsevier Science B.V. All rights reserved. doi:10.1016/S0920-9964(02)00526-1
54
M.S. Buchsbaum et al. / Schizophrenia Research 64 (2003) 53–62
patients compared to controls, and increased (relative to normal control values) dorsal putamen volume was found in previously medicated patients (Shihabuddin et al., 1998). Similar findings were reported in other subsequent studies (Corson et al., 1999; Gur et al., 1998), including greater increases in putamen than caudate in previously medicated patients (Gur et al., 1998). Interestingly, patients with schizotypal personality disorder had smaller putamens than either previously medicated patients with schizophrenia or controls (Shihabuddin et al., 2001). Image analysis using deformation-based morphometry also revealed increased putamen but not caudate size (Volz et al., 2000), and a recent MRI study demonstrated functional deficits in putamen but not caudate (Menon et al., 2001). Relatives of patients with schizophrenia also had smaller putamens, although only when gender and brain size were treated as controlled factors (Seidman et al., 1999). We hypothesized that putamen, and possibly caudate size, would be larger in patients with better outcome schizophrenia who responded to neuroleptics than in poor outcome patients who failed to respond. To address dorsoventral gradients in volume, we used high-resolution MRI to assess caudate and putamen volumes at five standardized proportional levels.
2. Methods 2.1. Subjects Thirty-seven patients (27 men, 10 women; ages [years]: M = 43, S.D. = 11.9, range = 20 –66; education [years]: M = 12.6, S.D. = 1.9) were recruited from the Mount Sinai and Bronx VA hospitals as well as the Pilgrim Psychiatric Center. Thirty-six patients were right-handed and one was ambidextrous, based on the Edinburgh Handedness Inventory (Oldfield, 1971). The patients were evaluated with the Comprehensive Assessment of Symptoms and History (CASH) (Andreasen et al., 1992) and diagnosed as having schizophrenia (n = 36) or schizoaffective disorder (n = 1) according to the DSM-IV criteria. The mean age of onset for these 37 patients is 21 (S.D. = 6.9) and the mean age for beginning neuroleptics is 25.6 (S.D. = 10.9). The patients’ mean number of hospitalizations (in months) is 40.4 (S.D. = 65). The onset age,
age of beginning neuroleptics and number of hospitalizations were not available for one of the patients. A battery of rating scales was administered on the week of the scan, including the Positive and Negative Syndrome Scale (PANSS; Kay et al., 1987). The psychopathology subscale scores were as follows: Positive (M = 21, S.D. = 9.8); Negative (M = 18, S.D. = 7.2); General (M = 33.3, S.D. = 12). The PANSS scores were not obtainable for one of the patients. 2.2. Group divisions and normal volunteers In addition, the schizophrenic patients were subdivided into poor outcome or Kraepelinian (n = 13) and good outcome or non-Kraepelinian (n = 24), as described elsewhere (Keefe et al., 1987). The Kraepelinian subgroups were characterized by continuous hospitalization or complete dependence for basic needs, unemployment and no evidence of remission of symptoms (Davis et al., 1998). This sample did not overlap with samples reported earlier (Buchsbaum et al., 1999; Shihabuddin et al., 2001). The poor and good outcome groups did not differ in age (47, S.D. = 9.0 vs. 41, S.D. = 12.1, t = 1.50, respectively) and age at which neuroleptic treatments began (22.2, S.D. = 13.8 vs. 26.8, S.D. = 6.4, t = 1.36, p = ns). The poor outcome patients, in comparison to good outcome patients, had an earlier age of onset (17.8, S.D. = 6.2 vs. 22.9, S.D. = 6.7, t = 2.21, p = 0.033) and higher scores on the PANSS Positive, Negative and General scales (27.6 vs. 17.3, 21.5 vs. 15.9 and 39.5 vs. 29.6, respectively, all t>2.3, p < 0.02). Medication history was evaluated by review of charts for the past 3 years. Since the majority of patients had changed medication type and dosage at least once during the past 3 years and multiple neuroleptic dosage was also common, simple characterization of the patients’ treatment history in chlorpromazine equivalents was not feasible. Therefore, to evaluate drug effects, we coded patients for the time of the MRI scan and for the predominant pattern over the past 3 years as off medication, typical neuroleptics, atypical neuroleptics and both. Thirty-seven normal volunteers (23 men, 14 women; ages [years]: M = 44.1, S.D. = 13.7, range = 22 –85; education [years]: M = 16, S.D. = 3.2) were recruited by word of mouth or advertisement. Thirty-
M.S. Buchsbaum et al. / Schizophrenia Research 64 (2003) 53–62
55
four controls were right-handed and two were lefthanded, based on the Edinburgh Handedness Inventory (Oldfield, 1971). All of the 37 normal controls were given a CASH interview to exclude history of psychiatric illness in themselves or in their firstdegree relatives.
the caudate and putamen are entirely merged. This distance was divided by six to yield five equally spaced slices for the caudate and putamen separately (Fig. 2) for tracing (e.g., most dorsal slice = 20, most ventral slice = 38, difference = 18, 18/6 = 3, slices 23, 26, 29, 32 and 35 are traced).
2.3. Image acquisition
2.5. Statistics
MRI acquisition used the Signa 5 system (GE Medical Systems, Milwaukee, WI) with a 3D-SPGR sequence (TR = 24 ms, TE = 5 ms, flip angle = 40j and slice thickness = 1.2 mm, matrix size 256 256).
Repeated-measures ANOVA or MANOVA was used in diagnostic group comparisons. Groups were independent dimensions for the whole population (schizophrenia, normal volunteers) and for good/poor outcome subgroups. Repeated measures were region (caudate, putamen), hemisphere (right, left), and slice level (1– 5, corresponding to 20 to 4 mm; Talairach and Tournoux, 1988). Group region and higher order interactions were examined to establish regional differences. Follow-up simple interactions were performed to identify the strongest sources of group interactions. We computed absolute size in cubic millimeters and relative size as the ratio of area of ROI/area of slice.
2.4. Automated edge finding An automated boundary-finding method based on the Sobel gradient filter provides a reproducible structure edge, with little operator variability (Shihabuddin et al., 1998). The caudate and putamen were outlined on the MRI by depositing points by mouse on the magnified and enhanced white structure edge using a semiautomated 3 3 local pixel maximum search. This placed the point at the center of the edge, enhancing interoperator consistency (Fig. 1). A spline curve was fit to the points and the ROI edge stored. Two tracers’ independent tracing of 10 subjects yielded ICC of 0.92 for the caudate and 0.98 for the putamen area. We determined the top of the caudate and putamen as the most dorsal axial slice showing a visible gray patch and the bottom as the slice in which
3. Results 3.1. Relative caudate and putamen sizes Patients with good outcome schizophrenia had larger relative mean putamen size (0.0129) than poor
Fig. 1. Left: Gradient filter transformed axial SPGR MRI slice. Dots indicate enhanced outline of putamen. Dots are placed on computerenhanced edge visually and adjusted by algorithm to fall on local (3 3 search maximum), and spline curve is fit to produce outline. If there are minor breaks in the outline, points are placed on either side of the break but not within the break. Outline values contain the two x coordinates for every y value and the MRI intensity values for every pixel within the outline. Right: Original MRI with dots.
56
M.S. Buchsbaum et al. / Schizophrenia Research 64 (2003) 53–62
M.S. Buchsbaum et al. / Schizophrenia Research 64 (2003) 53–62
57
Fig. 3. Relative putamen size in controls, poor and good outcome patients.
outcome patients (0.0123) or normal controls (0.0121), but not caudate size (group structure interaction, F = 3.77, df = 2, 71, p = 0.028). This enlargement was most marked for the dorsal putamen and right hemisphere (group slice structure hemisphere, F = 2.17, df = 8, 284, p = 0.030; Rao’s R = 2.31, p < 0.023, df = 8, 126). The main effect of diagnostic group was not significant, indicating that the effect was not general across the entire striatum. Follow-up tests for the caudate and putamen (Fig. 3) separately indicated that the putamen differences between good and poor outcome patients were significant (Rao’s R = 2.07, df = 8, 136, p = 0.043). Patients with schizophrenia had larger putamens than normal controls, whereas caudate sizes were similar (group region ventrodorsal level, F = 3.07,
df = 4, 288, p = 0.017; but Rao’s R = 2.17, df = 4, 69, p = 0.08; Fig. 4). Across caudate and putamen considered together, patients had larger dorsal area than normals ( F = 7.33, df = 1, 72, p = 0.0085). Post hoc ttests identified the difference in putamen sizes between normals (0.009, S.D. = 0.0020) and patients with schizophrenia (0.11, S.D. = 0.0021) to be greatest for the right dorsalmost slice (0.011, S.D. = 0.0021, t = 3.36, p = 0.0012); other individual slice levels did not reach statistical significance. 3.2. Absolute caudate and putamen sizes Patients with schizophrenia had larger putamens than normals, while caudate differences were small (Fig. 4, group structure dorsoventral level inter-
Fig. 2. Cortical levels and striatal tracing. Slices that contain the dorsalmost and ventralmost slice containing the caudate and putamen on the right and the left side are identified. Dorsally, this is the highest slice on which the head of the caudate is visible, and ventrally, the last. The interval is divided by the number of desired levels (5) plus 1. This 1/6 step, correct to three decimal places, is then added to the initial slice level and the number truncated to yield the first traceable slice. Five steps are generated in this way. Only slice levels containing a selected striatal outline are shown in the illustration. Note that this sometimes results in the left and right sides not being traced on the same slice level but creates a systematic set of five outlines placed proportionately in the caudate and putamen and suitable for multiway repeated-measures ANOVA. Absolute size can be generated by multiplying each slice area by the actual slice spacing. A program allows quick inspection of all striatal edges on all slice levels with a distinctive color for each region to facilitate checking of tracing quality and accuracy of hemisphere and structure filenaming.
58
M.S. Buchsbaum et al. / Schizophrenia Research 64 (2003) 53–62
Fig. 4. Increased size of putamen but not caudate in schizophrenia.
action, F = 2.99, df = 4, 288, p = 0.019). Good outcome patients had the largest putamen size (group structure interaction, F = 3.95, df = 2, 71, p = 0.023) and this was more marked at dorsal levels and in the right hemisphere (Rao’s R = 2.08, df = 8, 136, p = 0.042, for group slice structure hemisphere interaction). Poor outcome patients had smaller (196) striatal size (main effect of group, F = 5.87, df = 1, 35, p = 0.021) than good outcome patients (217), but other higher order interactions were not significant. Post hoc t-tests showed four areas significant, two-tailed: the right putamen (slice 1, t = 2.80, df = 1, 35, p = 0.008), right caudate (slice 3, t = 2.57, p = 0.014), right putamen (slice 3, t = 3.02, p = 0.005), right caudate (slice 5, t = 2.51, p = 0.016). 3.3. Age and age at first treatment Older normal volunteers had a smaller size of the caudate than younger volunteers (mean relative right caudate size vs. age, r = 0.53, df = 36, p = 0.001; left caudate, r = 0.42, p = 0.009) as well as the size of the putamen (r = 0.40, p = 0.015 and r = 0.07, p = ns, respectively). In patients with
schizophrenia, the age correlation was found for the left putamen (r = 0.54, p = 0.001) and mean of right and left putamen (r = 0.47, p = 0.005). Both the right and left putamen sizes were correlated with the age at which neuroleptics were first received (right putamen, r = 0.48, df = 36, p = 0.004; left putamen, r = 0.46, p = 0.006; mean of right and left, r = 0.50), indicating that individuals with larger putamens were treated at an earlier age. Post hoc analysis of the dorsal right putamen, since this was our strongest area of size difference, also revealed a significant correlation (r = 0.39, p = 0.024). Multiple regression to predict good vs. poor outcome with age, age of first neuroleptic treatment and volumes of dorsal putamen for the dorsalmost three slices was also significant with a significant beta weight for the mid-putamen slice [multiple R = 0.68, F = 2.96, df = 8, 27, p = 0.016, partial r for outcome vs. right mid-putamen (removing effects of age and age of first neuroleptic treatment) = 0.45, p = 0.01; beta weights right putamen, 0.51; age, 0.51; neuroleptic age, 0.51; other putamen levels had similar but not independently significant beta weights].
M.S. Buchsbaum et al. / Schizophrenia Research 64 (2003) 53–62
3.4. Caudate and putamen sizes and medication history There were no significant differences in type of medication treatment between the good and poor outcome patients. Analysis of predominant medication over the past 3 years as typical, atypical or both revealed similar distributions for good outcome patients (52%, 38%, 9%) and poor outcome patients (30%, 38%, 30%; chi-square = 2.9, df = 2, p = 0.23); the same analysis for time of scan (none, typical, atypical, both) also yielded nonsignificant distribution differences for good outcome patients (5%, 43%, 52%, 0%) and poor outcome patients (0%, 15%, 69%, 15%; chi-square = 6.1, df = 3, p = 0.10). There was no significant correlation between the number of years between first medication and the MRI scan (an approximate estimate of lifetime duration of medication treatment but uncorrected for the unknown number of months patients were unmedicated between first treatment and scan) in months and the absolute or relative size of the caudate or putamen. We also found no significant difference between patients on typical or atypical antipsychotic agents or both, currently or as predominant treatments over the past 3 years.
4. Discussion Striatal abnormalities have been extensively studied in patients with schizophrenia using techniques ranging from postmortem studies to structural and functional imaging. Striatal volume in schizophrenia has generally been found to be increased in patients who have been chronically medicated with neuroleptic medications and decreased in previously unmedicated patients, as we have reviewed elsewhere (Shihabuddin et al., 1998). We also found the dorsal right putamen (our region of greatest difference in the current study) to be smaller than control values to an equal extent in both never-medicated patients with schizophrenia and unmedicated patients with schizotypal personality disorder (Shihabuddin et al., 2001). While whole putamen volumes for never-medicated schizophrenic patients were not found smaller than control values in another study, in medicated patients, a correlation between both caudate and putamen
59
volumes and neuroleptic dose was found (Gur et al., 1998). However, not all studies have shown changes in striatal size with neuroleptic administration (Tauscher-Wisniewski et al., 2002) even after treatment for a year (Lang et al., 2001). These last authors investigated first-episode patients who qualified if they had received up to 12 weeks of treatment, so it is possible that size differences that might have been apparent in the patients when never previously treated were obscured by the first 12 weeks of medication. Other nonmedication-related factors might also possibly be involved. One study found increased putamen size in patients with schizophrenia who have antibodies to Borna disease virus (Waltrip et al., 1995). Our Kraepelinian patients are the most chronic patients who are in need of frequent lengthy hospitalization and are dependent on others for care. They usually are not responsive to medications and remain psychotic despite pharmacological interventions. These make them a unique population in which to study effects of medications on brain morphological changes. One might have expected them to have larger putamens because of the potential for longer and higher dose conventional neuroleptic treatment in this unresponsive group. Instead, their putamens were smaller than those of more responsive patients or normal controls. This suggests an association between drug responsiveness and striatal enlargement and the possibility that the widely observed striatal enlargement in medicated patients is associated with therapeutic improvement rather than merely a nonspecific effect of dopamine blockade. We were unable to show any significant relationship between duration of neuroleptic treatment or history of typical/atypical pharmacotherapy and putamen size, although the age at which neuroleptic treatment began was associated with smaller putamen size. The only two patients whose first neuroleptic treatments began before age 13 were in the poor outcome group. Less accuracy may be associated with the determination of age of onset than age of first neuroleptic treatment, but shifting diagnoses and lack of collateral information in older individuals limit rigorous interpretation of these historical data. However, the data were collected at a transitional therapeutic era when patients were being shifted from treatment with one or more conventional neuroleptics to atypical neuroleptics, so
60
M.S. Buchsbaum et al. / Schizophrenia Research 64 (2003) 53–62
calculating unambiguous ‘‘lifetime chlorpromazine equivalents’’ as computed in earlier studies was not really feasible or interpretable. Prospective studies in never previously medicated patients are necessary to fully address this issue, but the current data suggest the value of such longitudinal data and its potential for understanding individual differences in medication choice and response. Because the poor outcome patients had smaller putamens, it is necessary to consider the hypothesis that they were noncompliant in taking medications and actually ingested smaller doses of conventional neuroleptics than the good outcome patients. Our Kraepelinian patients are usually chronically hospitalized or living in a supervised setting where medications are administered to them, suggesting that their compliance might be equal to or better than that of unsupervised schizophrenics living independently. While it could be argued that some of these patients have been able to trick the staff and not take their psychiatric medications for many years, it does not seem likely that lifetime doses of neuroleptics were less on the average than in outpatients who had periods of noncompliance leading to successful inpatient treatment and release. It should be noted that we only reviewed records over the 3 years before imaging so that records were available on every patient; Kraepelinian patients might have had poorer medication compliance than non-Kraepelinian patients earlier in their illness. The only rigorous way to ensure that our findings are really related to medication exposures is by obtaining drug blood levels in a controlled dose monotherapy prospective study. Our finding of smaller putamens in poor outcome Kraepelinian patients following years of illness in the current sample might be associated with much smaller putamens at the onset of the illness than in good outcome patients. Because Kraepelinian patients have more severe psychopathology (Keefe et al., 1987), they might begin with greater size abnormalities and this might also contribute to their lesser responsiveness to typical neuroleptics (Harvey et al., 1991). While one report did not find first-episode patients to have small putamens (Gunduz et al., 2002), they traced the MRI on coronal sections and were not able to analyze dorsoventral levels separately as we did and were not able to assess effects limited to the dorsal or ventral striatum.
Our finding of smaller putamens in Kraepelinian patients might be associated with progressive loss of putamen volume in poor outcome Kraepelinian patients than good outcome non-Kraepelinian patients. Ventricular size has been shown to progressively enlarge over time in the poor outcome patients when compared to the good outcome patients, as reviewed elsewhere (Davis et al., 1998), and progressive enlargement was found associated with poor neuroleptic response patients (Garver et al., 1999). First episode studies of patients with schizophrenia tend to show less prominent reductions in the size of structures such as the hippocampus and temporal lobe (Niemann et al., 2000) than studies of more chronic patients, while ventricular size tends to be enlarged even in prodromal patients (Kurokawa et al., 2000). While longitudinal studies of medicated patients have not tended to confirm striatal size change (DeLisi et al., 1997) and postmortem studies have failed to find caudate neurodegeneration or neural injury (Falke et al., 2000), systematic prospective volumetric MRI studies relating drug response to disease-onset striatal size are not currently available. The greater effect in dorsal than ventral putamen is not easy to interpret because most receptor imaging studies have not provided statistical contrasts on the dorsoventral dimension. Elkashef et al. (2000) found DOPA uptake reduced in schizophrenics in dorsal caudate and ventral striatum, suggesting that our areas of volume reduction were the more normal DOPA uptake regions, although differences in region of interest methods make these comparisons limited. Nonresponders had less activation to neuroleptic treatment than responders in SPECT cerebral blood flow (Rodriguez et al., 1997) but dorsoventral contrasts were not provided. Our own studies also showed clinical improvement scores associated with greater FDG uptake in the striatum, and the largest correlation was between dorsal putamen increase and BPRS improvement ( 0.867) consistent with the dorsal rather than ventral putamen being important in clinical response (Buchsbaum et al., 1992). The limitations of this study include the lack of a premedication baseline scan and the heterogeneous medication treatment already noted above. In addition, additional examination of the striatum on coronal slices would have allowed anteroposterior dimensions of the caudate and the putamen to be evaluated.
M.S. Buchsbaum et al. / Schizophrenia Research 64 (2003) 53–62
Acknowledgements This work was supported by grants from the National Institute of Mental Health to Dr. Buchsbaum, ‘‘Normal metabolism and anatomy of the basal forebrain in man’’ (MH56489) and ‘‘Anatomy and function of the thalamus in schizophrenia’’ (MH60023) and by a VA Merit Award to Dr. Shihabuddin.
References Andreasen, N., Flaum, M., Arndt, S., 1992. The Comprehensive Assessment of Symptoms and History (CASH): an instrument for assessing diagnosis and psychopathology. Arch. Gen. Psychiatry 49, 615 – 623. Buchsbaum, M.S., Potkin, S.G., Marshall, J.F., Lottenberg, S., Teng, C., Heh, C.W., Tafalla, R., Reynolds, C., Abel, L., Plon, L., et al., 1992. Effects of clozapine and thiothixene on glucose metabolic rate in schizophrenia. Neuropsychopharmacology 6, 155 – 163. Buchsbaum, M.S., Hazlett, E.A., Haznedar, M.M., Spiegel-Cohen, J., Wei, T.C., 1999. Visualizing fronto-striatal circuitry and neuroleptic effects in schizophrenia. Acta Psychiatr. Scand., Suppl. 395, 129 – 137. Chakos, M., Lieberman, J., Bilder, R., 1994. Increase in caudate nuclei volume of first episode schizophrenia patients taking antipsychotic drugs. Am. J. Psychiatry 151, 1430 – 1436. Corson, P., Nopoulos, P., Miller, D., Arndt, S., Andreasen, N., 1999. Changes in basal ganglia volume over 2 years in patients with schizophrenia. Am. J. Psychiatry, 1200 – 1204. Davis, K.L., Buchsbaum, M.S., Shihabuddin, L., Spiegel-Cohen, J., Metzger, M., Frecska, E., Keefe, R.S., Powchik, P., 1998. Ventricular enlargement in poor-outcome schizophrenia. Biol. Psychiatry 43, 783 – 793. DeLisi, L.E., Sakuma, M., Tew, W., Kushner, M., Hoff, A.L., Grimson, R., 1997. Schizophrenia as a chronic active brain process: a study of progressive brain structural change subsequent to the onset of schizophrenia. Psychiatry Res. 74, 129 – 140. Elkashef, A.M., Doudet, D., Bryant, T., Cohen, R.M., Li, S.H., Wyatt, R.J., 2000. 6-(18)F-DOPA PET study in patients with schizophrenia. Positron emission tomography. Psychiatry Res. 100, 1 – 11. Falke, E., Han, L.Y., Arnold, S.E., 2000. Absence of neurodegeneration in the thalamus and caudate of elderly patients with schizophrenia. Psychiatry Res. 93, 103 – 110. Garver, D.L., Nair, T.R., Christensen, J.D., Holcomb, J., Ramberg, J., Kingsbury, S., 1999. Atrophic and static (neurodevelopmental) schizophrenic psychoses: premorbid functioning, symptoms and neuroleptic response. Neuropsychopharmacology 21, 82 – 92. Gunduz, H., Wu, H., Ashtari, M., Bogerts, B., Crandall, D., Robinson, D.G., Alvir, J., Lieberman, J., Kane, J., Bilder, R., 2002.
61
Basal ganglia volumes in first-episode schizophrenia and healthy comparison subjects. Biol. Psychiatry 51, 801 – 808. Gur, R., Maany, V., Mozley, P., Swanson, C., Bilker, W., Gur, R., 1998. Subcortical MRI volumes in neuroleptic-naive and treated patients with schizophrenia. Am. J. Psychiatry 155, 1711 – 1717. Harvey, P.D., Putnam, K.M., Davidson, M., Kahn, R.S., Powchik, P., McQueeney, R., Keefe, R.S., Davis, K.L., 1991. Brief neuroleptic discontinuation and clinical symptoms in Kraepelinian and non-Kraepelinian chronic schizophrenic patients. Psychiatry Res. 38, 285 – 292. Hokama, H., Shenton, M., Nestor, P., Kikinis, R., Levitt, J., Metcalf, D., Wible, C., O’Donnell, B., Jolesz, F., McCarley, R., 1995. Caudate, putamen and globus pallidus volume in schizophrenia. Psychiatry Res. Neuroimaging 61, 209 – 229. Kay, S.R., Fiszbein, A., Opler, L.A., 1987. The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr. Bull. 13, 261 – 276. Keefe, R.S., Mohs, R.C., Losonczy, M.F., Davidson, M., Silverman, J.M., Kendler, K.S., Horvath, T.B., Nora, R., Davis, K.L., 1987. Characteristics of very poor outcome schizophrenia. Am. J. Psychiatry 144, 889 – 895. Keshavan, M., Bagwell, W., Haas, G., Sweeney, J., Schooler, N., Pettegrew, J., 1994. Changes in caudate volume with neuroleptic treatment. Lancet 344, 1434. Kurokawa, K., Nakamura, K., Sumiyoshi, T., Hagino, H., Yotsutsuji, T., Yamashita, I., Suzuki, M., Matsui, M., Kurachi, M., 2000. Ventricular enlargement in schizophrenia spectrum patients with prodromal symptoms of obsessive-compulsive disorder. Psychiatry Res. 99, 83 – 91. Lang, D.J., Kopala, L.C., Vandorpe, R.A., Rui, Q., Smith, G.N., Goghari, V.M., Honer, W.G., 2001. An MRI study of basal ganglia volumes in first-episode schizophrenia patients treated with risperidone. Am. J. Psychiatry 158, 625 – 631. McCarley, R.W., Wible, C.G., Frumin, M., Hirayasu, Y., Levitt, J.J., Fischer, I.A., Shenton, M.E., 1999. MRI anatomy of schizophrenia. Biol. Psychiatry 45, 1099 – 1119. Menon, V., Anagnoson, R.T., Glover, G.H., Pfefferbaum, A., 2001. Functional magnetic resonance imaging evidence for disrupted basal ganglia function in schizophrenia. Am. J. Psychiatry 158, 646 – 649. Niemann, K., Hammers, A., Coenen, V.A., Thron, A., Klosterkotter, J., 2000. Evidence of a smaller left hippocampus and left temporal horn in both patients with first episode schizophrenia and normal control subjects. Psychiatry Res. 99, 93 – 110. Oldfield, R.C., 1971. The assessment and analysis of handedness: the Edinburgh inventory. Neuropsychologia 9, 97 – 113. Rodriguez, V.M., Andree, R.M., Castejon, M.J., Zamora, M.L., Alvaro, P.C., Delgado, J.L., Vila, F.J., 1997. Fronto-striato-thalamic perfusion and clozapine response in treatment-refractory schizophrenic patients. A 99mTc-HMPAO study. Psychiatry Res. 76, 51 – 61. Seidman, L.J., Faraone, S.V., Goldstein, J.M., Goodman, J.M., Kremen, W.S., Toomey, R., Tourville, J., Kennedy, D., Makris, N., Caviness, V.S., Tsuang, M.T., 1999. Thalamic and amygdalahippocampal volume reductions in first-degree relatives of patients with schizophrenia: an MRI-based morphometric analysis. Biol. Psychiatry 46, 941 – 954.
62
M.S. Buchsbaum et al. / Schizophrenia Research 64 (2003) 53–62
Shihabuddin, L., Buchsbaum, M., Hazlett, E., Haznedar, M., Harvey, P., Newman, A., Schnur, D., Spiegel-Cohen, J., Wei, T., Machac, J., Knesaurek, K., Vallabhojosula, S., Biren, M., Ciaravolo, T., Luu-Hsia, C., 1998. Dorsal striatal size, shape, and metabolic rate in neuroleptic-naive and previously medicated schizophrenic patients performing a verbal learning task. Arch. Gen. Psychiatry 55, 235 – 243. Shihabuddin, L., Buchsbaum, M., Hazlett, E., Silverman, J., New, A., Brickman, A., Mitropoulou, V., Nunn, M., Fleischman, M., Tang, C., Siever, L., 2001. Striatal size and relative glucose metabolic rate in schizotypal personality disorder and schizophrenia. Arch. Gen. Psychiatry 58, 877 – 884. Talairach, J., Tournoux, P., 1988. Co-planar Stereotaxic Atlas of the Human Brain Thieme, Stuttgart.
Tauscher-Wisniewski, S., Tauscher, J., Logan, J., Christensen, B., Mikulis, D., Zipursky, R., 2002. Caudate volume changes in first episode psychosis parallel the effects of normal aging: a 5-year follow-up study. Schizophr. Res. 58, 185 – 188. Volz, H., Gaser, C., Sauer, H., 2000. Supporting evidence for the model of cognitive dysmetria in schizophrenia—a structural magnetic resonance imaging study using deformation-based morphometry. Schizophr. Res. 46, 45 – 56. Waltrip II, R.W., Buchanan, R.W., Summerfelt, A., Breier, A., Carpenter Jr., W.T., Bryant, N.L., Rubin, S.A., Carbone, K.M., 1995. Borna disease virus and schizophrenia. Psychiatry Res. 56, 33 – 44.