Poor outcome in chronic schizophrenia is associated with progressive loss of volume of the putamen
Introduction
Striatal abnormalities have been postulated and described in patients with schizophrenia, but, as attested by their recent review (Brandt and Bonelli, 2008), still remain inconclusive. While most of the first-episode schizophrenia studies reported normal volumes of the caudate nucleus, with only a third revealing volumetric reductions, findings in chronic schizophrenia patients were equally divided between its enlargement and no volumetric change. Fewer studies have assessed volumes of the putamen, but with near unanimity in reporting no changes in first-episode and putaminal enlargement in chronic schizophrenia patients. Given these indications of striatal expansion in chronic schizophrenia and the rich dopaminergic innervation of the basal ganglia, a relationship between the acute exposure to antipsychotic agents and striatal enlargement has been proposed, with differential effects from the typical and atypical antipsychotics (Shihabuddin et al., 1998). Whether typical vs. atypical affiliation of the agents plays a differential role in striatal changes in the long run has not been firmly established (Gur et al., 1998, Mamah et al., 2007, Navari and Dazzan, in press, Zhou et al., 2003). Several short-term longitudinal studies appear to support enlargement of the caudate nucleus in first-episode and chronic schizophrenia patients following exposure to typical neuroleptic agents (Chakos et al., 1994, Keshavan et al., 1994, Lieberman et al., 2001) and atypical agents (Massana et al., 2005, Okugawa et al., 2007), others revealed no progressive changes or even decline in its density with mostly atypical agents (Glenthoj et al., 2007, Heitmiller et al., 2004, Lang et al., 2001, McClure et al., 2008, Stip et al., 2008, Tauscher-Wisniewski et al., 2005) and a typical agent (Glenthoj et al., 2007), or its enlargement with the typical and shrinkage with the atypical neuroleptization (Chakos et al., 1995, Corson et al., 1999, Lang et al., 2004, Scheepers et al., 2001). Two longer-term studies that compared schizophrenia patients and healthy subjects found no progressive changes in the caudate nucleus or decline in its density (DeLisi et al., 1997, van Haren et al., 2007) in patients over at least 4 years of follow-up. Brief exposure of schizophrenia patients to quetiapine was reported to result in decreased putaminal density (Stip et al., 2008) and to risperidone — in putaminal enlargement (Glenthoj et al., 2007), but the single longitudinal assessment of the putamen with normal control group published to date uncovered no morphometric differences between schizophrenia patients and healthy comparison subjects (Wang et al., 2008).
We previously reported larger putamens in schizophrenia patients with good outcome than poor-outcome (Kraepelinian) patients and proposed that rather than being a consequence of prolonged neuroleptic exposure putaminal enlargement may be a marker of responsiveness to antipsychotic treatment with the corollary that its shrinkage may be associated with poor clinical outcome (Buchsbaum et al., 2003). In the present study, we followed a cohort of chronic good-outcome and poor-outcome schizophrenia patients over a four-year period in order to compare longitudinal progression of volumes of both the caudate nucleus and putamen.
Section snippets
Subjects
49 patients with schizophrenia (age at baseline scan 42.69 ± 12.29 years) and 16 healthy subjects (age at baseline 41.63 ± 12.23 years, t63 = 0.30, p = ns) were scanned twice approximately 4 years apart (4.10 ± 0.54 years for schizophrenia patients and 4.22 ± 0.52 years for healthy subjects, t63 = 0.76, p = ns; see full sample description in Mitelman et al., 2009). Schizophrenia patients and healthy subjects did not significantly differ in major demographic characteristics. Based on the predominant pattern of
Results
At baseline, there were no significant differences in absolute and relative volumes of the caudate nucleus or putamen among any of the compared groups (Table 1). There was a trend towards lower relative right caudate volumes in schizophrenia patients than in healthy subjects (F1, 62 = 3.87, p = 0.054).
Absolute and relative volumes of the caudate nucleus and putamen dwindled over the time to follow-up in both schizophrenia patients and healthy subjects, with no significant between-group differences
Discussion
Poor outcome in patients with chronic schizophrenia is associated with a more pronounced shrinkage of the putamen, which begins approximately two decades after the onset of the disease. We have recently demonstrated that in contrast to the deceleration of cortical gray matter decline with age in this cohort of patients with good outcome, cortical shrinkage in the poor-outcome group as they age remains unabated (Mitelman et al., 2009). Present results may suggest the dynamic spread of
Role of funding source
The funding agencies had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication.
Contributors
Serge A. Mitelman participated in image processing, analyzed the data and wrote the manuscript. Emily L. Canfield and King-Wai Chu participated in image processing and analysis. Adam M. Brickman, Erin A. Hazlett and Lina Shihabuddin organized subject recruitment and scanning. Monte S. Buchsbaum designed the study and supervised image acquisition, processing and analysis.
Conflict of interest
The authors have no potential conflicts of interests to disclose.
Acknowledgements
This work was supported by NARSAD Young Investigator Award and NIMH MH 077146 grant to Serge A. Mitelman and by NIMH grants P50 MH 66392-01, MH 60023, and MH 56489 to Monte S. Buchsbaum.
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