Effects of clozapine and olanzapine on cortical thickness in childhood-onset schizophrenia
Introduction
Clozapine was the first atypical antipsychotic agent to be discovered and was the landmark in schizophrenia treatment due to its efficacy in treatment-refractory cases (Kane et al., 1988a). Despite the availability of many newer atypical agents with less detrimental side effect profiles, clozapine remains the most effective medication for treatment resistant schizophrenia (Kane et al., 1988b, Kane, 1992, Mcevoy et al., 2006). Childhood-onset schizophrenia (COS), the rare and severe pediatric form of the illness, is generally treatment-refractory. Thus, the majority of patients end up on clozapine (Gogtay and Rapoport, 2008). In the only head-to-head double-blind comparison trial of two atypical antipsychotic medications in COS, clozapine showed overall superiority to the atypical antipsychotic olanzapine (Shaw et al., 2006). The mechanism for this result remains unclear.
Progressive gray matter (GM) abnormalities are an established feature of schizophrenia. However, it remains unclear whether ongoing medication treatment influences cortical GM loss (Delisi et al., 2006, Gogtay, 2008). First-episode studies in adults and medication-naïve patients (Pantelis et al., 2003) with schizophrenia suggest that cortical abnormalities are likely to either precede or coincide with onset of psychosis and thus are less likely to be induced by medication (Hazlett et al., 2008). Studies in healthy first-degree relatives also suggest that GM loss could be a familial/trait marker and thus unlikely caused by drug treatment (Gogtay et al., 2007a, Goldman et al., 2009).
Some studies have suggested that exposure to typical antipsychotics is associated with increased basal ganglia and thalamic volumes (Gur et al., 1998), while exposure to atypical antipsychotics is associated with decreased basal ganglia volumes (Khorram et al., 2006, Corson et al., 1999, Scherk and Falkai, 2006). However, the differential effect of both typical and atypical antipsychotics on cortical GM volumes is unclear and findings are inconsistent. An earlier small study in patients with acute psychosis (n = 7) showed no GM volume changes in relation to haloperidol treatment (Garver et al., 2005). In contrast, a study by Lieberman et al. (2005b) (n = 164) found a reduction in frontal and total GM volumes among first-episode patients taking haloperidol, which was not seen with olanzapine. A follow-up study by the same group using cortical mapping methods and more frequent scan intervals (3 month; n = 36) showed that GM loss progressed in a parieto-frontal direction in haloperidol-treated patients, which was not seen in olanzapine-treated patients (Thompson et al., 2009). However, in both these studies the differential effects disappeared after one year.
A series of studies focusing on GM abnormalities in COS has shown widespread cortical loss that evolves in a parieto-frontal direction during adolescence (Giedd et al., 1999, Jacobsen et al., 1998, Rapoport et al., 1999, Thompson et al., 2001) merging into the adult pattern by early adulthood (Greenstein et al., 2006). Findings from longitudinal MRI studies of adolescent-onset psychosis also support the idea of progressive frontal GM changes (Reig et al., 2009, Moreno et al., 2005) bolstering support for COS as a progressive neurodevelopmental disorder with both early and late developmental aberrations (Arango et al., 2008). More recent studies with larger sample sizes have suggested that the GM thickness may be positively correlated to the overall functional outcome, thus raising the possibility that drug treatment could be influencing GM development (Greenstein et al., 2008, Van Haren et al., 2008). We decided to explore whether the superiority of clozapine uniquely influenced GM trajectory in COS by comparing it to olanzapine. We identified two COS samples where patients were consistently treated with either clozapine or olanzapine for at least two prospective scans and matched them for baseline clinical severity to minimize disease effects.
Section snippets
Subjects
COS patients were recruited nationwide and most were diagnosed after a thorough inpatient observation that included a complete medication washout. Exclusionary criteria include history of significant medical or neurological illness, substance abuse, or IQ below 70 prior to onset of psychotic symptoms; details are described elsewhere (McKenna et al., 1994). All patients were followed longitudinally at two-year intervals and anatomic MRI scans were obtained at each visit.
For this study, COS
Demographics and clinical data
Sample demographics for the medication groups are shown in Table 1. There were no significant differences with respect to age, handedness, or duration of illness between patients treated with clozapine and those treated with olanzapine at the initial scan (Table 1). When all scans were included, the clozapine group had a significantly higher proportion of males versus the olanzapine group (x2 = .002). As a result, sex was included as a covariate in the analyses. There were no significant
Discussion
We examined whether clozapine differentially alters cortical GM loss in COS compared to olanzapine. We found no differences in GM trajectories between the clozapine and olanzapine-treated patients suggesting that these medications do not differentially influence GM in COS. Similarly there were no significant differences in GM amount between the groups except for a small region in the right medial prefrontal cortex where the olanzapine-treated group showed thicker cortex compared to the
Role of funding source
The present research was funded by the Intramural Research Program (IRP) at the National Institute of Mental Health (NIMH) in Bethesda, MD.
Contributors
Anand Mattai M.D was the primary author of the manuscript.
Alex Chavez B.S., Deanna K. Greenstein Ph.D., and Liv Clasen Ph.D., performed the neuroimaging and statistical data analysis for the project.
Jennifer Bakalar B.A and Reva Stidd B.A. assisted with the composition and editing of the manuscript.
Judith L Rapoport M.D. and Nitin Gogtay M.D. coordinated the research design and execution for this project.
Conflict of Interest
The authors have nothing to disclose financially and report no conflicts of interest.
Acknowledgements
None.
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2014, Schizophrenia ResearchCitation Excerpt :To the best of our knowledge, the outcome in changes to cerebral structure has not been investigated in adult FE patients treated with clozapine. Clozapine and olanzapine did not show any differences in their effect upon cortical thickness in FE patients with early-onset schizophrenia (Mattai et al., 2010). Given that our patients exhibited only slight cortical thinning at follow-up, we cannot discard a protective effect for risperidone, and mainly clozapine (i.e., since most of the cases reaching the end of follow-up received this drug).