Effects of clozapine and olanzapine on cortical thickness in childhood-onset schizophrenia

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Abstract

Background

Little is known about the effects of antipsychotic medications on gray matter (GM) in schizophrenia. Although clozapine remains the most effective antipsychotic medication in treatment-refractory cases, it is unknown whether it has a differential effect on GM development.

Methods

In an exploratory analysis, we used automated cortical thickness measurements and prospectively scanned childhood-onset schizophrenia (COS) patients who were maintained on one medication. Two atypical antipsychotic medications, clozapine (n = 12, 37 scans) and olanzapine (n = 12, 33 scans) were compared with respect to effects on cortical development, in contrast to GM trajectories of matched controls.

Results

There were no significant differences in the trajectories of cortical thickness between the two treatment groups with the exception of a small circumscribed area in the right prefrontal cortex, where the olanzapine group showed thicker cortex. As expected, both groups showed thinner GM compared to matched controls.

Conclusions

Although these analyses do not rule out effects of antipsychotic medications on GM development in schizophrenia, they show no differential effect between clozapine and olanzapine on GM trajectory.

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.

References (47)

  • D. Moreno et al.

    Structural neuroimaging in adolescents with a first psychotic episode

    J. Am. Acad. Child Adolesc. Psych.

    (2005)
  • C. Pantelis et al.

    Neuroanatomical abnormalities before and after onset of psychosis: a cross-sectional and longitudinal MRI comparison

    Lancet

    (2003)
  • N.E. Van Haren et al.

    Progressive brain volume loss in schizophrenia over the course of the illness: evidence of maturational abnormalities in early adulthood

    Biol. Psychiatry

    (2008)
  • C. Arango et al.

    Longitudinal brain changes in early-onset psychosis

    Schizophr. Bull.

    (2008)
  • F.X. Castellanos et al.

    Quantitative brain magnetic resonance imaging in girls with attention-deficit/hyperactivity disorder

    Arch. Gen. Psychiatry

    (2001)
  • M.H. Chakos et al.

    Increase in caudate nuclei volumes of first-episode schizophrenic patients taking antipsychotic drugs

    Am. J. Psychiatry

    (1994)
  • P.W. Corson et al.

    Change in basal ganglia volume over 2 years in patients with schizophrenia: typical versus atypical neuroleptics

    Am. J. Psychiatry

    (1999)
  • P. Dazzan et al.

    Different effects of typical and atypical antipsychotics on grey matter in first episode psychosis: the AESOP study

    Neuropsychopharmacology

    (2005)
  • L.E. Delisi et al.

    Understanding structural brain changes in schizophrenia

    Dialogues Clin Neurosci

    (2006)
  • K.A. Dorph-Petersen et al.

    The influence of chronic exposure to antipsychotic medications on brain size before and after tissue fixation: a comparison of haloperidol and olanzapine in macaque monkeys

    Neuropsychopharmacology

    (2005)
  • N. Gogtay

    Cortical brain development in schizophrenia: insights from neuroimaging studies in childhood-onset schizophrenia

    Schizophr. Bull.

    (2008)
  • N. Gogtay et al.

    Cortical brain development in nonpsychotic siblings of patients with childhood-onset schizophrenia

    Arch. Gen. Psychiatry

    (2007)
  • N. Gogtay et al.

    Dynamic mapping of cortical development before and after the onset of pediatric bipolar illness

    J. Child Psychol. Psychiatry

    (2007)
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