A multimodal analysis of antipsychotic effects on brain structure and function in first-episode schizophrenia

Tyler A. Lesh, Costin Tanase, Benjamin R. Geib, Tara A Niendam, Jong H. Yoon, Michael J. Minzenberg, John D Ragland, Marjorie Solomon Friedman, Cameron S Carter

Research output: Contribution to journalArticle

73 Citations (Scopus)

Abstract

IMPORTANCE: Recent data suggest that treatment with antipsychotics is associated with reductions in cortical gray matter in patients with schizophrenia. These findings have led to concerns about the effect of antipsychotic treatment on brain structure and function; however, no studies to date have measured cortical function directly in individuals with schizophrenia and shown antipsychotic-related reductions of gray matter. OBJECTIVE: To examine the effects of antipsychotics on brain structure and function in patients with first-episode schizophrenia, using cortical thickness measurements and administration of the AX version of the Continuous Performance Task (AX-CPT) during event-related functional magnetic resonance imaging. DESIGN, SETTING, AND PARTICIPANTS: This case-control cross-sectional study was conducted at the Imaging Research Center of the University of California, Davis, from November 2004 through July 2012. Participants were recruited on admission into the Early Diagnosis and Preventive Treatment Clinic, an outpatient clinic specializing in first-episode psychosis. Patients with first-episode schizophrenia who received atypical antipsychotics (medicated patient group) (n = 23) and those who received no antipsychotics (unmedicated patient group) (n = 22) and healthy control participants (n = 37) underwent functional magnetic resonance imaging using a 1.5-T scanner. MAIN OUTCOMES AND MEASURES: Behavioral performance was measured by trial accuracy, reaction time, and d'-context score. Voxelwise statistical parametric maps tested differences in functional activity during the AX-CPT, and vertexwise maps of cortical thickness tested differences in cortical thickness across the whole brain. RESULTS: Significant cortical thinning was identified in the medicated patient group relative to the control group in prefrontal (mean reduction [MR], 0.27 mm; P < .001), temporal (MR, 0.34 mm; P = .02), parietal (MR, 0.21 mm; P = .001), and occipital (MR, 0.24 mm; P = .001) cortices. The unmedicated patient group showed no significant cortical thickness differences from the control group after clusterwise correction. The medicated patient group showed thinner cortex compared with the unmedicated patient group in the dorsolateral prefrontal cortex (DLPFC) (MR, 0.26 mm; P = .001) and temporal cortex (MR, 0.33 mm; P = .047). During the AX-CPT, both patient groups showed reduced DLPFC activity compared with the control group (P = .02 compared with the medicated group and P < .001 compared with the unmedicated group). However, the medicated patient group demonstrated higher DLPFC activation (P = .02) and better behavioral performance (P = .02) than the unmedicated patient group. CONCLUSIONS AND RELEVANCE: These findings highlight the complex relationship between antipsychotic treatment and the structural, functional, and behavioral deficits repeatedly identified in schizophrenia. Although short-term treatment with antipsychotics was associated with prefrontal cortical thinning, treatment was also associated with better cognitive control and increased prefrontal functional activity. This study adds important context to the growing literature on the effects of antipsychotics on the brain and suggests caution in interpreting neuroanatomical changes as being related to a potentially adverse effect on brain function.

Original languageEnglish (US)
Pages (from-to)226-234
Number of pages9
JournalJAMA Psychiatry
Volume72
Issue number3
DOIs
StatePublished - Mar 1 2015

Fingerprint

Antipsychotic Agents
Schizophrenia
Brain
Task Performance and Analysis
Prefrontal Cortex
Control Groups
Multimodal Analysis
Therapeutics
Magnetic Resonance Imaging
Temporal Lobe
Ambulatory Care Facilities
Psychotic Disorders
Reaction Time
Early Diagnosis
Healthy Volunteers
Cross-Sectional Studies
Cortical Thickness

ASJC Scopus subject areas

  • Arts and Humanities (miscellaneous)
  • Psychiatry and Mental health

Cite this

A multimodal analysis of antipsychotic effects on brain structure and function in first-episode schizophrenia. / Lesh, Tyler A.; Tanase, Costin; Geib, Benjamin R.; Niendam, Tara A; Yoon, Jong H.; Minzenberg, Michael J.; Ragland, John D; Friedman, Marjorie Solomon; Carter, Cameron S.

In: JAMA Psychiatry, Vol. 72, No. 3, 01.03.2015, p. 226-234.

Research output: Contribution to journalArticle

@article{677abc1177e04a68a9c3d9af7c41f5d8,
title = "A multimodal analysis of antipsychotic effects on brain structure and function in first-episode schizophrenia",
abstract = "IMPORTANCE: Recent data suggest that treatment with antipsychotics is associated with reductions in cortical gray matter in patients with schizophrenia. These findings have led to concerns about the effect of antipsychotic treatment on brain structure and function; however, no studies to date have measured cortical function directly in individuals with schizophrenia and shown antipsychotic-related reductions of gray matter. OBJECTIVE: To examine the effects of antipsychotics on brain structure and function in patients with first-episode schizophrenia, using cortical thickness measurements and administration of the AX version of the Continuous Performance Task (AX-CPT) during event-related functional magnetic resonance imaging. DESIGN, SETTING, AND PARTICIPANTS: This case-control cross-sectional study was conducted at the Imaging Research Center of the University of California, Davis, from November 2004 through July 2012. Participants were recruited on admission into the Early Diagnosis and Preventive Treatment Clinic, an outpatient clinic specializing in first-episode psychosis. Patients with first-episode schizophrenia who received atypical antipsychotics (medicated patient group) (n = 23) and those who received no antipsychotics (unmedicated patient group) (n = 22) and healthy control participants (n = 37) underwent functional magnetic resonance imaging using a 1.5-T scanner. MAIN OUTCOMES AND MEASURES: Behavioral performance was measured by trial accuracy, reaction time, and d'-context score. Voxelwise statistical parametric maps tested differences in functional activity during the AX-CPT, and vertexwise maps of cortical thickness tested differences in cortical thickness across the whole brain. RESULTS: Significant cortical thinning was identified in the medicated patient group relative to the control group in prefrontal (mean reduction [MR], 0.27 mm; P < .001), temporal (MR, 0.34 mm; P = .02), parietal (MR, 0.21 mm; P = .001), and occipital (MR, 0.24 mm; P = .001) cortices. The unmedicated patient group showed no significant cortical thickness differences from the control group after clusterwise correction. The medicated patient group showed thinner cortex compared with the unmedicated patient group in the dorsolateral prefrontal cortex (DLPFC) (MR, 0.26 mm; P = .001) and temporal cortex (MR, 0.33 mm; P = .047). During the AX-CPT, both patient groups showed reduced DLPFC activity compared with the control group (P = .02 compared with the medicated group and P < .001 compared with the unmedicated group). However, the medicated patient group demonstrated higher DLPFC activation (P = .02) and better behavioral performance (P = .02) than the unmedicated patient group. CONCLUSIONS AND RELEVANCE: These findings highlight the complex relationship between antipsychotic treatment and the structural, functional, and behavioral deficits repeatedly identified in schizophrenia. Although short-term treatment with antipsychotics was associated with prefrontal cortical thinning, treatment was also associated with better cognitive control and increased prefrontal functional activity. This study adds important context to the growing literature on the effects of antipsychotics on the brain and suggests caution in interpreting neuroanatomical changes as being related to a potentially adverse effect on brain function.",
author = "Lesh, {Tyler A.} and Costin Tanase and Geib, {Benjamin R.} and Niendam, {Tara A} and Yoon, {Jong H.} and Minzenberg, {Michael J.} and Ragland, {John D} and Friedman, {Marjorie Solomon} and Carter, {Cameron S}",
year = "2015",
month = "3",
day = "1",
doi = "10.1001/jamapsychiatry.2014.2178",
language = "English (US)",
volume = "72",
pages = "226--234",
journal = "JAMA Psychiatry",
issn = "2168-622X",
publisher = "American Medical Association",
number = "3",

}

TY - JOUR

T1 - A multimodal analysis of antipsychotic effects on brain structure and function in first-episode schizophrenia

AU - Lesh, Tyler A.

AU - Tanase, Costin

AU - Geib, Benjamin R.

AU - Niendam, Tara A

AU - Yoon, Jong H.

AU - Minzenberg, Michael J.

AU - Ragland, John D

AU - Friedman, Marjorie Solomon

AU - Carter, Cameron S

PY - 2015/3/1

Y1 - 2015/3/1

N2 - IMPORTANCE: Recent data suggest that treatment with antipsychotics is associated with reductions in cortical gray matter in patients with schizophrenia. These findings have led to concerns about the effect of antipsychotic treatment on brain structure and function; however, no studies to date have measured cortical function directly in individuals with schizophrenia and shown antipsychotic-related reductions of gray matter. OBJECTIVE: To examine the effects of antipsychotics on brain structure and function in patients with first-episode schizophrenia, using cortical thickness measurements and administration of the AX version of the Continuous Performance Task (AX-CPT) during event-related functional magnetic resonance imaging. DESIGN, SETTING, AND PARTICIPANTS: This case-control cross-sectional study was conducted at the Imaging Research Center of the University of California, Davis, from November 2004 through July 2012. Participants were recruited on admission into the Early Diagnosis and Preventive Treatment Clinic, an outpatient clinic specializing in first-episode psychosis. Patients with first-episode schizophrenia who received atypical antipsychotics (medicated patient group) (n = 23) and those who received no antipsychotics (unmedicated patient group) (n = 22) and healthy control participants (n = 37) underwent functional magnetic resonance imaging using a 1.5-T scanner. MAIN OUTCOMES AND MEASURES: Behavioral performance was measured by trial accuracy, reaction time, and d'-context score. Voxelwise statistical parametric maps tested differences in functional activity during the AX-CPT, and vertexwise maps of cortical thickness tested differences in cortical thickness across the whole brain. RESULTS: Significant cortical thinning was identified in the medicated patient group relative to the control group in prefrontal (mean reduction [MR], 0.27 mm; P < .001), temporal (MR, 0.34 mm; P = .02), parietal (MR, 0.21 mm; P = .001), and occipital (MR, 0.24 mm; P = .001) cortices. The unmedicated patient group showed no significant cortical thickness differences from the control group after clusterwise correction. The medicated patient group showed thinner cortex compared with the unmedicated patient group in the dorsolateral prefrontal cortex (DLPFC) (MR, 0.26 mm; P = .001) and temporal cortex (MR, 0.33 mm; P = .047). During the AX-CPT, both patient groups showed reduced DLPFC activity compared with the control group (P = .02 compared with the medicated group and P < .001 compared with the unmedicated group). However, the medicated patient group demonstrated higher DLPFC activation (P = .02) and better behavioral performance (P = .02) than the unmedicated patient group. CONCLUSIONS AND RELEVANCE: These findings highlight the complex relationship between antipsychotic treatment and the structural, functional, and behavioral deficits repeatedly identified in schizophrenia. Although short-term treatment with antipsychotics was associated with prefrontal cortical thinning, treatment was also associated with better cognitive control and increased prefrontal functional activity. This study adds important context to the growing literature on the effects of antipsychotics on the brain and suggests caution in interpreting neuroanatomical changes as being related to a potentially adverse effect on brain function.

AB - IMPORTANCE: Recent data suggest that treatment with antipsychotics is associated with reductions in cortical gray matter in patients with schizophrenia. These findings have led to concerns about the effect of antipsychotic treatment on brain structure and function; however, no studies to date have measured cortical function directly in individuals with schizophrenia and shown antipsychotic-related reductions of gray matter. OBJECTIVE: To examine the effects of antipsychotics on brain structure and function in patients with first-episode schizophrenia, using cortical thickness measurements and administration of the AX version of the Continuous Performance Task (AX-CPT) during event-related functional magnetic resonance imaging. DESIGN, SETTING, AND PARTICIPANTS: This case-control cross-sectional study was conducted at the Imaging Research Center of the University of California, Davis, from November 2004 through July 2012. Participants were recruited on admission into the Early Diagnosis and Preventive Treatment Clinic, an outpatient clinic specializing in first-episode psychosis. Patients with first-episode schizophrenia who received atypical antipsychotics (medicated patient group) (n = 23) and those who received no antipsychotics (unmedicated patient group) (n = 22) and healthy control participants (n = 37) underwent functional magnetic resonance imaging using a 1.5-T scanner. MAIN OUTCOMES AND MEASURES: Behavioral performance was measured by trial accuracy, reaction time, and d'-context score. Voxelwise statistical parametric maps tested differences in functional activity during the AX-CPT, and vertexwise maps of cortical thickness tested differences in cortical thickness across the whole brain. RESULTS: Significant cortical thinning was identified in the medicated patient group relative to the control group in prefrontal (mean reduction [MR], 0.27 mm; P < .001), temporal (MR, 0.34 mm; P = .02), parietal (MR, 0.21 mm; P = .001), and occipital (MR, 0.24 mm; P = .001) cortices. The unmedicated patient group showed no significant cortical thickness differences from the control group after clusterwise correction. The medicated patient group showed thinner cortex compared with the unmedicated patient group in the dorsolateral prefrontal cortex (DLPFC) (MR, 0.26 mm; P = .001) and temporal cortex (MR, 0.33 mm; P = .047). During the AX-CPT, both patient groups showed reduced DLPFC activity compared with the control group (P = .02 compared with the medicated group and P < .001 compared with the unmedicated group). However, the medicated patient group demonstrated higher DLPFC activation (P = .02) and better behavioral performance (P = .02) than the unmedicated patient group. CONCLUSIONS AND RELEVANCE: These findings highlight the complex relationship between antipsychotic treatment and the structural, functional, and behavioral deficits repeatedly identified in schizophrenia. Although short-term treatment with antipsychotics was associated with prefrontal cortical thinning, treatment was also associated with better cognitive control and increased prefrontal functional activity. This study adds important context to the growing literature on the effects of antipsychotics on the brain and suggests caution in interpreting neuroanatomical changes as being related to a potentially adverse effect on brain function.

UR - http://www.scopus.com/inward/record.url?scp=84925351972&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84925351972&partnerID=8YFLogxK

U2 - 10.1001/jamapsychiatry.2014.2178

DO - 10.1001/jamapsychiatry.2014.2178

M3 - Article

C2 - 25588194

AN - SCOPUS:84925351972

VL - 72

SP - 226

EP - 234

JO - JAMA Psychiatry

JF - JAMA Psychiatry

SN - 2168-622X

IS - 3

ER -