Elsevier

Schizophrenia Research

Volume 78, Issue 1, 1 October 2005, Pages 45-60
Schizophrenia Research

Review of longitudinal functional neuroimaging studies of drug treatments in patients with schizophrenia

https://doi.org/10.1016/j.schres.2005.05.009Get rights and content

Abstract

We systematically reviewed twentyone functional neuroimaging studies that used longitudinal designs to investigate the effects of medication treatments on brain functioning among patients with schizophrenia. The studies reviewed were comprised of functional magnetic resonance imaging and positron emission tomography research using a baseline and at least one follow-up. The present review summarizes the different effects of medication and disease status on brain function, with attention to functional normalization, specific drug effects, and comparisons of typical versus atypical antipsychotics. Particular emphasis is given to methodological limitations in the existing literature, including lack of reliability data, clinical heterogeneity among studies, and inadequate study designs and statistics. Suggestions are made for improving future longitudinal neuroimaging studies of treatment effects in schizophrenia.

Introduction

Among patients with schizophrenia, abnormalities in brain function and brain function changes due to neuroleptic medications are not yet fully understood. Understanding the disease process of schizophrenia, associated changes in brain function, and the effects of medications on brain response could lead to more effective and well-targeted treatments for patients with schizophrenia. Functional neuroimaging provides a tool to observe brain function and alterations in brain response with treatment that is likely to be more specific and sensitive than behavioral responses or volumetric measurements (Sharma, 2003). PET imaging, which detects concentrations of radio-active tracers in particular brain regions in vivo, has been used for a number of years to study blood flow and metabolism, and especially hypoperfusion and hypometabolism in patients with schizophrenia (Buchsbaum and Haier, 1987). More recently, fMRI has been used to assess task-related changes in the blood oxygen level dependent (BOLD) responses, related to neural activity in schizophrenia (Kindermann et al., 1997).

Previous reviews of neuroimaging work have covered cross-sectional studies that address brain function differences between patients with schizophrenia and healthy individuals at a single time point (Buchsbaum and Hazlett, 1997, DeLisi, 1999, Shenton et al., 2001). These reviews revealed consistent findings of abnormality in function of the frontal lobes, basal ganglia, and temporal lobes, particularly in the hippocampus, among patients with schizophrenia. Frontal lobe pathology, especially underactivity of blood flow and metabolism in this region compared to healthy controls, has been suggested to be related to well-known deficits in executive functioning that occur in schizophrenia (Buchsbaum, 1990). Lower metabolism and blood flow of the basal ganglia among patients with schizophrenia are consistent with dopaminergic hypotheses about the pathophysiology of the disorder (Buchsbaum, 1990, Buchsbaum et al., 1992). Functional abnormalities of the temporal lobes, hippocampus, and temporolimbic connections were also consistently observed, and are thought to be related to deficits in memory and visual and auditory hallucinations (Buchsbaum, 1990, Weinberger, 1997). Previous reviews, however, have not comprehensively covered longitudinal studies, which can help to disentangle the confounded effects of disease process from the effects of antipsychotic medication on brain function. The need for longitudinal neuroimaging studies, with sufficient sample size, has been previously identified in order to study age-related changes, disease course, and the effects of treatment in schizophrenia (Buchsbaum and Hazlett, 1997). A review and examination of key longitudinal functional neuroimaging studies can aid in understanding treatment effects and also guide future studies in this area.

Therefore, the present review focused on longitudinal studies in patients with schizophrenia, specifically those that measured physiological or neurochemical functioning of the brain at two time points during pharmacological treatment. These studies used functional magnetic resonance imaging (fMRI) and positron emission tomography (PET) or single photon emitted computed tomography (SPECT) to examine changes in brain function, blood flow and metabolism, and neuroreceptor and neurotransmitter activity due to drug treatments, while the subject was resting or performing mental tasks. Some studies included a control comparison group of healthy individuals, while others included treatment-control groups of patients with schizophrenia or groups with alternate treatments. In addition to summarizing the relevant methods and findings from each of the studies, this review highlights treatment effects (e.g., on- versus off-drug comparisons of brain function), normalization of brain function with treatment (e.g., lack of patient vs. control difference following treatment), and effects of typical versus atypical antipsychotics on brain function. We also focus on several important methodological issues, including the need for examination of reliability of neuroimaging methods in assessing brain function over time, sample size, design and analysis limitations, and clinical heterogeneity.

Section snippets

Methods

Searches were performed using the PubMed database from 1985 to 2004. Logical combinations of precise search terms were used. The following terms were used to perform searches (search terms italicized) Schizophrenia AND (fMRI OR PET OR SPECT) AND (reliability OR test–retest OR pre- post- OR treatment OR drug therapy OR pharmacotherapy OR change OR neuroplasticity OR prediction OR improvement OR clinical). Research involving techniques such as electrophysiology, encephalography, brain mapping,

Study findings

A total of 21 journal articles using fMRI, PET, or SPECT to study drug treatments of schizophrenia were selected for review. Of these, four articles used fMRI blood oxygen level dependent (BOLD) effect, seven used PET or SPECT regional cerebral blood flow (rCBF), 8 used PET glucose metabolism (GM), and two used PET to observe dopaminergic and serotonergic receptor activity. These articles, their design, and results are presented in Table 1.

There were three primary categories of results

Future directions

Two general themes emerged from this review of longitudinal studies of the effects of drug treatment on brain response among patients with schizophrenia. The first is that despite large differences in methodology and data presentation, some consistency of results was found. Specifically, decreases in cortical brain response and increases in basal ganglia response were seen in many studies, especially when atypical agents were contrasted to haloperidol treatment. Often, these changes were in the

References (43)

  • O. Sabri et al.

    Correlation of positive symptoms exclusively to hyperperfusion or hypoperfusion of cerebral cortex in never-treated schizophrenics

    Lancet

    (1997)
  • M.E. Shenton et al.

    A review of MRI findings in schizophrenia

    Schizophr. Res.

    (2001)
  • D.R. Weinberger et al.

    fMRI applications in schizophrenia research

    Neuroimage

    (1996)
  • D.A. Yurgelun-Todd et al.

    Functional magnetic resonance imaging studies of schizophrenic patients during word production: effects of D-cycloserine

    Psychiatry Res.

    (2005)
  • E.J. Bartlett et al.

    Effect of a haloperidol challenge on regional brain metabolism in neuroleptic-responsive and nonresponsive schizophrenic patients

    Am. J. Psychiatry

    (1998)
  • I. Berman et al.

    Regional cerebral blood flow changes associated with risperidone treatment in elderly schizophrenia patients: a pilot study

    Psychopharmacol. Bull.

    (1996)
  • M.S. Buchsbaum

    The frontal lobes, basal ganglia, and temporal lobes as sites for schizophrenia

    Schizophr. Bull.

    (1990)
  • M.S. Buchsbaum et al.

    Functional and anatomical brain imaging: impact on schizophrenia research

    Schizophr. Bull.

    (1987)
  • M.S. Buchsbaum et al.

    Striatal metabolic rate and clinical response to neuroleptics in schizophrenia

    Arch. Gen. Psychiatry

    (1992)
  • L.E. DeLisi et al.

    Positron emission tomography in schizophrenic patients with and without neuroleptic medication

    J. Cereb. Blood Flow Metab.

    (1985)
  • N. Franck et al.

    Cerebral blood flow changes associated with Schneiderian first-rank symptoms in schizophrenia

    J. Neuropsychiatry Clin. Neurosci.

    (2002)
  • Cited by (80)

    • Converging effects of diverse treatment modalities on frontal cortex in schizophrenia: A review of longitudinal functional magnetic resonance imaging studies

      2017, Journal of Psychiatric Research
      Citation Excerpt :

      Functional neuroimaging is one approach that enables observation of the functional alterations that can occur with a treatment in clinically-relevant timescales (Sharma, 2003). Among the techniques in this category, single photon emitted computed tomography (SPECT) and positron emission tomography (PET) have been used to identify changes in brain function, blood flow, metabolism and neuroreceptor and neurotransmitter activity due to drug treatments (Davis et al., 2005). Another approach, functional magnetic resonance imaging (fMRI) can be used to measure changes in the blood oxygen level dependent signal, an indicator of neuronal activity and brain function (Abbott et al., 2013).

    • Increased superior frontal gyrus activation during working memory processing in psychosis: Significant relation to cumulative antipsychotic medication and to negative symptoms

      2016, Schizophrenia Research
      Citation Excerpt :

      In the neural network models of WM, the prefrontal cortex (PFC) plays a critical role in functional interactions (Badre and Wagner, 2004; D'Esposito, 2007; Goldman-Rakic, 1995; Kraguljac et al., 2013) and it has been proposed that there is exaggerated and inefficient PFC activity in SZ (Callicott et al., 2000). Furthermore, a number of studies have shown normalization of brain function in patients taking antipsychotic medication (Davis et al., 2005; Honey et al., 1999; Lahti et al., 2004). However, little is known about whether this effect is only based on a change in local blood flow or is connected to the amelioration in cognitive impairment.

    View all citing articles on Scopus
    View full text