Effects of minocycline add-on treatment on brain morphometry and cerebral perfusion in recent-onset schizophrenia

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Abstract

Increasing evidence suggests that the tetracycline antibiotic minocycline has neuroprotective effects and is a potential treatment for schizophrenia. However, the mechanisms of action of minocycline in the CNS remain elusive. The aim of this study was to investigate the effects of minocycline on brain morphology and cerebral perfusion in patients with recent-onset schizophrenia after 12 months of a randomized double-blind, placebo-controlled clinical trial of minocycline add-on treatment. This study included 24 outpatients with recent-onset schizophrenia randomized for 12 months of adjuvant treatment with minocycline (200 mg/d) or placebo. MRI (1.5 T) and [99mTc]-ECD SPECT brain scans were performed at the end of the 12-month of trial. Between-condition comparisons of SPECT and MRI brain images were performed using statistical parametric mapping and analyzed by voxel-based morphometry (VBM). Minocycline adjuvant treatment significantly reduced positive and negative symptoms when compared with placebo. The VBM analysis of MRI scans showed that the patients in the placebo group had significant lower gray matter volumes in the midposterior cingulate cortex and in the precentral gyrus in comparison with the patients in the minocycline group. In addition, a decreased ECD uptake in the minocycline condition was observed in fronto-temporal areas. These results suggest that minocycline may protect against gray matter loss and modulate fronto-temporal areas involved in the pathophysiology of schizophrenia. Furthermore, minocycline add-on treatment may be a potential treatment in the early stages of schizophrenia and may ameliorate clinical deterioration and brain alterations observed in this period.

Introduction

Despite the great variety of antipsychotics currently available, longitudinal cohort studies with patients in their first episode of psychosis have shown aggravation in several psychopathological domains (McGlashan, 1998, Hoff et al., 1999, Lieberman, 1999, Stirling et al., 2003), as well as progressive gray matter loss and altered brain function, particularly in fronto-temporal areas (Lieberman, 1999, Cahn et al., 2002, Bachmann et al., 2004, Perez-Neri et al., 2006, Whitford et al., 2006, Koo et al., 2008, van Haren et al., 2008, Mane et al., 2009, Smieskova et al., 2009).

Increasing evidence points out that minocycline, a broad-spectrum tetracycline antibiotic, has neuroprotective effects in different neurological conditions (e.g., brain ischemia) (Domercq and Matute, 2004, Kim and Suh, 2009). Translational neuroscience data from both animal and human studies have shown that minocycline is a potential treatment for schizophrenia. In three studies with animal models of psychosis, the treatment with minocycline prevented or reversed the behavioral effects of administration of NMDA antagonists (Levkovitz et al., 2007, Zhang et al., 2007, Fujita et al., 2008). Subsequently, a case report and an open study with the addition of minocycline to the usual antipsychotic treatment of patients with schizophrenia showed significant improvement in positive, negative and cognitive symptoms (Miyaoka et al., 2007, Miyaoka et al., 2008). Adjunctive minocycline to clozapine was also effective in improving positive and negative symptoms of two super-refractory patients (Kelly et al., 2011). Additionally, a randomized double-blind placebo-controlled clinical trial of minocycline add-on treatment showed an improvement in negative and cognitive symptoms in patients with schizophrenia (Levkovitz et al., 2010), and another randomized double-blind placebo-controlled clinical trial demonstrated an improvement mainly in the negative symptoms (Chaudhry et al., 2012).

In spite of these findings, the effects of minocycline in the central nervous system remain elusive and have not been systematically investigated with neuroimaging techniques. The hypothesis of this study is that minocycline add-on treatment may improve diverse psychopathological domains of schizophrenia and prevent brain alterations (especially in fronto-temporal areas) that usually occur in the early course of schizophrenia. Hence, the aim of this study was to investigate the effects of minocycline on brain morphology and cerebral perfusion in patients with recent-onset schizophrenia after 12 months of a randomized double-blind, placebo-controlled clinical trial of minocycline added to the treatment as usual.

Section snippets

General context of the study

This research focused on the neuroimaging findings of a randomized double-blinded placebo-controlled study of minocycline add-on treatment. The clinical data of this study have already been published as part of a multi-site clinical trial that included patients from Brazil and Pakistan (Chaudhry et al., 2012). Hence, the aim of this study was to investigate the effects of minocycline on brain morphology and cerebral perfusion using MRI and 99mTc-ECD SPECT scans of the patients followed at the

Characteristics of the sample

Patient flow in the study is shown in the CONSORT Diagram available as e-supplement (S1). Six patients did not complete the study due to noncompliance, observing that there were more patients that did not complete the trial in the placebo group (n = 4) than in the minocycline group (n = 2). There was a need for modification of the prescription (dose escalation or switching antipsychotic) due to the worsening of psychotic symptoms in eight patients, five of which belonged to the placebo group and

Discussion

The present study observed that minocycline add-on treatment can improve positive and negative symptoms of patients with recent-onset schizophrenia. Furthermore, this is the first morphometric and functional neuroimaging study that evaluated minocycline's action in the CNS, indicating that minocycline adjuvant treatment in recent-onset schizophrenia may prevent some brain alterations observed in the early stages of this disorder. In addition, the effects of minocycline are associated with the

Role of funding source

This work was supported in part by grants from “Conselho Nacional de Desenvolvimento Científico e Tecnológico” (CNPq—Brazil) (302453/2011-3).

Contributors

Chaves, Zuardi, Dursun and Hallak conceived and designed the study, drafted relevant parts of the manuscript and reviewed it critically; Wichert-Ana, Ferrari, Santos, Crippa and Araújo conceived the neuroimaging assessment, took part in the acquisition of data and analysis of the results, and contributed to interpret findings and craft the discussion. Maia-de-Oliveira, Marque, Machado-de-Sousa and Guimarães took part in the acquisition of data and critically reviewed the manuscript. Bressan,

Conflicts of interest

The authors report no conflicts of interest.

Acknowledgments

The authors have no acknowledgments.

References (47)

  • D.L. Kelly et al.

    Adjunct minocycline to clozapine treated patients with persistent schizophrenia symptoms

    Schizophr. Res.

    (2011)
  • H.S. Kim et al.

    Minocycline and neurodegenerative diseases

    Behav. Brain Res.

    (2009)
  • Y. Levkovitz et al.

    Minocycline, a second-generation tetracycline, as a neuroprotective agent in an animal model of schizophrenia

    Brain Res.

    (2007)
  • J.A. Lieberman

    Is schizophrenia a neurodegenerative disorder? A clinical and neurobiological perspective

    Biol. Psychiatry

    (1999)
  • A. Mane et al.

    Progressive gray matter changes in first episode schizophrenia: a 4-year longitudinal magnetic resonance study using VBM

    Schizophr. Res.

    (2009)
  • T.H. McGlashan

    The profiles of clinical deterioration in schizophrenia

    J. Psychiatr. Res.

    (1998)
  • S.A. Mitelman et al.

    Volume of the cingulate and outcome in schizophrenia

    Schizophr. Res.

    (2005)
  • T. Miyaoka et al.

    Possible antipsychotic effects of minocycline in patients with schizophrenia

    Prog. Neuropsychopharmacol. Biol. Psychiatry

    (2007)
  • C.H. Salmond et al.

    Distributional assumptions in voxel-based morphometry

    Neuroimage

    (2002)
  • J. Stirling et al.

    Neurocognitive function and outcome in first-episode schizophrenia: a 10-year follow-up of an epidemiological cohort

    Schizophr. Res.

    (2003)
  • A.A. Valente et al.

    Regional gray matter abnormalities in obsessive-compulsive disorder: a voxel-based morphometry study

    Biol. Psychiatry

    (2005)
  • 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)
  • R. Wake et al.

    Characteristic brain hypoperfusion by 99mTc-ECD single photon emission computed tomography (SPECT) in patients with the first-episode schizophrenia

    Eur. Psychiatry

    (2010)
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