Effects of minocycline add-on treatment on brain morphometry and cerebral perfusion in recent-onset schizophrenia
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)
- et al.
Antipsychotic dose equivalents and dose-years: a standardized method for comparing exposure to different drugs
Biol. Psychiatry
(2010) - et al.
MRI-morphometric changes in first-episode schizophrenic patients at 14 months follow-up
Schizophr. Res.
(2004) - et al.
A voxel-based investigation of regional cerebral blood flow abnormalities in obsessive–compulsive disorder using single photon emission computed tomography (SPECT)
Psychiatry Res.
(2000) - et al.
Neuroprotection by tetracyclines
Trends Pharmacol. Sci.
(2004) - et al.
Anger in healthy men: a PET study using script-driven imagery
Biol. Psychiatry
(1999) - et al.
Detecting activations in PET and fMRI: levels of inference and power
Neuroimage
(1996) - et al.
Phencyclidine-induced cognitive deficits in mice are improved by subsequent subchronic administration of the antibiotic drug minocycline
Prog. Neuropsychopharmacol. Biol. Psychiatry
(2008) - et al.
A voxel-based morphometric study of ageing in 465 normal adult human brains
Neuroimage
(2001) - et al.
Automatic differentiation of anatomical patterns in the human brain: validation with studies of degenerative dementias
Neuroimage
(2002) - et al.
Does hypofrontality expand to global brain area in progression of schizophrenia?: A cross-sectional study between first-episode and chronic schizophrenia
Prog. Neuropsychopharmacol. Biol. Psychiatry
(2009)
Adjunct minocycline to clozapine treated patients with persistent schizophrenia symptoms
Schizophr. Res.
Minocycline and neurodegenerative diseases
Behav. Brain Res.
Minocycline, a second-generation tetracycline, as a neuroprotective agent in an animal model of schizophrenia
Brain Res.
Is schizophrenia a neurodegenerative disorder? A clinical and neurobiological perspective
Biol. Psychiatry
Progressive gray matter changes in first episode schizophrenia: a 4-year longitudinal magnetic resonance study using VBM
Schizophr. Res.
The profiles of clinical deterioration in schizophrenia
J. Psychiatr. Res.
Volume of the cingulate and outcome in schizophrenia
Schizophr. Res.
Possible antipsychotic effects of minocycline in patients with schizophrenia
Prog. Neuropsychopharmacol. Biol. Psychiatry
Distributional assumptions in voxel-based morphometry
Neuroimage
Neurocognitive function and outcome in first-episode schizophrenia: a 10-year follow-up of an epidemiological cohort
Schizophr. Res.
Regional gray matter abnormalities in obsessive-compulsive disorder: a voxel-based morphometry study
Biol. Psychiatry
Progressive brain volume loss in schizophrenia over the course of the illness: evidence of maturational abnormalities in early adulthood
Biol. Psychiatry
Characteristic brain hypoperfusion by 99mTc-ECD single photon emission computed tomography (SPECT) in patients with the first-episode schizophrenia
Eur. Psychiatry
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