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.
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 and 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 and 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 and 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 and 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 and 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.
