Minocycline for Schizophrenia

Minocycline has excellent penetration of the blood-brain barrier. In a mechanism that seems to be distinct from its antimicrobial properties, minocycline has anti-inflammatory and neuroprotective properties. These properties are thought to be related to some combination of its inhibition of inducible nitric oxide synthase (iNOS); caspase 1 and 3; p-38 mitogen-activated protein kinase (MAPK); cytochrome C release; cyclooxygenase-2 expression; prostaglandin E2 formation; and microglial activation. Minocycline has also been reported to have antiviral effects against HIV and antiprotozoal effects against Toxoplasma gondii. Its use in individuals with schizophrenia has been encouraged by its effects in rodent models of this disorder. In one study, minocycline attenuated the behavioral changes following the administration of an NMDA (N-methyl-D-aspartate)antagonist in mice. In another study, minocycline reversed the effects of an NMDA antagonist in rats. Some preliminary data also suggest that minocycline may be useful in patients with schizophrenia. Two case report series have been published, one including two patients with schizophrenia and the other including three patients with recent-onset acute paranoid schizophrenia. An open label study of 22 patients with treatment-resistant schizophrenia, using minocycline 150 mg/d for four weeks, reported an improvement in both positive and negative symptoms. Two double blind trials have been carried out. In one study, 73 patients with schizophrenia of less than five years' duration were randomized to minocycline 200 mg or placebo for 12 months: "all symptom measures improved significantly" especially in the negative symptoms. In the other study, 54 "early phase" (symptoms of less than five years) patients were randomized to minocycline 200 mg/d or placebo for six months; the authors reported a significant improvement in negative symptoms measured using Scale for the Assessment of Negative Symptoms (SANS) and Clinical Global Impressions scale (CGI) and a significant improvement in some test of executive function. These initial findings encourage further replication. First, these studies are of comparatively small size. Second, in countries like Ethiopia where options for the treatment of schizophrenia are limited, identifying a safe alternative to clozapine is important. Related to this, most patients have limited exposure to psychotropic medications. Third, exposure to alcohol and substances is generally believed to be lower in the Ethiopian setting. Finally, given our hypothesis that infectious agents as a cause of schizophrenia may be more important in low and middle income countries (LAMICs) such as Ethiopia, minocycline may prove more useful. In this regard, the trial will help to explore the etiology of schizophrenia. The investigators have experience in following-up a large cohort of patients with schizophrenia and in conducting randomized controlled trials of a similar nature, which makes this proposed study feasible.