Minocycline for Schizophrenia
Condition: Schizophrenia
MeSH terms: Schizophrenia
Study type: Interventional
Phase: Phase 4

Summary: 
      Schizophrenia is understood to be a heterogeneous brain condition with overlapping symptom
      dimensions. The negative symptom dimension, with its protean cognitive manifestations,
      responds poorly to treatment, which can be a particular challenge in countries where
      clozapine therapy is not available. Preliminary data indicates that minocycline may be
      beneficial adjunct in the treatment of schizophrenia: positive, negative, and cognitive
      symptoms. Persons with schizophrenia or schizoaffective disorder and recent onset
      schizophrenic episode or recent relapse who are prescribed minocycline in addition to
      standard antipsychotic medication will show greater symptom reduction, as measured by the
      Positive and Negative Syndrome Scale (PANSS) total score.
    

Detailed description: 
      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.
    

Intervention name(s): minocycline; placebo
Intervention type(s): Drug; Drug
Intervention MeSH terms: Minocycline
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment