Minocycline for the Treatment of Early-Phase Schizophrenia
Condition: Negative and Cognitive Symptoms in Schizophrenia
MeSH terms: Neurobehavioral Manifestations; Schizophrenia
Study type: Interventional
Phase: Phase 3

Summary: 
      Current antipsychotics have only a limited effect on two core symptoms of schizophrenia,
      negative symptoms and cognitive deficits. Minocycline is a second-generation tetracycline
      which has a beneficial effect in various neurological disorders. Recent findings in animal
      models and human case-reports suggest its potential for the treatment of these symptoms of
      schizophrenia. The current study aims to examine the efficacy of minocycline as add-on
      treatment for alleviating negative and cognitive symptoms in early-phase schizophrenia. The
      study will utilize a longitudinal double blind, randomized, placebo-controlled design with
      patients followed for six-months. Early-phase schizophrenia patients were recruited and
      randomly allocated to a minocycline or placebo treatment (2:1 ratio; 200 mg/day). The primary
      outcome measures are the Scale for Assessment of Negative Symptoms (SANS) and assessments of
      executive functions.
    

Detailed description: 
      Schizophrenia is a disorder characterized by disturbances in perception, thought, volition,
      socialization, psychomotor behavior and the sense of self. Although patients suffer from
      schizophrenia start from a point of relative normalcy or subtle impairment, following formal
      onset most patients experience, to some degree, clinical deterioration. This deterioration is
      manifest by the development of and increasing severity and persistence of psychotic and
      negative symptoms, cognitive impairment, and diminished social and functional capacity. The
      underlying causes of this clinical deterioration are not known, but is generally attributed
      to progression of the illness and associated with periods of active positive symptoms. The
      deterioration occurs primarily in the early stages of the illness and it is generally
      confined to the first 5 years after onset. It also does not progress in a linear fashion.
      Rather, after a period, patients stabilize at a level where they have persistent symptoms and
      are impaired in their social and vocational function. Despite the heterogeneity of symptoms
      among patients and their variability within patients across episodes, two distinct patterns
      have been discerned in long-term catamnestic studies of schizophrenia patients. First,
      negative symptoms tend to be less common and severe in the early stages of the illness and to
      increase in prevalence and severity in the later stages. In the early stages positive
      symptoms are more likely to dominate the clinical picture. Second, within the constellation
      of positive symptoms, formed or systematized delusions and hallucinations are more common in
      the earlier stages of illness, whereas thought disorganization, inappropriate affect, and
      motor symptoms are more common in the later stages of illness.

      Both MRI and MRS offer evidence, which is consistent with a neurodegenerative pathologic
      process in schizophrenia that occurs primarily but not exclusively in the early stage of the
      illness. Recent MRI studies of first-episode and childhood-onset schizophrenia samples using
      more rigorous and standardized methods have found cortical gray matter and ventricular system
      volume changes. The findings of volume reductions in cortical gray matter and increases in
      ventricular system volume can be described as consistent with a process causing
      pathomorphologic progression and neurodegeneration Investigators have considered the role of
      molecular mechanisms in the neuropathology of schizophrenia. In this context, proponents of
      neurodegenerative theories have suggested that the absence of gliosis and evidence of cell
      degeneration could be due to the fact that the pathophysiology involves a graded apoptosis
      rather than a fulminant necrotic process. Apoptosis is evanescent and difficult to detect
      histopathologically before or after the process unfolds. Studies have shown that various
      neurochemical events at the synapse can induce apoptosis. Such triggering actions include
      excessive glutamate stimulation, calcium influx reactive oxygen species all of that can
      induce caspase activation in dendrites. Local activation of caspases that initiate the
      apoptotic cascade can spread to the cell body or remain localized producing neurodegenerative
      synapse loss and synaptic remodeling. The reduced size and increased density of neurons, in
      the absence of decreased numbers of neurons or glia and decreased cortical thickness,
      indicate that cell processes and synaptic connections are reduced in schizophrenia. This is
      consistent with reports of decreased concentrations of synaptic proteins (e.g.,
      synaptophysin). These cell processes and synapses could be lost as a consequence of a
      neurochemically mediated (through dopamine and/or glutamate) synaptic apoptosis that would
      compromise cell function and alter brain morphology without, however, producing serious cell
      injury (and thus inducing glial reactions).

      Although some authors have suggested that pharmacologic treatment suppresses the symptoms of
      schizophrenia but does not alter the course of the illness or its potential progression,
      others have suggested that antipsychotic drugs in fact ameliorate the pathophysiologic
      process that causes psychotic symptoms and leads to clinical deterioration. Moreover,
      maintenance treatment studies have demonstrated the prophylactic effect of antipsychotic
      drugs in preventing relapse; treatment, then, may be responsible for mitigating the course of
      the illness and producing more favorable outcomes.

      Three lines of evidence suggest that the novel neurotransmitter Nitric Oxide (NO) play a
      central role in pathophysiology of schizophrenia. First, schizophrenia-like syndromes can be
      induced in humans by phencyclidine (PCP), a drug with marked psychomimetic properties. Recent
      studies indicate that the behavioral and biochemical effects of PCP in rats are blocked by
      Nitric Oxid synthase (NOS) inhibitors, suggesting that NO plays an important role in the
      pharmacological effects of PCP. Second, Postmortem brain tissue obtained at autopsy from
      schizophrenia and control demonstrate increased in NOS in the cerebellum and brainstem of
      schizophrenic patients. Third, NO play a role in learning and memory, which severly impaired
      in schizophrenia.

      Minocycline is a second-generation tetracycline used in humans, which effectively crosses the
      blood-brain barrier. Minocycline is commonly used by humans, because of its beneficial
      ant-imicrobial and anti-inflammatory properties. In addition, it has remarkable
      neuroprotective qualities in animal models of cerebral ischemia, traumatic brain injury, and
      Huntington's and Parkinson's disease. The neuroprotective effect of Minocycline is associated
      with marked inhibition of inducible NO synthase (iNOS), caspase 1 and caspase 3 expression,
      and p38 mitogen activated protein kinase (MAPK). Recently, it was found that Minocycline also
      inhibits cytochrome c release and delays progression of amyotrophic lateral sclerosis in
      mice.

      Because Minocycline may inhibit members of the caspase family, the MAP kinase pathway and NOS
      (which play central role in the neuroprotective effects of Minocycline in different model of
      brain-disease), we would like to test the neuroprotective effect of Minocycline in the early
      development (i.e.- at the first psychotic episode) of schizophrenia. The safety record of
      Minocycline and its ability to penetrate the blood-brain barrier are well known. Therefore,
      if this drug will be found to have neuroprotective effect in schizophrenia it may be a novel
      therapy.
    

Intervention name(s): Minocycline; Placebo (200 mg/day)
Intervention type(s): Drug; Drug
Intervention description(s): Minocycline as an add-on drug (200 mg/day)
Intervention MeSH terms: Minocycline
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary purpose: Prevention
Keywords: Minocycline; Schizophrenia; Negative symptoms; Cognitive