Role of Minocycline in First Episode Psychosis
Condition: First Episode Psychosis
MeSH terms: Psychotic Disorders; Mental Disorders
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      The purpose of this study is to determine whether the addition of minocycline or placebo to
      treatment as usual (TAU):

        1. prevents the accumulation of negative symptoms and intellectual decline following a
           first episode of non-affective psychosis; and

        2. whether minocycline stabilizes the efficacy of antipsychotics.
    

Detailed description: 
      Background:

      There is increasing clinical, neuropsychological and imaging evidence that schizophrenia
      involves a progressive process at the time of the first episode and later in life. However,
      it is not clear which systems are affected nor in which parts of the brain. In two Stanley
      first episode cohorts at Manchester (Stirling et al, 2004,) and in a group of elderly
      patients with schizophrenia (Gabrovska-Johnson et al 2004), evidence of deterioration in
      visuo-spatial functions has been found. This implies a right-hemisphere pathology. Other
      evidence suggests that the initiation of schizophrenia may involve left-sided pathology
      (Lawrie et al 2002) so it could be that right hemisphere pathology may follow left and give
      rise to the deficits of chronic schizophrenia (Gabrovska-Johnson et al 2004). If so, early
      treatment with a neuroprotective agent might prevent the accumulation of deficit symptoms and
      cognitive impairment.

      Minocycline is a tetracycline antibiotic with proven long-term high dose safety in humans, is
      routinely used to treat acne and rheumatoid arthritis demonstrating that it acts as a
      non-steroidal anti-inflammatory, as well as an antimicrobial drug. Minocycline, unlike
      tetracycline, crosses the blood-brain barrier. This and related compounds show
      neuroprotective properties in rat models of ischemic brain damage, in glutamate neurotoxicity
      in cell cultures and in a rat model of Huntington's disease in which it slowed progression
      (Chen et al, 2000; Yrjanheikki et al, 1999). Minocycline delays disease onset and extends
      survival in amyotrophic lateral sclerotic mice (Shan Zhu et al 2002).

      Minocycline has various properties including inhibition of capsases, inhibition of microglial
      activation, reduced cyclooxygenase-2 expression and reduced prostaglandin E (2) formation.
      Furthermore, it inhibits the formation of inducible nitric oxide - a mechanism of glial
      activation. All these mechanisms have been implicated in schizophrenia. All these mechanisms
      have been implicated in schizophrenia.

      Because of its broad spectrum of action, we consider minocycline is an important candidate
      molecule for the prevention of deterioration in schizophrenia. Based on the evidence so far
      we propose a randomised double blind placebo controlled study of minocycline added to
      treatment-as-usual (TAU) in first-episode psychosis.

      Study Hypotheses:

        -  A neurodegenerative process, initially most marked in the left hemisphere, in late
           adolescence is responsible for the onset of schizophrenia in those at risk.

        -  Continuation of this process after onset and its extension to the right hemisphere
           causes accumulation of deficit symptoms and cognitive decline.

        -  Glutamate antagonism may enhance the antipsychotic effects of dopamine receptor blockade
           and prevent attenuation of efficacy with long-term treatment.

      TREATMENT:

      Minocycline is a widely available antibiotic given in doses of 50mg twice daily increasing to
      200mgs per day. It has been used very widely and appears to be tolerated well. The study
      advisor, Dr. Serdar Dursun, has used doses of up to 200mg per day in the treatment of
      Huntington's disease (Denovan-Wright et al 2002).

      It is widely available in Pakistan and Brazil and given in doses of 50mg twice daily
      increasing to 100mg twice daily (in total 200mg per day) (British National Formulary: BNF
      maximum dose 200mg per day). As per counselling recommendations in the British National
      Formulary: "minocycline medication should be swallowed whole with plenty of fluid while
      sitting or standing", to allow effective absorption. Patients will be counselled that 'the
      study medication should be swallowed whole with plenty of fluid while standing or sitting.'

      Patients will be informed regarding reported side-effects as cited in the BNF these include;
      nausea, vomiting, diarrhoea, dysphagia, oesophageal irritation, anorexia, dizziness,
      tinnitus, vertigo, hypersensitivity reactions (rash, exfoliative dermatitis, urticaria,
      angioedema, anaphylaxis, pericarditis), headache, visual disturbances, hepatotoxicity,
      pancreatitis, antibiotic associated colitis, blood dyscrasias, exacerbation of systemic lupus
      erythematosus and myasthenia gravis, rarely photosensitivity, skin, teeth, conjunctiva, tears
      and sweat discoloration.

      NUMBER OF PATIENTS:

      Using data from the SOCRATES study, we are able to calculate that 40 patients per treatment
      arm will detect a group difference on the primary outcome measure, i.e, PANSS, giving a 85%
      chance of detecting a difference between treatment groups of 4 points. The power estimate is
      likely to be conservative as there are three treatment groups. The automated CSF measures
      will detect a 5% group difference with these sample sizes. A minimum of 52 completed patients
      will be necessary (26 completed patients per treatment group).

      Study Advisors:

      Prof Bill Deakin(design), Prof Serdar Dursun(scientific), Prof Shon Lewis (clinical), Dr John
      Stirling (cognition), Dr Paul Richardson (cognition), Prof Graham Dunn (analysis).
    

Intervention name(s): Minocycline; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): Minocycline + treatment as usual. 50 mg twice daily increasing to 200 mgs per day, increments of 50 mgs every 2 weeks.; Placebo + treatment as usual.
Intervention MeSH terms: Minocycline
Allocation: Randomized
Masking: Double
Primary purpose: Treatment
Keywords: First episode psychosis; Schizophrenia; Minocycline; neuroprotection; First episode non affective psychosis; With in first five years of illness