Amisulpride Augmentation in Clozapine-unresponsive Schizophrenia
Condition: Schizophrenia
MeSH terms: Schizophrenia
Study type: Interventional
Phase: Phase 4

Summary: 
      Schizophrenia is a mental health problem usually starting in the late teens/early twenties,
      and often lasting many years. The standard medication ('antipsychotics') for this problem is
      usually helpful, and if taken continually can keep people well, reducing the likelihood of
      further episodes. However, in up to one in three people with schizophrenia, the illness does
      not show much improvement with antipsychotic medication. For some of these 'resistant'
      illnesses, one particular antipsychotic, clozapine, can work well, but one disadvantage is
      the risk of a severe blood side effect which means that regular blood testing is necessary.
      If the response to clozapine treatment is disappointing, there is some evidence that adding
      another antipsychotic can sometimes produce more improvement. However, it seems that the
      added antipsychotic may need to be taken by the person for at least 10 weeks in order to work
      well. The investigators plan to test carefully the possible benefits and problems when the
      antipsychotic amisulpride or a dummy tablet ('placebo') is added to clozapine for 12 weeks in
      people whose schizophrenia illness has not been helped much by any antipsychotic medication
      on its own, and who are now taking clozapine, but again with not much improvement. The
      investigators have chosen amisulpride because its pharmacological action may be complementary
      to that of clozapine, and also it is less likely than some other antipsychotics to compound
      some of the characteristic side effects of clozapine, such as sedation, weight gain and other
      metabolic problems.

      Adjunctive amisulpride or placebo will be randomly assigned. The investigators expect that
      adding amisulpride will be more likely to cause an improvement than adding placebo. But the
      investigators should learn more about the risks and side effects of combining these two
      medications. Also, the investigators should gain a greater understanding of the possible
      benefits of adding another antipsychotic to clozapine in relation to particular problem
      symptoms, and a person's ability to live and work in the community.
    

Detailed description: 
      This 12-week, placebo-controlled RCT will be conducted in secondary care, specifically mental
      health services, at UK centres. The health technology to be assessed is the augmentation of
      clozapine treatment with another second-generation antipsychotic, amisulpride, which will be
      compared with placebo: 400mg amisulpride or 1 matching placebo capsule for the first 4 weeks,
      then the option of titrating up to 800mg amisulpride or 2 matching placebo capsules for the
      remaining 8 weeks. The study will be double-blind, with medication supplied as identical
      capsules containing either 400mg amisulpride or placebo. The optimum dose of clozapine at
      entry and subsequent augmentation will be achieved through a flexible dosing regimen whereby
      treating psychiatrists will be able to flexibly alter dose regimens to maximise clinical
      risk-benefit ratios; there will be opportunities for clinical titration of clozapine dose at
      two and six weeks. Any direct pharmacokinetic effect on clozapine levels will be assessed by
      pre- and post-augmentation plasma levels of clozapine, samples being taken at baseline and at
      the end of the 12 weeks. Recommended pharmacovigilance procedures will be followed.
      Clinicians will be asked not to prescribe any additional medication during the course of the
      study, and will be reminded of the drugs with potential adverse interactions, as mentioned in
      the SPCs for clozapine and amisulpride. Medication adherence will be assessed by 'pill count'
      and clozapine/norclozapine plasma level ratio.

      Therapeutic improvement will be assessed in terms of overall symptom severity, but also using
      broader, clinically-relevant outcome measures of social and occupational function and target
      symptoms and/or behaviours as well as overall health status and utility. Side effects will be
      systematically assessed. The costs and outcomes for a cost effectiveness acceptability and
      net benefit analysis will also be measured. The primary economic measure will be the
      incremental cost effectiveness ratio of clozapine augmentation, estimated as the net cost of
      clozapine augmentation divided by net QALY of clozapine augmentation.

      Twenty-four months will be allowed for recruitment of participants, plus 3 months for the
      final follow-up assessments.
    

Intervention name(s): Amisulpride; placebo
Intervention type(s): Drug; Drug
Intervention description(s): Clozapine augmentation with another second-generation antipsychotic, amisulpride (400mg amisulpride for the first 4 weeks, then the option of titrating up to 800mg amisulpride for the remaining 8 weeks).; Clozapine augmentation with 1 capsule placebo for the first 4 weeks, then the option of titrating up to 2 capsules placebo for the remaining 8 weeks).
Intervention MeSH terms: Amisulpride
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary purpose: Treatment