Treatment Study for Cognitive Deficits in Schizophrenia
Condition: Schizophrenia
MeSH terms: Schizophrenia
Intervention: MK-0777; MK-0777; placebo
Intervention description: MK-0777 GEM, 8 mg BID; MK-0777 GEM, 3 mg BID; 2 tablets placebo BID
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 63.0
Sex: All
Minimum age: 18 Years
Maximum age: 60 Years
Healthy volunteers: No
Keywords: Cognition; Schizophrenia

Summary:

      Patients with schizophrenia are characterized by a broad range of neurocognitive
      abnormalities. These include impairments in attention, including abnormalities in sensory
      gating; executive function; visual and verbal learning and memory; working memory; processing
      speed; and social cognition (Nuechterlein et al, 2004). These impairments are major
      determinants of poor functional outcome in patients with schizophrenia (Green, 1996; Green et
      al, 2004). Conventional antipsychotics have limited effects on these impairments. Second
      generation antipsychotics may have modest benefits for cognitive function, but whether this
      represents a direct cognitive enhancing effect has not been established. Regardless, patients
      continue to exhibit pronounced cognitive impairments despite adequate second generation
      antipsychotic treatment. Adjunctive pharmacotherapy may offer a viable approach for the
      treatment of cognitive impairments. Adjunctive agents can be used to modulate specific
      neurotransmitter systems that are hypothesized to be involved in the pharmacology of
      cognitive functions.

      The standard of care for schizophrenia is antipsychotic medications to treat psychotic
      symptoms. However, cognitive impairments remain and these impairments have been found to be
      significantly associated with the poor psychosocial function observed in patients with
      schizophrenia. There is a considerable preclinical rationale for the use of drugs that act at
      the Gamma-amino-buyric acid (GABA) α2 subunit as adjunctive treatments to target cognitive
      impairments. MK-0777 GEM (Merck-0777 Gel Extrusion Module) formulation provides an
      opportunity to directly test this mechanism.

      The purpose of the proposed study is to examine the efficacy and safety of two doses of MK
      (Merck) -0777 GEM, 3 mg BID (twice daily) and 8 mg BID (twice daily), in the treatment of
      cognitive impairments in patients with schizophrenia. Secondary goals are to determine
      whether MK-0777 has beneficial effects on measures of functional capacity and patient
      self-report of cognitive function.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Diagnosis: DSM IV/DSM IV TR schizophrenia (including disorganized, paranoid,
             undifferentiated, and catatonic subtypes)

          -  Capable of providing informed consent

          -  Duration of illness equal to or greater than one year

          -  Treated with one or two of the following second generation antipsychotics:
             risperidone, paliperidone, olanzapine, quetiapine, ziprasidone, or aripiprazole for
             the previous two months, with no change in dose in the last month.

          -  Meet the following symptom criteria:

               -  Brief Psychiatric Rating Scale (BPRS) Hallucinatory Behavior, Unusual Thought
                  Content or Conceptual Disorganization item score ≤ 4

               -  All Scale for the Assessment of Negative Symptoms global items ≤ 3

               -  Simpson-Angus Scale total score ≤ 6

               -  Calgary Depression Scale total score ≤ 10

          -  Meet the following cognitive performance criteria:

               -  Performance less than the maximum cutoff (in parentheses) for ONE of the
                  following MCCB tests: i.) Letter-number span (20); ii.) HVLT total (31); and
                  iii.) CPT d-prime (3.47)

               -  Able to complete the baseline MCCB validly

               -  Raw score ≥6 on the WTAR

        Exclusion Criteria:

          -  Current treatment (within 4 weeks) with conventional antipsychotics (e.g.
             fluphenazine, haloperidol) or clozapine

          -  Current treatment with psychotropic agents known to act at the GABAA receptor,
             including benzodiazepines; sedative-hypnotics other than trazadone and chloral
             hydrate; carbamazepine, gabapentin, lamotrigine, and valproic acid

          -  Current treatment with a drug that inhibits CYP3A4, including: cimetidine;
             cyclosporine; erythromycin or erythromycin-like drugs (e.g., azithromycin,
             clarithromycin); diltiazem; fluoxetine, fluovoxamine; itraconazole, ketoconazole or
             other systemic antifungal agents in the azole class; nefazodone; or induce CYP3A4,
             including: carbamazepine, modafinil; phenobarbital; phenytoin; rifampin; St. Johns
             wort; and troglitazone.

          -  Current treatment with psychotropic agents known to effect cognition: amphetamine;
             barbiturates; lithium; MAOIs; methylphenidate

          -  Current treatment with herbal preparations with possible psychotropic effects (e.g.,
             St. Johns wort, kava-kava, Valerian, S-Adenosyl Methionine [SAMe])

          -  Current treatment with systemic steroids

          -  DSM-IV diagnosis of alcohol or substance abuse (other than nicotine) within the last
             month or a DSM-IV diagnosis of alcohol or substance dependence within the last 6
             months

          -  Presence of PI or greater posterior subcapsular cataracts

          -  Uveitis with 1+ or greater flare or cells

          -  Nuclear or cortical cataracts

          -  History of significant head injury/trauma, as defined by one or more of the following:
             loss of consciousness (LOC) for more than 1 hour, seizures from the head injury, clear
             cognitive sequellae of the injury, or cognitive rehabilitation following the injury

          -  History of clinically significant neurological, metabolic, hepatic, renal,
             hematological, pulmonary, cardiovascular, gastrointestinal, and/or urological
             disorders.

          -  Clinically significant abnormalities in physical examination, ECG, or laboratory
             assessments

          -  A positive test for Hepatitis C antibody with concurrent evidence of impaired hepatic
             function (increased AST or ALT greater than 2 times the upper limit of normal) or
             positive tests for Hepatitis A antibody IgM fraction or Hepatitis B surface antigen,
             irrespective of the AST or ALT values.

          -  Pregnant women or women of child-bearing potential, either not surgically-sterile or
             using appropriate methods of birth control

          -  Women who are breast-feeding

          -  History of severe symptoms of benzodiazepine withdrawal (e.g., history of seizures or
             delirium associated with withdrawal)

          -  Received ECT treatment within the last 3 months

          -  Participated in a clinical trial of any other psychotropic medication within 2 months