Testing the Ability of JNJ-18038683 to Improve Cognition and Reduce Depressive Symptoms in Stable Bipolar Patients
Condition: Bipolar Disorder
MeSH terms: Bipolar Disorder; Depression
Study type: Interventional
Phase: Phase 2

Summary: 
      The goals of this study are to evaluate the efficacy of JNJ-18038683 in an 8 week trial to
      ameliorate the cognitive deficit and reduce residual depressive symptoms in 60 stable bipolar
      outpatients receiving treatment for depression. JNJ-18038683 will be studied and compared
      with placebo as adjunctive treatment to standard pharmacologic treatment for bipolar
      disorder.
    

Detailed description: 
      Most, but not all, patients with bipolar disorder (BPD) have clinically significant cognitive
      impairment. Impairment is present in both the manic and depressed phases of BPD, as well as
      in euthymic periods. The percentage of BPD patients with cognitive impairment (CIBD) varies
      among studies, with 40-60% representing the best estimate. The weight of the evidence
      supports no overall difference in the type and severity of cognitive impairment in any phase
      of BPD, i.e. it is a stable trait feature of BPD, albeit variable from one patient to
      another. The most commonly affected cognitive domains are speed of processing, declarative
      memory, attention and working memory. Although CIBD is milder in severity than the cognitive
      impairment associated with schizophrenia (CIAS), on average, as in schizophrenia, CIBD has a
      major impact on function and quality of life in most patients, particularly because the
      greater preservation of function of BPD enables them to engage in activities which are more
      dependent on intact cognitive function. Thus, it is highly likely that improvement in CIBD
      will have valuable clinical benefit, especially with regard to quality of life measures. It
      is reasonable to predict that treatments effective to improve CIBD could also be beneficial
      for CIAS. Efficacy for cognitive impairment is likely to be greater in BPD than
      schizophrenia, because the baseline severity is milder in the former. Despite this strong
      rationale for targeting CIBD, there has been minimal focus on clinical trials to improve
      CIBD, perhaps because so many resources have been devoted to the effort to treat CIAS, but
      lack of appreciation of the severity of CIBD and its importance as a determinant of
      functional outcome in BPD may be the most important factors.

      In a recent study of CIBD, using the MATRICS Consensus Cognitive Battery (MCCB), impairment
      was found in both treatment resistant BP I and II depressed inpatients within all MCCB
      domains. The greatest impairment was evident in speed of processing, declarative memory and
      attention. The impairment was numerically greater in BP I than BP II patients but the
      difference was not significant. Compared to normal controls, the deficits, in BP 1 patients,
      in speed of processing was 1.2SD, in attention, 1.0 SD, and in verbal learning, 1.8 SD. The
      least affected domain was visual learning, with a mean deficit of 0.8SD compared to normal
      controls. The mean composite score deficit was 1.25 SD. Medication for BPD, particularly mood
      stabilizers, may adversely affect some domains of cognition in BPD. However, antidepressant
      medications have not been found to affect the severity of cognitive impairment in major
      depression or BPD.

      Based on the pre-clinical, pro-cognitive effects of 5-HT7 antagonism in our laboratory, along
      with the reported pre-clinical antidepressant effects of JNJ-18038683, we propose to conduct
      a randomized, placebo- controlled parallel, design study to assess the effects of
      JNJ-18038683 on multiple domains of cognition and mood symptoms. Since our preclinical
      studies show that 5-HT7 receptor blockade is highly effective in improving declarative memory
      in rodents, the declarative memory measures will be the primary outcome measures.

      Due to the effect of JNJ-18038683 on depressive symptoms in preclinical paradigms, we will
      investigate the following in the clinical trial the potential antidepressant effect of
      JNJ-18038683 on patients with baseline MADRS score between 8 and 20.
    

Intervention name(s): JNJ-18038683; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): JNJ-18038683 10-20 mg/day tablet for 8 weeks; placebo tablet daily
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Bipolar; Depression; Cognition; Cognitive