Testing the Ability of JNJ-18038683 to Improve Cognition and Reduce Depressive Symptoms in Stable Bipolar Patients
- Registration Number
- NCT02466685
- Lead Sponsor
- Herbert Meltzer
- Brief 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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 60
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Placebo Placebo Placebo treatment for 8 weeks. JNJ-18038683 JNJ-18038683 Subjects will be randomized to receive JNJ-18038683 or placebo after the completion of the baseline assessments. Subjects randomized to JNJ-18038683 will receive 10 mg for one week, then titrate to 20 mg for the duration of the trial, with the provision for a single, downward dose adjustment for intolerance, based upon investigator judgment.
- Primary Outcome Measures
Name Time Method The 8-week Evaluation of Verbal Fluency Performance After Randomization Baseline and week 8 Change in a score of Verbal Fluency from baseline to week 8 A higher amount of change represents a better outcome V.F., as a primary outcome measure, is one of the Cognitive battery tests used to evaluate neurocognitive functions, i.e., speed of processing, attention/vigilance, working memory, verbal learning, and visual learning.
The way to calculate the score: the participant is asked to produce as many words as possible from a category in a given time and each correct word gets 1 score Min raw score:0 Max raw score:60
- Secondary Outcome Measures
Name Time Method Montgomery-Asberg Depression Rating Scale Baseline to week 8 Secondary outcome measures will include mean changes of the Montgomery-Asberg Depression Rating Scale (MADRS) total score from baseline to week 8.
The MADRS will be utilized to assess a subject's level of depressive symptoms and must be administered using a structured interview guide.
This scale consists of 10 items, each with seven defined grades of severity (zero to six), and min score of 0, and a max score of 60.
Higher values represent a worse outcome. Notably, mean changes were not statistically significant in both groups.Clinical Global Impression Severity of the Subject With Bipolar Disorder Scale( CGI-S in BP) Change From Baseline to Week 8 Baseline to 8 weeks We assessed the clinical global Impression severity (CGI-S) scores change in JNJ-18038683 and the placebo group as an additional endpoint.
The scale rates the subject's Severity of Illness (CGI-BPSeverity: mania, depression, and overall bipolar illness). Using ANCOVA analysis to assess changes from baseline to week 8, based on the least-square means and standard errors was the method.
CGI-S scores range from 0 to 7. Higher scores mean a worse outcome.
Trial Locations
- Locations (1)
Northwestern University Feinberg School of Medicine; Department of Psychiatry and Behavioral Sciences
🇺🇸Chicago, Illinois, United States