Testing the Ability of JNJ-18038683 to Improve Cognition and Reduce Depressive Symptoms in Stable Bipolar Patients

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.

• Experimental: 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.
  Intervention: Drug: JNJ-18038683
• Placebo Comparator: Placebo
  Placebo treatment for 8 weeks.
  Intervention: Drug: JNJ-18038683

Inclusion Criteria:

1. All participants must have signed an informed consent document indicating they understand the purpose of the study and the procedures required for the study and are willing to participate by complying with the study procedures and restrictions.
2. Male or female subjects of any race; between 18 to 60 years of age, inclusive.
3. Resides in a stable living situation, according to the investigator's judgment.
4. Diagnosis of bipolar disorder I or II for at least 1 year in duration, as established by the SCID-I, and verified with medical records and/or confirmation of diagnosis by treating clinician. Patients will be in a nonacute phase at the time of initial screening and have been so for at least 1 month.

5. No more than moderate clinical symptom burden severity, as defined by the following:

   • Montgomery Asberg Depression Rating Scale < 20
   • Young Mania Rating Scale <12
6. Subjects medically stable enough to complete an 8 week clinical trial, in the judgment of the investigator
7. Women of childbearing potential must have a negative pregnancy test at screening and baseline, and agree to use adequate protection (i.e. double barrier method) for birth control.
8. Antidepressant (AD) medications are allowed if the subject has been treated with a stable dose for at least 2 months before screening.
9. Subjects receiving a single mood stabilizer (e.g., lithium. valproate, or lamictal) are allowed if a stable dose has been maintained for at least 2 months prior to screening.
10. Subjects may be receiving one treatment of each the following groups: antidepressants, mood stabilizers, and atypical antipsychotics (that are not 5-HT7 antagonists; see Appendix 2), but not more than one from each group.
11. Patients with a history of compliance with a drug treatment regimen for bipolar disorder, as noted in medical/psychiatric history.
12. Able to complete cognition assessments in English
13. Subjects must demonstrate a substantive cognitive deficit, as measured by the Trails A and Hopkins Verbal Learning Test (HVLT) administered at the screening visit. Eligible subjects will have an established cognitive deficit as measured by both of these tests, falling between the 25th and 75th percentile, using comparative norms according to age, gender, and education.
14. Able to understand and complete cognition assessments

Exclusion Criteria:

1. Failure to perform screening or baseline examinations
2. Hospitalization within 8 weeks before screening, or change in mood stabilizing or antidepressant medication or dose within 2 months prior to screening
3. Subjects who have participated in another clinical study within the past 2 months.
4. Subjects with tardive dyskinesia.
5. Subjects with other DSM-V Axis I or Axis II primary diagnoses.
6. Diagnosis of alcohol or substance use disorder within the past 3 months.
7. Subject assessed to be at significant suicide risk based on responses to the Columbia Suicide Severity Rating Scale (C-SSRS).
8. History of myocardial infarction, unstable angina, uncontrolled hypotension or hypertension within 3 months before screening.
9. Clinically significant abnormality on screening ECG.
10. Alanine transaminase (ALT) or aspartate transaminase (AST) > 2.5 times the upper limit of normal (ULN).
11. History of stroke, brain tumor, head trauma with loss of consciousness, or other clinically significant neurological condition within 12 months before screening.
12. Subjects with other uncontrolled medical conditions, in the opinion of the investigator.
13. Atypical antipsychotic drugs which are 5-HT7 antagonists, , e.g. risperidone, lurasidone and clozapine, are not permitted but other antipsychotic drugs which lack 5-HT7 antagonism, e.g. olanzapine and quetiapine, will be permitted if the subjects are on a stable dose for at least 6 months prior to study onset.
14. Use of drugs known to be metabolized by CYP2D6 (see Appendix 2)
15. Use of CNS stimulants (e.g., Adderall, Ritalin)