MICA:Translational validation of 5HT7 antagonists for the treatment of cognitive impairment in bipolar disorder: a proof of concept neuroimaging study

Bipolar disorder is a serious mental health problem in which people experience repeated episodes of depression and elated mood. Bipolar disorder affects around 1.2 million people in the UK and costs around £5.2 billion per year. Around 60% of people with bipolar disorder experience problems with their attention and memory, known as cognitive impairment, which greatly affects the ability to work and hold relationships. Currently there are no effective drug treatments for cognitive impairment experienced by people with bipolar disorder. However, drugs which block a type of brain chemical receptor, called the 5HT7 receptor, may be a promising new treatment. The main aim of this study is to understand the effect of a medication called JNJ-18038683, which specifically blocks the 5HT7 receptor, on brain activity and cognitive performance. We will examine the effect of JNJ-18038683 in people with bipolar disorder who show evidence of cognitive impairment and also in healthy people. We plan to do this to determine whether JNJ-18038683 affects brain activity which occurs whilst performing attention and memory tasks, and whether JNJ-18038683 corrects impairments in brain activity and cognitive performance. We plan to recruit 34 people with bipolar disorder and 34 healthy people to take part in the study. Each person taking part in the study will be carefully screened for suitability and will then complete tests of attention and memory function which measures cognitive performance. They will then take 10mg JNJ-18038683 for one week and will be switched to placebo for one week, or vice versa, after a two-week drug free period. Some participants will take JNJ-18038683 first and some will take placebo first, and neither participants nor the staff running the study will know which medication has been taken. We will study the effects of JNJ-18038683 and placebo on brain activity and cognitive performance on day 7 of each treatment period. Brain activity will be measured using a brain scan called magnetic resonance imaging (MRI) which produces very detailed images of the structure and function of the brain. We will examine how JNJ-18038683 and placebo affects the levels of brain activity during the MRI scan by asking participants to complete thinking and mood tasks in the scanner and then analysing the level of brain activity this produces. We plan to assess whether JNJ-18038683 changes brain activity produced during these tasks, and in people with bipolar disorder whether JNJ-18038683 normalises brain activity, by comparing brain activity levels on day 7 of JNJ-18038683 and placebo treatments. We will also assess whether JNJ-18038683 improves cognitive performance by comparing memory and attention test results on day 7 of JNJ-18038683 and placebo treatments. We hope that these results will support the development of further large clinical treatment studies. When the study is complete we will publish its results in scientific journals and communicate this to people with bipolar disorder, mental health professionals and to the general public through press briefings and social media. Overall, we anticipate that this study will allow us to better understand the potential of 5HT7 blockers such as JNJ-18038683 for the treatment of cognitive impairment in people with bipolar disorder which we hope will lead to the development of new treatments.

Bipolar disorder is one the most disabling mental health disorders and is associated with widespread cognitive deficits. Cognitive impairment is an important treatment target in bipolar disorder as cognitive deficits are associated with poor functional outcomes. Importantly, there are no effective treatments for cognitive impairment in bipolar disorder. Converging evidence indicates that serotonin 5HT7 receptor antagonists have great potential as new treatments for cognitive impairment in bipolar disorder. However, no human mechanistic, proof of concept, studies are available which validate 5HT7 antagonists for the treatment of cognitive impairment in bipolar disorder. The aim of this study is to examine whether the selective 5HT7 antagonist JNJ-18038683 modulates cognition related brain activity (proof of target) and, in cognitively impaired people with bipolar disorder, impaired brain activity (proof of principle). We will also examine JNJ-18038683 effects on cognitive performance. The study will use a randomized, counterbalanced, double-blind, placebo controlled, cross-over design to examine the effects of one-week administration of JNJ-18038683 and placebo on cognition related brain activity and cognitive performance in 34 cognitively impaired people with bipolar disorder and 34 healthy controls. Participants will complete a baseline clinical and cognitive assessment visit where cognitive performance will be assessed using the ISBD-BANC cognitive battery. Participants will be assessed on day 7 of each treatment using functional MRI to determine effects on cognition and emotional processing brain activations and cerebral blood flow, and using the ISBD-BANC to determine effects on cognitive performance. The proposed research will provide new insights into the effects of 5HT7 receptor antagonism on brain function and cognitive performance which may validate 5HT7 receptor antagonism as a tractable treatment mechanism for cognitive impairment in bipolar disorder.

The following groups will benefit from this research: 1. People with bipolar disorder: This application is designed to principally benefit people with bipolar disorder by supporting the development of new treatments for cognitive impairment. People with bipolar disorder commonly experience cognitive impairments which significantly impacts on social and vocational functioning and there are no clinically effective treatments for these impairments. The proposed study will support the development of new treatments by potentially validating 5HT7 antagonism as a treatment mechanism through demonstrating improvements in functional brain activity associated with cognitive impairment and may predict clinically relevant long-term efficacy.
2. Mental health researchers: The study will provide the study research associate with skills in neuroimaging, and in the assessment of cognition and treatment effects. The study will benefit bipolar disorder researchers by establishing the effects of 5HT7 antagonism on brain function in cognitively impaired people with bipolar disorder and healthy participants. This may validate 5HT7 antagonists as potential treatments, provide data on 5HT7 antagonist effects on normal brain function, and demonstrate the feasibility of a pharmacological fMRI approach to the early screening of new compounds. The study findings may stimulate further neuroimaging studies and clinical trials. The study will benefit researchers in disorders related to bipolar disorder, such as schizophrenia and major depressive disorder where cognitive impairments also occur, as it will provide a framework to compare 5HT7 treatment effects on brain function across disorders using the bipolar and healthy participant group results as a comparator. 3. Life sciences industry: This research will be of great interest to our collaborators Johnson & Johnson, and to other life science companies, as it will provide human in vivo evidence of 5HT7 antagonist target engagement of cognitive and emotional brain circuits and whether JNJ-18038683 remediates impaired brain function in bipolar disorder. This may provide early evidence of JNJ-18038683 efficacy which would then support further clinical trials. The study complements a JNJ-18038683 phase 2 clinical trial in major depressive disorder which called for further work in this area (Bonaventure et al., 2012). 4. Mental health clinicians: This research will benefit mental health clinicians as it will further our understanding of the clinical potential of 5HT7 antagonists for the treatment of cognitive impairment in bipolar disorder which will support clinicians in discussing the potential for new treatments with their patients. 5. Cognitive psychologists: This research will benefit cognitive psychologists as it may demonstrate early improvements in cognitive function associated with 5HT7 antagonism which could then be explored in further clinical trials.
6. Healthcare stakeholders: This research will benefit stakeholders such as NICE and the British Association for Psychopharmacology, by examining the effectiveness of 5HT7 antagonist treatments for cognitive impairment in bipolar disorder. This evidence could be incorporated into future treatment guidelines when medications with 5HT7 antagonist properties are reviewed.
7. Bipolar disorder charities and the wider public: The study results will benefit service user organisations, such as Bipolar UK, and the wider public by raising public awareness of cognitive impairment in bipolar disorder and the potential for new treatments which can contribute towards mental health education and tackling stigma. 8. UK economy and the taxpayer: Bipolar disorder costs the United Kingdom £5.2 billion per year annually and costs around £342 million in direct NHS healthcare costs. This study is designed to provide a biological rationale for the development of a new treatment approach which if successful could reduce the vocational and social costs of bipolar disorder.