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Principal Investigator: Margaret Taylor Davis
Organization: YALE UNIVERSITY
Fiscal Year: 2024
Award: $798,272
Funding agency: National Institute of Mental Health
PROJECT SUMMARY
The goal of this study is to investigate the role of the kappa opioid receptor (KOR) in the symptomatology
of borderline personality disorder (BPD), a condition associated with alarmingly elevated risk for suicide
attempt (SA; up to 75%) and death by suicide (up to 10%). Despite BPD’s relatively low prevalence (1-5%),
epidemiological research has shown that up to 33% of suicide deaths in the general population are attributable
to BPD. Adding complexity, research suggests that significant sex differences exist in BPD with respect to both
symptoms’ presentation and neurobiology; BPD males have higher suicide risk, but less access to effective
treatment. Despite this, available treatments are largely not capable of addressing overall BPD symptom
severity or rapidly reducing suicide risk. Magnetic resonance imaging (MRI) studies have identified structural
and network alterations in BPD and have associated structural differences and dysregulation in a frontolimbic
circuit of regions with incidence of BPD and increased symptom severity, and suicidal behavior in BPD.
Investigation of molecular mechanisms responsible for BPD symptoms, and suicide risk specifically, is an
essential next step to both promote development of novel treatments and facilitate risk prevention in BPD.
Emerging evidence implicates KOR in BPD and suicidal behavior. KOR plays critical roles in emotion
regulation, social functioning, and impulsivity– all of which are both central to BPD and related to suicide risk.
Postmortem studies have shown an association between KOR and death by suicide. Further, a variety of
studies in both animals and humans have shown that KOR antagonists can produce antidepressant, anxiolytic,
and even anti-suicidal effects, though research also suggests men and women may respond differently to such
agents. Importantly, KOR agents’ effect on dopamine is modest relative to drugs of abuse, reducing concerns
about abuse potential. Based on support from novel pilot data using the same techniques, we now propose a
novel investigation of KOR availability in individuals with BPD relative to healthy adults (HA) using positron
emission tomography (PET), a brain imaging technique, and radioligand [11C]EKAP which binds selectively to
KOR in the brain (Aim 1a). We will also evaluate the association between KOR availability and SA history in
BPD (Aim 1b). Next, we will evaluate the association between impulsivity, emotion dysregulation, and BPD
symptom severity – key endophenotypes related to prognosis and suicide risk and resistant to treatment – and
KOR availability in BPD (Aim 2). Finally, we will evaluate sex differences in KOR availability in BPD and HA.
Results of this study will provide potentially critical insight into the relationship between this novel molecular
target, BPD symptom presentation, and suicidal behavior. Based on findings we will pursue funding for a larger
PET study to test potential non-addictive KOR targeted medications for both overall BPD symptom reduction,
and suicide risk.
Terms: <21+ years old><5-HT><5-Hydroxytryptamine><5HT><Address><Adult><Adult Human><Aeroseb-HC><Affect><Affective><Aggression><Aggressive behavior><Animals><Anti-Anxiety Agents><Anti-Anxiety Drugs><Anxiolytic Agents><Anxiolytics><Area><Attention><Autopsy><Binding><Borderline Personality Disorder><Brain><Brain Nervous System><Brain imaging><C-Fragment Endorphin><Central Lobe><Cetacort><Chronic><Chronic stress><Clinical><Clinical Trials><Cognitive Disturbance><Cognitive Impairment><Cognitive decline><Cognitive function abnormal><Cort-Dome><Cortef><Cortenema><Cortisol><Cortispray><Cortril><Data><Deliberate Self-Harm><Depressed mood><Dermacort><Development><Diagnostic><Differences between sexes><Differs between sexes><Disease><Disorder><Dissociation><Distress><Disturbance in cognition><Dopamine><Down-Regulation><Drugs><Dynorphins><Dysfunction><Eldecort><Encephalon><Enteramine><Epidemiologic Research><Epidemiologic Studies><Epidemiological Studies><Epidemiology Research><Functional disorder><Funding><Future><General Population><General Public><Goals><Hippophaine><History><Human><Hydrocortisone><Hydrocortone><Hydroxytyramine><Hytone><Imaging Procedures><Imaging Technics><Imaging Techniques><Impaired cognition><Impulsivity><Incidence><Individual><Insula><Insula of Reil><Intervention><Intervention Strategies><Investigation><Island of Reil><Life><Link><Lipotropin Fragment C><Low Prevalence><MR Imaging><MR Tomography><MRI><MRIs><Magnetic Resonance Imaging><Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance><Medication><Minor Tranquilizing Agents><Modern Man><Molecular><Molecular Interaction><Molecular Target><Morbidity><Morbidity - disease rate><NMR Imaging><NMR Tomography><Neurobiology><Nuclear Magnetic Resonance Imaging><Nutracort><Opiate Antagonist><Opiate Peptides><Opiate receptor antagonist><Opiates><Opioid><Opioid Antagonist><Opioid Peptide><Opioid receptor antagonist><PET><PET Scan><PET imaging><PETSCAN><PETT><Pain><Painful><Participant><Peripheral><Pharmaceutical Preparations><Physiopathology><Play><Positron Emission Tomography Medical Imaging><Positron Emission Tomography Scan><Positron-Emission Tomography><Prevention><Proctocort><Prognosis><Rad.-PET><Recording of previous events><Regulation><Research><Resistance><Risk><Risk Reduction><Role><Self-Injurious Behavior><Serotonin><Severities><Sex Differences><Sexual differences><Social Functioning><Stress><Suicide><Suicide attempt><Symptoms><System><Techniques><Testing><Treatment outcome><Underserved Population><Woman><Work><Zeugmatography><abuse liability><abuse potential><abused drug><abused drugs><adulthood><alleviate symptom><ameliorating symptom><anti-depressant agent><anti-depressant drugs><anti-depressants><anti-depressive agents><beta-Endorphin><beta-Lipotropin C Fragment><brain visualization><clinical relevance><clinically relevant><cognitive dysfunction><cognitive loss><decrease symptom><deliberate self harm><depressed><develop therapy><developmental><disease risk><disorder risk><drug abused><drug of abuse><drug/agent><drugs abused><drugs of abuse><effective therapy><effective treatment><emotion dysregulation><emotion regulation><emotional dysregulation><emotional regulation><endogenous opiate><endogenous opioids><endophenotype><epidemiologic investigation><epidemiology study><experience><fatal attempt><fatal suicide><fewer symptoms><function socially><functioning social><high risk><high risk group><high risk individual><high risk people><high risk population><histories><imaging study><in vivo><innovate><innovation><innovative><insight><intent to die><intentional self harm><intentional self injury><intervention development><interventional strategy><kappa opiate><kappa opioid><kappa opioid receptors><male><men><mortality><mu opioid receptors><necropsy><neurobiological><non fatal attempt><nonfatal attempt><novel><opiate deaths><opiate mortality><opioid deaths><opioid mortality><opioid overdose death><opioid related death><pain perception><pathophysiology><pharmacologic><positron emission tomographic (PET) imaging><positron emission tomographic imaging><positron emitting tomography><postmortem><pre-clinical><pre-clinical study><preclinical><preclinical study><psychiatric symptom><radiolabel><radiolabels><radioligand><radiotracer><receptor expression><receptor-mediated signaling><reduce risk><reduce risks><reduce suicidality><reduce suicide><reduce symptoms><reduce that risk><reduce the risk><reduce these risks><reduces risk><reduces the risk><reducing risk><reducing suicidality><reducing suicide><reducing the risk><relieves symptoms><resistant><response><risk-reducing><sadness><self harm><self injury><sex><sex based differences><sex-dependent differences><sex-related differences><sex-specific differences><social><social role><stress related disorder><suicidal><suicidal attempt><suicidal behavior><suicidal morbidity><suicidal mortality><suicidal risk><suicidality><suicide behavior><suicide death><suicide morbidity><suicide mortality><suicide mortality rate><suicide risk><suicides><symptom alleviation><symptom reduction><symptom relief><symptom treatment><symptomatic treatment><symptomatology><targeted agent><therapy development><treat symptom><treatment development><treatment risk><under served group><under served individual><under served people><under served population><underserved group><underserved individual><underserved people><β-Endorphin><κ opiate><κ opioid><κ opioid receptors><κ-OR><κOR><μ opioid receptors><μ-OR><μOR>