Project 3 takes postmortem neurotransmitter findings in suicides with MDD and radioligand development of the last five years and brings them together in a fashion that is best done with in vivo positron emission tomography (PET). We and others find abnormalities of the serotonergic system, principally the serotonin IA receptor (5-HTIA ) and serotonin transporter (5-HTT) postmortem in depressed suicides. We have pilot PET data indicating that low 5-HTT binding in the same brain regions as suicides in MDD suicide attempters compared with MDD nonattempters and healthy volunteers. This indicates a potential suicide-related biological endophenotype in suicides that may be detectable in MDD before the first suicide attempt. In this project we seek to determine whether this is an endophenotype that is present before the first suicide attempt or onset of MDD, and its relationship to childhood adversity. We have found that 5-HTT binding is lower in depressed patients with reported childhood adversity. Rodent studies indicate that early adversity alters 5-HTIA binding. Specifically, we hypothesize that [11C]DASB 5-HTT binding will be low in MDD attempters and childhood adversity will contribute to this effect. With our new agonist 5-HTIA radiotracer, [11C]CUMI-101, we predict higher 5-HTIA agonist binding in MDD attempters as seen in suicides. We hypothesize that the 5-HTIA and 5-HTT binding in MDD suicide attempters, compared with MDD nonattempters and controls, will parallel findings in suicides. Both PET tracers will be used in the same groups to determine which tracer is best to detect differences between the groups, and these data will be used by Dr. Ogden in P6. To determine if this is a potential endophenotype, we will scan a group of high-risk offspring of MDD attempters before their first suicide attempt or episode of MDD. In the last two years of the project we will study new neurotransmitter targets to expand our knowledge base about suicidal behavior. We will determine monoamine oxidase A (MAOA) levels in healthy volunteers and MDD suicide attempters. MAOA is upregulated in MDD and responsible for the degradation of synaptic serotonin, DA and NE. In the same patients/controls as for MAOA, we will evaluate the endogenous opioid neurotransmitter system, by quantifying the kappa opiod receptor. In collaboration with other Cores and Projects, we will examine the relationship between the binding measures, fMRI responses during appraisal, stress responses, aggressive traits and the effects of reported childhood adversity.
A complete understanding of the molecular basis of mood disorders and suicidal behavior, specifically with in vivo imaging technologies, furthers our models of the pathophysiology of suicidal behavior. Identification of a potential endophenotype related to risk of suicidal behavior will take us one step closer to the development of biomarkers that will potentially result in diagnostic and prognostic indicators to be used in individualized prevention and treatment strategies.
|Chaudhury, Sadia R; Singh, Tanya; Burke, Ainsley et al. (2016) Clinical Correlates of Planned and Unplanned Suicide Attempts. J Nerv Ment Dis 204:806-811|
|Silvers, Jennifer A; Hubbard, Alexa D; Chaudhury, Sadia et al. (2016) Suicide attempters with Borderline Personality Disorder show differential orbitofrontal and parietal recruitment when reflecting on aversive memories. J Psychiatr Res 81:71-8|
|Kumar, J S Dileep; Underwood, Mark D; Simpson, Norman R et al. (2016) Autoradiographic Evaluation of [(18)F]FECUMI-101, a High Affinity 5-HT1AR Ligand in Human Brain. ACS Med Chem Lett 7:482-6|
|Gilead, Michael; Boccagno, Chelsea; Silverman, Melanie et al. (2016) Self-regulation via neural simulation. Proc Natl Acad Sci U S A 113:10037-42|
|Curley, James P; Champagne, Frances A (2016) Influence of maternal care on the developing brain: Mechanisms, temporal dynamics and sensitive periods. Front Neuroendocrinol 40:52-66|
|Schneck, Noam; Miller, Jeffrey M; Delorenzo, Christine et al. (2016) Relationship of the serotonin transporter gene promoter polymorphism (5-HTTLPR) genotype and serotonin transporter binding to neural processing of negative emotional stimuli. J Affect Disord 190:494-8|
|Lawrence, Ryan E; Brent, David; Mann, J John et al. (2016) Religion as a Risk Factor for Suicide Attempt and Suicide Ideation Among Depressed Patients. J Nerv Ment Dis 204:845-850|
|Reeck, Crystal; Ames, Daniel R; Ochsner, Kevin N (2016) The Social Regulation of Emotion: An Integrative, Cross-Disciplinary Model. Trends Cogn Sci 20:47-63|
|Silvers, Jennifer A; Hubbard, Alexa D; Biggs, Emily et al. (2016) Affective lability and difficulties with regulation are differentially associated with amygdala and prefrontal response in women with Borderline Personality Disorder. Psychiatry Res 254:74-82|
|Yin, Honglei; Pantazatos, Spiro P; Galfalvy, Hanga et al. (2016) A pilot integrative genomics study of GABA and glutamate neurotransmitter systems in suicide, suicidal behavior, and major depressive disorder. Am J Med Genet B Neuropsychiatr Genet 171B:414-26|
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