Ramin V. Parsey - US grants

We are investigating the role of the dopaminergic system in bipolar and unipolar depression. We are performing baseline, dopamine depleted, and dopamine stimulated scans in people with depression and comparing these scans to those in healthy controls. This study will give us an in-vivo estimation of synaptic dopamine and aid in the diagnosis and treatment of patients with depression.

DESCRIPTION (Provided by Applicant): Structural and functional imaging studies have suggested a neurocircuitry of mood disorders that involves a limbicthalamic-cortical circuit (amygdala, thalamus, prefrontal cortex) and a limbic-striatal-pallidal-thalamic-cortical circuit. Abnormalities in a component of these circuits may affect the regulation of mood. Serotonin has been implicated in the pathophysiology of depression. Reports of fewer platelet serotonin transporters in major depression have rarely been extended to postmortem brain studies and neuroreceptor imaging studies in vivo. Serotonin transporter binding in the brainstem of depressed patients measured by SPECT is reportedly lower. ["C]McN5652 is a PET radioligand with high affinity for the serotonin transporter. Our group has developed kinetic modeling methods with this ligand that allow quantification of the serotonin transporter in subcortical and to a lesser extent in some cortical structures. We propose an in vivo study of the neurocircuitry of the serotonergic system in major depression. We predict that transporter binding will be decreased in depressed subjects in the midbrain, thalamus, putamen, hippocampus, and amygdala. Symptoms of depression have been correlated to serotonergic measures, including suicidal ideation, psychomotor retardation, and anxiety. We will correlate these measures of psychopathology with ["C]McN5652 binding. Correlations will help refine the neurocircuitry model of depression. Several lines of evidence suggest that serotonin dysfunction in depression may be a trait marker. Consequently, we will study both currently depressed (n=40) and remitted depressed subjects (N=20) while off medication, and compare both groups to healthy volunteers (N=20). We predict remitted depressed will not differ from currently depressed subjects. These results will greatly enhance our knowledge of the pathophysiology of major depression and help in our diagnosis, treatment, and design of future studies. This application for a Mentored Clinical Scientist Development Award has been submitted with the goal of supporting the development of the applicant's career as a psychiatric researcher. This research plan is intended to build on the candidate's prior work with neuroreceptor imaging in mood disorders. This application delineates plans for training and mentoring in the areas of the neurobiology of depression, cell and molecular physiology, pharmacology, neuroanatomy, statistical analysis, clinical diagnosis and ratings, teaching, brain imaging, and mathematical modeling necessary to enable the applicant to pursue an independent career of scientific inquiry in psychiatry. These goals will be met by a combination of didactic I course work and supervision.

DESCRIPTION (provided by applicant): Pharmacotherapeutic treatments are the most common intervention in the treatment of major depressive disorder (MDD). Response rates to the first antidepressant can be as low as 50-60%1 while clinically more meaningful remission rates are typically only between 20%2-35%1. Development of biological tests that would enable clinicians to select the correct class of antidepressant would significantly reduce morbidity and mortality associated with MDD by reducing the time to remission. We propose to evaluate potential biological tests that can predict remission from MDD when treated with a selective serotonin reuptake inhibitor (SSRI) and whether an individual patient is more likely to respond to a SSRI or a selective norepinephrine reuptake inhibitor (SNRI), the 2 most common classes of medication for MDD. We have shown that depressed patients have higher serotonin 1A (5-HT1A) binding potential than controls. Additionally, in a naturalistic treatment study we found MDD patients with higher 5-HT1A binding potential were less likely to remit to community based treatment. It has recently been shown that baseline serotonin transporter (5-HTT) availability in the midbrain, but not striatum3, predicts response to treatment with a SSRI.4 In our naturalistic study we show that remitters have higher 5-HTT binding potential in a regionally specific manner compared to non-remitters. The treatment protocol was not controlled in our pilot study and there were too few patients to determine if remission depended on the class of antidepressant. In this proposal, we propose to perform pretreatment positron emission tomography (PET) scans and have all patients receive a standardized treatment protocol of a SSRI followed by a SNRI in SSRI non-remitters. Escitalopram is the SSRI and desipramine the SNRI of choice because at the doses we will administer, they are highly selective for the respective transporters. We hypothesize that patients with high pre and postsynaptic 5-HT1A binding potential and low 5-HTT binding potential in the midbrain, amygdala, thalamus, and dorsal putamen will not remit to a SSRI and will remit to a SNRI. Finally, we will generate a predictive model of remission based on brain imaging outcome measures. Our overall goal is to reduce the trial and error associated with finding an effective antidepressant by using data from pre-treatment quantification of 5-HT1A receptors and 5-HTT to guide antidepressant treatment selection.

DESCRIPTION (provided by applicant): Major Depressive Disorder (MDD) is associated with structural, functional, and neurochemical alterations in key interrelated brain circuits involved in emotion, reward, and executive functioning. Current models of its etiology, including genetic expression, gene environment interactions, the monoamine hypothesis, and neurogenesis guided our choice of biomarkers. We propose to use biomarkers from several levels of organization that address one or more of these models and examine their ability to predict treatment remission. At the genetic level, we will examine epigenetic measures and the transcriptome. At the molecular level, the utility of measures of 5HT1a neuroreceptor binding using Position Emission Tomography and proteomics will be investigated. At the anatomical level, we will examine white matter tract integrity and regional decreases in cortical thickness. Functional assessments include electroencephalography, loudness dependent auditory evoked potentials, and neurocognitive performance. Clinical features will be studied as well, e.g. presence of anxious depression, family history of depression, and others. While receiving supportive clinical management, 300 patients will be observed medication free for 3 weeks, to diminish the influence of placebo response and minimize effects on biosignature assays. Those still meeting criteria after the 3 weeks will receive all aforementioned assessments. Patients then will be randomized in a doublemasked fashion to bupropion or escitalopram, two of the most commonly prescribed treatments for depression, with putatively distinct mechanisms of action. Treatment will be for 12-14 weeks. Treatment outcome will be remission, measures of symptomatic improvement, and assessment of adverse events. Non-remitters will be crossed over. Outcomes will be measured with both traditional and contemporary clinical assessments. Patients will be followed for 6 months after randomization to assess maintenance of response and remission. We will also use a comprehensive analysis algorithm, using novel statistical techniques for high dimensional data to develop an optimal predictive model of treatment outcome that includes all data recorded from all modalities. The statistical team will develop new strategies to address the complex data set to be generated by this study. The resulting optimized algorithm for predicting remission can serve as the basis for a new study intended to validate this tool for personalized treatment of depression. Data and biological materials collected in this project would become part of a repository, open to qualified individuals for additional analysis.

DESCRIPTION (provided by applicant): Bipolar disorder (BPD) is a brain disorder characterized by recurrent manic and major depressive episodes with a one year prevalence rate between 1-2%.1 BPD ranked 20th in terms of causes of loss of disability- adjusted life-years in 19992 and is associated with a life time suicide risk of up to a 19%.3 The main burden of illness in BPD is in the depressive pole. A deficiency of serotonin (5-HT) function has been postulated to underlie depressive episodes yet few studies have examined indices of 5-HT neurotransmission in the brain in BPD. It is widely acknowledged that there are significant gaps in the current identification and treatment of bipolar depression.5-8 Better understanding of the neurotransmission deficits in BPD may aid diagnosis, identification of biomarkers and treatment targets to facilitate treatment development and ultimately to assist in treatment selection. Our preliminary data with [11C]DASB shows lower binding in BPD. We propose to determine the extent and nature of abnormalities of 5-HTT binding in vivo using positron emission tomography (PET) in medication-free bipolar I depression. We hypothesize that BPD has lower 5-HTT binding compared to controls. We will also investigate the 5-HT effects of a common treatment for BPD, lithium. Discovered decades ago, lithium remains one of the few effective treatments in BPD, with evidence of mood stabilizing, antidepressant, antisuicidal, and even neuroprotective qualities and is considered to be first line treatment. The actions of lithium on 5-HT indices may be central to its antidepressive and antisuicidal properties. We hypothesize that lithium downregulates presynaptic 5-HT1A receptor binding, upregulates postsynaptic 5-HT1A binding, upregulates 5-HTT binding, and these molecular effects will be related to clinical improvement, both in depression and suicidality. 5-HT1A binding potential will be determined using [11C]WAY 100635. We propose to perform [11C]DASB and [11C]WAY 100635 scans in 38 medication free BPD I subjects during a major depressive episode and compare 5-HTT and 5-HT1A binding potential in 38 healthy volunteers. We will also examine the diagnostic specificity of lithium response by studying 10 unipolar depressed subjects in an identical manner. We will examine the pharmacological specificity of lithium by studying lamotrigine in BPD subjects. Finally, we will also assess the ability of baseline scanning to predict treatment response. All BPD subjects will be treated with lithium and have repeat scans with both radiotracers. Many with BPD do not tolerate lithium's side effect burden, and it has a narrow therapeutic window. In this grant period we will determine at which 5-HT protein(s) lithium exerts its antidepressant and antisuicidal properties. Ultimately this can lead to novel therapeutics that are better tolerated. We will independently advance our understanding of the molecular pathophysiology of BPD as well as characterize the mechanisms of action of lithium. PUBLIC HEALTH RELEVANCE: Bipolar disorder or manic depressive illness is a very common and devastating brain illness. Very little is known about the biological basis of this illness and less is known about the mechanism of action of our commonly prescribed medications. With this proposal we will significantly increase our understanding of both the illness and its treatment using state of the art brain imaging technologies.

DESCRIPTION (provided by applicant): Bipolar disorder (BPD) is a brain disorder characterized by recurrent manic and major depressive episodes with a one year prevalence rate between 1-2%.1 BPD ranked 20th in terms of causes of loss of disability- adjusted life-years in 19992 and is associated with a life time suicide risk of up to a 19%.3 The main burden of illness in BPD is in the depressive pole. A deficiency of serotonin (5-HT) function has been postulated to underlie depressive episodes yet few studies have examined indices of 5-HT neurotransmission in the brain in BPD. It is widely acknowledged that there are significant gaps in the current identification and treatment of bipolar depression.5-8 Better understanding of the neurotransmission deficits in BPD may aid diagnosis, identification of biomarkers and treatment targets to facilitate treatment development and ultimately to assist in treatment selection. Our preliminary data with [11C]DASB shows lower binding in BPD. We propose to determine the extent and nature of abnormalities of 5-HTT binding in vivo using positron emission tomography (PET) in medication-free bipolar I depression. We hypothesize that BPD has lower 5-HTT binding compared to controls. We will also investigate the 5-HT effects of a common treatment for BPD, lithium. Discovered decades ago, lithium remains one of the few effective treatments in BPD, with evidence of mood stabilizing, antidepressant, antisuicidal, and even neuroprotective qualities and is considered to be first line treatment. The actions of lithium on 5-HT indices may be central to its antidepressive and antisuicidal properties. We hypothesize that lithium downregulates presynaptic 5-HT1A receptor binding, upregulates postsynaptic 5-HT1A binding, upregulates 5-HTT binding, and these molecular effects will be related to clinical improvement, both in depression and suicidality. 5-HT1A binding potential will be determined using [11C]WAY 100635. We propose to perform [11C]DASB and [11C]WAY 100635 scans in 38 medication free BPD I subjects during a major depressive episode and compare 5-HTT and 5-HT1A binding potential in 38 healthy volunteers. We will also examine the diagnostic specificity of lithium response by studying 10 unipolar depressed subjects in an identical manner. We will examine the pharmacological specificity of lithium by studying lamotrigine in BPD subjects. Finally, we will also assess the ability of baseline scanning to predict treatment response. All BPD subjects will be treated with lithium and have repeat scans with both radiotracers. Many with BPD do not tolerate lithium's side effect burden, and it has a narrow therapeutic window. In this grant period we will determine at which 5-HT protein(s) lithium exerts its antidepressant and antisuicidal properties. Ultimately this can lead to novel therapeutics that are better tolerated. We will independently advance our understanding of the molecular pathophysiology of BPD as well as characterize the mechanisms of action of lithium.

Major depressive disorder (MDD) is one of the most heterogeneous disorders in psychiatry and first line treatments are inadequate for the majority of patients, likely because they do not target an individual?s subtype. Improving our understanding of MDD subtypes will allow us to (1) identify treatments that target subtype- specific pathophysiology and (2) determine which subgroup of MDD patients will best respond to these treatments, thus improving antidepressant outcomes. In a neuroinflammatory subtype, MDD may manifest via chronic neuroinflammation. The translocator protein (TSPO), located on the outer mitochondrial membrane of microglia and astrocytes, is regarded as a marker of this neuroinflammation and can be measured in vivo by positron emission tomography (PET). In support of a neuroinflammatory subtype of MDD, TSPO, measured by PET, was found to be elevated by 30% on average in the prefrontal cortex (PFC) in MDD relative to healthy individuals. Further, we have preliminary data from a repeated social defeat stress mouse model that shows elevated PFC TSPO and other elevated neuroinflammation markers in a subset of ?depressed?, non-resilient mice, and that this phenotype is reversed by elimination of TSPO expressing glial cells! To parallel this effect in humans, brain-penetrant anti-inflammatory medications such as celecoxib can be used. Celecoxib has antidepressant effects in MDD; however, the observed effect sizes are highly variable, likely reflecting the biological heterogeneity of MDD. We hypothesize that anti-inflammatory treatments such as celecoxib will be most effective in those with the neuroinflammatory subtype of MDD and that the mechanism of antidepressant action is through a reduction of neuroinflammation. We will test these hypotheses in parallel studies in humans in rodents. For the human aim, we will take advantage of an ongoing study of celecoxib efficacy currently being performed at Stony Brook Medicine (PI: Parsey) by recruiting participants who are already being treated with celecoxib (8 weeks, 400mg/day). 53 MDD participants will be enrolled, with 42 expected to complete the study involving TSPO PET imaging before and after treatment. We hypothesize that higher PFC TSPO (as measured by PET) prior to treatment will be correlated with better response to celecoxib and further, that reductions in PFC TSPO will be correlated to depression improvement after adjusting for covariates. In a parallel study in rodents, we hypothesize that PFC TSPO and other CNS inflammation markers in our repeated social defeat stress mouse model of depression will be elevated as measured by microPET, quantitative protein/mRNA level analysis, and reactive microglial morphology, when compared to wild type mice. Further, we hypothesize that elevated PFC TSPO and other neuroinflammatory markers will be reduced after celecoxib treatment. If mouse and human studies do not agree, this suggests that TSPO PET provides a clinically- relevant proxy of neuroinflammation. However, if our hypotheses are confirmed, this would validate that TSPO is a marker of the neuroinflammatory MDD subtype and a target of treatment.