Russell E. Poland - US grants

human therapy evaluation; mental disorder diagnosis; depression; sleep disorders; dexamethasone; bioperiodicity; thyrotropin releasing hormone; pharmacokinetics; hormone regulation /control mechanism; cortisol; chronotherapy; hormone therapy; saliva; blood chemistry; brain interhemispheric activity; diagnostic tests; human subject;

It is well established that abnormalities of the hypothalamic- pituitary-adrenal cortical (HPA) axis and sleep EEG parameters occur frequently in patients with major depression, endogenous and/or melancholic subtype. However, the reasons for and the mechanisms underlying these abnormalities remain obscure. The experiments outlined in this ADAMHA RSDA Level II application are designed to address fundamental issues related to the abnormalities of these physiologic systems. First, I plan to show that plasma ACTH and cortisol hypersecretion are synonymous with DST nonsuppression and not manifestations of two different abnormalities of the HPA axis. Second, I plan to show that DST nonsuppression is a pituitary-associated phenomena in that cortisol elevations are a consequence of increased ACTH secretion. To do so, I plan to concurrently measure both biologically and immunologically active plasma ACTH concentrations in plasma samples obtained at frequent intervals during the night under basal conditions and also after DEX administration. Third, I plan to test the hypothesis that ACTH hypersecretion/DST nonsuppression and reduced REM latency are closely linked within subjects, possibly on the basis of a common CNS abnormality underlying the dysregulation of both physiologic systems. The CNS neurotransmitter systems which might regulate both the HPA axis and REM sleep parameters will be studied with pharmacologic challenges. Normal volunteers and then patients will be given cholinegic (Ach) and serotinergic (5- HT) antagonists prior to or during sleep, and the expected reduction in nocturnal ACTH and cortisol secretion will be correlated with the degree of REM latency increase. Similarly, by the repeated administration of Ach and 5-TH antagonists, I will attempt to reproduce the REM latency and HPA axis abnormalities in normal volunteers. These challenge experiments will help to identify particular CNS neurotransmitter systems involved in the REM sleep and HPA abnormalities and to eventually establish neurotransmitter hierarchies (linkages) which underlie the regulation of these two physiologic systems in normals and depressed patients. As a complement to the human studies, studies in animals also will be performed to determine the neurotransmitter linkages associated with the regulation of the HPA axis. As a whole, both the human and animal studies will help to elucidate the neurochemical substrates and the physiologic significance of HPA axis and REM sleep abnormalities observed in patients with depression.

3,4-methylenedioxymethamphetamine (MDMA) is an important drug of abuse. Recent evidence indicates that MDMA can be neurotoxic to serotonergic (5-HT) systems in the brains of rats and nonhuman primates. However, it is unknown to what extent a functional impairment is associated with the neurochemical changes. Since the central nervous system is the predominant regulator of neuroendocrine function, with pituitary secretion of ACTH and prolactin being strongly influenced by 5-HT pathways in the brain, a potential functional measure of neurotoxicity would be to assess changes in the ACTH and prolactin response to 5-HT probes as well as to acute stress. Preliminary data in humans and animals indicate that exposure to MDMA does produce persistent neuroendocrine changes. The relationship between neurotoxicity, as assessed by neurochemical changes, and functional impairment, as measured by the neuroendocrine responses to 5-HT agonists and stress, will be determined over time in rats exposed to different dosages of MDMA. The threshold doses of MDMA necessary to produce functional alterations will be determined. The results of these studies will help to elucidate the pathophysiologic sequelae that can result from exposure to this drug of abuse, as well as guide future research studies of comparable nature in humans.

Direct and indirect evidence suggests muscarinic cholinergic systems are involved in depression. Rapid eye movement (REM) latency and neuroendocrine responses to cholinergic agonist administration are enhanced in adults with major depression. With the use of cholinergic agonists and antagonists, the involvement of muscarinic cholinergic systems in both adult and adolescent, depression will be delineated. Preliminary data with the muscarinic cholinergic antagonist scopolamine suggest that both adolescent and adult depressives respond comparably, but to a greater extent than normal age-matched controls, possible due to the hypoactivity of presynaptic cholinergic elements. Further, the data support the view that REM sleep and hypothalamic-pituitary-adrenal (HPA) axis abnormalities represent 'trait' and 'state' phenomena, respectively, At the preclinical level, preliminary data suggest that the "up-regulation" of muscarinic cholinergic systems involved in regulation of the HPA axis might not be due to a primary insult to muscarinic systems per se, but might be an adaptive response to "other" abnormalities. A greater understanding of the physiology and pathophysiology of muscarinic cholinergic systems in humans and animals, as revealed by the responses of REM latency in humans, and the HPA axis in both humans and animals to cholinergic challenges, will lead to findings that should help elucidate basic neurophysiologic mechanisms underlying depression, and have important clinical implications and applications to this major psychiatric disorder.

pharmacogenetics; biomedical facility; genotype; high performance liquid chromatography; gas chromatography mass spectrometry; radioimmunoassay;

Direct and indirect evidence suggests muscarinic cholinergic systems are involved in depression. Rapid eye movement (REM) latency and neuroendocrine responses to cholinergic agonist administration are enhanced in adults with major depression. With the use of cholinergic agonists and antagonists, the involvement of muscarinic cholinergic systems in both adult and adolescent, depression will be delineated. Preliminary data with the muscarinic cholinergic antagonist scopolamine suggest that both adolescent and adult depressives respond comparably, but to a greater extent than normal age-matched controls, possible due to the hypoactivity of presynaptic cholinergic elements. Further, the data support the view that REM sleep and hypothalamic-pituitary-adrenal (HPA) axis abnormalities represent 'trait' and 'state' phenomena, respectively, At the preclinical level, preliminary data suggest that the "up-regulation" of muscarinic cholinergic systems involved in regulation of the HPA axis might not be due to a primary insult to muscarinic systems per se, but might be an adaptive response to "other" abnormalities. A greater understanding of the physiology and pathophysiology of muscarinic cholinergic systems in humans and animals, as revealed by the responses of REM latency in humans, and the HPA axis in both humans and animals to cholinergic challenges, will lead to findings that should help elucidate basic neurophysiologic mechanisms underlying depression, and have important clinical implications and applications to this major psychiatric disorder.

fluoxetine; chemoprevention; psychobiology; drug adverse effect; 3,4 methylenedioxymethamphetamine; mental disorder chemotherapy; psychopharmacology; drug interactions; mental disorders; psychotropic drugs; clinical research; human subject;

To determine if acute or sub-chronic use of Wellbutrin SR is associated with either subjective or objective changes in sleep. This research will also determine if Wellburtrin SR shows similar effects on the stage distribution of sleep as those reported for Wellbutrin and other antidepressants metabolite.

To characterize the P450 isozyme involved in the metabolism of nicotine.

DESCRIPTION (adapted from applicant's abstract): The overall objective of the proposed research plan is a test of the neurodevelopmental hypothesis of schizophrenia. Diverse evidence suggests that schizophrenia has a neurodevelopmental component of unknown etiology in which injury to the brain occurs during early development. Epidemiologic studies indicate that human offspring exposed to developmental insults such as nutritional deficiencies, viral infection, obstetric complications, and stress are at higher risk for subsequent development of schizophrenia. Brain pathology which might be linked to the neurodevelopmental insults includes abnormal biochemistry as measured by proton (1H) magnetic resonance spectroscopy (MRS). The investigator proposes to link these biochemical abnormalities with the early life stress diathesis of schizophrenia by assessing whether the MRS findings in schizophrenia can be reproduced by early developmental insults in rats. The general design of the proposal includes the use of in vitro 1H MRS to characterize the effects of perinatal stress on the brain regional concentration of N-acetyl-aspartate (NAA) and myoinositol (MI). Behavioral, neuroendocrine, and neurochemical characteristics of perinatal stress would also be defined. Determinations would be conducted at 4 developmental time-points spanning 30-360 days of age and in 8 brain regions. In experiment I, the investigator proposes a characterization of the effects of prenatal stress in the form of repeated daily physical restraint of pregnant dams. Pups born from stressed or non-stressed moms will be cross-fostered at birth and reared by prenatally stressed or normal moms to yield four experimental groups. Experiment II would characterize the effect of postnatal stress in the form of maternal deprivation. Four experimental groups would be used to characterize the interaction of the prenatal stressor with the postnatal stress resulting from rearing by stressed versus non-stressed moms and maternally deprived versus normally reared animals. The investigator provides preliminary evidence that adult male offspring subjected to stress perinatally demonstrate decreased NAA in the left frontal cortex. The proposal would determine when during development this NAA change appears and if it is progressive in nature. The relationship among NAA concentration, and behavioral, neuroendocrine, and neurochemical measures of stress response would also be determined. The results of the proposed studies should provide basic information on potential links between the neurodevelopmental abnormalities and anomalies in adult neurochemistry defined by 1H MRS in schizophrenia.

Numerous studies indicate that ethnicity can influence the pharmacokinetics of a variety of pharmacologic agents. In part, this is due to differences in the act-ivity of P450 enzymes (mostly) in the liver which are involved in drug metabol-ism. In order to understand this issue further, evaluation of the pharmacokinet-ics of a new antidepressant, Reboxetine, in African-American, Asian (Chinese) and Caucasian normal volunteers will be done. Reboxetine is currently approved in Europe for the treatment of depression and currently Phase III studies are being performed with the compound.

DESCRIPTION: (provided by applicant) This is an R21 application to explore the development of an animal model to study the effects of parental and peripuberal exposure to nicotine. Nicotine remains an important drug of abuse worldwide. In the United States (U.S.), tobacco use is the single leading preventable cause of death. However, despite considerable negative publicity and health warnings, approximately 25 percent of the U.S. population still smoke. Aside from producing profound behavioral effects in the adult organism, nicotine also disrupts developmental processes in many species. Recent epidemiologic data suggest that fetal exposure to nicotine increases the risk for tobacco use during adolescence and adulthood, particularly in females. In addition, 75 percent of adult tobacco users report their first tobacco use occurred when they were "youngsters" (childhood or adolescence). In order to study this issue further, as well as to develop an animal model to elucidate potential underlying mechanisms, the effects of nicotine exposure during gestation on nicotine self-administration in adult male and female rat offspring will be studied. In addition, the effects of nicotine exposure during the periadolescent period on nicotine self-administration in adult offspring will be ascertained. It is hypothesized that nicotine exposure in utero will increase nicotine self-administration in adult offspring. Similarly, peripuberal exposure to nicotine also will increase nicotine self-administration during adulthood. The proposed studies will characterize the relationships between exposure to nicotine during critical periods of development and the acquisition, maintenance, extinction and re-initiation phases of nicotine self-administration. The results of these experiments should provide new and important insights on the relationships between prior nicotine exposure and nicotine-seeking behavior. In addition, since nicotine is considered as a "gateway" drug for the subsequent use of alcohol and other illicit drugs, the results of the proposed studies will lay the groundwork to further understand the factors which might increase vulnerability to drug addictions in general, and to nicotine abuse, in particular.

DESCRIPTION: (provided by applicant) Despite remarkable progress in recent decades in modern psychopharmacotherapy, patients vary substantially in their response to antidepressants, ranging from total remission to complete treatment failure. Adverse effects, often bothersome and occasionally life-threatening, continue to represent significant challenges to patients and clinicians. Mechanisms responsible for such variability remain poorly understood. In addition, although less appreciated, substantial cross-ethnic variations in psychotropic responses often exist. Recent developments in the field of pharmacogenetics indicate that genetic factors may account for a large part of these differences in response. Specific genetic polymorphisms affecting the function of the serotonin system has been postulated to predict the effect of antidepressants. Similarly, genetic mutations have been shown to exert a predominant influence on the expression of a number of drug-metabolizing enzymes, including most of the cytochrome P-450 enzymes (e.g., CYP2C19 and CYP3A4) that are responsible for the biotransformation of most antidepressants. Polymorphisms of genes controlling these enzymes have been found to be strongly associated with the propensity for various kinds of side effects. Capitalizing on these new developments, the proposed study will examine the predictive value of some of these genetic polymorphisms in 400 patients (200 African Americans and 200 Caucasians) with DSM-IV major depression prospectively treated with citalopram (CIT). It is postulated that mutations affecting the function of the serotonin transporter will predict responses to CU', whereas polymorphism of CYP2C 19 will be associated with the side effect profiles and pharmacokinetics of CIT. The inclusion of African Americans and Caucasians, whose genetic profiles for the serotonin transporter differ significantly from each other, will allow us to examine how these differences affect antidepressant response patterns, and whether the associations are 'replicable' across ethnicity. Also, the response of African Americans to antidepressants has rarely been studied in a systematic fashion, particularly in the context of controlled clinical trials. Thus, in addition to addressing issues related to clinical phannacogenetics, data derived from this three-site (Harbor-UCLA, UCLA\King-Drew and Cedars-Sinai Medical Centers) collaborative R0l project should also serve to bridge the knowledge gap regarding the treatment of African American patients suffering from major depression.

DESCRIPTION (provided by applicant): This is an Exploratory/Developmental Research (R21) grant application to the National Center for Complementary and Alternative Medicine in response to RFA AT-O1-002 to assess the usefulness of massage therapy for treatment of depression and improvement in the quality of life in patients with end of life AIDS. This study will define the clinical and biologic response to massage therapy in patients with AIDS and depression who are clinically stable and on a fixed medical regimen. Depression is a co-morbid condition in individuals with advanced HIV disease and has a negative impact on quality of life. Depression in HIV-infected patients also has been associated with a decrease in adherence to medications and progression of clinical disease. While pharmacologic therapy for depression have resulted in variable success in managing this problem, it is associated with an increase in the number of medications that these patients are required to take, potential for additional drug-drug interactions, and many adverse events. In patients with advanced stage HIV disease, palliative care is often a priority and identifying new treatment modalities that do not require additional medications while improve clinical symptoms and overall quality of life is of the utmost importance. Pilot studies with massage therapy have been performed in HIV-infected and uninfected individuals. These studies have shown a reduction in depression scores in HIV-uninfected subjects. In HIV-infected patients, massage therapy has been shown to improve quality of life measures and decrease plasma cortisol levels. The specific aims of this proposal are 1) to determine the effect of massage therapy on depression in subjects with advanced HIV disease, 2) to investigate the effect of massage therapy on quality of life in subjects with advanced HIV disease, and 3) to investigate the effect of massage therapy on plasma cortisol levels in subjects with advanced HIV disease. This study will randomize advanced stage HIV-infected subjects with depression in a 1:1:1 manner to massage therapy, "sham massage" or no physical intervention. The massage and "sham massage" groups will be treated for one hour, twice per week, for 8 weeks. All enrolled subjects will have depression measured (Hamilton Depression Scale) at baseline, weeks 1, 2, 4, 6 and 8, and quality of life (SF-36), and pain assessments (Gracely Pain Scale) at baseline, weeks 4 and 8. In addition, 24-hour urine free cortisol, lymphocyte subsets and HIV RNA measurements will be assessed at baseline and weeks 4 and 8. This will be a rigorously controlled clinical trial using validated measures to assess the clinical (depression and quality of life), and biologic (cortisol levels) effect of massage therapy on subjects with advanced stage HIV disease and clinical depression.