Donald Klein - US grants

Challenge with sodium lactate induces panic attacks in individuals who experience clinical panics, but not in normal controls. In terms of both clinical symptoms and response to pharmacotherapy, lactate induced panic attacks appear almost identical to naturally occurring clinical panics, providing researchers with an opportunity to study the mechanisms of a naturally occurring pathological state under laboratory conditions. Previous hypotheses of how lactate infusions precipitate panic--i.e., induction of hypoglycemia, hypocalcemia, alkalosis, peripheral catecholamine surge, beta adrenergic stimulation,--are not supported by findings to date. The data do suggest that lactate induced panics are mediated by central nervous system mechanisms, possibly CO2 hypersensitivity, and may reflect a trait rather than state vulnerability. The present proposal aims to clarify the mechanisms of lactate induced panic by comparative challenges designed to elucidate: a) the relative role and dose effect relationships of L or D lactate as respectively involved in metabolic pathways and physical mechanisms (e.g., calcium chelation); b) the importance of alkalosis (metabolic and respiratory), of increase in brain CO2, and of shift in redox balance; c) and the role of conditioning and anticipatory anxiety. Therefore, comparative trials of 0.5 DL lactate, 0.5M D-lactate, 0.5M L-lactate, bicarbonate, various levels of CO2 inhalation and room air hyperventilation are projected. Comparison of lactate and lactate preceded by acute clonidine and, separately, diazepam pretreatment will investigate, respectively, the possible role of the locus ceruleus in the final discharge pattern for panic and the priming function of anticipatory anxiety for lactate panicogenesis suggested by our studies thus far. Other goals of the current proposal are to see if successful behavioral therapy, like pharmacotherapy, can block lactate induced panic; to develop further objective psychophysiological indices of lactate induced panic; and to study the trait vs state nature of lactate vulnerability and antecedents of relapse by conducting a longitudinal clinical and rechallenge study. The long term significance of this research program lies in its contribution to further understanding the mechanisms of vulnerability to panic attacks, which has relevance for clarifying etiology, treatment, transmission and prevention.

Cocaine abuse is a major public health problem in the United States with no accepted pharmacologic treatment. We propose a placebo-controlled, randomized, double-blind outpatient study evaluating imipramine as a treatment for cocaine abuse in 80 chronic users. The study is designed to: 1) determine the efficacy of imipramine as an outpatient medication treatment for cocaine abuse 2) determine the efficacy of imipramine in blocking the cocaine euphoria and/or diminishing the craving for cocaine in abusers 3) examine the physiologic response to cocaine via a controlled laboratory challenge with cocaine before and after imipramine 4) determine the prevalence and types of psychiatric disorders in chronic cocaine abusers and contribute to the determination of whether "cocaine dependence" should be a part of the official nosology of mental disorders.

The goal of this 5-year proposal is to further develop a unique Mental Health Clinical Research Center for the multi-disciplinary study of anxiety disorders, anxiety symptoms and related disorders. Interlocking core facilities provide the resources for substantive research conducted both by the MHCRC participants and a wide range of other investigators within New York State Psychiatric Institute and collaborating institutions. The new MHCRC proposal expands our current 4 core facilities. These include the Research Assessment and Training Unit (Jean Endicott, Ph.D.), the Biological Studies Unit (Jack Gorman, M.D.), the Computer Center (Donald Ross, Ph.D.), the Analytical Psychopharmacology Unit (Thomas Cooper, M.A.). We are requesting funding for a new core, Molecular Genetics Unit, directed by Conrad Gilliam, M.D. This unit is already engaged in pedigree studies of panic and affective disorders, as well as schizophrenic disorders. We also wish to facilitate our studies of the diagnosis and treatment of anxiety disorders by developing Diagnostic and Recruitment Centers for normal volunteers and anxiety patients. Eric Hollander, M.D., a recent RSDA awardee, will facilitate the interaction of the Anxiety Clinic and the Biological Studies Unit by conducting biological challenge studies. The MHCRC at New York State Psychiatric Institute continues to be a model for the field of psychiatric research. It integrates major support from the city, state, university, a voluntary hospital, foundations, and federal project grants around a stable set of federally funded Core Facilities. The entire mechanism is devoted to research and training in the context of excellent patient care.

DESCRIPTION (provided by applicant): Panic disorder (PD) is a serious public health burden. It is enmeshed with depression, alcoholism, tobacco dependence, pulmonary disease and has been linked to sudden cardiac death and stroke. The panic attack is distinctively characterized by acute dyspnea, tidal volume hyperventilation and surprising lack of HPA activation. Risk for developing PD is markedly increased by childhood Separation Anxiety Disorder. Both CO2 sensitivity and separation anxiety are regulated by the endogenous opioid system that I hypothesize malfunctions in PD. Normal unresponsiveness to I.V. lactate may stem from an intact endogenous opioid system. When a naloxone infusion preceded intravenous lactate, a pilot study of twelve normal subjects demonstrated a sharp increase in tidal volume and dyspneic distress. Extensive experience indicates that normal subjects do not have this reaction to I.V. lactate alone. Further, this paradigmatic increase in tidal volume and dyspneic distress was not reinstated when subjects were reinfused with naloxone alone. Therefore, we propose to extend this pilot study to definitively demonstrate that naloxone pretreatment is necessary for normal subjects to react as PD subjects do to I.V. lactate. We propose a double blind, randomized three group design in 90 normal subjects: 1) naloxone preceding lactate, 2) saline preceding lactate, 3) naloxone preceding saline. Measures of panic symptoms, air hunger, respiratory and cardiac variables will be analyzed. It is known that PD has a low heart rate variability (HRV) that is lowered further during a lactate induced panic. This feature of PD has been considered an important cardiac risk factor. To further validate our model we will analyze its effects on normal HRV. Positive findings would provide the basis for a controlled study of specific anti-panic agents to test whether they can blockade this reaction. This would further validate this model. It may also suggest new approaches to anti-panic agents, such as mixed opiate agonist-antagonist.