Lawrence H Price, MD - US grants

psychotherapy; neurophysiology;

The goal of this research is to clarify the role of the serotonin (5-HT) and dopamine (DA) systems in mediating the effects of cocaine in humans. While the role of DA in mediating cocaine's effects has long been recognized interest in 5-HT has recently burgeoned. Previous work by our group has suggested that disruption of 5-HT function attenuates cocaine- induced euphoria. The present studies make use of the novel atypical neuroleptic risperidone, which has a unique pharmacological profile that includes significant antagonism at both the 5-HT2 and D2 receptors. Clozapine, which has a somewhat similar profile, is not suitable for studies of this type because of its significant adverse effects and toxicity. Preclinical findings suggest that 5-HT2/D2 receptor antagonism should be associated with an ability to block the effects of cocaine. Two studies are proposed to test this possibility. In the first, 15 subjects will undergo double-blind randomization to receive acute pretreatment with a single dose of risperidone 0, 2, or 4 mg, followed two hours later by a single challenge dose of intranasal cocaine. Responses to cocaine will be assessed in order to ascertain the effects of acute risperidone pretreatment. In the second study, 30 drug-free subjects will receive a single challenge dose of intranasal cocaine followed by double-blind parallel-groups randomization to two weeks of chronic treatment with risperidone or placebo. At the end of the risperidone treatment period, subjects will undergo a second intranasal cocaine challenge in order to ascertain the effects of chronic risperidone pretreatment on responses to cocaine. Physiological, behavioral, and psychological variables will be comprehensively assessed and systematically monitored during these studies. Neurobiological measures will include the following neurotransmitter systems indices: (1) DA--plasma homovanillic acid (HVA), growth hormone (GH), and prolactin; (2) 5-HT--cortisol and ACTH. Cocaine plasma levels will be assessed to control for pharmacokinetic effects and risperidone levels measured to control for bioavailability. We hypothesize that both acute and chronic administration of risperidone will antagonize the euphorigenic and other effects of cocaine. In addition to providing important data on cocaine's mechanism of action, these studies will be directly relevant to the development of risperidone as a possible clinical treatment for cocaine dependence.

This protocol reflects our efforts toward elucidating the role of serotonin in the pathogenesis of psychiatric illness. Currently we are examining the utility of this protocol in the study of serotonin dysfunction in adult pervasive development disorders and in Tourette's Syndrome.

DESCRIPTION (provided by applicant): Major depressive disorder (MDD) is a common, typically recurrent and disabling disorder, costing the U.S. over $44 billion/year in direct and indirect costs, and with point prevalence rates estimated at 5%-9% for women, and 2%-3% for men. More than one third of patients suffering from MDD appear to use alternative therapies in the U.S. Routinely prescribed in Europe for nearly 30 years and released four years ago in the U.S. as an over-the-counter dietary supplement, s-adenosyl-l-methionine (SAMe) has gained significant popularity as an agent marketed for improving mood and emotional well being. A number of relatively small double-blind studies have shown that parenteral or oral preparations of SAMe, compared with a number of standard tricyclic antidepressants, were generally equally effective, and tended to produce fewer side effects A relatively smaller number of studies have also examined the efficacy of SAMe compared to placebo, with the majority of these studies showing a significant advantage of SAMe over placebo. The recent report of the Southern California Evidence-Based Practice Center for the U.S. Department of Health and Human Services [Agency for Healthcare Research and Quality (AHRQ Publication 2002; http://www.ahrq.gov) ] states that "The results of these studies justify additional randomized clinical trials to evaluate the efficacy and tolerability of SAMe for treatment of depression." No adequately powered placebo-controlled study of SAMe in depression has ever been conducted in the U.S. We therefore propose a five-year, placebo-controlled, two-site study to assess the efficacy and safety of SAMe and of a standard selective serotonin reuptake inhibitor (SSRI), escitalopram in outpatients with MDD. This proposal is a parallel comparison of the efficacy and safety of SAMe, escitalopram, and placebo, with a crossover phase during which non-responders to any of these three treatments receive open-label treatment with the combination of escitalopram and SAMe. It is important to assess the efficacy of this combination therapy because patients frequently self-medicate with SAMe during standard antidepressant treatment. The primary aim of the proposed study is to test the acute antidepressant efficacy and tolerability of both SAMe and escitalopram, each compared to placebo, for the treatment of MDD. Secondary aims are to assess the acute effects of SAMe or escitalopram vs. placebo on remission rates, quality of life, and psychosocial functioning.

DESCRIPTION (provided by applicant): Major depressive disorder (MDD) is a common, typically recurrent and disabling disorder, costing the U.S. over $44 billion/year in direct and indirect costs, and with point prevalence rates estimated at 5%-9% for women, and 2%-3% for men. More than one third of patients suffering from MDD appear to use alternative therapies in the U.S. Routinely prescribed in Europe for nearly 30 years and released four years ago in the U.S. as an over-the-counter dietary supplement, s-adenosyl-l-methionine (SAMe) has gained significant popularity as an agent marketed for improving mood and emotional well being. A number of relatively small double-blind studies have shown that parenteral or oral preparations of SAMe, compared with a number of standard tricyclic antidepressants, were generally equally effective, and tended to produce fewer side effects A relatively smaller number of studies have also examined the efficacy of SAMe compared to placebo, with the majority of these studies showing a significant advantage of SAMe over placebo. The recent report of the Southern California Evidence-Based Practice Center for the U.S. Department of Health and Human Services [Agency for Healthcare Research and Quality (AHRQ Publication 2002; http://www.ahrq.gov) ] states that "The results of these studies justify additional randomized clinical trials to evaluate the efficacy and tolerability of SAMe for treatment of depression." No adequately powered placebo-controlled study of SAMe in depression has ever been conducted in the U.S. We therefore propose a five-year, placebo-controlled, two-site study to assess the efficacy and safety of SAMe and of a standard selective serotonin reuptake inhibitor (SSRI), escitalopram in outpatients with MDD. This proposal is a parallel comparison of the efficacy and safety of SAMe, escitalopram, and placebo, with a crossover phase during which non-responders to any of these three treatments receive open-label treatment with the combination of escitalopram and SAMe. It is important to assess the efficacy of this combination therapy because patients frequently self-medicate with SAMe during standard antidepressant treatment. The primary aim of the proposed study is to test the acute antidepressant efficacy and tolerability of both SAMe and escitalopram, each compared to placebo, for the treatment of MDD. Secondary aims are to assess the acute effects of SAMe or escitalopram vs. placebo on remission rates, quality of life, and psychosocial functioning.