Maurizio Fava - US grants

Since a serotonergic neurotransmission dysregulation has been postulated to underlie both affective and aggression disorders, we propose to compare the serotonergic function in two different subtypes of patients with major depressive disorder: Patients with and without anger attacks.

About half of the patients who respond to antidepressants improve as a result of the natural course of the illness or due to nonspecific or "placebo" effects rather than pharmacologic effects. Since current practice dictates drug maintenance for all responders to antidepressants, much continuation pharmacotherapy may be unnecessary. If "placebo" responses to an active drug could be identified, unnecessary medication could be discontinued, decreasing morbidity and cost knowing that initial improvement is attributable to a "placebo" effect would also permit more rational treatment of relapses during continuation treatment. Multiple studies have shown that the analysis of patterns of response to acute antidepressant treatment differentiate "true" or pharmacologic responses from "placebo' or nonspecific responses. Preliminary data presented in this proposal suggest that pattern analysis also distinguishes patients who require medication during continuation from those who do not. In this study, the predictive value of the acute response pattern will be tested prospectively using a placebo-controlled discontinuation design. Success in this would allow clinically useful recommendations for continuation treatment to be made based on the collection of relatively simple and easily acquired clinical data. The present study involves the enrollment of 700 patients with major depression at two sites. Responders to a 12-week acute trial of fluoxetine will be prospectively randomized for 24 weeks of double-blind continuation treatment based on their pattern of response ("placebo" or "true drugs type). In each group, 50% of the patients will be assigned to remain on fluoxetine and 50% will switch to placebo. Differences in relapse rates will be examined in the four groups.

We are proposing a five-year, double-blind, placebo-controlled trial on the smoking cessation efficacy of bupropion as an adjunct to the standard combination of group cognitive-behavioral therapy (CBT) plus nicotine replacement. Our primary aims are 1) to examine the additional benefit of adding the antidepressant bupropion to a standard treatment for smoking cessation of CBT and nicotine replacement among smokers who have a history of either current or past unipolar depressive disorders (major depressive disorder, dysthymia, and minor depression), and 2) to determine, if bupropion indeed improves in this population a smoker's odds of quitting, whether its effect is achieved mainly through its impact on the negative mood states associated with depression. In order to provide a powerful test of both hypotheses, this study will enroll only smokers with a history of either current or past unipolar depressive disorders. In addition, allowing the inclusion of patients with a history of unipolar depressive disorders makes the proposed study more clinically relevant and its findings more generalizable, as several studies suggest that, as the prevalence of smoking continues to diminish in the general population, an increasing percentage of those who remain smokers are patients with psychiatric illnesses, especially depression. We expect that the efficacy of the standard combination of group CBT plus nicotine replacement will be greatly enhanced by the addition of bupropion in all smokers, but that the addition of bupropion will be especially helpful to those smokers who currently suffer from clinically significant depressive symptoms. The study involves the enrollment over 48 months of 300 individuals. We predict that 50 percent of the enrolled patients will meet criteria for current unipolar depressive disorders. After the 12-week acute treatment phase, patients will be followed for 12 months. The study design therefore involves the random assignment of current or past history of unipolar depressed patients to two treatment conditions: 1) group CBT plus nicotine patch plus bupropion (current depressive disorder bupropion group, estimated n=75; past depressive disorder bupropion group, estimated n=75); 2) group CBT plus nicotine patch plus placebo (current depressive disorder placebo group, estimated n=75; past depressive disorder placebo group, estimated n=75).

The primary objective of this study was to determine whether there are changes in hypothalamic-pituitary-adrenal (HPA) axis activity associated with interruption of treatment with SSRIs, and if so, if the asociation is dependant upon drug half-life. The secondary objectives of this study are as follows: to collect comparative safeety data onmaintenance doses of fluoxetine, sertraline, or paroxetine by monitoring the reporting of spontaneous adverse events; to monitor the plasma concentrations of fluoxetine, sertraline, and paroxetine and their active metabolites following interruption of treatment, and to describe the relationship of the observed concentrations to discontinuation-emergent signs and symptoms (DESS) and stability of efficacy measures. The hypothesis tested was that HPA axis activation is a physiological marker of the dysphoric syndromes associated with short-acting SSRI withdrawal. To test this hypothesis, the investigators studied HPA axis function in patients treated with shorter-acting SSRIs as well as those in a control group treated with fluoxetine, a longer acting SSRI which does not appear to be associated with significant withdrawal symptoms.

Among drug dependence disorders, nicotine dependence is the most widely diffused, with a strong impact on the world's health and economy. The tobacco epidemic is a global problem; one-third of the worldwide population over 15 years of age or 1.1 billion people smoke. By the year 2025, the WHO estimates there will be 10 million tobaccorelated deaths per year worldwide. Smoking cessation treatment is highly cost-effective, and pharmacotherapy is universally recommended for treatment of nicotine dependence in the absence of specific contraindications. However, the majority of smokers do not quit even with treatment. Currently available treatments do not exploit recent advances inknowledge of neurobiologic mechanisms of addiction and reward that have made possible the development of rationally designed treatments targeting specifically those systems involved in nicotine reward circuitry. Existing and new pharmacotherapies along with prevention efforts are key to improving smoking cessation rates and reducing the premature and preventable morbidity and mortality associated with tobacco use. This RFA has prompted three organizations with longstanding interest in pharmacotherapy for nicotine dependence, Massachusetts General Hospital (MGH), McLean Hospital Brain Imaging Center (BIC), and GlaxoSmithKline (GSK), to join forces for the proposed NCDDG-MD/NA Group. The primary objective of this group is to identify and test promising compounds that affect critical neural systems in nicotine reward and craving. In this collaborative group project for drug discovery, we will combine screening of multiple potential lead compounds, with pre-clinical and clinical testing of two compounds and in vivo brain imaging measures. Specifically, we will 1) screen multiple lead compounds in neurochemistry, electrophysiology, behavioral and animal brain imaging assays, 2) screen multiple promising compounds identified in the preclinical work in a novel human 72 hour nicotine craving paradigm, 3) perform clinical trials to test the efficacy of the most promising two compounds for smoking cessation, compared with placebo and bupropion and 4) use in vivo neuroimaging to identify surrogate markers for treatment response and relapse in humans. This effort will advance our understanding of mechanisms involved in nicotine dependence, early abstinence/treatment response and relapse, will advance our understanding of what types of agents are effective in treating nicotine dependence, will test a battery of putative surrogate markers for clinical response aimed at accelerating the process by which effective drugs can be assessed for efficacy in nicotine dependence and will test two compounds for nicotine dependence in adequately powered trials. The compounds that we will investigate will be drawn from the large, existing portfolio of compounds under development for nicotine dependence at GSK. Each organization will make a unique contribution of personnel and resources to the implementation and success of the project.

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.

DESCRIPTION (provided by applicant): This collaborative R01 investigates the safety and efficacy of the glutamate-modulating and neuroprotective agent riluzole in a randomized double-blind placebo-controlled clinical trial (RCT) in patients with treatment- resistant depression (TRD). The recent findings of the STAR*D study highlight the fact that our current armamentarium of antidepressant medications, developed out of the monoamine hypothesis, has serious limitations. There is now emerging evidence that amino acid neurotransmitter (AANt) systems may also contribute to the pathophysiology of major depressive disorder (MDD), and that drugs targeting these systems may have potent antidepressant properties. Riluzole is currently approved by the US FDA for the treatment of amyotrophic lateral sclerosis (ALS). It has been shown to have a variety of neurobiological effects on glutamatergic function associated with the drug's neuroprotective and plasticity-enhancing properties. There have now been two recent open-label studies showing riluzole to be effective in TRD as well as several reports demonstrating riluzole's efficacy in bipolar depression, generalized anxiety disorder, and obsessive-compulsive disorder. However, no RCT has been performed in TRD. This randomized, double-blind, placebo-controlled trial, using a sequential parallel comparison design, evaluates the efficacy and safety of riluzole augmentation of the selective serotonin reuptake inhibitor citalopram in outpatients ages 18-65 with moderate TRD. Significance to Public Health: In this unique 5-year proposal, investigators from four institutions [Yale, MSSM, MGH and NIMH (MAP)] will conduct a RCT to examine the efficacy, safety and tolerability of adjunctive riluzole treatment in TRD. Demonstration of riluzole's benefit would represent a major advance for patients with difficult-to-treat depression, and may help elucidate our understanding of the pathophysiology of MDD and the mechanism of antidepressant action. Most immediately, since riluzole is already a FDA-approved medication that has been safely prescribed to thousands of patients with ALS, positive findings from this study could rapidly disseminate into clinical practice and would encourage further investigation of this strategy. Demonstrating riluzole's efficacy in TRD would open the door to the discovery of future medications targeting the glutamatergic system that could be used to fight this common and devastating disorder. PUBLIC HEALTH RELEVANCE: Although there are now more than 20 different antidepressant medications available in the US, treatment resistant depression remains a common problem, with serious medical and economic consequences. The high rates of treatment resistant depression likely reflect the fact that existing antidepressant treatments were almost exclusively developed out of the monoaminergic hypothesis of depression pathophysiology and therefore largely share a common mechanism of action. The increasingly recognized limitations of this approach to antidepressant drug development provides a strong impetus for exploration of novel antidepressant treatments with unique targets of action such as that proposed in this study.

Task Area - Phase 1 (Start-up/Preparation) activities include establishing the infrastructure including subcontractor performance sites, developing and finalizing the protocol, designing the database, computer system, and data management plans, submitting and responding to the Data Safety and Monitoring Board, and finalizing interaction with the 3rd party suppliers and the FDA and obtain documentation of access and approvals as required. Task area 2 ? Phase 2: Conduct Proof of Concept Clinical Trials activities include: beginning recruitment and conducting Proof of Concept (either drug or non-drug) trials, managing and coordinating all clinical trials according to the approved finalized protocols, performing clinical monitoring, interim and final data analysis, and preparing of draft and final reports on the study. The description of the approach and primary objectives of the RAPID Contract follows. The general approach required for this Indefinite Delivery Indefinite Quantity (IDIQ) Contract initiative will be to first establish a small team of clinical trial sites and subsequently to test identified interventions (pharmacologic and/or non-pharmacologic) in adequately powered Proof of Concept trials in humans. Trials will be initiated after promising interventions are identified by members of the team (including the NIMH Intramural Research Program), and approved by the RAPID steering committee and the NIMH Contracting Officer?s Representative (COR) (previously referred to as the Government Program Officer). The primary objectives of this contract are: ? To establish a small team of clinical trials sites to study ?Rapidly-Acting Treatments for Depression? (i.e., the ?RAPID-team?) that will focus on identifying and testing promising interventions (pharmacologic and/or non-pharmacological) that produce a substantial anti-depressant effect within 72 hours of initial administration. ? To perform randomized clinical trials testing such promising interventions (other than Ketamine Hydrochloride or sleep deprivation (total or partial)) in a well-characterized cohort of adult subjects (age 18-60) diagnosed with treatment-resistant depression.

DESCRIPTION (provided by applicant): Pharmacotherapy for smoking cessation is universally accepted as standard of care and is highly cost effective, although only approximately 20% who attempt cessation are successful on a given attempt and up to 90% of those who do quit relapse to smoking within one year, and most relapse within two weeks of quitting. Discovery of novel treatments to aid people who want to quit smoking for the long term is a clear public health priority. People smoke for rewarding effects of nicotine, but also to avoid withdrawal-emergent symptoms such as cognitive impairment. Nicotine withdrawal is associated with significant attentional impairment, a symptom that is strongly associated with relapse to smoking. Those with baseline cognitive impairment are also more likely to smoke and less likely to quit than those without such symptoms. In many cases, nicotine ameliorates baseline cognitive symptoms. This R-01 grant application is based on the hypothesis that pharmacotherapies that work through novel biological mechanisms to moderate baseline and withdrawal-emergent symptoms such as cognitive impairment hold the greatest promise for sustained abstinence. We propose to evaluate the effect of a novel, selective, oral, alpha-7 nicotinic acetylcholine receptor agonist, EVP 6124, that is in Phase II development with an active IND, and has been shown to improve cognitive performance in normal adults, and those with schizophrenia and dementia of the Alzheimer's type. To do so, we propose to conduct a Phase II, double-blind, proof of concept treatment trial, comprising 4 combinations of active treatment and placebo arms in a 2 by 2 factorial design (EVP 6124 plus NRT vs placebo plus NRT vs EVP 6124 plus placebo-NRT vs placebo plus placebo-NRT). All participants will attempt to quit smoking on study day 1 when study medications are initiated. NRT or placebo-NRT (active or placebo patch) will be continued for 6 weeks and then discontinued. Randomized oral medication will then be continued without NRT for an additional 6 weeks in a relapse prevention phase. Participants will be followed for relapse patterns for 2 weeks after oral treatment discontinuation, to week 14. Data on cognitive performance, smoking behavior, and tolerability will be collected at each weekly visit. This design will allow us to assess the assay sensitivity of the clinical trial itself (by comparing the placebo plus NRT arm with the placebo plus placebo-NRT arm) and to assess whether the selective alpha-7 nicotinic receptor agonist is effective as monotherapy (by comparing the EVP 6124 plus placebo-NRT arm with the placebo plus placebo-NRT arm) and/or in combination with NRT (by comparing EVP 6124 plus NRT arm with the placebo plus NRT arm). In so doing, we will discover if the selective alpha-7 nAChR agonist improves cognitive performance during nicotine taper and in early abstinence and if this effect is associated, compared to placebo, with greater sustained abstinence from tobacco smoking alone or in combination with NRT. PUBLIC HEALTH RELEVANCE: One in five Americans smoke tobacco. Each year over 430,000 people in the US and 5 million worldwide die from smoking-related illness, and the global mortality toll is rising. Clearly, more effective pharmacotherapies are urgently needed. In this study, we aim to discover whether a novel treatment will work alone or in combination with nicotine replacement to aid cessation and reduce relapse by minimizing nicotine withdrawal- induced cognitive impairment

DESCRIPTION (provided by applicant): There has been a significant decline in the number of research psychiatrists and research fellowships for psychiatrists in the past two decades (Fenton et al. 2004, Pincus et al. 2005). In order to begin to address this gap, it is critically important to provide early research training in psychiatry residency. Such training (a) promotes research literacy for all trainees, (b) encourages future participation of clinicians as research collaborators, (c) provides experience that can foster choosing a research career, (d) expands clinical knowledge through the formulation of patient-oriented research questions, (e) attracts medical students into psychiatry training, and (f) maintains and facilitates research interest among residents with investigative backgrounds (IOM 2003). In response to the critical shortage of physician-scientists and the IOM's recommendation, investigators at the Massachusetts General Hospital (MGH) Department of Psychiatry and McLean Hospital collaborated with the leadership of the MGH-McLean General Adult Psychiatry residency to develop and pilot a Research Concentration (RC) within the residency training program. The goal of the RC is to prepare residents for careers as investigators in academic psychiatry by facilitating greater exposure to research activities and training during residency. The pilot RC has had success in attracting and recruiting talented psychiatrist-scientists and developing an initial research education program. In this application, we propose developing a well-coordinated research education program with appropriate infrastructure that will attract clinician-scientists to careers in psychiatry and provide them both mentorship and research experience to prepare them for an independent investigator career in psychiatry and neuroscience following residency. The specific aims of the proposed research education training program are to: (1) attract and train excellent residents to become future psychiatrist-investigators in basic, translational, and patient-oriented research, by integrating core research and clinical didactic programming, as well as clinical and research rotations, during the four years of residency training program; (2) provide dedicated time and training for research over the course of the four-year residency through the RC track in the adult psychiatry residency training program; (3) increase the number of residents who benefit from the research education program; (4) broaden and deepen the research education program by providing greater and more intensive training in research literacy to all residents in the residency training program; (5) provide seed funding for pilot research projects designed by the residents enrolled in the RC program; and (6) partner with training and training evaluation programs within MGH and McLean Hospitals as well as the Harvard Catalyst, the Clinical and Translational Science Center (CTSC), so that all residents will benefit from the CTSC educational resources.

DESCRIPTION (provided by applicant): Major depressive disorder is a significant public health problem, disproportionately affecting women. Approximately 70% of patients do not respond or only partially respond to standard SSRI treatment despite adequate dosing. In our open-label pilot data, two-thirds of women with major depressive disorder who were resistant or partially resistant to antidepressants achieved a response to very low-dose, physiologic transdermal testosterone administration; one-third of women treated achieved remission after 8 weeks of therapy, with no hyperandrogenic side effects. We propose a collaborative, randomized, placebo-controlled trial to determine whether larger, multi-center trials are indicated to investigate whether low-dose testosterone is an efficacious and well-tolerated augmentation strategy in women with major depressive disorder and SSRI partial/nonresponse. We propose a collaborative, multidisciplinary study from two academic medical centers in order to increase sample size, accelerate recruitment and increase sample diversity.

Task Area - Phase 1 (Start-up/Preparation) activities include establishing the infrastructure including subcontractor performance sites, developing and finalizing the protocol, designing the database, computer system, and data management plans, submitting and responding to the Data Safety and Monitoring Board, and finalizing interaction with the 3rd party suppliers and the FDA and obtain documentation of access and approvals as required. Task area 2 ? Phase 2: Conduct Proof of Concept Clinical Trials activities include: beginning recruitment and conducting Proof of Concept (either drug or non-drug) trials, managing and coordinating all clinical trials according to the approved finalized protocols, performing clinical monitoring, interim and final data analysis, and preparing of draft and final reports on the study. The description of the approach and primary objectives of the RAPID Contract follows. The general approach required for this Indefinite Delivery Indefinite Quantity (IDIQ) Contract initiative will be to first establish a small team of clinical trial sites and subsequently to test identified interventions (pharmacologic and/or non-pharmacologic) in adequately powered Proof of Concept trials in humans. Trials will be initiated after promising interventions are identified by members of the team (including the NIMH Intramural Research Program), and approved by the RAPID steering committee and the NIMH Contracting Officer?s Representative (COR) (previously referred to as the Government Program Officer). The primary objectives of this contract are: ? To establish a small team of clinical trials sites to study ?Rapidly-Acting Treatments for Depression? (i.e., the ?RAPID-team?) that will focus on identifying and testing promising interventions (pharmacologic and/or non-pharmacological) that produce a substantial anti-depressant effect within 72 hours of initial administration. ? To perform randomized clinical trials testing such promising interventions (other than Ketamine Hydrochloride or sleep deprivation (total or partial)) in a well-characterized cohort of adult subjects (age 18-60) diagnosed with treatment-resistant depression.

DESCRIPTION (provided by applicant): Major depressive disorder (MDD) is a serious, debilitating illness that affects 16.6% of the US population in their lifetime. One of the most critical issues in developing new treatments is that in double-blind clinical trials the administration of placebo in MDD can often mimic the effects of FDA-approved antidepressants and lead to a significant improvement in approximately 35% of patients. At present the neurobiological mechanisms underlying placebo responses in MDD are unknown. We hypothesize that mesolimbic dopaminergic pathways implicated in reward anticipation, reinforcement learning, and expectation play a critical role in mediating placebo responses in MDD. In this research we will use integrated PET/fMRI imaging techniques, to compare simultaneously [11C]raclopride displacement (an indirect measure of endogenous dopamine release) and BOLD signals within the mesolimbic pathways in patients with MDD who are responders versus non-responders to placebo. The proposed research is profoundly innovative with respect to trial design, technology, and its multi-level integration, probing psychological an neurobiological constructs assumed to be crucially implicated in placebo response. A better understanding of the neurobiological basis of placebo effect has enormous potential for harnessing the healing capacity of placebo, developing new generations of clinical trials yielding better differentiation between novel antidepressants and placebo, and ultimately leading to new treatments for MDD.

The general approach required for this initiative will be to first establish a small team of clinical trial sites and subsequently to test identified interventions (pharmacologic and/or non-pharmacologic) in adequately powered Proof of Concept trials in humans. Trials will be initiated after promising interventions are identified by members of the team (including the NIMH Intramural Research Program), and approved by the RAPID steering committee and the NIMH Contracting Officer¿s Technical Representative (COTR) (sometimes also referred to as the Government Program Officer (GPO)). If any compound/intervention identified under this contract or in the field proves to be promising, the Government may choose to conduct a larger efficacy trial with that compound/intervention in lieu of other smaller Proof of Concept trials (see Tasks 4 and 5). All efforts within each task area outlined below will be controlled by task order procedures outlined in more detail in the contract. These procedures require the issuance of a task order request by NIMH, the Contractor¿s response/proposal to a request (including a technical approach and budget), and final NIMH approval to begin the task order. Costs shall not be incurred or reimbursed until a task order has been approved. The approved total cost is a ceiling that cannot be exceeded without further authorization. The emphasis and objective in this contract is to identify and test the most promising interventions for treatment resistant depression (either pharmacologic or non-pharmacologic).

The general approach required for this initiative will be to first establish a small team of clinical trial sites and subsequently to test identified interventions (pharmacologic and/or non-pharmacologic) in adequately powered Proof of Concept trials in humans. Trials will be initiated after promising interventions are identified by members of the team (including the NIMH Intramural Research Program), and approved by the RAPID steering committee and the NIMH Contracting Officer?s Technical Representative (COTR) (sometimes also referred to as the Government Program Officer (GPO)). If any compound/intervention identified under this contract or in the field proves to be promising, the Government may choose to conduct a larger efficacy trial with that compound/intervention in lieu of other smaller Proof of Concept trials (see Tasks 4 and 5). All efforts within each task area outlined below will be controlled by task order procedures outlined in more detail in the contract. These procedures require the issuance of a task order request by NIMH, the Contractor?s response/proposal to a request (including a technical approach and budget), and final NIMH approval to begin the task order. Costs shall not be incurred or reimbursed until a task order has been approved. The approved total cost is a ceiling that cannot be exceeded without further authorization. The emphasis and objective in this contract is to identify and test the most promising interventions for treatment resistant depression (either pharmacologic or non-pharmacologic).

Project Summary/Abstract There has been a significant decline in the number of research psychiatrists and research fellowships for psychiatrists in the past two decades (Fenton et al. 2004, Pincus et al. 2005). To address this gap, it is critically important to provide early research training in psychiatry residency. Such training (a) promotes research literacy for all trainees, (b) encourages future participation of clinicians as research collaborators, (c) provides experience that can foster choosing a research career, (d) expands clinical knowledge through the formulation of patient-oriented research questions, (e) attracts medical students into psychiatry training, and (f) maintains and facilitates research interest among residents with investigative backgrounds (IOM 2003). In response to this need, investigators at the Massachusetts General Hospital (MGH) Department of Psychiatry and McLean Hospital collaborated with the leadership of the MGH-McLean General Adult Psychiatry residency to develop a Research Concentration Program (RCP) within the residency training program. The goal of the RCP is to prepare residents for careers as investigators in academic psychiatry by facilitating greater exposure to research activities and training during residency. Through its first federally funded period, the RCP has been successful in attracting and recruiting talented psychiatrist-scientists and has developed an effective research education program. We have developed a well-coordinated research education program with appropriate infrastructure that has attracted clinician-scientists to careers in psychiatry and provided them both mentorship and research experience to prepare them for an independent investigator career in psychiatry and neuroscience following residency. The ongoing specific aims of this competitive renewal application for the research education training program are to: (1) attract and train excellent residents to become future psychiatrist-investigators in basic, translational, and patient-oriented research, by integrating core research and clinical didactic programming, as well as clinical and research rotations, during the four years of residency training; (2) provide dedicated time and training for research over the course of the four-year adult psychiatry residency training program; (3) increase the number of residents who benefit from the research education program; (4) broaden and deepen the research education program by providing greater and more intensive training in research literacy to all residents in the residency training program; (5) provide seed funding for pilot research projects designed by the residents enrolled in the RCP; and (6) partner with training programs within MGH and McLean Hospitals as well as the Harvard Catalyst, the Clinical and Translational Science Center (CTSC), so that all residents will benefit from the CTSC educational resources. Newly developed specific aims for this competitive renewal application are to (1) create an NIH K award grant writing and review program to facilitate an accelerated path to national level funding; and (2) create five research training tracks within the RCP with specific training curricula to build the residents' research skill set.

Project Summary The objective of the Early Phase Pain Investigation Clinical Network (EPPIC-Net) and EPPIC- Net initiatives is to rapidly and efficiently translate advances in the neurobiology of pain into treatments for people with chronic and acute pain, conditions associated with a significant burden to both patients and society. Challenges to the successful and efficient development of novel treatments for people with pain include inefficiencies in regulatory and institutional submissions and approvals, a variety of barriers to recruitment of subjects that slow down clinical research, inadequate quality assurance of trials, and a shortage of individuals trained and prepared to participate in and lead multicenter trials. The primary goal of the Clinical Coordinating Center (CCC) for EPPIC-Net is to promote and facilitate, from initial conception through final analysis, clinical trials in adult and pediatric populations with acute or chronic pain by providing efficient methodological, organizational and logistical support. The EPPIC-Net-CCC will adopt and establish processes aimed at dramatically increasing the efficiency of multicenter clinical trials, improving the overall quality of clinical trials, promoting patient recruitment and retention as well as increasing the number of clinical investigators and research staff well trained and passionate about leading and conducting multicenter clinical trials. The Specific Aim 1 of our proposal is to harness through a collaborative Clinical Coordinating Center multidisciplinary clinical research and data management expertise to provide the scientific leadership and infrastructure required to design and conduct multi-site Phase 2 clinical trials, biomarker validation studies, and deep phenotyping of patient populations to understand the biologic basis of a specific pain condition and its response to treatment. The Specific Aim 2 of our proposal is to expand the pool of experienced clinical Investigators and research staff to be participants and leaders of multicenter clinical research trials by providing education, training, resources and professional mentorship. Finally, the Specific Aim 3 of our proposal is to engage and mobilize federal, industry, foundations and patient partners by working with the EPPIC-Net Steering Committee (EPPIC-Net-SC), EPPIC-Net-DCC and Project Team Principal Investigators to conduct multi-site Phase 2 clinical trials, biomarker validation studies, and deep phenotyping of patient populations to understand the biologic basis of a specific pain condition and its response to treatment.