Dennis S. Charney - US grants

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Post-traumatic stress disorder (PTSD) is a chronic and common anxiety disorder that follows exposure to an overwhelming traumatic event. The majority of patients with PTSD also meet criteria for other psychiatric disorders and many attempt suicide. Despite its impact on society, little is known about the etiology or pathophysiology of this disorder. PTSD is responsive to pharmacological treatments such as selective serotonin reuptake inhibitors (SSRIs), but response rates rarely exceed 60%, and even fewer patients (20-30%) achieve clinical remission. Thus, there is a clear need to develop novel and improved therapeutics for PTSD. A growing body of preclinical studies suggests that activation of substance P (SP) and its NK1 receptor is anxiogenic and that NK1 antagonists, with chronic administration, exert significant dampening effects on this system. SP is a neuropeptide belonging to the tachykinin family, and has been implicated in several neurological and psychiatric illnesses. Excess activity of the SP-NK1 system thus stands as a prime candidate for involvement in the pathophysiology of anxiety disorders such as PTSD. We propose to investigate the efficacy of the highly specific NK1 antagonist GW597599 in PTSD in a placebo-controlled clinical trial. Furthermore, we propose to longitudinally investigate whether certain biological surrogate markers (neuroendocrine, neuroimaging) are predictive of treatment response. If a patient is already taking medication for PTSD and has achieved therapeutic response, he/she will not be tapered off effective medication(s) to participate in this study, and will not be eligible for the study. Taper and discontinuation of medications in preparation for this study will only occur in those patients who are not responding to medication treatment for PTSD. Hypotheses: 1)PTSD patients randomized to the NK1 antagonist GW597599 will achieve higher response rates acutely compared to patients randomized to placebo. 2)Biological surrogate makers involving neuroendocrine (CSF SP and NE) and neuroimaging function will be predictive of treatment response.

[unreadable] DESCRIPTION (provided by applicant): A major impetus for the creation of the Cooperative Drug Development Group (CDDG) for the Treatment of Mental Illness program is the sobering fact that available pharmacotherapies for major depression are suboptimal in terms of speed of onset, efficacy, and tolerability. Current medications for severe, chronic mood disorders are not based on pathophysiological models of illness, but rather are variations of monoaminergic-based therapies. The present application proposes a collaboration between 3 entities with the focused goal of accelerating antidepressant drug discovery: (1) the Departments of Psychiatry and Neuroscience of the Mount Sinai School of Medicine, (2) the NIMH Intramural Mood and Anxiety Disorders Program, and (3) Organon Pharmaceuticals. The primary aim of this collaboration is to test a candidate drug, Org 24448, in a phase II proof-of-concept clinical trial in adult patients with moderately treatment-resistant unipolar major depressive disorder. Org 24448 represents a new treatment approach for depression, by potentiating the AMPA receptor subfamily of ionotropic glutamate receptors. This drug has been shown to have antidepressant features in preclinical models, as well as cognitive-enhancing qualities. AMPA receptor activation has also been shown to increase expression of growth factors such as brain derived neurotrophic factor (BDNF). Since there is growing evidence from neuroimaging and post-mortem studies that severe mood disorders are characterized by alterations in intracellular signaling cascades and impairments of cellular plasticity and resilience, promoting BDNF may provide a mechanism for its therapeutic efficacy. In this 2-site, 8-week, randomized, placebo-controlled clinical trial, we aim to compare Org 24448 to placebo in patients ages 21 to 55, with a diagnosis of recurrent or chronic MDD (without psychotic features). Approximately 90 patients with major depression will be recruited at each site over 3 years, in order to randomize 70 patients at each site (140 patients total). Two sites are necessary to achieve the sample size of eligible patients in a relatively short period of time. As major depressive disorder continues to pose a significant public health problem, with high rates of morbidity and mortality, robust and well-tolerated new treatments are necessary. If initial studies are promising, this compound will be investigated for longer-term use with the aims of improving the long-term prognosis of this devastating chronic illness. [unreadable] [unreadable]

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Existing treatments for major depressive disorder (MDD) generally take weeks to months to exert their maximal benefit. Given the morbidity and mortality resulting from failure to treat depressive symptoms in a timely fashion, there is an urgent need to develop rapidly-acting treatments, as well as to identify optimal continuation treatment approaches. Ketamine, a high-affinity NMDA glutamate receptor antagonist, has been used as a standard intravenous (IV) anesthetic agent for many years in both pediatric and adult patients, with doses as high as 2 mg/kg. Beyond its well-established role in anesthesia and pain management, there is emerging evidence that ketamine may have rapid antidepressant properties for patients with severe mood disorders. Indeed, a recent placebo-controlled investigation replicated an earlier pilot study (Berman et al., 2000) and showed a robust acute antidepressant effect of a single dose of ketamine (0.5 mg/kg) in patients with treatment-resistant unipolar depression (Zarate et al., 2006), with many patients maintaining a mood improvement for several days. In order to fully capitalize on the therapeutic promise of IV ketamine for treatment resistant depression (TRD), two new issues will be addressed in this present study. First, it is important to identify the effectiveness of repeated doses of IV ketamine, in order to possibly prolong the antidepressant response beyond the acute effect of each individual administration. Second, it is crucial to identify the maximally effective while minimally aversive dose of IV ketamine that can be safely administered to outpatients over repeated doses. Patient acceptability of the drug regimen is key in ensuring the possible sustained benefit of IV ketamine. A final question pertains to the effect of ketamine treatment (both single and repeated dosing) on brain activity. We are adding functional imaging to this protocol in order to investigate (1) treatment-induced changes in task-related BOLD responses measured using functional magnetic resonance imaging (fMRI) and (2) treatment-induced changes in resting-state connectivity measured using functional connectivity MRI (fcMRI). This research protocol will test the efficacy of repeated IV ketamine administration in 20 patients with treatment-resistant MDD who exhibit an acute response to a single dose of IV ketamine. The dose to be used for repeated administration will be determined using the single-dose response. The main outcome measure is time to relapse following the antidepressant response to repeated dosing.

DESCRIPTION (provided by applicant): This application for NIH ARRA funds seeks to expand, improve, and consolidate space for laboratories, lab support, training, and related administration on the entire 23rd floor of the Annenberg Tower (Ann-23). The proposed project will support translational research at Mount Sinai School of Medicine by fully renovating Ann- 23, to improve functionality of laboratories, lab support, and administrative space. The requested renovations will affect 18,621 net square feet (29,500 gross square feet) and increase active research space from the current 57% of the floor to 73%. The floor currently supports $3.2 million in active grants. Immediate benefits of the proposed renovations will include relocation of peers and collaborators to the floor bringing an additional $1 million in active grants (total $4.2 million). Based on MSSM's current research-density benchmarks, the lab space created by the proposed improvements can support a projected additional $0.5 million in future research funding. The specific aims for this project are: o Expand laboratory space to accommodate ongoing growth of the research enterprise. o Redistribute functions so that ratio of lab, support, and office areas is in line with current standards. o Consolidate multi-disciplined programs to contiguous open lab space to improve safety, communication, administration, and training. o Expand BSL2+ core facility. o Support other program expansion in backfill spaces. Ann-23 is currently home to more than 85 staff, including PIs, postdocs, research fellows, research coordinators, administrative and other support staff. After the proposed improvements administrative space will be relocated to other floors resulting in an additional 42 research staff (127 people total) working on the floor. By consolidating, streamlining, and expanding laboratory space, the proposed project will enable Mount Sinai to strengthen the collaborations already under way by co-location of investigators working together on projects, and serve as a catalyst for new collaborations and joint programs, particularly in HIV-associated nephropathy, which is a shared focus of all the researchers to be housed on the floor.