Promising New Directions in Antidepressant Development

This chapter extends the discussion of novel mechanisms of action that may mediate antidepressant efficacy presented in the previous chapter and reviews findings concerning investigational antidepressants that are currently either in phase II or III clinical testing and for which data are available in the public domain. Six neuropeptides that are currently of interest in antidepressant drug development are discussed: corticotropin releasing hormone (CRH), substance P [also known as neurokinin 1 (NK1)], neuropeptide Y (NPY), galanin, vasopressin (VPN), and oxytocin. These six were chosen because there are animal and/or human data that support a potential role for each of them in the pathophysiology of clinical depression. The role of each of the six neuropeptides in the pathophysiology of depression is reviewed. Results in the public domain concerning investigational antidepressants affecting one of these mechanisms of action are available only for the first two neuropeptides—CRH and substance P. Data are described for R121919, a CRH-1 receptor antagonist, and for the substance P antagonist, MK-869. Note that there are other investigational antidepressants in phase I or early phase II testing for which efficacy data are either not available or not yet in the public domain which are not discussed in this chapter. The naturally occurring neuropeptides described in the first part of the chapter have multiple functions throughout the body and thus drugs acting on these peptides could produce multiple unwanted effects. For that reason, it might be desirable to design novel peptides that have therapeutic potential with minimal side effects. Findings concerning one such novel peptide are presented: INN 00835 (nemifitide) is a synthetic pentapeptide that has shown promise in preclinical and clinical trials as a future antidepressant.