Neuropeptide Medicines Still Waiting In The Wings

The ultimate proof of concept for neuropeptide approaches in psychiatry lies in emergence of clinically effective drugs. There is only one definitive example to date, and that is the family of opioidergic compounds. These drugs that mimic the effects of endogenous opioids are the most potent, generally effective analgesics. It is quite probable that opioid agonists could have other beneficial clinical effects related to emotional circuits (see below), but the use of these drugs is restricted by their high abuse potential, which in itself reflects the emotional value of the endogenous opioidergic systems.

At present, the only neuropeptidergic drugs that are approved for treating psychiatri-cally significant living problems are those that antagonize opioid receptors, for instance, naloxone and naltrexone. Their first approved use was in the treatment of narcotic overdoses as well as maintenance of opiate abstinence. Subsequent work indicated significant efficacy in the treatment of alcohol craving (O'Malley et al., 2002), which may reflect a general reduction in reward craving (de Wit etal., 1999) that extends even to gambling urges (Kim and Grant, 2001) and perhaps binge eating as well (Marrazzi et al., 1995). However, as we will discuss toward the end of this chapter, there have also been some off-label uses, such as for the treatment of self-injurious behaviors as well as certain symptoms of early childhood autism (Aman and Langworthy, 2000; Chabane et al., 2000). One can envision many additional indications, perhaps the most extreme being as a treatment for maladaptive social-addictive problems that lead to pedophilia, if we are correct in assuming that difficult-to-treat behavior arises, in part, from maladaptive patterns of opioid reward urges in the brain. Aside from such opioid-modulating drugs, no neuropeptide modulators have yet been accepted for routine psychiatric use.

The clinical opportunities for targeting precise psychiatric/emotional symptoms in this emerging field are more vast than commonly recognized, and there are currently increasing numbers of ongoing clinical initiatives. One of the more promising ones involves early work on the antidepressant effects of the proline-lycine-glycine (PLG) tripeptide that constitutes the "tail" of oxytocin (de Wied and van Ree, 1989). This work has been translated into a new generations of related neuropeptide agents, such as netamiftide (4,F-Phe-4-OH-Pro-Arg-Gly-Trp-NH2), which is reported to have a novel profile of antidepressant activity, including rapid onset (Feighner et al., 2001). The recognition that the Tyr-PLG (or Tyr-MIF-1) system, an endogenous opioid-modulating peptide system still searching for a function (Kastin et al., 2001), which may modulate brain reward (Nores et al., 1999), providing one potentially coherent account for the antidepressant effects. After all, opioids were recognized to have acute antidepressant effects long before the advent of modern psychiatry. At present, netamiftide remains on the fast track for development (being in Phase III trials), even though the last hurdle is often the greatest.

Among the most prominent three "near hits" so far have been (1) the use of Adrenocorticotropic Hormone (ACTH) fragments, such as Organon-2766, in the treatment of many neurological problems, including attentional/cognitive disorders in devel-opmentally impaired children (as detailed below); (2) a substance P neurokinin1 (NK1) receptor antagonists for depression (Kramer et al., 1998), which was placed on the back burner because it could not compete credibly with strong placebo effects in doubleblind trials (Enserink, 1999); and (3) there also continues to be widespread enthusiasm for the eventual use of corticotropin-releasing hormone (CRH) antagonists for the treatment of stress and anxiety (Reul and Holsboer, 2002), even though the initial agent used had problematic liver toxicity effects despite being otherwise well tolerated (Holsboer, 2001a,b). Then there are an enormous number of items that remain largely in the conceptual realm, ranging from the use of cholecystokinin (CCK) receptor blockers in the treatment of schizophrenia (Vanderhaeghen and Crawley, 1985) to the working hypothesis that vasopressin-related vectors may be beneficial in the treatment of depression (Scott and Dinan, 2002). Such emerging hypotheses will receive the most attention in this chapter.

If one were currently to select a single neuropeptide that has had the most promising and most widely evaluated track record in humans, it would be the first item in the above list (i.e., Org-2766). This peptide emerged gradually from David de Wied's work on memory enhancing ACTH-related peptides (Kovacs and de Wied, 1994). It also proved to have various interesting neuroprotective effects after peripheral nerve injury as well as following damage to certain central systems such as DA pathways (Strand, 1999). Subsequent work on structure activity relations led to localization of activity in the ACTH-(4-10) fragment and to the synthesis of an array of orally active synthetic peptides, the most promising of which was called Organon-2766 [H-Met(O(2))-Glu-His-Phen-D-Lys-Phe-OH]. This orally available, artificial peptide is about a thousand times as potent as the parent compound (ACTH 4-9), and has now been widely studied as a neuroprotective agent (e.g., van Rijzingen et al., 1996), and it has been reported to promote attentional-cognitive processes and in the treatment of autistic children, potentially by modulating opioid dynamics (Buitelaar et al., 1992). However, as is so common in the field, more recent studies have been less compelling than the earlier ones (Buitelaar et al., 1996). The commercial failure of this exceedingly safe and well tolerated peptide highlights the difficulties of taking agents that have been highly effective in preclinical studies to human applications. It is not clear why this is so, but perhaps future research will reveal that Org-2766 will prove to be more effective during the early rather than the later phases of certain disorders (e.g., for strokes, ADHD, and the prophylactic treatment of impending cognitive decline; Nyakas et al., 1995).

Funny Wiring Autism

Funny Wiring Autism

Autism is a developmental disorder that manifests itself in early childhood and affects the functioning of the brain, primarily in the areas of social interaction and communication. Children with autism look like other children but do not play or behave like other children. They must struggle daily to cope and connect with the world around them.

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