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Inhibitors of MAO-A and MAO-B in Psychiatry and Neurology.

ABSTRACT: Inhibitors of MAO-A and MAO-B are in clinical use for the treatment of psychiatric and neurological disorders respectively. Elucidation of the molecular structure of the active sites of the enzymes has enabled a precise determination of the way in which substrates and inhibitor molecules are metabolized, or inhibit metabolism of substrates, respectively. Despite the knowledge of the strong antidepressant efficacy of irreversible MAO inhibitors, their clinical use has been limited by their side effect of potentiation of the cardiovascular effects of dietary amines ("cheese effect"). A number of reversible MAO-A inhibitors which are devoid of cheese effect have been described in the literature, but only one, moclobemide, is currently in clinical use. The irreversible inhibitors of MAO-B, selegiline and rasagiline, are used clinically in treatment of Parkinson's disease, and a recently introduced reversible MAO-B inhibitor, safinamide, has also been found efficacious. Modification of the pharmacokinetic characteristics of selegiline by transdermal administration has led to the development of a new drug form for treatment of depression. The clinical potential of MAO inhibitors together with detailed knowledge of the enzyme's binding site structure should lead to future developments with these drugs.

SUBMITTER: Finberg JP

PROVIDER: S-EPMC5067815 | biostudies-other | 2016

REPOSITORIES: biostudies-other

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Inhibitors of MAO-A and MAO-B in Psychiatry and Neurology.

Finberg John P M JP Rabey Jose M JM

Frontiers in pharmacology 20161018

Inhibitors of MAO-A and MAO-B are in clinical use for the treatment of psychiatric and neurological disorders respectively. Elucidation of the molecular structure of the active sites of the enzymes has enabled a precise determination of the way in which substrates and inhibitor molecules are metabolized, or inhibit metabolism of substrates, respectively. Despite the knowledge of the strong antidepressant efficacy of irreversible MAO inhibitors, their clinical use has been limited by their side e ...[more]

PMID: 27803666

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Project description:ContextThere are growing concerns about effect size inflation and replication validity of association studies, but few observational investigations have explored the extent of these problems.ObjectiveUsing meta-analyses to measure the reliability of initial studies and explore whether this varies across biomedical domains and study types (cognitive/behavioral, brain imaging, genetic and "others").MethodsWe analyzed 663 meta-analyses describing associations between markers or risk factors and 12 pathologies within three biomedical domains (psychiatry, neurology and four somatic diseases). We collected the effect size, sample size, publication year and Impact Factor of initial studies, largest studies (i.e., with the largest sample size) and the corresponding meta-analyses. Initial studies were considered as replicated if they were in nominal agreement with meta-analyses and if their effect size inflation was below 100%.ResultsNominal agreement between initial studies and meta-analyses regarding the presence of a significant effect was not better than chance in psychiatry, whereas it was somewhat better in neurology and somatic diseases. Whereas effect sizes reported by largest studies and meta-analyses were similar, most of those reported by initial studies were inflated. Among the 256 initial studies reporting a significant effect (p<0.05) and paired with significant meta-analyses, 97 effect sizes were inflated by more than 100%. Nominal agreement and effect size inflation varied with the biomedical domain and study type. Indeed, the replication rate of initial studies reporting a significant effect ranged from 6.3% for genetic studies in psychiatry to 86.4% for cognitive/behavioral studies. Comparison between eight subgroups shows that replication rate decreases with sample size and "true" effect size. We observed no evidence of association between replication rate and publication year or Impact Factor.ConclusionThe differences in reliability between biological psychiatry, neurology and somatic diseases suggest that there is room for improvement, at least in some subdomains.

Project description:BackgroundThe traditional emphasis on developing high specificity pharmaceuticals ("magic bullets") for the treatment of Neurological and Psychiatric disorders is being challenged by emerging pathophysiology concepts that view disease states as abnormal interactions within complex networks of molecular and cellular components. So-called network pharmacology focuses on modifying the behavior of entire systems rather than individual components, a therapeutic strategy that would ideally employ single pharmacological agents capable of interacting with multiple targets ("magic shotguns"). For this approach to be successful, however, a framework for understanding pharmacological "promiscuity"--the ability of individual agents to modulate multiple molecular targets--is needed.Presentation of the hypothesisPharmacological promiscuity is more often the rule than the exception for drugs that target the central nervous system (CNS). We hypothesize that promiscuity is an important contributor to clinical efficacy. Modulation patterns of existing therapeutic agents may provide critical templates for future drug discovery in Neurology and Psychiatry.Testing the hypothesisTo demonstrate the extent of pharmacological promiscuity and develop a framework for guiding drug screening, we reviewed the ability of 170 therapeutic agents and endogenous molecules to directly modulate neurotransmitter receptors, a class of historically attractive therapeutic targets in Neurology and Psychiatry. The results are summarized in the form of 1) receptor-centric maps that illustrate the degree of promiscuity for GABA-, glycine-, serotonin-, and acetylcholine-gated ion channels, and 2) drug-centric maps that illustrated how characterization of promiscuity can guide drug development.Implications of the hypothesisDeveloping promiscuity maps of approved neuro-pharmaceuticals will provide therapeutic class-based templates against which candidate compounds can be screened. Importantly, compounds previously rejected in traditional screens due to poor specificity could be reconsidered in this framework. Further testing will require high throughput assays to systematically characterize interactions between available CNS-active drugs and surface receptors, both ionotropic and metabotropic.

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Inhibitors of MAO-A and MAO-B in Psychiatry and Neurology.

Publications

Inhibitors of MAO-A and MAO-B in Psychiatry and Neurology.

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