History and therapeutic use of MAO-A inhibitors: a historical perspective of mao-a inhibitors as antidepressant drug.

Since the first generation of MAO inhibitors was developed, more than fifty years ago, this family of drugs has been ups and downs over the last decades. Actually, interest in MAO inhibitors is reviving and the emergence of new advances in the rational design of molecules and new techniques to predict the in vivo behavior has encouraged the research for new drugs with therapeutic potential in this area. The classic MAOIs have been widely used as antidepressants during the two decades after its introduction in clinic. Based on observations made on MAO inhibition by these drugs, it has been postulated hypothesis that have contributed to a better understanding of the mechanism and management of depressive disorders. However, exaggerated concerns about food and drug interactions relegated these drugs from the pharmaceutical landscape. The correct interpretation and the contextualization of side effects and the recent research findings, in which MAO selective inhibitors appear as promising agents in the treatment of emerging and high prevalence diseases, are placing these drugs again into the scientific and pharmacological focus.

Monoaminergic neurotransmission: the history of the discovery of antidepressants from 1950s until today.

The 1950s saw the clinical introduction of the first two specifically antidepressant drugs: iproniazid, a monoamine-oxidase inhibitor that had been used in the treatment of tuberculosis, and imipramine, the first drug in the tricyclic antidepressant family. Iproniazid and imipramine made two fundamental contributions to the development of psychiatry: one of a social-health nature, consisting in an authentic change in the psychiatric care of depressive patients; and the other of a purely pharmacological nature, since these agents have constituted an indispensable research tool for neurobiology and psychopharmacology, permitting, among other things, the postulation of the first aetiopathogenic hypotheses of depressive disorders. The clinical introduction of fluoxetine, a selective serotonin reuptake inhibitor, in the late 1980s, once again revolutionized therapy for depression, opening the way for new families of antidepressants. The present work reviews, from a historical perspective, the entire process that led to the discovery of these drugs, as well as their contribution to the development of the neuroscientific disciplines. However, all of these antidepressants, like the rest of those currently available for clinical practice, share the same action mechanism, which involves the modulation of monoaminergic neurotransmission at a synaptic level, so that the future of antidepressant therapy would seem to revolve around the search for extraneuronal non-aminergic mechanisms or mechanisms that modulate the intraneuronal biochemical pathways.

Contribución de la iproniazida y la imipramina al desarrollo de la psiquiatría biológica: primeras hipótesis etiopatogénicas de los trastornos afectivos / The contribution of iproniazid and imipramine to the development of biological psychiatry: the first etiopathogenic hypotheses of affective disorders

En 1957 se introdujeron en la clínica los dos primeros antidepresivos, imipramina e iproniazida, agentes de dos familias farmacológicas distintas; los antidepresivos tricíclicos y los inhibidores de la monoaminooxidasa (IMAO), respectivamente. Estos fármacos revolucionaron la práctica clínica en la asistencia psiquiátrica de la época. Pero, además, el desarrollo de la imipramina y la iproniazida supuso la introducción de nuevos métodos para la evaluación de la actividad antidepresiva de distintas sustancias y permitió avanzar en el conocimiento de la etiopatogenia de los trastornos afectivos, al posibilitar el postulado de las hipótesis monoaminérgicas de las depresiones durante la década los sesenta, que planteaban una deficiencia funcional de la neurotransmisión noradrenérgica y/o serotoninérgica, con base en el efecto bloqueador de la recaptación sináptica de estas aminas por parte de la imipramina, o la inhibición de la monoaminooxidasa, en el caso de la iproniazida. Sobre estas primeras hipótesis neurobiológicas del origen de las enfermedades mentales, se fue construyendo paulatinamente lo que hoy conocemos como psiquiatría biológica (AU)

In 1957, the 2 first antidepressants introduced into clinical practice were imipramine and iproniazid. These agents belong to 2 different pharmacologic families: tricyclic antidepressants and monoamine oxidase inhibitors (MAOI), respectively. These drugs revolutionized clinical practice in psychiatry at that time. Moreover, the development of iproniazid and imipramine required the introduction of new methods to evaluate the antidepressant activity of different substances and led to advances in the knowledge of the etiopathogenesis of affective disorders. This allowed the monoaminergic hypothesis of depression to be postulated in the 1960s, which proposed a functional deficiency in noradrenergic and serotonergic neurotransmission, based on synaptic reuptake blocking of theses amines by imipramine or monoamine oxidase inhibition by iproniazid. On the basis of these first neurobiological hypotheses on the origin of mental illness, what is currently known as "biological psychiatry" gradually developed (AU)

Selegiline transdermal system: current awareness and promise.

Many monoamine oxidase inhibitors (MAOIs) have been used to treat major depressive disorder (MDD). However, the prescription of MAOIs has decreased considerably as a result of side effects such as tyramine-induced hypertensive crisis, which is also known as the 'Cheese Effect'. The drug delivery system itself can affect the bioavailability of certain drugs, which might influence the efficacy and tolerability of medications, as well as improve the compliance and reduce the incidence of recurrence and relapse. Therefore, there is a need for advanced drug delivery techniques that can evade the potentially hazardous toxic effects of the parent compound, including extended-release oral, cutaneous, intravesical and intravaginal routes, etc. In this context, the selegiline transdermal system (STS, EMSAM) was introduced with improved side effect profiles and efficacy compared with the conventional form of the selegiline oral tablet. STS allows the targeted inhibition of the monoamine A (MAO-A) and MAO-B isoenzymes with minimal effects on the MAO-A in the gastrointestinal and hepatic systems. Hence, STS can reduce the risk of interactions with tyramine-rich foods. Many fundamental clinical and preclinical studies have reported that 6 mg/24 h of STS is effective against MDD without the need for dietary restrictions with an equal efficacy and improved safety profile. In addition, STS might benefit MDD patients with atypical features or who are resistant to other antidepressants. Overall, familiarity with the properties and indications of STS will have the clinicians another option of biological treatments for MDD patients but subsequent more data including actual post-market clinical experiences will be mandatory.

Monoamine oxidase: isoforms and inhibitors in Parkinson's disease and depressive illness.

A few years after the foundation of the British Pharmacological Society, monoamine oxidase (MAO) was recognized as an enzyme of crucial interest to pharmacologists because it catalyzed the major inactivation pathway for the catecholamine neurotransmitters, noradrenaline, adrenaline and dopamine (and, later, 5-hydroxytryptamine, as well). Within the next decade, the therapeutic value of inhibitors of MAO in the treatment of depressive illness was established. Although this first clinical use exposed serious side effects, pharmacological interest in, and investigation of, MAO continued, resulting in the characterization of two isoforms, MAO-A and -B, and isoform-selective inhibitors. Selective inhibitors of MAO-B have found a therapeutic role in the treatment of Parkinson's disease and further developments have provided reversible inhibitors of MAO-A, which offer antidepressant activity without the serious side effects of the earlier inhibitors. Clinical observation and subsequent pharmacological analysis have also generated the concept of neuroprotection, reflecting the possibility of slowing, halting and maybe reversing, neurodegeneration in Parkinson's or Alzheimer's diseases. Increased levels of oxidative stress in the brain may be critical for the initiation and progress of neurodegeneration and selective inhibition of brain MAO could contribute importantly to lowering such stress. There are complex interactions between free iron levels in brain and MAO, which may have practical outcomes for depressive disorders. These aspects of MAO and its inhibition and some indication of how this important area of pharmacology and therapeutics might develop in the future are summarized in this review.

Mechanism of action of antidepressant medications.

The psychopharmacology of depression is a field that has evolved rapidly in just under 5 decades. Early antidepressant medications--tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs)--were discovered through astute clinical observations. These first-generation medications were effective because they enhanced serotonergic or noradrenergic mechanisms or both. Unfortunately, the TCAs also blocked histaminic, cholinergic, and alpha1-adrenergic receptor sites, and this action brought about unwanted side effects such as weight gain, dry mouth, constipation, drowsiness, and dizziness. MAOIs can interact with tyramine to cause potentially lethal hypertension and present potentially dangerous interactions with a number of medications and over-the-counter drugs. The newest generation of antidepressants, including the single-receptor selective serotonin reuptake inhibitors (SSRIs) and multiple-receptor antidepressants venlafaxine, mirtazapine, bupropion, trazodone, and nefazodone, target one or more specific brain receptor sites without, in most cases, activating unwanted sites such as histamine and acetylcholine. This paper discusses the new antidepressants, particularly with regard to mechanism of action, and looks at future developments in the treatment of depression.

[History of deprenyl--the first selective inhibitor of monoamine oxidase type B]. / Istoriia deprenil--pervogo selektivnogo ingibitora monoaminoksidazy tipa B.

(-)Deprenyl (Selegiline, Jumex, Eldepryl, Movergan), a close structural relative of phenylethylamine (PEA), is a drug with a unique pharmacological spectrum. Whereas PEA and its long-lasting variants, the amphetamines, are mixed-acting stimulants of the sympathetic system in the brain, they primarily enhance the impulse propagation generated release of catecholamines (catecholamine activity enhancer, CAE, effect) and displace catecholamines in higher concentration (catecholamine releasing effect). (-)Deprenyl is the first CAE substance in clinical use devoid of catecholamine releasing activity. (-)Deprenyl is a highly potent and selective, irreversible inhibitor of B-type monoamine oxidase (MAO), a predominantly glial enzyme in the brain. The activity of this enzyme significantly increases with age. (-)Deprenyl, the first selective inhibitor of MAO-B described in the literature, has become a universally used research tool for selectively blocking B-type MAO and is still the only selective MAO-B inhibitor in world wide clinical use. In contrast to MAO inhibitors which strongly potentiate the catecholamine releasing effect of tyramine, (-)deprenyl inhibits it and is free of the 'cheese effect', which makes it a safe drug. Because its lack of the catecholamine releasing activity (-)deprenyl is devoid of amphetamine like dependence capacity. Maintenance on (-)deprenyl selectively enhances superoxide dismutase (SOD) and catalase activity in the striatum and protects the nigrostriatal dopaminergic neurons from selective neurotoxins (6-hydroxydopamine, MPTP, DSP-4). Maintenance of an animal on (-)deprenyl prevents the characteristic age-related morphological changes in the neuromelanin granules of the neurocytes in the substantia nigra. Many other protective effects of (-)deprenyl, denoted as 'neuroprotective', 'trophiclike neurorescue', 'apoptosis reducing', etc, have been described. All the protective actions of (-)deprenyl are thought to be primarily related to the CAE effect of the drug. All in all, (-)deprenyl increases the activity of the nigrostriatal dopaminergic system and slows its age-related decline. Maintenance of male rats on (-)deprenyl delays the age-related loss of their capacity to ejaculate, slows the age-related decline of their learning capacity and prolongs their life. Parkinsonian patients on levodopa plus (-)deprenyl (10 mg daily) live significantly longer than those on levodopa alone. Parkinsonian patients maintained, after diagnosis, on (-)deprenyl, need levodopa significantly later than their placebo-treated peers. Maintenance on (-)deprenyl significantly improves the performance of patients with Alzheimer's disease. It is concluded that patients developing Parkinson's or Alzheimer's disease need to be treated daily with 10 mg (-)deprenyl from diagnosis until death, irrespective of other medication. Because of the peculiar pharmacological spectrum and safety of the drug it may be advisable to combat the age-related decline of the nigrostriatal dopaminergic neurons in man by taking 10-15 mg (-)deprenyl weekly during the postdevelopmental phase of life. Prophylactic (-)deprenyl medication may improve the quality of life in the latter decades, delaying the time of natural death and decreasing the susceptibility to age-related neurological diseases.

[Tribulin--a novel endogenous monoaminoxidase inhibitor (dedicated to the memory of Merton Sandler)]. / Tribulin--éndogennyi ingibitor monoaminoksidaz: (posviashchenie Mertonu Sandleru).

Tribulin is endogenous monoamine oxidase and benzidiazepine binding inhibitory activity extractable from biological tissues and body fluids into ethyl acetate. Tribulin output is increased in conditions of stress and anxiety. Several chemical components of tribulin have recently been identified. Isatin is a selective inhibitor of monoamine oxidase B. Esters of indoleacetic and 4-hydroxyphenylacetic acids and 4-hydroxyphenyletanol selectively inhibit monoamine oxidase A. Biomedical importance of tribulin and its components is discussed.

Monoamine oxidase inhibitors: reversible and irreversible.

Coincident with and in part fueling advances in diagnostic nosology and drug development, the recent resurgence of interest in monoamine oxidase inhibitors (MAOIs) is reviewed. Accidentally discovered nearly 40 years ago as the first true antidepressants, the MAOIs soon fell into disfavor due to concerns about toxicity and seemingly lesser efficacy compared with the newer tricyclic compounds. Now that we have better understanding of the nature of the hypertensive and hyperpyrexic interactions of MAOIs with other substances, these medications have assumed a role in the treatment of nonendogenous depressive and anxiety syndromes, especially in operationally defined "atypical depression." The discovery of two MAO isoenzymes has resulted in a new generation of selective inhibitors in the search for enhanced efficacy (i.e., clorgyline) or safety (i.e., l-deprenyl). Most promising is the emerging class of reversible selective MAO-type A inhibitors, such as moclobemide, which combine antidepressant potency with freedom from the risk of dangerous tyramine-type adverse interactions.