Antidepressants iproniazid

Thus, condensation of isoniazide with acetone at the basic nitrogen gives the corresponding Shiff base (8). Catalytic reduction affords the antidepressant, iproniazid (9). Addition of the same basic nitrogen to methyl acrylate by Michael condensation leads to the 3-amino ester (10). This is converted to the amide, nialamide (11), on heating with benzylamine. 

The first two antidepressants, iproniazid and imipramine, were developed in the same decade. They were shown to reverse the behavioural and neurochemical effects of reserpine in laboratory rodents, by inhibiting the inactivation of these monoamine transmitters (Leonard, 1985). Iproniazid inhibits MAO (monoamine oxidase), an enzyme located in the presynaptic neuronal terminal which breaks down NA, 5-HT and dopamine into physiologically inactive metabolites. Imipramine inhibits the reuptake of NA and 5-HT from the synaptic cleft by their transporters. Therefore, both of these drugs increase the availability of NA and 5-HT for binding to postsynaptic receptors and, therefore, result in enhanced synaptic transmission. Conversely, lithium, the oldest but still most frequently used mood stabiliser (see below), decreases synaptic NA (and possibly 5-HT) activity, by stimulating their reuptake and reducing the availability of precursor chemicals required in the biosynthesis of second messengers. 

Monoamine—Oxidase Inhibitors. In the mid-1950s, tuberculosis patients with depression being treated with iproniazid (42) were occasionally reported to become euphoric. This observation led to the discovery of irreversible monoamine—oxidase (MAO) inhibiting properties. Hydrazine and nonhydrazine-related MAO inhibitors were subsequentiy shown to be antidepressants (122). Three other clinically effective irreversible MAO inhibitors have been approved for treatment of major depression phenelzine (43), isocarboxazid (44), and tranylcypromine (45). 

Iproniazid was among the first psychotropic antidepressants to be discovered and introduced into the clinic. Although this inhibitor and others that followed... 

In contrast, iproniazid, introduced in 1951 for treatment of tuberculosis, induced euphoria and was described as a psychic energiser . In fact, these patients, when given iproniazid, could become quite disruptive and this action was regarded as an undesirable side-effect However, its beneficial effects in depression were soon recognised and it was regarded as the first effective antidepressant drug. Studies of peripheral sympathetic neurons, later extended to noradrenergic neurons in the brain, showed that iproniazid irreversibly inhibits the catalytic enzyme, monoamine oxidase (MAO). Because only cytoplasmic monoamines are accessible to MAO, inhibition of this enzyme first increases the concentration of the pool of soluble transmitter but this leads to a secondary increase in the stores of vesicle-bound transmitter i.e. the pool available for impulse-evoked release (Fillenz and Stanford 1981). 

It is important to note that claims for the effectiveness of iproniazid and imipramine were not based on placebo-controlled clinical trials. Instead, they were based on clinical impressions.6 In discovering the antidepressant effects of imipramine, Kuhn did not even use precise measurement, rating scales or statistics. His claim was that precise measurement led to stagnation rather than progress in medicine, and he preferred to rely on his extensive medical experience and artistic imagination instead.7... 

Despite the weakness of the data, the idea that iproniazid and imipramine were effective antidepressants came to be widely accepted. This is not really surprising, in the context of the times. In the 1950s and 1960s, the power of the placebo effect was just beginning to be recognized, and placebo-controlled clinical trials were rare. New treatments were often accepted on the basis of clinical experience and the testimony of experts in the field. 

Iproniazid and imipramine seemed to work as antidepressants, but how did they achieve their effects It would be another decade before the chemical-imbalance theory was launched. In 1965, Joseph Schildkraut at the National Institute of Mental Health in Washington, DC, published a groundbreaking paper in which he argued that depression was caused by a deficiency of the neurotransmitter norepinephrine in the gaps between neurons in the brain.8 Two years later Alec Coppen, a physician at West Park Hospital in Surrey, published another version of the chemical-imbalance theory. His version differed from Schildkraut s in that it put most of the blame on a different neurotransmitter, emphasizing serotonin rather than norepinephrine as the neurotransmitter that was lacking.9... 

Against this backdrop, researchers reported evidence that iproniazid, the antitubercular drug that was to become the first antidepressant, might increase norepinephrine and serotonin levels in the brain. How did it have this effect Recall that some of the neurotransmitter molecules released by a neuron are destroyed by enzymes in the synaptic cleft between the sending presynaptic neuron and the receiving postsynaptic neuron. When the neurotransmitter is a monoamine - like norepinephrine and serotonin - this process is called monoamine oxidase (MAO). As early as 1952 researchers at the Northwestern University Medical School in Chicago reported that iproniazid inhibited the oxidation of monoamines. This meant that iproniazid was a... 

There was a problem with this first version of the biochemical theory of depression. Iproniazid was not the only drug that had been reported to be effective as an antidepressant. Imipramine, the drug that had been tested by the Swiss psychiatrist Roland Kuhn, seemed to have similar effects. But imipramine is not an MAOI it does not inhibit the destruction of neurotransmitters in the synapse. So if antidepressants worked by inhibiting monoamine oxidase, why was imipramine effective How could its apparent effectiveness be reconciled with the chemical-imbalance theory ... 

Like the articles indicating that iproniazid and imipramine functioned as antidepressants, the conclusion that reserpine makes people depressed was based on clinical reports, rather than controlled trials. 

Iproniazid (4.272) was originally synthesized as a tuberculostatic drug but was found to be an antidepressant due to its inhibitory effect on monoamine oxidase. However, this compound had to be withdrawn from clinical use due to a high incidence of hepatotoxicity. The metabolism and the mechanism of toxification of iproniazid were found to be comparable to those of... 

Monoamine Oxidase inhibitors (MAOis). The first antidepressant discovered was iproniazid. This medication was developed in the early 1950s as a treatment for tuberculosis but was unexpectedly found to improve mood in depressed patients. It was later found that its antidepressant effect was due to its action on the MAO enzymes. Unfortunately, iproniazid was subsequently found to cause liver damage and was withdrawn from the market. 

Tricyclic Antidepressants (TCAs). Like iproniazid, the first TCA was also developed in the 1950s for another purpose. Imipramine (Tofranil) is structurally similar to the early antipsychotics and was hoped to provide an alternative to chlor-promazine (Thorazine). It proved to be a poor antipsychotic but was surprisingly found to be an effective antidepressant. The tricyclics are so named because a three-ringed structure forms the hub of the molecule. 

Iproniazid, an MAOI no longer available because of its hepatotoxicity, was the first effective antidepressant to be discovered it was introduced shortly before the discovery of imipramine. All MAOIs are presumed to have a similar mode of action, namely to inhibit the intra- and interneuronal metabolism of the biogenic amine neurotransmitters (noradrenaline, dopamine and serotonin). These amines are primarily metabolized by MAO-A (noradrenaline and serotonin) or MAO-B (dopamine). The irreversible MAOIs are inhibitors of MAO-A while selegiline (deprenyl), used as an adjunctive treatment for Parkinson s disease, is a selective, irreversible inhibitor of MAO-B. 

The toxic effects of the MAOIs are more varied and potentially more serious than those of the other classes of antidepressants in common use. Hepatotoxicity has been reported to occur with the older hydrazine type of MAOIs and led to the early demise of iproniazid the hepatotoxicity does not appear to be related to the dose or duration of the drug administered. 

The first inhibitors of flavin-dependent MAO that were developed for clinical use were hydrazines and hydrazides. The chance discovery that the antitubercular drug, 4-pyridine carboxylic acid hydrazide (isoniazid, 40), was also a potent MAO inhibitor led to the development of the related drug, iproniazid (41), used for the treatment of depressive illness. Although this compound demonstrated remarkable antidepressant action, its clinical value was seriously compromised by side effects [19]. 

Similar to the discovery of other psychiatric medications, the mood-enhancing effects of monoamine oxidase inhibitors (MAOIs) were identified serendipi-tously mood improvements were observed in patients with tuberculosis treated with iproniazid (Bloch et ah, 1954) The early enthusiasm for the MAOIs was based on significant and unprecedented antidepressant effects and the link between antidepressant efficacy and their... 

In the early 1950s, the MAOI iproniazid was tried to treat tuberculosis. Researchers noticed that even when iproniazid was not effective in treating the tuberculosis, many of their patients seemed to be happier. Soon, iproniazid was put to use to treat depression. Later, MAOIs became the first antidepressants shown to be effective for the treatment of social anxiety disorder, and have since been used in the treatment of all of the anxiety disorders. 

Shortly after iproniazid was shown to have antidepressant properties, imipramine was introduced as the first tricyclic antidepressant. These drugs received the name tricyclic because their structure contains three molecular rings. At first, imipramine was investigated as a possible treatment for the psychotic episodes associated with schizophrenia, a severe mental disorder that causes hallucinations and delusions, because it was chemically similar to another effective anti-schizophrenia drug. Imipramine did not reduce the severity of psychotic episodes, but it did elevate the mood of the patients who took it. In the late 1950s, it was released in the United States under the name Tofranil for the treatment of depression. 

Although many antibiotics are effective to some extent in arresting the progress of tuberculosis, none is uniformly successful. One of the most effective is isonicotinic hydrazide (73), available from methyl isonicotinate by reaction with hydrazine (B-75MI20903). Extensive clinical use of this agent showed the drug to possess an additional antidepressant effect and led to the development of iproniazid (74), an established antidepressant (53JOC994). 

The antidepressant properties of these earlier antidepressants were chance discoveries. Imipramine was first developed as a potential antipsychotic, but when Kuhn (2) tested the clinical efficacy of this agent, he found that it only benefited depressed schizophrenic patients. This observation prompted him to test it in patients who were suffering from melancholia. Iproniazid was developed as an antitubercular drug, but the observation that euphoria was a side effect led George Crane ( 3) to conduct clinical trials, which found it useful in purely depressed patients. A year later, Nathan Kline ( 4), following up on this observation, reported positive results when he administered iproniazid to another depressed group. 

The first generation of antidepressants, MAO (monoamine oxidase) inhibitors, inhibited neurotransmitter degradation by inhibiting monoamine deoxidase, a flavin containing enzyme, found in the mitochondria of neurons and other cell types, that oxidatively deaminates naturally occurring sympathomimetic monoamines, such as norepinephrine, dopamine, and serotonin within the presynapse. In 1952, isoniazid and its isopropyl derivative, iproniazid (1), were developed for the treatment of tuberculosis, where it was subsequently found that these agents had a mood enhancing effect on... 

Isoniazid and iproniazid are chemically similar drugs having different pharmacological effects they may both cause liver damage after therapeutic doses are given. Isoniazid is still widely used for the treatment of tuberculosis, but iproniazid is now rarely used as an antidepressant. 

When used with psychiatric patients, iproniazid showed mood elevation and heralded the first class of antidepressants—the monoamine oxidase inhibitors (MAOIs)—into psychiatric practice. 

In the 1950s Marsilid (the brand name of iproniazid) and Tofranil (imipramine) were manufactured and sold as antidepressant drugs. 

Antidepressants were first introduced into the market in the 1950s with the serendipitous discovery of the antidepressant effect of two drugs initially evaluated for other medical uses Iproniazide, a monoamine oxidase inhibitor (MAOI), and Imipramine, a tricyclic antidepressant (TCA). Since then, a whole new generation of chemically and pharmacologically unrelated compounds have been introduced, which appear to be safer and better tolerated due to a more specific mechanism of action. These include selective serotonin reuptake inhibitors (SSRIs), serotonin and... 

The discovery of the antidepressant effect of medications was coincidental to their use for other disorders. Initial work published in 1952 reported that iproniazid (originally used for the treatment of tuberculosis) could elevate mood. Although the use of iproniazid was discontinued due to toxicity, many other additional medications have been tested and approved for the treatment of depression. These include monoamine oxidase inhibitors, tricyclics, selective serotonin reuptake inhibitors, and a heterogeneous class of atypical drugs. 

The immediate uptake of iproniazid for use in people with depression illustrates the appetite that existed for a pharmacological treatment for this sort of problem. Kline himself later commented that probably no drug in history was so widely used so soon after the announcement of its application in the treatment of a specific disease. Kline attributed this partly to the fact that iproniazid was already available because it was a recognised treatment for tuberculosis, but he also records the feeling of the time that there was an overwhelming need for an effective antidepressant medication (Kline 1970, p. 202). 

Jacobsen suggested that the effects of the MAOI antidepressants such as iproniazid were clearly distinguishable from effects of stimulant drugs. Like Kline and colleagues, he assumed that their effects in depression were due to monoamine oxidase inhibition, but did not explain how they could be differentiated from stimulants which were also known to act in this way. 

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