Iproniazid Imipramine

Doxepine, Amitriptyline, Imipramine, Iproniazid, Pheniprazine Depression and anxiety... 

For instance, blurring of vision and diplopia are caused by the use of imipramine, iproniazid, chlorpromazine, thioridazine, and promethazine. Impairment of visual acuity is caused by chlorpropamide, tolbutamide, alcohol, chlorpromazine, phenylbutazone, indomethacin, chloroquine, sulfonamides, ethambutol, chloramphenicol, isonex, clioquinol, quinine, streptomycin, and paraaminosalicylate. Yellow vision (xanthopsia) has been traced to the use of sulfonamides, streptomycin, methaqualone, barbiturates, chlorothiazide,... 

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... 

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. 

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. 

Explain how imipramine and iproniazid affect the synaptic concentrations of serotonin and noradrenaline. 

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. 

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. 

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. 

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 action of imipramine, and to a lesser extent iproniazid, is not merely sedative and symptomatic, like that of the neuroleptics, but is curative. 

The discovery of the mood-elevating effect of MAO inhibitors was a classic example of serendipity in drug research. In 1951, isoniazid and its isopropyl derivative, iproniazid, were successfully introduced for the treatment of tuberculosis. In contrast to isoniazid, iproniazid was found to produce undesirable stimulation in some patients. In 1952, Zeller and his co-workers demonstrated that iproniazid was capable of inhibiting MAO, whereas isoniazid was ineffective (Zeller and Barsky 1952 Zeller et al. 1952). In 1956, Crane analyzed the psychiatric side-effects of iproniazid and came to the conclusion that it might be beneficial in the treatment of depression (Crane 1956). In 1957 Kline introduced it as a psychic energizer (Kline 1958). At the same time Kuhn discovered the antidepressant effect of imipramine (Kuhn 1957). This opened the way to the most powerful antidepressant therapy to date. 

The anti-depressants amitryptyline and imipramine, and their desmethyl analogues, inhibited the enzymic oxidation of both substrates but only at relatively high concentrations. It is significant that iproniazid, which owes its anti-depressant activity to its known inhibition of monoamine oxidase, had no effect on caeruloplasmin. 

It was observed (in the 1960s) that the antihistamine imipramine and the anti-tuberculosis drug iproniazid had antidepressant activities. Imipramine was found to inhibit neuronal uptake of noradrenaline and serotonin by pre-synaptic neurons in the brain. Iproniazid was found to inhibit monoamine oxidase, the enzyme that breaks down monoamines. Both these actions result in raised levels of monoamines at the synapse. In addition, drugs that reduce the availability of monoamines cause symptoms of depression. 

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