Imipramine, antidepressant effects

Selected for clinical trials as a compound to calm agitated patients, imipramine was relatively ineffective. However, it was observed to be effective in the treatment of certain depressed patients (38). Early studies on the mechanism of action showed that imipramine potentiates the effects of the catecholamines, primarily norepinephrine. This finding, along with other evidence, led to the hypothesis that the compound exerts its antidepressant effects by elevating norepinephrine levels at central adrenergic synapses. Subsequent studies have shown that the compound is a potent inhibitor of norepinephrine reuptake and, to a lesser extent, the uptake of serotonin, thus fitting the hypothesis that had been developed to explain the antidepressant actions ofMAOIs. 

Set against this background is the finding that the inhibition of [ H]noradrenaline uptake by the neuroleptic, chlorpromazine, is even greater than that of imipramine and yet chlorpromazine has no apparent antidepressant effects. This serves as a testimony... 

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. 

It has been known for over 25 years that many of the tricyclic antidepressants (TCAs), e.g. imipramine and amitriptyline, are potent inhibitors of both norepinephrine and 5-HT reuptake. Some tricyclic antidepressants, e.g. desipramine, inhibit the uptake of norepinephrine much more potently than the uptake of 5-HT. Thus, it was unclear for some time whether the inhibition of 5-HT uptake played any role in the antidepressant action of those TCAs that possessed this pharmacological property. Recently, however, effective antidepressants such as fluoxetine, paroxetine and sertraline have been marketed and these SSRIs are much more potent inhibitors of the uptake of 5-HT than that of norepinephrine (Fig. 13-8). Thus, selective inhibition of the uptake of either norepinephrine or 5-HT can result in an antidepressant effect (Ch. 55). 

Antidepressant Some animal models show antidepressant effects of lobelia extract (Subarnas et al. 1992). Similar to imipramine and mianserin, beta-amyrin palmitate shows antidepressant-like effects in the forced-swimming test (Subarnas et al. 1993a). Whereas mianserin and beta-amyrin palmitate reduce locomotor activity induced by methamphetamine, imipramine increases it. It potentiates sodium pentobarbital-induced sleep more potently than imipramine, but less than mianserin. Collectively, the effects of beta-amyrin palmitate in behavioral and physiological assays suggests it may work in a manner more similar to mianserin than imipramine. However, the mechanism of antidepressant-like effects of lobelia is uncertain. It may be through the beta-amyrin palmitate s ability to release norepinephrine (Subarnas et al. 1993b). An antidepressant effect of lobelia has not been established in humans. 

In a manner similar to imipramine, an ethanol extract of valerian root was found to prevent immobility induced by a forced-swimming test in rats, suggesting a potential antidepressant effect of valerian (Sakamoto et al. 1992). 

Kahn NH, Shelton SJ Defensive behaviors in infant rhesus monkeys environmental cues and neurochemical regulation. Science 243 1718-1721, 1989 Kahnowsky LB, Kennedy F Observations in electric shock therapy apphed to problems of epilepsy. J Nerv Ment Dis 98 56-67, 1943 Kampen D, Sherwin B Estrogen use and verbal memory in healthy postmenopausal women. Obstet Gynecol 83 979-983, 1994 Kane JM, Quitkin FM, Rifkin A, et al Lithium carbonate and imipramine in the prophylaxis of unipolar and bipolar 11 illness a prospective placebo-controlled comparison. Arch Gen Psychiatry 39 1065-1069, 1982 Kaneno S, Komatsu H, Fukamauchi F, et al Biochemical basis of antidepressant-effect of low dose of sulpiride. Japanese Journal of Psychiatry and Neurology 45 131-132, 1991... 

Looking back on it today, it would seem that chance played a smaller role in the discovery of the antidepressant effect of imipramine. The antimanic effect of lithium had already been recognized although lithium was only being used in a few clinics and the recently discovered antipsychotic effect of... 

Once the antidepressant effect of imipramine had been recognized, a large number of imipramine-like compounds with no really novel features were developed and marketed (Chapter 1). According to the Swedish pharmacologist Arvid Carlsson (1998), the next step occurred as follows "During the 1960s the mechanism of action of imipramine was generally believed to be a blockade of norepinephrine reuptake. However, late in the same decade this... 

This was put forward in 1965 by J. Schildkraut and states that some, if not all, depressions are the consequence of an absolute or relative deficiency of catecholamines, particularly norepinephrine, at functionally important adrenergic receptor sites in the brain (Schildkraut, 1965, p. 509). The evidence brought forward in support of this hypothesis was impressive (Table 4.2) because it covered both clinical and multifarious pharmacological findings. The antidepressant effect of imipramine and of the monoamine oxidase (MAO) inhibitors was attributed to the fact that these medicaments bring about an increased supply of functionally available catecholamines at the synapse ... 

Grunder G, Wetzel H, Schloer R, et al. Subchronic antidepressant treatment with venlafaxine or imipramine and effects on blood pressure assessment by automatic 24 hour monitoring. Pharmacopsychiatry 1993 26 155. 

We can predict whether or not a given patient is likely to respond well to an antidepressant like imipramine by how dramatically the alterations of sleep that are typical of depression are reversed. This fact has two important implications first, it makes the delay more tolerable because a positive outcome is easier to anticipate than an uncertain one and second, it means that there is more than a casual tie between the immediate sleep effects and the delayed antidepressant effect. Perhaps the link is even causal. How so ... 

Physostigmine, given intravenously, counteracts both the peripheral and central side effects of atropine and other anticholinergic drugs such as thioridazine (neuroleptic), imipramine (antidepressant), and benztropine (antiparkinsonian medication). 

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... 

Since Kuhn s paper on imipramine, it has been believed that antidepressants are most effective in severe depression. Many people, who are sceptical of their widespread use for milder cases, maintain that antidepressants are nevertheless effective and necessary in severe depression. It has also been suggested that the reason some studies find little difference between antidepressants and placebo is because they are conducted with people with mild depression, who dilute the antidepressant effect (National Institute for Clinical Excellence 2004). The National Institute for Clinical Excellence guidelines on the treatment of depression have gone as far as to suggest recently that antidepressants should not be prescribed to people with mild depression, and should only be used in cases of moderate and severe depression. However there is actually little evidence for the presumption that antidepressants are effective in severe depression. 

The correct answer = B The tricyclic antidepressants and especially imipramine are effective in this condition because it contracts the internal sphincter of the bladder. Fluoxetine and trazodone act at serotonin receptors and have no effect on bladder function. Tranylcypromine is an MAO inhibitor with serious side effects. 

Some antidepressants—specifically, tricyclics like imipramine (trade name Tofranil) and amitryptiline (trade name Elavil)—are thought to exert their antidepressant effect through inhibition of a reuptake mechanism that sucks back the neurotransmitters from the synapse into the neuron for storage and future use, a process mentioned in Chapter 1. The resulting net effect is an increase of these molecules at the synapse and thus a more robust neurotransmission. A different category of antidepressants—monoamine oxidase inhibitors (MAOIs)—display a different mechanism of action but with the same net effect of increasing norepinephrine and serotonin neurotransmission they inhibit the metabolism (breakdown) of the molecules stored in the neurons, thus creating more abundant supplies for neurotransmission. 

A 30% ethanol extract of the Japanese valerian root ( Hokkai-Kisso ) extract (4.1 g/kg and 5.7 g/kg) and imipramine (20 mg/kg) also demonstrated statistically significant antidepressant effects compared to placebo as measured by the forced swimming test in rats (26). As in the Oshima study, kessyl glycol diacetate exhibited no antidepressant activity in the forced swimming test. Because the forced swimming test can be affected by stimulants, anticholinergics, and antihistamines as well as antidepressants, the effect of the valerian extract on reserpine-induced hypothermia, a test for antidepressant activity and inhibition of neuronal reuptake of monoamines, was measured. Both valerian (11.2 g/kg) and imipramine (20 mg/kg) reversed reserpine-induced hypothermia, suggesting that the antidepressant effect of valerian is caused by reuptake of monoamine neurotransmitters, as with conventional antidepressants. 

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. 

Antidepressant effects of valerian were identified by Oshima and associates using a methanol extract of Valeriana fauriei roots (Oshima et al., 1995). They found a strong antidepressant activity in mice as measured by the forced swimming test. One active component isolated was a-kessyl alcohol, a volatile oil component. At 30 mg/kg intraperitoneally, a-kessyl alcohol exhibited an effect similar to imipramine, a commonly used antidepressant. Kessanol and... 

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