Depression isocarboxazid

MAOI agents was synthesized and tested for antidepressant properties. Three MAOI agents are approved in the United States for use in major depression isocarboxazid (Marplan), phenelzine Nardil), and tranylcypromine (Parnate). 

Isocarboxazid is an MAO inhibitor, which blocks activity of enzyme MAO, thereby increasing monoamine (e.g., epinephrine, norepinephrine, serotonin) concentrations in CNS. It is indicated in the treatment of depression. Isocarboxazid (30 mg/kg) is a monoamine oxidase inhibitor (MAO) indicated for the treatment of depressed patients who have become refractory to tricyclic antidepressants... 

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). 

Isocarboxazid is a powerful MAO inhibitor. As with phenelzine, isocarboxazid is used for depressions that do not respond to other drugs. Marplan is a synonym of isocarboxazid. 

Withdrawal. Withdrawal may be associated with nausea, vomiting, and malaise. Coexisting symptoms Tranylcypromine and isocarboxazid may aggravate coexisting symptoms in depression, such as anxiety and agitation. 

Examples of monoamine oxidase inhibitors are phenelzine, tranylcypromine, isocarboxazid and mo-clobemide. They are indicated for atypical depression. Changes in the neurotransmitter levels are seen in several days but the clinical effect may lag by several weeks. Phenelzine is a non-selective hydrazine-type monoamine oxidase inhibitor while the also non-selective inhibitor tranylcypromine is of the non-hydrazine-type. Phenelzine, tranylcypromine and isocarboxazid are irreversible inhibitors. Phenelzine is partly metabolized by acetylation and slow acetylators are more prone to toxicity. It has anxiolytic properties and superior efficiacy in treating severe anxiety. 

The potential for toxicity that is associated with the administration of the MAOIs restricts their use in major depression. Hepatotoxicity is likely to occur with isocarboxazid or phenelzine, since hydrazine compounds can cause damage to hepatic parenchymal cells. This is true particularly for patients identified as slow acetyla-tors (see Chapter 4) of hydrazine compounds. Fortunately, the incidence of hepatotoxicity is low with the available agents. 

In the United States, the three MAOIS available for the treatment of psychiatric conditions are phenelzine (Nardil), tranylcypromine (Parnate), and isocarboxazid (Marplan). All three agents have indications for adult major depression (>16 years old) and, more specifically, atypical depression (anergia, hypersomnia, hy-perphagia, somatization, and anxiety symptoms). Although not indicated for anxiety, the MAOIs can also be particularly helpful in treatment of these disorders. Selegiline or L-deprenyl (Eldepryl) is also available in the United States and indicated for symptoms of Parkinson s disease and depression. 

Structurally, all MAOIs are either hydralazines or nonhydralazines. Iproniazid, the first MAOI used for depression, is a hydralazine. There are currently two hydralazines available, phenelzine and isocarboxazid. Tranylcypromine is a nonhydralazine with a unique structure. Although tranylcypromine is considered to be a reversible inhibitor of MAO, clinically, the return of normal enzymatic activity is delayed, similar to phe-... 

Monoamine oxidase inhibitors such as phenelzine and isocarboxazid (Fig. 5.37) are used clinically for the treatment of depression. These compounds also form complexes with... 

During clinical studies of iproniazid (201) in the treatment of tuberculosis it was found to have a mood-elevating effect. It was later found to be an inhibitor of monoamine oxidase (MAO), the enzyme which oxidatively deaminates such neurotransmitters as noradrenaline and serotonin, and it was tried in the treatment of depression in 1957. Other MAO inhibitors were introduced later, most of them being hydrazine derivatives. Heterocyclic examples include isocarboxazid (202) and nialamide (203). They are toxic and cause dangerous hypertensive crises if food with a high tyramine content is eaten, and on this account their use is limited. 

The monoamine oxidase inhibitors are used occasionally to treat depression. The hydrazine derivatives consist of isocarboxazid (Marplan) and phenelizine sulfate (Nardil). The nonhydrazine derivatives include tranylcypromine (Parnate). 

Patients should not use dextromethorphan if they are taking any drug in the class known as monoamine oxidase inhibitors (MAOI), including phenelzine (Nardil), isocarboxazid (Marplan), and tranylcypromine (Parnate), which are used in the treatment of depression. The combination of MAOIs with dextromethorphan can lead to toxic levels of dextromethorphan in the blood. 

Monoamine oxidase (MAO) is a mitochondrial enzyme found in neural and other tissues, such as the gut and liver. In the neuron, MAO functions as a safety valve to oxidatively deaminate and inactivate any excess neurotransmitter molecules (norepinephrine, dopamine, and serotonin) that may leak out of synaptic vesicles when the neuron is at rest. The MAO inhibitors may irreversibly or reversibly inactivate the enzyme, permitting neurotransmitter molecules to escape degradation and therefore to both accumulate within the presynaptic neuron and to leak into the synaptic space. This causes activation of norepinephrine and serotonin receptors, and may be responsible for the antidepressant action of these drugs. Three MAO inhibitors are currently available for treatment of depression phenelzine [FEN el zeen], isocarboxazid [eye soe kar BOX a zid], and tranylcypromine [tran ill SIP roe meen] no one drug is a prototype. Use of MAO inhibitors is now limited because of the complicated dietary restrictions required of patients taking MAO inhibitors. 

Q14 MAOIs, such as phenelzine and isocarboxazid, affect the sympathetic nervous system by inhibiting one or both forms of brain monoamine oxidase. Their sympathomimetic effects can produce a feeling of well-being and increased energy, which is helpful for depressed patients. However, psychosis may occur in a susceptible individual or may follow over-administration of these agents. An increase in sympathomimetic action (such as occurs with use of amphetamines, which increase the release of noradrenaline) can result in a lethal hypertensive crisis. In addition, a hypertensive crisis can also be initiated if the patient consumes a diet rich in amines foods with a high amine content include cheese, pickles, broad beans and wine. 

Mood disorders can be associated with eating disorders (especially in adolescent females), and isocarboxazid can be used to treat both depression and bulimia... 

Larsen JK, Rafaelsen OJ. Long-term treatment of depression with isocarboxazide. Acta Psychiatr Scand 1980 62(5) 456-63. 

Clinically important, potentially hazardous interactions with alcohol, amprenavir, arbutamine, cholestyramine, clonidine, CNS depressants, epinephrine, formoterol, guanethidine, isocarboxazid, linezolid, MAO inhibitors, phenelzine, QT interval prolonging agents, quinolones, selegiline, sparfloxacin, sympathomimetics, tranylcypromine... 

Clinically important, potentially hazardous interactions with acyclovir, alcohol, amphetamines, barbiturates, CNS depressants, fluoxetine, furazolidone, general anesthetics, glycopyrrolate, glycopyrronium, isocarboxazid, linezolid, lithium, MAO inhibitors, moclobemide, phenelzine, phenobarbital, phenothiazines, rasagiline, ritonavir, selegiline, sibutramine, SSRIs, tranquilizers, tranylcypromine, tricyclic antidepressants, val acyclovir... 

The monamine oxidase inhibitor, iproniazid, was the first useful antidepressant drug. Unfortunately, it proved too toxic for clinical use. Since its effect was observed, many monamine oxidase inhibitors have been prepared. Most have shown an antidepressant effect, but unfortunately, many of the newer agents also exhibited serious toxic effects. At present, the most commonly employed monoamine oxidase inhibitors are isocarboxazid, phenelzine, and nialamide. These agents exert a highly useful effect in the depressed patient. 

Antidepressants are divided into the following classes the dibenzapine derivatives are called tricyclic antidepressants and include imipramine (Tofranil), desipramine (Norpramin), amitriptyline (Elavil), nortriptyline (Aventyl), protriptyline (Vivactil), and doxepin (Adapin). The monoamine oxidase inhibitors are nsed occasionally to treat depression. The hydrazine derivatives consist of isocarboxazid (Marplan) and phenelzine sulfate (Nardil). The nonhydrazine derivatives inclnde tranylcypromine (Parnate). L-Tryptophan is the only member of the monoamine precnrsors nsed to treat depression. The newer and second-generation antidepressants inclnde amoxapine, doxepin, flnoxetine, maprotiline, trazodone, mianserin, alprazolam, and bnpropion (see also Tables 5 throngh 7). 

A positive correlation exists between the degree of platelet MAO inhibition and the clinical response of patients with depression for phenelzine and isocarboxazid, bnt not necessarily tranylcypromine. 

Theoretically, methyidopa might cause hypertension in patients treated with non-selective MAOIs, by releasing catecholamines into the circulation On the basis of this the manufacturers of some MAOIs and methyidopa contraindicate concurrent use. Nevertheless, there do not appear to be any reports of hypertension occurring as a result of concurrent use. Conversely, the UK manufacturer of isocarboxazid mentions that it may potentiate the hypotensive effect of methyidopa. MAOIs alone have hypotensive effects and additional blood pressure lowering effects have been reported in a few patients given pargyline (an MAOI formerly used in the treatment of hypertension) with methyidopa. Note that the potential depressant adverse effects of methyidopa may make it an unsuitable drug for patients with depression. 

In contrast, there are a number of other uncontrolled studies and reviews describing the beneficial use of an MAOI with a tricyclic antidepressant. In addition, one study has reported switching 178 patients from tricyclics to MAOIs within 4 days or less. Of these patients, 63 were given the MAOI while still being tapered from the tricyclic, all without any apparent problems. Nevertheless, in a 6-week randomised doubleblind trial, the combinations of phenelzine or isocarboxazid plus trimi-pramine were less effective than trimipramine alone in patients with mild to moderate depression. Similarly, in a smaller randomised open study, the combination of amitriptyline and tranylcypromine was no more effective than either drug alone. ... 

Knowledge of the role of the adrenocorticosteroids in disordered behaviour 2,o9 91has contributed to a practical therapeutic result. Combined administration of dexamethasone with an antidepressant (imipra mine, amitriptyline or isocarboxazid) gave a rapid onset of favourable action in 1 cases of depression (ref. 68, p. 27). Other memorabilia from the clinical literature included a proposed relationship between drug effects and patients body height92 and the state of the weather93. 

Monoamine Oxidase Inhibitors (MAOIs) Phenelzine Isocarboxazid Tranylcypramine Moclobemide See BNF See BNF See BNF For depression Pressor effect can cause hypertensive crisis if MAOIs combined with certain foods and other medications Moclobemide is a reversible MAOI, less likely to cause pressor effect (tyramine advice still applies) also licenced for social phobia. Dangerous hypertension if eat high tyramine foods. 

A number of new MAO inhibitors were described in 1971 however, because of the limited clinical utility of these agents in the treatment of depression, they will not be reviewed in detail. Nonetheless, several of these substances are noteworthy. Sydnophene ( ) was Included in a series of sydnonimines examined for MAO-inhibitory activity. It demonstrated mild stimulant and antidepressive actions in extensive clinical studies in Russia. Another MAO-inhibitor, clorgiline (32. M B 9302) had antidepressive activity its clinical effects were similar to those of imipramine. Proportions of two forms of MAO (Type A, B) were found to vary in different areas of rat brain. The type A enzyme, predominant in sympathetic nerves, acted on both 5-HT and tyramlne and was Inhibited by 32. whereas type B-MAO was insensitive to and acted on tyramine, but not 5-HT. In humans, tranylcypromine and isocarboxazid Increased 5HT, NE and dopamine levels in various brain areas however, the effect of tranylcypromine was significantly greater than that of the other two on dopamine in the caudate nucleus and hypothalamus. In vitro. Lilly 516 1 ( ), like harmaline, preferentially blocked MAO oxidation of 5-HT, whereas tranylcypromine and pargyline selectively inhibited the oxidation of tyramine. ... 

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