Depression tranylcypromine

CgHjiN. Liquid, b.p. 79 C. Used as the hydrochloride, C HnN HCI, with m.p. 164°C. Tranylcypromine is an inhibitor of monamine oxidase and is administered orally in the treatment of depressive illness. 

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). 

Incorporation of the phenethyl moiety into a carbocyclic ring was at first sight compatible with amphetamine-like activity. Clinical experience with one of these agents, tranylcypromine (79), revealed the interesting fact that this drug in fact possessed considerable activity as a monamine oxidase inhibitor and as such was useful in the treatment of depression. Decomposition of ethyl diazoacetate in the presence of styrene affords a mixture of cyclopropanes in which the trans isomer predominates. Saponification gives acid 77. Conversion to the acid chloride followed by treatment with sodium azide leads to the isocyanate, 78, via Curtius rearrangement. Saponification of 78 affords tranylcypromine (79). 

The monoamine oxidase inhibitors (MAOIs) phenelzine and tranylcypromine increase the concentrations of NE, 5-HT, and DA within the neuronal synapse through inhibition of the monoamine oxidase (MAO) enzyme system. Both drugs are nonselective inhibitors of MAO-A and MAO-B. Selegiline is available as a transdermal patch for treatment of major depression. It inhibits MAO-A and MAO-B in the brain, but has reduced effects on MAO-A in the gut. 

Shopsin, B., Friedman, E., and Gershon, S. (1976) Parachlorophenylalanine reversal of tranylcypromine in depressed patients. Arch. Gen. Psychiatry, 33 1051-1058. 

These mediators probably play significant roles in CNS functions consistent with the stimulant effects of MAO inhibitors on mood and psychomotor drive and their use as antidepressants in the treatment of depression (A). Tranylcypromine is used to treat particular forms of depressive illness as a covalently bound suicide substrate, it causes long-lasting inhibition of both MAO isozymes, (MAOa, MAOb). Moclobemide reversibly inhibits MAOa and is also used as an antidepressant. The MAOb inhibitor selegiline (deprenyl) retards the cat-obolism of dopamine, an effect used in the treatment of parkinsonism (p. 188). 

As with the MAO inhibitor drugs described above, tranylcypromine is also used for depressions that do not respond to other drugs. Synonyms of this drug are transamin, par-modalin, pamate, and others. 

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. 

The pharmacological inhibition of the serotonin eliminating enzyme MAO is used in the therapy of depression and hypertension. Tranylcypromine is an irreversible unselective MAO inhibitor which displays numerous interactions with amine-containing food and monoamine-related drugs, resulting in evenmally fatal hypertensive crisis, cranial hemorrhage, arrhythmias and seizure can occur. The coadministration with speciflc serotonin reuptake inhibitors (SSRI) can result in similar effects and is therefore contraindicated. Moclobemide, on the other hand, is a reversible inhibitor of MAOa, one of the two enzyme subtyppes (MAOa, MAOb) which is void of most interactions see with tranylcypromine. 

Due to the frequent unwanted effects and, in case of tranylcypromine, the numerous and dangerous interactions MAO-inhibitors are more and more replaced by the much less problematic SSRIs. Compounds belonging to this group are citalopram, escitalopram, fluoxetine, paroxetine and sertraline. They are used clinically in the therapy of depression, bulimia and obsessive-compulsive disorders. All SSRIs show a slow onset of action (1-2 weeks). They may induce insomnia and weight loss. The antidepressant ven-lafaxine inhibits both, serotonin and noradrenaline re-uptake and might therefore additionally induce hypertension. 

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. 

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). 

Tranylcypromine ( rans-2-phenylcyclopropylamine, TCP, 8a) has close structural similarity to amphetamine (2-amino-1-phenylpropane) and is known as a nonhydrazine, nonselective, and irreversible inhibitor of both MAO A and B. It is also a potent reversible inhibitor of CAOs [36,37], Tranylcypromine has an important clinical use for treatment of certain depressive illnesses, particularly of nonendo-genous and atypical depressions and depressions associated with anxiety, agitation, phobias, and anergia [38-40], In combination with lithium, it is also applied for treatment of refractory depression [41], Recent reports also discussed MAO inhibitors as useful agents against neurodegenerative disorders such as Parkinson s or Alzheimer s diseases [42], Despite impressive clinical successes, clinical use of tranylcypromine and other MAO inhibitors is limited by various problems, including the cheese effect discussed in Section 1,... 

J.M. Flimmelhoch, C.Z. Fuchs, J.B. Symons, A double blind study of tranylcypromine treatment of major anergic depression, J. Nerv. Ment. Dis. 170 (1982) 628-634. 

K. White, J. Razani, B. Cadow, R. Gelfand, R. Palmer, G. Simpson, R.B. Sloane, Tranylcypromine vs. nortriptyline vs. placebo in depressed out patients A controlled trial, Psychopharmacology 82 (1984) 258-262. 

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-... 

Amsterdam JD Use of high dose tranylcypromine in resistant depression, in Refractory Depression. Edited by Amsterdam JD. NewYork, Raven, 1991,pp 123-130 Amsterdam JD, Berwish N Treatment of refractory depression with combination re-serpine and tricyclic antidepressant therapy. J Clin Psychopharmacol 7 238-242, 1987... 

Amsterdam JD, Berwish N High dose tranylcypromine treatment in refractory depression. Pharmacopsychiatry 22 21-25, 1989... 

Himmelhoch JM, Thase ME, Mallinger AC, et al Tranylcypromine versus imipramine in anergic bipolar depression. Am J Psychiatry 148 910-916, 1991... 

Results of crossover studies indicate that lithium is efficacious in treating acute depression in bipolar subjects unequivocally (36%, 29/80) and partially (43%. 34/80). respectively (Xomberg and Pope, 1993 Keck and McElroy, 2002). Various antidepressants have shown variable rates of efficacy in the treatment of acute bipolar depression, i.e. desipramine (50%), maprotiline (67%), imipra-mine (40 60%), tranylcypromine (87%), moclobemide (53%) and fluoxetine (60%) (Keck and McElroy, 2002). Among the anticonvulsants, valproic add and lamotrigine appear to have some potential efficacy in the treatment of acute bipolar depression (Calabrese et al., 1992, 1999 Fatemi et al., 1997). 

The efficacy of phenelzine and tranylcypromine has now been well established by several large, double-blind studies, which found them equal to tertiary amine TCAs and clearly superior to placebo (Table 7-11 and Table 7-12) (185). Other studies indicate that atypical depressions may respond better to MAOIs and typical depressions to TCAs however, most find that their similarities are more obvious than their differences ( 186). One research group has suggested that anergic, bipolar patients respond particularly well to tranylcypromine and other MAOIs ( 187). Extensive clinical experience indicates the MAOIs are often effective when TCAs have failed. 

Shopsin B, Freedman E, Gershon S. PCPA reversal of tranylcypromine effects in depressed patients. Arch Gen Psychiatry 1976 33 811-819. 

Thase ME, Mallinger AG, McKnight D, et al. Treatment of imipramine-resistant recurrent depression, IV a double-blind crossover study of tranylcypromine for anergic bipolar depression. Am J Psychiatry 1992 149 195-198. 

Monoamine oxidase inhibitors (eg, tranylcypromine, phenelzine) are older antidepressants that are occasionally used for resistant depression. They can cause severe hypertensive reactions when interacting foods or drugs are taken (see Chapters 9 and 30), and they can interact with the selective serotonin reuptake inhibitors (SSRIs). 

Monoamine oxidase (MAO) inactivates serotonergic and catecholanunergic neurotransmitters MAO (A and B) inhibitors exhibit mood elevatmg properties 5-FIuoro-OC-methyltryptamine (19) is an important MAO A-selective inhibitor In the treatment of certain depressive illnesses, 4-fluorotranylcypromine (20b) is 10 tunes more potent than the parent tranylcypromine (TCP, 20a) The enhanced in vivo activity may be due to increased lipophilicity of 20b and/or to blockade of metabolic para hydroxylation [52]... 

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. 

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