Selegiline Antidepressants

More than 40 medications have been investigated but none have shown consistent efficacy for primary cocaine or amphetamine dependence. These medications include dopaminergic agonists, antidepressants, and more recently disulfiram, selegiline, and a cocaine vaccine (see Table 5—2 for summary). Studies have been relatively brief and have focused on abstinence initiation rather than on relapse prevention, but even these modest treatment goals have not been attained. The focus in the discussion that follows is on pharmacotherapies for cocaine dependence, because very few clinical trials have been completed with amphetamine-dependent patients. Furthermore, none of the studies of amphetamine dependence have shown results different from those described for cocaine dependence (Rawson et al. 2002b Srisurapanont et al. 2001). 

The discovery that MAO has two isoenzymes with different distributions, substrate specificity and inhibitor sensitivity has helped to rehabilitate the MAOIs to some extent. These isoenzymes are the products of different genes on the X-chromosome and share about 70% sequence homology. Whereas noradrenaline and 5-HT are metabolised preferentially by MAOa, tyramine and dopamine can be metabolised by either isoenzyme. Selective inhibitors of MAOa (e-g- moclobemide Da Prada et al. 1989) should therefore be safe and effective antidepressants whereas the selective MAOb inhibitor, selegiline, should not have any appreciable antidepressant activity (Table 20.5). 

Yet another MAOI is selegiline (Eldepryl). Unlike the other MAOls, selegiline is seldom used to treat depression. At low doses, selegiline only inhibits the M AO-B enzyme. Therefore, it increases dopamine activity but does not have any pronounced effect on norepinephrine or serotonin. For this reason, it has been less useful as an antidepressant however, its primary use has been to treat Parkinson s disease. Of course, this selectivity for dopamine suggests that it may be helpful for ADHD as well. 

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. 

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). 

Inhibitors codeine, encainide, flecainide, fluoxetine, haloperidol, hydrocodone, 4-methoxy-amphetamine, metoprolol, mexiletine, oxycodone, paroxetine, propafenone, propoxyphene, risperidone, selegiline (deprenyl), thioridazine, most tricyclic antidepressants, timolol Fluoxetine, haloperidol, paroxetine, quinidine... 

Dmg-induced serotonin syndrome is generally mild and resolves when the offending drugs are stopped. However, it can be severe and deaths have occurred. A large number of drugs have been implicated including tricyclic antidepressants, monoamine oxidase inhibitors (MAOIs), selective serotonin re-uptake inhibitors (SSRIs), pethidine, lithium, and dextromethorphan. The most severe type of reaction has occurred with the combination of selective serotonin re-uptake inhibitors and monoamine oxidase inhibitors. Both non-selective MAOIs such as phenelzine and selective MAOIs such as moclobemide and selegiline have been implicated. 

MAOIs had been reserved as a last line of treatment, used only when other classes of antidepressant drugs had failed, because of the mentioned potentially lethal dietary and drug interactions. However, in 2006 a patch form of the drug selegiline, called Emsam, was approved for use by the FDA. When applied transdermally the drug does... 

Selegiline should not be coadministered with tricyclic antidepressants or selective serotonin uptake inhibitors because of the possibility of a severe adverse drug reaction (e.g., hyperpyrexia, agitation, delirium, coma). 

The MAOIs are as effective as the heterocyclic antidepressants and the newer agents, such as the SSRIs. However, at least two forms of life-threatening toxicity (hepatotoxicity and dietary tyramine-induced hypertensive crisis ) have been associated with their chronic use. For this reason, the MAOIs are not considered first-line agents in the treatment of depression. They are generally reserved for treatment of depressions that resist therapeutic trials of the newer, safer antidepressants. However, a new transdermal formulation of selegiline undergoing clinical trials demonstrates antidepressant efficacy without concerns of liver toxicity or dietary tyramine-induced hypertension. 

The MAO-B inhibitor, l-deprenyl, has been approved by the FDA for use in Parkinson s disease. At the lower dose range, it does not interact with tyramine. As mentioned earlier, there is preliminary evidence of antidepressant efficacy for a transdermal delivery system for selegiline. This formulation does not interact with tyramine to produce a hypertensive crisis (181). 

Neither selegiline nor rasagiline should be taken by patients receiving meperidine. They should be used with care in patients receiving tricyclic antidepressants or serotonin reuptake inhibitors because of the theoretical risk of acute toxic interactions of the serotonin syndrome type (see Chapter 16), but this is rarely encountered in practice. The adverse effects of levodopa may be increased by these drugs. 

Arguably the first modern class of antidepressants, monoamine oxidase inhibitors (MAOIs) were introduced in the 1950s but are now rarely used in clinical practice because of toxicity and potentially lethal food and drug interactions. Their primary use now is in the treatment of depression unresponsive to other antidepressants. However, MAOIs have also been used historically to treat anxiety states, including social anxiety and panic disorder. In addition, selegiline is used for the treatment of Parkinson s disease (see Chapter 28). 

Banisterine and selegiline might elicit an antidepressant action by inhibiting MAO. 

From the evidence available to date, the reversible, short-acting MAO inhibitor moclobemide, which is available in several countries (but not the USA), appears to be relatively free of this interaction. (The selective MAO-B inhibitor selegiline loses selectivity at antidepressant dosage. Because its action is on the enzyme that metabolizes dopamine, it is most useful in the treatment of Parkinson s disease [Chapter 28 Pharmacologic Management of Parkinsonism Other Movement Disorders].)... 

Drugs and chemicals are known to cause activated interaction. The depressant action of opioid drugs is enhanced by drugs acting on the central nervous system (CNS) such as alcohol, anesthetics, anxiolytics, hypnotics, tricyclic antidepressants, and antipsychotics. Concomitant administration of opioid analgesics and monoamine oxidase inhibitors (MAOIs) should be avoided, or extra care should be taken if such a therapy is inevitable. Fatal reactions are reported when treated along with selegiline. Interactions also are reported with cyclizine, cimetidine, mexiletine, cisapride, metoclopramide, or domperidone. 

The free phenols that are produced in the brain (when they break off during the reaction with AChE), are related to the drug selegiline (Fig. 12.8), which is a monoamine oxidase B (MAO-B) inhibitor, so that they also exhibit such inhibitory activity. MAO-B inhibitors are helpful in Parkinson s disease, mainly because they cause an increase in the level of dopamine, and are also antidepressants. These compounds are currently under investigation as treatment for Alzheimer s disease complicated by other cognitive deficits. 

Antidepressant drugs of various classes (tricyclics, MAO inhibitors, SSRIs) have broad efficacy in generalized anxiety and in panic disorder, but SSRIs are now the treatments of choice (2,3). Selegiline has been used to treat Parkinson s disease. Other drugs that have MAO inhibitory activity, but are not used as such, include deb-risoquine, linezolid, and isoniazid. 

MAOIs TCAs-AMITRIPTYLINE CLOMIPRAMINE DESIPRAMINE IMIPRAMINE NORTRIPTYLINE t risk of stroke, hyperpyrexia and convulsions, t plasma concentrations of TCAs, with risk of toxic effects, t risk of serotonin syndrome and of adrenergic syndrome with older MAOIs. Clomipramine may trigger acute confusion in Parkinson s disease when used with selegiline TCAs are believed to also act by inhibiting the reuptake of serotonin and norepinephrine, increasing the risk of serotonin and adrenergic syndromes. The combination of TCAs and antidepressants can t risk of seizures Very hazardous interaction. Avoid concurrent use and consider the use of an alternative antidepressant. Be aware that seizures occur with overdose of TCAs just before cardiac arrest... 

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