Moclobemide effects

Reversible Inhibitors of Monoamine Oxidase. Selective MAO-A inhibitors, which aie leveisible (so-called RIMAs), have also been developed, theiefoie substantially leduciag the potential foi food and dmg iateiactions. Indeed, the tyiamine-potentiating effects of these dmgs is much reduced compared with the irreversible MAO inhibitors. The RIMAs represent effective and safer alternatives to the older MAO inhibitors. The only marketed RIMAs ate toloxatone [29218-27-7] and moclobemide (55). The latter is used widely as an effective, weU-tolerated antidepressant. 

Because of their lack of selectivity and their irreversible inhibition of MAO, the first MAOIs to be developed presented a high risk of adverse interactions with dietary tyramine (see Chapter 20). However, more recently, drugs which are selective for and, more importantly, reversible inhibitors of MAO-A (RIMAs) have been developed (e.g. moclobemide). These drugs are proving to be highly effective antidepressants which avoid the need for a tyramine-free diet. 

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). 

Both these predictions are borne out by clinical experience despite the snag that only MAOb is found in serotonergic neurons (Saura et al. 1996). So far, there is no explanation for this anomaly. However, the lack of a tyramine-induced pressor effect with moclobemide probably owes more to the fact that it acts as a reversible inhibitor of MAOa (RIMA) than to its isoenzyme selectivity. Its reversible inhibition of MAOa means that, should tyramine ever accumulate in the periphery, it will displace... 

In addition to this serious diet-drug interaction, irreversible MAOIs also potentiate the effects of sympathomimetic drugs like ephedrine found in over-the-counter cold remedies and recreational stimulants like amphetamine. The MAOIs also interact with drugs that increase synaptic concentrations of 5-HT, such as the tricyclic antidepressant clomipramine and the herbal SSRI antidepressant St John s wort (Hypericum spp.). The resulting serotonin syndrome is characterised by hyperthermia and muscle rigidity. While devoid of these side effects the reversible MAO-A inhibitor moclobemide has yet to establish itself as a first-line alternative to the SSRIs. 

Monoamine Oxidase Inhibitors (MAOIs). Early studies also evaluated the effectiveness of the MAOl phenelzine. Phenelzine, relative to TCAs, provided greater benefit for PTSD however, its usefulness is limited by its potential for drug and food interactions. A recent open label study suggests that the reversible MAOI moclobemide might be helpful for PTSD. It is not available in the United States. 

MAOIs, although effective, are also problematic for routine use in the treatment of BN. First, like the TCAs, MAOIs have a propensity for lowering blood pressure. Additionally, bulimia patients, who are by definition prone to impulsive out of control eating, are not ideal candidates to maintain the strict tyramine-free diet restrictions imposed by MAOIs. Thus, they run a substantial risk of precipitating dangerous hypertensive crises through dietary noncompliance while taking MAOIs. It remains unclear whether the reversible MAOIs such as moclobemide will prove effective in the treatment of BN without the risks associated with other MAOIs. 

Bromocriptine is a dopamine agonist acting by direct stimulation of the dopamine receptors. In Parkinson s disease, it is reserved for use in patients who are intolerant to levodopa or in whom levodopa alone is not sufficient. Orphenadrine is an antimuscarinic indicated in Parkinson s disease. Antimuscarinics tend to be more effective than levodopa in targeting tremor rather than rigidity and bradykinesia. Moclobemide is an antidepressant referred to as a reversible monoamine oxidase inhibitor (RIAAA) type A. 

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). 

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. 

MAOI/RIMA Panic disorder Social anxiety disorder PTSD Significant short- and long-term side-effects special dietary requirements moclobemide better tolerated Significant overdose toxicity (less with moclobemide) Reported... 

Therapeutic efficacy by selective MAO-A inhibitors (such as clorgyline or moclobemide) in major depressions strongly suggests that MAO inhibition at central serotonin or norepinephrine synapses or both is responsible for the antidepressant properties of these agents. However, since complete MAO-A inhibition is achieved clinically within a few days of treatment, while the antidepressant effects of these drugs are not observed for 2 to 3 weeks, suggests that additional actions must be involved. 

Monoamine oxidase inhibitors. The monoamine oxidase inhibitors (MAOIs) inhibit the intracellular catabolic enzyme monoamine oxidase. There are two types of monoamine oxidase MAO-A and MAO-B, both of which metabolize tyramine and dopamine. In addition, MAO-A preferentially metabolizes norepinephrine, epinephrine, and serotonin, and MAO-B preferentially metabolizes phenylethylamine (an endogenous amphetamine-like substance) and N-methylhistamine (Ernst, 1996). Some MAOIs are selective for A or B and some are nonselective (mixed). In addition, irreversible MAOIs (e.g., phenelzine, tranylcypromine) are more susceptible to the cheese effect than are the reversible agents (e.g., moclobemide). 

Some evidence indicates that social phobia responds to SSRls, and case reports and studies with fluoxetine [B. Black et al. 1992 Van Ameringen et al. 1993), fluvoxamine [Mendels et al. 1995), paroxetine [Pitts et al. 1996 Ringold 1994), and sertraline [Katzelnick et al. 1995) have reported positive results. Although the full details of these studies have not been published, it seems that SSRls might well prove, in due course, to be effective treatments for social phobia. At the moment, the only treatment licensed for social phobia is moclobemide, which is a reversible inhibitor of monoamine oxidase-A [Nutt and Montgomery 1996 Versiani et al. 1992), and it is possible that it... 

Studies by Schneier et al. (F. Schneier, personal communication, June 1994) and two large, unpublished, multicenter international collaborative trials involving several hundred patients have yielded more modest effects, with less striking but still clinically meaningful superiority of moclobemide over placebo. 

The reversible, selective MAOls are an effective and relatively safe treatment alternative for social phobia. Moclobemide is currently not available in the United States, although it is available and widely used in other countries. Brofaromine has been discontinued entirely for commercial reasons. 

Based on some intriguing case reports (Jenike et al. 1983), a trial with a monoamine oxidase inhibitor (MAOI) may be an option in OCD patients who have comorbid panic disorder. In a double-blind trial, both phenelzine and clomipramine were found to be effective in reducing symptoms in OCD, as reflected on two of four OC measures [Vallejo et al. 1992). None of the patients in this study had panic disorder. This study suggests that MAOIs may be helpful in some patients with OCD even in the absence of panic disorder. However, in an earlier comparison trial, clomipramine, but not the MAOI clorgiline, resulted in significant reduction in OC symptoms [Insel et al. 1983b). Additional studies are needed to evaluate the place of MAOIs (including the newer reversible inhibitors of monoamine oxidase A [RIMAs], such as moclobemide) in the pharmacotherapy of OCD. 

Blois R, Gaillard JM Effects of moclobemide on sleep in healthy human subjects. Acta Psychiatr Scand Suppl 360 63-75, 1990... 

London E, Fanelh RJ, Kimes A, et al Effects of chronic nicotine on cerebral glucose utilization in the rat. Brain Res 520 208-214, 1990 Lonnqvist J, Sihvo S, Syvalahti E, et al Moclobemide and fluoxetine in atypical depression a double-blind trial. J Affect Disord 32 169-177, 1994 Loo H, Malka R, Defance R, et al Tianeptine and amitriptyline controlled double-blind trial in depressed alcoholic patients. Neuropsychobiology 19 79-85, 1988... 

Montgomery SA, Brown RE, Clark M Economic analysis of treating depression with nefazodone v. imipramine. Br J Psychiatry 168 768-771, 1996 Monti JM Effect of a reversible monoamine oxidase-A inhibitor (moclobemide) on sleep of depressed patients. Br J Psychiatry Suppl 155 61-65, 1989 Monti JM, Alterwain P, Monti D The effects of moclobemide on nocturnal sleep of depressed patients. J Affect Disord 20 201-208, 1990 Montkowski A, Holsboer F Absence of cognitive and memory deficits in transgenic mice with heterozygous disrupt of the brain-derived neurotrophic factor gene. J Psychiatr Res [in press)... 

The side effects of antidepressants, sometimes very unpleasant, olten lead patients to interrupt their treatment or to reduce the drug dose, which involves a great risk in view of the high relapse rate and danger of suicide in depression. The newer antidepressants, such as trazodone, fluoxetine and other SSRIs and moclobemide, are characterized by better tolerability and lower toxicity and are therefore preferred in the treatment of outpatients and elderly patients (Rudorfer and Potter, 1989). A detailed list of general and specific common side effects associated with the newer generation of antidepressants is seen in Table 1.7. 

Reports are on hand relating to more recent antidepressants such as bupropion, citalopram (Fairweather ei ul., 1997), fluoxetine (Gelfin et ul.. 1998). moclobemide (Dingemanse et ul., 1998) and paroxetine (Brauer et ul.. 1995). These products, in agreement with their clinical profiles, produce fewer subjective effects and generally less sedation in healthy subjects than the older... 

A larger set of placebo-controlled studies show conclusively that imipramine is also effective for the treatment of panic disorders. Other agents shown to be effective in panic disorders include the SSRIs paroxetine, sertraline, fluvoxamine, fluoxetine and citalopram. Generally, initial treatment of moderate to severe panic disorders may require the initiation of a short course of benzodiazepines e.g. clonazepam (0.5 1 mg twice daily), and an SSRI. The patient will obtain immediate relief from panic attacks with the benzodiazepine whereas the SSRI may take 1 6 weeks to become effective. Once a patient is relieved of initial panic attacks, clonazepam should be tapered and discontinued over several weeks and SSRI therapy continued thereafter. There are no pharmacological treatments available for specific phobias, however controlled trials have shown efficacy for several agents, e.g. phenelzine, moclobemide. clonazepam, alprazolam, fluvoxamine. sertraline and paroxetine in the treatment of social phobia (Roy-Byrne and Cowlev, 2002). 

Mociobemide Moclobemide is a reversible, selective, MAO-A inhibitor currently available in other countries but not in the United States. An open-label study in 20 patients with PTSD suggested that moclobemide was effective at the end of 12 weeks of treatment, with 11 patients no longer meeting criteria for PTSD ( 286). Controlled, double-blind studies should be conducted to confirm these findings. 

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