Moclobemide SSRIs

ANTIDEPRESSANTS-duloxetine, moclobemide, SSRIs - escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, TCAs - amitriptyline, clomipramine, desipramine, doxepin, imipramine... 

CYP2D6 TCAs, SSRIs, haloperidol, mirtazepine, zuclopenthoxil, venlafaxine, sertraline CYP2C19 TCAs, mephenytoin, diazepam, moclobemid, venlafaxine... 

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. 

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. 

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. 

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. 

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). 

A number of antidepressant drugs, particularly SSRIs, can increase plasma prolactin concentrations, although galactorrhea is uncommon. In a prescription event monitoring survey of about 65 000 patients, compared with SSRIs, moclobemide was associated with a relative risk of galactorrhea of 6.7 (95% Cl = 2.7, 15) (727). However, this was substantially less than the risk associated with the dopamine receptor antagonist risperidone (relative risk compared with SSRIs 32 95% Cl = 14, 70). 

Overdose of moclobemide by itself rarely appears to give rise to serious problems. This is in contrast to overdose with conventional monoamine oxidase inhibitors, which can cause fatal 5HT toxicity. However, if patients take moclobemide together with serotonergic antidepressants, such as SSRIs or clomipramine, 5HT toxicity is common. 5HT toxicity occurred in 11 of 21 patients who took overdoses of moclobemide and serotonergic agents but in only one of 33 patients who took moclobemide alone (13). Consistent with this, four patients died, presumably of 5HT toxicity, after co-ingesting 3,4-methyle-nedioxymethamphetamine (MDMA, ecstasy) and moclobemide (14). 

However, the use of antidepressants in completed suicide showed an upward trend, while the use of more violent methods (gassing, hanging) fell During this time prescription of moclobemide and two SSRIs (citalopram and fluoxetine) increased, while that of tricyclics (mainly doxepin and amitriptyline) remained steady. The mean annual fatal toxicity index was highest for tricyclics, such as doxepin, trimipramine, and amitripyline, and lowest for SSRIs. 

There are many other ways in which SSRIs can interfere with sexual function, for example by causing loss of sexual interest and erectile difficulties. In an open, prospective study of 1000 Spanish patients taking a variety of antidepressants, there was an overall incidence of sexual dysfunction of 59% (15). The highest rates, 60-70%, were found with SSRIs (including fluvoxamine) and venlafax-ine. The lowest rates were found with mirtazepine (24%), nefazodone (8%), and moclobemide (4%). Spontaneous resolution of this adverse effect was uncommon - 80% of subjects had no improvement in sexual function over 6 months of treatment. 

This case report confirms the serious consequences of combined overdosage of moclobemide with drugs that potentiate brain serotonin function (see also the monograph on SSRIs). 

In the 1980s an entirely new class of antidepressant arrived with the SSRIs, firstly fluvoxamine immediately followed by fluoxetine (Prozac). Within 10 years, the SSRI class accounted for half of antidepressant prescriptions in the United Kingdom. Further developments in the evolution of the antidepressants have been novel compounds such as venlafaxine, reboxetine, nefazodone and mirtazapine, and a reversible monoamine oxidase inhibitor, moclobemide. 

Most MAOIs are irreversible and the effects take weeks to stabilize. Chemically, they fall into a number of groups, including hydrazines, such as pheneizine and iproniazid, propargylamines, such as pargyline, chlorgyline and selegiline, and cyclopropylamines, such as tranylcypromine. A reversible inhibitor that may be safer under some circumstances is moclobemide. The use of MAOIs has declined and tricyclics and the SSRIs are being used more. See antidepressants. 

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... 

Fewer adverse effects were reported among moclobemide-treated patients compared with selective serotonin reuptake inhibitor (SSRI)-treated patients. Since moclobemide does not induce orthostatic hypotension, does not possess anticholinergic properties, and is not cardiotoxic, it is very well suited among the MAOIs for the treatment of depression. Moclobemide has limited potential to elicit a hypertensive crisis, because the pressor effect of tyramine from food is only marginally potentiated compared with tranylcypromine. The pressor effect of tyramine is normalized within 3 days of cessation of treatment with moclobemide. The combination of SSRIs and moclobemide has good efficacy in cases of refractory depression, but there is controversy as to whether toxic side-effects such as serotonin syndrome can result from this combination. Currently, more studies are needed before this combination can be recommended. Acute overdose with MAOIs causes agitation, hallucinations, hyperpyrexia, hyperreflexia, convulsions, and death. The most dangerous MAOIs in overdose are the irreversible non-selective MAOIs. T2s-27... 

Few data are available about paroxetine interactions with MAOIs, even though they might be similar to those of other selective serotonin reuptake inhibitors (SSRIs). Clinically significant or severe interactions have not been found to date. Administered together in patients with depression, moclobemide and paroxetine or fluoxetine appeared to produce adverse effects indicative of potentiated serotonergic activity. 

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