Compare the antidepressant MAOIs and SSRIs in terms of pharmacokinetics, pharmacodynamics and mode of action.

a.       PHARMACOKINETICS

The monoamine oxidase inhibitors (MAOIs) are readily absorbed from the gastrointestinal tract.

The hydrazide inhibitor phenelzine is acetylated in the liver and manifests differences in elimination depending on the acetylation phenotype of the individual. However, inhibition of MAO persists even after these drugs are no longer detectable in plasma. Therefore, conventional pharmacokinetic parameters (half-life, etc) are not very helpful in governing dosage. It is prudent to assume that the drug effect will persist for from 7 days (tranylcypromine) to 2 or 3 weeks (phenelzine) after discontinuance of the drug whiles the pharmacokinetic parameters of these SSRIs eg. fluoxetine is notable for the long half-life of its active metabolite, norfluoxetine (7–9 days at steady state). This long t 1/2 has allowed for the introduction of a formulation for once-weekly dosing. Fluoxetine inhibits various drug-metabolizing enzymes, which has led to a number of significant drug-drug interactions with other antidepressants and with other drugs as well. Sertraline and paroxetine have pharmacokinetic parameters similar to those of tricyclics. Citalopram and fluvoxamine resemble fluoxetine.

The most likely pharmacokinetic interactions are between the potent inhibitors of P450 2D6,

paroxetine and fluoxetine, and those drugs highly dependent on this pathway for clearance (eg,

desipramine, nortriptyline, flecainide. Actual instances of clinically significant interactions are extremely rare, there being only a handful of case reports after cumulative exposure of more than 50 million patients to these SSRI drugs. Inhibition of P450 3A4 could possibly occur at high concentrations of nefazodone and fluvoxamine and block the metabolism of the many substrates of this isoform.

b.      PHARMACODYNAMICS

MAO inhibitors block a major degradative pathway for the amine neurotransmitters, which permits more amines to accumulate in presynaptic stores and more to be released. Some of the second-generation antidepressants have similar effects on amine neurotransmitters, while others have mild or minimal effects on reuptake or metabolism. In contrast, trazodone, nefazodone, and mirtazapine stand out as agents in which antagonism of subtypes of serotonin receptors (5-HT2A or 5-HT2C) may be important in their action. Mirtazapine is unique in including antagonism of 2 norepinephrine receptors as presumably contributing to its therapeutic effects. Bupropion has been found to alter the output of norepinephrine in humans following chronic administration through some as yet unidentified primary mechanism as well as occupying about 25% of dopamine uptake pumps in the brain as revealed by positron emission tomography. Since it has been shown that effective doses of SSRIs occupy 80% of serotonin uptake sites, the clinical relevance of 25% dopamine uptake occupancy is uncertain. Thus, even the newest antidepressants can still be categorized as working through serotonergic and noradrenergic effects with the possibility of a role for dopamine. A potential dopaminergic mechanism has often been invoked as relevant to the efficacy of MAOIs.

Many of the pharmacodynamic interactions of antidepressants with other drugs have already been discussed. Sedative effects may be additive with other sedatives, especially alcohol. Patients taking tricyclics should be warned that use of alcohol may lead to greater than expected impairment of driving ability. MAO inhibitors, by increasing stores of catecholamines, sensitize the patient to indirectly acting sympathomimetics such as tyramine, which is found in some fermented foods and beverages, and to sympathomimetic drugs such as diethylpropion, phenylpropanolamine, or botanicals containing ephedrine. Such sensitization can result in dangerous and—rarely—fatal hypertensive reactions. The serious interaction between MAO inhibitors and selective serotonin reuptake inhibitors has been mentioned; the serotonin syndrome is potentially lethal and must be avoided.

c.       MODE OF ACTION

MAOIs act by inhibiting the activity of monoamine oxidase, thus preventing the breakdown of monoamine neurotransmitters and thereby increasing their availability. There are two isoforms of monoamine oxidase, MAO-A and MAO-B. MAO-A preferentially deaminates serotonin, melatonin, epinephrine and norepinephrine. MAO-B preferentially deaminates phenylethylamine and trace amines. Dopamine is equally deaminated by both types. Many formulations have forms of fluoride attached to assist in permeating the blood-brain barrier, which is suspected as a factor in pineal gland effects whiles SSRIs act by blocking the reuptake of serotonin in the synaptic cleft thereby increasing the levels of serotonin (increases brain activity).