Mirtazapine

Mirtazapine is an antidepressant launched in the Netherlands. Mirtazapine is a potent antagonist of presynaptic α2 receptors as well as a moderately potent 5-HT antagonist. Studies suggested that blockade of α2-adrenoceptors, but not inhibition of noradrenaline uptake, is involved in the mechanism of the antidepressant action of mirtazapine. Mirtazapine has demonstrated efficacy in various studies in depressed patients, being equal or more potent than mianserin, amitriptyline, etc. and exhibiting less anticholinergic and gastrointestinal side effects and low cardiovascular toxicity. In addition to its antidepressant effects, studies in animals indicated that mirtazapine has anxiolytic andor hypnotic activity.

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An a 2-Adrenergic blocker. An analogue of Mianserin. Antidepressant

Mirtazapine (Remeron) enhances both serotonergic and noradrenergic neurotransmission. By blocking presynaptic α₂-adrenoceptors, mirtazapine causes release of norepinephrine. Indirectly, through noradrenergic modulation of serotonin systems, mirtazapine also causes increased release of serotonin. It is an antagonist at the 5-HT_2A, 5HT_2C, 5-HT₃, and histamine receptors but has minimal affinity for muscarinic or α₁-receptors. Mirtazapine does not inhibit neuronal reuptake of serotonin or norepinephrine.Weight gain and sedation are common side effects; sedation necessitates dosing at bedtime. Mirtazapine does not have significant effects on cytochrome P450 isoenzymes.

Mirtazapine (Remeron) is another example of tetracyclicα2-blockers that shows selectivity for α2-receptorsversus 1-receptors. Blockade of central α2-receptors resultsin an increased release of NE and serotonin. This hasprompted its use as an antidepressant. This agent also hasactivity at nonadrenergic receptors. It is a potent blockerof 5-HT2 and 5-HT3 serotonin receptors and at histamineH1-receptors.

Animal studies indicate that the efficacy of mirtazapine as an antidepressant results from enhancing central noradrenergic and serotonergic activity, possibly through blocking central presynaptic α2-adrenergic receptors. Blocking these receptors inhibits the negative feedback loop, which increases the release of NE into the synapse. Mirtazapine also is a potent antagonist at 5-HT2 and 5-HT3 receptors, and it shows no significant affinity for 5-HT1A or 5-HT1B receptors. Additionally, it displays some anticholinergic properties, and it produces sedative effects (because of potent histamine H1 receptor antagonism) and orthostatic hypotension (because of moderate antagonism at peripheral α1-adrenergic receptors). Its antidepressant effect is comparable to the TCAs and may be better than some SSRIs, especially in patients with depression of the melancholic type, but at higher doses, it may cause drowsiness and weight gain. The drug generally is well tolerated, producing no more adverse events (including anticholinergic events) than the SSRIs and fewer adverse events than the TCAs.
Mirtazapine absorption is rapid and complete, with a bioavailability of approximately 50% as a result of first-pass metabolism. The rate and extent of mirtazapine absorption are minimally affected by food. Dose and plasma levels are linearly related over a dose range of 15 to 80 mg. The elimination half-life of the (–)-enantiomer is approximately twice that of the (+)-enantiomer. In females of all ages, the elimination half-life is significantly longer than in males (mean half-life, 37 versus 26 hours).

Mirtazapine is a piperazinodibenzoazepine antidepressant that is an isostere of the antidepressant mianserin. A seemingly simple isosteric replacement of an aromatic methine group (CH) in mianserin with a nitrogen to give a pyridine ring (mirtazapine) has profound effects on the physicochemical properties, pharmacokinetics, mechanisms of action, and antidepressant activities. Profound differences between receptor affinity and transporter affinity, pharmacokinetics, regioselectivity in the formation of metabolites, and toxicity are observed for mianserin and mirtazapine and their antidepressant mechanisms of action. The pyridine ring increases the polarity of the molecule and decreases the measured partition coefficient and the basicity. Mianserin is a potent inhibitor of NET , whereas mirtazapine has negligible effects on the inhibition of NET (pKi = 7.1 vs. 5.8 respectively).