Mirtazapine

Mirtazapine (Remeron, Avanza, Zispin) is a tetracyclic antidepressant (TeCA) used primarily in the treatment of depression. It is also sometimes used as a hypnotic, antiemetic, and appetite stimulant, and for the treatment of anxiety, among other indications. Along with its close analogues mianserin and setiptiline, mirtazapine is one of the few noradrenergic and specific serotonergic antidepressants (NaSSAs).

Esmirtazapine, the (S)-(+)-enantiomer of mirtazapine, is currently under development for the treatment of insomnia and menopausal symptoms by the same company that produced mirtazapine.

Medical uses

Mirtazapine's primary use is the treatment of major depressive disorder. Mirtazapine has been found to be useful in the treatment of generalized anxiety disorder, social anxiety disorder, obsessive-compulsive disorder, panic disorder, post-traumatic stress disorder, seasonal affective disorder, insomnia, nausea and vomiting, diminished appetite and associated weight loss, and itching as well, and it may be prescribed off-label for these conditions.

Efficacy and tolerability

Mirtazapine has been found to be one of the most effective antidepressants available and has a generally tolerable side effect profile. In a major systematic review published in 2009 which compared the efficacy and tolerability of 12 popular antidepressants, mirtazapine was found to be superior to all of the included SSRIs and SNRIs, reboxetine, bupropion, and mianserin in terms of antidepressant efficacy, while it was average in regards to tolerability. Mirtazapine has been demonstrated to be superior to trazodone as well. Mirtazapine has also been shown to be equal in efficacy to many of the TCAs, including amitriptyline, doxepin, and clomipramine, but with a much improved tolerability profile. One study compared the combination of venlafaxine and mirtazapine versus the MAOI tranylcypromine and found them to be equally effective, though the MAOI was much less tolerable in terms of side effects and drug interactions. headaches such as migraines, tension headaches, post-dural puncture headaches and cluster headaches, hyperemesis gravidarum, irritable bowel syndrome, gastroparesis, dysgeusia, undifferentiated somatoform disorder, autism and other pervasive developmental disorders, and neuroleptic-induced akathisia.

Adverse effects

Common side effects of mirtazapine: dizziness, blurred vision, sedation, somnolence, malaise/lassitude, increased appetite and subsequent weight gain, dry mouth, constipation, enhanced libido and sexual function, and vivid, bizarre, lucid dreams or nightmares.

Rarer side effects: agitation/restlessness, irritability, aggression, apathy and/or anhedonia (i.e., inability to experience pleasurable emotions), excessive mellowness or calmness, difficulty swallowing, shallow breathing, decreased body temperature, miosis, nocturnal emissions, spontaneous orgasm, loss of balance, and restless legs syndrome. Mirtazapine has also occasionally been reported to cause mild hallucinogenic effects in some patients, including mental imagery, auditory and visual hallucinations. Most of these side effects are generally mild and become less prominent over time.

Discontinuation

Mirtazapine and other antidepressants may cause a withdrawal upon discontinuation. It should be noted that withdrawal effects from most psychoactive drugs (such as antidepressants) are common; but may be less severe than seen with some benzodiazepines. A gradual and slow reduction in dose is recommended in order to minimize withdrawal symptoms. Effects of sudden cessation of treatment with mirtazapine may include depression, anxiety, panic attacks, vertigo, restlessness, irritability, decreased appetite, insomnia, diarrhea, nausea and vomiting, flu-like symptoms such as allergies and pruritus, headache, and sometimes hypomania/mania.

Interactions

The potential for dangerous drug interactions with mirtazapine is considered to be very low, if not completely negligible. As a serotonin receptor antagonist, mirtazapine will not cause serotonin syndrome at any dose, nor is it capable of causing tyramine-induced hypertensive crisis, unlike the SSRIs and MAOIs, respectively. In fact, mirtazapine can actually be used to treat serotonin syndrome. However, mirtazapine is said to be an indirect agonist of the 5-HT1A receptor, which can contribute to serotonin syndrome when combined with other serotonergic drugs.

Mirtazapine in combination with an SSRI, SNRI, or TCA as an augmentation strategy is safe and is often used therapeutically. However, mirtazapine has been associated with inducing hypertension in clonidine-treated patients.

Overdose

Mirtazapine is relatively safe if an overdose is taken. Unlike the TCAs, mirtazapine shows no significant cardiovascular adverse effects at 7 to 22 times the maximum recommended dose. One case in which 1,200 mg was ingested proved non-fatal.

12 fatalities have been attributed to mirtazapine overdose in literature. However, the fatal toxicity index (FTI: deaths per million prescriptions) for mirtazapine is only 3.1 (95% CI: 0.1 to 17.2). This is similar to that observed with SSRIs.

Pharmacology

Pharmacodynamics

Mirtazapine is an antagonist/inverse agonist at the following receptors:

5-HT_2A receptor (K_i = 69 nM)

5-HT_2B receptor (K_i = ? (~20-fold lower than for 5-HT_2A/_2C))

5-HT_2C receptor (K_i = 39 nM)

5-HT₃ receptor (K_i = ? (similar to 5-HT_2A/_2C))

5-HT₇ receptor (K_i = 265 nM)

α₁-adrenergic receptor (K_i = 608 nM)

α_2A-adrenergic receptor (K_i = 20 nM)

α_2C-adrenergic receptor (K_i = 18 nM)

H₁ receptor (K_i = 1.6 nM)

mACh receptors (K_i = 794 nM)

As well as an inhibitor of the following transporters:

Norepinephrine transporter (K_i = 4,600 nM)

All affinities listed were assayed using human materials except those for α₁-adrenergic and mACh which are for rat tissues, due to human values being unavailable.

Antagonization of the α₂-adrenergic receptors which function largely as autoreceptors and heteroreceptors enhances adrenergic and serotonergic neurotransmission, notably central 5-HT_1A receptor-mediated transmission in the dorsal raphe nucleus and hippocampus. Indirect α1-adrenoceptor-mediated enhancement of 5-HT cell firing and direct blockade of inhibitory α2-heteroreceptors located on 5-HT terminals are held responsible for the increase in extracellular 5-HT. Because of this, mirtazapine has been said to be a functional "indirect agonist" of the 5-HT_1A receptor. Unlike most conventional antidepressants, however, mirtazapine is not a reuptake inhibitor and has no appreciable affinity for the serotonin, norepinephrine, or dopamine transporters, nor is it an MAOI or have any efficacy at inhibiting/inducing any other enzyme for that matter.

More recent findings suggest that mirtazapine also possesses a second antidepressant property, which is likely to be just as important as its actions at the α₂-adrenergic receptor in mitigating depression, mirtazapine's secondary antidepressant properties are likely to be mediated by its blockade of serotonin receptors, notably 5-HT_2C. The 5-HT_2C receptor normally works to inhibit the release of the neurotransmitters dopamine and norepinephrine in various parts of the brain, notably in the pleasure centers such as the ventral tegmental area (VTA). By blocking it, mirtazapine disinhibits dopamine and norepinephrine activity in these areas, causing a pronounced antidepressant and anxiolytic response. Indeed, the novel antidepressant agomelatine acts primarily as a 5-HT_2C receptor antagonist and has antidepressant efficacy at least comparable to that of the SSRIs and SNRIs.

Antagonism of the 5-HT_2A and 5-HT_2C receptors has beneficial effects on anxiety, sleep and appetite, as well as sexual function regarding the latter receptor. Additionally, antagonism of the 5-HT₃ receptor, the mechanism of action of antiemetic ondansetron, significantly improves pre-existing symptoms of nausea, vomiting, diarrhea, and general irritable bowel syndrome in afflicted individuals. Mirtazapine may be used as an inexpensive antiemetic alternative to ondansetron. Mirtazapine appears to enhance memory function as well and reverses scopolamine-induced memory deficits in rodents, effects which may be attributed to 5-HT₃ antagonism. In contrast to mirtazapine, the SSRIs, SNRIs, TCAs, and MAOIs all increase the general activity of the 5-HT_2A, 5-HT_2C, and 5-HT₃ receptors, leading to a host of negative changes and side effects, the most prominent of which include anorexia, insomnia, sexual dysfunction (impaired libido and anorgasmia), nausea, and diarrhea, among others. As a result, mirtazapine is often used in conjunction with these drugs to reduce their side effect profile and to produce a stronger antidepressant effect.

Mirtazapine is a very strong H₁ receptor antagonist and as a result, it can cause powerful sedative and hypnotic effects.

Pharmacokinetics

Mirtazapine is typically prescribed in doses ranging from 15 mg to 45 mg. However, in severely depressed individuals, doses as high as 120 mg have been used with success. Mirtazapine has a half-life of approximately 20–40 hours. Like most other antidepressants, because of the therapeutic-latency mirtazapine may require as long as 2–4 weeks until the therapeutic benefits of the drug become evident.

Chemistry

Mirtazapine is a racemic mixture of enantiomers and the (S)-(+)-enantiomer is known as esmirtazapine.

A four step chemical synthesis of mirtazapine has been published.

History

Mirtazapine was introduced by Organon International in the United States in 1990 for the treatment of depression.

References

Further reading

External links

Mirtazapine - Drugs.com

Remeron - Rxlist.com

Mirtazapine - MedicineNet.com

Mirtazapine - MedlinePlus

Mirtazapine - About.com

U.S. National Library of Medicine: Drug Information Portal - Mirtazapine

Category:Tetracyclic antidepressants Category:Antiemetics Category:Alpha blockers Category:Serotonin antagonists Category:H1 receptor antagonists