Mirtazapine

Mirtazapine is an antidepressant introduced by Organon International in 1996 used for the treatment of moderate to severe depression. Mirtazapine has a tetracyclic chemical structure and is classified as a noradrenergic and specific serotonergic antidepressant (NaSSA). It is the only tetracyclic antidepressant, other than Ludiomil, that has been approved by the Food and Drug Administration to treat depression. Because of its unique pharmacologic profile, mirtazapine is virtually devoid of anticholinergic effects, serotonin-related side effects,^[1] and adrenergic side effects (orthostatic hypotension and sexual dysfunction). Antihistaminic side effects of drowsiness and weight gain are prominent. It is most useful as an add-on medication to enhance the effectiveness of agents such as duloxetine and venlafaxine in severe and treatment-resistant depression. Mirtazapine is relatively safe if an overdose is taken.^[2]

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Trade Names

Mirtazapine is marketed under the tradenames:

• Remeron® in Brazil, Canada, Czech Republic, Finland, Israel, Italy, Mexico, Netherlands, Norway, Pakistan, Sweden, Switzerland, Turkey and the U.S.;
• Zispin® in Ireland & the UK;
• Remergil® in Germany;
• Norset® in France;
• Rexer® in Spain;
• Remergon® in Belgium;
• Mirtabene® in Austria;
• Avanza®, Mirtazon® and Axit® in Australia;
• Mirtaz® in India and Srilanka; and
• Promyrtil® in Chile.
• Noxibel® in Bolivia.
• Remeron®, Mirzaten® and Mizapin Sol® in Hungary.

Indications

Approved

Mirtazapine is primarily used to treat the symptoms of mild to severe depression.^[3]

Unapproved/Off-label/Investigational

There is also evidence that mirtazapine can be used to treat panic disorder (PD),^[4] generalized anxiety disorder (GAD),^[5] obsessive-compulsive disorder (OCD),^[6] post traumatic stress disorder (PTSD)^[7] sleep apnea, ^[1] and pruritus.^[8] Mirtazapine has not been reported to be effective in the prophylactic treatment of chronic tension headache.^[9] This drug has also been shown to improve symptoms in Gastroparesis patients.

Veterinary

Anecdotal evidence also suggests that mirtazapine may be effective in treating certain vomiting or anorexia-related conditions in dogs and cats. Any such use is still off-label, however. Mirtazapine is NOT recommended for elderly dogs with renal weakness.

Mechanism of action

It is thought to work by blocking presynaptic alpha-2 adrenergic receptors that normally inhibit the release of the neurotransmitters norepinephrine (noradrenaline) and serotonin, thereby increasing active levels in the synapse.

Side effects

Interestingly, its side-effect profile can be used for benefit in certain clinical situations. The drowsiness, increased appetite, and weight gain that it causes are useful in patients with depressive disorders with prominent sleep and appetite disturbances. In addition, it is quite useful in patient situations in which patients suffer from nausea, since it also antagonizes the 5-HT₃ receptor, the target of the popular anti-emetic ondansetron (Zofran®).

At lower dosages, such as 7.5 mg, mirtazapine is primarily antihistaminergic, causing sedation, which can be beneficial in depressed patients who have difficulty falling asleep. At doses higher than 15 mg, its effect is primarily in inducing the release of norepinephrine, and is thus less sedating.^{[citation needed]}

Side effects occurring commonly:

• Mild visual hallucinations (when taken during the day or when awake)
• Increased appetite
• Vivid dreams / Nightmares as a result of regular intake
• Weight gain
• Increase in cholesterol, independent of weight gain
• Drowsiness, especially at lower doses and during the first few weeks of treatment
• Dizziness, coupled often with the effects of sickness
• Headache
• General or local swelling

Side effects occurring rarely:

• Excessive urinating when taken with alcohol
• Mania
• Seizures
• Tremor
• Muscle twitching and Restless Legs Syndrome
• Pins and needles
• Rash and skin eruptions
• Pain in the joints or muscles
• Low blood pressure
• Higher blood pressure
• Obesity

Dangerous side effects

If you experience any of these, tell your doctor immediately. You will need to consult your doctor for taper-off instructions. Sudden withdrawal from antidepressants can cause serious symptoms. However, sudden withdrawal can be used (under supervision of the appropriate medical services) when the risks of continuing the antidepressant during a 'taper-off' phase are too great.

• An allergic reaction; signs of swelling of the lips, face and tongue, difficulty in breathing, rash or itching (especially affecting the whole body) or feeling faint.
• Signs of infection such as fever, sore throat, mouth ulcers or stomach upset.
• Jaundice (yellowing of the skin and/or eyes).
• Agranulocytosis

Dosage

The usual starting dose for mirtazapine is 15 mg once daily, usually at bedtime (because of its sedative nature and the possibility of disturbed visual perception). Doses may be increased, following medical advice, every 1-2 weeks up to a dose of 45 mg. It may be taken with or without food. Dispersible tablets (SolTab® orally disintegrating tablets) can even be taken without water.

Pregnancy and Lactation

• Pregnancy : Sufficient data in humans is lacking. The use should be justified by the severity of the condition to be treated.
• Lactation : Sufficient data in humans is also lacking. Additionally, Mirtazapine may be found in the maternal milk in significant concentrations. The use in breastfeeding women should be carefully weighed against possible risks.

Drug-Drug Interactions

Because of the sedative effects of Mirtazapine, excessive sedation may result when it is used with other sedating substances, such as alcohol or benzodiazepines. According to official prescribing information from Organon, mirtazapine should not be used within 14 days of the use of an MAOI because of the risk of serious effects such as hypertensive emergency and hyperthermia.

References

1. ^  Gillman, PK (2006). "A systematic review of the serotonergic effects of mirtazapine: implications for its dual action status". Human Psychopharmacology Clinical and Experimental 21 (2): 117-25. PMID 16342227.
2. ^  Burrows GD, Kremer CM. (1997). "Mirtazapine: clinical advantages in the treatment of depression.". Journal of Clinical Psychopharmacology 17 (2S): 34S-39S. PMID 9090576.
3. ^  Velazquez C, Carlson A, Stokes KA, Leikin JB. (2001). "Relative safety of mirtazapine overdose.". Veterinary and Human Toxicology 43 (6): 342-344. PMID 11757992.
4. ^  Gorman JM (1999). "Mirtazapine: clinical overview.". Journal of Clinical Psychiatry 60 (17): 9-13. PMID 10446735.
5. ^  Baldwin DS, Anderson IM, Nutt DJ, Bandelow B, Bond A, Davidson JR, den Boer JA, Fineberg NA, Knapp M, Scott J, Wittchen HU (2005). "Evidence-based guidelines for the pharmacological treatment of anxiety disorders: recommendations from the British Association for Psychopharmacology.". Journal of Psychopharmacology 19 (6): 567-596. PMID 16272179.
6. ^  Goodnick PJ, Puig A, DeVane CL, Freund BV (1999). "Mirtazapine in major depression with comorbid generalized anxiety disorder". Journal of Clinical Psychiatry 60 (7): 446-448. PMID 10453798.
7. ^  Koran LM, Gamel NN, Choung HW, Smith EH, Aboujaoude EN (2005). "Mirtazapine for obsessive-compulsive disorder: an open trial followed by double-blind discontinuation". Journal of Clinical Psychiatry 66 (4): 515-520. PMID 15816795.
8. ^  Baldwin DS, Anderson IM, Nutt DJ, Bandelow B, Bond A, Davidson JR, den Boer JA, Fineberg NA, Knapp M, Scott J, Wittchen HU (2005). "Evidence-based guidelines for the pharmacological treatment of anxiety disorders: recommendations from the British Association for Psychopharmacology.". Journal of Psychopharmacology 19 (6): 567-596. PMID 16272179.
9. ^  Davis MP, Frandsen JL, Walsh D, Andresen S, Taylor S. (2003). "Mirtazapine for pruritus.". Journal of pain and symptom management 25 (3): 288-291. PMID 12614964.
10. ^  Bendtsen L, Jensen R (2004). "Mirtazapine is effective in the prophylactic treatment of chronic tension-type headache.". Neurology 62 (10): 1706-1711. PMID 15159466.
11. ^  Gillman, PK (2006). "A systematic review of the serotonergic effects of mirtazapine: implications for its dual action status". Human Psychopharmacology Clinical and Experimental 21 (2): 117-25. PMID 16342227.