Remeron (Mirtazapine)
Remeron®, Remeron® SolTab™
Classification:
Psychotropic Agents
- Antidepressants
- Heterocyclic antidepressants
Description: Mirtazapine is an antidepressant that is not chemically related to any other class of antidepressants. It belongs to a unique class known as piperazinoazepines and is a tetracyclic compound. Mirtazapine possesses an anxiolytic effect that may be useful in depressed patients who have a coexisting anxiety disorder. The drug may also improve sleep patterns associated with depression. Mirtazapine is associated with fewer ADRs than tricyclic antidepressants and is better tolerated. Compared to the tricyclics and some SSRIs, mirtazapine may have a faster onset of antidepressant efficacy, with maximal effects within 2 - 4 weeks of adequate dosage selection. Selective blockade of specific serotonin receptors by mirtazapine is thought to help to minimize certain side effects (e.g., sexual dysfunction and weight gain) typical of other antidepressants. Off label uses of mirtazapine are still being explored, including efficacy for various neurologic-induced tremors. Initial FDA approval of mirtazapine was granted June 14, 1996 for the treatment of depression in adults. An orally disintegrating tablet was approved in January 2001. On April 9, 2002 the drug received FDA-approval for use in maintaining a response in adults with major depressive disorder. Phase III trials of mirtazapine are in progress for the treatment of depression in children 7 - 18 years of age.
On October 15, 2004 the FDA directed manufacturers of all antidepressants to include a Black Box warning, expanded warning statements, and clinical trial results detailing the increased risk of suicidality in children and adolescents. A Patient Medication Guide (MedGuide) will also accompany all prescriptions for antidepressants. The FDA is currently assessing the risk of suicidality in adults taking antidepressants and a final report is expected by mid- to late 2006.
Mechanism of Action: The primary mechanism of action of mirtazapine is antagonism at central pre-synaptic alpha2-receptors. Normally, these receptors are involved in a negative feedback loop and activation causes inhibition of further norepinephrine (NE) release. By blocking pre-synaptic alpha2-receptors, mirtazapine defeats negative feedback to the presynaptic nerve and causes an increase in NE release. Antagonism at central alpha2-receptors is 10-fold higher than at peripheral alpha2-receptors which results in a reduced incidence of peripheral adverse effects. Mirtazapine also antagonizes several subtypes of serotonin (5-HT) receptors. The drug is a weak antagonist at 5-HT1 receptors and a potent antagonist at 5-HT2 (particularly subtypes 2A and 2C) and 5-HT3 receptors. Blockade of these receptors may result in a lower incidence of certain adverse effects such as anxiety, insomnia, and nausea that occur with other agents like the selective serotonin reuptake inhibitors (SSRIs). Serotonergic neurons also contain alpha2-receptors, called heteroreceptors and blockade of heteroreceptors results in enhanced release of 5-HT. The increased amount of 5-HT released interacts with 5-HT1 receptors which may be relevant to the antidepressant and anxiolytic effects of mirtazapine. Mirtazapine has no effects on the reuptake of either NE or 5-HT. In addition, mirtazapine exhibits significant antagonism at H1-receptors. Histamine H1-receptor blockade is generally associated with sedation, however, the enhancement of NE release may offset the sedative potential of the drug at higher doses. Mirtazapine has minimal activity at dopaminergic and muscarinic receptors.
Pharmacokinetics: Mirtazapine is administered orally. Following oral administration, mirtazapine is rapidly and completely absorbed. Peak plasma concentrations are reached within about 2 hours after an oral dose. Food has minimal effects on both the rate and extent of absorption and does not require adjustments in the dose. Absolute bioavailability is about 50%. Plasma protein binding is approximately 85% over a concentration range of 0.01 to 10 mcg/ml. Mirtazapine steady-state plasma levels are reached within 5 days. Antidepressant actions can onset within 1 - 2 weeks, with maximal therapeutic efficacy within 2 - 4 weeks following the selection of an effective dose.
Metabolism is extensive after oral administration and occurs via demethylation and hydroxylation followed by glucuronide conjugation. In vitro data indicate that cytochrome P450 2D6 and 1A2 are involved in the formation of the 8-hydroxy metabolite, whereas the cytochrome P4503A isoenzyme group is responsible for the formation of the N-desmethyl and N-oxide metabolite. Several unconjugated metabolites have pharmacologic activity but are present at very low plasma levels. Elimination occurs via the urine (75%) and the feces (15%). The ( - ) enantiomer has an elimination half-life that is about twice that of the (+) enantiomer. The elimination half-life of mirtazapine is long and ranges 20 - 40 hours across age and gender subgroups, so dosage increases should take place no sooner than every 7 - 14 days.
Mirtazapine Tablets(Tab 15 mg)
Special Populations: Gender, age, and organ dysfunctions may affect the pharmacokinetics of mirtazapine. Females of all ages exhibit significantly longer elimination half-lives than males (mean half-life of 37 hours for females vs. 26 hours for males). The oral clearance of mirtazapine is reduced in elderly patients. Following administration of mirtazapine 20 mg/day for 7 days clearance was reduced in the elderly compared to younger adults. Elderly males exhibited a 40% lower clearance while elderly females had a 10% lower clearance when compared to younger adults. In patients with renal impairment, oral clearance may be reduced by 30 - 50% compared to normal subjects. Following a single 15 mg oral dose, patients with moderate hepatic impairment had roughly 30% reduction in clearance, compared to normal subjects.
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References
. Bremner JD. A double-blind comparison of Org 3770, amitriptyline, and placebo in major depression. J Clin Psychiatry 1995;56:519 - 25.
. Smith WT, Glaudin V, Panagides J, et al. Mirtazapine vs. amitriptyline vs. placebo in the treatment of major depressive disorder. Psychopharmacol Bull 1990;26:191 - 6.
. Institute for Clinical Systems Improvement (ICSI). Major depression in adults for mental health care. Bloomington (MN): Institute for Clinical Systems Improvement (ICSI); 2004 May. Available on the World Wide Web at http://www.guideline.gov
. Care Management Institute, Kaiser Permanente. Adult primary care depression guidelines. Oakland (CA): Kaiser Permanente; 2004 Apr. Retrieved October 27, 2005. Available on the World Wide Web at http://www.guidelines.gov
. American Psychiatric Association practice guideline for the treatment of patients with major depressive disorder. Am J Psychiatry 2000;157(4 Suppl):1 - 45.
[ Revised 3/20/2006 3:25:00 PM ]
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