Milnacipran

Milnacipran is an antidepressant of the serotonin-norepinephrine reuptake inhibitor class.

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History

Milnacipran has been approved and sold in Austria since September 1998 under the brand name Ixel®. Cypress Bioscience bought the exclusive rights for approval and marketing of the drug for any purpose in the US and Canada in 2003 from the manufacturer Pierre Fabre; the approval procedure in both countries is ongoing. In Chile, under the "Ixel" brand name is being sold by Silesia Laboratories.

Pharmacology

Milnacipran inhibits norepinephrine and serotonin reuptake in a 3:1 ratio, in practical use this means a balanced (equal) action upon both transmitters. The serotonin reuptake inhibition is likely to improve depression, while the norepinephrine reuptake inihibition probably improves chronic pain. Milnacipran exerts no significant actions on postynaptic H1, alpha-1, D1, D2, and muscarinic receptors, as well as on benzodiazepine/opiate binding sites.^[1][2][3]. In a clinical trial with over 1,000 depressed patients milnacipran showed results comparable to imipramine and superior to SSRIs, but in a different study^[4] it was inferior to clomipramine. A meta-analysis of 6 studies involving more than 1,000 patients showed no distinction between milnacipran and SSRIs in efficacy or discontinuation rates, including discontinuation for side effects or lack of efficacy.^[5] As with other antidepressants, 1 to 3 weeks may elapse before significant antidepressive action becomes clinically evident.

Pharmacokinetics

Milnacipran is well absorbed after oral dosing and has a bioavailability of 85%. Meals do not have an influence on the rapidity and extent of absorption. Peak plasma concentrations are reached 2 hours after oral dosing. The elimination half-life of 8 hours is not increased by liver impairment and old age, but by significant renal disease. Milnacipran is conjugated to the inactive glucuronid and excreted in the urine as unchanged drug and conjugate. Only traces of active metabolites are found. Enzymes of the CYP class do not play a role in the metabolism of Milnacipran.

Indications & Dosage

Milnacipran is used to treat:

• Moderate to severe clinical depression (Major Depression)
• Chronic pain

The recommended dose for depression is 50mg 2 times daily (after an initial phase of 50mg daily as single dose on days 1 to 4). The dose should be decreased in patients with renal disease. The dosage for the other indications has not been well established so far.

Milnacipran is available in 25mg and 50mg capsules.

After successful treatment of the acute depressive episode, patients should be maintained on Milnacipran for several months (normally 9 months) in order to prevent relapse of depression.

Experimental Uses

In experimental studies Milnacipran showed useful activity as adjunct in the therapy of Fibromyalgia and Lupus, both conditions with potentially devastating effects. In Fibromyalgia the drug improved pain, mood, and fatigue compared to placebo. In Lupus patients pain was alleviated and a sense of well-being was provided.

On January, 5th., 2006, Forest Pharmaceuticals and Cypress Bioscience agreed to commence a phase III multicenter study encompassing 1,200 patients with Fibromyalgia. On May 22nd, 2007, the phase III study demonstrated statistically significant therapeutic effects of Milnacipran as a treatment of fibromyalgia syndrome. At this time, only initial top-line results are available and further analyses will be completed in the coming weeks.^[6]

In April 2007, Progress in Neuro-Psychopharmacology & Biological Psychiatry published an article that presented the case of an adult Attention-deficit hyperactivity disorder (ADHD) patient who found that milnacipren alleviated her symptoms of inattention and hyperactivity. Considering that Milnacipran has fewer side effects than comparable drugs, the authors of the article concluded that it could be studied and developed as an alternative treatment for ADHD ^[7].

Side effects

Side effects include itching, nausea, vertigo, increased anxiety, sweats, shivering, dysuria and testicle pain. Milnacipran does not seem to have a negative impact on sexual functions. The incidence of cardiovascular and anticholinergic side effects was significantly lower compared to TCAs as a controlled study with over 3,300 patients revealed. Cases of hypertension, hypotension and tachycardia have been noted. Elevation of liver enzymes without signs of symptomatic liver disease has been infrequent. Mood swing to mania has also been seen and dictates termination of treatment. In psychotic patients emergence of delirium has been noticed. Milnacipran has a low incidence of sedation but improves sleep (as well duration and quality) in depressed patients. In agitated patients or those with suicidal thoughts additive sedative/anxiolytic treatment is usually indicated.

Interactions

• MAOIs, Lithium - serotoninergic syndrome, potentially lethal
• 5-HT1AD-Agonists - coronary vasoconstriction with risk of angina pectoris and myocardial infarction
• Epinephrine, Norepinephrine (also in local anesthesia) - hypertensive crisis and possible arrhythmias
• MDMA - hypertensive crisis
• Clonidine - antihypertensive action of Clonidine may be antagonized
• Digitalis - hemodynemic actions increased
• Alcohol - no interactions known

Contraindications

Administration of milnacipran should be avoided in individuals with the following:

• Known hypersensitivity to Milnacipran (absolute contraindication)
• Patients under 15 years of age (no sufficient clinical data)
• Concomitant treatment with irreversibe and reversible (MAO-B) MAO-Inhibitors, Digitalis-Glycosids and 5-HT1D-Agonists (e.g. Sumatriptan) - absolute contraindications -

Administration of milnacipran should be done with caution in individuals with the following:

• Concomitant treatment with parenteral Epinephrine, Norepinephrine, with Clonidine and reversible MAO-A-Inhibitors (Moclobemid, Toloxaton).
• Advanced renal disease (decreased dosage required)
• Hypertrophy of the prostate gland (possibly urination hesitancy induced), with hypertension and heart disease (tachycardia may be a problem) as well as with open angle glaucoma

Milnacipran should not be used during pregnancy because it may cross the placenta barrier and no clinical data exists on harmful effects in humans and animal studies. Milnacipran is contraindicated during lactation because it is excreted in the milk, and it is not known if it is harmful to the newborn.

References

1. ^ Moret C, Charveron M, Finberg JP, Couzinier JP, Briley M (1985). "Biochemical profile of midalcipran (F 2207), 1-phenyl-1-diethyl-aminocarbonyl-2-aminomethyl-cyclopropane (Z) hydrochloride, a potential fourth generation antidepressant drug". Neuropharmacology 24 (12): 1211-9. PMID 3005901.
2. ^ Briley M, Prost JF, Moret C (1996). "Preclinical pharmacology of milnacipran". International clinical psychopharmacology 11 Suppl 4: 9-14. PMID 8923122.
3. ^ Puozzo C, Panconi E, Deprez D (2002). "Pharmacology and pharmacokinetics of milnacipran". International clinical psychopharmacology 17 Suppl 1: S25-35. PMID 12369608.
4. ^ Leinonen E, Lepola U, Koponen H, Mehtonen OP, Rimon R (1997). "Long-term efficacy and safety of milnacipran compared to clomipramine in patients with major depression". Acta psychiatrica Scandinavica 96 (6): 497-504. PMID 9421348.
5. ^ Papakostas GI, Fava M (2007). "A meta-analysis of clinical trials comparing milnacipran, a serotonin--norepinephrine reuptake inhibitor, with a selective serotonin reuptake inhibitor for the treatment of major depressive disorder". European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology 17 (1): 32-6. doi:10.1016/j.euroneuro.2006.05.001. PMID 16762534.
6. ^ Forest Laboratories (May 22, 2007). Forest Laboratories, Inc. and Cypress Bioscience, Inc. Announce Positive Results of Phase III Study for Milnacipran as a Treatment for Fibromyalgia Syndrome.
7. ^ Kako Y, Niwa Y, Toyomaki A, et al (2007). "A case of adult attention-deficit/hyperactivity disorder alleviated by milnacipran". Prog. Neuropsychopharmacol. Biol. Psychiatry 31 (3): 772-5. doi:10.1016/j.pnpbp.2006.12.017. PMID 17300859.