Mirtazapine (Remeron)

A fairly new anti-depressant, but no longer patented, which is unrelated to any other U.S. medication although is similar to mianserin which is marketed in Europe.  It is a dual action anti-depressant, increasing both serotonin and norepinephrine by presynaptic alpha2-adrenergic blockade.  It original cost $61-$305/month for 15-75 mg/day have fallen considerable.  Mirtazapine appears to work as well as other anti-depressants and possibly slightly better than some.  It has a fair number of side-effects including weight gain.  Fortunately, severe weight gain appears uncommon.  It does have a good sleep effect.

In the Organon Pharmaceuticals 6-week trials of 453 on mirtazapine, 16% discontinued because of side-effects.  This is about average for an anti-depressant.  The most common side-effects leading to discontinuation were sleepiness (somnolence) (10.4%) and nausea (1.5%).  In all, 54% of patients reported some sleepiness, 17% increased appetite, 12% weight gain, and 7% dizziness.  Dry mouth (25%) and constipation (13%) were also common.  The drowsiness can interfere with driving ability, although for many patients the drowsiness clears up after a couple weeks.  Mirtazapine can increase cholesterol levels.  

In clinical trials with 2796 patients, two developed the serious side-effect of agranulocytosis (few white blood cells) and one neutropenia (few neutrophil, a type of white blood cell).  In two this occurred in the second week and in one after two months.  Symptoms to be on the look out for include fever and signs of infection.  These should lead to an immediate test for white blood cells to be sure that it is just a normal illness. 

Mirtazapine is taken at bedtime.  The starting dose is a single 15 mg tablet. It can be increased to 45 mg at bedtime if necessary. Its half-life is 20-40 hours, so the blood level on 15 mg at bedtime will gradually increase over the first week.  Because of this and because anti-depressants work gradually, no dosage increase should be tried in the first two weeks.  Smaller doses, e.g. one every other night, should be given to the elderly, especially anyone with kidney impairment.

Thase Meta-Analysis Says Mirtazapine Better and Faster than SSRIs: 16th European College of Neuropsychopharmacology Congress in Prague, pooled the data from 12 clinical trials. 1485 patients on mirtazapine, 1485 on SSRIs such as fluoxetine, paroxetine, citalopram, sertraline and fluvoxamine. Michael Thase, Univ Pittsburgh, 29% on mirtazapine responded after two weeks vs. 20% on SSRIs. After four weeks, response rates 50% versus 42%. 12% on mirtazapine were in remission after two weeks vs. 7% on SSRIs. After four weeks, 28% versus 22%.  (Ed: Mirtapazine is slightly better than SSRIs, but no better at all than much cheaper tricyclics such as nortriptyline, imipramine and amitriptyline.  Thase is one of the researchers who knows the value of bethanechol but refuses to allow its usage in studies with imipramine or amitriptyline which inevitably makes these have more side-effects.)

Amitriptyline as Good as Mirtazapine in 8 DB Study Depression with Anxiety Meta-analysis Finds: Mirtazapine was tested vs. a placebo in all and vs. amitriptyline in 4. Both meds help decreased anxiety the same amount. Jan Fawcett, Rush Presby-St Luke, J Clin Psychiatry 59:123-7.

Fluoxetine as Good as Mirtazapine: In an 8-week DB PC study of 297 severely depressed adults, mirtazapine 15-60 mg/day did as well as fluoxetine 20-40 mg/day and both did better than placebo. No statistically significant differences were noted between the two groups in change from baseline HDRS-17 score at any time point; both treatments were associated with large (~15 points) decreases by study end. No significant between-group differences were observed for the majority of quality-of-life measures. Mirtazapine produced better improvements on 'sleeping assessment 1' (14.9 vs 13.7, p = 0.028) and 'sleeping assessment 2' (p = 0.013) than fluoxetine. Mirtazapine-treated patients experienced a mean weight gain of w pounds compared with a mean decrease in weight of 1 pound for fluoxetine-treated patients (p < 0.001). Some gained much more. Comparison of the effects of mirtazapine and fluoxetine in severely depressed patients. Versiani M, Moreno R, et al. Federal University of Rio de Janeiro, Rio de Janeiro, Brazil. CNS Drugs. 2005;19(2):137-46

Imipramine-Lithium Better than Mirtazapine-Lithium: A 100 inpatient DB PC study of imipramine vs. mirtazapine. Those not responding after 4 weeks (mirtazapine 35, imipramine 22) had lithium added to 0.5-1.0 mmol/L. 36% mirtazapine-lithium v 52% imipramine-lithium responded. Brujin Rotterdam, J Clin Psych 98;59:657

Imipramine did Better than Mirtazapine: In a DB study, 107 severely depressed were treated to preset blood levels for 4 weeks. Imipramine response was 50% vs. a 22% mirtazapine response rate. A double-blind, fixed blood-level study comparing mirtazapine with imipramine in depressed in-patients. Bruijn JA, Moleman P, Mulder PG, van den Broek WW, van Hulst AM, van der Mast RC, van de Wetering BJ. Psychopharmacology (Berl) 1996 Oct;127(3):231-7

Paroxetine: Mirtazapine Faster Than Paroxetine with Elderly: A Stanford University study of 255 depressed patients in a DB found a 50% decrease in the HDRS depression score in 27 days for mirtazapine vs. 40 days for paroxetine and fewer side-effects. May have been industry funded. Am J Geriatr Psychiatry 2002 Sep-Oct;10(5):541-50

Paroxetine: Mirtazapine = Paroxetine although Faster: A DB PC study of 197 adults with MDD treated for 24 weeks with mirtazapine 30-45mg/d vs. paroxetine 20-30mg/d found mirtazapine significantly better at weeks 1 and 4, but not thereafter. A randomized, double-blind, 24-week study comparing the efficacy and tolerability of mirtazapine and paroxetine in depressed patients in primary care. Wade A, Crawford GM, Angus M, Wilson R, Hamilton L. Int Clin Psychopharmacol. 2003 May;18(3):133-41

Trazodone: Mirtazapine Better than Trazodone in DB: 200 MDD 6 wk 24-72mg mirtazapine vs 150-450 mg trazodone. Mirtazapine is more effective than trazodone: a double-blind controlled study in hospitalized patients with major depression. van Moffaert M, de Wilde J, Vereecken A, Dierick M, Evrard JL, Wilmotte J, Mendlewicz J. Belgium: Int Clin Psychopharmacol 1995 Mar;10(1):3-9

Venlafaxine: Mirtazapine at Least as Good as Venlafaxine with Fewer Side-Effects: J Clin Psychopharmacol 2001 Aug;21(4):425-31. A DB study of 155 patients with MDD who had been hospitalized with melancholic features.  They were treated for 8 weeks with either mirtazapine or venlafaxine. There was a 15% venlafaxine dropout rate due to side-effects vs. 5% for mirtazapine.

Mirtazapine Augmentation Better Than Placebo: 26 adult outpatients with persistent major depression despite adequate antidepressant monotherapy were randomized to receive 4 weeks of mirtazapine or placebo augmentation. Mirtazapine was begun at 15 mg at bedtime, with possible titration to 30 mg at bedtime per physician's discretion after week 1. RESULTS: Categorical positive response rate at end point was 64% for active drug and 20% for placebo. Carpenter, Brown Univ, Biol Psychiatry 2002 Jan 15;51(2):183-8 (Ed: Presumably, these are different patients from the 24 below.)

Mirtazapine Adjunct Helps Refractory Depression Although Side-Effects: Drug inhibits same alpha2-adrenoceptors as yohimbine. Mirtazapine 15-30 mg QHS was added to initial anti-depressant that was not adequately effective in the 24 patients (SSRIs, venlafaxine, desipramine or bupropion). 55% of patients were also on benzodiazepines and 10% anti-psychotics. The study found a dramatic response, always within 2 weeks but 25% got wt gain, 20% somnolence, side-effects of blocking histamine H1 receptors which oddly was much more prominent at 15 mg HS than at 30 mg. Linda Carpenter, Brown Univ, J Clin Psychiatry 60:45-9, 1/99; Similar results in 21 pts either not responding to SSRIs or S-E with 14 doing well but seven dropping out, 5 for S-E of weight gain or somnolence. Fava, MGH, APA 5/30/98. Dry mouth, sedation, and increases in appetite and body weight are the most common adverse effects. (Ed: Poor study since there was no justification given to continuing the first inadequate anti-depressant. Perhaps, after failing on mirtazapine alone, first could be restarted if it had been partially effective.)

NE and 5-HT Anti-Depressants May Be Faster: dual-acting antidepressants, i.e. those that affect both monoamine systems, such as tricyclic antidepressants and the noradrenergic and specific serotonergic antidepressant mirtazapine, may have greater efficacy and a faster onset of action than drugs that act on a single monoamine system only, such as the selective serotonin reuptake inhibitors (SSRIs). Cell firing is reduced by SSRIs in the short-term, but is increased by mirtazapine, probably due to its actions on both NA (via alpha(2) antagonism) and 5-HT (via alpha(1)-stimulation by NA). Hum Psychopharmacol 2002 Jun;17 Suppl 1:S17-22. Meta-analysis of clinical trials suggests that venlafaxine has a more rapid onset of action than selective serotonin reuptake inhibitors (SSRIs), and the same may also be true for milnacipran and mirtazapine. Int Clin Psychopharmacol 2002 Jun;17 Suppl 1:S13-24

Early Improvement Good Predictor for Either Paroxetine or Mirtazapine: Improvement (20% decrease in HAM-D) occurred in a majority of the analyzed patients within 2 weeks (mirtazapine: 72.7% of 109 patients; paroxetine: 64.9% of 103 patients). Early improvement was a highly sensitive predictor of later stable response or stable remission for both drugs. NPV approached maximum values as early as week 2 for mirtazapine and week 3 for paroxetine. After 2 weeks of treatment with mirtazapine and 3 weeks with paroxetine, almost none of the patients who had not yet improved became a stable responder or stable remitter in the later course. U Mainz. Early improvement under mirtazapine and paroxetine predicts later stable response and remission with high sensitivity in patients with major depression. Szegedi A, Muller MJ, Anghelescu I, Klawe C, Kohnen R, Benkert O. J Clin Psychiatry 2003 Apr;64(4):413-20

Weight Gain: Psychiatrists name mirtazapine as especially prone to increase weight. However, in one DB study of 78 patients taking mirtazapine, they gained only 1.4 kg (3.1 lb) across the 40 weeks of continuation therapy. J Clin Psychiatry 2001 Oct;62(10):782-8. (Ed: Other studies report considerably more weight gain.)

Paroxetine, Fluvoxamine Increase Mirtazapine Levels: Paroxetine inhibits the metabolism of mirtazapine, as shown by increases of approximately 17% and 25% of the 24 h AUC's of mirtazapine and its demethyl metabolite, respectively. Mirtazapine did not alter the pharmacokinetics of paroxetine. Paroxetine inhibits P450 2D6. Hum Psychopharmacol 2001 Aug;16(6):449-459. Fluvaxomine may increase level by 300%. Ann Pharmacother 2001 Oct;35(10):1221-3. Fluvoxamaine & Mirtazapine have caused serotonin syndrome. tremors,restlessness, twitching, flushing, diaphoresis, and nausea,symptoms that are consistent with serotonin syndrome in 26 yo female. Ann Pharmacother 2001 Oct;35(10):1217-20

Fluvoxamine/Mirtazapine Interaction: 3 cases with increased mirtazapine levels 3-4 fold and one with serotonin syndrome (twitching, agitation, tremors, restless, diaphoresis, flushing, fasciculations, nausea). Drug Alerts 12/01

Thomas E. Radecki, M.D., J.D.

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