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wikitox:2.1.11.9.2.4.2_mirtazapine

TETRACYCLIC ANTIDEPRESSANTS

DRUGS INCLUDED

Maprotiline
Mirtazapine
Mianserin

OVERVIEW

These atypical antidepressants have relatively low toxicity in overdose when taken on their own. The most common symptoms are tachycardia, mild hypertension and mild CNS depression. They do not produce serotonin toxicity. Apart from maprotiline, there is no association with QT prolongation, seizure activity or delirium in isolated ingestions.

MECHANISM OF TOXIC EFFECTS

Mirtazapine and mianserin are potent presynaptic antagonists of central alpha adrenoreceptors (α2»α1), promoting monoamine release (noradrenaline and serotonin (5-HT)). Mirtazapine also acts as an antagonist at both 5-HT2 and 5-HT3 receptors. Therefore, the released 5-HT exerts its effects specifically on 5-HT1 receptors (1). Occasional misundersttod case reports have suggested mirtazapine may contribute to serotonin toxicity, however an understanding of the pathophysiology of serotonin toxicity and a large case series suggest there is no relationship(2). Maprotiline selectively inhibits noradrenaline reuptake into the presynaptic neuron with little or no effect upon serotonin reuptake.

Mirtazapine itself does not significantly inhibit noradrenergic or serotonergic re-uptake. However, it is a potent antihistamine leading to sedation and has weak anti-muscarinic activity.(3,4) Maprotiline can cause coma, QRS widening, ventricular tachycardia, torsades des pointes and cardiac arrest. Seizures can develop. CNS depression may persist for days.

KINETICS IN OVERDOSE

There is no information on these drugs kinetics in overdose – data on kinetics in therapeutic use are available.

Absorption

Mirtazapine is well absorbed in therapeutic doses and peak plasma concentrations are achieved in 2 h. Oral bioavailability is approximately 50%, due to first pass metabolism. Mianserin also has a large first-pass effect with 30% bioavailability.

Distribution

Both drugs have significant plasma protein binding and large volumes of distribution.

Metabolism - Elimination

Mirtazapine is predominantly metabolised in the liver and is a substrate for CYP 1A2, 2D6 and 3A4. The metabolites are not believed to have significant pharmacological or toxicological importance. The elimination half-life ranges from 20 to 40 hours in therapeutic doses.(4)

CLINICAL EFFECTS

Mirtazapine has been observed in two case series to show minimal effects other than tachycardia, mild hypertension and minor CNS depression (2,5). Mianserin is not well studied. Maprotiline appears to be more toxic producing coma, QRS widening, ventricular tachycardia, torsades des pointes and cardiac arrest. Seizures can develop. CNS depression may persist for days.

Adverse effects of mirtazapine in therapeutic doses include sedation, dry mouth, increased appetite and weight gain.(6) Although mianserin may rarely cause agranulocytosis, this does not appear to be a dose-related effect.(7) In mice studies the oral LD50 for mirtazapine ranged from 600–720 mg/kg and in rats 320–490 mg/kg. (The highest recommended dose for mirtazapine is 45 mg/day although higher doses have been used in clinical trials.(6))

A few deaths have been attributed by UK coroners to mirtazapine and mianserin overdose. However, the fatal toxicity index (FTI: deaths per million prescriptions) for mirtazapine and mianserin are only 3.1 (95% CI: 0.1 to 17.2) and 3.3 (0.7 to 9.5) respectively. This is similar to that observed with SSRIs.(8)

Mirtazapine

There have been a small number (< 20) of case reports of mirtazapine in overdose published (9–15) and two larger case series (2,5) Other than sedation, no major sequelae have been reported. Concentrations in reported cases have been up to 2300 microg/L(12) and doses up to 1350 mg,(2) without seizures or arrhythmias reported. An abstract of a German case series, based on follow-up of 73 overdoses where a Poisons Centre was consulted, reported no deaths and only one serious complication (an arrhythmia (not specified) after an overdose of 600 mg). The maximum dose ingested in this series was 2250 mg. Over half the patients remained asymptomatic.(16) Berling et al reviewed 89 single agent mirtazapine ingestions and showed the lowest GCS was 10, all within 6 hours with no complications or ICU admission (2). There were no cases of seizures, serotonin toxicity, delirium or QT prolongation.

Mianserin

Data on mianserin are even more limited but qualitatively similar. A few patients with serious arrhythmias (heart block and ventricular fibrillation) have been reported but other toxic effects are usually minor.(17–19).

Maprotiline

Maprotiline appears to be more like a tricyclic antidepressant in overdose with a high hazard index for death(20). It can cause seizures in overdose (17.5%, 95% CI: 9.8–29.4%)(21), QT interval prolongation, torsades des pointes and sudden cardiac death(22).The cardiac effects appear to be mediated by inhibition of G protein-activated inwardly rectifying K+ channels(23).

INVESTIGATIONS

ECG

An ECG is the only investigation required in clinically uncomplicated patients.

DIFFERENTIAL DIAGNOSIS

The spectrum of toxicity is non-specific but most closely resembles that of antipsychotic drugs (tricyclic antidepressants for maprotiline) with sedation, hypotension, minor anticholinergic signs and minor ECG changes (coma, seizures and cardiac arrhythmias for maprotiline).

TREATMENT

The spectrum of toxicity is non-specific but most closely resembles that of antipsychotic drugs (tricyclic antidepressants for maprotiline) with sedation, hypotension, minor anticholinergic signs and minor ECG changes (coma, seizures and cardiac arrhythmias for maprotiline).

GI Decontamination

Patients who present within one hour of a very large ingestion (> 1000 mg) or who have co-ingested other drugs should be consider for activated charcoal. Patients should be observed for several hours.

Elimination enhancement

There is no evidence of enhanced elimination with forced diuresis, urinary pH manipulation, haemodialysis or haemoperfusion.

LATE COMPLICATIONS

Discharge after clinical toxicity has resolved. There are no specific long term sequelae.

REFERENCES

1. de Boer T. The pharmacologic profile of mirtazapine. J.Clin.Psychiatry 1996;57 Suppl 4:19–25.
2.Berling I, Isbister GK. Mirtazapine overdose is unlikely to cause major toxicity. Clin Toxicol (Phila). 2014 Jan;52(1):20–4. doi.
3. Fawcett J, Barkin RL. Review of the results from clinical studies on the efficacy, safety and tolerability of mirtazapine for the treatment of patients with major depression. J Affect.Disord. 1998;51(3):267–85.
4. Timmer CJ, Sitsen JM, Delbressine LP. Clinical pharmacokinetics of mirtazapine. Clin Pharmacokinet. 2000;38(6):461–74.
5. Waring WS, Good AM, Bateman DN. Lack of significant toxicity after mirtazapine overdose: a five-year review of cases admitted to a regional toxicology unit. Clin Toxicol (Phila). 2007;45(1):45–50.
6. Bremner JD, Wingard P, Walshe TA. Safety of mirtazapine in overdose. J Clin Psychiatry 1998;59(5):233–5.
7. Inman WH. Blood disorders and suicide in patients taking mianserin or amitriptyline. Lancet 1988;2(8602):90–2.
8. Buckley N, McManus P. Fatal toxicity of serotonergic antidepressants. BMJ 2002 Dec 7;325(7376):1332–3.
9. Velazquez C, Carlson A, Stokes KA, Leikin JB. Relative safety of mirtazapine overdose. Vet Hum Toxicol 2001;43(6):342–4
10. Gerritsen AW. Safety in overdose of mirtazapine: a case report. J Clin Psychiatry 1997;58(6):271.
11. Hoes MJ, Zeijpveld JH. First report of mirtazapine overdose. Int.Clin Psychopharmacol. 1996;11(2):147.
12. Holzbach R, Jahn H, Pajonk FG, Mahne C. Suicide attempts with mirtazapine overdose without complications. Biol.Psychiatry 1998;44(9):925–6.
13. Montgomery SA. Safety of mirtazapine: a review. Int.Clin Psychopharmacol. 1995;10 Suppl 4:37–45.
14. Raja M, Azzoni A. Mirtazapine overdose with benign outcome. Eur.Psychiatry 2002;17(2):107.
15. Retz W, Maier S, Maris F, Rosler M. Non-fatal mirtazapine overdose. International Clinical Psychopharmacology 1998;13(6):277–9.
16.Schaper A, Farber E, Ebbecke M, Desel H. Suicide with mirtazapine – hardly possible. J.Toxicol.Clin.Toxicol. 2002;40(3):343–4.
17. Hla KK, Boyd O. Mianserin and complete heart block. Hum Toxicol 1987;6(5):401–2.
18. Haefeli WE, Schoenenberger RA, Scholer A. Recurrent ventricular fibrillation in mianserin intoxication. Br.Med.J. 1991;302(6773):415–6.
19. Newman B, Crome P. The clinical toxicology of mianserin hydrochloride. Vet Hum Toxicol 1979;21 Suppl:60–2
20. White N, Litovitz T, Clancy C. Suicidal antidepressant overdoses: a comparative analysis by antidepressant type. J Med Toxicol. 2008Dec;4(4):238–50.
21. Reichert C, Reichert P, Monnet-Tschudi F, Kupferschmidt H, Ceschi A, Rauber-Lüthy C. Seizures after single-agent overdose with pharmaceutical drugs: analysis of cases reported to a poison center. Clin Toxicol (Phila). 2014 Jul;52(6):629–34.
22. Vieweg WV, Wood MA. Tricyclic antidepressants, QT interval prolongation, and torsade de pointes. Psychosomatics. 2004 Sep-Oct;45(5):371–7.
23. Kobayashi T, Washiyama K, Ikeda K. Inhibition of G protein-activated inwardly rectifying K+ channels by various antidepressant drugs. Neuropsychopharmacology.2004 Oct;29(10):1841–51.

8-Dec-2014

wikitox/2.1.11.9.2.4.2_mirtazapine.txt · Last modified: 2018/09/01 09:00 (external edit)