Author: Daniele Di Corcia Date: 15/06/2011
Patient:
■ 64 year old ■ Female ■ Weight 85 kg ■ Height 167 cm
History:
■ Psychiatric treatment ■ Chronic depression
Adverse Event Resulted In: ■ Death
Depression is a common psychiatric disease, affecting about 20% of people during their lifetime. Severe depression is also a major risk factor for suicide, and up to 15% of the patients hospitalized for depression eventually commit suicide(1). In order to treat these common mental illness, several antidepressants drugs are daily prescribed by physicians. The use of antidepressants has substantially increased worldwide during the past two decades and several new antidepressant drugs have been introduced, gradually replacing tricyclic antidepressants (TCAs), such as amitriptyline,clomipramine, doxepine and imipramine, which have been available since the 1960s. The new generation of antidepressants is designed on the basis of molecule targeting, with focus on serotonine level control. Drugs such as citalopram, fluoxetine, paroxetine and sertraline, acting as selective serotonin reuptake inhibitors, have become increasingly popular for the treatment of depression (2). Other antidepressant drugs include the monoamino-oxidase inhibitor moclobemide, and other mixed-uptake inhibitors (mirtazapine, nefazodone and venlafaxine). Ingestion of TCAs is still an important cause of suicidal death, as serious poisoning from TCAs lead to cardiac disturbances, respiratory depression, metabolic acidosis, convulsion and coma. Even if SSRIs are considered to be less toxic than the TCAs (3), numerous case reports have shown that the newer antidepressants may also cause severe intoxication (4). Among the antidepressants, Mirtazapine is a tetracyclic piperazinoazepine compound, structurally related to mianserin, which has been used since 1994 as an antidepressant. Mirtazapine is a strong α2 antagonist, enhancing noradrenergic and serotonergic neurotransmission, without inhibiting the serotonin re-uptake (Figure 1). Daily doses for adults are normally in the range of 15-45 mg. The oral bioavailability is approximately 50% (5). Adverse effects associated with mirtazapine therapy include somnolence, dizziness, agitation, hypertension and loss of appetite. Overdosage may cause disorientation, drowsiness and tachycardia (Mirtazapine Side Effects)
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Figure 1
A 64-year-old woman (weight 85 kg, height 167 cm) with a previous history of chronic depression was found dead on the kitchen floor of her apartment. She had attempted to commit suicide in the year 2000. Since then, she was under psychiatric treatment. On the table next to her, many packaging of pharmaceutical drugs, suggesting the occurrence of drug-related suicidal death. Specifically, the police seized: 4 boxes of Mirtazapina EG® 30 mg (mirtazapine) containing seven empty blister packs, originally corresponding to 105 tablets. It was not known whether the woman had started consuming this pack in a previous time, so it was not possible to estimate the amount of drug possibly ingested by the victim the day of her death. No letters nor explanation of her act were found in the apartment. The death was reported to the Public Prosecutor’s office which took jurisdiction of the case. At the autopsy, the decedent did not show any specific pathology and appeared well-nourished. Internal examination presented no evidence of any trauma to account for her death. Therefore, our laboratory received the responsibility to determine whether massive drug assumption could be taken into account as the cause of the death. The specimen sampled during the autopsy included heart blood, urine and gastric content.
The presence of mirtazapine was confirmed by LC-MS/MS in all specimens. The heart blood concentration of mirtazapine was 20.3 mg/L. In order to interpret this finding, some considerations are needed. In eight postmortem cases in which mirtazapine was identified but did not contribute significantly to the cause of death, the mirtazapine concentration in heart blood was found to be approximately equal to the one present in peripheral blood, indicating that postmortem redistribution was not a factor to be taken into account in evaluating the postmortem blood concentrations (6). Moreover, several mirtazapine metabolites are known to have some pharmacological activity but they are not believed to significantly contribute to the overall effects of the drug, due to their low plasma concentrations (7). Thus, the pharmacological level of mirtazapine is generally expressed by its parent drug concentration. The serum therapeutic concentration of mirtazapine ranges from 0.02 to 0.1 mg/L (8), but no published data are available about its toxic concentration. In a single fatal case in which mirtazapine was the only ingested drug, the postmortem blood concentration was found at 2.7 mg/L (9). In the case reported here, the mirtazapine blood concentration is much higher than the expected therapeutic level, so there are good reasons to presume that a toxic level may have been reached.
The fatal case reported in the present study, involving the intake of mirtazapine, suggests that the synergic pharmacological effects of this drug is likely to account for the decease. The agreement between the authoptic examination executed by forensic pathologists and the toxicological findings presented here are consistent with the suicidal hypothesis beyond any reasonable doubt.
References:
1. D.N. Juurlink, M.M. Mamdani, A.Kopp and D.A. Redelmeier, The risk of suicide with selective serotonin reuptake inhibitors in the elderly, Am. J. Psychiatry, 163:813-821 (2006) 2. E. Kringlen, S. Torgersen, V. Cramer, A Norwegian psychiatric epidemiological study, Am J Psychiatry, 158:1091–1098 (2001) 3. D.J. Pounder and G.R. Jones. Postmortem drug redistribution—a toxicological nightmare. Forensic Sci. Int. 45: 253–263 (1990) 4. M. Reis, T. Aamo, J. Ahlner and H. Druid, Reference concentrations of antidepressants. A compilation of postmortem and therapeutic levels, J. Anal. Toxicol., 31:254-264 (2007) 5. R.C. Baselt, Disposition of Toxic Drugs and Chemicals in Man, 7th ed., Biomedical Publications, Foster City, CA (2004) 6. K.A. Moore, B. Levine, M.L. Smith, S. Saki, J. Schames, J.E. Smialek, Tissue distribution of mirtazapine (Remeron) in postmortem cases, J. Anal. Toxicol, 23(6):541-543 (1999) 7. Physicians’ desk reference, Medical Economics Company, Montvale, NJ (1997) 8. E.G.C. Clarke, Clarke’s Isolation and Identification of Drugs in Pharmaceutical, Body Fluids and Post-mortem Materials, 3rd ed., The pharmaceutical Press, London, 2005 9. M.D. Robertson, P.S. Ng and S.B. Gore, Death due to mirtazapine (Remeron) toxicity. Presented at the annual meeting of the Society of Forensic Toxicologists, Puerto Rico, October 12, 1999
