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Review Article Bleeding in a Depressed dementia Patient Re- lated with Mirtazapine replacing Duloxetine Geidong Kong Shenzhen Mental Health Centre, Shenzhen, China *Corresponding Author : Geidong Kong, Shenzhen Mental Health Centre, No. 1080, Cuizhu Road, Luohu District, Shenzhen, Shenzhen, China. Received : November 06, 2023 Accepted: November 07, 2023 Published : December 05, 2023 Antidepressants are widely used to treat depression in demen- tia since it is a prevalent and significant comorbidity [1]. There is no evidence to support the theory that mirtazapine, rather than duloxetine, may be a more effective treatment for depressive patients with dementia in some older people. All age groups may tolerate mirtazapine [2], and an overdose on its own is gen- erally safe and does not cause delirium in any of the patients. To date, there have been five cases documented of miratap- ine-induced delirium; one case involved a depressed patient with early Lewy body type senile dementia, and two significant cases involved depressed individuals with slight memory im- pairment or a small lacuna of the left basal ganglia, the latter two [3-6] experiencing hyponatremia. In the absence of hypo- natremia, we described a case of delirium in a depressed pa- tient with Alzheimer’s dementia that was linked to mirtazapine replacing duloxetine. Due to a case that has been documented, an 86-year-old woman with Alzheimer’s disease experienced delirium following her administration of duloxetine. A 69-year-old woman named Ms. Z was admitted to our depart- ment due to depression. She went to a mental health clinic be- cause of low mood, waist pain, and backache. Major depressive illness was the diagnosis made. For eight months, she had been treated with 60 mg of duloxetine each day (up to 90 mg). Three months ago, she ceased medication due to improvement in her symptoms, although she still had lethargy and palpitations. For two months, she had been experiencing palpitations, sleepless- ness, abrupt weight loss, decreased appetite, dejection, retar- dation, bad memory, guilt, and feelings of worthlessness. She had also occasionally entertained thoughts of suicide. The re- sults of the brain CT scan after admission were consistent with cerebrovascular illness and indicated “right basal ganglia isch- emic focus or lacunar infarction” (these findings are not regard- ed abnormal in a lady of this age). Major depressive disorder was identified as the diagnosis. Duloxetine 60 mg per day was administered to the patient for 12 days, and then 90 mg per day. There were no improvements seen; instead, the patient’s anxiousness was getting worse and she had trouble falling asleep. Day 14 saw the beginning of 30 mg of mirtazapine daily and a reduction of 30 mg of duloxetine. The drug duloxetine was stopped on day 15. On the other hand, extreme anxiety was noted. Even after mirtazapine was increased to 45 mg dai- ly on day 18, the patient continued to experience palpitations, sleeplessness, and chest discomfort despite having normal blood pressure and heart rate. Thus, lorazepam 2 mg or alpra- zolam 0.8 mg per day were paired with mirtazapine, respec- tively, while clonazepam 1 mg was administered intravenously. The patient’s mental state significantly changed on day 22, and she appeared to be experiencing a disruption in consciousness. Mirtazapine was stopped for the patient after severe dizziness and visual hallucinations were noticeable at night. The patient was diagnosed with drug-induced delirium. A brain MRI scan on day 28 revealed “dual basal ganglia ischemic focus or lacunar in- farction,” which is broadly in line with the admission diagnosis. Olanzapine 2.5 mg was administered at night to treat the pa- tient’s delirium since they were unable to sleep and were wan- dering the ward [8]. By day 34, her delirium had disappeared, but her dementia was still evident in her impaired memory and visuospatial skills. According to her daughter, the patient actu- ally experienced memory problems a year ago. The diagnosis of dementia, namely Alzheimer’s disease, was changed after the subject’s minimal state examination resulted in an 18/30 score and the inability to draw clock face components. The patient’s anxiousness was treated with venlafaxin 75 mg daily after she complained of palpitations. The patient returned home on day 42, feeling less anxious. The subject provided written informed consent. www.directivepublications.org Page - 1 The Journal of Clinical Pathology
Review Article The topic states that depending on when delirium first appears and when medications are taken, drugs like duloxetine and mir- tazapine, which are processed by the cytochrome P450 (CYP) enzyme system in the liver, may directly cause delirium [9]. The main isoforms involved in metabolising mirtazapine, a weak in- hibitor of CYP isozymes, in vitro have been shown to be CYP2D6 and, to a lesser extent, CYP1A2. This drug has little inhibitory ef- fects on the different CYP isoforms and seems to have a low risk of drug pharmacokinetic interactions [10]. It has been demon- strated that taking fluvoxamine 50 mg daily, a strong inhibitor of several CYP isoforms, and mirtazapine 30 mg daily togeth- er caused increases in plasma levels that were three and four times greater.Therefore, the metabolism of mirtazapine may be mediated via the inhibitory impact on CYP2D6. Duloxetine has a clinically negligible inhibition on CYP1A2, which is the primary enzyme involved in its extensive hepatic metabolism. Further- more, duloxetine is a mild CYP2D6 inhibitor. Numerous drug interaction studies have assessed the possibility of duloxetine to alter other medications. For instance, duloxetine 60 mg twice daily for three weeks enhanced the Cmax and AUC of desip- ramine [12,13]. This example suggests that delirium happens when the daily dose of mirtazapine (45 mg) is administered and the daily dose of duloxetine (30 mg) is reduced. It follows that the use of the serotonin and norepinephrine reuptake inhibitor duloxetine and the noradrenergic and selective serotonergic antidepressant mirtazapine causes elevated blood concentra- tions of mirtazapine, improving the reuptake of norepinephrine and serotonin [9]. The pathophysiology of delirium has been linked to a central increase in serotonin and norepinephrine [14], however the precise mechanism causing delirium has not been fully elucidated. It’s still possible that the patient’s height- ened sensitivity to serotonin and norepinephrine’s actions in their brain contributed to the delirium that developed. Considering the prevalence and favourable tolerability of mir- tazapine in older and co-occurring depression patients [2,15], one should be mindful of the possibility of infrequent but severe delirious episodes. It is advised to start treatment with a com- paratively low dosage. Furthermore, in patients whose physical conditions make them more susceptible to this adverse effect, the replacement of a robust CYP2D6 inhibitor, such as dulox- etine, with mirtazapine should be done gradually to prevent medication interactions. References 1. Steffens DC, Fisher GG, Langa KM Potter GG, Plassman BL (2009) Prevalence of depression among older Americans: the Aging, Demographics and Memory Study. Int Psycho- geriatr 21: 879-888. 2. Tsutsumi T, Sugawara H, Ito R, Asano M, Shimizu S, et al. (2016) Identifying predictive clinical characteristics of the treatment efficacy of mirtazapine monotherapy for major depressive disorder. Neuropsychiatr Dis Treat 12: 2533- 2538. 3. Berling I, Isbister GK (2014) Mirtazapine overdose is un- likely to cause major toxicity. Clinical Toxicol 52: 20-24. 4. Ladino M, Guardiola VD, Paniagua M (2006) Mirtazapine- induced hyponatremia in an elderly hospice patient. J Pal- liat Med 9: 258-260. 5. Bailer U, Fischer P, Küfferle B, Stastny J, Kasper S (2000) Occurrence of mirtazapine-induced delirium in organic brain disorder. Int Clin Psychopharmacol 15: 239-244. 6. Ghosh A, Hegde A, Grover S (2014) Mirtazapine-associat- ed hyponatremia presenting as delirium[J]. Indian J Phar- macol 46: 448. 7. Suzuki Y, Saito M, Someya T (2012) Delirium associated with duloxetine in a depressed patient with Alzheimer’s dementia. Psychiatry Clin Neurosci 66: 166-166. 8. Neufeld KJ, Yue J, Robinson TN, Inouye SK, Needham DM (2016) Antipsychotic Medication for Prevention and Treat- ment of Delirium in Hospitalized Adults: A Systematic Re- view and Meta- Analysis. J Am Geriatr Soc 64: 705-714. 9. Spina E, Trifirò G, Caraci F (2012) Clinically significant drug interactions with newer antidepressants. CNS drugs 26: 39-67. 10. Störmer E, von Moltke LL, Shader RI, et al. (2000) Metabo- lism of the antidepressant mirtazapine in vitro: contribu- tion of cytochromes P-450 1A2, 2D6, and 3A4. Drug Metab Dispos 28: 1168-1175. www.directivepublications.org Page - 2 The Journal of Clinical Pathology
Review Article 11. Anttila AK, Rasanen L, Leinonen EV (2001) Fluvoxamine augmentation increases serum mirtazapine concentra- tions three-to fourfold. Ann Pharmacother 35: 1221-1223. 12. Skinner MH, Kuan HY, Pan A, Sathirakul K, Knadler MP, et al. (2003) Duloxetine is both an inhibitor and a substrate of cytochrome P4502D6 in healthy volunteers. Clin Phar- macol Ther 73: 170-177. 13. Lobo ED, Bergstrom RF, Reddy S, Quinlan T, Chappell J, et al. (2008) In vitro and in vivo evaluations of cytochrome P450 1A2 interactions with duloxetine. Clinical pharmaco- kinet 47: 191-202. 14. White S (2002) The neuropathogenesis of delirium. Re- views Clin Gerontol 12: 62-67. 15. Schatzberg AF, Kremer C, Rodrigues HE, Murphy GM Jr, Mirtazapine vs. Paroxetine Study Group (2002) Dou- ble-blind, randomized comparison of mirtazapine and paroxetine in elderly depressed patients. Am J Geriatr Psychiatry 10: 541-550. www.directivepublications.org Page - 3 The Journal of Clinical Pathology
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