Letters to the Editor
Hemorrhages During Escitalopram–Venlafaxine–
Mirtazapine Combination
Treatment of Depression
Dear Editor:
Selective serotonin reuptake inhibitors (SSRIs) may cause bleeding (1–3), probably by increasing platelet release of serotonin, which increases platelet aggregation. I report on a patient who experienced bleeding during treatment for depression when escitalopram, venlafaxine, and mirtazapine were combined but not when the same drugs were used alone.
Case Report
A man, aged 60 years, with major depressive disorder had been treated for 12 months with many antidepressants, both alone and in combination, with mild improvement. All SSRIs had been used alone at maximum dosage. The maximum dosages of venlafaxine alone and mirtazapine alone (which increase serotonin and norepinephrine) had also been used. The patient improved with escitalopram 20 mg daily. Two months later, because his depressive symptoms persisted, venlafaxine and mirtazapine were added to escitalopram. His mirtazapine dosage was 15 mg daily, and his venlafaxine dosage was 150 mg daily. One week later, the patient noted mild hemorrhages from his nose and rectum. These progressively worsened during the following 3 weeks, but not to the point of requiring emergency treatment. The patient then spontaneously gradually reduced the dosages of mirtazapine, venlafaxine, and escitalopram. Mirtazapine was reduced to 7.5 mg daily, venlafaxine to 100 mg daily, and escitalopram to 15 mg daily. In 1 week, the bleeding decreased. He continued weekly tapering the medications to escitalopram 5 mg daily, venlafaxine 37.5 mg daily, and mirtazapine 7.5 mg daily after 3 weeks. During tapering, the amount of nose and rectal blood loss progressively decreased; it stopped when the final dosages were reached. As well, the patient’s depression remitted. He experienced no serotonin syndrome.
This patient has also been taking omeprazole 20 mg daily for stomach ulcers he developed years ago, as well as, for some years, the antihypertensive irbesartan (an angiotensin II receptor inhibitor) 300 mg daily.
The onset of hemorrhages when mirtazapine and venlafaxine were added to escitalopram and the dosage–response relation between bleeding and dosages of these drugs suggest a causal link: Because previous treatments with escitalopram, venlafaxine, and mirtazapine, used alone, did not cause hemorrhages, it appears that this drug combination may have caused them. Escitalopram and venlafaxine (by blocking serotonin reuptake) and mirtazapine (by increasing serotonin release) may have increased serotonin to levels not reached with previous treatments, leading to hemorrhage by platelet aggregation. Its unlikely that the patient had a bleeding stomach ulcer, because fresh blood was seen from his nose and rectum; it is also unlikely that omeprazole increased blood levels of these drugs by blocking CYP2C19. Further, irbesartan does not inhibit P450 cytochromes. Escitalopram and mirtazapine have several metabolic pathways, and venlafaxine is metabolized by CYP2D6 (4). Therefore, pharmacokinetic interactions are unlikely to have caused the hemorrhages. Pharmacodynamic interactions leading to high levels of serotonin are a more likely cause. Escitalopram is a potent inhibitor of serotonin reuptake; venlafaxine less potently inhibits serotonin reuptake; and mirtazapine increases serotonin by blocking alpha-2 adrenergic heteroreceptors (5).
For treatment-resistant depression, clinicians should take care when combining several antidepressants that increase serotonin, bearing in mind that this combination may result in hemorrhages.
References
1. de Abajo FJ, Rodriguez LA, Montero D. Association between selective serotonin reuptake inhibitors and upper gastrointestinal bleeding: population based case-control study. BMJ 1999;319:1106–9.
2. Layton D, Clark DW, Pearce GL, Shakir SA. Is there an association between selective serotonin reuptake inhibitors and risk of abnormal bleeding? Results from a cohort study based on prescription event monitoring in England. Eur J Clin Pharmacol 2001;57:167–76.
3. Dalton SO, Johansen C, Mellemkjaer L, Norgard B, Sorensen HT, Olsen JH. Use of selective serotonin reuptake inhibitors and risk of upper gastrointestinal tract bleeding: a population-based cohort study. Arch Intern Med 2003;163:59–64.
4. Cozza KL, Armstrong SC, Oesterheld JR. Drug interaction principles for medical practice. Washington (DC): American Psychiatric Association; 2003.
5. Baldessarini RJ. Drugs and the treatment of psychiatric disorders. Depression and anxiety. In: Hardman JG, Limbird LE, Goodman Gilman A, editors. Goodman & Gilman’s the pharmacological basis of therapeutics. 10th ed. New York: McGraw-Hill; 2001. p 447–83.
Franco Benazzi, MD
Forlí, Italy
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