Duloxetine is a dual reuptake inhibitor of synaptic serotonin and norepinephrine. In contrast to other dual reuptake inhibitor antidepressants, duloxetine appears to exert clinically demonstrable effects on both noradrenergic and serotonergic neurotransmission at starting doses.[2] It is described as an SNRI (selective serotonin norepinephrine reuptake inhibitors). The efficacy of duloxetine for depression has been established in controlled trials using 40-120 mg/day. The most frequently observed adverse events with duloxetine are nausea, dry mouth and somnolence.[3] Other side-effects attributed to the drug are constipation, diarrhea, decreased appetite, weight loss and feeling of fatigue, dizziness, hypohidrosis, decreased libido and erectile dysfunction.
The authors have not come across any reported case of bleeding associated with duloxetine. This side-effect has been reported with drugs having serotonin reuptake inhibition as their main action. The SSRI medications are well known to cause prolonged bleeding after surgery, gastrointestinal and vaginal bleeding. The incidence with each of the antidepressants is not currently available, but it has been reported with fluoxetine, escitalopram, sertraline, paroxetine, venlafaxine and bupropion. The odds ratio of 3 has been suggested for SSRI with higher serotonin reuptake inhibition, while intermediate ones have an odds ratio of 1.7 to cause bleeding. Weinrieb et al . in a metanalysis with literature search on MEDLINE from 1966 to 1st September 2004 reviewed seven retrospective analytical studies and 24 case reports of bleeding in 43 different people. Analytical studies supported an association between SSRI consumption and upper gastrointestinal bleeding and perioperative bleeding, although there is little evidence linking SSRI use with intracerebral hemorrhage.[4]
SSRI have been shown to inhibit nitric oxide synthase, which leads to decreased production of nitric oxide from the nitric oxide donor, L-arginine. Nitric oxide is essential to activate guanylate cyclase for stimulating the formation of cyclic guanosine monophosphate (cGMP), which acts to relax smooth muscle and regulate platelet aggregation. This reduced cGMP may be responsible for SSRI-induced bleeding. The exact pathophysiology of duloxetine-induced bleeding is not known but may be associated with the same mechanism.[5] The impairment of the platelet aggregation could be a possible mechanism of occurrence of the event. It may also be advisable to provide ulcer protective agents to old patients and patients who are taking anti-inflammatory agents when SSRI are prescribed to them. Physicians should be aware of this side-effect when prescribing duloxetine to their patients and more cautious postmarketing surveillance is needed to ascertain any new side-effect.
However, the observed side-effects in this particular case might be worth considering as in this case the parameters of platelet count, bleeding time, clotting time, APTT and PTT were within the normal range. Moreover, the absence of the effect with fluoxetine and escitalopram in the past might point to a novel mechanism of the side-effect.
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