What are the considerations for using mirtazapine in patients with microvascular dysfunction and medication-induced thrombocytopenia?

From the Guidelines

Mirtazapine should be used with extreme caution in patients with microvascular dysfunction and medication-induced thrombocytopenia, considering alternative treatments due to its potential to exacerbate thrombocytopenia and affect microvascular function. When considering the use of mirtazapine in these patients, it's crucial to weigh the risks and benefits, particularly given the potential for drug interactions and the impact on platelet counts. For instance, patients with severe renal impairment or those taking strong CYP3A4 and P-gp inhibitors require careful consideration due to potential interactions with other medications, as noted in the context of direct oral anticoagulants 1.

Key Considerations

• Microvascular Dysfunction: Mirtazapine's alpha-1 adrenergic antagonism can cause vasodilation, potentially affecting microvascular function. Thus, if used, it should be started at lower doses (7.5-15mg nightly) with gradual titration and close monitoring of cardiovascular parameters.
• Medication-Induced Thrombocytopenia: Given mirtazapine's association with blood dyscrasias, including thrombocytopenia, it should generally be avoided in these cases. If deemed necessary, regular complete blood count (CBC) monitoring is crucial, especially during the initial months of treatment.
• Monitoring: Baseline platelet counts should be obtained before starting mirtazapine, with follow-up counts at weeks 2,4,8, and then quarterly. Any significant drop in platelet count should prompt immediate reevaluation of the medication.
• Alternative Treatments: SSRIs (except paroxetine) or SNRIs may offer safer alternatives for patients with microvascular dysfunction and medication-induced thrombocytopenia, considering their side effect profiles and potential for interactions.

Clinical Decision Making

In clinical practice, the decision to use mirtazapine in patients with these conditions should be made on a case-by-case basis, prioritizing the patient's safety and the potential benefits of the medication against the risks. The mechanism of mirtazapine's impact on platelets, involving serotonergic effects and alpha-adrenergic activity, underscores the need for cautious use and monitoring. As evidenced by considerations for direct oral anticoagulants in patients with cancer and thrombocytopenia 1, careful management and monitoring are key to minimizing risks and optimizing outcomes.

From the FDA Drug Label

Agranulocytosis In premarketing clinical trials, 2 (1 with Sjögren’s Syndrome) out of 2796 patients treated with mirtazapine tablets developed agranulocytosis [absolute neutrophil count (ANC) < 500/mm3 with associated signs and symptoms, e.g., fever, infection, etc.] and a third patient developed severe neutropenia (ANC < 500/mm3 without any associated symptoms). If a patient develops a sore throat, fever, stomatitis, or other signs of infection, along with a low WBC count, treatment with mirtazapine should be discontinued and the patient should be closely monitored

The main considerations for using mirtazapine in patients with microvascular dysfunction and medication-induced thrombocytopenia are:

• Monitoring for signs of agranulocytosis or severe neutropenia, such as fever, infection, or low WBC count
• Discontinuing treatment with mirtazapine if any of these signs occur and closely monitoring the patient
• Being aware of the potential increased risk for serotonin syndrome when using mirtazapine with other serotonergic drugs 2 Key points to consider:
• Mirtazapine may increase the risk of agranulocytosis or severe neutropenia
• Patients with microvascular dysfunction and medication-induced thrombocytopenia may be at higher risk for these adverse events
• Close monitoring and prompt discontinuation of mirtazapine are essential if any signs of agranulocytosis or severe neutropenia occur 2

From the Research

Considerations for Using Mirtazapine in Patients with Microvascular Dysfunction and Medication-Induced Thrombocytopenia

• Mirtazapine is a noradrenergic and specific serotonergic antidepressant (NaSSA) that can be effective in treating major depression, but its use in patients with microvascular dysfunction and medication-induced thrombocytopenia requires careful consideration 3.
• The drug has been associated with immune thrombocytopenia, a condition characterized by low platelet count due to immune-mediated destruction of platelets 4.
• The glycoprotein IIb/IIIa complex is the target in mirtazapine-induced immune thrombocytopenia, and the diagnosis can be made using platelet serology tests, such as the monoclonal antibody immobilization of platelet antigens assay (MAIPA assay) 4.
• Drug-induced immune thrombocytopenia can be treated by withholding the causative drug and, in severe cases associated with bleeding, by platelet transfusion 5.
• The mechanism behind drug-induced thrombocytopenia is either a decrease in platelet production (bone marrow toxicity) or an increased destruction (immune-mediated thrombocytopenia), and pseudothrombocytopenia, an in vitro effect, has to be distinguished from true drug-induced thrombocytopenia 5.
• Mirtazapine has a novel mechanism of action, increasing noradrenergic and serotonergic neurotransmission via blockade of central α2-adrenergic auto- and heteroreceptors, and has been shown to be effective in treating major depression, with a rapid onset of action and a high sustained remission rate 6.
• However, the use of mirtazapine in patients with microvascular dysfunction and medication-induced thrombocytopenia requires careful monitoring of platelet count and careful evaluation of the causal relationship between the drug and the thrombocytopenia 4, 5.

Key Points to Consider

• Mirtazapine can cause immune thrombocytopenia, and patients with a history of thrombocytopenia or microvascular dysfunction should be carefully monitored 4, 5.
• The diagnosis of drug-induced immune thrombocytopenia requires a careful evaluation of the causal relationship between the drug and the thrombocytopenia, and the use of platelet serology tests 4, 5.
• Mirtazapine has a novel mechanism of action and can be effective in treating major depression, but its use in patients with microvascular dysfunction and medication-induced thrombocytopenia requires careful consideration of the potential risks and benefits 6, 3.