Discontinue Mirtazapine Immediately
Given the persistent and worsening neutropenia despite stopping antipsychotics, mirtazapine should be discontinued immediately as it carries a documented risk of agranulocytosis and severe neutropenia, while sertraline can be continued with close monitoring.
Rationale for Stopping Mirtazapine
Hematologic Risk Profile
Mirtazapine carries a specific FDA black box warning for agranulocytosis, with 2 out of 2,796 patients in premarketing trials developing agranulocytosis (absolute neutrophil count <500/mm³) and a third developing severe neutropenia (ANC <500/mm³), with onset detected as early as day 9 of treatment 1.
The FDA label explicitly states that if a patient develops signs of infection along with a low white blood cell count, mirtazapine should be discontinued and the patient closely monitored 1.
Agranulocytosis associated with mirtazapine occurs in approximately 1 in 1,000 patients and, while usually reversible when the medication is stopped, represents a serious and potentially life-threatening adverse effect 2.
Fatal agranulocytosis has been documented with mirtazapine use in combination with other psychotropics, including a case report of a patient on lamotrigine, mirtazapine, quetiapine, and venlafaxine who developed severe neutropenia (ANC 18 cells/mm³) and died from septic shock despite treatment 3.
Sertraline's Lower Hematologic Risk
Sertraline's FDA label lists agranulocytosis, aplastic anemia, pancytopenia, leukopenia, and thrombocytopenia only as rare postmarketing reports without specific incidence data or black box warnings 4.
The hematologic adverse effects with sertraline appear to be significantly less common and less well-documented compared to mirtazapine's established risk profile 4.
Clinical Timeline Analysis
Pattern Suggests Drug-Induced Neutropenia
Your patient's granulocyte count started at 1.68, briefly improved to 2.4, then progressively declined to 1.3,1.5,1.2, and finally 1.1 despite stopping both Risperdal and Abilify.
The continued decline after stopping antipsychotics strongly suggests that one of the remaining medications (Zoloft or mirtazapine) is the culprit, as antipsychotic-induced neutropenia typically improves within days to weeks of discontinuation.
The temporal pattern does not clearly implicate sertraline, which has been on board throughout without initial neutropenia, whereas mirtazapine's known early-onset risk (as early as day 9) fits the clinical picture 1.
Immediate Management Steps
Discontinuation Protocol
Stop mirtazapine immediately given its documented agranulocytosis risk and the patient's declining granulocyte count 1.
Continue sertraline while monitoring closely, as it has lower documented hematologic risk and abrupt discontinuation could destabilize psychiatric symptoms 4.
Monitor for signs of infection (fever, sore throat, stomatitis) which would indicate urgent need for complete blood count and potential hospitalization 1.
Monitoring Requirements
Obtain complete blood count with differential within 24-48 hours of stopping mirtazapine to establish baseline post-discontinuation.
Repeat CBC weekly for the first month, then biweekly for the second month to ensure recovery of granulocyte counts.
If counts continue to decline after stopping mirtazapine, then discontinue sertraline as well and consider that both medications may be contributing.
Psychiatric Management Considerations
Alternative Antidepressant Selection
Once hematologic parameters normalize, consider switching to an antidepressant with minimal hematologic risk if continued antidepressant therapy is needed.
Avoid clozapine permanently in this patient, as it requires baseline WBC count of at least 3,500/mm³ and carries the highest risk of agranulocytosis among psychiatric medications 5.
Medical Consultation Priority
The medical consultation you're obtaining is appropriate and urgent given the progressive neutropenia.
Hematology consultation may be warranted to rule out primary bone marrow disorders and to guide management if counts do not recover after medication discontinuation 5.
Critical Pitfalls to Avoid
Do not wait for counts to drop further before acting—the current granulocyte count of 1.1 (assuming this represents absolute granulocyte count in thousands/mm³ = 1,100/mm³) is already concerning and approaching levels where infection risk increases substantially.
Do not discontinue both medications simultaneously without a plan for psychiatric symptom management, as this could precipitate psychiatric decompensation.
Do not restart mirtazapine in this patient even if counts normalize, as rechallenge carries high risk of recurrent and potentially more severe agranulocytosis 1, 6.