Mirtazapine
induced neutropenia: A case report and systematic review
Kharel H1; Anjum Z1;
Kharel Z2; Avalos Sugastti EF1; Verghese BG1;
Kouides PA2
1. Department
of Internal Medicine, Rochester General Hospital, New York, USA.
2. Department of Hematology Oncology, Mary M.
Gooley Hemophilia Center, Rochester General Hospital, 14621, Rochester, NY, USA.
Keywords: mirtazapine, neutropenia, G-CSF.
Mail: himalkharel1995@gmail.com
Resumen
Introducción. Mirtazapina
es un antidepresivo de uso común y que estimula el apetito. A pesar de que en
estudios precomercialización la incidencia de neutropenia inducida por
mirtazapina fue de 1.1/1000, la literatura sobre este tema es escasa.
Presentación de caso. Una
mujer de edad avanzada se presenta inicialmente con neutropenia, sepsis y
lesiones vesiculares en piel que no respetan dermatoma luego de 6 meses de
haber iniciado mirtazapina. Otras causas probables de su neutropenia y lesiones
vesiculares incluyen, entre otros, virus del herpes simplex, virus de varicela
zoster, parvovirus, deficiencia de vitamina B12, lupus sistémico eritematoso,
los cuales son excluidos como causas probables. Luego de varios estudios, incluida
biopsia de piel, se le diagnostica una agranulocitosis inducida por mirtazapina
y foliculitis producida por S. aureus. Los neutrófilos se normalizan una
vez que la paciente interrumpe la mirtazapina y luego de la administración de
factor estimulante de colonias de granulocitos.
Materiales y métodos.
PUBMED, EMBASE, Google Scholar y la base de datos CNKI fueron utilizados
como motores de búsqueda, y la declaración PRISMA fue utilizada para elaborar
el artículo.
Resultados y discusión.
11 estudios y 14 reportes de caso de neutropenia inducida por mirtazapina
fueron encontrados en la literatura. Generalmente, el inicio de la neutropenia
se dio en semanas a meses de haber empezado la mirtazapina. Se han reportado 2
casos en los que, luego de haber iniciado nuevamente la mirtazapina, hubo una
rápida reducción en el número de neutrófilos debido a la memoria inmunológica.
Inhibidores de la recaptación de serotonina e inhibidores de la recaptación de
serotonina/noradrenalina fueron administrados de forma segura en 3 casos. El
tratamiento es conservador e incluye la interrupción del agente causal.
Summary
Introduction. Mirtazapine is a commonly used
antidepressant with appetite stimulating effects. Although premarketing trials
estimate the incidence to be 1.1 per 1000, there is a paucity of literature on
this topic.
Case presentation. Elderly female
presented with neutropenic sepsis and non-dermatomal vesicular rash around 6
weeks after initiation of mirtazapine. Other causes of neutropenia and rash,
including, but not limited to, herpes simplex virus, varicella zoster virus,
parvo virus, vitamin B12 deficiency, systemic lupus erythematosus were ruled
out. After extensive testing, including skin biopsy, she was diagnosed to have
concomitant mirtazapine induced agranulocytosis and staphylococcal
folliculitis. Her neutropenia resolved after discontinuation of mirtazapine and
administration of G-CSF.
Materials and methodology. Literature
search was performed in PUBMED, EMBASE, Google Scholar and CNKI database
and manuscript was developed using PRISMA statement and checklist.
Results and discussion. Literature search
revealed 11 studies with 14 reported cases of mirtazapine induced neutropenia. Onset
of neutropenia on first time exposure was usually within weeks to months. There
were two reports of repeat exposure causing rapid drop in ANC due to immunologic
memory. SSRIs and SNRIs were safely started in three cases. Treatment is mainly
supportive with discontinuation of offending agent.
Introduction
Mirtazapine
is a commonly used tetracyclic antidepressant with sedative, anti-emetic and
appetite stimulant effects(1). It has a relatively good safety
profile with most common adverse effects being drowsiness, hypercholesterolemia
and weight gain(2). Neutropenia is a
rare side effect of mirtazapine. In premarketing clinical trials, the incidence
of mirtazapine induced neutropenia was estimated to be 3.1 cases per 1000 to
2.2 cases per 10000(2). However, there is remarkably little
literature of this condition. We, hereby, present a case report on mirtazapine
induced agranulocytosis and perform a systematic review of this topic.
Case
report
A
86 year-old Caucasian female with past medical history of dementia,
hypothyroidism, paroxysmal atrial fibrillation and chronic kidney disease
presented from a nursing home with high grade fever, lethargy and skin rash for
two days. She was found to be febrile and hypotensive. She was frail and
lethargic. Physical examination revealed irregular rhythm of heart with a
systolic murmur, normal breath sounds, non-tender abdomen and a non-dermatomal
vesicular rash in bilateral buttocks and lower back.
Laboratory
findings revealed white blood cell (WBC) count of 0.3×109/L (normal
range 4 to 11 ×109/L) with absolute neutrophil count (ANC)
of 0×109/L (normal range 1.5 to 8×109/L), hemoglobin
11g/dL (normal range 12 to 16 g/dL), acute kidney injury (AKI) with creatinine
of 1.4 mg/dL with baseline of 0.8 mg/dL, total bilirubin 2.6 (normal range 0.1
to 1.2 mg/dL), alkaline phosphatase of 332 U/L (normal range 44 to 147 U/L),
lactate of 2.9 mmol/L (normal range 0 to 2.0 mmol/dL) with normal platelet
count, normal aspartate transaminase and alanine transaminase. Chest X-ray
demonstrated focal opacity in the right lower lung. She was treated initially
as severe sepsis, likely due to pneumonia, with fluid resuscitation and empiric
antibiotics. She remained hemodynamically stable after that.
Her
blood counts two weeks before were normal and there was no documented episode
of neutropenia in the past. She was not on any chemotherapeutic medications.
She was started on tablet mirtazapine 7.5 mg daily 6 weeks ago for major
depressive disorder, and its dose was increased to 30 mg 4 weeks ago. It was
the only new medication she was on. Other home medications included
acetaminophen, aspirin, calcium carbonate, senna, levothyroxine, ferrous
sulphate, melatonin, multivitamin and polyethylene glycol. The trend of blood
counts is shown in figure 1.
Vitamin
B12 and folate were normal. Infectious disease workup was negative for
Blastomyces antibody, Mycoplasma antibody, Herpes simplex virus 1-2 PCR,
Varicella zoster virus PCR, Ehrlichia chaffeensis antibody, Parvovirus PCR and
Human immunodeficiency virus. Blood culture, fungal dimorphic culture and acid
fast bacilli culture did not reveal any growth. The culture of skin lesions
showed methicillin sensitive Staphylococcus aureus. Skin biopsy revealed
bacteria and necrotic skin lesions but did not show viral cytopathic effect.
Immunohistochemical stain for Herpes simplex virus 1-2 and Varicella zoster virus
was negative. Anti-nuclear antibody and anti-neutrophil cytoplasmic antibody
were negative. Based on these results, it was concluded that the patient had
Staphylococcus aureus folliculitis along with mirtazapine induced agranulocytosis.
As
the ANC was 0×109/L without recovery after 3 days of stopping
mirtazapine, she was started on G-CSF at dose of 300 micrograms per day for 3
days, which caused ANC to recover to 2.1×109/L. She was discharged
back to her nursing home. Complete blood count done a month after discharge
showed persistent recovery of ANC ranging between 5.7 to 7.5×109/L.
Figure
1. Trend of ANC throughout hospitalization
Preferred
Reporting Items for Systemic review and Meta-Analysis (PRISMA) statement and
PRISMA checklist were used for manuscript development(3).
Literature search
Literature search was performed in PUBMED,
Google Scholar, EMBASE and Chinese National Knowledge Infrastructure (CNKI)
database for studies published prior to April, 2023. Search keywords included
“mirtazapine”, “remeron”, “neutropenia” and “agranulocytosis”. Boolean search
operators “AND” and “OR” were used to link the keywords.
Eligibility criteria
Inclusion criteria include articles with
case description of patients with suspected or confirmed mirtazapine induced
neutropenia. No language restrictions were applied. Review articles, animal
studies and articles which do not meet the criteria of neutropenia were
excluded. Neutropenia was defined as ANC less than 1500(4). Title
and abstracts with or without the full text were screened. Two authors (HK and
ZK) screened, retrieved and excluded the studies.
Data extraction
The data extracted included age, sex, time
of onset of neutropenia after initiation of drug, initial clinical
presentation, dose of mirtazapine used, absolute neutrophil count at nadir,
recovery in days, need for cytokine support, outcome of neutropenic episode and
antidepressant regimen used in future.
Results
The literature search initially yielded
3060 results in Google Scholar, 28 results in PUBMED/MEDLINE, 25 results
in EMBASE and 1 result in CNKI database. After excluding the duplicates and
those not meeting the inclusion criteria, 11 studies were included in our
systematic review. The PRISMA flowchart is shown in the figure 2. Three studies(5-7)
couldn’t be retrieved. Four studies(8-11) were excluded because the
ANC at nadir was greater than 1500.
The eligible case reports are summarized
in table 1, while other studies are summarized in table 2.
Fig 2. PRISMA flowchart
Discussion
Mirtazapine is a commonly used tetracyclic antidepressant with a good safety profile. With newer
immunomodulatory effects of mirtazapine being recently discovered, the use of
mirtazapine is expected to increase even more (22) .
In the aforementioned case, given the temporal relationship of neutropenia with
drug, recovery after discontinuation and absence of infectious or autoimmune
causes, the diagnosis of mirtazapine induced agranulocytosis was made. Naranjo adverse drug reaction probability
scale in our case indicated a probable causal relationship between mirtazapine
and neutropenia(23).The skin rash was due to Staphylococcus aureus
folliculitis.
According to
premarketing trials, mirtazapine induced neutropenia occurs in approximately
1.1/1000 patients(2) . However, this had a very large confidence
interval due to its inclusion of only 2796 subjects. Interestingly there is a
paucity of literature regarding this condition with only 7 case reports as
summarized in table 1 and three in the observational cohort study of
mirtazapine prescription event monitoring among 13554 patients for 2 years(19).
This relative absence of cases supports the hypothesis that the incidence of
mirtazapine induced neutropenia is significantly lower compared to the finding
reported by the premarketing trial. However, we have to also consider that
frequency reported through case reports may be misleading as it is not compared
with the frequency at which the drug is prescribed. In addition, different studies
do not have a consistent threshold below which neutropenia is defined and some
of the studies, which used higher threshold for definition of neutropenia i.e.
greater than 1500/mm3 were excluded from the review.
The mechanisms of mirtazapine
induced neutropenia are not well known. Just like any other drug mediated
neutropenia, the potential causes include immune mediated destruction or direct
toxicity(24).Typically immune mediated pathophysiology occurs about
1-6 months after initiation of the drug and typically occurs after dose has
been increased(24). The delay in onset has been hypothesized due to
the time it takes for selective T cells to proliferate(25). Type 2
and type 4 hypersensitivity have been implicated in immune mediated
neutropenia. Testing for anti-drug antibodies may be unnecessary, as the
anti-drug antibodies may either be the cause or result of immune mediated
injury(25). The onset of mirtazapine induced neutropenia ranged from
1 day to 8 months after initiation of the drug with majority of cases occurring
within 1 month after initiation of mirtazapine ( 2,12,13,16,18 ) .
In two cases, there was
a rapid drop of ANC within few days of exposure to mirtazapine. In one of the
cases, there was a distant neutropenic episode with amitriptyline and in the
other there was a prior neutropenic reaction with mirtazapine itself(13,17).
These may be due to immunologic memory (26) . Cross reactivity between tricyclic and
tetracyclic antidepressants is possible with a few cases reported in the
literature(27).
Review of literature
revealed 14 cases of mirtazapine induced neutropenia which has been summarized
in tables 1 and 2. In four instances of reported mirtazapine induced
neutropenia, the neutrophil count was in a decreasing trend but the definition
of neutropenia was not fulfilled with ANC >1500(8-11). There was
no specific age predisposition with age ranging from 29 to 72. Three cases (12,14,16 ) presented with febrile neutropenia, while
other cases were asymptomatic. There was concomitant new onset thrombocytopenia
in two cases(12,15).
Before attributing
neutropenia to medication, other potential causes of neutropenia should be
excluded, first including but not limited to viral infection, vitamin B12,
folate, autoimmune workup and ideally a bone marrow biopsy. Such investigations
were performed only in 3 cases(12,14,15) which included bone marrow
biopsy in 2 cases(12,14). Other cases were presumed to be mirtazapine
induced neutropenia given the temporal relationship and improvement of counts
after discontinuation of the drug( 13,16,17 ).
All the cases showed full recovery, except for a single case of death secondary
to neutropenic sepsis (14) .
The treatment is mainly
supportive with prompt discontinuation of offending agent as the mainstay of
therapy. Only one case required cytokine support with 300 mcg daily of filgrastim (14) .
Cytokine support in drug induced neutropenia is controversial, with the only
randomized controlled trial not showing benefits. However, the limitation in
the RCT was lower than usual dose of G-CSF (100-200 microgram per day) (28) . This is
unlike our case where a higher dose of 300 microgram per day was used. However,
a systematic review of 980 reported cases found shorter duration of neutropenia
and less fatal complications with use of G-CSF(29).
Alternate
antidepressants from other classes have been reported to be safely initiated in
patients with mirtazapine induced neutropenia. There are reports of patients who
subsequently tolerated sertraline, escitalopram and venlafaxine well (12,13,16) .
However, there was one episode of cross reactivity between tricyclic and
tetracyclic antidepressants (27) .
There were no cross-reactivity events with selective serotonin reuptake inhibitor
(SSRI) and serotonin norepinephrine reuptake inhibitor (SNRI).
Conclusion
Mirtazapine
induced neutropenia is a rare complication of a commonly used drug. It should
be considered in the differential of new onset neutropenia. Treatment is mainly
supportive, along with discontinuation of the offending agent. G-CSF use can be
considered. SSRI and SNRI may be considered in the future, while TCA should be
avoided.
Author contributions: HK wrote part of the
case report and performed literature search, ZA wrote part of the case report,
ZK performed literature search and wrote a part of discussion, EFAS wrote a
part of discussion and the summary, BGV helped with literature search, proof
reading and edited the manuscript, PAK helped with proof reading and was
involved in direct patient care.
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