# 21 - 29.21 Mirtazapine

# 29.21 Mirtazapine

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 29.21 Mirtazapine
Mirtazapine (Remeron) is unique among drugs used to treat major depression in that it
increases both norepinephrine and serotonin through a mechanism other than reuptake
blockade (as in the case of tricyclic agents or SSRIs) or monoamine oxidase inhibition
(as in the case of phenelzine or tranylcypromine). Mirtazapine is also more likely to
reduce rather than cause nausea and diarrhea, the result of its effects on serotonin 5-HT3
receptors. Characteristic side effects include increased appetite and sedation.
PHARMACOLOGIC ACTIONS

Mirtazapine is administered orally and is rapidly and completely absorbed. It has a halflife of about 30 hours. Peak concentration is achieved within 2 hours of ingestion, and
steady state is reached after 6 days. Plasma clearance may be slowed up to 30 percent
in persons with impaired hepatic function, up to 50 percent in those with impaired renal
function, up to 40 percent slower in elderly men, and up to 10 percent slower in elderly
women.
The mechanism of action of mirtazapine is antagonism of central presynaptic α2adrenergic receptors and blockade of postsynaptic serotonin 5-HT2 and 5-HT3 receptors.
The α2-adrenergic receptor antagonism causes increased firing of norepinephrine and
serotonin neurons. The potent antagonist of serotonin 5-HT2 and 5-HT3 receptors serves
to decrease anxiety, relieve insomnia, and stimulate appetite. Mirtazapine is a potent
antagonist of histamine H1 receptors and is a moderately potent antagonist at α1adrenergic and muscarinic-cholinergic receptors.
THERAPEUTIC INDICATIONS
Mirtazapine is effective for the treatment of depression. It is highly sedating, making it
a reasonable choice for use in depressed patients with severe or long-standing insomnia.
Some patients find the residual daytime sedation associated with initiation of treatment
to be quite pronounced. However, the more extreme sedating properties of the drug
generally lessen over the first week of treatment. Combined with the tendency to
sometimes cause a ravenous appetite, mirtazapine is well suited for depressed patients
with melancholic features such as insomnia, weight loss, and agitation. Elderly
depressed patients in particular are good candidates for mirtazapine; young adults are
more likely to object to this side effect profile.
Mirtazapine’s blockade of 5-HT3 receptors, a mechanism associated with medications
used to combat the severe gastrointestinal side effects of cancer chemotherapy agents,
has led to the use of the drug in a similar role. In this population, sedation and
stimulation of appetite clearly could be seen as being beneficial instead of unwelcome
side effects.
Mirtazapine is often combined with SSRIs or venlafaxine to augment antidepressant
response or counteract serotonergic side effects of those drugs, particularly nausea,
agitation, and insomnia. Mirtazapine has no significant pharmacokinetic interactions
with other antidepressants.
PRECAUTIONS AND ADVERSE REACTIONS
Somnolence, the most common adverse effect of mirtazapine, occurs in more than 50
percent of persons (Table 29.21-1). Persons starting mirtazapine should thus exercise
caution when driving or operating dangerous machinery and even when getting out of
bed at night. This adverse effect is why mirtazapine is almost always given before sleep.
Mirtazapine potentiates the sedative effects of other CNS depressants, so potentially

sedating prescription or over-the-counter drugs and alcohol should be avoided during
use of mirtazapine. Mirtazapine also causes dizziness in 7 percent of persons. It does not
appear to increase the risk for seizures. Mania or hypomania occurred in clinical trials
at a rate similar to that of other antidepressant drugs.
Table 29.21-1
Adverse Reactions Reported with Mirtazapine
Mirtazapine increases appetite in about one-third of patients. Mirtazapine may also
increase serum cholesterol concentration to 20 percent or more above the upper limit of
normal in 15 percent of persons and increase triglycerides to 500 mg/dL or more in 6
percent of persons. Elevations of alanine transaminase levels to more than three times
the upper limit of normal were seen in 2 percent of mirtazapine-treated persons as
opposed to 0.3 percent of placebo control subjects.
In limited premarketing experience, the absolute neutrophil count dropped to
500/mm3 or less within 2 months of the onset of use in 0.3 percent of persons, some of
whom developed symptomatic infections. This hematologic condition was reversible in
all cases and was more likely to occur when other risk factors for neutropenia were
present. Increases in the frequency of neutropenia have not, however, been reported
during the extensive postmarketing period. Persons who develop fever, chills, sore
throat, mucous membrane ulceration, or other signs of infection should nevertheless be
evaluated medically. If a low white blood cell count is found, mirtazapine should be
immediately discontinued, and the infectious disease status should be followed closely.
A small number of persons experience orthostatic hypotension while taking
mirtazapine. Although no data exist regarding the effects on fetal development,
mirtazapine should be used with caution during pregnancy.
Mirtazapine use by pregnant women has not been studied, but because the drug may
be excreted in breast milk, it should not be taken by nursing mothers. Because of the risk
of agranulocytosis associated with mirtazapine use, persons should be attuned to signs
of infection. Because of the sedating effects of mirtazapine, persons should determine
the degree to which they are affected before engaging in driving or other potentially
dangerous activities.
DRUG INTERACTIONS
Mirtazapine can potentiate the sedation of alcohol and benzodiazepines. Mirtazapine

should not be used within 14 days of use of an MAOI.
LABORATORY INTERFERENCES
No laboratory interferences have yet been described for mirtazapine.
DOSAGE AND ADMINISTRATION
Mirtazapine is available in 15-, 30-, and 45-mg scored tablets. Mirtazapine is also
available in 15-, 30-, and 45-mg orally disintegrating tablets for persons who have
difficulty swallowing pills. If persons fail to respond to the initial dose of 15 mg of
mirtazapine before sleep, the dose may be increased in 15-mg increments every 5 days
to a maximum of 45 mg before sleep. Lower dosages may be necessary in elderly
persons or persons with renal or hepatic insufficiency.
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Schatzberg AF, Kremer C, Rodrigues HE, Murphy GM Jr. Double-blind, randomized comparison of mirtazapine and
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