ADIS DRUG EVALUATION Drugs 1999 Apr; 57 (4): 607-631

0012-6667/99/0004-0607/$25.00/0

© Adis International Limited. All rights reserved.

Mirtazapine
A Review of its Use in Major Depression
Kristin J. Holm and Anthony Markham
Adis International Limited, Auckland, New Zealand

Various sections of the manuscript reviewed by:

H. Ågren, Karolinska Institute, Division of Psychiatry, Huddinge University Hospital, Huddinge, Sweden;
S. Agyropoulos, Psychopharmacology Unit, School of Medical Sciences, University of Bristol, Bristol,
England; J.D. Bremner, Bremner Research Institute, Olympia, Washington, USA; N. Haddjeri, Department
of Psychiatry, McGill University, Montréal, Québec, Canada; R.M.A. Hirschfeld, Department of Psychiatry,
University of Texas Medical Branch, Galveston, Texas, USA; S. Hood, Psychopharmacology Unit, School of
Medical Sciences, University of Bristol, Bristol, England; O.J. Høyberg, Department of Psychiatry, Fylkes
Hospital I Molde, Molde, Norway; S. Kasper, Department of General Psychiatry, University of Vienna,
Vienna, Austria; B.E. Leonard, Department of Pharmacology, National University of Ireland, Galway,
Ireland; G. Stimmel, School of Pharmacy, University of Southern California, Los Angeles, California, USA;
M. Van Moffaert, Department of Psychology, University Hospital, Gent, Belgium; W. Wittgens, Department
of Geriatric Psychiatry, Hans-Prinzhorn Hospital, University of Witten-Hedecke, Hemer, Germany.

Data Selection
Sources: Medical literature published in any language since 1966 on mirtazapine, identified using AdisBase (a proprietary database of Adis
International, Auckland, New Zealand), Medline and EMBASE. Additional references were identified from the reference lists of published
articles. Bibliographical information, including contributory unpublished data, was also requested from the company developing the drug.
Search strategy: AdisBase search terms were ‘mirtazapine’, ‘6-azamianserin’, ‘azamianserin’, ‘mepirzapin’, ‘Org-3770’ and ‘depression’.
Medline and EMBASE search terms were ‘mirtazapine’ and ‘depression’. Searches were last updated 11 March 1999.
Selection: Studies in patients with major depression who received mirtazapine. Inclusion of studies was based mainly on the methods section
of the trials. When available, large, well controlled trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic,
pharmacokinetic and pharmacoeconomic data are also included.
Index terms: mirtazapine, depression, pharmacodynamics, pharmacokinetics, therapeutic use, dosage and administration, pharmaco-
economics.

Contents
Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 608
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 610
2. Overview of Pharmacodynamic Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 611
2.1 Mechanism of Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 611
2.1.1 Long Term Adaptive Changes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 611
2.2 Effects on Sleep and Psychomotor Function . . . . . . . . . . . . . . . . . . . . . . . . . . . . 612
2.3 Other Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 613
3. Pharmacokinetic Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 613
3.1 Specific Patient Groups . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 614
4. Therapeutic Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 614
4.1 Noncomparative Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 615
4.1.1 In the Elderly . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 615
4.2 Comparisons with Placebo . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 617
4.3 Comparisons with Other Antidepressant Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . 618
4.3.1 Tricyclic Antidepressants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 619
608 Holm & Markham

4.3.2 Selective Serotonin Reuptake Inhibitors and Atypical Antidepressants . . . . . . . . . 621

4.4 Cost-Effectiveness Analyses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 622
5. Tolerability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 623
5.1 Adverse Event Profile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 623
5.1.1 Comparisons with Other Antidepressants . . . . . . . . . . . . . . . . . . . . . . . . . . 624
5.1.2 In the Elderly . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 624
5.2 Effects on Laboratory Parameters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 625
5.3 Suicidal Tendencies and Overdose . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 625
6. Dosage and Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 626
6.1 Drug Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 626
7. Place of Mirtazapine in the Management of Major Depression . . . . . . . . . . . . . . . . . . . . 626

Summary
Abstract Mirtazapine is a noradrenergic and specific serotonergic antidepressant (NaSSA)
which has predominantly been evaluated in the treatment of major depression.
The drug had equivalent efficacy to tricyclic antidepressants and it was at least
as effective as trazodone in the majority of available short term trials in patients
with moderate or severe depression, including those with baseline anxiety symp-
toms or sleep disturbance and the elderly. A continuation study also showed that
sustained remission rates were higher with mirtazapine than with amitriptyline
and that the drugs had similar efficacy for the prevention of relapse. There is some
evidence for a faster onset of action with mirtazapine than with the selective
serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitors (SSRIs). Mirtazapine
was more effective than the SSRI fluoxetine at weeks 3 and 4 of therapy and it
was also more effective than paroxetine and citalopram at weeks 1 and 2, respec-
tively, in short term assessments (6 or 8 weeks). Preliminary data suggest that the
drug may be effective as an augmentation or combination therapy in patients with
refractory depression.
Anticholinergic events and other events including tremor and dyspepsia are
less common with mirtazapine than with tricyclic antidepressants. There was a
greater tendency for SSRI-related adverse events with fluoxetine than with
mirtazapine, but, overall, mirtazapine had a similar tolerability profile to the SSRIs.
Increased appetite and bodyweight gain appear to be the only events that are
reported more often with mirtazapine than with comparator antidepressants. In
vitro and in vivo data have suggested that mirtazapine is unlikely to affect the
metabolism of drugs metabolised by cytochrome P450 (CYP)2D6, although few
formal drug interaction data are available.
Conclusions: Mirtazapine is effective and well tolerated for the treatment of
patients with moderate to severe major depression. Further research is required
to define the comparative efficacy of mirtazapine in specific patient groups, in-
cluding the elderly and those with severe depression. Clarification of its efficacy
as an augmentation therapy and in patients with refractory depression and its role
in improving the efficacy and reducing the extrapyramidal effects of antipsy-
chotic drugs would also help to establish its clinical value. The low potential for
interaction with drugs that are metabolised by CYP2D6, including antipsychotics,
tricyclic antidepressants and some SSRIs, may also make mirtazapine an im-
portant option for the treatment of major depression in patients who require poly-
therapy. Mirtazapine also appears to be useful in patients with depression who
present with anxiety symptoms and sleep disturbance.

© Adis International Limited. All rights reserved. Drugs 1999 Apr; 57 (4)
Mirtazapine: A Review 609

Pharmacodynamic Mirtazapine enhances noradrenergic and 5-HT1A-mediated serotonergic neuro-

Properties transmission via antagonism of central α2-adrenergic autoreceptors and hetero-
receptors and postsynaptic blockade of 5-HT 2 and 5-HT3 receptors. The drug does
not inhibit noradrenaline (norepinephrine) or serotonin reuptake. Mirtazapine has
low in vitro affinity for central and peripheral dopaminergic, cholinergic and
muscarinic receptors, but has high affinity for central and peripheral histamine
H1 receptors. However, it appears that the antihistaminergic effects of the drug
are counteracted by noradrenergic transmission when the drug is commenced at
dosages ≥15 mg/day, i.e. within the recommended dosage range.
Single doses of mirtazapine 15 or 30mg had beneficial effects on symptoms
of sleep disturbance commonly seen with depression, including increased night-
time wakenings, a reduction in the amount of slow wave sleep and a reduction
in REM latency, according to electrophysiological studies in patients and
volunteers. Night-time administration of mirtazapine 15 to 30 mg/day for 15 days
produced slight, but statistically significant, impairment in tracking and actual
driving performance in healthy volunteers; however, this was not thought to be
sufficient to reduce the safety of motor vehicle operation.
There have been no detailed reports of the cardiovascular effects of mirtazap-
ine in humans.
Overview of Mirtazapine has linear pharmacokinetics over the recommended dose range (15
Pharmacokinetic to 45mg). It has a mean elimination half-life of 20 to 40 hours following oral
Properties administration and is therefore suitable for once daily administration. Up to
85% of an oral dose is excreted in the urine and the remainder is excreted in the
faeces. In patients with hepatic and renal impairment, the clearance of mirtazapine
is reduced and dosage increases should be performed with caution. Steady-state
plasma concentrations are reached after approximately 5 days’ therapy. Age,
gender and the intake of a high-fat meal do not affect the pharmacokinetic pa-
rameters of mirtazapine. In vitro and in vivo studies indicate that mirtazapine is
unlikely to affect the metabolism of drugs metabolised by cytochrome P450
(CYP)1A2, CYP3A4 and CYP2D6 isoenzymes (including tricyclic antidepres-
sants, antipsychotics and some SSRIs); however, few formal drug interaction
studies are available.
Therapeutic Efficacy In well designed clinical studies with an antidepressant comparator, the propor-
tion of responders according to the Hamilton Depression Rating Scale (HDRS)
generally ranged from 51 to 80% with mirtazapine. In short term studies (4 to 7
weeks), the drug was as effective as amitriptyline, clomipramine and doxepin,
and it was at least as effective as trazodone, in patients with moderate or severe
depression, including those with baseline anxiety symptoms or sleep disturbance
or the elderly. Mirtazapine was less effective than imipramine in a single study
performed in a heterogeneous population including previous nonresponders to
antidepressants. Single comparisons between mirtazapine and selective serotonin
reuptake inhibitors (SSRIs) demonstrated superior efficacy for mirtazapine ver-
sus fluoxetine at weeks 3 and 4, versus paroxetine at week 1 and versus citalopram
at week 2, suggesting an earlier onset of efficacy with mirtazapine than with the
SSRIs (total assessment times were 6 or 8 weeks). Mirtazapine had equivalent
efficacy to the SSRIs at study end-point. In trials where additional scales were
used to assess antidepressant efficacy, quality of life, general psychopathology,
global functioning and global clinical impression, changes in scores correlated
with HDRS results.

© Adis International Limited. All rights reserved. Drugs 1999 Apr; 57 (4)
610 Holm & Markham

In a continuation trial, mirtazapine was associated with higher sustained

remission rates than amitriptyline and the drugs had similar efficacy for the pre-
vention of relapse. Initial evidence suggests that mirtazapine may also be effec-
tive as an augmentation or combination therapy with a number of other classes
of antidepressant in patients with refractory depression.
Mirtazapine was more cost effective than fluoxetine or amitriptyline for the
treatment of major depression from the perspectives of the national health
funder in France and Austria, despite high acquisition costs for the drug in these
countries.
Tolerability Data from meta-analyses of placebo-controlled trials indicate that dry mouth,
drowsiness/sedation, increase in appetite and bodyweight gain are the most com-
mon adverse experiences with short term (5 to 6 weeks) mirtazapine therapy. A
reduction in the incidence of sedation-related symptoms over time with higher
mirtazapine dosages was seen in some studies and is thought to have a pharma-
cological basis.
Anticholinergic symptoms and events such as drowsiness, tremor and dyspep-
sia tend to occur less frequently with mirtazapine than with tricyclic anti-
depressants or trazodone. Typical SSRI adverse events were less common with
mirtazapine than with fluoxetine and placebo, although overall mirtazapine ap-
pears to have a similar tolerability profile to those of the SSRIs fluoxetine,
citalopram and paroxetine. Increased appetite and bodyweight are the only events
that have been reported to be more common with mirtazapine than with antide-
pressant comparators. The drug appears to be well tolerated in elderly patients.
Mirtazapine has not been associated with clinically significant changes in vital
signs in clinical trials. Changes in laboratory parameters with mirtazapine are
rare. The available data indicate that mirtazapine does not increase the incidence
of suicide attempts in patients with depression compared with active comparators,
although this parameter was not specifically assessed in clinical trials of any
antidepressant. Patients have recovered without adverse sequelae from mirtazap-
ine overdose at doses of up to 30 times the recommended daily amount.
Dosage and The recommended oral dosage of mirtazapine in adults and elderly patients with
Administration depression is 15 to 45 mg/day. Elderly patients and those with hepatic or renal
insufficiency should be closely supervised when dosages are increased. Mirtazap-
ine should be taken as a single evening dose. The drug should not be given to
patients who are taking monoamine oxidase inhibitors or during pregnancy.

1. Introduction Preliminary studies in small patient groups and

Mirtazapine has been described as a noradren-
ergic and specific serotonergic antidepressant
(NaSSA).[1] It is the 6-aza derivative of the tetra-
cyclic antidepressant mianserin. It enhances the
transmission of both noradrenaline (norepineph-
rine) and serotonin (5-hydroxytryptamine; 5-HT)
without inhibiting reuptake of either neurotrans-
mitter.[2-4]
case reports suggest that mirtazapine is effective
and well tolerated in the treatment of post-traumatic
stress disorder,[5] primary anxiety disorders,[6] cen-
tral post-stroke pain[7] and a number of depressive
disorders including dysthymic disorder,[8] recur-
rent brief depression,[9] seasonal affective disor-
der,[10] premenstrual syndrome[11] and menopausal
depression.[12] This review focuses on the use of
mirtazapine in patients with major depression.

© Adis International Limited. All rights reserved. Drugs 1999 Apr; 57 (4)
Mirtazapine: A Review
2. Overview of
Pharmacodynamic Properties
Mirtazapine is a racemate, and both the S(+)-
and R(–)-enantiomers are pharmacologically ac-
tive.[13] The parent compound is responsible for
most of the pharmacological activity of mirtaza-
pine and it appears that demethylmirtazapine, the
only pharmacologically active metabolite,[14] makes
only a small contribution to the activity of the drug
(3 to 6%).[15]
2.1 Mechanism of Action
Although it is widely accepted that depression
results from central noradrenaline and/or serotonin
depletion, the exact pathophysiology of the disease
remains to be elucidated.[16] The antidepressant ac-
tivity of mirtazapine is thought to result from com-
bined noradrenergic and serotonergic effects.[14,17]
In particular, its pharmacological profile is charac-
terised by antagonism of central α2-adrenergic auto-
receptors and heteroreceptors and postsynaptic
blockade of serotonin 5-HT2 and 5-HT3 receptors,
causing enhancement of 5-HT1A-mediated sero-
tonergic and noradrenergic neurotransmission.[4]
The mechanism of action of mirtazapine has pre-
viously been discussed in detail in reviews by
Davis & Wilde,[4] Kasper et al.[14] and Stimmel et
al.[6] The activity of mirtazapine at receptor bind-
ing sites is summarised in table I.
The method by which mirtazapine enhances
serotonergic transmission suggests that the drug
may have a faster onset of action than the selective
serotonin reuptake inhibitors (SSRIs). Studies in
animal models have shown that the serotonergic
firing rate is increased soon after the administra-
tion of mirtazapine (in contrast to the SSRIs, which
reduce the firing rate soon after administration)
[reviewed by Pinder[18]]. Initial clinical data, from
comparisons between mirtazapine and citalopram,
paroxetine or fluoxetine, generally support this ob-
servation (section 4.3.2).[19-21] Furthermore, the
antagonism of 5-HT2 and 5-HT3 receptors by
mirtazapine indicate that, theoretically, the drug
may have anxiolytic effects, improve sleep and
© Adis International Limited. All rights reserved.
611
avoid typical SSRI adverse effects (such as agita-
tion, restlessness, sexual dysfunction, nausea, vomit-
ing and headache).[18] Available data suggest that
this may be the case, as discussed in sections 2.2,
4.1 and 5.1.1.
2.1.1 Long Term Adaptive Changes
The lag time that is often observed between an-
tidepressant administration and clinical response
suggests that antidepressants may act via an adap-
tive process.[22] Long term administration of clas-
sical antidepressants has been associated with down-
regulation of β-adrenoceptors[16] and 5-HT1A[23]
and 5-HT2 receptors,[24] although controversy sur-
rounds the role of these receptors as a marker of
antidepressant efficacy.[23] Receptor changes after
long term mirtazapine administration have re-
cently been studied in animal models. From the
information available, mirtazapine appears to
cause some of the same long term adaptive receptor
changes as classical antidepressants. Two weeks’
mirtazapine administration in rats caused signifi-
cant down-regulation of 5-HT2 receptors (p < 0.006
Table I. Overview of the effects of mirtazapine at receptors (re-
viewed by Davis & Wilde,[4] Stimmel et al.[6] and Kasper et al.[14])
Noradrenergic receptor activity
Antagonist activity at central α2-adrenergic autoreceptors and
heteroreceptors
Enhances noradrenaline (norepinephrine) neurotransmission (by
blockade of α2-adrenergic autoreceptors)
Little affinity for α1-adrenergic adrenoceptors
Does not inhibit noradrenaline reuptake
Serotonergic receptor activity
Antagonist activity at 5-HT2 and 5-HT3 receptor subtypes
Low affinity for 5-HT1 receptor subtypes, thus allowing an
indirect agonistic effect at 5-HT1A receptors
Enhances 5-HT1A-mediated serotonergic neurotransmission (by
increase of serotonergic raphe cell firing and facilitation of
serotonin release)
Does not inhibit serotonin reuptake
Activity at other receptors
Low in vitro affinity for central and peripheral dopaminergic,
cholinergic and muscarinic receptors
Does not inhibit dopamine reuptake
High affinity for central and peripheral histamine H1 receptors
(antihistaminergic effects appear to be counterbalanced by
noradrenergic effects at dosages ≥15 mg/day)
Drugs 1999 Apr; 57 (4)
612
vs control) and slightly reduced the density of β1-
adrenoceptors (difference versus control not sig-
nificant) in the frontal cortex. However, long term
mirtazapine administration had no direct effects on
5-HT1A receptor function in rats, according to the
hypothermic response to 8-OH-DPAT.[23]
Serotonergic neurotransmission has been shown
to be enhanced during long term (21-day) mirtaz-
apine administration in rats as a result of desens-
itisation of α2-adrenergic heteroreceptors and the
sustained increase of serotonergic raphe cell firing.
The antidepressant activity of mirtazapine is
thought to be at least partly a result of this adaptive
change.[25]
2.2 Effects on Sleep and
Psychomotor Function
Electrophysiological studies in patients[26] and
volunteers[27,28] have shown that single doses of
mirtazapine 15 or 30mg have beneficial effects on
symptoms of sleep disturbance commonly seen with
depression, including increased night-time waken-
ings, a reduction in the amount of slow wave sleep
and a reduction in REM latency. The improvement
in sleep architecture was better with mirtazapine
than with placebo in a total of 38 healthy volunteers
participating in 2 double-blind studies.[27,28] In a
placebo-controlled crossover study in 6 healthy
male volunteers that expressed data in 30 sec epoch
counts,[27] mirtazapine 30mg significantly reduced
mean night-time waking versus placebo (18 vs 124,
p < 0.01). Sleep was also significantly deeper with
mirtazapine than with placebo in this study, as
shown by a reduction in stage 1 sleep and an in-
crease in stage 3 sleep with mirtazapine (51 vs 94,
p < 0.01 and 167 vs 99, p < 0.05).[27] Furthermore,
mirtazapine was reported to be the only drug to
consistently improve sleep efficiency in a compar-
ison of mirtazapine 15mg, amitriptyline 25mg and
the combination of both antidepressants in a study
of 32 healthy volunteers that was reported briefly
(statistical analysis not reported).[28] Active treat-
ments produced reductions from baseline in sleep
latency (by 29 to 35 min), intermittent awake time
(5 to 11 min) and time in stage 1 sleep (3 to 17 min).
© Adis International Limited. All rights reserved.
Holm & Markham
Increases from baseline in time in stage 3 and 4
sleep (by 11 to 25 min) and REM latency (81 to 162
min) were also recorded with the antidepressants.
Placebo did not have beneficial effects on these
parameters. Amitriptyline and the combination of
amitriptyline and mirtazapine, but not mirtazapine
alone, prolonged the relative duration of stage 2
sleep.[28]
In a noncomparative pilot study in patients with
depression (n = 5) which was reported as an ab-
stract,[26] sleep latency decreased from 16.2 to 5.3
min, total sleep time increased from 344.8 to 415 min
and sleep efficiency increased from 79.1 to 91.3
min from baseline after 1 week of treatment with
mirtazapine 15 mg/day (all p < 0.05). Similar results
were seen at week 2 after mirtazapine 30 mg/day
(numerical values and p values not given).[26] In
another multiple dose study, overall sleep quality
was rated equivalent between placebo and mirtaz-
apine 15 to 30 mg/day when the drug was given for
15 days, according to volunteers’ subjective sleep
assessments.[29] The beneficial effects of mirtazap-
ine on sleep in volunteers are supported by efficacy
data in patients (see sections 4.1 and 4.3).
The effects of night-time administration of mir-
tazapine (the recommended timing; section 6) on
psychomotor function and actual driving perfor-
mance have been assessed in a double-blind ran-
domised study in 18 young healthy volunteers.[29]
Driving performance was assessed using the High-
way Driving Test which measures the ability of
individuals to maintain a steady lateral position
when driving a motor vehicle at a constant speed.
Mirtazapine 15 mg/day produced slight, but statis-
tically significant, impairment in tracking and driv-
ing performance on day 2 of treatment, and a daily
dose of 30mg resulted in driving impairment on
day 16 (all p < 0.05 vs placebo).[29] However, the
effects of mirtazapine on psychomotor perfor-
mance were reported to be smaller than those seen
in studies where the drug was taken in the morn-
ing.[30] Driving impairment with mirtazapine was
less than that previously reported in individuals
with a blood alcohol concentration of 0.5 mg/ml
and was not thought to be sufficient to reduce the
Drugs 1999 Apr; 57 (4)
Mirtazapine: A Review
safety of motor vehicle operation. Moreover, doub-
ling the mirtazapine dose from 15 to 30 mg/day over
time did not cause greater impairment than the ini-
tial dose.[29]
2.3 Other Effects
Mirtazapine has been shown to enhance the ef-
ficacy and reduce the adverse effects associated
with antipsychotic drugs in animal models.[31,32]
The inhibitory effect of haloperidol and atypical
antipsychotics (e.g. quetiapine) on apomorphine-
induced climbing behaviour in mice was enhanced
by subcutaneous mirtazapine at doses of the anti-
depressant that alone were not able to inhibit this
behaviour. Inhibition of this behaviour is proposed
to correspond with clinical antipsychotic poten-
tial.[31] In addition, subcutaneous mirtazapine at-
tenuated the cataleptic response induced by halo-
peridol[31] or chlorpromazine,[32] indicating that the
drug may also reduce the extrapyramidal adverse
effects associated with antipsychotic drugs.
It has been reported that mean plasma choles-
terol levels increase by 3% after 6 weeks’ mirtazap-
ine treatment.[33] However, no significant changes
in low density lipoprotein cholesterol or triglycer-
ide levels were detected in a recent briefly reported
placebo-controlled double-blind randomised cross-
over trial in 36 healthy volunteers.[34] Moreover,
there was a tendency for high density lipoprotein
cholesterol levels to increase from baseline in
mirtazapine recipients (p = 0.052).[34]
There have been no detailed reports of the car-
diovascular effects of mirtazapine in humans, al-
though the effects of short and long term therapy
on vital signs have been reported in therapeutic
trials (section 5). A double-blind randomised study
in 8 hospitalised patients with depression (mean
age 50 years) is the only trial to have specifically
assessed the cardiovascular effects of mirtazap-
ine.[35] The drug did not normalise patients’ pre-
existing autonomic cardiovascular dysfunctions
(thought to be common in unmedicated patients
with depression) and it had a moderate cardiac va-
gal inhibitory effect in these patients, as demon-
© Adis International Limited. All rights reserved.
613
strated by statistically significant increases in heart
rate and heart rate variability.[35]
3. Pharmacokinetic Properties
The pharmacokinetic properties of mirtazapine
have been studied in healthy volunteers and in pa-
tients and have been well documented in a number
of reviews.[6,14,36] An overview of relevant single
dose data is presented in table II.
Mirtazapine has linear pharmacokinetics over
the recommended dose range (15 to 45 mg/day)
and steady-state plasma concentrations are reached
after about 5 days’ treatment.[37] The drug is suit-
able for once daily administration, given that it has
a mean elimination half-life of 20 to 40 hours.[14]
The pharmacokinetics of mirtazapine appear to be
enantioselective.[15]
Mirtazapine is extensively metabolised in the
liver; the cytochrome P450 (CYP) isoenzymes
CYP1A2, CYP2D6 and CYP3A4 are mainly re-
sponsible for the biotransformation of the agent.
An in vitro study showed that mirtazapine was a
competitive inhibitor of these CYP isoenzymes,
with mean inhibition constant (Ki) values at least
10-fold higher than those observed with fluvoxam-
ine, fluoxetine and ketoconazole (table III).[13]
Table II. Overview of the pharmacokinetic parameters of single
dose oral mirtazapine 15 to 45 mg/day in healthy volunteers
Cmax (mg/L) 0.04-0.11[37]
tmax (h) 2.2-2.9[37]
t1⁄2 (h) 20-40[14]
AUC (ng/L • h) 0.22-0.25[38]
Bioavailability (%)a
≈50[38]
Plasma protein binding (%) ≈85[1]
Major metabolic pathways 8-hydroxylation,
N(2)-demethylation,
N(2)-oxidation[13]
Cytochrome P450 (CYP) isoenzymes 1A2, 2D6, 3A4[13]
involved in metabolism
Excretion:
≤85[1]
urine (%)
faeces (%) ≤15[1]
a After single or multiple doses of mirtazapine 15mg.
AUC = area under the plasma concentration-time curve; Cmax = peak
plasma concentration; tmax = time to achieve Cmax; t1⁄2 = elimination
half-life.
Drugs 1999 Apr; 57 (4)
614
Mirtazapine is unlikely to inhibit the metabolism
of drugs metabolised by CYP1A2 and CYP3A4, in-
cluding tricyclic antidepressants, antipsychotics
and some SSRIs, whereas a relatively low Ki value
of mirtazapine for CYP2D6 (table III) indicated a
potential for inhibition of the metabolism of drugs
with high affinity for this isoenzyme. However, an
in vivo study in extensive and poor metabolisers of
debrisoquine indicates that CYP2D6 plays a minor
role in the elimination of mirtazapine.[13] There-
fore, it is unlikely that mirtazapine would affect the
metabolism of drugs metabolised by CYP1A2,
CYP3A4 or CYP2D6 isoenzymes.
3.1 Specific Patient Groups
Data from a study in elderly men with cirrhosis
(published as an abstract) indicate that mirtazapine
dosage increases should be performed with caution
in patients with hepatic impairment. The hepatic
clearance of mirtazapine was significantly reduced
in the presence of cirrhosis.[39]
Data have recently become available on the phar-
macokinetic parameters of a single oral dose of
mirtazapine 15mg in 38 volunteers with moderate
or severe renal failure (mean glomerular filtration
rate 1.32 and 0.12 L/h, respectively).[40] Mean time
to peak plasma concentration (tmax) and the area
under the plasma concentration-time curve (AUC)
values for mirtazapine were significantly higher
and oral clearance was significantly lower in pa-
tients with moderate or severe renal failure than in
healthy volunteers or individuals with mild renal
failure (mean glomerular filtration rate 6.0 and
3.66 L/h, respectively) [p ≤ 0.05 for all compari-
Table III. In vitro inhibition of cytochrome P450 (CYP) isoenzymes
by mirtazapine and selected inhibitors (data from Dahl et al.[13])
CYP isoenzyme Inhibitor
CYP1A2 Mirtazapine
Fluvoxamine
CYP2D6 Mirtazapine
Fluoxetine
CYP3A4 Mirtazapine
Ketoconazole
Ki = inhibition constant.
© Adis International Limited. All rights reserved.
Holm & Markham
sons]. The mean peak plasma concentration (Cmax)
was significantly higher in individuals with severe
renal failure than in healthy volunteers or those with
mild renal failure (p ≤ 0.05), although the elimina-
tion half-life was slightly, but not significantly, in-
creased in the presence of moderate or severe renal
failure.[40] Mirtazapine was well tolerated in patients
with renal impairment; however, studies on the ef-
fects of repeated drug administration are required
and dosage increases should be performed with
caution in these patients.
Data from 41 healthy adult (25 to 48 years) or
elderly (65 to 74 years) volunteers suggest that
gender- and age-related effects on the pharmacoki-
netic parameters of mirtazapine are not clinically
significant and dosage adjustments were not rec-
ommended on the basis of these differences.[41]
Furthermore, the intake of a high-fat meal did not
affect mirtazapine absorption or elimination in
young healthy male volunteers.[42]
4. Therapeutic Efficacy
The efficacy of mirtazapine for the short term
treatment of major depression has been assessed in
a number of comparative double-blind randomised
trials (see sections 4.2 and 4.3), which were of 4 to
7 weeks’ duration. In addition, 8-week results are
available for a 6-month trial. There was 1 compar-
ative continuation (≤2 years) trial. Studies were
generally well designed.
The main clinical assessment tool used in these
studies was the Hamilton Depression Rating Scale
(HDRS). In general, patients were considered to be
responders if they had a ≥50% reduction in HDRS
score from baseline. Remission and relapse rates
(the proportion of patients with 17-item HDRS
scores ≤7 and ≥16, respectively) at study end-point
were also reported in a few studies. A number of
Ki (μmol/L)
other scales were also used to assess antidepressant
159
0.18
efficacy: the Montgomery-Åsberg Depression Rat-
41.1 ing Scale (MADRS), the Beck Self Rating Depres-
4.08 sion Scale (BSRDS) and the Zung Depression
210 Scale (ZDS). Other assessment scales included the
0.07-0.15 Brief Psychiatric Rating Scale (BPRS), Clinical
Global Impression (CGI) scale, General Psychiat-
Drugs 1999 Apr; 57 (4)
Mirtazapine: A Review
ric Impression Global Assessment Scale (GAS),
Quality of Life Enjoyment and Satisfaction Ques-
tionnaire (QLESQ) and Visual Analogue Mood
Rating Scale (VAMRS).
Hospitalised patients and outpatients meeting
DSM-III,[43] DSM-III-R[44] or DSM-IV[45] criteria
for major depression were included. Patients had
moderate or severe (17-item HDRS score 18 to 24
or ≥25, respectively) depression at baseline. Mean
baseline HDRS scores were ≥25 in a number of
studies (tables IV and V) indicating that many pa-
tients had severe depression at baseline. However,
the proportion of patients with severe disease was
documented in few trials. Most clinical trials of
mirtazapine involved patients between the ages of
18 and 65 years, although 2 comparative studies
specifically considered elderly patients with a
mean age of 62[46] and 71[47] years and 2 non-
comparative trials included patients aged ≥52[48]
and >55[49] years.
Most studies had a 3- to 7-day placebo washout
period, and patients with a ≥25% decrease in the total
HDRS score during this period were excluded.
Mirtazapine was taken orally at night and, in the
majority of trials, dosage regimens were titrated
according to patients’ responses. Initial dosages of
5 to 20 mg/day and maximum dosages of 35 to 80
mg/day were given in all studies apart from one, in
which patients received higher dosages (40 to 100
mg/day).[50] Initial and maximum mirtazapine dos-
ages were higher in hospitalised patients than in
outpatients, as were mean dosages (≈20 mg/day in
outpatients and ≈50 mg/day in hospitalised pa-
tients).
Most analyses were performed on an intention-
to-treat basis and included all randomised patients
who had ≥1 postbaseline efficacy assessment and
had received ≥1 dose of study medication. A num-
ber of studies stated that end-point analyses were
performed using the last observation carried for-
ward method.
4.1 Noncomparative Studies
Mirtazapine 15 to 45 mg/day was effective in
2 large noncomparative studies which included
© Adis International Limited. All rights reserved.
615
10 405 [51] or 2460[52] hospitalised patients and out-
patients with major depression (both were reported
as abstracts). CGI response rates were 72[52] and
82%[51] after 6 weeks’ mirtazapine therapy (statisti-
cal analyses versus baseline not performed); HDRS
scores were not assessed.[51,52]
In one of these trials, mirtazapine therapy was
associated with a reduction from baseline in the
proportion of patients experiencing anxiety symp-
toms, sleep disturbance and agitation (results pre-
sented graphically).[51] Similarly, in a study that
specifically considered patients with depression
and high baseline anxiety symptoms and sleep dis-
turbance (presented as an abstract), mirtazapine 15
to 60 mg/day for 3 months improved both symp-
toms in 67 to 70% of 539 outpatients.[53] These data
are supported by polysomnographic assessments
of the effects of mirtazapine on sleep in patients
and volunteers (section 2.2) and comparative stud-
ies in patients (section 4.3).
The efficacy of various augmentation and com-
bination strategies involving mirtazapine has been
assessed in noncomparative pilot studies (most
have yet to be published in full). Augmentation
therapy, the addition of an agent to an antidepres-
sant regimen with the intention of enhancing the
efficacy of the regimen, or combination therapy,
the concomitant use of multiple therapies, may be
used in treatment-resistant patients and in those
who are only partially responsive to treatment.[54]
The addition of mirtazapine 15 to 30 mg/day to anti-
depressant therapy, including fluoxetine, paroxet-
ine, sertraline or venlafaxine, (n = 20), [55] maprotil-
ine augmentation of mirtazapine 90 mg/day (n =
2)[56] and combination therapy with mirtazapine 30
to 90 mg/day and citalopram (n = 6)[57] have been
reported to improve response rates in patients with
refractory depression. 55% of patients responded to
therapy at week 4 when mirtazapine was added to
a number of antidepressants including fluoxetine
and paroxetine;[55] response rates were not given
in the other studies.[56,57]
4.1.1 In the Elderly
Two noncomparative studies, which were briefly
reported, have assessed the efficacy of mirtazapine
Drugs 1999 Apr; 57 (4)
 616
© Adis International Limited. All rights reserved.

Table IV. Efficacy of once daily mirtazapine (M) compared with tricyclic antidepressants, with or without a placebo (PL) comparison, for the treatment of moderate to severe major
depression in prospective double-blind studies of 4 to 7 weeks’ duration

Reference (trial Dosage Evaluable patients Methods of assessment Mean baseline Responders No. of Overall
design, duration [mg/day (mean)] [no. (type)] score/reduction from (%)a withdrawals efficacy
of treatment) baseline at end-point because of
LOE/other reasons
HDRS MADRS

Comparisons with amitriptyline (A)

Bremner[62] (db, M 5-35 (22) 50b (outpatients) 17-item HDRS, MADRS, 28.3/14.2c* 37.7/14.8c* 62c* 3/6 M ≡A
r, 6wk) ZDS, CGI M > PL
A > PL

A 40-280 (133) 50b 27.3/12.2c* 36.4/12.5c* 48c* 3/7

PL 50b 26.6/7.8c 36.6/8.0c 24c 7/5

Høyberg et al.[47] M 15-45 56 (outpatients and 21-item HDRS, MADRS, 26.7/12.0 32.5/15.3 74d 6/7 M ≡A
(db, mc, r, 6wk) hospitalised patients aged CGI
60 to 85 years)

A 30-90 59 25.7/14.3 30.3/17.3 81d 5/6

Mullin et al.[65] M 20-60 71 (outpatients and 17-item HDRS, MADRS 22.5/10.8 30.8/14.8 54 6/9 M ≡A
(db, mc, r, 5wk) hospitalised patients)

A 75-225 71 22.6/11.9 30.1/15.8 58 4/14

Smith et al.[63] M 5-35 (18) 47 (outpatients) 17-item HDRS, MADRS, 23.4/11.0* 28.6/12.9* 53 NR M ≡A
(db, mc, r, 6wk) ZDS, CGI M > PL
A > PL

A 40-280 (111) 47 23.7/12.8* 28.1/15.3* 55 NR

PL 46 23.3/6.8 27.5/6.7 30 NR

Zivkov & de M 20-60 (53) 113 (hospitalised patients) 21-item HDRS, BPRS, GAS 28.0/15.2 NA 72 8/11 M ≡A
Jongh[66] (db,
mc, r, 6wk)

A 75-225 (197) 111 27.6/15.6 NA 72 8/12

Comparison with clomipramine (C)

Drugs 1999 Apr; 57 (4)

Holm & Markham

Richou et al.[67] M 20-80 (47) 87 (hospitalised patients) 21-item HDRS, MADRS, 27.7/14.8c 35.2/21.4c 80 4/20 M≡C
(db, mc, r, 6wk) GAS, BPRS

C 50-200 (114) 86 26.7/15.7c 33.8/22.3c 86 7/20

Mirtazapine: A Review 617

(at dosages of 15 to 60 mg/day) in elderly patients

with depression.[48,49] One analysis was performed
retrospectively in hospitalised patients with a high
rate of somatic or neurological comorbidity (n =
141)[48] and the other was a prospective trial in
hospitalised patients and outpatients (n = 325).[49]
A very good clinical response to mirtazapine was
reported in the retrospective analysis, particularly
in patients with prominent agitation, anxiety symp-
toms or sleep disturbance (no further details were
provided).[48] Depressed mood was ‘much’ or
‘very much’ improved after 3 months’ therapy in
80% of participants in the prospective trial; similar
improvements were observed for anxiety (75%)
and sleep disturbance (80%) at study end-point.[49]

4.2 Comparisons with Placebo

A number of short term trials (5 to 6 weeks)

have indicated that mirtazapine 5 to 60 mg/day is
significantly more effective than placebo as treat-
ment for moderate to severe major depression (re-
viewed by Davis & Wilde[4]). These results have
been confirmed in recent meta-analyses, which in-
cluded 194[58] and 249[59] mirtazapine recipients
(and similar numbers of placebo recipients) who
had participated in double-blind randomised pub-
lished and unpublished trials of 5 or 6 weeks’ du-
ration.[58,59] Mirtazapine was also determined to be
significantly more effective than placebo in one of
the meta-analyses that specifically considered pa-
tients with severe depression (p ≤ 0.01).[59] Some
trial data were common to both meta-analyses and
some data discussed by Davis & Wilde[4] were also
included in the meta-analyses.[58,59] A third meta-
analysis of double-blind randomised 6-week trials
demonstrated that mirtazapine was associated with
significantly greater improvements in HDRS scores
for anxiety factors than placebo. Reductions in
scores from baseline with mirtazapine and placebo
were 3.2 and 1.9, respectively, for anxiety/agitation
at end-point and 0.45 and 0.36, respectively, for anx-
iety/somatisation at week 6 (both p ≤ 0.05).[60]
In addition, mirtazapine ≤35 mg/day was more
effective than placebo in the continuation trial of
up to 2 years’ duration.[61] This study also included

© Adis International Limited. All rights reserved. Drugs 1999 Apr; 57 (4)
 Mirtazapine: A Review
© Adis International Limited. All rights reserved.

Comparison with doxepin (D)

Marttila et al.[68] M 20-60 (37) 83b (outpatients and 17-item HDRS, MADRS, 22.0/13.6 29.0/17.7 65 4/6 M≡D
(db, mc, r, 6wk) hospitalised patients) BPRS, GAS, BSRDS

D 75-300 (189) 80b 22.4/14.3 29.3/17.8 62 4/13

Comparison with imipramine (I)

Bruijn et al.[50] M 40-100 (76) 54 (hospitalised patients) 17-item HDRS, MADRS 26.1/6.5 37.5/10.7c 20.4e 0/3 I>M
(db, r, 4-7wk)
I 38-450 (236) 53 26.5/10.7 36.2/15.4c† 43.4e† 0/7

a Defined as patients with a ≥50% reduction in HDRS score at end-point, unless otherwise specified.
b Number of enrolled patients (number of evaluable patients not given).
c Values estimated from graph.
d Patients ‘much’ or ‘very much’ improved on CGI scale at end-point.
e Assessments made after predefined drug blood concentrations had been maintained for 4 weeks.
BPRS = Brief Psychiatric Rating Scale; BSRDS = Beck Self Rating Depression Scale; CGI = Clinical Global Impression; db = double-blind; GAS = General Psychiatric Impression
Global Assessment Scale; HDRS = Hamilton Rating Scale for Depression; LOE = lack of efficacy; MADRS = Montgomery-Åsberg Depression Rating Scale; mc = multicentre;
NA = not applicable; NR = not reported; r = randomised; ZDS = Zung Depression Scale; ≡ indicates no statistically significant difference from comparator at study end-point;
> indicates a statistically significant difference (p < 0.05) vs comparator at study end-point; * p ≤ 0.05 vs placebo; † p < 0.01 vs mirtazapine.
Drugs 1999 Apr; 57 (4)

617
618 Holm & Markham

Table V. Efficacy of once daily mirtazapine (M) compared with selective serotonin reuptake inhibitors or the atypical antidepressant trazodone,
with or without a placebo (PL) comparison, for the treatment of moderate to severe major depression in prospective randomised double-blind
studies of 6 weeks’ duration
Reference Dosage Evaluable Methods of Mean baseline Responders No. of Overall
[mg/day patients assessment score/reduction from (%)a withdrawals efficacy
(mean)] [no. (type)] baseline at end-point because of
HDRS MADRS LOE/other
reasons

Comparison with fluoxetine (F)

Wheatley et M 15-60 (40) 60 (outpatients 17-item HDRS, 26.0/14.2 NA 66b 3/14 M ≥ Fc
al.[21] and hospitalised VAMRS, QLESQ,
patients) CGI
F 20-40 (24) 63 26.1/10.3 NA 44b 5/16

Comparison with paroxetine (P)

Benkert et M 15-45 133 (outpatients) 17-item HDRS NR NA 58e 24 M ≥ Pf
al.[19]d P 20-40 128 NR NA 45e 24

Comparisons with trazodone (T)

Halikas[46] M 5-35 (20) 49 (outpatients 21-item HDRS, 24.6/11.0bg* 25.3/9.0bg 51g 1/10 M≡T
aged ≥55 years) MADRS, ZDS, M > PL
CGI T ≡ PL
T 40-280 48 24.6/8.6bg 26.1/8.6bg 41g 2/14
(151)
PL 49 23.5/7.6bg 23.9/5.4bg 35g 5/9
van Moffaert M 24-72 100h 17-item HDRS, 29.2/15.7b 36.3/19.4b 61 16/10 M ≥ Ti
et al.[73] (hospitalised MADRS, BPRS,
patients) GAS, BSRDS
T 150-450 100h 27.5/13.1b 35.7/17.5b 51 13/10
a Defined as patients with a ≥50% reduction in HDRS score at end-point, unless otherwise specified.
b Values estimated from graph.
c Statistically significant differences in favour of mirtazapine for change from baseline in HDRS scores at weeks 3 and 4 and HDRS re-
sponse rates at week 4 but no significant differences at end-point.
d Abstract.
e Response rates at week 4 (rates at end-point not given).
f Statistically significant differences in favour of mirtazapine for change from baseline in HDRS scores at week 1 and HDRS response
rates at weeks 1 and 4 but no significant differences at end-point.
g Results at week 6 (values at end-point not given).
h Number of enrolled patients (number of evaluable patients not given).
i Statistically significant differences in favour of mirtazapine on all rating scales at week 6 except MADRS.
BPRS = Brief Psychiatric Rating Scale; BSRDS = Beck Self Rating Depression Scale; CGI = Clinical Global Impression; GAS = General
Psychiatric Impression Global Assessment Scale; HDRS = Hamilton Rating Scale for Depression; LOE = lack of efficacy; MADRS =
Montgomery-Åsberg Depression Rating Scale; NA = not applicable; NR = not reported; QLESQ = Quality of Life Enjoyment and Satisfaction
Questionnaire; VAMRS = Visual Analogue Mood Rating Scale; ZDS = Zung Depression Scale; ≡ indicates no statistically significant difference
from comparator at study end-point; > indicates a statistically significant difference (p < 0.05) vs comparator at study end-point; ≥ indicates
that the first agent was significantly more effective (p ≤ 0.05) than the second agent at some assessment times apart from end-point; * p <
0.05 vs placebo.

amitriptyline as a comparator and is discussed fur- 4.3 Comparisons with Other

ther in section 4.3.1. Antidepressant Drugs
Mirtazapine has shown a significantly earlier
onset of action than placebo in some studies (p ≤ Davis & Wilde[4] in their review reported that
0.05), as assessed using HDRS scores.[46,62-64] mirtazapine has similar efficacy to the tricyclic

© Adis International Limited. All rights reserved. Drugs 1999 Apr; 57 (4)
Mirtazapine: A Review 619

antidepressants amitriptyline, clomipramine and cluded 217 patients, are shown in figure 1. Patients
doxepin in outpatients and hospitalised patients in the continuation study had participated in 6-
with major depression. The drug was also reported week double-blind randomised placebo-controlled
to be at least as effective as the atypical antide- trials, and investigators considered that all would
pressant trazodone.[4] Subsequent research con-
firms many of these findings and provides data re- Placebo (n = 57)
garding the relative efficacies of mirtazapine and Amitriptyline (n = 86)
Mirtazapine (n = 74) †
SSRIs (tables IV and V). HDRS response rates 80
*
generally ranged from 51 to 80% with mirtazapine

Sustained remission rate (% of patients)

*
in trials with an antidepressant comparator. *
60
4.3.1 Tricyclic Antidepressants

Hamilton Depression Rating Scale Scores

Most studies evaluating the comparative effi- 40

cacy of mirtazapine during the clinical develop-

ment programme have used amitriptyline as the
20
comparative agent. Similar HDRS response rates
(48 to 72%) with mirtazapine and amitriptyline
have been observed in a number of double-blind
0
randomised 5- or 6-week comparisons in outpa-
tients and hospitalised patients with moderate to
severe major depression.[62,63,65,66] Mirtazapine 30
and amitriptyline also improved HDRS scores for
depression-related symptoms, including anxiety
25
and sleep disturbance, to a similar extent in the 2
trials that reported changes in these factors in
Relapse rate (% of patients)

younger adults.[65,66] However, a comparison in el- 20

derly patients (aged 60 to 85 years)[47] reported a
significantly better improvement with amitripty-
line than with mirtazapine in the HDRS cognitive
disturbance factor at end-point (p ≤ 0.05) [table IV].[47]
Meta-analyses have confirmed the equivalent
efficacy of mirtazapine and amitriptyline for treat-
ing major depression. These analyses considered
data from short term double-blind randomised stud-
ies in a total of 580 outpatients with major depres-
sion,[58] 344 patients with depression and high
baseline anxiety[60] and 405 severely depressed pa-
tients (mean baseline 17-item HDRS score 29). [69]
In the double-blind placebo-controlled ≤2-year
continuation trial,[61] relapse rates were lower and
sustained remission rates were higher at study end-
point in mirtazapine recipients than in amitripty-
line recipients, although between-group differences
were significant (p = 0.008) only for sustained re-
mission rates. Results from this trial, which in-
15
*
10
*
5 * *
0
Week 20 End-point
Fig. 1. Comparative efficacy of mirtazapine, amitriptyline and
placebo in a long term trial for the treatment of major depression
[treatment period ≤2 years (mean 8 months)].[61] Patients who
were considered to be responders to treatment during 6-week
double-blind randomised trials continued with the same medi-
cation during this double-blind continuation study. Remission
rates were defined as the proportion of patients with 17-item
HDRS scores ≥7, and relapse rates were defined as the propor-
tion of patients with 17-item HDRS scores ≥16 and those who
withdrew from the study because of lack of efficacy. * p ≤ 0.05
vs placebo; † p ≤ 0.05 vs amitriptyline.

© Adis International Limited. All rights reserved. Drugs 1999 Apr; 57 (4)
620
benefit from further treatment with the study med-
ication.[61]
In the only comparison between mirtazapine
and imipramine in patients with major depres-
sion,[50] the response rate was significantly higher
with imipramine (table IV). However, response
rates were low in both groups of hospitalised pa-
tients included in this double-blind randomised
comparison (20.4 vs 43.4%; p = 0.019) [response
rates with mirtazapine in comparative studies in
inpatients have generally been about 70 to 80%].
The study population was highly heterogeneous
and included previous nonresponders to antide-
pressants and patients with psychotic and bipolar
disorders. Study drug dosages were adjusted accor-
ding to predefined blood concentrations: 200 to
300 μg/L for imipramine and 50 to 100 μg/L for
mirtazapine. While imipramine has been shown to
have optimal efficacy at the chosen concentra-
tions,[50] the efficacy of mirtazapine has not been
shown to relate to particular plasma concentrations
of the drug.[70] The dosages received were higher
than those recommended for both drugs and were
40 to 100 (mean 76) mg/day for mirtazapine and
38 to 450 (mean 236) mg/day for imipramine.[50] A
subsequent study[71] has reported the effects of the
addition of lithium to mirtazapine or imipramine
therapy in patients who were nonresponders (n =
100) in the initial trial by Bruijn et al.[50] A high
proportion of patients in the subsequent study had
psychotic disorders (29%). The results from this
study are discussed below because MADRS re-
sponse rates were used to compare the antidepres-
sant efficacy of each drug in combination with lith-
ium.[71]
A 6-week double-blind randomised comparison
between clomipramine and mirtazapine[72] has in-
dicated that the agents have similar efficacy in pa-
tients with severe depression, supporting the re-
sults of a previous double-blind randomised trial
(table IV).[67] Most of the 90 patients from both
groups remitted; mean 17-item HDRS scores at
end-point were 8.8 and 7.6 for mirtazapine and
clomipramine recipients, respectively.[72] The trial
© Adis International Limited. All rights reserved.
Holm & Markham
was reported as an abstract and few data were pro-
vided.
Response rates at study end-point were similar
in mirtazapine and doxepin recipients (65 vs 62%)
in a 6-week double-blind randomised multicentre
trial which is the only published comparison be-
tween the 2 drugs (table IV).[68]
Other End-Points
In the studies that assessed depressive symp-
toms using the MADRS, changes in scores corre-
lated with HDRS results. Improvements in depres-
sive symptoms were similar for mirtazapine and
amitriptyline,[47,62,63,65] clomipramine[67] and doxe-
pin.[68] In the comparison between mirtazapine and
imipramine,[50] MADRS scores were significantly
better in the imipramine group than in the mirtaz-
apine group at the final assessment of the 6-week
trial (20.8 vs 26.8, p = 0.026) [results estimated
from a graph]. In the subsequent trial which com-
pared the efficacy of either mirtazapine or imipra-
mine with lithium addition, the proportion of re-
sponders according to the MADRS was higher in
patients receiving imipramine (64%) than in those
receiving mirtazapine (48%) [p value not given].[71]
A statistical model showed significant benefits of
imipramine therapy and subsequent lithium addi-
tion over the same strategy involving mirtazapine
(p < 0.05).[71]
In studies that used the CGI to assess changes in
depressive symptoms (amitriptyline was compared
with mirtazapine in all of these trials),[47,62,63] both
agents produced equivalent changes in scores from
baseline at study end-point. In the only comparison
between mirtazapine and tricyclic antidepressants
that reported CGI response rates, 74 and 81% of
elderly mirtazapine and amitriptyline recipients,
respectively, were responders (‘much’ or ‘very much’
improved).[47]
With respect to other end-points (BPRS, BSRDS,
GAS and ZDS), improvements were seen in pa-
tients taking mirtazapine, doxepin, and amitripty-
line.[62,63,66-68] No statistical differences between
active drugs were documented in studies reporting
results at final assessments.[63,67,68]
Drugs 1999 Apr; 57 (4)
Mirtazapine: A Review
4.3.2 Selective Serotonin Reuptake Inhibitors
and Atypical Antidepressants
Hamilton Depression Rating Scale Scores
Mirtazapine was shown to have significantly
superior efficacy to the SSRI fluoxetine at weeks
3 and 4 in a recent 6-week double-blind random-
ised trial (p < 0.05) [fig. 2]. The improvement in
HDRS scores from baseline also tended to be better
in mirtazapine than fluoxetine recipients at study
end-point (p = 0.054) [table V]. The difference in
HDRS scores between groups was reported to fa-
vour mirtazapine by 3.7 to 4.2 points at weeks 3, 4
and 6, which is a clinically relevant effect. In ad-
dition, more mirtazapine than fluoxetine recipients
were classified as responders according to HDRS
scores [table V], although between-group differ-
ences were significant only at week 4 (p = 0.006).
The proportion of patients in remission at end-
point was similar in the mirtazapine (23.3%) and
fluoxetine (25.4%) groups. Improvements in HDRS
scores for anxiety/somatisation, sleep disturbance
and retardation were better in the mirtazapine than
the fluoxetine group but, again, differences were
60 Fluoxetine (n = 63)
Mirtazapine (n = 60)
Reduction from baseline in HDRS score (%)
50
40
30
20
10
0 tazapine vs paroxetine; p values not given for the
1 2
Week
Fig. 2. Comparative efficacy of mirtazapine and fluoxetine in
outpatients and hospitalised patients with major depression.[21]
Reductions from baseline in Hamilton Depression Rating Scale
(HDRS) scores during treatment in a 6-week randomised,
double-blind, multicentre study. Values were estimated from a
graph. Baseline HDRS scores were 26.0 in mirtazapine re-
cipients and 26.1 in fluoxetine recipients. *p < 0.05 vs fluoxetine.
© Adis International Limited. All rights reserved.
621
not statistically significant. About 58% of mirtaza-
pine recipients and 52% of fluoxetine recipients in
this trial were severely depressed at baseline.[21]
Two double-blind randomised trials (available
as abstracts) have compared the efficacy of mirtazap-
ine with that of the SSRIs citalopram or paroxe-
tine.[19,20] Mirtazapine and citalopram were reported
to improve anxiety symptoms and sleep distur-
bance substantially and to a similar extent after the
first 8 weeks of a 6-month trial.[20] In addition, both
therapies were reported to have been associated
with high HDRS response rates, although response
rates and changes in HDRS scores from baseline
were not documented.[20] Mirtazapine was signifi-
cantly (p ≤ 0.05) superior to paroxetine in terms of
improvements in HDRS scores and HDRS factor
scores at various assessment times.[19] HDRS re-
sponse rates and the reduction in HDRS scores
were equivalent between groups at study end-
point. The significant differences, in favour of
mirtazapine over paroxetine, were observed for the
improvement in HDRS scores from baseline at
week 1, overall HDRS response rates at weeks 1
and 4 (fig. 3), anxiety/somatisation at weeks 1, 3
and 4 and end-point, sleep disturbance at weeks 1
and 2 and end-point, agitation at weeks 1 and 2,
* somatic complaints at weeks 1, 3, 4 and 6 and end-
point.[19]
*
The mechanism of action of mirtazapine sug-
gests that the agent could have a faster onset of
action than the SSRIs (section 2.1). This effect has
been observed for the available comparisons be-
tween mirtazapine and fluoxetine, citalopram and
paroxetine.[19-21] Indeed, mirtazapine was associ-
ated with significantly greater improvements in
HDRS scores than paroxetine and citalopram at
weeks 1 and 2, respectively (p = 0.0004 for mir-
3 4 6 comparison with citalopram).[19,20]
Mirtazapine and trazodone were associated
with similar response rates at study end-point in 2
double-blind randomised 6-week trials (table
V).[46,73] In one of the trials,[73] which included 200
hospitalised patients, the improvement in HDRS
scores from baseline and response rates (78 vs 61%)
Drugs 1999 Apr; 57 (4)
622
70 Paroxetine (n = 128)
Mirtazapine (n = 133)
60
HDRS response rate (%)
50
40
30
* scales, were similar between study drugs in agree-
20
10
0 study in hospitalised patients (p ≤ 0.05 for all com-
7 14 21 28
Day
Fig. 3. Comparative efficacy of mirtazapine and paroxetine in
outpatients with major depression.[19] Response rates [the pro-
portion of patients with a ≥50% reduction in 17-item Hamilton
Depression Rating Scale (HDRS) scores from baseline] in a
6-week randomised, double-blind, multicentre study. Values
were estimated from a graph. *p < 0.05 vs paroxetine.
were significantly better (p ≤ 0.05) with mirtazap-
ine than with trazodone at day 42, but not at study
end-point. In addition, there was a tendency for a
greater improvement in HDRS anxiety/somatisa-
tion and retardation scores with mirtazapine than
with trazodone (0.05 < p < 0.10) in this study.[73]
146 elderly patients participated in the other trial,
which was placebo-controlled; response rates at
end-point were 51% with mirtazapine and 41%
with trazodone.[46]
Other End-Points
In the comparison of mirtazapine and fluox-
etine,[21] secondary end-points indicated that the
drugs had similar efficacy for the treatment of
major depression. As with HDRS results, more
mirtazapine than fluoxetine recipients were classi-
fied as CGI responders at end-point (63.3 vs 54.0%),
although between-group differences were not sig-
nificant. Results for the VAMRS showed that pa-
tients became more relaxed, energetic, calm and
tranquil and, according to the QLESQ, their quality
of life improved after both mirtazapine and flu-
oxetine therapy with no differences between
© Adis International Limited. All rights reserved.
Holm & Markham
groups.[21] Mirtazapine was reported to improve
MADRS and CGI-Quality of life scores to a signif-
* icantly greater extent than citalopram at day 14;
similar improvements in these parameters were
seen in both groups at study end-point.[20]
In comparisons between mirtazapine and trazo-
done, improvements in depressive symptoms at
study end-point, according to the MADRS and CGI
ment with changes in HDRS scores.[46,73] BPRS
scores at days 28 and 42 and end-point and BSRDS
and GAS scores at day 42 were significantly better
in mirtazapine than in trazodone recipients in the
42
parisons).[73] However, there were no between-
group differences in ZDS scores in the study in
elderly patients.[46]
4.4 Cost-Effectiveness Analyses
Two studies, available as abstracts, have specif-
ically assessed the pharmacoeconomic implications
of mirtazapine use in Austria[74] and in France.[75]
Both compared the cost effectiveness of mirtaza-
pine with that of amitriptyline and fluoxetine; they
used decision analysis models and included direct
costs[74] or both indirect and direct costs.[75] Anal-
yses were conducted from the perspective of the
Austrian Sick Fund[74] or the French Social Security
Fund[75] and results were modelled over a 6- or
7-month period, respectively. Assumptions were
based on clinical trial data, published trials and in-
terviews with expert panels.[74,75]
Results from these studies showed that mirtaz-
apine was more cost effective than both fluoxetine
and amitriptyline.[74,75] The cost per successfully
treated patient was 15 000 to 18 000 schillings (1997/
1998 values) less with mirtazapine than with both
comparators in the Austrian study[74] and 24 000 to
26 000 francs less in the French study[75] (year not
stated). Results were shown to be robust to sensi-
tivity analyses.[74,75]
Although the acquisition cost of mirtazapine
was greater than that of fluoxetine or amitriptyline
in Austria, mirtazapine was associated with savings
derived from the management of adverse events
Drugs 1999 Apr; 57 (4)
Mirtazapine: A Review
and Sick Fund payments versus amitriptyline and
savings derived from hospitalisation and the man-
agement of treatment dropouts versus fluoxet-
ine.[74] In the French analysis, both direct health-
care costs and indirect costs per patient were lower
in mirtazapine recipients than in fluoxetine and
amitriptyline recipients.[75]
5. Tolerability
Tolerability data relating to mirtazapine are avail-
able from large noncomparative trials, a number of
short term comparative trials (predominantly 5 to
8 weeks’ duration) and a comparative continuation
trial of up to 2 years’ duration.
5.1 Adverse Event Profile
The most common events reported by 12 865 pa-
tients who received mirtazapine 15 to 45 mg/day
for 6 weeks in either of 2 noncomparative trials
were somnolence (1.3 and 5.9%), dizziness (1.3 and
2.4%), dry mouth (1.0 and 1.3%) and bodyweight
gain (0.4 and 2.1%) [both trials were presented as
abstracts].[51,52] Restlessness, nausea or headache
also each occurred in 1 to 2.1% of patients in the
smaller study (n = 2460).[52] Similarly, dry mouth,
drowsiness, excessive sedation, increased body-
weight and increased appetite were reported signif-
icantly more frequently with mirtazapine than with
placebo (p ≤ 0.05) in 2 meta-analyses.[58,76] Con-
versely, headache, bodyweight decrease and in-
somnia were significantly more common with pla-
cebo than with mirtazapine (p ≤ 0.05). The
analyses included results from placebo-controlled
trials in 359 mirtazapine recipients from the clini-
cal trial development programme[76] and 194
mirtazapine recipients from studies of 6 weeks’ du-
ration.[58]
Data from the double-blind continuation trial of
up to 2 years’ duration that included a total of 217
patients showed that bodyweight gain was the only
event experienced by significantly more mirtazap-
ine than placebo recipients (18.9 vs 0%, p < 0.05).[61]
The mean bodyweight increase with mirtazapine
was 1.4kg, whereas placebo-treated patients had a
mean reduction in bodyweight (0.1kg). The pro-
© Adis International Limited. All rights reserved.
623
portion of patients with a clinically relevant in-
crease in bodyweight (≥7%) was 12.7% with mir-
tazapine and 3.6% with placebo.[61]
In some trials, the incidence of sedation-related
symptoms (including somnolence) decreased after
the first week of treatment, despite increasing dos-
ages of mirtazapine.[62,65,68] This was also the case
for dry mouth in 1 trial.[67] Indeed, the preliminary
report of a pooled incidence study,[77] which in-
cluded data from 824 mirtazapine recipients who
had participated in placebo-controlled trials, showed
that higher initial dosages of mirtazapine (≥15
mg/day) were associated with a lower incidence of
somnolence than subtherapeutic dosages of <15
mg/day. This effect is likely to be a result of the
pharmacological profile of mirtazapine (table I).[14]
Case reports[78] and pilot studies[79,80] have shown
that sexual dysfunction (anorgasmia and decreased
libido), one of the most common adverse events seen
with SSRIs,[81] resolves when mirtazapine is added
to, or substituted for, patients’ SSRI regimens. Fur-
thermore, an analysis of placebo-controlled trials
(presented as an abstract) reported that mirtazapine
was associated with decreased libido in only 4% of
the 359 treated patients of either gender, an inci-
dence equivalent to, or lower than, that seen with
placebo.[82]
Data published so far indicate that mirtazapine
has a low potential for inducing seizures. Monitor-
ing during the clinical trial programme and post-
marketing period in The Netherlands identified
seizure development in only 1 patient (incidence
0.04%) with mirtazapine.[76] The patient had a his-
tory of seizures during previous clomipramine ther-
apy. Since that review, grand mal seizure has been
reported in 1 additional mirtazapine recipient with
a history of seizures participating in a comparative
trial.[67]
No clinically relevant changes in blood pressure
or heart rate were detected in mirtazapine recipi-
ents included in the majority of trials discussed in
section 4.[62,63,65-68,73,83] These data support the con-
clusions of the previous review, which reported that
blood pressure and heart rate are not significantly
different in mirtazapine and placebo recipients.[4]
Drugs 1999 Apr; 57 (4)
624
5.1.1 Comparisons with Other Antidepressants
Treatment withdrawal because of adverse
events occurred in up to 14% of mirtazapine re-
cipients in trials with active comparators. With-
drawal rates were similar between active treatment
groups.[21,46,47,62,63,65-68,73,83]
Comparisons with Tricyclic
Antidepressants or Trazodone
Tolerability data from short and long term com-
parisons between mirtazapine and tricyclic antide-
pressants or trazodone discussed in section 4.3 indi-
cated a general trend for a lower incidence of events
such as drowsiness, tremor, dyspepsia and anticho-
linergic symptoms, including dry mouth, constipa-
tion and blurred vision, with mirtazapine than with
comparator antidepressants.[47,61-63,65-68,73,83] In-
creased appetite and bodyweight gain, in 2 trials,
were the only events reported to have been experi-
enced by significantly more recipients of mirtazap-
ine than of comparator drugs.[21,46] Adverse events
were not assessed in the comparison between mir-
tazapine and imipramine.[50]
A significantly greater proportion of amitrip-
tyline than mirtazapine recipients experienced dry
mouth and sweating[66] or constipation and dys-
pepsia[62] in two 6-week double-blind randomised
studies and dry mouth, drowsiness, constipation
and tremor in a continuation trial of up to 2 years’
duration (all p ≤ 0.05).[61] In the only trial compar-
ing mirtazapine with clomipramine, tremor was re-
ported by a significantly greater proportion of
clomipramine than mirtazapine recipients; in this
6-week double-blind randomised trial which in-
cluded hospitalised patients, relative proportions
were 22.0 vs 8.7% at week 3 and 16.1 vs 3.5% at
week 6 (both p = 0.03).[67]
Comparisons with SSRIs
In a recent double-blind randomised compar-
ison of mirtazapine and fluoxetine, tolerability pro-
files were generally similar between groups and
there were no significant between-group differences
for any adverse event.[21] Serotonin-related adverse
events, including nausea, vomiting, headache and
insomnia, occurred in a greater proportion of flu-
oxetine (38.8%) than mirtazapine (24.2%) recip-
© Adis International Limited. All rights reserved.
Holm & Markham
ients.[21] These results concur with those from the
clinical trials development programme, in which
serotonin-related events were less common with
mirtazapine than with placebo.[1] Anticholinergic
events (dry mouth or blurred vision) were more com-
mon with mirtazapine (25.8%) than with fluoxetine
(6.0%). Other adverse events reported by >5% of
mirtazapine or fluoxetine recipients were dizziness
(7.6 vs 9.0%), drowsiness (10.6 vs 7.5%), fatigue
(6.1 vs 4.5%) and somnolence (18.2 vs 13.4%).[21]
Mirtazapine was also reported to have a similar
tolerability profile to the SSRIs citalopram and
paroxetine in 2 double-blind randomised trials
that are available as abstracts.[19,20] Nausea and
sweating were significantly more common with
citalopram than with mirtazapine, whereas in-
creased appetite and bodyweight were signifi-
cantly more common with mirtazapine (p values
not given).[20] A greater proportion of mirtazapine
than citalopram recipients had a clinically relevant
increase in bodyweight in this study. Similarly, in
the comparison between mirtazapine and paroxet-
ine,[19] influenza-like symptoms and complaints of
bodyweight gain were more frequently reported by
mirtazapine than paroxetine recipients (9.6 vs 3.7%
and 14.8 vs 3.7%, respectively), whereas vomiting,
tremor and sweating were reported by 0.7 to 2.2%
of patients in the mirtazapine group and 5.2 to 7.5%
of patients in the paroxetine group. The incidence
of orgastic dysfunction was lower in mirtazapine
than paroxetine recipients (3.1 vs 13.5%).[19] Nei-
ther of the 2 comparative trials involving mirtazap-
ine and fluoxetine[21] or citalopram[20] reported that
any treatment was associated with sexual dysfunc-
tion.
5.1.2 In the Elderly
Mirtazapine was well tolerated in 105 elderly
patients included in either of 2 double-blind ran-
domised trials that compared mirtazapine with
trazodone (n = 146)[46] or amitriptyline (n = 115)[47]
and in 2 noncomparative trials in a total of 466
patients that were presented as abstracts.[48,49] In
the comparative trials in elderly patients, the ad-
verse event profile of mirtazapine was similar to
that seen in younger patients: dry mouth, somno-
Drugs 1999 Apr; 57 (4)
Mirtazapine: A Review
lence/ fatigue, constipation and dizziness were the
most commonly reported events in the elderly.[46,47]
Dry mouth and constipation were significantly
more common in elderly patients (n = 131) than in
those aged ≤65 years (n = 1247) in a pooled anal-
ysis of data; however, the higher incidence of these
events was thought to be related to the aging pro-
cess.[76] The only event that was significantly more
common with mirtazapine than active comparators
in elderly patients was increased appetite. This
symptom was reported by 24% of mirtazapine re-
cipients compared with only 4% of trazodone re-
cipients in one of the studies conducted in 146 el-
derly outpatients (mean age 62 years) [p ≤ 0.05].
The mean increase in bodyweight was 1.3kg with
mirtazapine.[46] No adverse event was significantly
more frequent in mirtazapine than comparator drug
treatment groups.[46,47]
Cardiovascular events were uncommon in el-
derly mirtazapine recipients participating in com-
parative trials[46,47] and the drug was reported to
have a favourable tolerability profile in the non-
comparative retrospective analysis, where 62% of
the 141 patients had cardiovascular disorders.[48]
Furthermore, changes in blood pressure and heart
rate tended to be less with mirtazapine than with
amitriptyline[47] and trazodone.[46]
5.2 Effects on Laboratory Parameters
The majority of trials discussed in section 4.3
(including a study with a treatment period of up to
2 years) reported that there was no change in lab-
oratory parameters after treatment with mirtazap-
ine.[46,47,61-63,65,66,68,73] Changes in laboratory pa-
rameters with mirtazapine, most of which are rare,
have included increases in liver enzyme,[67] serum
cholesterol and serum triglyceride levels[58] and
neutropenia.[1]
5.3 Suicidal Tendencies and Overdose
In therapeutic trials discussed in section 4.3, it
was generally stated that patients with known ac-
tive suicidal tendencies were excluded, as is rou-
tine in the clinical trials development programme
of all antidepressants. Thus, the interpretation of
© Adis International Limited. All rights reserved.
625
data relating to suicidal tendencies is affected.
Studies did not report HDRS suicidality item scores;
however, the incidence of suicide attempts and ac-
tive suicide in clinical trials was similar for mirtaz-
apine and active comparators, with isolated inci-
dents occurring in 2 trials.[67,73]
Intentional overdose of antidepressants is one
of the most common methods of suicide in de-
pressed patients.[84] Data suggest that tricyclic anti-
depressants are more likely than other antidepres-
sant classes to be associated with fatal overdose
and it is generally accepted that older tricyclic an-
tidepressants are associated with a fatal outcome
from cardiovascular complications at doses of 15
to 20 mg/kg.[84] Somnolence and tachycardia were
typical symptoms after an overdose of mirtazapine
(doses up to 1500mg or 30 times the maximum
recommended daily dose of 45 mg/day) in male
and female patients during postmarketing surveil-
lance and clinical trials.[76,85-89] All patients for
whom follow-up information is available have
recovered from mirtazapine overdose without ad-
verse sequelae after observation or therapies in-
cluding gastric lavage and activated charcoal. No
patient was reported to have had a seizure. Patients
ranged in age from 3 to 90 years old.[76,85-89] One
case of respiratory depression has been reported
(after mirtazapine 1350mg and alprazolam 60mg)
in a patient who was also unresponsive to verbal
stimuli and had no gag reflex. The patient was ex-
tubated after 2 days’ ventilatory assistance; how-
ever, the outcome of the episode is unknown be-
cause the patient was lost to follow-up.[85] Mild
leucocytosis was detected in a patient after mirta-
zapine 1500mg was taken.[86]
Conclusions can not be made regarding the ef-
fects of mirtazapine taken concomitantly with
other neuropsychotherapeutic drugs, including
antidepressants, in overdose.[85] A fatality has been
reported in a patient who took mirtazapine 30 to 45mg
with an overdose of amitriptyline and chlorprothix-
ene; amitriptyline toxicity was thought to be the
cause of death.[90] Other patients have recovered after
taking mirtazapine overdoses with midazolam,[87]
dothiepin,[88] amitriptyline,[86] lorazepam,[89] alpraz-
Drugs 1999 Apr; 57 (4)
626
olam or clonazepam.[85] However, CNS depression
was more pronounced in patients taking mirtazap-
ine and other CNS depressants concomitantly in
overdose than in patients taking an overdose of
mirtazapine alone.[85]
6. Dosage and Administration
It is recommended that mirtazapine therapy is
started at a dosage of 15 mg/day and that this is
gradually titrated upward depending on individual
response in adults and elderly patients.[91,92] A re-
cent study suggests that an initial dosage of 30
mg/day may be preferable in terms of improving
some aspects of sleep as it has equivalent tolerabil-
ity to an initial dosage of 15 mg/day.[93] The max-
imum effective dose is usually 45 mg/day. It is rec-
ommended that mirtazapine be taken as a single
evening dose.[91,92]
Elderly patients and patients with hepatic or re-
nal insufficiency should be closely supervised when
dosages are increased.[91,92]
Mirtazapine is not currently recommended for
use during pregnancy or lactation because its safety
has not been established in these situations,[91]
apart from a single case report of the uneventful use
of the drug during pregnancy.[94] The drug should
not be given to patients who are taking monamine
oxidase inhibitors or within 2 weeks of completing
therapy with these agents.[91]
6.1 Drug Interactions
Mirtazapine is considered to have a low potential
for interaction with coadministered drugs because
it only weakly inhibits the cytochrome P450 system
(see section 3).[13,14] However, few clinical drug in-
teraction data are available for mirtazapine.
Coadministration of mirtazapine and diaze-
pam[30] or lithium[95] did not affect the pharmaco-
kinetics of either drug. In addition, mirtazapine did
not affect the rate of ethanol (alcohol) absorption.
However, cognitive and motor performance were
impaired when mirtazapine was coadministered
with ethanol or diazepam.[1] Changes in Cmax and
AUC values for amitriptyline after coadministra-
tion of mirtazapine were not considered to be clin-
© Adis International Limited. All rights reserved.
Holm & Markham
ically relevant (Cmax and AUC reduced by 23 and
13%, respectively, in female volunteers, and Cmax
increased by 23% in male volunteers).[96]
Case reports have described possible drug inter-
actions when mirtazapine was given for major de-
pression: hypomania after the addition of mirtazap-
ine 15 mg/day to sertraline 250 mg/day,[97] psychosis
after the addition of mirtazapine 15 to 60 mg/day
to levodopa, pergolide, selegiline and memantine
in a 44-year-old patient with Parkinson’s disease[98]
and hypertension after the addition of mirtazapine
15 to 30 mg/day to amitriptyline 25 mg/day.[99] All
patients recovered after mirtazapine was discon-
tinued.[97-99]
7. Place of Mirtazapine in the
Management of Major Depression
Depression is a common illness, which often has
a chronic course and is associated with a high de-
gree of morbidity and mortality.[100] The under-
treatment of depression is of concern:[101] it has
been estimated that fewer than one-third of patients
who are diagnosed as being depressed receive a
prescription for antidepressants, and the majority
of patients with the illness are not diagnosed.[100]
The total direct and indirect costs associated
with depression have been estimated to be $US26
billion to $US43.7 billion (1990 values) in the US
and £3.4 billion (1992 values) in the UK.[100] Al-
though assessments vary widely because of the in-
clusion of different costs, it is agreed that costs
relating to depression form a large proportion of
healthcare budgets, [100] and available data suggest
that it is generally cost effective to treat depres-
sion.[101]
Over the past 40 years, a number of drugs have
become available to treat depression. The older ‘first
generation’ drugs include the tricyclic antidepres-
sants and the monoamine oxidase inhibitors, while
the newer ‘second generation’ drugs include the
SSRIs, reversible inhibitors of monoamine oxidase
A, serotonin and noradrenaline reuptake inhibitors
and other pharmacologically distinct drugs includ-
ing mirtazapine, trazodone, bupropion and nefazo-
done.[102] Newer antidepressants have been devel-
Drugs 1999 Apr; 57 (4)
Mirtazapine: A Review
oped primarily in response to concerns about the
tolerability of tricyclic antidepressants and mono-
amine oxidase inhibitors and toxicity after tricyclic
antidepressant overdose.[103] Indeed, currently avail-
able antidepressants appear to generally have equiv-
alent efficacy,[104] and clinically significant im-
provement is usually seen in 65 to 75% of patients
after treatment with any therapy.[102] The SSRIs
have replaced the tricyclic antidepressants as the
preferred first-line therapy for major depression and
they are now the most widely used antidepressant
class.[105] However, there are concerns that the
SSRIs may not be as effective as the tricyclic anti-
depressants for the treatment of certain patient
groups, including those with severe or therapy-
resistant depression.[106]
Previous reviews have established that mirtaza-
pine has superior efficacy to placebo.[4,14] Clinical
evidence suggests that short term mirtazapine ther-
apy is as effective as a number of currently avail-
able antidepressants including amitriptyline, clo-
mipramine and doxepin, and that it is at least as
effective as trazodone. Imipramine has been shown
to be associated with better HDRS response rates
than mirtazapine in a single comparison; however,
response rates were lower than would be expected
with both drugs. Mirtazapine was more effective
than the SSRI fluoxetine at weeks 3 and 4 of ther-
apy, and more effective than paroxetine and citalo-
pram at weeks 1 and 2, respectively. These data indi-
cate an earlier onset of action with mirtazapine
than with the SSRIs. However, efficacy data are
available only from single comparisons with each
SSRI and two of these trials are yet to be published
in full.
Initial data from placebo-controlled continua-
tion studies (the standard design for long term tri-
als) suggest that mirtazapine is associated with
higher sustained remission rates than amitriptyline
and that it has equivalent efficacy to amitriptyline
for the prevention of relapse in patients who re-
spond to short term therapy. This is important,
since it is currently recommended that antidepres-
sant therapy is continued for at least 4 months after
an acute response.[107] The ability of mirtazapine
© Adis International Limited. All rights reserved.
627
to prevent relapse needs to be investigated further
with different antidepressant comparators, includ-
ing SSRIs in order to determine the relative long
term efficacy of mirtazapine.
The unique pharmacological profile of mir-
tazapine, i.e. enhancement of noradrenergic and
5-HT1A-mediated serotonergic neurotransmission,
and the tolerability and pharmacokinetic profiles
of the drug may offer benefits over other existing
antidepressants.[18]
Tolerability data from a number of trials showed
that mirtazapine was less likely to be associated
with anticholinergic effects and other events in-
cluding drowsiness, tremor and dyspepsia than tri-
cyclic antidepressants. There was a greater ten-
dency for SSRI-related adverse events (including
headache, nausea and vomiting) with fluoxetine
and citalopram than with mirtazapine, although,
overall, mirtazapine had a similar tolerability pro-
file to the SSRIs. Increased appetite and body-
weight gain were the only events that were more
common with mirtazapine than with comparator
antidepressants.
Mirtazapine is associated with histamine H1 re-
ceptor antagonist effects: somnolence, drowsiness,
dry mouth, increased bodyweight and increased
appetite were the most common adverse events re-
ported with mirtazapine in noncomparative trials
(each were reported in <6% of patients). However,
preliminary data suggest that these effects are
counteracted by the noradrenergic effects of mir-
tazapine when the drug is commenced at dosages
≥15 mg/day, i.e. within the recommended dosage
range.
Mirtazapine has been shown to be effective in
patients with moderate or severe depression in-
cluding those with anxiety symptoms or sleep dis-
turbances. It has also been effective and well toler-
ated in elderly patients, with similar efficacy to
amitriptyline and trazodone. Its lack of effect on
vital signs in clinical studies may be important in
this latter patient group, although detailed data on
the cardiovascular effects of the drug are lacking.
In vivo and in vitro data suggest that mirtazapine
has a low potential for interaction with drugs
Drugs 1999 Apr; 57 (4)
628
metabolised by the CYP isoenzymes CYP1A2,
CYP3A4 and CYP2D6 (including tricyclic antide-
pressants, antipsychotics and some SSRIs). Al-
though clinical data on interactions with antide-
pressants are limited, mirtazapine may therefore
prove to be useful when patients are taking con-
comitant medications or as a combination or aug-
mentation therapy for the treatment of patients with
therapy-resistant depression. Indeed, mirtazapine
is theoretically an ideal augmentation therapy for
other antidepressants in view of its unique mecha-
nism of action. The ability of mirtazapine to reduce
extrapyramidal adverse effects associated with an-
tipsychotics in animal models may also prove valu-
able in patients requiring concomitant antidepres-
sant and antipsychotic therapy.
Despite high acquisition costs for mirtazapine
in France and Austria, the drug was more cost effec-
tive than fluoxetine or amitriptyline for the treat-
ment of major depression from the perspectives of
the national health funder. Further studies are re-
quired to determine whether these findings can be
extended to health systems in other countries.
In summary, mirtazapine is effective and well
tolerated for the treatment of patients with moder-
ate to severe major depression. Further research
is required to define the comparative efficacy of
mirtazapine in specific patient groups, including
the elderly and those with severe depression. Clari-
fication of its efficacy as an augmentation therapy
and in patients with refractory depression and its
role in improving the efficacy and reducing the ex-
trapyramidal effects of antipsychotic drugs would
also help to establish its clinical value. The low
potential for interaction with drugs that are meta-
bolised by CYP2D6, including antipsychotics, tri-
cyclic antidepressants and some SSRIs, may also
make mirtazapine an important option for the treat-
ment of major depression in patients who require
polytherapy. Mirtazapine also appears to be useful
in patients with depression who present with anxi-
ety symptoms and sleep disturbance.
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Correspondence: Kristin J. Holm, Adis International Lim-
ited, 41 Centorian Drive, Private Bag 65901, Mairangi Bay,
Auckland 10, New Zealand.
E-mail: demail@adis.co.nz
Drugs 1999 Apr; 57 (4)