Lack of significant toxicity after mirtazapine overdose: five-year review of cases admitted to a regional toxicology unit.
ABSTRACT Mirtazapine is a comparatively new antidepressant that selectively blocks central alpha2-adrenergic autoreceptors and postsynaptic 5-HT2 and 5-HT3 receptors, causing reduced neuronal norepinephrine and serotonin reuptake. The prevalence of mirtazapine prescribing has steadily risen; however, comparatively little information is available regarding the clinical features associated with mirtazapine overdose.
To characterize the toxic features that result from mirtazapine overdose.
We performed a retrospective case analysis of patients admitted to the Toxicology Unit of the Royal Infirmary of Edinburgh between January 2000 and December 2004 after stated mirtazapine overdose. Casenotes were examined for clinical, laboratory, and electrocardiographic safety data.
There were 117 mirtazapine cases where the median (interquartile range) stated dose ingested was 450 mg (240-785 mg). Conscious level was reduced in 27.2% of patients and there was a higher incidence of tachycardia (30.4%) than predicted from normal reference range values (p < 0.001). There was no evidence of any other significant clinical, laboratory, or electrocardiographic abnormality.
Severe toxic features could be attributed to other co-ingested drugs or alcohol. The adverse clinical effects attributable to mirtazapine overdose appeared mild and predictable. Mirtazapine overdose appears to be associated with fewer features of severe toxicity than previously reported for other antidepressants.
- [show abstract] [hide abstract]
ABSTRACT: The neurochemical and autonomic pharmacological profile of 1,2,3,4,10, 14b-hexahydro-2-methyl-pyrazino[2,1-a]pyrido[2,3-c]pyrido[2, 3-c]  benzazepine [+/-)Org 3770) and the related antidepressant drug, mianserin, have been compared. The uptake of [3H]noradrenaline ([3H]NA) in vitro was weakly affected by (+/-)Org 3770 (pKi = 5.6) in contrast to mianserin (pKi = 7.4). Both (+/-)Org 3770 and mianserin facilitated the release of [3H]NA in slices of cortex. The effects of NA mediated by alpha 2-adrenoceptors on the release of both [3H]NA or [3H]serotonin ([3H]5-HT) were antagonized by (+)Org 3770 with pKi values of 8.4 and 8.1, respectively. However, (-)Org 3770 only antagonized the effect of NA on the release of [3H]5-HT (pA2 = 7.7). The binding of [3H]rauwolscine to alpha 2-adrenoceptors was inhibited by (+/-)Org 3770 and mianserin with identical affinity (pKi = 7.0), whereas the binding of [3H]prazosin to alpha 1-adrenoceptors was less potently affected by (+/-)Org 3770 (pKi = 6.4) than by mianserin (pKi = 7.1). A similar difference was found for alpha 1- and alpha 2-adrenoceptors in vas deferens of the rat. The binding of [3H]mianserin to 5-HT2 receptors was less potently blocked by (+/-)Org 3770 (pKi = 8.1) than by mianserin (pKi = 9.4) while the binding of [3H]mepyramine to histamine-1 receptors was more potently affected by (+/-)Org 3770 (pKi = 9.3) than by mianserin (pKi = 8.75). The binding of [3H]quinuclidinylbenzilate to muscarinic cholinergic receptors was blocked equally by (+/-)Org 3770 (pKi = 6.1) and mianserin (pKi = 6.3). Similar data on tryptamine-D, histamine-1 and muscarinic cholinergic receptors in isolated organs were obtained. A prominent role for the blockade of alpha 2-adrenoceptors in the therapeutic effects of mianserin and (+/-)Org 3770 in depression is suggested, probably excluding a role of inhibition of the uptake of NA.Neuropharmacology 05/1988; 27(4):399-408. · 4.11 Impact Factor
- [show abstract] [hide abstract]
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 symptoms 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, respectively, 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, including 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 antipsychotic 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 important option for the treatment of major depression in patients who require polytherapy. Mirtazapine also appears to be useful in patients with depression who present with anxiety symptoms and sleep disturbance.Drugs 05/1999; 57(4):607-31. · 4.63 Impact Factor
- [show abstract] [hide abstract]
ABSTRACT: Efficacy data were available from 405 severely depressed patients (baseline 17-item Hamilton Rating Scale for Depression-HAMD scores > or = 25) participating in randomized, double-blind, amitriptyline-controlled studies of mirtazapine. Main efficacy variable were changes from baseline in the group mean 17-item HAMD scores and responder rates. Secondary efficacy variables were changes in depressed mood item on the HAMD and in factors derived from the 17-item HAMD scale. Treatment with either mirtazapine or amitriptyline resulted in robust reductions of baseline HAMD scores and in similar and high percentages of responders. Both drugs produced favourable effects on depressed mood and on symptoms commonly associated with depression, such as anxiety, sleep and vegetative disturbances. There were neither statistically significant nor clinically relevant differences between mirtazapine and amitriptyline at any assessment point nor at endpoint. The results demonstrate that the new antidepressant mirtazapine and the tricyclic antidepressant amitriptyline are equally effective in the treatment of severely depressed patients.European Neuropsychopharmacology 06/1997; 7(2):115-24. · 4.60 Impact Factor
Clinical Toxicology (2007) 45, 45–50
Copyright © Informa Healthcare
ISSN: 1556-3650 print / 1556-9519 online
Lack of significant toxicity after mirtazapine overdose:
A five-year review of cases admitted to a regional
W. STEPHEN WARING, ALISON M. GOOD, and D. NICHOLAS BATEMAN
Scottish Poisons Information Bureau, Royal Infirmary of Edinburgh, Edinburgh, Scotland, United Kingdom
Introduction. Mirtazapine is a comparatively new antidepressant that selectively blocks central ?2-adrenergic autoreceptors and post-
synaptic 5-HT2and 5-HT3receptors, causing reduced neuronal norepinephrine and serotonin reuptake. The prevalence of mirtazapine
prescribing has steadily risen; however, comparatively little information is available regarding the clinical features associated with
Aims. To characterize the toxic features that result from mirtazapine overdose.
retrospective case analysis of patients admitted to the Toxicology Unit of the Royal Infirmary of Edinburgh between January 2000 and
December 2004 after stated mirtazapine overdose. Casenotes were examined for clinical, laboratory, and electrocardiographic safety
Results. There were 117 mirtazapine cases where the median (interquartile range) stated dose ingested was 450 mg (240–785
mg). Conscious level was reduced in 27.2% of patients and there was a higher incidence of tachycardia (30.4%) than predicted from
normal reference range values (p<0.001). There was no evidence of any other significant clinical, laboratory, or electrocardiographic
Conclusions. Severe toxic features could be attributed to other co-ingested drugs or alcohol. The adverse clinical effects
attributable to mirtazapine overdose appeared mild and predictable. Mirtazapine overdose appears to be associated with fewer features of
severe toxicity than previously reported for other antidepressants.
Methods. We performed a
Electrocardiograph, Safety monitoring, Drug toxicity
Mirtazapine (Zispin®, Remeron®) was developed by
Organon, and first became available for clinical use in
2001. It is a 6-aza analogue of the tetracyclic antidepressant
mianserin (1). Unlike other antidepressants that inhibit neuro-
transmitter uptake, the pharmacological effects of mirtaza-
pine in the central nervous system are thought to be due
to the blockade of presynaptic ?2-adrenergic receptors and
postsynaptic 5-HT2and 5-HT3receptors, which results in an
increased noradrenergic and 5-HT1A-mediated serotonergic
activity (2,3). Mirtazapine also has a high affinity for central
histamine1receptors (4). Clinicaltrialsshowmirtazapinetobe
at least as efficacious as tricyclic antidepressants and selective
depression (5,6). Furthermore, mirtazapine appears to have an
earlier onset of action than other antidepressants; possibly as a
result of its unique mechanism of action (7). It is available in a
Received 27 September 2005; accepted 30 November 2005.
Address correspondence to Dr. W. Stephen Waring, Scottish
Poisons Information Bureau, Royal Infirmary of Edinburgh, 51
Little France Crescent, Edinburgh EH16 4SA, Scotland, United
Kingdom. E-mail: firstname.lastname@example.org
bedtime or occasionally in divided doses.
The use of mirtazapine has progressively increased after it
became available, and prescription monitoring suggests that
it is free of any major adverse clinical effects across large
patient populations (9). A number of other adverse effects
include drowsiness, increased appetite and weight gain, dizzi-
ical features associated with mirtazapine overdose. Therefore,
we wished to examine the clinical features after a mirtazapine
overdose among patients admitted to the Toxicology Unit of
the Royal Infirmary of Edinburgh, and to examine laboratory
and electrocardiographic safety variables so as to better char-
acterize the toxicity profile of mirtazapine.
We performed a retrospective review of casenotes from
patients admitted to our unit between January 2000 and
December 2004, inclusive, after taking a mirtazapine
W.S. Waring et al.
overdose. Cases were identified from a local register of
patients attending the Royal Infirmary of Edinburgh. While
community toxicological advice is available to medical
professionals in the United Kingdom via the National Poisons
Information Service, this is unlikely to have reduced the
number of patients attending the hospital because little was
known about the potential toxic effects of mirtazapine at the
time of the study. Our local policy is that patients attending
the Emergency Department after drug ingestion are admitted
to our Toxicology Unit for ongoing medical care and psychi-
atric review. Patients will be admitted to the High Depen-
dency Unit (HDU) if non-invasive ventilatory support is
likely to be required, and to the Intensive Treatment Unit
(ITU) if invasive ventilatory support, haemodialysis or other
critical care intervention is likely to be required. Patients in
all of these areas were included in the study.
A standardized data collection sheet was used, and data
were linked to a unique hospital code so as to preserve
patient anonymity. The date and time of overdose, stated
amount ingested, type and amount of any co-ingested drug or
alcohol, time elapsed between ingestion and hospital atten-
dance, age and gender, and any history of previous overdose,
drug or alcohol dependence were recorded. Clinical data
recorded were symptoms reported on arrival at the hospital,
Glasgow Coma Scale, heart rate, blood pressure, respiratory
rate, temperature, and oxygen saturation. Laboratory data
examined were serum urea, creatinine, electrolytes, creati-
nine kinase, and liver biochemistry. Automated electrocar-
diographic intervals PR, QRSD, QT and QTc were recorded,
where QTc represented the QT interval after Bazett’s
Where more than one clinical, laboratory or electrocardio-
graphic variable had been documented, the most abnormal
value was used in safety data analysis.
Data on community prescribing of mirtazapine was obtained
from the Lothian Health Board, which pertains to the same
patient population as served by our hospital. The data are
expressed as General Practitioner prescriptions items for
mirtazapine per quarter for the whole population of Lothian
Normality tests found that data were not distributed para-
metrically and, therefore, median and interquartile ranges
were used as descriptive statistics with population ranges
quoted where appropriate. Abnormal variables were iden-
tified as those outside the normal 95% population refer-
ence values, and statistical significance determined by bino-
mial tests. StatsDirect™ statistical software version 2.2.2
(StatsDirect Ltd., Cheshire, UK) was used to perform post-
hoc binomial power calculations, and to examine correla-
tions between stated mirtazapine dose and safety variables.
Pearson’s r-values were subjected to Fisher’s transforma-
tion to give for 95% confidence intervals, and p <0.05 was
accepted as statistically significant in all cases.
Between 2000 and 2004, 153 admission records contained
mention of mirtazapine or Zispin®. Medical casenotes were
available for all of these, but 36 were excluded because
patients had not reported taking a mirtazapine overdose, and
the remaining 117 cases were included in the formal data
analyses. The frequency of patients admitted to our unit after
ingesting mirtazapine has risen over the study period, and is
consistent with increasing numbers of mirtazapine prescrip-
tions issued in our region (Fig. 1).
Median (interquartile range) [population range] age was 35
y (26–46 y) [18–80 y], and 71 (60.7%) ingestions occurred in
women. The median stated amount of mirtazapine ingested
was 450 mg (240–785 mg) [30–2520 mg], and patients had
presented to the hospital 1.6 h (1.1–3.2 h) [0.5–48.0 h] after
ingestion. Deliberate self-inflicted trauma (e.g., self-cutting)
was evident in three patients (2.6%) at the time of presenta-
tion to hospital.
Co-ingested drugs and alcohol
Mirtazapine overdose was associated with co-ingestion of
alcohol in 69 patients (59.0%), other drugs in 70 patients
(59.8%), both alcohol and other drugs in 45 patients (38.5%),
and neither in 23 patients (19.7%). Mirtazapine overdose was
associated with co-ingestion of one other drug in 36.8%, two
other drugs in 11.1%, and three or more other drugs in 12.0%.
e t i
o i t
p i r
Fig. 1. Quarterly numbers of patients admitted to the hospital
after mirtazapine overdose during 2000–2004, and corresponding
numbers of prescriptions issued locally.
The most commonly co-ingested medications were benzo-
diazepines (20.6%), other antidepressants (15.0%), antipsy-
chotics (10.8%), acetaminophen (7.8%), opiates (6.9%), and
co-codamol (acetaminophen-codeine combination, 3.9%). To
better characterize the potential effects of mirtazapine in over-
dose, data were examined across three groups: (1) the whole
population, (2) the subgroup of patients who had not co-
ingested other drugs, and (3) the further subgroup who had
not co-ingested other drugs or alcohol.
Clinical safety data
On arrival to the hospital, 27.2% of patients reported drowsi-
ness or fatigue, and the remainder were asymptomatic. Six
patients had reduced Glasgow Coma Scale (GCS) <14
(5.1%). In these six, the stated amount of ingested mirtazapine
was 720 mg (450–1020 mg), and five patients had co-ingested
alcohol. In one patient, GCS was 3 on arrival to hospital, 1.5
h after taking mirtazapine 210 mg with large quantities of
chlorpromazine and alcohol; this patient was monitored in a
High Dependency Unit but recovered quickly and no specific
treatment was needed. Another patient presented with GCS
6, 3 h after taking unknown quantities of mirtazapine, carba-
mazepine, promethazine and diazepam, and required tempo-
rary invasive ventilation in the Intensive Care Unit.
Vital signs were documented in the casenotes in 115
patients (98.2%), and the occurrence of abnormal values
is summarized in Table 1. Heart rate was 87 min−1(76–
103 min−1), and systolic and diastolic blood pressures were
125 mmHg (114–140 mmHg) and 71 mmHg (63–80 mmHg),
respectively. Respiratory rate was 16 min−1(14–18 min−1),
oxygen saturation was 97% (95–98%), and body temperature
was 36.5?C (36.2–37.0?C).
Laboratory and electrocardiographic safety data
The prevalence of abnormal values is presented in Table 1,
and correlations between stated mirtazapine dose and safety
variables are presented in Table 2. Laboratory data were
available for 103 patients (88.0%). No major electrolyte
disturbance was documented in any patient. Mild hyperna-
traemia (7.8%, p = 0.004) and mild hypokalaemia (15.5%,
p<0.001) were found in patients who had co-ingested other
drugs or alcohol, and high ALT (7.8%, p = 0.004) and
GGT (12.6%, p<0.001) were found in patients who had
co-ingested other drugs. There was no significant correla-
tion between stated mirtazapine dose and serum sodium or
An electrocardiograph was available for 103 patients
(88.0%). Median PR interval 151 ms (140–162 ms), QRS 86
ms (79–92 ms), QT 342 ms (322–368 ms), and QTc 416 ms
Table 1. Summary of abnormal clinical, laboratory and electrocardiograph findings are shown as absolute number and percentage in
Study population (n=117)
No co-ingested drugs (n=47)
No co-ingested drugs or alcohol (n=23)
PR >200 ms
QRSD >120 ms
QTc >450 ms
*p<0.05, **p<0.005, ***p<0.001 by binomial testing, assuming a 0.025% population chance.
W.S. Waring et al.
Table 2. Correlation between stated amount of mirtazapine
ingested and safety variables
Fisher’s z transform
−0.130 to 0.271
−0.192 to 0.203
−0.162 to 0.233
−0.213 to 0.235
−0.298 to 0.127
−0.275 to 0.152
−0.049 to 0.362
0.059 to 0.452
−0.314 to 0.139
−0.223 to 0.237
−0.091 to 0.400
−0.301 to 0.112
−0.168 to 0.248
−0.257 to 0.388
−0.126 to 0.108
*p < 0.05.
(401–429 ms). A 30-year-old man had a short-lived episode
of supraventricular tachycardia 19 hours after claiming to
have taken mirtazapine 600 mg, acetaminophen 10 g and
2 pints of lager, which was asymptomatic and terminated
spontaneously (Fig. 2).
Fig. 2. Short-lived episode of supraventricular tachycardia (A)
in a 30-year-old man who alleged to have ingested mirtazapine
600 mg, acetaminophen 10 g and 2 pints of lager 19 hours earlier,
which reverted spontaneously to sinus rhythm (B). Electrocardio-
gram gridlines represent 1 mm divisions, calibrated at 25 mm/s and
Clinical course and outcome
Gut decontamination methods were not routinely adminis-
tered after mirtazapine ingestion. Two patients were admitted
to a critical care facility, and the remaining patients were
managed solely in a general medical ward. Twelve patients
(10.3%) required specific treatment; 11 of these received N-
acetylcysteine for concomitant acetaminophen ingestion. One
patient with fever and high serum creatinine kinase received
a single dose of cyproheptadine for suspected serotonergic
syndrome; however, he was subsequently diagnosed with
pneumonia and received oral antibiotics. One patient had a
lower urinary tract infection and was treated with antibiotics
and intravenous fluids.
The duration of stay in the hospital was 1 day [0–8 days];
104 patients (88.9%) were discharged home and 13 (11.1%)
transferred to a psychiatric facility for further assessment
and treatment. Thirteen patients (11.1%) required more than
one overnight stay in hospital, including two who had taken
mirtazapine alone: one of these required treatment for a
urinary tract infection, and the other needed to wait for an
available bed in a psychiatric hospital.
To the best of our knowledge, these findings represent the
largest series of mirtazapine overdose patients reported thus
far. A significant number of patients in this study had co-
ingested alcohol and other drugs, as would be anticipated in
such a patient group. A wide range of doses of mirtazapine
were claimed to have been ingested, up to an acute ingestion
of 2520 mg.
The major complication observed after mirtazapine inges-
tion was drowsiness and reduced conscious level in almost
28% of patients, but this did not necessitate any specific inter-
vention in patients who had ingested mirtazapine alone. This
is likely due to antagonism of central histamine1receptors,
for which mirtazapine has a high affinity (4). In therapeutic
doses, sedation is mild and thought to be offset by increased
noradrenergic activity (11). In the present study, ventilatory
support was required for one patient who had co-ingested
large amounts of other sedative drugs, whereas mirtazapine
itself did not appear to cause significant respiratory depres-
sion in the overall study group, even after large quantities
were stated to have been taken.
Tachycardia was common after mirtazapine ingestion, and
the heart rate observed in our patients (median 87 min−1,
range 54–140 min−1) was consistent with a comparable
patient group after ingestion of SSRI antidepressants (median
87 min−1, range 54–171 min−1), but less than after inges-
tion of tricyclic antidepressants (96 min−1, 60–180 min−1) or
venlafaxine (100 min−1, 56–138 min−1) (12). Tachycardia is
unlikely to have been caused by baroreceptor reflex activation
because significant hypotension was not observed. Mirtaza-
pine might have increased heart rate as a direct or indirect
drug effect, but this seems unlikely given that no dose-effect
relationship was observed, and tachycardia has not been noted
in previous studies. Other factors might have contributed to
increased heart rate in our patient group, including anxiety,
alcohol withdrawal and dehydration; however, the role of
these could not be addressed directly by the present study.
Mirtazapine overdose was not associated with any signifi-
cant prolongation of PR, QRS or QT intervals, suggesting that
cardiotoxicity is not a feature. This is reassuring because other
antidepressants have been found to have cardiotoxic effects
in overdose. For example, tricyclic antidepressant ingestion
is associated with prolonged QRS duration and increased risk
of potentially fatal arrhythmias (13). Recent safety concerns
have been raised in view of the emerging cardiotoxic effects
of venlafaxine, particularly in elderly patients and those with
prolongation of the QRS interval, and is associated with
a substantially increased risk of arrhythmias and seizures,
our patients, a short-lived asymptomatic episode of supraven-
tricular tachycardia was observed during cardiac monitoring.
and asymptomatic finding in young people (19).
An earlier study showed that venlafaxine overdose caused
seizures in 13.7% of patients, compared to 3.5% for tricyclic
antidepressants (p<0.01) and 1.3% for SSRIs (p<0.001);
(1.4–13.8) versus tricyclic antidepressants (p = 0.009) (12).
The present study found no evidence of increased seizure risk
risk of seizures, assuming a background frequency of 0.1%.
2.6%, assuming 95% confidence intervals.
Overall, our findings suggest that mirtazapine ingestion
is associated with only mild clinical features. There were
no significant adverse effects on any of the clinical, labora-
tory or ECG variables studied, and no specific treatment was
required, apart from those required by patients with concomi-
tant disease or who had co-ingested other drugs. A number
of clinical reports of patients who have taken a mirtazapine
overdose have been published previously, which suggest that
it is comparatively non-toxic (20–29). Two patients presented
with drowsiness and miosis, mimicking the effects of possible
opiate ingestion (21). In two patients that ingested 30–50
times the normal daily dose, plasma concentrations 100–500
times higher than normal, but no significant toxic features
were noted (22). A patient that ingested mirtazapine 375 mg,
and had a plasma concentration 10–25 times higher than
normal, had sinus tachycardia but no other toxic features (23).
One patient is reported to have ingested mirtazapine 1200 mg
and lorazapam 20 mg, and presented with reduced conscious
level, hypothermia and rhabdomyolysis, and required inva-
sive ventilation but made a full recovery (27). Rhabdomy-
olysis has been reported elsewhere after mirtazapine over-
dose and during therapeutic use, which was self-limiting in
both cases (28,29). One published case describes a successful
suicide attempt in a patient who had ingested mirtazapine,
sertraline and amitriptyline in combination, although the
mode of death was uncertain (30).
Based on our experience of treating these 117 cases, we
propose that patients presenting to the Emergency Depart-
ment after ingesting mirtazapine alone are unlikely to develop
toxic features beyond 4 hours post-ingestion, and such
patients could be considered for discharge home after this
period providing that an appropriate psychiatric evaluation
has been undertaken. Patients who have ingested mirtaza-
pine in a mixed drug overdose are at greater risk of adverse
effects and should be observed for clinical features of toxi-
city, which will depend predominantly on the co-ingested
agent. Co-ingestion of alcohol, benzodiazepines or opioids
exacerbates the sedative effects of mirtazapine and can be
associated with significant respiratory depression.
A key limitation of the study is that the lack of observed
toxic features does not exclude the possibility of toxic effects
of mirtazapine ingestion. With a sample size of 117 patients,
the risk of serious toxicity might be as high as 2.53% within
95% confidence intervals. A further limitation is that esti-
mation of the amounts ingested relied on the patients’ own
account, and plasma concentrations of mirtazapine were not
available to confirm the extent of drug exposure. Nonetheless,
the study sample was unselected, and likely to be represen-
tative of patients encountered in the everyday clinical situa-
tion elsewhere. Collection of data from different institutions
would have been useful for confirming the generalizability
of our findings to other patient populations.
Overall, these data are reassuring and do not raise any specific
concerns over the use of mirtazapine in high-risk patient
groups. They are consistent with emerging case reports and
review articles that suggest mirtazapine is comparatively non-
toxic in overdose.
We wish to thank Mome Mukherjee of the Health Intel-
ligence and Policy Unit, Lothian NHS Board for providing
data on mirtazapine prescription numbers, and Lisa Galloway
of the Royal Infirmary of Edinburgh for retrieving the patient
1. de Boer TH, Maura G, Raiteri M, de Vos CJ, Wieringa J, Pinder
RM. Neurochemical and autonomic pharmacological profiles of the
6-aza-analogue of mianserin, Org 3770 and its enantiomers. Neurophar-
macology 1988; 27:399–408.
2. Davis R, Wilde MI. Mirtazapine: a review of its pharmacology and
therapeutic potential in the management of major depression. CNS
Drugs 1996; 5:389–402.
W.S. Waring et al.
3. Stimmel GL, Dopheide JA, Stahl SM. Mirtazapine: an antidepressant
with noradrenergic and specific serotonergic effects. Pharmacotherapy
4. Holm KJ, Markham A. Mirtazapine: a review of its use in major depres-
sion. Drugs 1999; 57:607–631.
5. Kasper S, Zivkov M, Roes KC, Pols AG. Pharmacological treatment
of severely depressed patients: a meta-analysis comparing efficacy
of mirtazapine and amitriptyline. Eur Neuropsychopharmacol 1997;
6. Amini H, Aghayan S, Jalili SA, Akhondzadeh S, Yahyazadeh O,
Pakravan-Nejad M. Comparison of mirtazapine and fluoxetine in the
treatment of major depressive disorder: a double-blind, randomized
trial. J Clin Pharm Ther 2005; 30:133–138.
7. Schatzberg AF, Kremer C, Rodrigues HE, Murphy GM Jr. Mirtazapine
vs. Paroxetine Study Group. Double-blind, randomized comparison of
mirtazapine and paroxetine in elderly depressed patients. Am J Geriatr
Psychiatry 2002; 10:541–550.
8. Konstantinidis A, Stastny J, Ptak-Butta J, Hilger E, Winkler D,
Barnas C, Neumeister A, Kasper S. Intravenous mirtazapine in the
treatment of depressed inpatients. Eur Neuropsychopharmacol 2002;
9. Biswas PN, Wilton LV, Shakir SA. The pharmacovigilance of mirtaza-
pine: results of a prescription event monitoring study on 13554 patients
in England. J Psychopharmacol 2003; 17:121–126.
10. Luo S, Michler K, Johnston P, Macfarlane PW. A comparison of
commonly used QT correction formulae: the effect of heart rate on the
QTc of normal ECGs. J Electrocardiol 2004; 37(Suppl):81–90.
11. Winokur A, Sateia MJ, Hayes JB, Bayles-Dazet W, MacDonald MM,
Gary KA. Acute effects of mirtazapine on sleep continuity and sleep
architecture in depressed patients: a pilot study. Biol Psychiatry 2000;
12. Whyte IM, Dawson AH, Buckley NA. Relative toxicity of venlafaxine
and selective serotonin reuptake inhibitors in overdose compared to
tricyclic antidepressants. QJM 2003; 96:369–374.
13. Bailey B, Buckley NA, Amre DK. A meta-analysis of prognostic indi-
cators to predict seizures, arrhythmias or death after tricyclic antide-
pressant overdose. J Toxicol Clin Toxicol 2004; 42:877–888.
14. MHRArecent adviceon SSRIs.
2005, at http://medicines.mhra.gov.uk/ourwork/monitorsafequalmed/
15. Combes A, Peytavin G, Theron D. Conduction disturbances associated
with venlafaxine. Ann Intern Med 2001; 134:166–167.
16. Peano C, Leikin JB, Hanashiro PK. Seizures, ventricular tachycardia,
and rhabdomyolysis as a result of ingestion of venlafaxine and lamot-
rigine. Ann Emerg Med 1997; 30:704–708.
17. Kelly CA, Dhaun N, Laing WJ, Strachan FE, Good AM, Bateman DN.
Comparative toxicity of citalopram and the newer antidepressants after
overdose. J Toxicol Clin Toxicol 2004; 42:67–71.
18. Khalifa M, Daleau P, Turgeon AJ. Mechanism of sodium channel block
by venlafaxine in guinea pig ventricular myocytes. J Pharmacol Exp
Ther 1999; 291:280–284.
19. Strickberger SA, Ip J, Saksena S, Curry K, Bahnson TD, Ziegler
PD. Relationship between atrial tachyarrhythmias and symptoms. Heart
Rhythm 2005; 2:125–131.
20. Hoes MJ, Zeijpveld JH. First report of mirtazapine overdose. Int Clin
Psychopharmacol 1996; 11:147.
21. Langford NJ, Ferner RE, Patel H, Munyame C, Hamlyn AN.
Mirtazepine overdose and miosis. J Toxicol Clin Toxicol 2003;
22. Holzbach R, Jahn H, Pajonk FG, Mahne C. Suicide attempts with
mirtazapine overdose without complications. Biol Psychiatry 1998;
23. Velazquez C, Carlson A, Stokes KA, Leikin JB. Relative safety of
mirtazapine overdose. Vet Hum Toxicol 2001; 43:342–344.
24. Raja M, Azzoni A. Mirtazapine overdose with benign outcome. Eur
Psychiatry 2002; 17:107.
25. Garlipp P, Bruggemann BR, Machleidt W. A non-fatal mirtazapine
overdose in a suicide attempt. Aust N Z J Psychiatry 2003; 37:
26. Gerritsen AW. Safety in overdose of mirtazapine: a case report. J Clin
Psychiatry 1997; 58:271.
27. Retz W, Maier S, Maris F, Rosler M. Non-fatal mirtazapine overdose.
Int Clin Psychopharmacol 1998; 13:277–279.
28. Kuliwaba A. Non-lethal mirtazapine overdose with rhabdomyolysis.
Aust N Z J Psychiatry 2005; 39:312–313.
29. Khandat AB, Nurnberger JI Jr, Shekhar A. Possible mirtazapine-
induced rhabdomyolysis. Ann Pharmacother 2004; 38:1321.
30. Wenzel S, Aderjan R, Mattern R, Pedal I, Skopp G. Tissue distribu-
tion of mirtazapine and desmethylmirtazapine in a case of mirtazapine
poisoning. Forensic Sci Int 2006; 156:229–236.
31. Ciuna A, Andretta M, Corbari L, Levi D, Mirandola M, Sorio
A, Barbui C. Are we going to increase the use of antidepres-
sants up to that of benzodiazepines? Eur J Clin Pharmacol 2004;