This document provides an overview of antidepressant toxicity, including tricyclic antidepressant (TCA), selective serotonin reuptake inhibitor (SSRI), and monoamine oxidase inhibitor (MAOI) toxicity. It discusses the clinical presentation, mechanisms, risk assessment, and management of toxicity for each class. TCA toxicity can cause cardiac conduction delays, arrhythmias and hypotension. SSRI overdoses rarely cause toxicity on their own but serotonin syndrome can occur with combinations. MAOI toxicity results from interactions causing increased monoamine levels and produces adrenergic effects like hypertension. Management involves supportive care, sodium bicarbonate for TCA cardiac issues, benzodiazepines for seizures/agitation, and cy

1. Antidepressant
toxicity
clinical toxicology presentation
compiled by: Mastewal S.(clinical pharmacy
cand.)
1
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2. Outline
2
 TCA toxicity
 SSRI Toxicity
 MAOI toxicty
 Monitoring and prevention of antidepresant toxicity
 Reference
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3. introduction: TCA toxicity
 Between the late 1950s and the late 1980s, tricyclic
antidepressants (TCAs) were used extensively in
the management of depression and other
psychiatric disorders.
 Although selective serotonin reuptake inhibitors
(SSRIs) and other agents have supplanted TCAs as
first line therapy in the management of depression,
TCAs are still used for depression and other
indications including migraine, pain, and insomnia.
 Consequently, TCA poisoning, which can be life-
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 Tricyclic antidepressants
 Amitriptyline
 Imipramine
 Nortriptyline
 Doxepin
 Dothiepin
 Clomipramine
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5. Incidence
5
 According to the database, TCA overdose
accounted for 1.12 exposures per 10,000 population
in 1992.
 Recently, the trend for antidepressant overdose has
shifted more towards SSRIs.
 However, the rate of hospitalization is higher in
cases of TCA overdose compared to SSRI, because
of the narrower therapeutic index with TCAs.
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6. Clinical presentation and
mechanism of toxicity
 History — It is important to learn the particular
tricyclic antidepressant (TCA) ingested and the
amount, and whether the patient took any other
agents.
 In the event of mental status changes, information
can be obtained from emergency medical
personnel, police, family, friends, pharmacists,
psychiatrists, and primary care clinicians.
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7.  Overview of physical findings — Signs of TCA
poisoning typically include sedation, but may also
include confusion, delirium, or hallucinations.
 Cardiac conduction delays, arrhythmias,
hypotension, and anticholinergic toxicity (eg,
hyperthermia, flushing, dilated pupils) are also
common.
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 The clinical course of patients with TCA
poisoning can be unpredictable, and patients
who present immediately after ingestion may
initially be well-appearing, only to deteriorate
rapidly, due to the variable absorption kinetics
described above.
 In most cases, acute TCA ingestions of 10 to
20 mg/kg lead to significant cardiovascular
and central nervous system (CNS) toxicity.
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9. 9
 Cardiovascular toxicity — Sinus tachycardia is
common in TCA overdose, likely due to
anticholinergic (vagolytic) effects and
hemodynamic decompensation causing a reflex
tachycardia.
 Hypotension is common following significant TCA
poisoning, and mortality from TCA overdose is
due largely to refractory hypotension. Hypotension
is primarily secondary to peripheral alpha-1
adrenergic receptor antagonism. Cardiac
conduction abnormalities may also contribute to
hypotension. 10/17/2023

10. 10
 Ventricular tachycardia and ventricular
fibrillation (VT and VF) occur in approximately
4 percent of TCA overdose cases. VT and VF
are more common in severe poisonings (eg,
displaying severe acidosis, or hypotension),
particularly those involving extreme QRS
prolongation.
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 CNS toxicity — Mental status changes, such as a
decreased level of consciousness (due to
antihistaminic effects) or, less frequently, delirium (due
to anticholinergic effects), are common following TCA
overdose.
 TCA poisoning can cause seizures, likely due to the
an GABA-A receptor antagonism. Most seizures are
brief and self-limited, but some are associated with
cardiovascular deterioration, including hypotension
and ventricular arrhythmia. Maprotiline has been
associated with a greater frequency of seizures and
arrhythmias than other TCAs.
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 Anticholinergic toxicity — TCAs have
anticholinergic effects and signs of TCA
poisoning can include hyperthermia, flushing,
dilated pupils that respond poorly to light,
delirium, intestinal ileus, and urinary retention.
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13. Risk assessment
13
 General approach — Laboratory studies and other diagnostic testing are
directed toward establishing the diagnosis, estimating the severity of
intoxication, and ruling out additional toxicities.
 Routine laboratory evaluation of the poisoned patient should include the
following:
●An electrocardiogram, to assess conduction abnormalities,
●Fingerstick glucose, to rule out hypoglycemia
●Acetaminophen and salicylate levels, to rule out these common co-
ingestants
●Pregnancy test for women of childbearing age
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 An EKG should be obtained early in the
management of these patients, and any evidence
of sodium and/or potassium channel blockade
should be promptly addressed.
 Prolongation of QRS, due to sodium channel
blockade of more than 100 milliseconds, is
predictive of seizures while QRS > 160
milliseconds is predictive of arrhythmia.
 An R/S ratio in AVR of 0.7 or more and an R wave
in the AVR lead more than 3 mm is strongly
predictive of seizures and arrhythmias.
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 In addition to basic lab investigations,
including levels of possible co-investments,
such as acetaminophen and aspirin, a CT
scan of the head to rule out other causes of
altered mental status should be done if
clinically indicated.
 It should be noted that TCA levels do not
correlate with toxicity, but may be helpful in
diagnosing an unknown overdose when the
clinical symptoms and signs point to a possible
TCA ingestion. 10/17/2023

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 Any sign of toxicity warrants admission in an
intensive care setting for at least 24 hours.
Asymptomatic patients should be continuously
monitored for signs of toxicity, changes in vital
signs, and EKG for at least 6 hours
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17. Management
17
 General management – Most patients respond well to standard
care.
•Supportive care – Initial treatment of TCA overdose includes
assessing and securing the patient's airway, breathing, and circulation.
Intravenous (IV) boluses of isotonic saline are used to treat
hypotension.
•Gastrointestinal decontamination – In patients who present within two
hours of TCA ingestion and have no suspicion for bowel obstruction,
ileus, or perforation, we activated charcoal use 1 g/kg (maximum dose
50 g) orally.
•Do not use physostigmine or class 1A/1C antiarrhythmic agents –
Class IA (eg, procainamide) and Class IC antiarrhythmics (eg,
flecainide) are also contraindicated.
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 Management of specific toxicities
 Cardiac toxicity – In patients with TCA poisoning with
ECG demonstrating QRS duration >100 msec or any
ventricular arrhythmia, sodium bicarbonate therapy
(Grade 1B).
 The initial dose of sodium bicarbonate is 1 to 2
mEq/kg IV.
 In adults, this may be given as two to three 50 mEq
(50 mL) vials or prefilled syringes of 8.4% sodium
bicarbonate given as a rapid IV push through a large-
bore IV.
•Seizures – Reasonable initial options in adults include
diazepam 5 mg IV or lorazepam 2 mg IV.
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19. 19
 Refractory toxicity – In the uncommon circumstance
that sodium bicarbonate and other initial resuscitative
measures are ineffective, the following are alternative
treatments:
-Refractory hypotension: norepinephrine iv, hypertonic
saline
-Refractory arrhythmias: magnesium, lidocaine
-Impending cardiac arrest: lipid emulsion infusion
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20. Introduction: SSRI Toxicity
20
 Selective serotonin reuptake inhibitors (SSRIs)
were introduced in the late 1980s for the
treatment of depression.
 They are generally much safer in overdose
than tricyclic antidepressants (TCAs) and
monoamine oxidase inhibitors (MAOIs).
Commonly used SSRIs include fluoxetine,
sertraline, paroxetine, fluvoxamine, citalopram,
and escitalopram.
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 SS represents a group of signs and symptoms that
manifest in the neuromuscular, autonomic nervous,
and gastrointestinal systems, in which
concentrations of serotonin receptors are the
highest
 Less frequently, SS can be precipitated by an
overdose of a single SSRI
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 SS is often caused by combinations of SSRIs with
other proserotonergic agents, including the
following:
► Monoamine oxidase inhibitors (MAOIs)
► TCAs
► Trazodone (Desyrel)
► Serotonin-norepinephrine reuptake inhibitors
(SNRIs)
► Norepinephrine-dopamine reuptake inhibitors
► Lithium
► Opioids
► Amphetamines and cocaine 10/17/2023

23. Incidence
23
 The American Association of Poison Control Centers
reported over 50,000 overdose cases in 2016 where
SSRIs were mentioned; of these reported cases, 102
were fatal, but in all but one of these fatalities co-
ingestants were involved.
 Sertraline and fluoxetine were the SSRIs most
commonly taken in excess.
 One study analyzing 469 SSRI overdoses reported
serotonin toxicity in 14% of cases
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24. Clinical presentation and
mechanism of toxicity
24
 serotonergic projections to the thalamus and cortex
result in effects on sleep-wake cycles, mood,
thermoregulation, appetite, pain perception, and
sexual function.
 Excess 5-HT in these pathways causes
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 ANS effects include diaphoresis, mydriasis,
hypertension, tachycardia, hyperthermia,
piloerection, and muscular rigidity.
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 Due to the high levels of serotonin in gastric and
intestinal mucosal enterochromaffin cells, the most
common minor adverse effects of SSRI therapy are
gastrointestinal; eg, abdominal cramping, nausea,
and diarrhea.
 SSRIs have also been shown to moderately increase
the risk of upper gastrointestinal bleeding
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 Most cases fully resolve without residual deficits if
supportive care has been provided.
 The prognosis is generally favorable.
 Most fatalities occur within the first 26 hours.
 Patients who remain asymptomatic for 6-8 hours
after ingestion are unlikely to require further
treatment.
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28. Risk assessment
28
 Patients requiring assessment
 Any symptomatic patients
 All patients with deliberate self-poisoning or
significant accidental ingestion of serotonergic
agents
 Patients who have co-ingested a number of
serotonergic agents are at significantly greater risk
of serotonin toxicity
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30. Management
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 A minimum of 2 weeks should elapse between
termination of an SSRI or MAOI and initiation of a
new one.
 Drugs with a longer half-life (ie, fluoxetine) require
up to 5 weeks of wash out.
 Elderly patients and those taking liver Mixed
Function Oxidases inhibitors may require an
extended wash-out period as well.
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33. Introduction: MAOI toxicity
33
 MAOI poisoning is classified into the following 3
subtypes:
►Actual poisoning from an overdose is uncommon
►Drug-food interaction is so-called tyramine reaction
or cheese reaction.
 It is usually rapid in onset, occurring within 17-90
minutes after ingestion. Most symptoms resolve in 6
hours.
 Fatalities have been reported due to complications
from hypertensive emergencies.
►Drug-drug interactions
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34. Incidence
34
 There has been a 60% decrease in cases of MAOI
exposures in the United States over the last 25
years.
 In 2015, only 208 cases of MAOI exposures were
reported to poison control centers.
 Single exposures to MAOIs accounted for 90 of the
cases.
 Adults accounted for 71 of these cases, and 28
cases were intentional ingestions.
 Death due to MAOI exposure is rare
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35. Clinical presentation and
mechanism of toxicity
35
 The toxic effects of MAOIs are observed when their
inhibitory effects on monoamine oxidase are
compounded by drug-food interactions, overdose or
drug-drug interactions.
 Without MAO to break down epinephrine,
norepinephrine, dopamine, serotonin, and tyramine,
the storage, and release of these monoamines are
increased.
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 Increased adrenergic tone produces findings of
tachycardia, hyperthermia, myoclonus, hypertension,
and agitation.
 The time course can range from minutes for a drug-
food interaction to several hours in a pure MAOI
overdose.
 Though many of the symptoms of MAOI toxicity are
nonspecific, much of the suspicion for MAOI toxicity
will come from the patient history.
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 A complete list of medications, supplements, both
current and recently discontinued, should be obtained
as there can be significant latency between ingestions
and development of symptomatology.
 Signs of MAOI toxicity are non-specific as well. Mild
signs include agitation, diaphoresis, tachycardia and
mild temperature elevation.
 Signs of moderate disease include altered mental
status, tachypnea, vomiting, dysrhythmias,
hyperthermia, and hypertension.
 Severe signs include severe hyperthermia, seizures,
central nervous system (CNS) depression, coma,
cardiorespiratory depression, muscle rigidity and
myoclonus. 10/17/2023

38. 38
 Though similar to other hyperthermic toxidromes,
there are a few ways in which MAOI toxicity can be
distinguished.
 MAOI toxicity can present with diaphoresis whereas
an anticholinergic syndrome should have dry skin.
 Additionally, MAOI toxicity is much more likely to
present with generalized or ocular clonus than
neuroleptic malignant syndrome.
 A "ping-pong" gaze has also been described in
MAOI toxicity
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39. Risk evaluation
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40. Management
40
 Rx starts with the assessment of the patient’s
airway, breathing, and circulation as well as the
interventions to maintain a patent airway, adequate
ventilation, and circulation.
 Patients may be significantly dehydrated due to
hyperthermia and should be given intravenous
fluids.
 Treat seizures and/or agitation with
benzodiazepines.
 Cyproheptadine can be considered a third-line
treatment after hydration and benzodiazepines.
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41. 41
 12 mg by mouth (nasogastric/orogastric tube) with
additional 2 mg doses every two hours as needed
for symptomatic control.
 If the time of ingestion was within one hour,
activated charcoal could be considered by either
emergency medical services during transport or by
emergency department providers.
 The patient’s airway may need to be secured before
charcoal administration. Gastric lavage should be
considered in a patient with a life-threatening
ingestion. 10/17/2023

42. 42
 There are no antidotes for MAOI toxicity.
Hemodialysis is ineffective in removing the drug
from the body.
 Rapid correction of hyperthermia is vital.
 Cooling by evaporative heat loss (wetting skin and
creating air flow with fans) is an effective treatment.
 If the patient has signs of severe MAOI toxicity,
covering the body with ice or immersing the patient
in an ice bath may be necessary.
 Antipyretics likely will not be adequate treatment.
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 Patients may present hypertensive, but treatment
specifically for hypertension is usually not necessary.
 If needed, a short-acting agent such as nitroprusside
or phentolamine is suggested as beta-blockers may
result in unopposed alpha stimulation.
 Hospital admission and observation is recommended
for any patient with symptoms persisting more than
six hours.
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44. Monitoring and prevention of
antidepressant toxicity
44
Here are some key considerations:
1. Baseline assessment: Before starting
antidepressant therapy, a comprehensive medical
history, physical examination, and baseline laboratory
tests should be conducted.
2. Dose optimization: antidepressants have a narrow
therapeutic index, meaning that the dose must be
carefully adjusted to achieve therapeutic effects
without causing toxicity.
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45. 45
3. ECG monitoring: antidepressants can cause
cardiac toxicity, such as QT interval prolongation and
ventricular arrhythmias.
4. Regular follow-ups: Frequent follow-up
appointments with healthcare professionals are
necessary to assess the patient's response and
monitor for any signs of toxicity. This includes
evaluating for side effects, assessing mood and
suicidal ideation, and adjusting the treatment plan
accordingly. 10/17/2023

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5. Avoiding drug interactions: antidepressant can interact
with various medications, leading to an increased risk of
toxicity. Healthcare providers should review the patient's
medication profile and carefully consider potential
interactions before prescribing antidepressant.
Communication with the patient regarding any over-the-
counter medications or herbal supplements they may be
taking is also important.
6. Patient education: Patients should be educated about
the signs and symptoms of antidepressant toxicity, such as
dizziness, confusion, rapid heartbeat, seizures, and
changes in blood pressure. Clear instructions on what to
do in case of an overdose or adverse effects should be
provided. 10/17/2023

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 If antidepresant toxicity is suspected,
immediate medical attention should be sought.
This information is not comprehensive and
does not replace professional medical advice.
It is important to consult with a healthcare
provider for personalized guidance on
monitoring and preventing antidepressants
toxicity.
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48. Reference
48
 https://www.ncbi.nlm.nih.gov/books/NBK459386/
 Austin clinical toxicology service guideline
 https://www.poison.org/articles/snri
 Gummin DD, Mowry JB, Spyker DA, et al. 2017
Annual Report of the American Association of
Poison Control Centers' National Poison Data
System (NPDS): 35th Annual Report. Clin Toxicol
(Phila) 2018; 56:1213.
 Katzung Basic & Clinical Pharmacology, 15th edition
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49. 49
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