I.

Prevalence and Indications for Prescribed Tricyclic Medications

- Definition and classification of TCAs

- Prevalence of TCA use in the community

- Common indications for prescribing TCAs

- Potential reasons for the observed increase in TCA toxicity cases

Labbate LA Fava M Rosenbaum JF. Handbook of Psychiatric Drug Therapy. 6th ed. Philadelphia:
Wolters Kluwer; 2014. https://public.ebookcentral.proquest.com/choice/publicfullrecord.aspx?
p=3418030. Accessed July 19 2023.

Australia ranks highly among OECD countries in terms of antidepressant use 1 , with approximately
7% of adults estimated to be using antidepressants each day 2 . Prevalence of antidepressant use has
been rising for decades, in parallel with increased diagnosis of mental disorders, improved access to
treatment, better tolerability of pharmacotherapies, expanding indications for use, and longer
treatment durations 3-5.

Antidepressants are the most common medicines for treating depression and anxiety, conditions that
affect about 4% and 14% of Australians each year, respectively 6

women use antidepressants at a rate 2-fold higher than men, with the highest use among older
women aged 65 years or over 7 8. Moreover, antidepressant use increased at a higher rate among
children and adolescents compared to other age groups in between 2009 and 2012 9 10; this is
despite concerns of increased risk of suicidal ideation and self-harm in this population 11.
Across the globe, the COVID-19 pandemic brought about increased levels of distress, as people
experienced the fear of acquiring the infection, social isolation, food and job insecurity 12. Relative
to other jurisdictions worldwide, Australia had low rates of COVID-19 cases in the first year of the
pandemic (88.2/100,000 population), with 909 deaths as of February 28, 2021 13. Nonetheless,
several surveys reported that in the early months of the pandemic large proportions of adults
experienced moderate to severe symptoms of depression (27%-46%) and moderate to severe
symptoms of anxiety (21%-41%). These surveys also reported higher rates of depression and anxiety
symptoms among women 14-16 and younger people 17 18.
From 2015 to 2019, prevalent antidepressant use increased for both sexes, from 159.3 to 170.4 per
1,000 females (+7.0%) and from 93.3 to 101.8 per 1,000 males (+9.2%)

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 [1].
Consequently, TCA poisoning, which can be life-threatening, remains a significant
clinical issue.

The tricyclic antidepressant agents hold an important place in the history of

treatments for depression. They were the first class of antidepressant
compounds to be widely used in depression and remained the first-line
treatment for more than 30 years. 
The tricyclic antidepressants are named after their chemical structure, which consists
of a three-ring central structure plus a side chain [3].

The nature of the side chain appears to be important for the tricyclics’
function. The tertiary tricyclic agents—amitriptyline, imipramine, and
clomipramine—are more potent in blocking the serotonin transporter. The
secondary tricyclics are much more potent in blocking the norepinephrine
transporter
The use of tricyclic and tetracyclic antidepressants to treat depression began with
reports in 1958 that imipramine was particularly effective for melancholic depression,
marked by symptoms such as psychomotor retardation, anergia, dysphoria,
hopelessness, and diurnal variation [1,2].

 In Australia, medicines-related harm is linked to an estimated 250,000 hospital admissions

and 400,000 emergency department presentations each year. 3 Of all preventable harm in
healthcare, medicines account for the highest proportion. 4

Medicine use is considered off-label when used for an indication, at a dose, via a route of
administration, or in a patient group that is not included in the product information approved
by the Therapeutic Goods Administration (TGA).5,6 While the majority of prescribers and
pharmacists are familiar with the term ‘off-label prescribing’, awareness among patients is
low.7 Not all off-label medicine use is inappropriate, and there are conditions for which an
off-label medicine is the treatment of choice. 8 However, patients should be informed that
their treatment is off-label and be engaged in a full and open discussion regarding benefits
and risks.

The proportion of medicine use that is considered off-label varies by therapeutic class and
patient group. An estimated 40–75% of antipsychotic use among adults and 36–93% of use
among children is considered off-label.9 Off-label antipsychotic use includes prescribing of
quetiapine for insomnia and anxiety, and risperidone and aripiprazole for attention deficit
hyperactivity disorder, anxiety and mood disorders. The antidepressant mirtazapine and
antiepileptics gabapentin and pregabalin are often prescribed off-label for insomnia. 10 High
rates of off-label antipsychotic, antidepressant and antiepileptic medications can be
attributed to the exclusion of people with mental health disorders from randomised
controlled trials (RCTs), overlap in symptoms between different mental health disorders, and
high rates of treatment switching within and between medicine classes.8
Quetiapine is an atypical antipsychotic agent with structural similarities to the tricyclic
antidepressants (TCA).
One reason for persistent high rates of off-label use is the lack of incentives for
pharmaceutical companies to seek approval for new indications, particularly if the
anticipated revenue does not offset the time and cost of undertaking additional research
and obtaining regulatory approvals.6 

Between July 2013 and June 2019, 239 944 patients in Australia
commenced antidepressant treatment. Of these, 22% (52 694
patients) received a second treatment (a new class of treatment after a
period of discontinuation or additional antipsychotic therapy) and 6%
(15 741 patients) received a third treatment. Patients were initially
prescribed primarily selective serotonin reuptake inhibitors (SSRIs;
52% of prescriptions) or tricyclic antidepressants (TCAs; 25%), even
though TCAs are not recommended for first-line treatment. Fewer
than one-quarter of patients were prescribed serotonin–
noradrenaline reuptake inhibitors (13%) or other agents (10%).
General practitioners (GPs) were more likely to initiate TCAs than
psychiatrists (22% v. 7%).
In general, however, newer generations of antidepressants are better
tolerated than tricyclic antidepressants (TCAs) or monoamine oxidase
inhibitors (MAOIs), and switching usually occurs because of lack of
response.
Overall, the most commonly prescribed individual antidepressants
were amitriptyline (19%), escitalopram (19%), sertraline (15%),
mirtazapine (11%) and fluoxetine (7%); together these constituted
71% of all prescriptions. The most commonly prescribed
antidepressants remained the same when only patients who were
active in the most recent 12 months of the study period were
considered.
GPs and psychiatrists showed different patterns of prescribing.
Psychiatrists tended not to initiate TCAs and most often initiated
people on an SSRI (Table 3). GPs also favoured SSRIs but tended to
prescribe TCAs more often than psychiatrists (21.9% v. 3.6% of
treatment 1 prescriptions).
Prescribing of TCAs and NaSSAs increased with age. The proportion of
TCAs increased from 10.6% of prescriptions in people aged up to 25
years to 35.4% of those aged above 65 years, and the proportion of
NaSSAs increased from 10.0% to 18.9% from the youngest to oldest
age groups.
First-line TCAs were more commonly prescribed by GPs, who
prescribed the majority of all first-line antidepressants (77% in our
study).
Greater proportions of TCA prescriptions by GPs may reflect off-label
prescribing for other conditions such as insomnia, post-traumatic
stress disorder, social phobia, panic disorder or chronic pain; they may
also be due to familiarity with prescribing TCAs.
It is also important to note that the dosing and indication of
antidepressants is not strictly adhered to; in addition to the obvious
overlap between depression and anxiety (previously discussed), many
antidepressants are used off-label to treat conditions such as insomnia
and pain, especially in the case of TCAs.

- Offlabel prescribing. Not for depression. Do not have to adhere strictly to the dose
regime.
- Covid depression
- The fact that TCA’s tend to be second line treatment with higher adverse side effects.
Those who fail to cure their depression and can be assumed to have more serius
depression are then given the more dangerous antidepressant drug that is
subsequently easier to overdose with.

II. Action of TCAs at the Cellular Level

- Mechanism of action of TCAs on neurotransmitters (serotonin, norepinephrine, and dopamine)

- Effects on synaptic reuptake and receptor binding

- Impact on cardiac ion channels and conduction system

Nelson JC. Tricyclic and tetracyclic drugs. In: The American Psychiatric Association Publishing
Textbook of Psychopharmacology, Fifth Edition, Schatzberg AF, Nemeroff CB (Eds), American
Psychiatric Association Publishing, Arlington, VA 2017. p.305.

DeBattista, C. Antidepressant agents. In: Basic and Clinical Pharmacology, 11th ed, Katzung, BG,
Masters, SB, Trevor, AJ (Eds), McGraw-Hill Lange, New York 2009.

Inhibition of presynaptic neurotransmitter reuptake (norepinephrine and

serotonin) is the primary mechanism for the therapeutic effects of tricyclic
antidepressants (TCAs).
Following overdose, the following cellular effects often produce important
clinical consequences:

●Blockade of cardiac fast sodium channels

●Antagonism of central and peripheral muscarinic acetylcholine receptors
●Antagonism of peripheral alpha-1 adrenergic receptors
●Antagonism of histamine (H1) receptors
●Antagonism of CNS gamma-aminobutyric acid (GABA) A receptors

In therapeutic use, TCAs are rapidly absorbed from the gastrointestinal tract,
reaching maximal plasma concentrations within two to eight hours. TCAs are
lipophilic and highly bound to plasma and tissue proteins and thus have a large
volume of distribution (Vd), ranging from 10 to 50 L/kg. The fraction of the drug
found in the plasma is usually highly bound to alpha-1 acid glycoprotein. TCAs
are primarily metabolized by the liver, undergoing phase one metabolism
primarily via CYP 2D6 and phase 2 glucuronidation. Many phase one
metabolites are pharmacologically active and may persist in the plasma for 12
to 24 hours [2-4]. Depending upon the TCA, the half-life of the parent
compound can range from 7 to 58 hours. Approximately 70 percent of the total
dose is renally excreted as inactive metabolites; the remainder is eliminated
primarily via the biliary system, with a small amount excreted unchanged in the
urine. Enterohepatic recirculation can delay final elimination of a large fraction
of the drug [5,6].
Important changes make it impossible to extrapolate overdose kinetics from
kinetics measured during therapeutic dosing. Absorption may be delayed,
largely due to decreased gut motility from anticholinergic effects. Bioavailability
may be increased as metabolic pathways become saturated, reducing the first
pass metabolism. Acidemia, which frequently complicates overdose, may
increase the amount of free drug due to effects on plasma glycoprotein
binding. Genetic polymorphisms of CYP2D6 resulting in a decreased rate of
elimination, may become more relevant following overdose [7]. The sum total
of these effects is often delayed absorption, an increased proportion of active
drug, and delayed excretion.

The absorption, distribution, metabolism, and elimination of tricyclics are well-

described [4-7].

Tricyclics are absorbed in the small intestine rapidly and nearly completely. The
medication then enters the portal circulation and undergoes first-pass
metabolism in the liver; for most tricyclics, approximately 50 percent of the
drug is metabolized in this manner. The medication then enters the systemic
circulation and binds to proteins, which for most tricyclics exceeds 90 percent. It
is only the free fraction that is active. Tricyclics are widely distributed
throughout the body, including the brain, because they are lipophilic.

Metabolism and elimination occurs largely in the liver. The hepatic CYP
isoenzymes that metabolize the tricyclics include 2D6, 1A2, 3A4, 1C19, which
demethylate the side chain of tertiary amines to secondary amines and
hydroxylate the central ring structure. Many of the metabolites have
antidepressant activity. As an example, the demethylated metabolite
of amitriptyline is nortriptyline, and the demethylated metabolite
of imipramine is desipramine.
The elimination half-life for the tricyclics and related drugs averages about 24
hours. The exception is amoxapine, which averages about eight hours.

Clinical Manifestations of TCA Toxicity

Most concerning is that all of the tricyclic and tetracyclic antidepressants are
dangerous in overdose. In contrast to the SSRIs, the cyclic antidepressants can be fatal
in doses as little as 10 times the daily dose [3]. The toxicity is usually due to
prolongation of the QT interval, leading to arrhythmias. Overdose of cyclic
antidepressants can also cause anticholinergic toxicity and seizures. Furthermore,
these medications are highly lipophilic and protein bound and are therefore not
effectively removed by hemodialysis (see "Tricyclic antidepressant poisoning"). Thus,
clinicians should avoid using cyclic antidepressants in outpatients who appear to be at
high risk of intentional overdose.

A. Cardiovascular Effects

- QT prolongation and risk of ventricular dysrhythmias

- Hypotension and bradycardia

- Mechanisms behind cardiovascular effects with supporting rationale

All of the cyclic antidepressants are potentially cardiotoxic and should be

avoided in susceptible individuals with heart disease [14]. (See 'Cardiac
evaluation' below.)
At therapeutic serum levels, tricyclic antidepressants can cause orthostatic
hypotension, which is one of the most common reasons for discontinuing them
[15]. Orthostasis is most likely to occur in patients with preexisting postural
hypotension, is aggravated by concurrent antihypertensive medications and
dehydration, and often occurs at low tricyclic serum levels. Blockade of alpha-
adrenergic receptors is the primary cause.

Tricyclic antidepressants can cause electrocardiogram changes, benign or otherwise.

The primary concern is prolongation of the QT interval, particularly when tricyclics are
co-administered with other medications (eg, other psychotropic medications, certain
antimicrobials, and antiarrhythmic drugs) that can prolong the QT interval (table 3).
Patients with acquired long QT syndrome are at risk for ventricular arrhythmias, most
notably polymorphic ventricular tachycardia, which may result in sudden cardiac arrest.
The approach to the diagnosis and management of acquired long QT syndrome is
discussed in detail separately. (See "Acquired long QT syndrome: Clinical
manifestations, diagnosis, and management".)

Tricyclics can also reduce heart rate variability, slow intracardiac conduction, and cause
various arrhythmias including tachycardia, ventricular fibrillation, and ventricular
premature complexes. Tricyclics do not reduce cardiac contractility or output.

The decrease in cardiac conduction has been likened to the effects of Class 1A
antiarrhythmics such as quinidine, and at therapeutic levels, tricyclics have mild
antiarrhythmic effects on ventricular excitability and ventricular premature beats [3].
However, tricyclics can cause heart block in patients with preexisting conduction delay.
Clinicians should avoid using these drugs in patients with underlying conduction
system disease.

In patients with ischemic heart disease, tricyclics can increase cardiac work and
decrease heart rate variability, possibly increasing the risk of sudden death [3]. Patients
on high doses of cyclic antidepressants (300 mg or more amitriptyline or equivalent)
may also be at increased risk for sudden cardiac death even in the absence of
underlying heart disease [16]. In addition, tricyclic antidepressant users have a higher
risk of myocardial infarction compared with SSRI users; it is not clear whether this is
due to deleterious effects of the tricyclic antidepressants themselves, protective effects
of SSRIs, or both [17].

It is not clear if tricyclics at therapeutic doses cause major cardiac complications

in patients with normal hearts:

●In an eight-year, prospective observational study of adults with no known

history of cardiovascular disease (n = 14,784, including 324 treated with
tricyclics), several outcomes were evaluated after controlling for
confounding factors [18]. Use of tricyclics was associated with a 35 percent
increased risk of cardiovascular events (cardiovascular death, nonfatal
myocardial infarction, coronary surgical procedures, stroke, or heart
failure). However, all-cause mortality was not associated with use of
tricyclics.

https://pubmed-ncbi-nlm-nih-gov.ezproxy.usc.edu.au/2051505/

Cardiac conduction abnormalities occur during tricyclic antidepressant (TCA) poisoning

because TCAs inhibit the fast sodium channels in the His-Purkinje system and
myocardium. This inhibition decreases conduction velocity, increases the duration of
repolarization, and prolongs absolute refractory periods (figure 1) [8,9]. These effects
are similar to those of the Vaughan-Williams Class IA antiarrhythmic drugs such
as quinidine. Mechanisms that contribute to hypotension during overdose include
decreased contractility from reduced calcium influx into ventricular myocytes, blockade
of rapid sodium channels, and peripheral vasodilatation from blockade of alpha 1
adrenergic receptors [10].

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 [14,15]. Cardiac conduction abnormalities may also contribute to
hypotension.
Ventricular tachycardia and ventricular fibrillation (VT and VF) occur in
approximately 4 percent of TCA overdose cases [16]. VT and VF are more
common in severe poisonings (eg, displaying severe acidosis, or hypotension),
particularly those involving extreme QRS prolongation.

Other possible ECG findings with TCA poisoning include prolongation of the PR and QT
intervals, block within the His-Purkinje system, and intraventricular conduction delay
(eg, bundle branch block). Because of its relatively longer refractory period, the right
bundle branch is especially sensitive to block from TCA overdose [23]. Several reports
have described a Brugada type pattern following TCA overdose, with the incidence
ranging from 2.3 to 15 percent following overdose [24,25]. These conduction system
abnormalities may contribute to the hypotension seen in TCA poisoning. Although QT
prolongation is common in TCA overdose, the polymorphic ventricular tachycardia
associated with QT prolongation, Torsade de Pointes (TdP), is not.

QRS duration — The most prominent electrocardiographic manifestation of

TCA toxicity is widening of the QRS interval. In one prospective series, patients
with a QRS duration less than 100 msec did not suffer a seizure or a ventricular
arrhythmia; those with a QRS duration >100 msec had a 26 percent chance of
seizure; and those with a QRS duration >160 msec had a 50 percent chance of a
ventricular arrhythmia [26]. Although some authors have questioned the utility
and reproducibility of QRS duration analysis [22,27,28], other studies confirm
the predictive value of QRS duration for seizure and ventricular arrhythmia [29-
31]. In the setting of a TCA overdose, we consider a QRS interval duration
greater than 100 msec an indication for bicarbonate therapy.  (See "Basic
approach to delayed intraventricular conduction".)
As a result of this differential conduction delay, R wave amplitude in lead aVR
(RaVR) and the ratio of R:S wave amplitude in aVR (R/SaVR) are significantly
higher in patients with a TCA overdose compared to matched controls [30]. One
cohort study noted that the risk of seizures and ventricular arrhythmias was
increased in patients with RaVR >3 mm, R/SaVR >0.7, and QRS duration >100
msec [30].

B. Central Nervous System Effects

- Seizures and their underlying mechanisms

- Delirium and altered mental status

- Rationale for CNS effects of TCAs

All of the cyclic antidepressants can lower seizure threshold. Seizures are directly
related to dose and serum level and are thus more likely to occur at higher doses (and
in overdoses) [3]. As an example, clomipramine has a seizure rate of 0.5 percent at
doses up to 250 mg/day, which increases to 1.7 percent at doses above 250
mg/day. Maprotiline (not available in the United States) has a seizure rate of 0.4
percent, which increases when doses exceed 225 mg/day. Imipramine has a seizure
rate of 0.1 percent at doses up to 200 mg/day, and the rate increases to 0.6 percent at
higher doses. Amitriptyline and doxepin have seizure rates of 1 to 4 percent at doses of
250 mg/day to 450 mg/day, depending upon the study.

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 antagonist effects of TCAs
on the GABA-A receptor [17,18]. Most seizures are brief and self-limited, but
some are associated with cardiovascular deterioration, including hypotension
and ventricular arrhythmia [19,20]. Maprotiline has been associated with a
greater frequency of seizures and arrhythmias than other TCAs [21].

C. Anticholinergic Effects

- Dry mouth, blurred vision, and urinary retention

- Psychomotor agitation and hyperthermia

- Explanation for anticholinergic effects in TCA toxicity

The tricyclics block muscarinic acetylcholine receptors and cause anticholinergic effects
such as blurred vision, constipation, dry mouth (which may lead to dental caries), and
urinary retention [3]. In addition, these anticholinergic effects can cause tachycardia,
ocular crisis in patients with narrow-angle glaucoma, and confusion and
delirium. Amoxapine, maprotiline (not available in the United States), desipramine,
and nortriptyline are least likely to cause any of these problems.

The cyclic antidepressants block histamine receptors and cause sedation, increased
appetite leading to weight gain, confusion, and delirium. The most potent
antihistaminic drugs are maprotiline (not available in the United States) and the tertiary
tricyclics amitriptyline, doxepin, and trimipramine. The sedative properties are
sometimes harnessed for patients with insomnia, but more benign options are
available.

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.

IV. Evidence-Based Management of TCA Toxicity

A. Initial Assessment and Supportive Care

- Importance of prompt recognition and initial stabilization

- Monitoring vital signs, ECG, and neurological status

- Airway management and respiratory support if required

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.

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
(table 1) [3,4,11,12]. 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 [13]. 

Laboratory studies and other diagnostic testing are directed toward

establishing the diagnosis, estimating the severity of intoxication, and ruling
out additional toxicities. (See "General approach to drug poisoning in adults".)

Routine laboratory evaluation of the poisoned patient should include the

following:
 ●An electrocardiogram, to assess for cardiac conduction abnormalities
(this is particularly important in tricyclic antidepressant [TCA] ingestions)
●Fingerstick glucose, to rule out hypoglycemia as the cause of any
alteration in mental status
Monitoring and overview of conduction abnormalities — Cardiac conduction
abnormalities are common in patients with TCA poisoning. Therefore, obtaining
an electrocardiogram (ECG) immediately upon presentation is essential in
patients with known or suspected TCA poisoning (table 1). Arrhythmias from a
TCA overdose can develop quickly and ECGs should be obtained frequently until
the patient has been free of any symptoms or signs of cardiac toxicity for
several hours. We suggest obtaining an ECG approximately every hour, but
more frequent studies are needed if the patient manifests signs of
cardiotoxicity or conduction abnormalities are evident on the initial ECG or a
cardiac monitor.

The following signs suggest cardiotoxicity:

●Prolongation of the QRS >100 msec

●Abnormal morphology of the QRS (eg, deep, slurred S wave in leads I and
aVL) (waveform 1)
●Abnormal size and ratio of the R and S waves in lead aVR: R wave in aVR
>3 mm; R to S ratio in aVR >0.7
These signs are used as important tools in diagnosis, risk stratification, and
management (waveform 2A-D). However, none is completely reliable in the individual
patient, and significant toxicity can occur despite falsely reassuring indices [22].
Preexisting conduction delay may also complicate interpretation. We view prolongation
of the QRS duration >100 msec as a sign of potential cardiac toxicity, and as an
indication for a trial of therapy with intravenous (IV) sodium bicarbonate.

Cyclic antidepressants have been associated with heart block, ventricular

arrhythmias, and sudden death. Before initiating treatment with any of the
cyclic antidepressants, patients must be screened for cardiac conduction
system disease, which precludes the use of these medications.

A typical history should include questions about known heart disease (including
congenital or acquired long QT syndrome); any cardiac symptoms such as
syncope, palpitations, dyspnea on exertion, shortness of breath, or chest pain;
and the use of other drugs that can prolong the QT interval (table 3) [20]. In
addition, clinicians should ask about a family history of heart disease,
particularly sudden death, cardiac dysrhythmias, or cardiac conduction
disturbances.
Baseline screening laboratory tests should include serum potassium to rule out
hypokalemia (algorithm 1) [20]. In addition, a baseline electrocardiogram (ECG)
is obtained for patients with any of the following:
●Age ≥40 years
●Cardiac symptoms
●Treatment with drugs that can prolong the QT interval

Tricyclics are generally contraindicated in patients with a corrected QT interval

>500 milliseconds

The diagnosis of TCA poisoning is primarily made on clinical evaluation due to

the limitations of quantitative and qualitative testing. Clinically, the diagnosis of
TCA poisoning is made based upon a history of ingestion, symptoms and signs
consistent with the diagnosis, and characteristic ECG findings.

Signs of TCA poisoning typically include sedation, but may also include
confusion, delirium, or hallucinations. Sinus tachycardia and other arrhythmias,
hypotension, cardiac conduction delays, and anticholinergic toxicity
(hyperthermia, flushing, dilated pupils, intestinal ileus, urinary retention, and
sinus tachycardia) are also common. Of note, patients with TCA poisoning can
appear stable but deteriorate rapidly, and significant toxicity can occur despite
falsely reassuring ECG findings.

ECG findings suggestive of cardiotoxicity include: prolongation of the QRS >100

msec; abnormal morphology of the QRS (eg, deep, slurred S wave in leads I and
aVL); and, abnormal size and ratio of the R and S waves in lead aVR (R wave in
aVR >3 mm; R to S ratio in aVR >0.7), or possibly a Brugada pattern.

The differential diagnosis of patients presenting with toxicity from tricyclic

antidepressants (TCAs) is broad given the range of clinical findings (decreased
level of consciousness, seizures, anticholinergic effects, hypotension, and
widening of the QRS interval) associated with this poisoning. In addition to
being common in TCA toxicity, these findings are associated with a number of
other poisonings:

●Decreased level of consciousness may be caused by sedative-hypnotic

drugs, anti-epileptic drugs, alcohols, opioids and opiates, carbon
monoxide, cyanide and hydrogen sulfide, and antipsychotics;
●Seizures may be seen with cocaine, salicylates, methylxanthines (caffeine
and theophylline), metals (eg, lead), and other therapeutic agents such
as bupropion, tramadol, propoxyphene and baclofen;
●Anticholinergic effects (primarily muscarinic) may be sequelae of
poisoning from diphenhydramine and other
antihistamines, carbamazepine, cyclobenzaprine, amantadine, clozapine,
 phenothiazines, procainamide, quinidine, and trihexyphenidyl, among
others;
●Hypotension with reflex tachycardia may result from poisoning from
various antihypertensives, such as alpha-adrenoreceptor antagonists,
nitrates, and dihydropyridine calcium channel antagonists (such
as nifedipine, nimodipine, amlodipine and felodipine);
●QRS widening may be due to other sodium channel antagonists, such
as diphenhydramine, phenytoin, propoxyphene, cocaine and the class 1A
and 1C Vaughn Williams antiarrhythmics.

Generally speaking, it is the constellation of the above findings (particularly

depressed mental status, peripheral anticholinergic signs, and evidence of
sodium channel antagonism on ECG) that strongly suggests TCA poisoning.
Other drugs that can mimic this specific clinical picture
include diphenhydramine and possibly carbamazepine, although the former is
less known for depressed mental status and controversy exists regarding the
risk of fatal arrhythmias [39].

Initial management of the patient with a tricyclic antidepressant (TCA) overdose

centers on evaluating and, if necessary, securing the patient's airway,
breathing, and circulation. TCA poisoned patients are frequently moribund and
require intubation for airway protection and ventilation. In hypotensive
patients, avoid induction agents that may worsen hypotension. Supplemental
oxygen should be administered as needed. 

Initial resuscitation includes the following measures:

●Sodium bicarbonate to treat cardiac toxicity, as manifested by a

prolonged QRS complex or ventricular arrhythmia. (See 'Sodium
bicarbonate for cardiac toxicity' below.)
●Isotonic saline given as intravenous (IV) boluses to treat hypotension. IV
boluses of 250 to 500 mL can be given and repeated based upon patient
response.
●Benzodiazepines for control of agitation. We suggest lorazepam (1 mg IV)
or diazepam (5 mg IV), repeated at 5 to 10 minute intervals as needed.
Benzodiazepines should be used judiciously, as agitation can rapidly give
way to profound sedation (from antihistaminic effects).

Initial resuscitation includes the following measures:

●Sodium bicarbonate to treat cardiac toxicity, as manifested by a

prolonged QRS complex or ventricular arrhythmia. (See 'Sodium
bicarbonate for cardiac toxicity' below.)
 ●Isotonic saline givenas intravenous (IV) boluses to treat hypotension. IV
boluses of 250 to 500 mL can be given and repeated based upon patient
response.
●Benzodiazepines for control of agitation. We suggest lorazepam (1 mg IV)
or diazepam (5 mg IV), repeated at 5 to 10 minute intervals as needed.
Benzodiazepines should be used judiciously, as agitation can rapidly give
way to profound sedation (from antihistaminic effects).

Frequent reassessment of patients with known or suspected TCA intoxication is

essential, as their level of alertness can change quickly. Patients may manifest
psychomotor agitation and delirium in the initial hours after ingestion, only to
develop progressive obtundation and coma in later stages. Thus, close
monitoring, including pulse oximetry and a cardiac monitor, is necessary. In
patients requiring treatment with sodium bicarbonate, an arterial line makes it
easier to perform frequent pH testing.

B. Specific Antidotal Therapy

- Use of sodium bicarbonate for cardiac stabilization

- Dosage and administration rationale

- Monitoring and titration considerations

 Sodium bicarbonate is the standard initial therapy for hypotension or arrhythmia due
to TCA toxicity. Sodium bicarbonate therapy is indicated in patients with TCA poisoning
who develop widening of the QRS interval >100 msec or a ventricular arrhythmia.

The initial dose of hypertonic sodium bicarbonate is ____

It is useful to run a continuous 12-lead ECG during the infusion to demonstrate the
presence (or absence) of narrowing of the QRS complex, a decrease in the R wave
amplitude in lead aVR, or resolution of any arrhythmia (waveform 1 and figure 2).

Should a widened QRS interval fail to narrow following bolus therapy

with sodium bicarbonate, we still suggest that an IV infusion of sodium
bicarbonate be started, absent an alternative diagnosis. Failure of a widened
QRS to respond to bolus therapy does not exclude the possibility of TCA toxicity,
and systemic acidemia potentiates the effects of TCA poisoning [41].
Frequent arterial blood pH measurements should be obtained during treatment
with sodium bicarbonate. We recommend a goal pH of 7.50 to 7.55. Volume
overload, hypokalemia, hypernatremia, and metabolic alkalosis may result from
prolonged bicarbonate infusions, and clinical and laboratory parameters must
be followed closely to avoid these complications. We measure the arterial pH
hourly until it is the therapeutic range and stable. Thereafter, measurements
may be obtained every four to six hours. The serum potassium concentration
should be measured concurrently with the arterial pH.

Most patients with TCA-induced QRS interval prolongation appear to respond

to sodium bicarbonate therapy. According to retrospective case series, 80 percent of
patients with an increased QRS interval demonstrated a decrease in response to
treatment, while 90 percent of hypotensive patients increased their blood pressure
[41,43].

The benefit of sodium bicarbonate is probably due to both an increase in serum pH

and the increase in extracellular sodium. The increase in serum pH favors the neutral
(ie, non-ionized) form of the drug, making it less available to bind to sodium channels
[42,44]. Increasing the extracellular sodium concentration increases the
electrochemical gradient across cardiac cell membranes, potentially attenuating the
TCA-induced blockade of rapid sodium channels (see 'Pharmacology' above). The
rationale for this therapy is based in part upon studies using animal models of TCA
poisoning showing that hypertonic sodium bicarbonate narrows the QRS complex,
improves systolic blood pressure, and controls ventricular arrhythmias [43-48].
However, there is a conspicuous absence of randomized trials in humans, and most
evidence of efficacy is based upon clinical experience [41,48].

We do not perform tracheal intubation for the purpose of hyperventilation or routinely

hyperventilate intubated patients as a means to achieve serum alkalinization.
Hyperventilation increases serum pH by reducing pCO2. In a retrospective case series,
decreasing pCO2 (to a mean 36 mmHg) along with administration of sodium
bicarbonate led to a more rapid reduction in QRS duration and greater increase in
serum pH [49]. However, given the paucity of data, we do not consider this a routine
practice.

C. Other Interventions

- Gastric decontamination and use of activated charcoal

- Hemodialysis as an option in severe toxicity cases

- Supportive measures for anticholinergic effects

TCA-induced seizures are likely caused largely by central GABA-A receptor inhibition. It
is therefore logical to treat seizures with benzodiazepines, which act on GABA-A
receptors, rather than antiepileptic medications acting on sodium channels,
notably phenytoin. Data from various animal models of drug-induced seizure as well as
clinical experience support this approach [50]. In the unusual case that
benzodiazepines are ineffective, barbiturates may be used to control seizures.
However, they are considered second-line therapy due to their adverse effects upon
blood pressure. Lastly, propofol, which acts both on GABA receptors and NMDA
receptors, may be used [50].

Levetiracetam has been proposed for the management of drug-induced seizures, and

evidence of its effectiveness following TCA overdose is found in small retrospective
case series [50,51]. Given the limited data, we generally do not recommend
levetiracetam, but it may be used in cases refractory to all other interventions.

MUST CONSULT FOR QAS as it is a relative contraindication

After the airway, breathing, and circulation have been secured, attention may be
turned to gastrointestinal decontamination. Unless bowel obstruction, ileus, or
perforation is suspected, we suggest treatment with 1 g/kg of activated charcoal
(maximum dose 50 g) in patients who present within two hours of ingestion. Charcoal
should be withheld in patients who are sedated and may not be able to protect their
airway, unless tracheal intubation is performed first. However, tracheal intubation
should not be performed solely for the purpose of giving charcoal [52,53].
(See "Gastrointestinal decontamination of the poisoned patient".)

As a general rule, we do not recommend whole bowel irrigation or multidose charcoal

as these have not been shown to improve outcomes. Gastric lavage may be
contraindicated in the setting of arrhythmias due to increased vagal tone.

There are no clear, established criteria for determining when sodium

bicarbonate therapy has failed and adjunct therapy should be given. One reasonable
approach is to begin giving adjunct therapies to any patient who remains hypotensive
with a wide QRS interval despite treatment with sodium bicarbonate that includes two
separate bolus doses and adequate alkalinization with a sodium bicarbonate infusion,
as described above. Because refractory toxicity is uncommon and suggests that the
patient will be difficult to manage, we recommend consultation with a medical
toxicologist or poison control center in such cases.

Refractory hypotension
Vasopressors — Vasopressors are indicated in patients with hypotension
refractory to sodium bicarbonate and aggressive IV fluid resuscitation therapy.
Direct-acting alpha adrenergic agonists (eg, norepinephrine or phenylephrine)
are preferred because they counter the alpha adrenergic antagonist effects of
TCAs. The IV infusion of the selected vasopressor is titrated to effect.
A small retrospective study of TCA-poisoned patients demonstrated a universal
response to norepinephrine infusion, including patients who had previously
failed to respond to dopamine infusion [54].
Hypertonic (3 percent) saline — We suggest that hypertonic saline be used
only when hypotension is refractory to all other first line treatments,
including sodium bicarbonate and aggressive fluid resuscitation. Patients who
remain unstable following adequate alkalinization, as determined by arterial
pH, and whose hypotension has failed to improve despite aggressive IV fluid
resuscitation and treatment with a direct acting vasopressor
(eg, norepinephrine) may be treated with hypertonic saline. We give a 100 mL IV
bolus of 3 percent saline; if symptoms persist, two more doses can be given at
ten minute intervals. No additional hypertonic saline should be given and the
serum sodium concentration should be monitored.
Some toxicologists advocate hypertonic (3 percent) saline as an alternative
to sodium bicarbonate therapy. However, reports about its effectiveness are
conflicting and there is no clear benefit over sodium bicarbonate. Hypertonic
saline therapy improves hypotension, but, with the exception of one case
report, there is little evidence that it improves arrhythmias [55].

Refractory arrhythmias
Magnesium — We do not recommend magnesium as a first line therapy for
TCA poisoning, but it may be used as an adjunct treatment in patients whose
arrhythmia is unresponsive to sodium bicarbonate. There are no standard
dosing recommendations for magnesium in this setting. One reasonable
approach is to give 1 to 2 g over 15 minutes or faster, if the patient is in cardiac
arrest.
A randomized trial, several case reports, and animal studies support the use of
IV magnesium to help control arrhythmias caused by TCA poisoning but
refractory to sodium bicarbonate therapy [56-58]. In a randomized trial of 72
patients with TCA poisoning, those treated with magnesium in addition to
sodium bicarbonate therapy experienced lower mortality than those treated
with sodium bicarbonate alone [59].

AMIODARONE

Lidocaine — Lidocaine (Class IB) has been used to treat TCA poisoning with some
encouraging results, but we do not advocate its routine use as a first line therapy
[60,61]. We suggest lidocaine only be considered when sodium bicarbonate therapy is
ineffective (ie, arrhythmia persists). Should lidocaine be needed, we suggest standard
anti-arrhythmic doses, including a bolus dose (1 to 1.5 mg/kg IV), followed by an
infusion (1 to 4 mg/minute). Phenytoin, another Class IB agent, has been studied in
TCA poisoning but its use is controversial and not generally recommended.
(See 'Unhelpful and contraindicated therapies' below.)
V. Public Health Interventions for Safe and Therapeutic Use of TCAs

- Importance of public education on safe use and storage of TCAs

- Raising awareness among prescribers about TCA toxicity and risk factors

- Collaboration with mental health professionals and addiction services

Overall, the therapeutic index of TCAs is narrow, and the therapeutic range for each specific
TCA is dependent on the drug prescribed. Because of the narrow therapeutic index of TCAs,
patients should be monitored closely for symptoms of toxicity, i.e., QRS-widening on
electrocardiogram (ECG), tremors, confusion, muscle rigidity, and coma.[23]
All patients starting a TCA need screening for pre-existing cardiac conditions, including
prolonged QTc intervals, heart disease, and a family history of arrhythmias. Patients who test
positive for pre-existing heart conditions may need additional evaluation by a cardiologist
before initiating treatment. Additionally, these patients require regular monitoring for the
presence of new cardiac symptoms. Patients with low potassium blood concentrations should
have periodical monitoring to reduce the risk of arrhythmias.[31] In patients over the age of
50, obtaining an ECG is recommended.
All patients starting a TCA or presently taking a TCA should be monitored for worsening
depressive symptoms or new-onset suicidal thoughts or behaviors. It may be helpful to
monitor the blood concentrations of TCAs in non-adherent patients, have decreased
tolerability or little response to the drug. However, there is mixed evidence on the
effectiveness of blood concentration monitoring on clinical outcomes.[7]
Tricyclic antidepressants are contraindicated in several populations and with the concomitant
use of various medications. TCAs should not be prescribed if there is a family history of QTc
interval prolongation or sudden cardiac death. Hypersensitivity reactions to a TCA drug are
considered an absolute contraindication. However, patients with a hypersensitivity reaction to
a particular TCA drug may be prescribed a different member of the class with caution. TCAs
should not be used concomitantly with monoamine oxidase inhibitors (MAOI), e.g.,
phenelzine, due to the risk of developing serotonin syndrome.[37] Also, patients must have
discontinued MAOI for at least 14 days before starting a TCA medication. Combining TCAs
with SSRIs is not advised as a combination of these agents has been shown to increase
plasma concentrations of TCAs and the risk of serotonin syndrome.[38][39]
TCA use requires caution in individuals with angle-closure glaucoma as its anticholinergic
effects may increase the risk of an acute ocular crisis.[40] TCAs should be used with caution
in patients with a history of seizures, as TCAs may lower the seizure threshold, and in
patients with urinary retention, as its anticholinergic properties may worsen this symptom.
[29][32] Clinicians should generally avoid TCAs in patients with coronary artery disease
(CAD). However, CAD is not an absolute contraindication.[41] Because cytochrome P450
enzymes metabolize TCAs in the liver, caution is necessary when prescribing TCAs to
patients with hepatic injury. Specifically, among the TCAs, clomipramine has been shown to
have the highest rate of drug-induced liver injury, so clomipramine is not preferred in patients
with non-optimal liver function.[42]
Tricyclic antidepressants (TCAs) are a class of antidepressants that are commonly prescribed
for off-label use today. Although TCAs may be prescribed for MDD, they are seldom
prescribed as a first-line treatment due to their unfavorable adverse effect profile, i.e.,
anticholinergic, antihistamine, and antiadrenergic effects, and because there are many safer
alternatives available, such as SSRIs. However, TCAs may be prescribed for MDD if more
conservative antidepressant pharmacotherapy has failed. Regardless of the indications for
TCAs, patients who require treatment with TCAs need the involvement of an
interprofessional team to help maintain patient safety.
Coordination between a patient's primary care physician, psychiatrist, and possibly
cardiologist if cardiac function abnormalities are present is essential for maintaining patient
stability and preventing adverse outcomes. Patient monitoring for suicidal intent is necessary
to avoid toxicity and overdose.[50] Communication between a cardiologist and a prescribing
physician is essential to prevent cardiotoxic outcomes in patients with predisposing risk
factors for cardiac dysfunction.[31]
Pharmacists should have involvement in the care of patients prescribed TCAs. Pharmacists
can confirm the appropriate dosage and can recognize critical drug-drug interactions. Also,
TCAs primarily undergo metabolism in the liver, so pharmacists can reduce the risk of
interaction with other drugs by identifying the concomitant drugs that influence hepatic
metabolism.[51] Nurses can assist in assessing patient adherence and monitoring patients for
adverse effects. Open and frequent communication between all interprofessional healthcare
team members should occur to ensure the best possible patient care outcomes. [Level 5]

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