By : Dr Rokhsareh Meamar, MD.Ph.D

Associate professor of Medical sciences

In the name of God

The 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.

Most SSRIs demonstrate a high degree of

serum protein binding, and most have a long

elimination half-life, with sustained

biological activity due to active metabolites.

Paroxetine and fluvoxamine are unusual in

that they have no active metabolites.

In overdose, SSRI elimination times are

further prolonged by the saturation of

metabolic enzymes and by delayed absorption,

especially for sustained-release preparations.

Due to fluoxetine's active metabolite

norfluoxetine and to the slow elimination of

both, significant accumulation of these drugs

and delays in reaching a steady state can

occur. Significant serum concentrations can

persist even four to five weeks after

discontinuation of fluoxetine. This can result

in adverse drug interactions and toxicity, if a

new antidepressant or serotonergic medication

is introduced for up to a month after fluoxetine

is stopped.

Many studies comparing the ingestion of SSRIs with

other antidepressants have found that SSRIs rarely

produce fatality or serious sequelae.

SSRIs are significantly less toxic than tricyclic

antidepressants (TCAs) and monoamine oxidase

inhibitors (MAOIs).

It is also important to note the potential disparity in

toxicity between SSRIs and SNRIs. SNRIs such as

venlafaxine have been associated with greater risk of

significant toxicity and mortality in overdose

Isolated SSRI ingestions generally produce

mild symptoms, although SSRI intoxication

can infrequently produce serotonin syndrome,

seizures, CNS depression, or various

cardiac abnormalities. Citalopram and

escitalopram are structurally different from the

other SSRIs and potentially more toxic in

overdose.

SSRIs (except for citalopram and escitalopram) have

a wide therapeutic window: ingestion of up to 30

times the daily dose typically produces minor or no

symptoms.

While ingestion of 50 to 75 times the daily dose can

cause vomiting, mild CNS depression, or tremor.

Most fatalities are reported with either extremely

large doses (greater than 150 times the daily dose)

or with the presence of coingestants such as ethanol

or benzodiazepines.

Patients with severe disease may develop

acute hyperthermia, hypertension, tachycardia,

agitated delirium, and muscle rigidity. Unless

aggressive intervention is instituted promptly,

these patients can go on to develop

rhabdomyolysis, metabolic acidosis, renal

failure, seizures, disseminated intravascular

coagulation, and shock.

Serotonin syndrome rarely occurs after

isolated SSRI ingestions, but severe episodes

can occur following either a mixed

serotonergic ingestion or changes made in

therapeutic SSRI dosing. Serotonin

syndrome caused by isolated SSRI ingestion

tends not be severe.

sertraline, paroxetine, and fluvoxamine

were most likely to cause a serotonin

syndrome.

SSRI ingestions are unlikely to cause seizures

or severe CNS depression. Seizures have been

noted to occur in 1 to 2 percent of SSRI

overdoses, but they are typically short and

self-limited. However, based on United States

poison center data, seizure is a relatively

common consequence of isolated citalopram

overdose.

SSRIs do not have significant cardiotoxicity.

Unlike the TCAs, they are typically not

associated with QRS prolongation or

ventricular tachycardia.

Citalopram, which is structurally unlike the

other SSRIs, is the most cardiotoxic: ingestion

is associated with prolongation of the QTc

interval, which can predispose a patient to

torsade de pointes.

Escitalopram ingestions too can cause similar

cardiotoxicity.

In therapeutic dosing, SSRIs (specifically

paroxetine) may cause hyponatremia, most

likely via the syndrome of inappropriate

antidiuretic hormone secretion. The elderly

appear to be at greatest risk of this

complication.

The average mean time to response (at least 50

percent reduction in baseline depression rating

scale score) to citalopram was six weeks.

Suggest an initial dose of 20 mg in the

morning. Older patients and those sensitive to

side effects can be started at a dose of 10 mg.

The dose range is 20 to 40 mg once per day.

The dose can be titrated up in increments of 10

or 20 mg per day, every one or four weeks.

Clinicians should not prescribe citalopram at

doses greater than 40 mg per day. The United

States Food and Drug Administration issued a

warning that citalopram causes dose-

dependent QT interval prolongation, which

can lead to a life-threatening cardiac

arrhythmia, torsade de pointes.

Citalopram has the greatest potential for serious toxicity

compared with other SSRIs. Citalopram is a racemic bicyclic

phthalane derivative that is structurally different from the other

SSRIs. It acts as a highly selective serotonin reuptake inhibitor,

but unlike other SSRIs, also has anti-histaminergic properties.

In citalopram ingestions of less than 600 mg, symptoms tend to

be mild and include nausea, dizziness, tachycardia, tremor,

and somnolence. With larger ingestions, citalopram can cause

serious cardiac and neurologic toxicity. It has been associated

with a 9 percent incidence of serotonin syndrome in isolated

ingestion, but rarely are cases severe. In rare instances,

citalopram ingestions have been associated with metabolic

acidosis.

Anecdotal evidence and cohort analysis suggest thatcitalopram is the most cardiotoxic SSRI.

With moderate (approximately 600 mg) to large(approximately 1900 mg) ingestions, citalopram hasbeen associated with a variety of cardiac conductiondisturbances.

Animal studies have shown a correlation between highserum levels of drug and both prolonged QTc anddeath.

In therapeutic dosing, citalopram has not been found toprolong the QTc interval nor was there a relationshipnoted between drug concentration and the QTc interval.

Other cardiac changes noted with citalopram

ingestions include

I. left bundle branch block ,

II. right bundle branch block

III. ventricular extra beats

IV. sinus bradycardia, sinus tachycardia

V. supraventricular tachycardia

VI. ST segment changes

VII.several case of ventricular fibrillation

In clinical trials of therapeutic dosing, only 0.3

percent of patients treated with citalopram had a

seizure, compared with 0.5 percent of patients taking

placebo. There are many reports, however, of

citalopram ingestions causing seizures.

The majority of citalopram-induced seizures is brief

and self-limited, and unlikely to result in

neurologic sequelae.

The minimum stated citalopram dose

associated with seizures in the absence of co-

ingested drugs was 400 mg.

Co-ingestion of a tricyclic antidepressant or

venlafaxine confers a 15-fold increased risk

of seizures.

The strongest predictors of seizures in this

patient series were ingestion of high

citalopram dosages and co-ingestion of

drugs capable of lowering seizure threshold.

Since most selective serotonin reuptake inhibitor (SSRI)

ingestions develop minimal or no toxicity, the broad goal of

management should be to provide supportive care and to

minimize potentially unneeded and harmful interventions.

Serotonin agonists, such as meperidine, must be avoided in

patients with SSRI ingestions or in those who have serotonin

syndrome, so as not to precipitate worse toxicity.

Most patients with SSRI ingestions have good outcomes with

supportive care alone.

Seizures typically respond to treatment with

benzodiazepines, such as lorazepam or

diazepam.

Patients who develop serotonin syndrome are

treated with supportive care, discontinuation

of the offending agent, and, depending upon

the severity of illness, a serotonin antagonist,

such as cyproheptadine.

Because citalopram and escitalopram potentially

have a cardiotoxic metabolite, patients with these

ingestions should receive an ECG at least 6 hours

after their ingestion. If these patients have any signs

of QTc or QRS prolongation, or an increasing QTc

interval compared to the initial ECG, or have

experienced a dysrhythmia, they should be admitted

for cardiac monitoring and observation until their

ECG intervals normalize.

Magnesium therapy to prevent torsades should be

given to patients with any of these findings. The dose

of magnesium sulfate in adults is 2 g over 2 minutes,

which can be repeated after 10 to 15 minutes if the

rhythm is not terminated. If there is clinical effect, a

magnesium infusion at a rate of 2 to 10 mg/min may

be helpful until the QTc interval is less than 500

msec.

For wide QRS complex tachycardia associated with

ingestion of these agents, treatment with boluses of

sodium bicarbonate, followed by a bicarbonate

infusion, if there is subsequent narrowing of the QRS

complex.

We suggest that a single dose of activated

charcoal (AC) be administered for

gastrointestinal (GI) decontamination typical

dose is 50 g in adults and 1 g/kg in children

The greatest benefit from charcoal

decontamination occurs if given within 1 to 2

hours following the ingestion. Multiple dose

charcoal and charcoal additives such as

magnesium citrate or sorbitol NOT be given.

Thank you for your Attention