Critical Care Medicine

TE-tricyclic and newer antidepressants

Tricyclic and newer antidepressants

Tricyclic Antidepressants: Currently available tricyclic antidepressants include amitriptyline (Elavil), amoxapine (Asendin), clomipramine (Anafranil), desipramine (Norpramin), doxepin (Silenor), imipramine (Tofranil), maprotiline (Ludiomil), nortriptyline (Pamelor), protriptyline (Vivactil), and trimipramine (Surmontil).

Newer Antidepressants:Currently available noncyclic antidepressants include bupropion (Wellbutrin, Zyban), citalopram (Celexa), duloxetine (Cymbalta), escitalopram (Lexapro), fluoxetine (Prozac), fluvoxamine (Luvox), mirtazapine (Remeron), paroxetine (Paxil), sertraline (Zoloft), trazodone (Desyrel), and venlafaxine (Effexor). Nefazodone (Serzone) was withdrawn from the US market owing to its risk of hepatotoxicity.

1. Description of the problem

Tricyclic Antidepressants

Tricyclic antidepressants (TCA) are used for treatment of depression, neuralgic pain, migraines, enuresis, and attention deficit hyperactivity disorder (ADHD). Prior to the 1990s, TCAs were the most commonly used medications for the treatment of depression. Acute overdose involving TCAs can result in severe cardiovascular (CV) and central nervous system (CNS) toxicity. With the advent of newer noncyclical antidepressants in the 1980s and 1990s, the prevalence of TCA toxicity declined dramatically. However, TCA use is rising again owing to new indications such as treating chronic pain.

Newer Antidepressants

Noncyclic antidepressants, which include selective serotonin reuptake inhibitors (SSRIs) and atypical antidepressants (which have mechanisms in addition to serotonin reuptake inhibition) are now the most common pharmacologic treatment for depression and are generally much better tolerated in overdose than TCAs. Despite much higher prevalence of use and overdose for SSRIs, patients with TCA overdose continue to have higher rates of hospitalization (78.7% vs 64.7%) and mortality (0.73% vs 0.14%).

The SSRIs include citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline. The atypical antidepressants include bupropion, duloxetine, mirtazapine, trazodone, and venlafaxine.

Since being introduced in the 1980s noncyclical antidepressants have become first-line pharmacologic treatment for depression, due in large part to their safety profile and the narrow therapeutic window and severe toxicity associated with TCAs. SSRIs are also used to treat obsessive-compulsive disorder, panic disorder, chronic pain, and other conditions.

Tricyclic Antidepressants

Initial clinical findings after TCA overdose may be minimal with normal mental status and mild tachycardia. However, progression of toxicity is unpredictable and may be rapid with life-threatening cardiovascular and CNS dysfunction developing within hours. Typical toxic syndromes involve anticholinergic effects, CV effects, and seizures. A classic presentation involves a patient who is initially awake and talking then abruptly loses consciousness and has a seizure with ensuing hemodynamic instability.

In general, ingestion of 10 to 20mg/kg of most TCAs constitutes a moderate to serious exposure where coma and CV effects are expected.

Anticholinergic effects include tachycardia, delirium, sedation/coma, dilated pupils, decreased bowel sounds, dry skin, and urinary retention. Directly mediated CV toxicity manifests as abnormal cardiac conduction, arrhythmias, and hypotension. Ventricular dysrhythmias and refractory hypotension are the most common fatal abnormalities after cyclic antidepressant poisoning.

Typical electrocardiographic (ECG) findings include sinus tachycardia, various degrees of atrioventricular (AV) block, and prolongation of the PR, QRS, and QT intervals. Prolongation of the QRS complex greater than 100 milliseconds is a reliable predictor of serious CV and CNS toxicity requiring rapid corrective treatment. Consequently, wide-complex tachycardia is a hallmark of life-threatening TCA toxicity.

Newer Antidepressants

As a class of medications, noncyclic antidepressants are generally safe in overdose, with a wide therapeutic window., For SSRIs, in general, doses in excess of 10 times the usual therapeutic dose are usually tolerated without serious toxicity. Non-SSRI noncyclic antidepressants are exceptions to this rule; bupropion, trazodone, and mirtazapine can cause problems even in mild-to-moderate overdose.

SSRIs have a favorable side effect profile. The major toxicity seen with most agents are gastrointestinal and less commonly CNS depression with ataxia, sedation, and possibly coma. Seizures have been reported with the majority of SSRIs, though a few specific agents carry higher risk.

Serotonin syndrome is associated with most SSRIs and can occur when a drug is taken alone or when taken in conjunction with other SSRIs or monoamine oxidase inhibitors (MAOIs). There is also an association of increased risk of suicidal behavior with use of many antidepressants, especially in children.

Tricyclic Antidepressants

Initial management should focus on standard supportive treatment of airway, breathing, and circulation. Obtain a 12-lead ECG on presentation to assess for abnormal cardiac conduction and initiate continuous cardiac monitoring. Other useful studies include electrolytes, Blood urea nitrogen]], creatinine, creatinine phosphokinase (CPK), urinalysis for myoglobin, blood gas, and chest x-ray.

While many urine drug screen assays can detect TCAs, such tests provide little to no utility in guiding acute management. If QRS duration greater than 100 milliseconds is observed, consider giving ampules of sodium bicarbonate as an intravenous bolus with repeat doses as needed until the QRS complex narrows. If the patient has a seizure, control the airway, then continue with aggressive sodium bicarbonate therapy and hemodynamic support.

Patients with significant TCA toxicity should be admitted to the intensive care unit. Consultation with a medical toxicologist or poison center for further guidance is advised.

Newer Antidepressants

Drug-specific toxicities include hypotension, and priapism due to peripheral alpha-adrenergic blockade is seen with trazodone and mirtazapine. Seizures are seen more commonly with bupropion, citalopram, and venlafaxine. Sinus bradycardia with hypotension and QT interval prolongation is seen with citalopram and escitalopram.

2. Emergency Management

Tricyclic Antidepressants

TCA toxicity may cause sudden decompensation of a previously asymptomatic patient. Maintain a patent airway and assist ventilation as needed. Evaluate for co-ingestants including acetaminophen and salicylates. Treat hypotension with intravenous (IV) fluids and pressors if needed, seizures with benzodiazepines, and cardiac conduction abnormalities with sodium bicarbonate. Consider cardiac pacing for bradyarrhythmias and high-degree AV blocks. In severe cases unresponsive to other interventions, consider lipid resuscitation therapy or extra-corporeal oxygenation (cardiopulmonary bypass or ECMO).

Monitor vital signs and ECG in asymptomatic patients for at least 6 hours, and admit patients to an intensive care setting for at least 24 hours if there are any signs of toxicity.

If a potentially toxic dose has been ingested within the previous 1 to 2 hours, consider use of activated charcoal in an alert patient with a secure airway. Consider gastric lavage for large ingestions (>20–30mg/kg).

TCAs are extensively protein-bound and have large volumes of distribution, and are therefore not amenable to enhanced elimination; hemodialysis and hemoperfusion are not effective treatments. In contrast, large volume of distribution and high lipophilicity make TCAs potentially amenable to lipid resuscitation therapy. There are case reports of refractory cardiac arrest successfully resolving following lipid therapy.

Newer Antidepressants

Always start with evaluation of airway, breathing, and circulation, and initiate supportive care as indicated.

Noncyclic antidepressant toxicity rarely causes sudden decompensation of a previously asymptomatic patient. Other co-ingestants or other causes should be considered prior to ascribing such a sudden deterioration to noncyclic antidepressants. Seizures can occur and are more likely with certain drugs; however, when a patient presents with seizure, etiologies other than SSRI overdose also must be considered.

Given the generally wide therapeutic window for noncyclical antidepressants, use of activated charcoal should be judged on a case-by-case basis. In general, consider giving activated charcoal if a patient presents within 1 hour of ingestion and took a dose greater than 10 times the usual therapeutic dose. Do not give activated charcoal to a patient with sedation or a potentially compromised airway.

3. Diagnosis

Tricyclic Antidepressants

The first key to diagnosis is history. However, as history is often limited, TCA toxicity should be suspected in any patient with lethargy, coma, or seizures, accompanied by QRS interval prolongation.

If any ingestion is suspected, obtain a 12-lead ECG to evaluate for QRS prolongation greater than 100 milliseconds. QRS duration greater than 120 milliseconds suggests severe toxicity. Another characteristic change seen on ECG is a prominent R-wave in lead aVR, defined as R wave greater than 3mm in height or R:S ratio greater than 0.7.

If a clear history of ingestion is obtained and initial ECG is normal, observation and continuous cardiac monitoring is indicated for development of toxicity. If a patient is asymptomatic with no ECG changes after 6 hours of observation, he or she may be safely discharged home.

Urine drug screen assays are able to detect several different TCA drugs; however, such screens are limited in several ways. Drug screens are qualitative and will detect drugs present at therapeutic levels; hence a positive result does not reflect toxic concentrations. In addition, there are some TCA medications that are not detected at all by these screens. Consequently, using urine drug screens to dictate decision-making in an acute overdose situation is not recommended.

Newer Antidepressants

The first key to diagnosis is a history of ingestion. Without such a history, one should suspect a noncyclical antidepressant overdose in patients with a history of depression who develop lethargy, coma, and seizures. If a 12-lead ECG shows QRS prolongation, this suggests tricyclic antidepressant overdose.

Patients presenting with signs and symptoms suggestive of serotonin syndrome (confusion, myoclonus, hyperreflexia, tremor, incoordination, hyperthermia) can suggest noncyclical antidepressant overdose, and a careful medication history should be obtained.

Evaluation should start with a glucose check and 12-lead ECG. Other useful tests to obtain include electrolytes, renal function panel, pulse oximetry and continuous cardiac monitoring.

Tricyclic Antidepressants

Plasma levels of some TCAs can be measured in clinical laboratories. However, given the immediate availability of ECG and characteristic signs and symptoms of overdose, there is no clinical utility in obtaining plasma TCA levels for emergency management.

Newer Antidepressants

There are no routinely available specific confirmatory tests to confirm ingestion of noncyclical antidepressants.

4. Specific Treatment

Tricyclic Antidepressants

For sinus rhythm with a QRS greater than 100 ms: Sodium bicarbonate 1 to 2mEq/kg IV bolus; may repeat every 3 to 5 minutes until QRS less than 100ms or to target serum pH 7.50 t0 7.55. If there is good response and the QRS duration improves to less than 100 ms, then starting a bicarbonate infusion to maintain the serum pH between 7.50 and 7.55 can be helpful. Add 3 ampules sodium bicarbonate to 1 liter D5-water and run initially at a rate that is 1.5 times the patient’s maintenance fluid rate, then adjust as necessary to maintain the pH target.

For wide-complex tachycardia: Sodium bicarbonate as described above, and consider also lidocaine 1mg/kg slow IV bolus followed by 20 to 50mcg/kg/min. Other possible considerations include hypertonic saline and magnesium sulfate 25 to 50mg/kg IV over 2 minutes (max 2 g). Also correct hypoxia, acidosis, and hypotension.

For torsades de pointes: Magnesium sulfate as above, and then consider overdrive pacing.

For hypotension: 0.9% NaCl boluses, correct hypoxia and acidosis, sodium bicarbonate bolus to target serum pH 7.50 to 7.55, dopamine followed by norepinephrine if patient unresponsive to dopamine or go straight to using norepinephrine.

For seizures: Benzodiazepines, intubate, correct hypoxia and acidosis, barbiturates if refractory to benzodiazepines. Next, initiate infusion of propofol if barbiturates fail. If still refractory to propofol, consider paralysis and general anesthesia with continuous electroencephalographic (EEG) monitoring. Do not initiate neuromuscular paralysis without simultaneous use of general anesthestic agents or high-dose barbiturates.

Refractory toxicity: Consider IV lipid resuscitation therapy with Intralipid 20% emulsion 1.5mL/kg bolus over 5 minutes, then infusion of 0.25 to 0.5mL/kg/min for 30 to 60 minutes. Consider ECMO, cardiopulmonary bypass.

Newer Antidepressants

The mainstay therapy for noncyclical antidepressant toxicity is good supportive care. For patients with suspected serotonin syndrome, there is evidence that cyproheptadine may be beneficial due to serotonin antagonism. Methysergide is an alternative agent to antagonize serotonin syndrome.

Tricyclic Antidepressants

Do not use procainamide or other type Ia or Ic antiarrhythmic agent for wide-complex tachycardia as these drugs may aggravate cardiotoxicity.

There is no role for hemodialysis in the management of tricyclic antidepressant drug overdose, due to extensive drug-protein binding and large volumes of distribution.

Newer Antidepressants

Cyproheptadine dosing: 4 mg PO or NG every hour for 3 doses.

Methysergide dosing: 2mg PO or NG every 6 hours for 3 doses.

There is no role for hemodialysis in the management of noncyclical antidepressant drug overdose due to extensive drug-protein binding and large volumes of distribution.

5. Disease monitoring, follow-up and disposition

Tricyclic Antidepressants

If a clear history of ingestion is obtained and initial ECG is normal, observation and continuous cardiac monitoring for development of toxicity is indicated. If a patient is asymptomatic with no ECG changes after 6 hours of observation, he or she may be safely discharged home. Admit patients to an intensive care setting for at least 24 hours if there are any signs of toxicity.

Even in settings of severe toxicity with prolonged QRS and seizures, complete recovery is possible with rapidly instituted and aggressive treatment. For patients who survive the first 10 hours after an acute overdose without severe toxicity, the prognosis is generally good. Prognosis must be tempered in cases of cardiac arrest, as patients may suffer neurologic sequelae despite return of spontaneous circulation.

Patients who survive to discharge are expected to make a full recovery.

Newer Antidepressants

Most patients will be discharged from the emergency department following acute overdose and should have appropriate psychiatric disposition. After a 6-hour observation period, patients who are asymptomatic with a normal ECG can be medically cleared. An exception to this rule is patients who overdose on citalopram or escitalopram. These patients should be admitted for 24-hour cardiac monitoring for QT-prolongation and increased risk of ventricular dysrhythmias.

Patients with suspected serotonin syndrome should be admitted to an intensive care unit. Follow-up and monitoring after overdose should be with psychiatry as there is no specific medical issue that will need to be addressed. Patients are expected to make a full recovery.

Pathophysiology

Tricyclic Antidepressants

TCAs slow phase 0 depolarization of the action potential in cells of the His-Purkinje system and cardiac myocytes by inhibiting recovery of fast sodium channels. Impaired depolarization slows the propagation of ventricular depolarization, which manifests as prolongation of the QRS interval on the ECG.

In addition, TCAs have antimuscarinic, vasodilatory, and sympathomimetic effects that combine to produce tachycardia. Hypotension is caused by direct myocardial depression via disrupted sodium channel function and impaired excitation-contraction coupling, and also by alpha-adrenergic blockade resulting in vasodilatation.

Central anticholinergic and antihistaminic effects cause CNS symptoms of agitation, delirium, and sedation. The mechanism leading to seizures is incompletely understood but thought to be due to increased norepinephrine, muscarinic antagonism, sodium channel alteration, and GABA inhibition.

Newer Antidepressants

Serotonin is a neurotransmitter with CNS receptors that affect mood, sleep, appetite, and pain. Peripheral serotonin receptors increase gastrointestinal motility, stimulate nociceptive nerve endings, stimulate smooth muscle contraction, and play a role in vomiting. Excess serotonin, which occurs via inhibition of reuptake into nerve terminals, is the primary effect of SSRIs.

Epidemiology

Tricyclic Antidepressants

The use of TCAs has decreased over the past 20 years, due in large part to SSRIs supplanting TCAs as the primary pharmacotherapy for depression. Other medical indications for TCAs have emerged and include chronic pain, obsessive-compulsive disorder, and enuresis and ADHD in children.

Children under 6 years of age account for approximately 12% of all TCA exposures reported to poison centers.

Compared to SSRIs, patients with TCA overdose continue to have higher rates of hospitalization (78.7% vs 64.7%) and mortality (0.73% vs 0.14%).

Newer Antidepressants

SSRIs are the predominant class of medications used for pharmacologic treatment of depression and thus are commonly prescribed and widely available. Consequently there are many instances of overdose though the vast majority of overdoses result in only minor, if any, effects. Death due to SSRI overdose alone is rare.

Prognosis

Tricyclic Antidepressants

Mortality following TCA overdose is 0.73%. Those who survive generally have a full recovery.

Newer Antidepressants

Noncyclical antidepressants typically cause relatively minor toxicity when taken alone, but can cause more serious effects including serotonin syndrome when combined with other SSRIs or other types of drugs. The vast majority of patients recover completely from an acute overdose.

What's the evidence?

McKenzie, MS, McFarland, BH. "Trends in antidepressant overdoses". Pharacoepidemiol Drug Saf. vol. 16. 2007. pp. 513-23.

(Update on changing incidence and severity of antidepressant ingestions.)

Thanacoody, HK, Thomas, SH. "Tricyclic antidepressant poisoning: cardiovascular toxicity". Toxicol Rev. vol. 24. 2005. pp. 205-14.

Boegevig, S, Rothe, A, Tfelt-Hansen, J, Hoegberg, LC. "Successful reversal of life threatening cardiac effect following dosulepin overdose using intravenous lipid emulsion". ClinToxicol. vol. 49. 2011. pp. 337-9.

Blackman, K, Brown, SF, Wilkes, GJ. "Plasma alkalinization for tricyclic antidepressant toxicity: a systematic review". Emerg Med. vol. 13. 2001. pp. 204-10.

Boyer, EW, Shannon, M. "The serotonin syndrome". N Engl J Med. vol. 352. 2005. pp. 1112-20.

(Complications of SSRI.)

Catalano, G, Catalano, MC, Epstein, MA, Tsambiras, PE. "QTc interval prolongation associated with citalopram overdose: a case report and literature review". Clin Neuropharmacol. vol. 24. 2001. pp. 158-62.

Morazin, FM, Lumbroso, A, Harry, P. "Cardiogenic shock and status epilepticus after massive bupropion overdose". Clin Toxicol. vol. 45. 2007. pp. 794-7..

Nelson, JC. "Safety and tolerability of the new antidepressants". J Clin Psychiatry. vol. 58. 1997. pp. 26-31.

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