The electrocardiographic manifestations of cyclic antidepressant therapy and overdose: a review

Cyclic antidepressants may cause changes in the electrocardiogram at therapeutic or toxic serum levels. The most serious complications of cyclic antidepressant toxicity are dysrhythmias, hypotension, and seizures. It is predominantly the cardiotoxic effects that cause mortality. Once cardiotoxicity is evident, the treatment of choice is serum alkalinization, preferably by sodium bicarbonate therapy. In order to predict which overdose patients are at high risk for complications, electrocardiographic criteria have been identified as reliable screens. For "first generation" tricyclic antidepressants, QRS prolongation (particularly greater than 100 msec) and a terminal 40-ms frontal plane axis greater than 120 degrees are the most sensitive. This article reviews antidepressant pharmacology, electrocardiographic manifestations of antidepressant cardiotoxicity, and approaches to treatment of antidepressant-induced conduction disturbances and dysrhythmias.     

Lead Intoxication in Urban Dogs

While the clinical toxicity of tricyclic antidepressants, particularly the development of seizures and arrhythmias, has been strongly correlated with a QRS interval of ≥ 100 msec on electrocardiography, the resolution pattern of QRS abnormalities remains poorly defined. We prospectively monitored 22 consecutive patients who were referred to a regional poison center after a tricyclic antidepressant ingestion associated with a QRS interval of > 100 msec. An ECG was obtained every 6–8?h in all patients until the QRS interval was < 100 msec. Among enrolled patients the mean maximal QRS interval was 145 msec. Ten patients (45.5%) developed seizures while 6 (27%) developed cardiac arrhythmias. The time from ingestion to the last ECG demonstrating a widened QRS interval was a median 12.3?h (range 1–70 h); the time from ingestion to the first ECG with a QRS < 100 msec was a median 19.3?h (range 3–78 h). No patients developed seizures or life-threatening cardiac arrhythmias after the QRS interval was < 100 msec. Ten patients received sodium bicarbonate while 12 did not. There were no significant differences in the duration of QRS widening between the two groups. These data suggest that the typical period of QRS prolongation after severe tricyclic antidepressant ingestion is 12–18?h but may be as long 3 d. The factors which determine the duration of QRS widening are unclear. Sodium bicarbonate may not reduce the total duration of QRS disturbances.     

Bicarbonate therapy for the cardiovascular toxicity of amitriptyline in an animal model

The beneficial hemodynamic effects of sodium bicarbonate as treatment for tricyclic antidepressant poisoning were investigated in an animal model. Seven adult dogs (17.5 to 20 kg) were poisoned by an intravenous infusion of amitriptyline. Toxicity was defined as a doubling of the initial QRS width. A continuous infusion was used to maintain toxicity for 30 minutes after which 44.5 mEq of sodium bicarbonate was administered intravenously. Five of the animals survived to completion of the experiment. Three of the surviving animals developed dysrhythmias. All dysrhythmias ceased within one minute of administration of sodium bicarbonate. An increase in mean blood pressure (P less than .05) and serum pH (P less than .05) and a decrease in mean QRS width (P less than .05) occurred following administration of sodium bicarbonate. The maintenance of toxicity for 30 minutes suggests that this model can be used for future studies of tricyclic antidepressant poisoning.     

Tricyclic antidepressant and cardiovascular drug interactions.

Tricyclic antidepressants have anticholinergic, adrenolytic and quinidine-like activity. These actions result in a variety of cardiac and blood pressure effects. Tricyclic antidepressants can reverse the antihypertensive effect of guanethidine and clonidine. Orthostatic hypotension may be increased with diuretics and hydralazine. Myocardial depression may occur with lidocaine, phenytoin or propranolol. Dangerous additive effects may result from concomitant use of a tricyclic antidepressant and either quinidine or procainamide.     

The Effect of Oral Deferoxamine on Iron Absorption in Humans

Introduction.Tricyclic antidepressant (TCA) poisoning is a relatively common occurrence and remains a significant cause of mortality and morbidity. Deaths from TCA toxicity are typically due to cardiovascular events such as arrhythmias and hypotension. Cardiovascular toxicity may be multifactorial. However, the primary mechanism is a TCA-induced membrane-depressant or “quinidine-like” effect on the myocardium resulting in slowing down of phase 0 depolarization of the cardiac action potential and subsequent impairment of conduction through the His-Purkinje system and myocardium. This effect is manifest as QRS prolongation on the EKG, atrioventricular (AV) block, and impairment in automaticity leading to hypotension and ventricular dysrhythmia. Primary treatment strategies include sodium bicarbonate, hypertonic saline, and correction of any conditions that may aggravate this toxicity such as acidosis, hyperthermia, and hypotension. In cases of severe TCA toxicity, administration of sodium bicarbonate may be insufficient to correct the cardiac conduction defects. Use of lidocaine or phenytoin, both Vaughan Williams Class IB antiarrhythmic agents, has been reported as an effective adjunctive therapy in cases of severe cardiotoxicity.?Methods.?Thirty articles of interest were identified by searching PubMed, abstracts from meetings, and the reference sections of related primary and review articles and toxicological texts. Role of lidocaine and phenytoin. Lidocaine and phenytoin also cause sodium channel blockade, but unlike Class IA or IC agents do not depress phase 0 depolarization in healthy cardiac tissue. Lidocaine and phenytoin dissociate relatively quickly from cardiac sodium channels. Sodium channels have faster recovery times after exposure to lidocaine (1–2 s) and phenytoin (0.71 s), than with some TCAs such as amitriptyline (13.6 s), but not others (e.g., imipramine at 1.6 s). In experimental models of amitriptyline poisoning, lidocaine co-administration resulted in decreased sodium channel blockade compared to amitriptyline alone. This correlated with clinical improvement, including normalization of QRS interval, improved hypotension, and decreased mortality. It is postulated that lidocaine's rapid binding to the sodium channel may directly displace slower acting agents from the channel, leaving more channels unbound, and therefore be able to facilitate cardiac conduction. Phenytoin may act through a similar mechanism as lidocaine, although experimental studies suggest that it does not compete directly for the same sodium channel binding site as TCAs. Allosteric modulation of the TCA binding site may occur in the setting of phenytoin use. The evidence for using phenytoin in treating TCA-induced sodium channel blockade is less convincing than that for lidocaine. Human trials are limited to case series and, in most human exposures in which there appeared to be efficacy, the toxicity was not severe.?Conclusions.?Although there appears to be more evidence for the use of lidocaine than phenytoin as adjunctive treatment for TCA-associated cardiotoxicity, specific clinical indications and dosing recommendations remain to be defined. We recommend the use of lidocaine in cases in which cardiotoxicity (arrhythmias, hypotension) is refractory to treatment with sodium bicarbonate or hypertonic saline, or in which physiological derangement (e.g., severe alkalosis or hypernatremia) limits effective use of these primary strategies.     

Effects of high dose alpha-1-acid glycoprotein on desipramine toxicity in rats

Tricyclic antidepressants are bound extensively to alpha-1-acid glycoprotein (AAG) in serum. It has been suggested that the extent of drug-protein binding may influence the magnitude of cardiotoxicity associated with tricyclic antidepressant overdose. To study this question, desipramine (DMI), 45 mg/kg, was administered i.p. to anesthetized rats, producing an increase in QRS duration of 86.4 +/- 20.5% and a decrease in systolic blood pressure of 28.1 +/- 13.2%. Groups of six rats then received human AAG, 2.2 g/kg i.v. over 30 min, 4.4 g/kg i.v. over 60 min or control infusions of albumin. The serum AAG concentration increased to 29 times normal after AAG, 2.2 g/kg, and 46 times normal after AAG, 4.4 g/kg. The serum DMI concentration did not change with albumin infusion but increased 4.7-fold (1.9 +/- 0.7 to 9.0 +/- 1.6 micrograms/ml) after AAG, 2.2 g/kg, and 6.7-fold (2.3 +/- 0.5 to 15.7 +/- 7.0 micrograms/ml) after AAG, 4.4 g/kg. AAG infusion at either dose had no effect on systolic blood pressure compared to albumin. Animals treated with AAG, 2.2 g/kg, had less QRS prolongation 30 min after AAG infusion than animals treated with albumin (41 +/- 13% vs. 64 +/- 8%, P less than .01) but no difference in QRS duration was observed between groups after the higher dose (4.4 g/kg) of AAG or albumin. Cardiac DMI concentrations 90 min after AAG or albumin treatments did not differ.(ABSTRACT TRUNCATED AT 250 WORDS)     

Efficacy and mechanism of action of sodium bicarbonate in the treatment of desipramine toxicity in rats

Alkalinization of the blood by administration of sodium bicarbonate or hyperventilation is widely recommended for treatment of cardiac toxicity due to tricyclic antidepressant overdose, yet its efficacy and mechanism of action are poorly defined. We studied the effects and possible mechanism of action of 1 M NaHCO3 on desipramine (DMI) toxicity in anesthetized, paralyzed rats. Administration of DMI (45 mg/kg i.p.) produced a mean increase in QRS duration of 142% and a mean decrease in mean arterial pressure of 46%. Treatments were administered i.v. 35 min after DMI and their effects were assessed 10 min later. NaHCO3 (1 M) at doses of 3 and 6 mEq/kg decreased mean QRS duration 15 +/- 5 and 24 +/- 6%, respectively (mean +/- S.D.) and was superior to no treatment (P less than .01). NaCl (1 M) was as effective as NaHCO3 in decreasing QRS duration, as was 1 M NaHCO3 supplemented with 48 mM KCl. Respiratory alkalosis and 10% mannitol did not decrease QRS duration. NaHCO3, NaCl and NaHCO3/KCl all produced comparable increases in mean arterial blood pressure. Respiratory alkalosis and mannitol did not increase mean arterial pressure, but did prevent the decline seen in control animals. Acidosis produced by ventilation with 10% CO2 exacerbated QRS prolongation due to DMI. In acidotic animals, NaHCO3 and NaCl were equally effective in reversing QRS prolongation and hypotension. Correction of respiratory acidosis by discontinuation of inhaled CO2 did not improve QRS duration or mean arterial pressure.(ABSTRACT TRUNCATED AT 250 WORDS)     

Tricyclic antidepressant overdose at Westmead and Mount Druitt Hospitals

Tricyclic antidepressants are frequently taken in overdose and may be lethal. In this study, over nearly four years, there was only one death from tricyclic antidepressant overdose at the Westmead Hospital, that patient being transferred comatose and probably brain-dead after a cardiac arrest at another hospital. The pharmacology of tricyclic antidepressants is reviewed and recommendations are made for the treatment of overdose.     

Sodium bicarbonate to correct widened QRS in a case of flecainide overdose

A 16-yr-old male attempted suicide by ingesting approximately 4000 mg of flecainide. He developed coma, hypotension, and ventricular tachycardia. In addition to supportive care and antidysrhythmics, he received intravenous sodium bicarbonate for the wide complex dysrhythmia. Animal studies and anecdotal human experience have suggested that increasing the extracellular sodium improves cardiac conduction in flecainide toxicity. The patient's QRS narrowed immediately following sodium bicarbonate infusion. Sodium bicarbonate may be useful in the treatment of widened QRS and ventricular ectopy resulting from flecainide toxicity.     

Tricyclic antidepressants and histamine H1 receptors.

Tricyclic antidepressants and some structurally related compounds were tested for their ability to antagonize histamine H1 and muscarinic acetylcholine receptors of cultured mouse neuroblastoma cells. As a group, tertiary amine tricyclic antidepressants tended to be more potent than secondary amine drugs at both receptors. The most potent antihistamine, doxepin hydrocholoride, was about 4 times more potent than amitriptyline hydrochloride, about 800 times more potent than diphenhydramine hydrochloride, and about 8,000 times more potent than desipramine hydrochloride, the least potent tricyclic antidepressant at both the histamine H1 and the muscarinic acetylcholine receptors. All tricyclic drugs except desipramine hydrochloride were more potent as antihistamines than as anticholinergics. Doxepin hydrochloride and amitriptyline hydrochloride may be the most potent antihistamines known, and the antihistaminic potencies of these and the other tricyclic antidepressant drugs may relate directly to their ability to cause sedation and drowsiness in patients.     

Relative toxicity of venlafaxine and selective serotonin reuptake inhibitors in overdose compared to tricyclic antidepressants

BACKGROUND: Selective serotonin reuptake inhibitors (SSRIs) and venlafaxine have been regarded as less toxic in overdose than tricyclic antidepressants (TCAs). Within the TCAs, dothiepin has greater toxicity. Venlafaxine may be more toxic than SSRIs. AIM: To assess the toxicity in overdose of venlafaxine and SSRIs compared to TCAs, and of dothiepin compared to other TCAs. DESIGN: Cohort study of prospectively collected data from the Hunter area, NSW, Australia. METHODS: First admissions with antidepressant deliberate self-poisoning (DSP) (November 1994 to April 2000) were identified; the presence of seizures, life-threatening arrhythmias, coma, serotonin toxicity or ICU admission, and QRS duration were noted. RESULTS: There were 538 admissions, with no deaths. The odds ratio (OR) for seizures with dothiepin vs. other TCAs was 3.4 (95%CI 1.2-9.9). Seizures occurred in 7/51 (14%) venlafaxine overdoses; all patients with seizures consumed > or =900 mg. The OR for seizures vs. TCAs was 4.4 (95%CI 1.4-13.8). Coma was less likely with venlafaxine and SSRIs. SSRIs, but not venlafaxine, were less likely to prolong the QRS to > or =100 ms. ICU admission was less likely for SSRIs. Serotonin toxicity was much more common with venlafaxine and SSRIs. DISCUSSION: Venlafaxine and dothiepin are pro-convulsant in overdose. Venlafaxine is more likely to cause serotonin toxicity, but less likely to cause coma than TCAs. SSRIs are less likely to cause coma, require ICU admission, or prolong the QRS, but are more likely to cause serotonin toxicity. Antidepressants other than TCAs or venlafaxine should be considered in patients at risk of seizure or suicide.     

Managing antidepression overdoses

Depression is a physiological disorder that is medically treated by increasing the bodily amount of one or all of the following neurotransmitters: serotonin, dopamine and norepinephrine. Although there are seven distinct classes of antidepressants, prehospital care professionals should at minimum be able to distinguish the monoamine oxidase inhibitors (MAOIs), tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), and newer antidepressants that are none of these. Monoamine oxidase inhibitors have severe, potentially life-threatening interactions with a variety of medications, including the paramedic drug meperidine, as well as with many common foods. An overdose of tricyclic antidepressants can cause lethal cardiac irregularities. Tricyclics are toxic to children in very small doses. A patient who has overdosed on TCAs may be walking and talking when you first arrive, then quickly deteriorate and die before your eyes. The treatment for TCA overdose is sodium bicarbonate; refer to your medical direction for dosages and indications. A common indication of TCA overdose, secondary to the patient's having access to the drugs, is widening of the QRS complex to greater than 0.12 seconds. Serotonin syndrome is often the result of taking a new generation antidepressant, such as an SSRI, while there is still TCA or MAOI in the bloodstream.     

Fluoxetine-induced cardiotoxicity with response to bicarbonate therapy

This report describes a patient with an acute intentional fluoxetine exposure who developed unique cardiovascular and neurovascular toxicity. The patient presented with lethargy and cardiac conduction delays (QRS 110 msec, QT_c 458 msec) and developed a delayed seizure. On admission, therapy with intravenous sodium bicarbonate promptly narrowed the QRS to 90 msec. A comprehensive toxicology screen demonstrated only a serum fluoxetine concentration of 901 ng/mL (therapeutic range, 37–301), a serum norfluoxetine concentration of 451 ng/mL (29–329) and a serum acetaminophen concentration of 174 mg/L. Tricyclic antidepressants were specifically noted to be absent. A self-limiting generalized seizure was witnessed 16 hours after ingestion. At this time the bicarbonate infusion had been ceased and the QRS interval was not prolonged. The patient improved over time and no other apparent causes for the observed clinical effects could be discovered. Emergency physicians need to be aware of the uncommon occurrence of fluoxetine-induced cardiotoxicity and the potential benefit of sodium bicarbonate therapy.     

Antidepressants for chronic neuropathic pain

Tricyclic antidepressants have been used to manage pain for several decades, and are superior treatments for some patients suffering from neuropathic pain. Unfortunately, older antidepressants have dose-limiting side effects that can lead to drug intolerance. The most common are anticholinergic side effects, although some patients experience sexual dysfunction. Cognitive impairment, sedation, and orthostatic hypotension also are relatively common. Taking an overdose of tricyclic antidepressants can be lethal in overdose. Several weeks of therapy may be required before antinociception occurs, but tricyclic antidepressants in optimal doses appear to be the most effective treatment for neuropathic pain; this is supported by systematic reviews comparing them with other agents. Newer medications such as atypical antidepressants and anticonvulsants may be overtaking older antidepressants, but they should not be overlooked as important options for the management of pain.     

Incidence of tricyclic antidepressant-like complications after cyclobenzaprine overdose

Background

The cyclobenzaprine structure is similar to amitriptyline; however, tricyclic antidepressant (TCA)-like wide complex dysrhythmia has not been reported. Our objective was to determine the incidence of TCA-like effects in cyclobenzaprine overdoses as reported to 6 poison centers for 2 years. We compared the incidence of these effects to amitriptyline overdoses collected during the same period.

Methods

We performed a retrospective review of 2 years of cases as reported to the Texas Poison Center Network. We identified sole ingestions of cyclobenzaprine and of amitriptyline. Cases had a recorded clinical outcome and clinical effect. A trained reviewer used a standard data collection sheet within a secured electronic database. One investigator audited a random sample of charts.

Results

We identified 3974 cases of cyclobenzaprine calls. Of these, we collected 209 cases of acute overdoses without coingestions. There were no deaths. No cases of cyclobenzaprine ingestions were reported to have died or have a wide QRS or ventricular dysrhythmia. Seizures were reported in 2 cases; however, both were unrelated to cyclobenzaprine. Hypotension was reported in 1.4% (3/209) of cases, and a vasopressor was used in one case (0.5%). Patients with an amitriptyline overdose were more likely to have seizure, coma, tachycardia, a wide QRS or ventricular dysrhythmia, and have received sodium bicarbonate or be intubated.

Conclusions

Cyclobenzaprine overdoses were not reported to cause widened QRS, ventricular dysrhythmias, or seizures, and hypotension was rarely reported. Tricyclic antidepressant-related effects occurred more often in our comparison group of amitriptyline overdoses.     

Serial electrocardiographic changes as a predictor of cardiovascular toxicity in acute tricyclic antidepressant overdose.

Tricyclic antidepressant agents continue to be a leading cause of significant morbidity and mortality in reported poisonings involving pharmaceutical agents. Although the history and physical examination play an important role in the assessment of patients with tricyclic antidepressant overdose, the presence of anticholinergic features on examination cannot predict the severity of the overdose. Several clinical variables, in particular electrocardiographic (ECG) changes, have been proposed as a guide to determine the severity of the tricyclic antidepressant poisoning. The authors describe a patient with tricyclic antidepressant overdose who presented with altered mental status and whose serial ECG changes played a significant role in diagnosing and predicting the impending cardiovascular toxicity. The role of ECG changes in making the diagnosis and assessing the severity of the tricyclic antidepressant overdose is reviewed.     

Antidepressants and antiepileptic drugs for chronic non-cancer pain

The development of newer classes of antidepressants and second-generation antiepileptic drugs has created unprecedented opportunities for the treatment of chronic pain. These drugs modulate pain transmission by interacting with specific neurotransmitters and ion channels. The actions of antidepressants and antiepileptic drugs differ in neuropathic and non-neuropathic pain, and agents within each medication class have varying degrees of efficacy. Tricyclic antidepressants (e.g., amitriptyline, nortriptyline, desipramine) and certain novel antidepressants (i.e., bupropion, venlafaxine, duloxetine) are effective in the treatment of neuropathic pain. The analgesic effect of these drugs is independent of their antidepressant effect and appears strongest in agents with mixed-receptor or predominantly noradrenergic activity, rather than serotoninergic activity. First-generation antiepileptic drugs (i.e., carbamazepine, phenytoin) and second-generation antiepileptic drugs (e.g., gabapentin, pregabalin) are effective in the treatment of neuropathic pain. The efficacy of antidepressants and antiepileptic drugs in the treatment of neuropathic pain is comparable; tolerability also is comparable, but safety and side effect profiles differ. Tricyclic antidepressants are the most cost-effective agents, but second-generation antiepileptic drugs are associated with fewer safety concerns in elderly patients. Tricyclic antidepressants have documented (although limited) efficacy in the treatment of fibromyalgia and chronic low back pain. Recent evidence suggests that duloxetine and pregabalin have modest efficacy in patients with fibromyalgia.     

Hypotension in severe tricyclic antidepressant overdose

Sixty four patients who presented to the emergency department following severe acute tricyclic antidepressant (TCA) overdose (defined as an antidepressant ingestion associated with a QRS interval greater than or equal to 0.10 seconds, TCA level greater than or equal to 500 ng/mL, or grade IV coma) were prospectively evaluated to determine the incidence of hypotension and the factors associated with its development. Among these patients, the mean antidepressant level was 1,094 ng/mL. The overall frequency of admission hypotension (systolic BP less than 95 mmHg) was 34% (22 of 64 patients). Using regression analysis, systolic BP showed poor correlation with TCA level (r = -.37) and maximal QRS interval (r = -.17) following severe TCA overdose. Using multivariate analysis with a logistic regression model, the influence of BP (as well as TCA level, QRS interval, and coingestion of another drug) was evaluated on four clinical outcomes: seizures, arrhythmias, aspiration pneumonia, and pulmonary edema. The occurrence of arrhythmias and pulmonary edema was significantly associated (inversely) with hypotension (P less than .01). Seizures and aspiration pneumonia were unrelated to admission BP. These results suggest that hypotension is common after severe TCA overdose and occurs independently of TCA level and prolongation of the QRS interval. Hypotension is strongly associated with the development of arrhythmias and pulmonary edema. Seizures and aspiration pneumonia may occur regardless of initial BP.     

Criteria for admitting patients with tricyclic antidepressant overdose

Several investigators have recently developed guidelines for determining which patients with tricyclic antidepressant overdose should be hospitalized. The width of the QRS complex on the ECG and several clinical parameters have been proposed to identify patients at risk for major complications. To validate these, we developed an algorithm and then applied it to 45 patients who had overdosed on tricyclic antidepressants. This algorithm correctly predicted which patients required admission, whether due to present or impending complications, and which patients could have been discharged without morbidity or mortality. We conclude that use of the modified algorithm can identify patients with tricyclic antidepressant overdose who can be safely discharged from the emergency department.