Antidepressant Overdose Research Articles

A Critical Reconsideration of the Clinical Effects and Treatment Recommendations for Sodium Channel Blocking Drug Cardiotoxicity

The cardiac sodium channel is comprised of proteins that span the cardiac cell membrane and form the channel pore. Depolarisation causes the proteins to move and open the sodium channel. Once the channel is open (active conformation), sodium ions move into the cell. The channel then changes from the active conformation to an inactive conformation - the channel remains open, but influx of sodium ions ceases. Recovery occurs as the channel moves from the inactive conformation back to the closed conformation and is then ready to open following the next depolarisation. Sodium channel blocking drugs (NCBDs) occupy receptors in the channel during the active and inactive conformations. The drug dissociates from most of the channel receptors during recovery, but the time it takes the drug to dissociate slows recovery. The slowed recovery prolongs conduction time, the main toxicity of NCBD overdose. Conduction time is further prolonged if heart rate increases as there are more available active and inactive conformations/unit time, which increases channel receptor binding sites for the NCBD. In addition to prolonging conduction time, NCBDs also decrease inotropy. Treatment of NCBD cardiotoxicity has been based on in vitro and animal experiments, and case reports. Assumptions based on this evidence must now be reassessed. For example, canines consistently develop ventricular tachycardia (VT) when tricyclic antidepressants (TCAs) are administered. Much of the literature discussing NCBD cardiotoxicity assumes that TCA poisoning induces VT in humans with the same regularity that occurs in canines. Seemingly, in support of this assumption was the finding that patients with remote myocardial infarction developed VT when therapeutically ingesting a NCBD. However, conduction is prolonged in myocardium that is or has been ischaemic. NCBD prolong conduction more in previously ischaemic myocardium than in normal myocardium, which causes nonuniform conduction and allows the development of re-entrant arrhythmias such as VT. Although some nonuniform conduction may occur in the healthy heart following a NCBD overdose, there is no evidence that nonuniform conduction occurs to the extent that it will cause re-entrant arrhythmias in this setting. Using various animal models and a variety of NCBDs, sodium ions, bicarbonate ions and alkalosis have been compared for the treatment of ventricular arrhythmias, hypotension and mortality. The results of these experiments have been extrapolated to NCBD overdose in humans. Animal models and single treatment approaches may have narrowed our scope. More recent evidence indicates that properties of each individual NCBD may require unique treatment. There is limited evidence that glucagon, which increases initial sodium ion influx into the cardiac cell, should be considered early in the treatment of cardiotoxicity. Another consideration may be treatment of NCBD with faster kinetics. Conduction time is decreased if a NCBD occupying the receptor is replaced by a NCBD that moves off and on the receptor more quickly. There is less evidence for this treatment, as risk may be greater. With greater understanding of the sodium channel and NCBDs, we must reassess our approach to the treatment of patients with healthy hearts who overdose on NCBD.

Tissue Injury from Tricyclic Antidepressants Used as Local Anesthetics

Neurotoxicity has been reported with tricyclic antidepressants (TCAs) used as local anesthetics. We examined the hypothesis that TCAs cause tissue injury, particularly myotoxicity, as occurs with many local anesthetics. Animals were given sciatic nerve injections with 0-80 mM doxepin, amitriptyline, or bupivacaine (1.5 mL for histological studies, 0.3 mL for neurobehavioral studies). Four days after injection, the TCAs caused ischemic tissue injury. Subcutaneous tissue showed expansion and hardening, with hemorrhage and adhesion to overlying skin. Muscle was diffusely pale. Histopathology showed coagulative necrosis of muscle and surrounding soft tissues, with thrombus formation in vasculature near affected areas. These findings were much reduced with bupivacaine. TCA-injected and bupivacaine-injected animals also developed characteristic local anesthetic myotoxicity. Amitriptyline proved less potent than bupivacaine as a local anesthetic: the concentrations required to provide 100 min of nerve block were 20 mM and 3 mM, respectively. Some animals receiving large concentrations of amitriptyline developed spontaneous recrudescence of nerve blockade or had irreversible nerve blockade, both of which may reflect nerve injury. Neither finding occurred in animals injected with bupivacaine. TCAs do not appear to offer any advantages over conventional local anesthetics and do appear to risk substantially increased toxicity.

Part 7.4: Monitoring and Medications

This section provides an overview of monitoring techniques and medications that may be useful during CPR and in the immediate prearrest and postarrest settings. ### Assessment During CPR At present there are no reliable clinical criteria that clinicians can use to assess the efficacy of CPR. Although end-tidal CO2 serves as an indicator of cardiac output produced by chest compressions and may indicate return of spontaneous circulation (ROSC),1,2 there is little other technology available to provide real-time feedback on the effectiveness of CPR. ### Assessment of Hemodynamics #### Coronary Perfusion Pressure Coronary perfusion pressure (CPP = aortic relaxation [diastolic] pressure minus right atrial relaxation phase blood pressure) during CPR correlates with both myocardial blood flow and ROSC (LOE 3).3,4 A CPP of ≥15 mm Hg is predictive of ROSC. Increased CPP correlates with improved 24-hour survival rates in animal studies (LOE 6)5 and is associated with improved myocardial blood flow and ROSC in animal studies of epinephrine, vasopressin, and angiotensin II (LOE 6).5–7 When intra-arterial monitoring is in place during the resuscitative effort (eg, in an intensive care setting), the clinician should try to maximize arterial diastolic pressures to achieve an optimal CPP. Assuming a right atrial diastolic pressure of 10 mm Hg means that the aortic diastolic pressure should ideally be at least 30 mm Hg to maintain a CPP of ≥20 mm Hg during CPR. Unfortunately such monitoring is rarely available outside the intensive care environment. #### Pulses Clinicians frequently try to palpate arterial pulses during chest compressions to assess the effectiveness of compressions. No studies have shown the validity or clinical utility of checking pulses during ongoing CPR. Because there are no valves in the inferior vena cava, retrograde blood flow into the venous system may produce femoral vein pulsations.8 Thus palpation of a pulse in the femoral triangle may indicate venous rather than arterial …

Child and Adolescent Suicides in Virginia: 1987 to 2003

The aim of this study was to better understand suicides in children and adolescents using records from the Office of the Medical Examiner of Virginia from 1987 to 2003. Suicide accounted for 16.8% of unnatural deaths. Suicide rates were highest for Caucasians. Guns were the most common method of death for suicides, followed by hanging and poisoning. Poisoning other than carbon monoxide accounted for 7.8% of suicides, with tricyclic antidepressants (TCAs) the most identifiable poison. Female youths were 10 times more likely to die from TCAs than male youths, after adjusting for race and age. Guns and hanging were the principal methods of suicide. Among the antidepressants, TCAs have been the most common poisons used in suicide. Increasing age was a powerful determinant of suicide. Some patients may have stockpiled their TCAs for a while before their TCA overdose. Other suicide victims may have used TCA supplies from family members. Hence, some of the suicide victims may not have taken TCAs on a regular basis before committing suicide. Further exploration of TCA-induced suicidal thoughts is needed. Conclusions cannot be made at the time about the precise role that TCAs played in TCA-induced suicide reported in our study.

Effects of Amiodarone in a Porcine Model of Tricyclic Antidepressant Poisoning

Study Objectives: Amiodarone is recommended for the treatment of wide complex tachycardias of unknown focus. Sodium bicarbonate is the appropriate treatment for wide complex tachycardias secondary to tricyclic antidepressant overdoses. In cases of unknown tricyclic ingestions, the effects of treating a wide complex tachycardia with amiodarone are not well known and could conceivably be harmful. The objective of this study is to compare the effects of sodium bicarbonate, amiodarone, and placebo in treating wide complex tachycardia secondary to nortriptylline poisoning.

Postmortem Distribution of Tramadol, Amitriptyline, and Their Metabolites in a Suicidal Overdose

A case report involving a 34-year-old white male who was found dead at home by his roommate is presented. At the time of his death, he was being treated with tramadol/acetaminophen, metaxalone, oxycodone, and amitriptyline. The decedent's mother stated that he had been taking increasing amounts of pain medication in order to sleep at night. There were no significant findings at autopsy; however, toxicology results supported a cause and manner of death resulting from suicidal mixed tramadol and amitriptyline toxicity. This case reports the tissue and fluid distribution of tramadol, amitriptyline, and their metabolites in an acutely fatal ingestion in an effort to document concentrations of these analytes in 12 matrices with respect to one another to assist toxicologists in difficult interpretations.

Brugada Syndrome following Tricyclic Antidepressant Overdose

The Brugada syndrome, a pro-arrhythmogenic repolarization abnormality, is becoming increasingly recognised as a cause of collapse and sudden cardiac death. We report a case of a 48-year-old man with a tricyclic overdose and a delayed presentation of the Brugada pattern in the ICU. This case raises the need for clinicians to be aware of the Brugada pattern and those patients potentially at risk.

Electrical storm in the ICD era

Electrical storm (ES), arbitrarily defined as the occurrence of three or more separate episodes of ventricular tachycardia or fibrillation within a 24 h period, remains a difficult clinical entity to manage. The occurrence of multiple episodes in a short time frame has been described in a wide variety of clinical situations, ranging from the early post-myocardial infarction setting to the critically ill post-operative patient (e.g. electrolyte disturbance) to the patient who has an overdose of tricyclic antidepressants. There is little doubt that most of these patients died suddenly in the pre-implantable cardioverter defibrillator (ICD) era, when not monitored in an intensive or coronary care unit, as many did not survive the first episode of tachycardia. Fortunately, many ventricular arrhythmias (torsades de pointes, polymorphic ventricular tachycardia, even, exceptionally, ventricular fibrillation) can be self-terminating, so that intervention with defibrillation is not always required to survive the initial event. A patient with an ICD, however, will present with repetitive shocks (or antitachycardia pacing) from the device, a particularly psychologically and emotionally taxing experience, as it is very likely that he survives until he can get to the hospital. In this issue of Europace, Gatzoulis et al., describe a cohort of patients with ICDs in whom ES supervened [1]. ES occurred in 18.9% of the … *Corresponding author. Department of Cardiology, Erasmus MC, Dr. Molewaterplein 40, NL-3015 GD Rotterdam, The Netherlands. Tel.: +31 10 463 2699; fax: +31 10 463 2701. E-mail address: j.mekel{at}erasmusmc.nl

Amitriptyline Abuse and Misuse

Deaths related to amitriptyline toxicity are relatively common and are typically related to suicidal overdose. A less well-recognized situation of amitriptyline intoxication occurs when the drug is abused for its euphorigenic effects. An amitriptyline-related death due to a mixed drug intoxication is presented. Death investigation revealed that the death was accidental rather than suicidal. The case serves to remind forensic investigators that not all amitriptyline overdose deaths represent suicides. A segment of the population is known to abuse amitriptyline.

Are selective serotonin re-uptake inhibitors associated with an increased risk of self-harm by antidepressant overdose?

Are selective serotonin re-uptake inhibitors associated with an increased risk of self-harm by antidepressant overdose?

The Management of Tricyclic Antidepressant Poisoning

Although there have been descriptive, uncontrolled clinical reports of removal of tablet debris by gastric lavage, there have been no clinical studies that have demonstrated that this has any impact on outcome in patients with tricyclic antidepressant (TCA) poisoning. There is also the possibility that lavage may increase drug absorption by pushing tablets into the small intestine. Furthermore, gastric lavage in patients with TCA poisoning may induce hypoxia and a tachycardia potentially increasing the risk of severe complications such as arrhythmias and convulsions. In view of the paucity of evidence that gastric lavage removes a significant amount of drug and the risk of complications associated with the procedure, the routine use of gastric lavage in the management of patients with TCA poisoning is not appropriate. Volunteer studies have shown generally that activated charcoal is more likely to reduce drug absorption if it is administered within 1 hour of drug ingestion. In the one volunteer study that looked at later administration of activated charcoal, there was a 37% decrease in plasma concentration associated with administration of activated charcoal at 2 hours post-ingestion. There have been no clinical studies that enable an estimate of the effect of activated charcoal administration on outcome in the management of patients with TCA poisoning. Volunteer studies have shown that multiple-dose activated charcoal increases the elimination of therapeutic doses of amitriptyline and nortriptyline, but not of doxepin or imipramine; however, these studies cannot be directly extrapolated to the management of patients with TCA poisoning. There have been no well designed controlled studies that have assessed the impact of multiple-dose activated charcoal in the management of patients with TCA poisoning. Because of the large volume of distribution of TCAs, it would not be expected that their elimination would be significantly increased by multiple-dose activated charcoal.Haemoperfusion, haemodialysis and the combination of these procedures do not result in significant removal of TCAs and are not recommended in the management of patients with TCA poisoning.

Evaluation of Relationship Between Arterial and Venous Blood Gas Values in the Patients with Tricyclic Antidepressant Poisoning

Introduction. Determination of arterial blood gas (ABG) values is essential in the evaluation of patients with TCA poisoning. The relationship between arterial and venous blood gas pH has not been established in TCA poisoning. In TCA poisoning, blood vessels vasodilatation due to antidepressant-induced α-blockade and also metabolic acidosis may lead to arterialization of venous blood, which in turn enhances the relationship between ABG and VBG parameters. Therefore this study was designed to evaluate the relationship between ABG and VBG pH values in TCA poisoned patients. Methods. This prospective study was performed in the Poisoning Emergency Department of Noor Hospital, Isfahan, Iran. Samples for arterial and venous blood gas analysis were obtained during initial evaluation of TCA-poisoned patients and 30 min after treatment with sodium bicarbonate. The venous blood gas samples were collected with samples for other blood tests at the time of intravenous line insertion. Laboratory data were recorded on a database form initiated in the emergency department and analyzed by paired student t-test. The degree of agreement between the arterial and venous pH measurements was evaluated by Bland and Altman method. Results. Data from 50 TCA-poisoned patients were analyzed. There were significant differences between mean differences of ABG and VBG parameter values on the initial evaluation. There was also a relationship between arterial and venous pH on the initial evaluation. Conclusion. In TCA poisoning, the peripheral venous pH measurement is a valid and reliable substitute for arterial pH.

Management of the Cardiovascular Complications of Tricyclic Antidepressant Poisoning

Experimental studies suggest that both alkalinisation and sodium loading are effective in reducing cardiotoxicity independently. Species and experimental differences may explain why sodium bicarbonate appears to work by sodium loading in some studies and by a pH change in others. In the only case series, the administration of intravenous sodium bicarbonate to achieve a systemic pH of 7.5-7.55 reduced QRS prolongation, reversed hypotension (although colloid was also given) and improved mental status in patients with moderate to severe tricyclic antidepressant poisoning. This clinical study supports the use of sodium bicarbonate in the management of the cardiovascular complications of tricyclic antidepressant poisoning. However, the clinical indications and dosing recommendations remain to be clarified. Hypotension should be managed initially by administration of colloid or crystalloid solutions, guided by central venous pressure monitoring. Based on experimental and clinical studies, sodium bicarbonate should then be administered. If hypotension persists despite adequate filling pressure and sodium bicarbonate administration, inotropic support should be initiated. In a non-randomised controlled trial in rats, epinephrine resulted in a higher survival rate and was superior to norepinephrine both when the drugs were used alone or when epinephrine was used in combination with sodium bicarbonate. Sodium bicarbonate alone resulted in a modest increase in survival rate but this increased markedly when sodium bicarbonate was used with epinephrine or norepinephrine. Clinical studies suggest benefit from norepinephrine and dopamine; in an uncontrolled study the former appeared more effective. Glucagon has also been of benefit. Experimental studies suggest extracorporeal circulation membrane oxygenation is also of potential value. The immediate treatment of arrhythmias involves correcting hypoxia, electrolyte abnormalities, hypotension and acidosis. Administration of sodium bicarbonate may resolve arrhythmias even in the absence of acidosis and, only if this therapy fails, should conventional antiarrhythmic drugs be used. The class 1b agent phenytoin may reverse conduction defects and may be used for resistant ventricular tachycardia. There is also limited evidence for benefit from magnesium infusion. However, class 1a and 1c antiarrhythmic drugs should be avoided since they worsen sodium channel blockade, further slow conduction velocity and depress contractility. Class II agents (beta-blockers) may also precipitate hypotension and cardiac arrest.

Tricyclic Antidepressant Poisoning

Tricyclic antidepressants remain a common cause of fatal drug poisoning as a result of their cardiovascular toxicity manifested by ECG abnormalities, arrhythmias and hypotension. Dosulepin and amitriptyline appear to be particularly toxic in overdose. The principal mechanism of toxicity is cardiac sodium channel blockade, which increases the duration of the cardiac action potential and refractory period and delays atrioventricular conduction. Electrocardiographic changes include prolongation of the PR, QRS and QT intervals, nonspecific ST segment and T wave changes, atrioventricular block, right axis deviation of the terminal 40 ms vector of the QRS complex in the frontal plane (T 40 ms axis) and the Brugada pattern (downsloping ST segment elevation in leads V1-V3 in association with right bundle branch block). Maximal changes in the QRS duration and the T 40 ms axis are usually present within 12 hours of ingestion but may take up to a week to resolve. Sinus tachycardia is the most common arrhythmia due to anticholinergic activity and inhibition of norepinephrine uptake by tricyclic antidepressants but bradyarrhythmias (due to atrioventricular block) and tachyarrhythmias (supraventricular and ventricular) may occur. Torsade de pointes occurs uncommonly. Hypotension results from a combination of reduced myocardial contractility and reduced systemic vascular resistance due to alpha-adrenergic blockade. Life-threatening arrhythmias and death due to tricyclic antidepressant poisoning usually occurs within 24 hours of ingestion. Rapid deterioration is common. Level of consciousness at presentation is the most sensitive clinical predictor of serious complications. Although a QRS duration >100 ms and a rightward T 40 ms axis appear to be better predictors of cardiovascular toxicity than the plasma tricyclic drug concentration, they have at best moderate sensitivity and specificity for predicting complications.

Suicide in severe depression related to treatment

The objective of the present study was to assess the association between depressive characteristics and completed suicide despite adequate antidepressant therapy in severe depression and to investigate the frequency of lethal antidepressant overdoses. A record evaluation of 98 suicide victims with a primary severe depression had been performed. These had been admitted to the Department of Psychiatry, Lund University Hospital between 1956 and 1969 and followed up to 1998. Psychomotor retardation was related to completed suicide after ECT. The estimated frequency of lethal intoxication with antidepressants was low: 3% of the suicides.

Antidepressants and Suicide Risk in the United States, 1985–1999

The role of antidepressants in suicide prevention is a major public health question. An association was hypothesized between the increase in the use of non-tricyclic antidepressant medications in the United States and the decline in the suicide rate during the years 1985-1999. The relationships between the suicide, antidepressant prescription, unemployment, and alcoholic beverage consumption rates were studied using generalized linear models. Suicide rates by antidepressant overdose were compared in selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs). From 1985 to 1999, the suicide rate fell 13.5%, with a greater decline among women, and antidepressant prescription rates increased over 4-fold, with the increase mostly due to SSRIs. Prescription rates for SSRIs and other second-generation antidepressants were both inversely associated with suicide rates (p = .03 and p = .02, respectively). In a multivariable analysis adjusting for unemployment and alcoholic beverage consumption rates, SSRI antidepressant prescription rates remained inversely associated with the national suicide rate (p = .03). Females received twice as many antidepressant prescriptions compared with males. The commonest prescription indication was mood disorders, the condition most often associated with suicide. SSRIs were associated with a lower risk of suicide by antidepressant overdose compared with TCAs. The decline in the national suicide rate (1985-1999) appears to be associated with greater use of non-tricyclic antidepressants. Treatment of a greater proportion of mood disorders with SSRIs and other second-generation non-tricyclic antidepressants may further reduce the suicide rate. Controlled studies of the antisuicidal properties of antidepressants are needed in high-risk depressed patient populations.

Prolonged gastric emptying half-time and gastric hypomotility after drug overdose

A prospective study was undertaken to determine if gastric motility and emptying are altered by the ingestion of overdoses of tricyclic antidepressants, acetaminophen, opioid-acetaminophen mixtures, carbamazepine or phenytoin. Gastric scintigraphy was used to measure gastric emptying half-time and assess gastric motility in 104 patients at initial presentation and again at follow-up (n = 85). Patients were imaged for 5 hours after being given 20 MBq of 99mTc tin colloid to drink. Drug serum levels were measured on all patients at initial presentation and at follow-up. We observed markedly prolonged gastric emptying half-times and severe hypomotility at initial presentation compared with follow-up in the vast majority of patients, except for a small group of patients with phenytoin poisoning. Twelve patients had gastric emptying half-times of over 300 minutes, a further 14 had half-times of over 200 minutes and 21 others had half-times of over 120 minutes. Poisoning is associated with hypomotility and a marked delay in gastric emptying that could influence the clinical course and patient management. These abnormalities may not be due to a direct effect of the ingested drug and factors such as stress may play a role.

Hemoperfusion in a child with amitriptyline intoxication

Tricyclic antidepressant overdose is one of the most common causes of serious drug poisoning in children and adults. We report a 17-month-old girl with severe amitriptyline intoxication. She was admitted to hospital because of lethargy and seizures. It was estimated that she took approximately 75 mg/kg of amitriptyline 2 h before admission. On examination she was comatose, had ventricular tachycardia and multifocal clonic seizures. Intravenous fluid, per oral activated charcoal, diazepam, lidocaine, and sodium bicarbonate infusion were given. However, there was no response to this therapy, and the patient remained in a deep coma with cardiac arrhythmias and seizures. Hemoperfusion (HP) was performed for 2 h. During this procedure, cardioversion was used six times due to ventricular fibrillation. She had a very good clinical response to HP and no complication was observed. We suggest that HP may be an effective treatment in children with severe amitriptyline intoxication.

In reply

We would like to thank Dr. Seger for highlighting the many variances that currently exist in treating tricyclic antidepressant overdose. She has shown that there is no consensus among clinical toxicologists regarding the initiation, composition, or endpoints of alkalinization therapy for tricyclic antidepressant overdose.1 We agree that this case report does not answer the fundamental question: What is the best therapy or set of therapies for treating tricyclic antidepressant overdose? Only observational or experimental studies in human beings will ever answer these questions.

How Risky Are Tricyclic Antidepressants

Overdoses of tricyclic antidepressants (TCAs) are cardiotoxic, but scientists debate the cardiac risk at standard doses. These investigators used 5