Tricyclic antidepressant poisoning

Tricyclic antidepressant poisoning causes predictable electrocardiographic abnormalities and can be lethal. Cardiac arrhythmias, hypotension, seizures, and coma are common. Sodium bicarbonate is still considered the treatment of choice for severe toxicity, although a variety of supportive measures may be taken. Hypertonic saline appears to be a promising alternative. A QRS interval longer than 100 ms appears to be a better predictor of serious complications than is an elevated serum tricyclic antidepressant level. Cardiovascular toxicity is classically manifested as ventricular dysrhythmias, hypotension, heart block, bradyarrhythmias, or asystole. Activated charcoal binds tricyclic antidepressants. Give 30 to 50 g orally or by nasogastric tube with or without a cathartic (sorbitol 0.5 g/kg or 30 g of magnesium sulfate). Sodium bicarbonate is indicated if the QRS duration is more than 100 ms or the terminal right-axis deviation is more than 120 degrees. The suggested dosage is 1 to 2 mEq/kg, repeated as needed. Tricyclic antidepressants are used not only for depression but also for chronic pain syndromes, obsessive-compulsive disorder, panic and phobic disorders, eating disorders, migraine prophylaxis, and peripheral neuropathies.     

"Lipid rescue" for tricyclic antidepressant cardiotoxicity

Background

Tricyclic antidepressant (TCA) toxicity results predominantly from myocardial sodium-channel blockade. Subsequent ventricular dysrhythmias, myocardial depression, and hypotension cause cardiovascular collapse. Animal studies have demonstrated the effectiveness of intravenous lipid-emulsion in treating TCA cardiotoxicity.

Case Report

We report a case of dothiepin (tricyclic antidepressant) overdose causing refractory cardiovascular collapse, which seemed to be successfully reversed with lipid-emulsion therapy (Intralipid^®; Fresenius, Cheshire, UK).

Conclusions

Lipid emulsions are a potentially novel therapy for reversing cardiotoxicity seen in TCA overdose. Research is required into the role of lipid emulsion in the management of poisoning by oral lipophilic agents.     

Treatment of Acute Lead Intoxication — Choice of Chelating Agents and Supportive Therapeutic Measures

Abstract

This is a report of an intentionally administered overdose of dimenhydrinate to a 4 month-old infant who subsequently presented with status epilepticus, coma, and life threatening ventricular dysrhythmias. Initial toxicologic analysis of the serum by fluorescence polarization immunoassay was positive for tricyclic antidepressants. Repeat analysis of the serum at 6 hours post ingestion by gas chromatography mass spectrometry analysis defined diphenhydramine 4.8 μg/mL. The infant was managed with IV sodium bicarbonate as utilized in tricyclic antidepressant intoxication. The dysrhythmias resolved and the infant recovered without sequelae.     

Management of depression in the elderly

Primary care physicians have a vital role to play in identifying depression in their elderly patients. Diagnosis may be difficult, because symptoms are atypical and frequently include psychomotor agitation, somatic symptoms, and complaints of memory loss. Patients with medical illnesses, such as cancer, postmyocardial infarction, stroke, Parkinson's disease, and early Alzheimer's disease are particularly vulnerable to depression. Drugs that may cause depressive symptoms are digitalis at toxic levels, beta-blockers, centrally acting antihypertensives, immunosuppressants, and nonsteroidal anti-inflammatory agents. Cyclic antidepressants are the drugs of first choice. Selection depends on the patient's physical health and current medications and the side effect profile of the drug. Side effects are more pronounced in old age because of drug accumulation owing to slowed clearance. Troublesome side effects are anticholinergic effects, orthostatic hypotension, sedation, cardiotoxicity, and weight gain. The most useful antidepressants for geriatric patients are the secondary amines, desipramine and nortriptyline. The second-generation drug trazodone has the advantage of causing the least anticholinergic effects, but it is very sedating. Before treatment, the patient should have an electrocardiogram, liver function tests, tonometry, sitting and standing blood pressures, evaluation of urinary symptoms for outflow obstruction, review of current medications, and estimation of suicide risk. Cyclic antidepressants are contraindicated during recovery from myocardial infarction, in heart disease when there is severe impairment of myocardial performance, in seizure disorders, and in the presence of glaucoma or a large prostate. Drug interactions that may cause trouble can occur with epinephrine, MAO inhibitors, thyroid hormone, cimetidine, and centrally acting antihypertensives. Dosage should start low, increasing usually by 25 mg every 4 to 5 days until a therapeutic level is reached. Failure of a noradrenergic antidepressant after 4 to 5 weeks can be followed by a trial of a serotonergic drug. Drug serum level monitoring is useful for imipramine, desipramine, and nortriptyline. Monoamine oxidase inhibitors are effective in many elderly patients who are resistant to TCAs. Sympathomimetic drugs must be avoided with MAOIs. Elderly patients are at high risk of toxicity and drug interactions with lithium. Electroconvulsive therapy is useful for patients who do not respond to drug treatment, but medical complications, particularly cardiovascular, often occur in patients 75 or older. Many patients relapse after ECT. Psychotherapy together with pharmacotherapy may be the optimal treatment for elderly depressives. Older patients are more likely to become chronically depressed than younger patients. The risk of suicide in depressed elderly males is high, particularly in those with psychosocial problems, and depression rises with age.     

Hyperkalemia: ECG manifestations and clinical considerations

Hyperkalemia is a common cause of electrolyte induced cardiac conduction disturbance. A well-defined series of changes at the cellular level leads to characteristic evolutionary changes in the surface electrocardiogram. Initial high T waves and shortened intervals give way to prolongation of conduction and lethal dysrhythmias as the serum potassium level rises. The patterns of electrocardiographic changes associated with hyperkalemia are reviewed and an outline of appropriate therapeutic interventions.     

Improvement of Cardiac Conduction after Hyperventilation in Tricyclic Antidepressant Overdose

Abstract

Three patients with severe cardiotoxicity secondary to tricyclic antidepressant (TCA) overdosage were treated with induced mechanical hyperventilation. All three demonstrated marked QRS narrowing, reflecting improved intracardiac conduction, after hyperventilation therapy. Such therapy may help to prevent or abolish ventricular dysrhythmias, often a feature of life-threatening TCA overdoses.     

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.     

Antidepressants in the treatment of migraine headache

Antidepressants, particularly tricyclic antidepressants, have been a mainstay in the prophylactic therapy of migraine. The tricyclic antidepressants amitriptyline, nortriptyline, and doxepin have been the major agents for prophylactic treatment of migraine. These cause significant side effects in some patients. The high-affinity selective serotonin reuptake inhibitors and other newer antidepressants have been disappointing and much less effective in the treatment of migraine. In patients who are depressed with severe migraine, a tricyclic antidepressant may treat both conditions; however, the addition of a newer atypical antidepressant may be needed.     

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.     

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.     

Antidepressant adherence patterns in older patients: use of a clustering method on a prescription database

According to the World Health Organization, depression will become the second most important cause of disability worldwide by 2020. Our objective was to identify patterns of adherence to antidepressant treatments in older patients using several indicators of adherence and to characterize these patterns in terms of medication exposure. We conducted a retrospective cohort study using the French National Health Insurance reimbursement database. Incident antidepressant users aged more than 65 were included from July 1, 2010, to June 30, 2011, and followed up for 18 months. Antidepressant and other psychotropic drugs (opioids, benzodiazepines, antipsychotics, anti‐epileptics) were recorded. Adherence to antidepressant treatment was assessed by several measures including proportion of days covered, discontinuation periods, persistence of treatment, and doses dispensed. Patients were classified according to their adherence patterns using a mixed clustering method. We identified five groups according to antidepressant adherence. One group (n = 7505, 26.9%) was fully adherent with regard to guidelines on antidepressant use. Two patterns of nonadherent users were identified: irregular but persistent users (n = 5131, 18.4%) and regular but nonpersistent users (n = 9037, 32.4%). Serotonin reuptake inhibitors were the most frequently dispensed antidepressant class (70.6%), followed by other antidepressants (43.3%, mainly serotonin–norepinephrine reuptake inhibitors and tianeptine) and tricyclic antidepressants (TCAs) (13.4%). Nonadherent users more frequently had a dispensing of TCA, opioid, and anti‐epileptic medication than adherent users. Health policies to improve adherence to antidepressant treatment may require better training of physicians and pharmacists, insisting on the important role of the continuation period of antidepressant treatment.     

Results compared for tricyclic antidepressants as assayed by liquid chromatography and enzyme immunoassay

The tricyclic antidepressants amitriptyline, nortriptyline, imipramine, and desipramine in serum of patients taking one of the drugs were quantified in two laboratories by high-performance liquid chromatography (HPLC) and enzyme-multiplied immunoassay (EMIT; Syva). Results for split samples were highly correlated, but EMIT gave higher results in most cases, and the slopes of the correlation lines for each analyte were greater than 1. Detection limits for the two procedures were such that 18% of the EMIT results for the drug(s) were considered negative, as compared with 4% of the HPLC results. Additional assay of desmethyl or hydroxy antidepressant metabolites by HPLC did not explain the higher EMIT results. The relatively high detection limit for EMIT greatly limits its use in therapeutic drug monitoring, where low concentrations of tricyclic antidepressants are as important as high ones for dose adjustment or determination of compliance. Other problems with EMIT measurement of tricyclic antidepressants are discussed.     

Assessing physostigmine's contraindication in cyclic antidepressant ingestions

Ingestion of cyclic antidepressant medications or prolongation of the electrocardiographic QRS interval are commonly considered as contraindications to the use of physostigmine as an antidote for antimuscarinic toxicity. This dictum seems to stem from a few well-publicized cases in which administration of physostigmine was temporally associated with the development of asystole. Before the report of these cases, physostigmine was more frequently used and had been considered a first-line antidote for both the neurologic and cardiac toxic effects of cyclic antidepressant overdose. This apparent inconsistency, and a resurgence of interest in physostigmine as an antidote, begs the question of the appropriateness of this drug's contraindication in all cyclic antidepressant ingestions. Review of the published clinical and experimental evidence provides little support for the clinical utility of using electrocardiographic criteria or the ingestion of cyclic antidepressants as contraindications to the use of physostigmine.     

Is it possible to predict the activity of a new antidepressant in animals with simple psychopharmacological tests?

Behavioural tests for predicting antidepressant activity in the animal provide a closer approximation than other tests of states of depression in man but are often long and costly to perform (except the behavioural despair test). The tests proposed here presuppose a pharmacological interaction (except the Porsolt test) but are simple enough to allow screening: included are antagonism of reserpine hypothermia, ptosis and akinesia; antagonism of effects induced by oxotremorine; antagonism of high-dose apomorphine; and potentiation of yohimbine toxicity. In combination with the study of motor activity in the mouse, these tests allow assessment of the specificity of antidepressant activity by establishing a ratio between the "antidepressant" dose and the "stimulant" or "sedative" dose. It can be predicted that a substance will be antidepressant and sedative or stimulant at the same dose if the ratio is close to 1; if the ratio is less than 1, at antidepressant doses the substance will be very sedative or stimulant according to the case. The specificity of the tests discussed can be debatable. Antagonism of reserpine-induced hypothermia indicates substances with direct or indirect beta-mimetic activity, ptosis antagonism, substances with alpha-adrenergic (not antidepressants) or serotoninergic (possibly antidepressants) activity; and akinesia antagonism, a direct or indirect dopaminergic activity (sometimes found in antidepressants) with psychostimulant activity. The oxotremorine test is related to the anticholinergic activity of substances, except in the case of hypothermia antagonism. The high-dose apomorphine test seems to be specific for substances inhibiting norepinephrine reuptake. The yohimbine test is simple to carry out, relatively inexpensive and does not fail to screen any molecule known to be effective to-date. The behavioural despair test is a good complement for screening except for drugs having a beta-agonist activity, it appears that this test is dependent on functional relationships between alpha 2 and serotonergic systems.     

ANTIDEPRESSANTS IN THE ELDERLY

Antidepressants are effective in the treatment of depression but their use in the elderly merits special attention. In general, the tertiary amine tricyclic antidepressants (TCAs) tend to produce significant side-effects in the elderly. In contrast, nortriptyline, desipramine and lofepramine are better tolerated than other TCAs. The newer antidepressants including the selective serotonin reuptake inhibitors are useful alternatives in the treatment of depression in the elderly. As pharmacokinetic studies show that higher steady-state plasma levels of tertiary amine antidepressants may be found in the elderly than in the younger population, a lower dosage is recommended. However, the need for a lower dose in the elderly is less certain for the secondary amine TCAs. The optimum duration of continuation and maintenance antidepressant therapy requires further study. For delusional depression, there is evidence to support the superiority of ECT and combination antipsychotic/antidepressant treatment over antidepressant alone. The ultimate choice of antidepressant will be a balance of efficacy, safety, acceptability and cost.     

Antidepressants and seizures: emphasis on newer agents and clinical implications

Seizures are a known, relatively rare, consequence of antidepressant treatment. Risk estimates vary depending on the study, source of data and patient population, predisposed vs. nonpredisposed. For newer antidepressants (e.g. selective serotonin reuptake inhibitors, bupropion, mirtazepine, etc.), the risk is generally considered to be low (0.0%-0.4%) and not very different from the incidence of first seizure in the general population (0.07%-0.09%). Risk with tricyclic antidepressants at effective therapeutic doses is relatively high (0.4% to 1-2%). Seizure following overdose is a significant and relatively frequent event for some antidepressants. Patients being considered for antidepressant treatment should be screened for predisposition to seizures. Predisposed patients should receive antidepressants cautiously. The seizure potential of antidepressants in patients without a predisposition is low, especially for newer antidepressants. Seizure risk, along with other drug-related considerations, e.g. weight gain, sexual dysfunction and sedation, should be considered when prescribing an antidepressant.     

Antidepressant drug treatment for poststroke depression: retrospective study

The records of 60 patients evaluated psychiatrically for major depression after stroke were reviewed retrospectively. Forty-two patients were treated with one of several "cyclic" antidepressant drugs, and 18 received no drug treatment. Objective ratings, based on current standard criteria for "major depression" (DSM-III), were used to establish degree of depression at initial evaluation and within six weeks after the start of treatment. Overall, improvement in depression was no greater in treated than in untreated patients. However, a subgroup (40%) of drug-treated patients was identified with a substantial (greater than or equal to 40%) improvement in depression ratings. Only three (17%) untreated patients showed a comparable improvement within a similar time period. Eighteen (43%) of the drug-treated patients experienced minor side effects (especially mild sedation), but only three (7%) experienced major side effects that required cessation of treatment. The degree of initial depression was not correlated with the degree of motor or functional disability among patients. These results suggest that antidepressants may constitute safe and effective treatment for some patients with poststroke depression, and further studies of the pathophysiology and treatment of this disorder are indicated.     

Antidepressant-induced sexual dysfunction

OBJECTIVE: To review the evidence regarding antidepressant-induced sexual dysfunction and address implications for treatment strategy and health plan coverage policies for antidepressant medications. DATA SOURCES: Primary articles were identified by a MEDLINE and HealthSTAR search to identify English-language studies published between January 1986 and July 2000. Search terms included sexual dysfunction or sexual function and antidepressants, fluoxetine, sertraline, paroxetine, fluvoxamine, citalopram, venlafaxine, nefazodone, bupropion, and mirtazapine. A cross-check of references cited in 10 published reviews yielded additional in-scope articles. STUDY SELECTION AND DATA EXTRACTION: Approximately 200 articles were identified, including 8 randomized controlled trials and numerous open-label studies, case series, and case reports. Of the randomized controlled trials, only 5 were designed to evaluate the incidence of sexual dysfunction associated with antidepressant treatment. Three additional randomized controlled trials included a structured assessment of sexual dysfunction within an efficacy trial. Data extraction excluded case reports, letters, and other limited study designs. A panel survey augmented published reports. DATA SYNTHESIS: Sexual dysfunction is a relatively common adverse effect of many of the antidepressants in common use today. Rates of sexual dysfunction observed in clinical practice may be higher than those reported in the product information for several agents. Selective serotonin-reuptake inhibitors (SSRIs) appear to be the class of antidepressants most likely to cause sexual dysfunction. Published studies suggest that between 30% and 60% of SSRI-treated patients may experience some form of treatment-induced sexual dysfunction. Bupropion and nefazodone appear to be much less likely to cause sexual dysfunction (相似文献   

Pharmacologic profile of fezolamine fumarate: a nontricyclic antidepressant in animal models

Fezolamine [N,N-dimethyl-3,4-diphenyl-1H-pyrazole-1-propanamine-(E)-2- butenedioate] is a new, nontricyclic agent under investigation as a potential antidepressant. In vitro, it was 3 to 4 times more selective in blocking synaptosomal uptake of [3H]norepinephrine than uptake of [3H]serotonin or [3H]dopamine. In classical behavioral tests using monoamine-depleted animals, it prevented the depressant effects of reserpine and tetrabenzine. In addition, it was active in the "behavioral despair" procedure. Its potency in three of these models was similar to that of standard tricyclics (e.g., imipramine, amitriptyline) or newer nontricyclic antidepressants (e.g., bupropion). In the mouse mydriasis and oxotremorine antagonism models, anticholinergic properties of fezolamine were weak or absent compared with imipramine and amitriptyline. Locomotor activity in mice was not increased by fezolamine at doses 2 to 16 times greater than effective antidepressant doses, suggesting the absence of central nervous system stimulant properties. Fezolamine did not inhibit monoamine oxidase activity in ex vivo studies and, unlike pargyline, did not produce locomotor hyperactivity in mice pretreated with L-tryptophan. In vitro studies using canine Purkinje tissue suggest that fezolamine has significantly less ability to depress myocardial conduction parameters than similar concentrations of imipramine. In a myocardially infarcted cat model, plasma levels of fezolamine 19 to 28 times greater than those achieved with imipramine were required before inducing significant depression of cardiac function and mean arterial pressure. Fezolamine, unlike imipramine, did not increase sinus rate. Fezolamine may thus show antidepressant efficacy in man with minimal anticholinergic or cardiovascular side effects common to tricyclic antidepressants.     

Preferential reduction of binding of 125I-iodopindolol to beta-1 adrenoceptors in the amygdala of rat after antidepressant treatments.

This study utilized quantitative receptor autoradiography to examine the effects of repeated administration of antidepressants to rats on the binding of the beta adrenoceptor antagonist, 125I-iodopindolol (125I-IPIN) to either beta-1 or beta-2 adrenoceptors in various regions of brain. Antidepressants were selected to represent various chemical and pharmacological classes including tricyclic compounds (desipramine and protriptyline), monoamine oxidase inhibitors (clorgyline, phenelzine and tranylcypromine), atypical antidepressants (mianserin and trazodone) and selective inhibitors of the uptake of serotonin (citalopram and sertraline). Additionally, rats were treated with various psychotropic drugs that lack antidepressant efficacy (cocaine, deprenyl, diazepam and haloperidol). Repeated treatment of rats with desipramine, protriptyline, clorgyline, phenelzine, tranylcypromine or mianserin reduced the binding of 125I-IPIN to beta-1 adrenoceptors in many brain areas. Only in the basolateral and lateral nuclei of the amygdala did all six of these antidepressants significantly reduce 125I-IPIN binding to beta-1 adrenoceptors. In these amygdaloid nuclei, the magnitude of the reduction in the binding of 125I-IPIN caused by each of these drugs was comparable to or greater than the reduction in binding produced in any other region of brain. Reductions of binding of 125I-IPIN after antidepressant treatments were not consistently observed in the cortex, the area of brain examined most often in homogenate binding studies. Only the monoamine oxidase inhibitors caused reductions in the binding of 125I-IPIN to beta-2 adrenoceptors, and this effect was generally localized to the amygdala and hypothalamus. Repeated treatment of rats with citalopram, sertraline, or trazodone or with drugs lacking clinical antidepressant efficacy caused no significant effects on the binding of 125I-IPIN to either subtype of beta adrenoceptor in any region of brain. These results demonstrate that amygdaloid beta-1 adrenoceptors are particularly susceptible to regulation by certain antidepressant treatments and implicate the amygdala as an important site of action for antidepressants with pharmacological activity on noradrenergic neurons.