Original Author: Paul Perry, Ph.D, BCPP
Latest Revisers: Paul Perry, Ph.D, BCPP, Vicki Ellingrod,
Pharm.D., BCPP
Creation Date: 1996
Last Revision Date: April 2002
Peer Review Status: Internally Peer Reviewed
INTRODUCTION
In 1980 amitriptyline (Elavil) was the eleventh most commonly mentioned drug for emergency room admissions in the Drug Abuse Warning Network (DAWN System) in the United States (Callahan 1979, Frommer et al 1987). Of 3536 drug abuse deaths reported by the medical examiners in the DAWN system between October, 1979 and September, 1980, 298 (8.9%) involved amitriptyline. These figures were exceeded only by alcohol-in-combination (30.6%), heroin/morphine (22.7%) diazepam (8.7%) methadone (9.0%) and d-propoxyphene (8.6%). Overdose with non-TCA antidepressants is increasing as prescription of these agents is increasing.
In 1983 the annual number of TCA overdoses was estimated at 500,000 (Frommer et al 1987). Data collected by the American Association of Poison Control Centers and the National Institute on Drug Abuse in 1986 indicate tricyclic overdoses constitute 75% of reported cases of antidepressant overdose (Drug Abuse Warning Network 1980). This trend has changed with prescribing patterns and SSRIs are now more commonly taken in overdoses than TCAs (Litovitz 2000).
A typical profile of a TCA overdose victim is female, between 20 and 29 years of age, single, employed, living alone, and without prior history of drug abuse or suicide attempts. Over 70% of successful TCA suicides do not reach a health care facility (Frommer et al 1987).
TRICYCLIC ANTIDEPRESSANTS (TCA)
The TCAs include amitriptyline, imipramine, nortriptyline, desipramine, doxepin, protriptyline, and trimipramine. No evidence exists to indicate toxicity differs significantly among the TCAs.
Pharmacokinetics
In therapeutic doses, the TCAs are normally completely absorbed usually within two hours. However, following an overdose they are absorbed slowly because they are ionized in the acid stomach and then slow peristalsis as well as cause gastric dilatation (Callahan 1979, Frommer et al 1987).
Tissue distribution is dependent upon two factors: TCA lipid solubility, which is high when unionized; and TCA dissociation at various pH levels, which favors ionization (decreased tissue entry) at low pHs, such as in the stomach (Callahan 1979, Frommer et al 1987).
Following hepatic metabolism, about five percent of the daily dose is excreted in the bile and enters an enterohepatic cycle whereby it is reabsorbed. Additionally, another 5 to 16% is excreted daily into the gastric juices, since TCAs have a pKa of 9.5 and are highly ionized at acid pHs, thereby favoring concentration in the acid stomach. Both gastric and biliary excreted TCAs are reabsorbed in the small intestine and are eventually excreted in the urine following hepatic glucuronidation. In therapeutic doses, 40% of the daily dose appears in the urine within 24 hours, but in overdoses, only 3 to 10% is excreted within 24 hours because of metabolic saturation (Callahan 1979, Frommer et al 1987).
Studies usually report no correlation between TCA plasma levels and ingested dose. This is because the amount of TCA in the plasma in comparison to the tissues is small, e.g., myocardial levels are 5 times plasma levels (Frommer et al 1987). Also, the hepatic metabolism of TCAs produce hydroxylated metabolites which maybe more cardiotoxic than the parent compounds. Hydroxylated metabolites are not routinely reported with TCA clinical assays. At toxic levels the metabolic pathway can become saturated. TCA half-lives are reported to range in overdoses from 25 to 8l hours (Gamble and Peterson 1986). Plasma protein binding decreases with a decrease in pH. At a pH of 7.5, 98% of the TCA is protein bound but at a pH of 6.7 only 82% is bound. Therefore, in an acidotic patient free TCA levels can increase by 9 times (Callahan 1979, Frommer et al 1987).
The drug overdose history correlates reasonably well with the clinical outcome. Generally, at less than 20 mg/kg, few fatalities are found; 35 mg/kg is the approximate LD50; and at > or = 50 mg/kg, death is likely (Spiker and Biggs 1976). Patients have survived ingestions of 10 g of amitriptyline (Burks et al 1974), but overdoses as small as 500 mg have been fatal. (Manoquerra Weaver 1977). Postmortem studies of TCA overdose suggest that blood levels exceeding 1000 ng/ml are usually toxic and may be associated with a fatality, while concentrations above 6000 ng/ml are usually fatal (Hebb et al 1982).
SIGNS AND SYMPTOMS
Overdose of TCA primarily affects the parasympathetic nervous system, CNS, and cardiovascular systems.
Cardiac
The cardiovascular effects of TCAs have the greatest potential for causing morbidity and mortality due to conduction disturbances and hypotension. In 35 patients with acute overdosage of amitriptyline or imipramine 71% had tachycardia, 51% hypotension, 11% prolonged PR interval, 29% prolonged PRS, 86% prolonged QTc and 30% PVCs (Langou et al 1980). The order of appearance, sinus tachycardia, right axis deviation, repolarization disturbances of intraventricular conduction (right or left bundle branch block), ventricular arrhythmias, atrioventricular conduction defects, profound bradycardia with variable atrioventricular block, and cardiac arrest (Dumovic et al 1976). These effects are due to three major pharmacologic effects.
Anticholinergic effects cause increased heart rate and mildly increased blood pressure. Sinus tachycardia appears very early, is almost universal, and is one of the most sensitive signs of TCA intoxication. Many have no other cardiovascular toxicity. The anticholinergic mechanism probably does not contribute significantly to the severe cardiotoxic effects of TCA overdose.
The second mechanism of TCA cardiotoxicity involves the blockade of norepinephrine uptake at the adrenergic presynaptic endings. TCAs block norepinephrine reuptake, leading to an accumulation in the synapse and initially an increased stimulation of both central and peripheral adrenergic neurons. Clinically, the increased adrenergic stimulation is first seen as tachycardia, mild hypertension, and mildly increased cardiac output, all of which can be reversed by b-blockers. None of these findings is life threatening; however, sufficient adrenergic stimulation can cause ventricular ectopy and sinus tachycardia, the latter occurring in 70% of overdoses. It is not known if these arrhythmias are caused by excessive adrenergic stimulation. Eventually, norepinephrine depletion may occur and contribute to decreased myocardial contractility and hypotension.
The third mechanism is the "quinidine-like" or membrane-stabilizing" effect. Membrane stabilizers depress excitability in nerve and heart tissue. TCAs increase the refractory period, raise the stimulation threshold, decrease cardiac conduction velocity (especially the HIS bundles of the intraventricular conduction system), and severely decrease ventricular automaticity. A-V nodal conduction (A-H) time is not affected.
The ECG typically demonstrates a QRS duration > or = 100 msec in severe overdose. Unfortunately, about 25% of the normal population will have a QRS duration of 100 msec, so such an ECG finding is not pathognomonic of TCA toxicity. Values of 140 msec or more are not uncommon. Though some studies have reported a correlation between a QRS interval > or =200 msec and a plasma level > or =1,000 ng/ml as well as other severe complications, such as seizures, hypotension, coma, arrhythmias, cardiac arrest, and death, this is not consistently reported (Dumovic et al 1976, Foulke and Albertson 1987, Frommer et al 1987). The conduction defect is dose-dependent. Bundle branch blocks, usually right, are also common, appearing early and persisting late. First degree heart block is common, but is usually not a problem. The Q-T interval is also prolonged, but the technical difficulties of measuring it limit its usefulness.
Membrane stabilization not only causes conduction blocks, but also may predispose the patient to reentry arrhythmias such as ventricular tachycardia. Ventricular fibrillation and bigeminy also occur. Terminally, profound bradycardia with varying A-V block leads to idioventricular rhythm and cardiac arrest. Myocardial damage itself with ECG changes and elevated cardiac enzymes have been reported. Cardiac arrest is seen in 4% to 12% and mortality ranges from 0 to 20%; the median is about 5%. The differential diagnosis of ventricular tachycardia in TCA overdose is complicated by the fact that a broad, sinusoidal QRS, ST elevation, T-wave changes, and tachycardia are all common. A combination of these factors may cause the ECG pattern to be indistinguishable from that created by ventricular tachycardia. The diagnosis must be made with caution.
The membrane-stabilizing effect depresses not only cardiac conduction, but also myocardial contractility.
Vascular
A third of human overdoses will have a systolic blood pressure below 100 mm Hg and 10% will be below 80 mm Hg (Shannon et al 1988). Hypotension occurs independently of TCA level and prolongation of the QRS interval. It is, however, strongly associated with the development of arrhythmias.
Decreased myocardial contractility is present even with normal blood pressure, and falls faster than the blood pressure. In animals, mean blood pressure remained at 40 to 70 mm Hg, despite almost unmeasurable cardiac contractility, then reportedly dropped suddenly to zero.
Another possible cause of hypotension is that TCAs, which are phenothiazine analogs, possess potent direct vascular alpha-adrenergic blocking qualities. TCAs block norepinephrine uptake not only in the myocardium, but also in blood vessels. This may help explain the direct vasodilator effect demonstrated in isolated limb studies in dogs and man. In whole animals, however, peripheral vascular resistance seems to be well maintained even in the face of hypotension, which was attributed to myocardial depression alone. The exact role of this alpha-adrenergic blocking property in hypotension remains to be clarified. As previously mentioned, norepinephrine depletion may reduce myocardial contractility and play a role in later onset hypotension.
The interplay of these three cardiotoxic effects in the clinical state is obviously complex. In addition, hypoxia, pH and vagal stimulation further alter the balance. Hypoxia, seizures, acidosis, intubation, and any sympathetic nervous system stimulation can trigger or alter arrhythmias or induce cardiac arrest. Relatively minor fluctuations in tissue concentrations or binding may significantly change the clinical state. The phases and progression of cardiac toxicity may vary from patient to patient. Although knowing the general range and order of appearance of cardiac symptoms, the patient's particular clinical conditions must dictate treatment.
Neurologic
The central anticholinergic action of the TCA can produce delirium and hallucinations. However, approximately 50% of overdosed patients are comatose on admission. The onset of the coma is usually within six hours of the ingestion, lasts on the average 24 hours, and seldom persists longer than 48 hours. Twitching, jerking, and myoclonic movements are seen in more than 40%. Grand mal seizures, a major complication in 10% to 20% of cases, can be seen even with therapeutic doses. Pyramidal nervous system signs are often prominent, especially in the comatose patient. Hyperreflexia is seen in about half; a positive extensor plantar response in about 25%; and clonus in about 5%. Extrapyramidal signs, such as nystagmus, ataxia, and dysarthria, are much less common and are, of course, early signs before the onset of coma (Callahan 1979, Frommer et al 1987).
Temperature elevation occurs in 20% of patients with another 20% of patients being hypothermic (Petit et al 1976).
Pulmonary
Assisted ventilation which correlates with a plasma level of > 1000 ng/ml is required in 20 to 40% of overdoses (Petit et al 1976). Pulmonary edema and aspiration pneumonia occurred in 13% and 17%, respectively, of patients admitted with severe TCA overdose (Shannon and Lovejoy 1987). Pulmonary edema was strongly correlated with hypotension in one study (Dumovic et al 1976). This most likely occurs secondary to fluids administered for hypotension.
Gastrointestinal
The anticholinergic effects of TCAs include dry mouth, decreased GI motility and delayed gastric emptying (Dumovic et al 1976). This effect may result in delayed removal of the drug from the bowel and prolonged continuous absorption (Foulke and Albertson 1987).
Urogenital
Urinary retention occurs in 10% of patients secondary to anticholinergic actions (Dumovic et al 1976).
Musculoskeletal
Muscle twitching and decreased DTRs may be present (Dumovic et al 1976).
Ophthalmic
Often mydriasis occurs with the pupils poorly reactive or non-reactive to light (Dumovic et al 1976).
TIME COURSE OF OVERDOSE
Goel has defined three functional stages of TCA overdose (Goel and Shanks 1974). In stage I, there is always some responsiveness to pain; cardiac effects are largely limited to supraventricular tachycardia; and patients are usually well in 24 hours. In stage II, patients convulse and/or need respiratory support; manifest A-V and interventricular conduction blocks; and recover in 24 to 48 hours. In stage III, respiratory arrest, convulsions, and hypotension are common; ventricular arrhythmias frequent; and cardiac arrest a possibility. A patient may progress rapidly through these phases (Frommer et al 1987).
TREATMENT (Rumack 1982)
Patient Disposition
There is an obvious concern in overdose that one can never be certain what a patient ingested. Due to this, some clinicians recommend keeping all patients on a monitored bed for 24 hours, regardless of presenting symptoms.
Prevention of Absorption (Rumack 1982)
Cardiovascular System (Rumack 1982)
If alkalinization is ineffective, phenytoin maybe effective. It is dosed 100 mg IV administered over 3 min and repeated q5min until the arrhythmia ceases or a 1000 mg total dose is reached. Arrhythmias which do not respond to alkalinization and phenytoin may respond to lidocaine 1 mg/kg/dose, repeated q20min if needed. Lidocaine maintenance dose of 10-40 ug/kg/min given by continuous IV infusion may be begun concurrently with the loading dose.
Finally, if necessary, propranolol may be used at a dose of 1 mg IV q2-5min until a response is seen or until a maximum of 20 mg has been given. This should be used with caution because of the hemodynamic instability in these patients and potential danger from the presence of a beta-blocker should reduced myocardial contractility occur.
Patients with sinus tachycardia generally do not need to be treated.
Central Nervous System (Rumack 1982)
Seizures may be treated with diazepam 10 mg IV, followed by loading doses of phenytoin, if they are repeated.
Physostigmine (Rumack 1982)
Physostigmine is not an "antidote" for TCA overdose. Popularity of use in the 1970s has waned. Anticholinergic effects of the TCAs explain few of the adverse cardiac events making physostigmine ineffective in severe arrhythmias. Physostigmine has produced bronchoconstriction, sinus bradycardia, heart block, cardiac standstill and seizures. Relative contraindications to the use of physostigmine include asthma, gangrene, cardiovascular disease, and mechanical obstruction of the gastrointestinal or urogenital tract. Since physostigmine will not alter the outcome of a TCA overdose, it is not recommended as a component of treatment.
Renal (Rumack 1982)
Respiratory System (Rumack 1982)
SECOND-GENERATION ANTIDEPRESSANTS
MAPROTILINE
Maprotiline (Ludiomil) is the only tetracyclic antidepressant available in the US.
Pharmacokinetics (Alkalay et al 1980, Riess et al 1975)
Maprotiline is slowly but completely absorbed after oral administration. Peak plasma levels are obtained 8 to 24 hours after a single dose.
Maprotiline is widely distributed to all tissues and has a mean apparent volume of distribution of 22.6 L/kg. The drug in plasma is 88% bound to proteins.
Maprotiline is almost completely metabolized and about 60% of these metabolites appear in the urine. The principle metabolite is the desmethyl derivative. This metabolite and the parent compound are transformed into minor metabolites by hydroxylation. Desmethylmaprotiline and maprotiline-N-oxide have pharmacological properties similar to the parent drug in animals. The elimination half-life of maprotiline is 27 to 58 hours.
The recommended daily dose of maprotiline is 150 to 300 mg. Therapeutic and toxic blood levels of maprotiline or its metabolites have not been defined (Pinder et al 1977).
Signs and Symptoms
Acute poisoning with maprotiline causes symptoms similar to those produced by TCAs. Signs and symptoms included drowsiness, seizures, coma, anticholinergic signs, tachycardia, bradycardia, cardiac arrest, hypotension, and hypertension. One of the five children had repeated convulsions after ingesting 525 mg (Crome and Newman 1977).
A comparison of maprotiline cases with TCA poisoning cases suggests that delirium and seizures (25%) are more common with maprotiline, while cardiac arrhythmias are similar in occurrence (Frommer et al 1987, Park and Proudfoot 1977, Petit et al 1976).
Treatment (Rumack 1982)
Treatment is the same as for TCA overdose. Repeated administration of charcoal and magnesium sulfate may be effective in reducing absorption of maprotiline because of its slow absorption rate.
AMOXAPINE
Amoxapine is the desmethyl metabolite of the dibenzoxazepine antipsychotic, loxapine. It possesses pharmacologic properties common to antidepressants and antipsychotics. Amoxapine overdose are characterized by less cardiovascular effects but more CNS events compared to TCAs.
Litovitz and Troutman published the results of a survey of amoxapine overdoses reported to two regional poison centers (Litovitz and Troutman 1983). The authors reviewed all ingestions reported to poison centers in Washington, DC and New Mexico over an 18-month period between 1980 and 1982. Of all reported overdoses, 479 included heterocyclic antidepressants, 33 of which were amoxapine. Fifteen of the amoxapine overdose patients developed "substantial toxic conditions." Eight (24%) became comatose. Thirteen (39%) had supraventricular tachycardia. Twelve (36%) suffered seizures. Hyperthermia developed in three patients (9%), all of whom sustained prolonged convulsions. Two patients (6%) developed a coagulopathy, and one of these had profuse hemorrhage. Five patients (15.2%) died. By contrast, of 446 patients who took excessive amounts of other antidepressants, 19 (4%) had seizures and three (less than 1%) died.
Pharmacokinetics
Peak plasma amoxapine levels occur approximately 1 hour after ingestion of a therapeutic dose. Amoxapine is hydroxylated by the liver and has an average half-life of 8 hours. The half-lives of the 2 major metabolites are 6.5 and 30 hours. The drug is 90% bound to plasma proteins (Amoxapine Monograph 1980).
The recommended amoxapine dose of adults is 200 to 300 mg per day. Daily doses of 600 mg have used in the treatment of depression. Therapeutic levels of amoxapine have been reported to be less than 100 ng/ml (Amoxapine Monograph 1980).
Signs and Symptoms
In 5 cases, known doses of 1000, 2000, 2100, 2700 and 3900 of amoxapine were ingested (Browne et al 1982, Goldberg and Spector, Hekimian et al 1978, Ross and Rogers 1981). The patients ingesting 2000 and 3900 mg of amoxapine had levels on admission of 2509 and 648 ng/ml, respectively (Goldberg and Spector). The patients did not show the cardiovascular, gastrointestinal, urogenital and ophthalmic effects often associated with the TCAs. However, 4 of 5 cases developed multiple seizures, severe metabolic acidosis and deep coma. These findings are similar to what has been reported with overdoses of loxapine (Bock et al 1982, Pumariega et al 1982, Reynolds et al 1979, Tam et al 1979). Neurologic findings include a negative or positive corneal reflex, negative or positive dolls eyes, positive babinski bilaterally and decerebration of decortication to noxious stimuli. EEG findings demonstrated diffuse cerebral dysfunction. In are recently reported case, a woman died after a 2 g acute ingestion, which is the lowest reported lethal dose (Munger and Effron 1988).
Recently, renal failure associated with amoxapine overdose has been reported. In a report of about 50 cases of overdose of amoxapine, eight (16%) were complicated by acute renal failure, beginning by the third day after overdose and in all cases reversed within two weeks (Pumariega et al 1982). The mechanism of the renal failure is unknown. Amoxapine may have a direct nephrotoxic effect or renal failure may be an effect of rhabdomyolysis, which results from hypoxia and seizures (Gelenberg 1983).
Time Course of Overdose
Symptoms of overdose occur within 4 hours of ingestion. Seizures and metabolic acidosis may last up to 12 hours. The most distressing finding is the continuation of neurologic deficits. Coma may last 3 weeks. At 1 month and 3 months after overdosing 2 patients demonstrated ataxia, recent memory impairment, dysarthric speech, impaired judgment, and positive babinskis.
Treatment
Intervention in amoxapine overdose should be directed toward combating initiation of seizure activity, and maintaining functional acid-base status with methods described under TCAs (Amoxapine Monograph 1980, Rumack 1982).
Although the etiology of amoxapine-induced renal failure is unclear. Jennings et al (1983) recommend immediate hydration with intravenous saline as a means to protect the kidney in cases of amoxapine overdose. They contend that the high resulting rate of urine flow can diminish nephrotoxic reactions from a variety of drugs and also can prevent the renal failure that may follow rhabdomyolysis. They recommend, therefore, aggressive volume expansion with isotonic saline (up to 500 ml/hr for the first three to four hours of hospitalization, with appropriate cardiovascular monitoring), together with diuresis with loop diuretics (e.g., furosemide [Lasix and other]) or mannitol. Because amoxapine, like other antidepressants, is tightly bound to plasma and tissue protein, hemodialysis is of little use in reducing toxic blood levels. A role for hemoperfusion in amoxapine overdoses is unclear, although hemoperfusion has not proved useful with tricyclic overdoses.
Comment
The mechanism of neurotoxicity in amoxapine overdose is not known. The severe metabolic acidosis and/or recurrent seizure activity secondary to high amoxapine levels may have contributed to the permanent neurotoxicity in some case reports. Renal failure occurs in about 1 out of 7 cases and requires close monitoring (Pumariega et al 1982). Serious cardiac complications are less common with amoxapine than with TCAs (Gelenberg 1983).
TRAZODONE
Henry and Ali (1983) have described the trazodone overdose experience of the London center of the United Kingdom National Poisons Information Service (NPIS) between August 1980 and March 1982. The NPIS was consulted about 47 overdoses involving. Twenty cases involved trazodone alone. The US trazodone overdose literature was reviewed in 1986 with experience in 294 cases (Gamble and Peterson 1986).
Pharmacokinetics (Georgotas et al 1982)
Trazodone is well absorbed following oral administration with concentrations shown to peak within two hours (according to animal data). The drug is highly protein bound, with 89-95% the calculated range. The drug's active metabolite, m-chlorophenylpiperazine (m-CPP) may contribute to the pharmacologic activity of trazodone. Trazodone is highly metabolized in the liver by hydroxylation, pyridine ring, splitting, oxidation and N-oxidation, with <1% of the unchanged drug appearing in the urine and feces. It is noteworthy that m-CPP, the trazodone metabolite, is eliminated from the body at a slower rate than trazodone. However, no data are available correlating trazodone or trazodone/m-CPP blood levels to therapeutic effect. The drug is eliminated from the body in a biphasic pattern with the blood and brain representing the alpha-elimination phase compartment and the liver, lungs and kidneys representing to beta-elimination phase compartment. An alpha-elimination phase half-life of 4.4 hours and beta-elimination phase half-life of 7-8 hours have been calculated.
Signs And Symptoms
In the NPIS report 20 adults ingested trazodone alone in a mean dose of 1.5 g. Symptoms included drowsiness (9), dizziness (4), shivering (2) and nausea (2). Individually noted symptoms included coma, vomiting, tinnitus, tachycardia, hypotension, dyspnea, feeling cold, myalgia, urinary incontinence, dry mouth, and headache.
In the US overdose cases, only 9 of 294 cases resulted in fatality. Each of the fatalities resulted from ingestion of trazodone in combination with other drugs and/or alcohol. The remaining patients had uneventful recoveries (Gamble and Peterson 1986). . Ingestions as high as 6-9 grams have resulted in an uneventful recovery (Ayd 1984).
Treatment
No treatment other than gastric lavage, emesis, and supportive care is recommended for trazodone. Patients with a history of seizures or cardiovascular disease should be followed more closely.
BUPROPION
Seizures are the most significant manifestation of bupropion intoxication. At doses less than 450 mg/day, seizures occur in 0.4% of patients (Davidson, 1989). Estimates of the incidence of seizures at more than 450 mg/day vary from 2-4% (Davidson, 1989; Burroughs Wellcome Company, 1991). Among 38 bupropion overdoses reported to the manufacturer, 34 had seizures. There were no reports of status epilepticus or chronic epilepsy resulting from the intoxication (Gittelman, 1993). In a 3 year retrospective review of 58 cases of "pure" bupropion overdoses, 21% experienced seizures (Spiller et al, 1994). The mean ingestion among patients experiencing seizures was 3,078 mg (575-6000 mg) compared to 2,148 mg (200-6300 mg) among other symptomatic patients who did not experience a seizure. Multiple seizures occurred in 2 patients. Tachycardia occurred in 43% of the cases. No fatalities were reported. At least 14 fatalities have been reported involving bupropion. In six cases bupropion was the only drug ingested (Gittelman, 1993). In the two fatalities with details included, both patients died of complications of status epilepticus following an ingestion of 16 grams of bupropion (personal communication, Burroughs Wellcome Company, 1995). The highest known exposure to bupropion is 17 grams. This patient recovered without sequelae and did not have a seizure, possibly because of concomitant benzodiazepine ingestion (personal communication, Burroughs Wellcome Company, 1995). Several cases of bupropion overdose involving ECG changes suggestive of intraventricular conduction delays have been reported (Shrier et al 2000, Fresh et al 1999, Paris and Saucier 1998). One patient ingested 1.5 grams and developed a ventricular rate of 150 beats/min, QTc interval of 600 ms, and QRS interval of 100 ms. These changes resolved without treatment. Another patient ingested 23 grams, developed seizures, and deteriorated with a fatal cardiac dysrythmia (Harris et al 1997). Thus, while serious cardiac toxicity is rare in bupropion overdose, it can occur.
SEROTONIN REUPTAKE INHIBITORS
One of the major advantages of SSRIs is that they appear to be relatively safe in the event of an overdose (Grimsley et al, 1992; Henry 1992). There is only one reported fatality in a patient taking an SSRI alone, fluoxetine (Kincaid et al, 1990). Fluoxetine and fluvoxamine have the longest record of safety among the SSRIs (Borys et al, 1992; Borys et al, 1990; Garnier et al, 1993). Patients who attempt suicide via fluoxetine overdose may experience tachycardia or bradycardia, convulsions, depressed ST segments on ECG, increased diastolic blood pressure, drowsiness, agitation or potentiated adverse effects seen at therapeutic doses (Henry 1992). Fluvoxamine produces similar manifestations (Garnier et al, 1993). For paroxetine and sertraline, complete recovery has been reported in the limited number of patients who have taken an overdose (Grimsley et al, 1992). For paroxetine, ingestions as high as 850 mg have resulted in complete recovery (Boyer and Blumhardt, 1992). For sertraline, ingestions as high as 2.6 grams have not produced any significant sequelae (Doogan, 1991). Both Nefazodone and Venlafaxine have not been found to be toxic in overdose. The highest reported ingestion with no fatality for each is 11.2 grams and 2.75 grams respectively (Ellingrod and Perry, 1994 and 1995). Mirtazepine, a novel antidepressant with serotonergic activity, has been taken in 30 times the maximum recommended dose with sedation (that required intubation in some cases) being the only notable adverse effect (Sarko 2000).
SSRI overdoses often produce no symptoms (Sarko 2000). Self-limited symptoms that occur most commonly include tachycardia, drowsiness, tremor, nausea, and vomiting. Serotonin syndrome may occur, especially if other serotonergic drugs are co-ingested, and the presentation of SSRI overdose can mimic that of serotonin syndrome. Seizures and cardiotoxicity (widened QRS and QTC intervals) may occur in large overdoses. Sinus bradycardia has occurred in fluvoxamine overdose. Seizures are generally brief and respond to benzodiazepines. Cardiac dysrythmias resolve without treatment within 24 hours, but do respond to usual treatments if necessary. Sodium bicarbonate can be helpful if QRS prolongation is seen. Activated charcoal should be administered as per normal guidelines for overdoses.
MONOAMINE OXIDASE INHIBITORS (MAOI)
A 1986 review reported 125 cases of MAOI overdose in the US (Gamble and Peterson 1986). Three patients died.
SIGNS AND SYMPTOMS
Symptoms following an overdose of a MAOI may not be evident for 6 to 12 hours after ingestion. Symptoms include tremors, neuromuscular weakness, diaphoresis, agitation, mental confusion, tachypnea, hypertension, tachycardia, hyperthermia, miosis, increased deep tendon reflexes, involuntary movements, seizures, headache, dizziness, and precordial pain. Severe toxicity leads to coma, profound hypotension, bradycardia, and asystolic arrest. If the MAOI has been combined with tyramine-containing foods or sympathomimetic drugs, severe hypertension may occur (Ciocatto et al 1972, Rumack 1982, Tollefson 1983).
Data on lethal doses in man are difficult to evaluate because of the possibility of drug interactions in precipitating the same symptoms seen in overdose. However, there are six reported deaths from phenelzine in doses of 385-750 mg and four deaths from tranylcypromine in doses of 170-7850 mg (Rumack 1982). This information has been recently updated with 3 deaths in 125 cases (Gamble and Peterson 1986).
TREATMENT
Cardiovascular System (Rumack 1982)
Central Nervous System (Rumack 1982)
Renal
The excretion of tranylcypromine is increased seven-fold by decreasing urinary pH from 8 to 5 (Turner et al 1967). Hemodialysis has been associated with rapid recovery from tranylcypromine (Matter et al 1965) and phenelzine (Versaci et al 1964) intoxications.
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