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Seizures due to maprotiline overdose
CASE REPORT antidepressant, maprotitine, overdose; drug overdose, maprotiline; maprotiline, overdose
Seizures Due to Maprotiline Overdose Maprotdline, a new tetracyclic antidepressant, has a pattern of toxicity that is different from that of tricyclics. Maprotiline overdosage appears more likely to cause seizures but less likely to cause the peripheral autonomic and cardiac manifestations seen with tricyclics. Two cases of rnaprotiline overdose resulting in seizures without significant ant!cholinergi c or cardiotoxic effects are presented. Both patients were treated acutely with gastric emptying and were observed to have no further seizures during subsequent drugfree hospital and outpatient follow up. Physostigmine salicylate has been used as an antidote for the anticholinergic syndrome of tricyclic overdosel but probably offers less in maprotiline overdose. Careful observation for seizures appears to be warranted. [Northup L, Reed G, McAnal!ey B, Anderson RJ: Seizures due to m a p r o t i l i n e overdose. A n n Ernerg Mect June 1984;13:468-470.] INTRODUCTION Maprotiiine is a tetracyclic antidepressant drug. It has a four-ring chemical structure instead of the three-ring structure of the tricyclic antidepressants, and it is thought to act by inhibiting reuptake of norepinephrine at nerve endings. 1-3 Although marketed in Europe for the past decade, maprotiline has been available in the United States only since the spring of 1981.4 Compared to conventional tricyclics, maprotiline may have the advantage of fewer anticholinergic side effects.5, 6 Several case reports from Europe and Canada, however, cite seizures in patients using maprotiline.7-14 We present two cases of maprotiline overdose complicated by seizures despite few signs of anticholinergic or cardiotoxic effects.
Laurel Northup, MD* Gary Reed, MD* Bill McAnalley, PhDt Ron J Anderson, MD* Dallas, Texas From the Division of Ambulatory CareEmergency Medicine, Department of Internal Medicine, University of Texas Health Science Center at Dallas,* and the Southwestern lnstitute of Forensic Sciences,I- Dallas,Texas. Received for publication December 8, 1981. Revision received May 27, 1982. Accepted for publication July 16, 1982. Address for reprints: Laurel Northup, MD, Department of Internal Medicine, University of Texas Health Science Center at Dallas, 5323 Harry Hines BouLevard, Dallas, Texas 75235.
CASE REPORTS Case N u m b e r One A 23-year-old woman was treated with maprotitine, 150 mg/day, for nine days. She then increased her dosage to 300 to 350 mg daily and, after another three days, experienced a grand mal seizure. There was no personal or family history of seizures and no history of head trauma, e!ectroconvulsive therapy, or alcohol or other drug use. Pulse was 120/min and regular. Blood pressure was 132/80 m m Hg. Neurologic examination was normal. ECG showed sinus tachycardia at a rate of 120/min with normal conduction. Complete blood count, electrolytes, and calcium were within normal limits, as was the cerebrospinal fluid on lumbar puncture. An EEG taken after four days of hospital observation with no medications was interpreted as normal. The patient was discharged to resume maprotiline at a dosage of 150 mg daily. Eight weeks later she presented to the emergency department (ED)after ingesting 1,250 mg maprotiline in an impulsive suicidal gesture, having learned that she was pregnant. On arrival 30 minutesafter ingestion, she was alert with a blood pressure of 126/90 rnm Hg and a regular pulse of 100/min. Two hours after the ingestion, she suddenly had a grand rnal seizure without focal signs. After the seizure she was awake but lethargic, confused, and diaphoretic. Her physical examination was otherwise normal. An ECG revealed sinus tachycardia of 120/min, with normal conduction. Electrolytes, arterial blood gases, and blood count were normal. A urinary
13:6 June 1984
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MAPROTI LI NE OVERDOSE Northup et al
h u m a n chorionic gonadotropin test was positive. A blood t o x i c o l o g y screen revealed a maprotiline level of 0.83 mg/L (830 ng/mL) and was negative for alcohol or other drugs. After a benign hospital course of five days, she was discharged with a tricyclic and has experienced no further seizures in nine months of follow-up. Case N u m b e r T W o A £7-year-old woman ingested approximately 1 g maprotiline with an u n k n o w n a m o u n t of estrogen pills several hours after drinking heavily. In the ED she was lethargic and disoriented, with a regular pulse of ll0/min and blood pressure of 140/70 m m Hg. Two grand mal seizures occurred. The serum level of maprotiline was 1.5 mg/L, and the level of alcohol was 0.028 mg%. Her ECG was normal with the exception of transient J-point elevation in lead V3. Serum electrolytes, blood count, and urinalysis were normal. She had a history of seizure attributed to alcohol withdrawal eight years previously. She underwent gastric lavage with the recovery of pill fragments, followed by administration of activated charcoal. She received 500 mg phenytoin by slow IV push following each of her two seizures. She was admitted for observation. Maprotiline was undetectable in the serum ten hours after her arrival'in the ED. Her ECG and mental status returned to normal, and no additional seizures occurred during her two-day hospital stay.
DISCUSSION Our first patient was similar to a number of European cases7,8,Io-12,14 in that she experienced seizures despite having no historical, physical, or laboratory evidence for an epileptic predisposition. Seizures have occurred following acute overdosage (ingestions ranging from 425 to 3,200 mg)7,s and during regular m a i n t e n a n c e therapy.9-12 In the latter situation, dosages have ranged from 75 to 300 mg daily, and seizures usually occurred within a few days to one month after starting treatment or increasing the dosage. An association of seizures on maprotiline with oral contraceptive use has been noted; 13 a similar hormonal milieu (due to our first patient's early pregnancy) may have contributed to her susceptibility. Seizures usually have been of the grand mal variety without localizing 98/469
signs, a l t h o u g h one m a n t a k i n g maprotiline showed complex behavior consistent with a temporal lobe focus demonstrated by EEG. 14 In addition to 225 mg maprotiline per day, he was also taking lorazepam, methaqualone, and diphenhydramine. Seizures in patients taking multiple drugs, as in our Case 2, cannot be attributed clearly to maprotiline alone. Concurrent use of other psychoactive drugs, such as phenothiazines, or withdrawal from alcohol, barbiturates, or benzodiazepines may also lower seizure threshold, is The e p i l e p t o g e n i c p o t e n t i a l of maprotiline must be viewed in perspective. All tricyclic agents have been n o t e d to lower the s e i z u r e threshold in both human beings and animals.16 This effect presumably is related to the postulated mechanism of action, the potentiation of central adrenergic synapses by blocking reuptake of norepinephrine at nerve endings. Early clinical trials with maprotiline revealed a low incidence of seizures, with 17 cases reported in more than 26,000 patients. 17 In sharp contrast to earlier reports, the British Committee on Safety of Medications found that during a 15-month period maprotiline was implicated in 42% (112/266) of reported antidepressantassociated convulsions, although it claimed only a 3.6% market share of antidepressants prescribed during that time.18 Our patients' blood levels of maprotiiine at the time of their seizures were, respectively, 0.83 and 1.5 mg/L. Three other cases of patients with seizures at blood levels of 0.317, I2 0.237, and 0.236 mg/L have been reported.9 Maprotiline blood levels have not yet been reported in other patients with seizure activity or in cases of poisoning. At therapeutic doses maproti]ine is approximately equipotent to the tricyclics a m i t r i p t y l i n e and imipramine.2 Serious clinical consequences generally follow ingestions of more than 1 gl9 of a tricyclic drug with blood levels over 1.0 mg/L.2O,21 In five cases of suicide with maprotiline in which dosage could be ascertained, the lethal dose was more than 3 g in one case when taken alone, and varied from 2 to 10 g when combined with such other drugs as tricyciic antidepressants, sedatives, or hypnotics. 22 Full recovery has followed overdoses of 1.6 to 5 g.23 Thus it would seem that our patients' doses and levels of maprotiline represented substantial Annals of Emergency Medicine
but probably sublethal ingestions. The prompt treatment they received (gastric emptying) probably prevented m a x i m u m drug absorption, thereby reducing the peak maprotiline level that usually appears nine to 16 hours after ingestion.3 Anticholinergic effects are common in both acute overdose and long-term administration of conventional tricyclic a n t i d e p r e s s a n t s because of blockade of muscarinic receptors in the autonomic and central nervous systems. Peripheral anticholinergic effects have been fewer and less severe with maprotiline than with tricyclic agents in several controlled trials of m a i n t e n a n c e antidepressant therapy.2,3,5,6 In m a p r o t i l i n e poisoning, however, central effects such as delirium and seizures are reported more commonly than with tricyclics.8,23 In keeping with these results, our patients showed a striking absence of peripheral anticholinergic effects. Thus maprotiiine's toxicity to the central nervous system may exceed its peripheral antichoIinergic effects. It follows that physostigmine salicylate, an anticholinesterase inhibitor used to reverse the anticholinergic syndrome of tricyclic overdose, should be used cautiously (if at all) in cases of maprotiline poisoning because it may cause convulsions.24,25 Neither of our patients had notable cardiac effects from maprotiline, with the exception of mild rate increases. A British survey has d o c u m e n t e d a slightly lower incidence of cardiac complications with maprotiline (11/48, or 2 3 % ) t h a n with tricyclic (127/436, or 29%} overdoses, although convulsions were significantly more common with maprotiline (12/48, or 25% versus 46/436, or 11%; P < .01).TM Cardiac toxicity appears to be no worse for maprotiline than for tricyclic agents, ;tlthough seizures appear to be a more frequent complication of maprotiline use,
SUMMARY Maprotiline has toxic effects generally similar to those of tricydics, with some important differences. In particular the relative thresholds for epilept o g e n i c , a n t i c h o l i n e r g i c , and cardiovascular side effects are different. Maprotiline poisoning may be more likely to be complicated by seizures, but autonomic and cardiac manifestations tend to occur less frequently. Grand mal seizures may occur without preceding anticholinergic symp13:6 June 1984
toms or cardiac conduction or r h y t h m disturbances.
Convulsion following maprotiline overdose, letter. Br Med J 1975;2:275.
The authors thank Barnee Goldberg for her skillful preparation of the manuscript.
8. Park J, Proudfoot AT: Acute poisoning with maprotiline hydrochloride. Br Med J 1977;1:1573.
REFERENCES 1. Baumann PA, Maitre L: Neurobiochemical aspects of maprotiline (Ludiorail ®} action. J Int Med Res 1979;7:391396. -2. Stimmel GL: Maprotiline. Drug IntelI Clin Pharm 1980;14:585-590. 3. Pinder RM, Brogden RN, Speight TM, et al: Maprotiline: A review of its pharmacological properties and therapeutic efficacy in mental depressive states. Drugs 1977;13:321-352. 4. Maprotiline (Ludiomil ®) Another antidepressant. M e d Lett Drugs Ther 198t;23:58-59. 5. Botter PA: A clinical double-blind comparison of maprotiline and amitriptyline in depression. Curr Med Res Opin 1976;3:634-641. 6. Singh AN, Saxena B, Gent M, et al: Maprotiline (Ludiomil, Ciba 34,276-BA) and imipramine in depressed outpatients: A double-blind clinical study. Curr Ther Res 1976;19:451-462. 7. Meek D, Bott MH, Mamtora H, et al:
9. Gupta RN, Molnar G, Gupta ML: Estimation of maprotiline in serum by gaschromatography, with use of a nitrogenspecific detector. Clin C h e m 1977;23: 1849-1852. 10. Shepherd GAA, Kerr F: Maprotiline hydrochloride and grand-mal seizures, letter. Br Med J 1978;1:1523. 11. Hall MJ, Russell RI: Maprotiline hydrochloride and grand-real seizures, letter. Br Med J 1978;2:961. 12. Marks P, Anderson J, Vincent R, et al: Epileptiform seizures with maprotiline hydrochloride. Postgrad Med J 1979;55: 742. 13. Burley D, Jukes A, Steen J: Maprotiline hydrochloride and grand-real seizures, letter. Br Med J 1978;2:1230. 14. Milne HB: Epileptic homicide: Druginduced. Br J Psychiatry 1979;134:547548. 15. Toone BK, Fenton GW: Epileptic seizures induced by psychotropic drugs. Psychol Med 1977;7:265-270. 16. Trimble MR: Non-monoamine oxidase inhibitor antidepressants and epilep-
sy: A review. Epilepsia 1978;19:241-250. 17. Trimble MR: New antidepressant drugs and the seizure threshold. Neuropharmacology 1980;19:1227-1228. 18. Edwards JG: Antidepressants and convulsions. Lancet 1979;2:1368-1369. 19. Thorstrand C: Clinical features in poisonings by tricyclic antidepressants with special reference to the ECG. Acta Med Scand 1976;199:337-344. 20. Spiker DG, Weiss AN, Chang SS, et al: Tricyclic antidepressant overdosage: Clinical presentation and plasma levels. Clin Pharmacol Ther 1975;18:539-546. 21. Biggs JT, Spiker DG, Petit JM, et al: Tricyclic antidepressant overdose: Incidence of symptoms. J A M A 1977;238: 135-138. 22. Jukes AM: Maprotiline (Ludiomil®): Side-effects and overdosage. J Int Med Res 1975;3(suppl 2):126-131. 23. Crome P, Newman B: The problem of tricyclic a n t i d e p r e s s a n t poisoning. Postgrad Med J 1979;55:528-532. 24. Newton RW: Physostigmine salicylate in the treatment of tricycIic antidepressant overdosage. JAMA 1975;231: 941-943. 25. Physostigmine for tricyclic antidepressant overdosage. Med Lett Drugs Ther 1980;22:55.
ACEP Funding for Emergency Medicine Fellowships Beginning July 1, 1985, the American College of Emergency Physicians will award funds for fellowship stipends to support research related to emergency medicine. Four fellowship stipends of $25,000 each will be awarded to nonprofit institutions that possess the basic facilities for research. Institutions interested in applying should request application forms by writing to the Research Committee, ACEP, PO Box 619911, Dallas, Texas 75261-9911. The deadline for submitting applications is November 1, 1984. Notification of awards will be made by February 1, 1985. 13:6 June 1984
Annals of Emergency Medicine
470/99
Seizures Due to Maprotiline Overdose Maprotdline, a new tetracyclic antidepressant, has a pattern of toxicity that is different from that of tricyclics. Maprotiline overdosage appears more likely to cause seizures but less likely to cause the peripheral autonomic and cardiac manifestations seen with tricyclics. Two cases of rnaprotiline overdose resulting in seizures without significant ant!cholinergi c or cardiotoxic effects are presented. Both patients were treated acutely with gastric emptying and were observed to have no further seizures during subsequent drugfree hospital and outpatient follow up. Physostigmine salicylate has been used as an antidote for the anticholinergic syndrome of tricyclic overdosel but probably offers less in maprotiline overdose. Careful observation for seizures appears to be warranted. [Northup L, Reed G, McAnal!ey B, Anderson RJ: Seizures due to m a p r o t i l i n e overdose. A n n Ernerg Mect June 1984;13:468-470.] INTRODUCTION Maprotiiine is a tetracyclic antidepressant drug. It has a four-ring chemical structure instead of the three-ring structure of the tricyclic antidepressants, and it is thought to act by inhibiting reuptake of norepinephrine at nerve endings. 1-3 Although marketed in Europe for the past decade, maprotiline has been available in the United States only since the spring of 1981.4 Compared to conventional tricyclics, maprotiline may have the advantage of fewer anticholinergic side effects.5, 6 Several case reports from Europe and Canada, however, cite seizures in patients using maprotiline.7-14 We present two cases of maprotiline overdose complicated by seizures despite few signs of anticholinergic or cardiotoxic effects.
Laurel Northup, MD* Gary Reed, MD* Bill McAnalley, PhDt Ron J Anderson, MD* Dallas, Texas From the Division of Ambulatory CareEmergency Medicine, Department of Internal Medicine, University of Texas Health Science Center at Dallas,* and the Southwestern lnstitute of Forensic Sciences,I- Dallas,Texas. Received for publication December 8, 1981. Revision received May 27, 1982. Accepted for publication July 16, 1982. Address for reprints: Laurel Northup, MD, Department of Internal Medicine, University of Texas Health Science Center at Dallas, 5323 Harry Hines BouLevard, Dallas, Texas 75235.
CASE REPORTS Case N u m b e r One A 23-year-old woman was treated with maprotitine, 150 mg/day, for nine days. She then increased her dosage to 300 to 350 mg daily and, after another three days, experienced a grand mal seizure. There was no personal or family history of seizures and no history of head trauma, e!ectroconvulsive therapy, or alcohol or other drug use. Pulse was 120/min and regular. Blood pressure was 132/80 m m Hg. Neurologic examination was normal. ECG showed sinus tachycardia at a rate of 120/min with normal conduction. Complete blood count, electrolytes, and calcium were within normal limits, as was the cerebrospinal fluid on lumbar puncture. An EEG taken after four days of hospital observation with no medications was interpreted as normal. The patient was discharged to resume maprotiline at a dosage of 150 mg daily. Eight weeks later she presented to the emergency department (ED)after ingesting 1,250 mg maprotiline in an impulsive suicidal gesture, having learned that she was pregnant. On arrival 30 minutesafter ingestion, she was alert with a blood pressure of 126/90 rnm Hg and a regular pulse of 100/min. Two hours after the ingestion, she suddenly had a grand rnal seizure without focal signs. After the seizure she was awake but lethargic, confused, and diaphoretic. Her physical examination was otherwise normal. An ECG revealed sinus tachycardia of 120/min, with normal conduction. Electrolytes, arterial blood gases, and blood count were normal. A urinary
13:6 June 1984
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MAPROTI LI NE OVERDOSE Northup et al
h u m a n chorionic gonadotropin test was positive. A blood t o x i c o l o g y screen revealed a maprotiline level of 0.83 mg/L (830 ng/mL) and was negative for alcohol or other drugs. After a benign hospital course of five days, she was discharged with a tricyclic and has experienced no further seizures in nine months of follow-up. Case N u m b e r T W o A £7-year-old woman ingested approximately 1 g maprotiline with an u n k n o w n a m o u n t of estrogen pills several hours after drinking heavily. In the ED she was lethargic and disoriented, with a regular pulse of ll0/min and blood pressure of 140/70 m m Hg. Two grand mal seizures occurred. The serum level of maprotiline was 1.5 mg/L, and the level of alcohol was 0.028 mg%. Her ECG was normal with the exception of transient J-point elevation in lead V3. Serum electrolytes, blood count, and urinalysis were normal. She had a history of seizure attributed to alcohol withdrawal eight years previously. She underwent gastric lavage with the recovery of pill fragments, followed by administration of activated charcoal. She received 500 mg phenytoin by slow IV push following each of her two seizures. She was admitted for observation. Maprotiline was undetectable in the serum ten hours after her arrival'in the ED. Her ECG and mental status returned to normal, and no additional seizures occurred during her two-day hospital stay.
DISCUSSION Our first patient was similar to a number of European cases7,8,Io-12,14 in that she experienced seizures despite having no historical, physical, or laboratory evidence for an epileptic predisposition. Seizures have occurred following acute overdosage (ingestions ranging from 425 to 3,200 mg)7,s and during regular m a i n t e n a n c e therapy.9-12 In the latter situation, dosages have ranged from 75 to 300 mg daily, and seizures usually occurred within a few days to one month after starting treatment or increasing the dosage. An association of seizures on maprotiline with oral contraceptive use has been noted; 13 a similar hormonal milieu (due to our first patient's early pregnancy) may have contributed to her susceptibility. Seizures usually have been of the grand mal variety without localizing 98/469
signs, a l t h o u g h one m a n t a k i n g maprotiline showed complex behavior consistent with a temporal lobe focus demonstrated by EEG. 14 In addition to 225 mg maprotiline per day, he was also taking lorazepam, methaqualone, and diphenhydramine. Seizures in patients taking multiple drugs, as in our Case 2, cannot be attributed clearly to maprotiline alone. Concurrent use of other psychoactive drugs, such as phenothiazines, or withdrawal from alcohol, barbiturates, or benzodiazepines may also lower seizure threshold, is The e p i l e p t o g e n i c p o t e n t i a l of maprotiline must be viewed in perspective. All tricyclic agents have been n o t e d to lower the s e i z u r e threshold in both human beings and animals.16 This effect presumably is related to the postulated mechanism of action, the potentiation of central adrenergic synapses by blocking reuptake of norepinephrine at nerve endings. Early clinical trials with maprotiline revealed a low incidence of seizures, with 17 cases reported in more than 26,000 patients. 17 In sharp contrast to earlier reports, the British Committee on Safety of Medications found that during a 15-month period maprotiline was implicated in 42% (112/266) of reported antidepressantassociated convulsions, although it claimed only a 3.6% market share of antidepressants prescribed during that time.18 Our patients' blood levels of maprotiiine at the time of their seizures were, respectively, 0.83 and 1.5 mg/L. Three other cases of patients with seizures at blood levels of 0.317, I2 0.237, and 0.236 mg/L have been reported.9 Maprotiline blood levels have not yet been reported in other patients with seizure activity or in cases of poisoning. At therapeutic doses maproti]ine is approximately equipotent to the tricyclics a m i t r i p t y l i n e and imipramine.2 Serious clinical consequences generally follow ingestions of more than 1 gl9 of a tricyclic drug with blood levels over 1.0 mg/L.2O,21 In five cases of suicide with maprotiline in which dosage could be ascertained, the lethal dose was more than 3 g in one case when taken alone, and varied from 2 to 10 g when combined with such other drugs as tricyciic antidepressants, sedatives, or hypnotics. 22 Full recovery has followed overdoses of 1.6 to 5 g.23 Thus it would seem that our patients' doses and levels of maprotiline represented substantial Annals of Emergency Medicine
but probably sublethal ingestions. The prompt treatment they received (gastric emptying) probably prevented m a x i m u m drug absorption, thereby reducing the peak maprotiline level that usually appears nine to 16 hours after ingestion.3 Anticholinergic effects are common in both acute overdose and long-term administration of conventional tricyclic a n t i d e p r e s s a n t s because of blockade of muscarinic receptors in the autonomic and central nervous systems. Peripheral anticholinergic effects have been fewer and less severe with maprotiline than with tricyclic agents in several controlled trials of m a i n t e n a n c e antidepressant therapy.2,3,5,6 In m a p r o t i l i n e poisoning, however, central effects such as delirium and seizures are reported more commonly than with tricyclics.8,23 In keeping with these results, our patients showed a striking absence of peripheral anticholinergic effects. Thus maprotiiine's toxicity to the central nervous system may exceed its peripheral antichoIinergic effects. It follows that physostigmine salicylate, an anticholinesterase inhibitor used to reverse the anticholinergic syndrome of tricyclic overdose, should be used cautiously (if at all) in cases of maprotiline poisoning because it may cause convulsions.24,25 Neither of our patients had notable cardiac effects from maprotiline, with the exception of mild rate increases. A British survey has d o c u m e n t e d a slightly lower incidence of cardiac complications with maprotiline (11/48, or 2 3 % ) t h a n with tricyclic (127/436, or 29%} overdoses, although convulsions were significantly more common with maprotiline (12/48, or 25% versus 46/436, or 11%; P < .01).TM Cardiac toxicity appears to be no worse for maprotiline than for tricyclic agents, ;tlthough seizures appear to be a more frequent complication of maprotiline use,
SUMMARY Maprotiline has toxic effects generally similar to those of tricydics, with some important differences. In particular the relative thresholds for epilept o g e n i c , a n t i c h o l i n e r g i c , and cardiovascular side effects are different. Maprotiline poisoning may be more likely to be complicated by seizures, but autonomic and cardiac manifestations tend to occur less frequently. Grand mal seizures may occur without preceding anticholinergic symp13:6 June 1984
toms or cardiac conduction or r h y t h m disturbances.
Convulsion following maprotiline overdose, letter. Br Med J 1975;2:275.
The authors thank Barnee Goldberg for her skillful preparation of the manuscript.
8. Park J, Proudfoot AT: Acute poisoning with maprotiline hydrochloride. Br Med J 1977;1:1573.
REFERENCES 1. Baumann PA, Maitre L: Neurobiochemical aspects of maprotiline (Ludiorail ®} action. J Int Med Res 1979;7:391396. -2. Stimmel GL: Maprotiline. Drug IntelI Clin Pharm 1980;14:585-590. 3. Pinder RM, Brogden RN, Speight TM, et al: Maprotiline: A review of its pharmacological properties and therapeutic efficacy in mental depressive states. Drugs 1977;13:321-352. 4. Maprotiline (Ludiomil ®) Another antidepressant. M e d Lett Drugs Ther 198t;23:58-59. 5. Botter PA: A clinical double-blind comparison of maprotiline and amitriptyline in depression. Curr Med Res Opin 1976;3:634-641. 6. Singh AN, Saxena B, Gent M, et al: Maprotiline (Ludiomil, Ciba 34,276-BA) and imipramine in depressed outpatients: A double-blind clinical study. Curr Ther Res 1976;19:451-462. 7. Meek D, Bott MH, Mamtora H, et al:
9. Gupta RN, Molnar G, Gupta ML: Estimation of maprotiline in serum by gaschromatography, with use of a nitrogenspecific detector. Clin C h e m 1977;23: 1849-1852. 10. Shepherd GAA, Kerr F: Maprotiline hydrochloride and grand-mal seizures, letter. Br Med J 1978;1:1523. 11. Hall MJ, Russell RI: Maprotiline hydrochloride and grand-real seizures, letter. Br Med J 1978;2:961. 12. Marks P, Anderson J, Vincent R, et al: Epileptiform seizures with maprotiline hydrochloride. Postgrad Med J 1979;55: 742. 13. Burley D, Jukes A, Steen J: Maprotiline hydrochloride and grand-real seizures, letter. Br Med J 1978;2:1230. 14. Milne HB: Epileptic homicide: Druginduced. Br J Psychiatry 1979;134:547548. 15. Toone BK, Fenton GW: Epileptic seizures induced by psychotropic drugs. Psychol Med 1977;7:265-270. 16. Trimble MR: Non-monoamine oxidase inhibitor antidepressants and epilep-
sy: A review. Epilepsia 1978;19:241-250. 17. Trimble MR: New antidepressant drugs and the seizure threshold. Neuropharmacology 1980;19:1227-1228. 18. Edwards JG: Antidepressants and convulsions. Lancet 1979;2:1368-1369. 19. Thorstrand C: Clinical features in poisonings by tricyclic antidepressants with special reference to the ECG. Acta Med Scand 1976;199:337-344. 20. Spiker DG, Weiss AN, Chang SS, et al: Tricyclic antidepressant overdosage: Clinical presentation and plasma levels. Clin Pharmacol Ther 1975;18:539-546. 21. Biggs JT, Spiker DG, Petit JM, et al: Tricyclic antidepressant overdose: Incidence of symptoms. J A M A 1977;238: 135-138. 22. Jukes AM: Maprotiline (Ludiomil®): Side-effects and overdosage. J Int Med Res 1975;3(suppl 2):126-131. 23. Crome P, Newman B: The problem of tricyclic a n t i d e p r e s s a n t poisoning. Postgrad Med J 1979;55:528-532. 24. Newton RW: Physostigmine salicylate in the treatment of tricycIic antidepressant overdosage. JAMA 1975;231: 941-943. 25. Physostigmine for tricyclic antidepressant overdosage. Med Lett Drugs Ther 1980;22:55.
ACEP Funding for Emergency Medicine Fellowships Beginning July 1, 1985, the American College of Emergency Physicians will award funds for fellowship stipends to support research related to emergency medicine. Four fellowship stipends of $25,000 each will be awarded to nonprofit institutions that possess the basic facilities for research. Institutions interested in applying should request application forms by writing to the Research Committee, ACEP, PO Box 619911, Dallas, Texas 75261-9911. The deadline for submitting applications is November 1, 1984. Notification of awards will be made by February 1, 1985. 13:6 June 1984
Annals of Emergency Medicine
470/99