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Antidepressants
Poisonous substances
Antidepressants
Antidepressant drugs
D Nicholas Bateman
Tricyclic antidepressants • Amitriptyline • Amoxapine • Clomipramine • Dothiepin (dosulepin) • Doxepin • Imipramine • Lofepramine • Nortriptyline • Protriptyline • Trimipramine
Abstract Antidepressant drugs differ in their relative toxicities. The most hazardous are monoamine oxidase inhibitors and tricyclics. Features include arrhythmias, convulsions and cardiovascular effects. Management should be as active as necessary to reduce arrhythmia risk by aggressive correction of acidosis and use of sodium bicarbonate to shorten QRS duration if prolonged. Venlafaxine and citalopram are the most toxic of the newer drugs.
Tricyclic-related compounds • Maprotiline • Mianserin • Trazodone • Viloxazine Selective re-uptake inhibitors and related drugs Serotonin • Citalopram • Escitalopram • Fluoxetine • Fluvoxamine • Paroxetine • Sertraline
Keywords antidepressants, monoamine oxidase inhibitors; poisoning; selective noradrenaline re-uptake inhibitor; selective serotonin re-uptake inhibitor; tricyclic antidepressants
Antidepressants may be classified into four principal groups (Table 1). The tricyclics and the irreversible monoamine oxidase inhibitors (MAOIs) are the most toxic.1 Selective serotonin reuptake inhibitors (SSRIs) are generally safer in overdose,2 but the least toxic is mirtazapine.
Serotonin and noradrenaline • Duloxetine • Venlafaxine Noradrenaline • Reboxetine
Tricyclic antidepressants and related drugs Tricyclic antidepressants probably produce their therapeutic effects by blocking the uptake of monoamines in adrenergic or serotonergic nerve endings in the brain. Many first-generation tricyclic antidepressants also have clinically significant anticholinergic properties. In overdose, the direct effect of these agents on ion channels becomes important, they act as sodium channel blockers, and this is probably responsible for variations in the toxicity of the different types of antidepressant. Cardiotoxicity and convulsion is the usual mechanism of death in patients severely poisoned with tricyclics.3–7 Hypotension due to alpha adrenoceptor blockade is a feature of severe poisoning.4 Lofepramine is the safest tricyclic, probably because its metabolite desipramine is formed relatively slowly and is present in lower concentrations than the parent compound. Dothiepin (dosulepin) seems to be the most toxic tricyclic in overdose; it causes convulsions and cardiac effects (Table 2).8 Concern about the toxicity of tricyclic drugs in overdose has resulted in
Presynaptic alpha blocker (increases transmitter release) • Mirtazapine Monoamine oxidase inhibitors Irreversible • Isocarboxazid • Phenelzine • Tranylcypromine Reversible • Moclobemide (reversible monoamine oxidase type A inhibitor) Other drugs • Flupenthixol (major tranquillizer) • Thioxanthine (antidepressant at low doses, toxicity as for phenothiazines) • Tryptophan (amino acid) Table 1
increased use of selective serotonin re-uptake inhibitors (SSRIs) and related compounds.
D Nicholas Bateman MD FRCP FRCPE FBPharmacolS FBTS is Professor in Clinical Toxicology and Director of the National Poisons Information Service (Edinburgh Unit) at the Royal Infirmary, Edinburgh, UK. He is the PastPresident of the European Association of Poison Centres and Clinical Toxicologists. Competing interests: none declared.
MEDICINE 35:11
Clinical features: symptoms of tricyclic antidepressant poisoning usually appear within 4 hours of overdose; initially, these features reflect anticholinergic actions (dry mouth, blurred vision, sinus 587
© 2007 Elsevier Ltd. All rights reserved.
Poisonous substances
Convulsions are another potentially life-threatening complication of antidepressant poisoning; they probably result from a combination of effects of tricyclics on the brain, including amine re-uptake and anticholinergic effects. They should be controlled with intravenous diazepam, though this carries a risk of respiratory depression and patients may require subsequent ventilation. If they are paralysed, appropriate EEG cerebral monitoring should be instituted to detect continuing electrical activity. Left untreated this will cause brain damage. Hyperthermia is also reported.10 Specific problems – anticholinesterases (e.g. physostigmine) are no longer advocated in tricyclic poisoning because their effects are short-lived and they may produce convulsions, confusional states and hypotension. In the recovery phase, many patients become acutely disturbed and may need sedation; a long-acting benzodiazepine (e.g. diazepam) is best. Measurement of plasma levels in tricyclic poisoning is usually unhelpful, unless the diagnosis is doubted. Doses of 2 g or more are invariably associated with severe intoxication lasting for several hours.
Relative toxicity of dothiepin (dosulepin)8 Dothiepin (dosulepin)
Other tricyclic antidepressants
Adjusted odds ratios (95% confidence limit) of seizures and arrhythmias with dothiepin (dosulepin) vs other tricyclics
• Number of cases • Seizures
67 9 (13%)
• Arrhythmias
4 (6%)
220 5 (2%) (p < 0.001) 7.1 (2.2–23.2) 3 (1%) (p = 0.054) 3.4 (0.7–16.3)
Table 2
tachycardia and drowsiness). Pyramidal signs (brisk reflexes and extensor plantar responses) may also develop. In more severe poisoning, coma, convulsions, respiratory depression, hypotension and electrocardiogram abnormalities (prolongation of the QRS interval and other intraventricular conduction disturbances, secondary to sodium channel blockade) may occur.9 Further complications of poisoning include hypoxia from respiratory depression, acidosis (respiratory and metabolic) and hypokalaemia.
SSRIs The toxicity of SSRIs following overdose is considerably less than that of conventional tricyclic drugs. Citalopram and its isomer escitalpram are the most toxic in overdose.11–13 Clinical features: the principal clinical features include nausea, vomiting, agitation and tachycardia. Convulsions may develop after large overdoses (>1.5 g) and, rarely, deaths have occurred.12,14 If SSRIs are taken in combination with drugs with serotonergic effects (e.g. tryptophan) or an MAOI, there is a risk of serotonergic syndrome (restlessness, hyperpyrexia, rhabdomyolysis and renal failure).
Management: the anticholinergic effects of tricyclic antidepressants delay gastric emptying; activated charcoal should be considered particularly in patients who have taken a potentially serious overdose (>750 mg in an adult) and present within 1 hour of ingestion. Later administration will be less effective. Many clinical toxicologists no longer consider gastric lavage appropriate, because it may wash the tricyclic into the duodenum, leading to more rapid drug absorption and an increased risk of acute toxicity. Patients should therefore be monitored carefully and given activated charcoal, (50–100 g); there is evidence that a large (single) dose of activated charcoal significantly reduces drug absorption. There is no role for repeated oral doses of activated charcoal in the management of tricyclic antidepressant overdose. Patients with severe tricyclic poisoning require careful supportive management. Acid–base balance should be monitored and acidosis (which increases the risk of cardiac arrhythmias) should be corrected.9 Arrhythmias should be managed with bolus doses of 8.4% sodium bicarbonate (aim – pH 7.5); this treatment may abolish arrhythmias even in patients without acidosis. Unless cardiac output is significantly compromised, anti-arrhythmic drugs are not used because they have negative inotropic and membrane effects, which may aggravate the adverse effects of tricyclics on the myocardium. Arrhythmias are uncommon in patients who are conscious, and GCS less than 8 is an indication of a potentially serious ingestion.3 The risk of arrhythmias decreases with time; they are unlikely to arise de novo 12 hours or more after an overdose. In patients who have suffered a cardiac arrest secondary to antidepressant poisoning, prolonged cardiac massage is indicated and may result in full recovery.
MEDICINE 35:11
Management of poisoning with SSRIs is supportive and symptomatic. Serotonergic syndrome requires more intensive therapy, particularly for hyperpyrexia. 5HT antagonists (cyproheptadine, olanzapine or chlorpromazine) have been used anecdotally for this purpose. Dantrolene will reduce muscle spasm and paralysis, and ventilation may be required in severe cases.
Selective noradrenaline re-uptake inhibitors (SNRIs) Venlafaxine is an inhibitor of serotonin and noradrenaline reuptake. It is mid-way in toxicity profile between SSRIs and tricyclics.15 It causes cardiac arrhythmias and convulsions in overdose, but has no anticholinergic activity. Increased muscle activity results in rises in creatine kinase.16 Management is similar to that for tricyclic antidepressants. Mirtazapine This drug has a low toxic hazard when taken alone in overdose. It causes sedation and little other effect.17,18
MAOIs Irreversible MAOIs Traditional (irreversible) MAOIs are now an uncommon cause of poisoning, principally because they are not often prescribed. They may be fatal when taken in overdose.19,20 MAOIs block 588
© 2007 Elsevier Ltd. All rights reserved.
Poisonous substances
intracellular monoamine oxidase and increase intracellular monoamine concentrations (noradrenaline/norepinephrine and 5hydroxytryptamine). In overdose, the clinical features reflect this action; there is a prominent increase in noradrenergic outflow.
study of antidepressant drug overdoses. J Emerg Med 1997; 15: 439–45. 3 Bateman DN. Tricyclic antidepressant poisoning: central nervous system effects and management. Toxicol Rev 2005; 24: 181–86. 4 Thanacoody HK, Thomas SH. Tricyclic antidepressant poisoning: cardiovascular toxicity. Toxicol Rev 2005; 24: 205–14. 5 Taboulet P, Michard F, Muszynski J, et al. Cardiovascular repercussions of seizures during cyclic antidepressant poisoning. J Toxicol Clin Toxicol 1995; 33: 205–11. 6 Liebelt EL, Francis PD, Woolf AD. ECG lead aVR versus QRS interval in predicting seizures and arrhythmias in acute tricyclic antidepressant toxicity. Ann Emerg Med 1995; 26: 195–201. 7 Buckley NA, O’Connell DL, Whyte IM, Dawson AH. Interrater agreement in the measurement of QRS interval in tricyclic antidepressant overdose: implications for monitoring and research. Ann Emerg Med 1996; 28: 515–19. 8 Buckley NA, Dawson AH, Whyte IM, Henry DA. Greater toxicity in overdose of dothiepin than of other tricyclic antidepressants. Lancet 1994; 343: 159–62. 9 Shannon M, Liebelt EL. Toxicology reviews: targeted management strategies for cardiovascular toxicity from tricyclic antidepressant overdose: the pivotal role for alkalinization and sodium loading. Pediatr Emerg Care 1998; 14: 293–98. 10 Hantson P, Benaissa M, Clemessy JL, Baud FJ. Hyperthermia complicating tricyclic antidepressant overdose. Intensive Care Med 1996; 22: 453–55. 11 Kelly CK, Upex A, Spencer EP, Flanagan RJ, Bateman DN. Adult respiratory distress syndrome and renal failure associated with citalopram overdose. Hum Exp Toxicol 2003; 22: 103–05. 12 Kelly CK, Dhaun N, Laing WJ, Strachan FE, Good AM, Bateman DN. Comparative toxicity of citalopram and the newer antidepressants after overdose. J Toxicol Clin Toxicol 2004; 42: 67–71. 13 Isbister GK, Bowe SJ, Dawson A, Whyte IM. Relative toxicity of selective serotonin reuptake inhibitors (SSRIs) in overdose. J Toxicol Clin Toxicol 2004; 42: 277–85. 14 Gross R, Dannon PN, Lepkifker E, Zohar J, Kotler M. Generalized seizures caused by fluoxetine overdose. Am J Emerg Med 1998; 16: 328–29. 15 Whyte IM, Dawson AH, Buckley NA. Relative toxicity of venlafaxine and selective serotonin reuptake inhibitors in overdose compared to tricyclic antidepressants. QJM 2003; 96: 369–74. 16 Oliver JJ, Kelly C, Jarvie D, Denieul S, Bateman DN. Venlafaxine poisoning complicated by a late rise in creatine kinase: two case reports. Hum Exp Toxicol 2002; 21: 463–66. 17 Schaper A, Färber E, Ebbeke M, Desel H. Suicide with mirtazapine hardly possible. J Toxicol Clin Toxicol 2002; 40: 343–44. 18 Waring WS, Good AM, Bateman DN. Lack of significant toxicity after mirtazapine overdose: a five-year review of cases admitted to a regional toxicology unit. Clin Toxicol 2007; 45: 45–50. 19 Iwerson S, Schmoldt A. Three suicide attempts with moclobemide. J Toxicol Clin Toxicol 1996; 34: 223–25. 20 Lichtenwalner MR, Tully RG, Cohn RD, Pinder RD. Two fatalities involving phenelzine. J Anal Toxicol 1995; 19: 265–66.
Clinical features: the effects of MAOIs may take 12–14 hours to develop. The principal features are: • CNS and autonomic dysfunction • agitation • abnormal movements • hyper-reflexia • muscular rigidity • convulsions • sweating • hyperpyrexia • hyperventilation • tachycardia • hypotension or hypertension • urinary retention • coma Management: therapy should be supportive and should avoid sympathomimetic agents. Parenteral diazepam or chlorpromazine should be used to control agitation, though chlorpromazine (which has α-adrenergic blocking properties) may aggravate hypotension. Ventilation is sometimes required for respiratory embarrassment caused by muscle spasm; dantrolene may reduce spasm. Specific problems – it is important to remember that acute interactions can occur when MAOIs are given concomitantly with opiates, sympathomimetic drugs, levodopa or anaesthetic agents, leading to dramatic rises in blood pressure. These are best managed with α-blockers (e.g. phentolamine, phenoxybenzamine) given by slow infusion or with nitrate infusions. Reversible MAOIs Moclobemide is relatively selective for monoamine oxidase A. This selectivity may be lost in overdose, however, and this is particularly relevant in mixed overdose. Features similar to classical MAOI poisoning may then develop, and should be treated appropriately. L-tryptophan L-tryptophan alone is innocuous in overdose, but care should be taken not to confuse it with a combined antidepressant–neuroleptic product with a similar proprietary name (Triptafen). In combination with MAOIs, tryptophan may cause serotonergic syndrome. ◆
References 1 Buckley NA, McManus PR. Fatal toxicity of serotoninergic and other antidepressant drugs: analysis of United Kingdom mortality data. BMJ 2002; 325: 1332–33. 2 Phillips S, Brent J, Kulig K, Heiligenstein J, Birkett M. Fluoxetine versus tricyclic antidepressants: a prospective multicenter
MEDICINE 35:11
589
© 2007 Elsevier Ltd. All rights reserved.
Antidepressants
Antidepressant drugs
D Nicholas Bateman
Tricyclic antidepressants • Amitriptyline • Amoxapine • Clomipramine • Dothiepin (dosulepin) • Doxepin • Imipramine • Lofepramine • Nortriptyline • Protriptyline • Trimipramine
Abstract Antidepressant drugs differ in their relative toxicities. The most hazardous are monoamine oxidase inhibitors and tricyclics. Features include arrhythmias, convulsions and cardiovascular effects. Management should be as active as necessary to reduce arrhythmia risk by aggressive correction of acidosis and use of sodium bicarbonate to shorten QRS duration if prolonged. Venlafaxine and citalopram are the most toxic of the newer drugs.
Tricyclic-related compounds • Maprotiline • Mianserin • Trazodone • Viloxazine Selective re-uptake inhibitors and related drugs Serotonin • Citalopram • Escitalopram • Fluoxetine • Fluvoxamine • Paroxetine • Sertraline
Keywords antidepressants, monoamine oxidase inhibitors; poisoning; selective noradrenaline re-uptake inhibitor; selective serotonin re-uptake inhibitor; tricyclic antidepressants
Antidepressants may be classified into four principal groups (Table 1). The tricyclics and the irreversible monoamine oxidase inhibitors (MAOIs) are the most toxic.1 Selective serotonin reuptake inhibitors (SSRIs) are generally safer in overdose,2 but the least toxic is mirtazapine.
Serotonin and noradrenaline • Duloxetine • Venlafaxine Noradrenaline • Reboxetine
Tricyclic antidepressants and related drugs Tricyclic antidepressants probably produce their therapeutic effects by blocking the uptake of monoamines in adrenergic or serotonergic nerve endings in the brain. Many first-generation tricyclic antidepressants also have clinically significant anticholinergic properties. In overdose, the direct effect of these agents on ion channels becomes important, they act as sodium channel blockers, and this is probably responsible for variations in the toxicity of the different types of antidepressant. Cardiotoxicity and convulsion is the usual mechanism of death in patients severely poisoned with tricyclics.3–7 Hypotension due to alpha adrenoceptor blockade is a feature of severe poisoning.4 Lofepramine is the safest tricyclic, probably because its metabolite desipramine is formed relatively slowly and is present in lower concentrations than the parent compound. Dothiepin (dosulepin) seems to be the most toxic tricyclic in overdose; it causes convulsions and cardiac effects (Table 2).8 Concern about the toxicity of tricyclic drugs in overdose has resulted in
Presynaptic alpha blocker (increases transmitter release) • Mirtazapine Monoamine oxidase inhibitors Irreversible • Isocarboxazid • Phenelzine • Tranylcypromine Reversible • Moclobemide (reversible monoamine oxidase type A inhibitor) Other drugs • Flupenthixol (major tranquillizer) • Thioxanthine (antidepressant at low doses, toxicity as for phenothiazines) • Tryptophan (amino acid) Table 1
increased use of selective serotonin re-uptake inhibitors (SSRIs) and related compounds.
D Nicholas Bateman MD FRCP FRCPE FBPharmacolS FBTS is Professor in Clinical Toxicology and Director of the National Poisons Information Service (Edinburgh Unit) at the Royal Infirmary, Edinburgh, UK. He is the PastPresident of the European Association of Poison Centres and Clinical Toxicologists. Competing interests: none declared.
MEDICINE 35:11
Clinical features: symptoms of tricyclic antidepressant poisoning usually appear within 4 hours of overdose; initially, these features reflect anticholinergic actions (dry mouth, blurred vision, sinus 587
© 2007 Elsevier Ltd. All rights reserved.
Poisonous substances
Convulsions are another potentially life-threatening complication of antidepressant poisoning; they probably result from a combination of effects of tricyclics on the brain, including amine re-uptake and anticholinergic effects. They should be controlled with intravenous diazepam, though this carries a risk of respiratory depression and patients may require subsequent ventilation. If they are paralysed, appropriate EEG cerebral monitoring should be instituted to detect continuing electrical activity. Left untreated this will cause brain damage. Hyperthermia is also reported.10 Specific problems – anticholinesterases (e.g. physostigmine) are no longer advocated in tricyclic poisoning because their effects are short-lived and they may produce convulsions, confusional states and hypotension. In the recovery phase, many patients become acutely disturbed and may need sedation; a long-acting benzodiazepine (e.g. diazepam) is best. Measurement of plasma levels in tricyclic poisoning is usually unhelpful, unless the diagnosis is doubted. Doses of 2 g or more are invariably associated with severe intoxication lasting for several hours.
Relative toxicity of dothiepin (dosulepin)8 Dothiepin (dosulepin)
Other tricyclic antidepressants
Adjusted odds ratios (95% confidence limit) of seizures and arrhythmias with dothiepin (dosulepin) vs other tricyclics
• Number of cases • Seizures
67 9 (13%)
• Arrhythmias
4 (6%)
220 5 (2%) (p < 0.001) 7.1 (2.2–23.2) 3 (1%) (p = 0.054) 3.4 (0.7–16.3)
Table 2
tachycardia and drowsiness). Pyramidal signs (brisk reflexes and extensor plantar responses) may also develop. In more severe poisoning, coma, convulsions, respiratory depression, hypotension and electrocardiogram abnormalities (prolongation of the QRS interval and other intraventricular conduction disturbances, secondary to sodium channel blockade) may occur.9 Further complications of poisoning include hypoxia from respiratory depression, acidosis (respiratory and metabolic) and hypokalaemia.
SSRIs The toxicity of SSRIs following overdose is considerably less than that of conventional tricyclic drugs. Citalopram and its isomer escitalpram are the most toxic in overdose.11–13 Clinical features: the principal clinical features include nausea, vomiting, agitation and tachycardia. Convulsions may develop after large overdoses (>1.5 g) and, rarely, deaths have occurred.12,14 If SSRIs are taken in combination with drugs with serotonergic effects (e.g. tryptophan) or an MAOI, there is a risk of serotonergic syndrome (restlessness, hyperpyrexia, rhabdomyolysis and renal failure).
Management: the anticholinergic effects of tricyclic antidepressants delay gastric emptying; activated charcoal should be considered particularly in patients who have taken a potentially serious overdose (>750 mg in an adult) and present within 1 hour of ingestion. Later administration will be less effective. Many clinical toxicologists no longer consider gastric lavage appropriate, because it may wash the tricyclic into the duodenum, leading to more rapid drug absorption and an increased risk of acute toxicity. Patients should therefore be monitored carefully and given activated charcoal, (50–100 g); there is evidence that a large (single) dose of activated charcoal significantly reduces drug absorption. There is no role for repeated oral doses of activated charcoal in the management of tricyclic antidepressant overdose. Patients with severe tricyclic poisoning require careful supportive management. Acid–base balance should be monitored and acidosis (which increases the risk of cardiac arrhythmias) should be corrected.9 Arrhythmias should be managed with bolus doses of 8.4% sodium bicarbonate (aim – pH 7.5); this treatment may abolish arrhythmias even in patients without acidosis. Unless cardiac output is significantly compromised, anti-arrhythmic drugs are not used because they have negative inotropic and membrane effects, which may aggravate the adverse effects of tricyclics on the myocardium. Arrhythmias are uncommon in patients who are conscious, and GCS less than 8 is an indication of a potentially serious ingestion.3 The risk of arrhythmias decreases with time; they are unlikely to arise de novo 12 hours or more after an overdose. In patients who have suffered a cardiac arrest secondary to antidepressant poisoning, prolonged cardiac massage is indicated and may result in full recovery.
MEDICINE 35:11
Management of poisoning with SSRIs is supportive and symptomatic. Serotonergic syndrome requires more intensive therapy, particularly for hyperpyrexia. 5HT antagonists (cyproheptadine, olanzapine or chlorpromazine) have been used anecdotally for this purpose. Dantrolene will reduce muscle spasm and paralysis, and ventilation may be required in severe cases.
Selective noradrenaline re-uptake inhibitors (SNRIs) Venlafaxine is an inhibitor of serotonin and noradrenaline reuptake. It is mid-way in toxicity profile between SSRIs and tricyclics.15 It causes cardiac arrhythmias and convulsions in overdose, but has no anticholinergic activity. Increased muscle activity results in rises in creatine kinase.16 Management is similar to that for tricyclic antidepressants. Mirtazapine This drug has a low toxic hazard when taken alone in overdose. It causes sedation and little other effect.17,18
MAOIs Irreversible MAOIs Traditional (irreversible) MAOIs are now an uncommon cause of poisoning, principally because they are not often prescribed. They may be fatal when taken in overdose.19,20 MAOIs block 588
© 2007 Elsevier Ltd. All rights reserved.
Poisonous substances
intracellular monoamine oxidase and increase intracellular monoamine concentrations (noradrenaline/norepinephrine and 5hydroxytryptamine). In overdose, the clinical features reflect this action; there is a prominent increase in noradrenergic outflow.
study of antidepressant drug overdoses. J Emerg Med 1997; 15: 439–45. 3 Bateman DN. Tricyclic antidepressant poisoning: central nervous system effects and management. Toxicol Rev 2005; 24: 181–86. 4 Thanacoody HK, Thomas SH. Tricyclic antidepressant poisoning: cardiovascular toxicity. Toxicol Rev 2005; 24: 205–14. 5 Taboulet P, Michard F, Muszynski J, et al. Cardiovascular repercussions of seizures during cyclic antidepressant poisoning. J Toxicol Clin Toxicol 1995; 33: 205–11. 6 Liebelt EL, Francis PD, Woolf AD. ECG lead aVR versus QRS interval in predicting seizures and arrhythmias in acute tricyclic antidepressant toxicity. Ann Emerg Med 1995; 26: 195–201. 7 Buckley NA, O’Connell DL, Whyte IM, Dawson AH. Interrater agreement in the measurement of QRS interval in tricyclic antidepressant overdose: implications for monitoring and research. Ann Emerg Med 1996; 28: 515–19. 8 Buckley NA, Dawson AH, Whyte IM, Henry DA. Greater toxicity in overdose of dothiepin than of other tricyclic antidepressants. Lancet 1994; 343: 159–62. 9 Shannon M, Liebelt EL. Toxicology reviews: targeted management strategies for cardiovascular toxicity from tricyclic antidepressant overdose: the pivotal role for alkalinization and sodium loading. Pediatr Emerg Care 1998; 14: 293–98. 10 Hantson P, Benaissa M, Clemessy JL, Baud FJ. Hyperthermia complicating tricyclic antidepressant overdose. Intensive Care Med 1996; 22: 453–55. 11 Kelly CK, Upex A, Spencer EP, Flanagan RJ, Bateman DN. Adult respiratory distress syndrome and renal failure associated with citalopram overdose. Hum Exp Toxicol 2003; 22: 103–05. 12 Kelly CK, Dhaun N, Laing WJ, Strachan FE, Good AM, Bateman DN. Comparative toxicity of citalopram and the newer antidepressants after overdose. J Toxicol Clin Toxicol 2004; 42: 67–71. 13 Isbister GK, Bowe SJ, Dawson A, Whyte IM. Relative toxicity of selective serotonin reuptake inhibitors (SSRIs) in overdose. J Toxicol Clin Toxicol 2004; 42: 277–85. 14 Gross R, Dannon PN, Lepkifker E, Zohar J, Kotler M. Generalized seizures caused by fluoxetine overdose. Am J Emerg Med 1998; 16: 328–29. 15 Whyte IM, Dawson AH, Buckley NA. Relative toxicity of venlafaxine and selective serotonin reuptake inhibitors in overdose compared to tricyclic antidepressants. QJM 2003; 96: 369–74. 16 Oliver JJ, Kelly C, Jarvie D, Denieul S, Bateman DN. Venlafaxine poisoning complicated by a late rise in creatine kinase: two case reports. Hum Exp Toxicol 2002; 21: 463–66. 17 Schaper A, Färber E, Ebbeke M, Desel H. Suicide with mirtazapine hardly possible. J Toxicol Clin Toxicol 2002; 40: 343–44. 18 Waring WS, Good AM, Bateman DN. Lack of significant toxicity after mirtazapine overdose: a five-year review of cases admitted to a regional toxicology unit. Clin Toxicol 2007; 45: 45–50. 19 Iwerson S, Schmoldt A. Three suicide attempts with moclobemide. J Toxicol Clin Toxicol 1996; 34: 223–25. 20 Lichtenwalner MR, Tully RG, Cohn RD, Pinder RD. Two fatalities involving phenelzine. J Anal Toxicol 1995; 19: 265–66.
Clinical features: the effects of MAOIs may take 12–14 hours to develop. The principal features are: • CNS and autonomic dysfunction • agitation • abnormal movements • hyper-reflexia • muscular rigidity • convulsions • sweating • hyperpyrexia • hyperventilation • tachycardia • hypotension or hypertension • urinary retention • coma Management: therapy should be supportive and should avoid sympathomimetic agents. Parenteral diazepam or chlorpromazine should be used to control agitation, though chlorpromazine (which has α-adrenergic blocking properties) may aggravate hypotension. Ventilation is sometimes required for respiratory embarrassment caused by muscle spasm; dantrolene may reduce spasm. Specific problems – it is important to remember that acute interactions can occur when MAOIs are given concomitantly with opiates, sympathomimetic drugs, levodopa or anaesthetic agents, leading to dramatic rises in blood pressure. These are best managed with α-blockers (e.g. phentolamine, phenoxybenzamine) given by slow infusion or with nitrate infusions. Reversible MAOIs Moclobemide is relatively selective for monoamine oxidase A. This selectivity may be lost in overdose, however, and this is particularly relevant in mixed overdose. Features similar to classical MAOI poisoning may then develop, and should be treated appropriately. L-tryptophan L-tryptophan alone is innocuous in overdose, but care should be taken not to confuse it with a combined antidepressant–neuroleptic product with a similar proprietary name (Triptafen). In combination with MAOIs, tryptophan may cause serotonergic syndrome. ◆
References 1 Buckley NA, McManus PR. Fatal toxicity of serotoninergic and other antidepressant drugs: analysis of United Kingdom mortality data. BMJ 2002; 325: 1332–33. 2 Phillips S, Brent J, Kulig K, Heiligenstein J, Birkett M. Fluoxetine versus tricyclic antidepressants: a prospective multicenter
MEDICINE 35:11
589
© 2007 Elsevier Ltd. All rights reserved.