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The prevalence of serotonin syndrome increases over the past several years as more serotonergic medications are being used in clinical practice. It is a potentially lethal condition caused by excessive serotonergic activity. Common causes of serotonin syndrome are the use of prescription medications, illicit drugs, or a combination of substances, leading to an increase in the activity of serotonin in the central and peripheral nervous system. The clinical symptoms range from mild to severe. We report a case of a 25-year-old woman with polysubstance abuse, including cocaine, who presented with confusion, rigidity, high-grade fever, and reduced biventricular function on echocardiogram. Based on the combination of substance used history, clinical presentation, and echocardiogram findings, she was diagnosed with serotonin syndrome complicated by takotsubo cardiomyopathy. She improved after being treated in the intensive care unit and was discharged from the hospital. This patient demonstrates the importance of recognizing and promptly initiating management of serotonin syndrome in order to improve morbidity and mortality.

Fluvoxamine is a selective serotonin reuptake inhibitor that has been considered relatively safe in overdose. At therapeutic and supratherapeutic concentrations, fluvoxamine affects cardiac conduction, prolongs QTc interval, causes hypotension, obtundation, and can increase propensity for seizures. A man in his 60s was found dead at his home with a postmortem fluvoxamine peripheral blood concentration of 4.9 mg/L, and a liver concentration of 440 mg/kg. His cause of death was determined to be acute fluvoxamine toxicity., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Duloxetine is a second-generation selective serotonin and norepinephrine reuptake inhibitor used primarily for the treatment of depression. Relatively few fatalities have been reported in association with its use. Similarly, there are no known reports that provide a comprehensive analysis of blood, fluid and tissue samples in an overdose setting. Herein we present a fatal case of duloxetine toxicity with both the highest reported post-mortem blood concentration and a comprehensive toxicological analysis of duloxetine in femoral blood, vitreous humor, liver tissue, urine and gastric contents. In doing so, we hope to provide data that can assist both toxicologists and forensic pathologists with assessing duloxetine toxicity in the future., (Published by Oxford University Press 2015. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

Background: Citalopram is a selective serotonin reuptake inhibitor (SSRI) with cardiac and neurologic toxicities as well as the potential for serotonin syndrome. In most instances, patients recover fully from toxic ingestions of SSRIs. We describe a fatal case of a citalopram overdose., Case Report: A 35-year-old woman presented to the emergency department after having witnessed seizures at home. An empty citalopram prescription bottle was located, and an intentional overdose was suspected. At the scene, she was found to be in cardiac arrest with pulseless electrical activity and underwent cardiopulmonary resuscitation, including intravenous epinephrine and bicarbonate. In the emergency department, her physical exam was notable for cough and gag reflexes and movement in all extremities with increased muscle tone and tachycardia. Her initial postresuscitation ECG showed sinus rhythm with QRS 92 ms and QTc 502 ms. Her temperature was initially normal, but she rapidly became febrile to 41.8 °C shortly after admission. She was treated symptomatically and with cyproheptadine for suspected serotonin syndrome (SS) but became increasingly hemodynamically unstable over the next 6 h and then developed torsades des pointes (TdP) progressing to pulseless, wide complex tachycardia. She underwent cardiopulmonary resuscitation (CPR) for approximately 50 min but ultimately expired. Postmortem serum analysis revealed a citalopram concentration of 7300 ng/mL (therapeutic range 9-200 ng/mL) and THC, but no other non-resuscitation drugs or substances., Case Discussion: Citalopram overdoses often have only mild to moderate symptoms, particularly with ingestions under 600 mg in adults. However, with higher doses, severe manifestations have been described, including QTc prolongation, TdP, and seizures. Serotonin syndrome has also been described in SSRI overdose, and our patient exhibited signs consistent with SS, including increased muscle tone and autonomic dysregulation. Our patient's serum concentration suggests a massive overdose, with major clinical effects, possible SS, and death., Conclusions: Although most patients recover from citalopram overdose, high-dose ingestions can produce severe effects and fatalities may occur. In this case, it is likely that the patient's delayed presentation also contributed significantly to her death. The clinician must be aware of the potential for large ingestions of citalopram to produce life-threatening effects and monitor closely for the neurologic, cardiovascular, and other manifestations that, in rare cases, can be fatal.

We describe a case of pendular nystagmus as a previously unreported side effect of venlafaxine, and speculate to its importance in the recognition of the serotonin syndrome. In particular, we discuss the importance of identifying incomplete forms of the syndrome, such as those presenting with predominantly ocular manifestations, as is in our case.

This case demonstrates an acute presentation of unwitnessed seizure causing typical injuries. Progress in hospital was complicated by worsening autonomic disturbance and agitation, typical for serotonin syndrome, suspected in light of recent selective serotonin reuptake inhibitor antidepressant initiation. Supportive care required treatment in the intensive care unit setting but full recovery ensued. This case not only reminds clinicians of the potential pitfalls in assessing postictal injured patients, but also that serotonin syndrome requires a high-index of diagnostic suspicion given the range of presenting features. Management ranges from simple withdrawal of the offending agent to specific therapies such as a cyproheptadine.

Introduction: We report a case of ethcathinone and methylone poisoning with severe clinical toxicity. This is to our knowledge the first case reported in the medical toxicology literature., Case Report: A 22-year-old woman was brought to the emergency department following several episodes of tonicoclonic seizures, a few hours after ingesting "legal ecstasy". The patient needed intubation for recurrent seizures, and she was found to have severe hyponatremia (120 mmol/L) that was corrected with hypertonic saline. The patient's mental status improved rapidly, and she was extubated the day following her admission. However, she developed prolonged rhabdomyolysis (CK 34.537 U/L) that required a 6-day hospitalisation., Discussion: The seizures and the hyponatremia may be explained by the MDMA-like characteristics of methylone that may induce inappropriate secretion of antidiuretic hormone mediated via the serotonin system. The combination of methylone and ethcatinone (both acting like serotonin reuptake inhibitors) might have contributed to neurologic manifestations compatible with serotonin toxicity, although our patient never had autonomic instability. Our patient had a prolonged period of rhabdomyolysis which may also be explained by excessive serotonin activity resulting in an increased motor hyperactivity. The public has to be aware of this growing health problem. Clinicians must report future cases of toxicity related to the use of cathinone synthetic derivatives in order to increase our knowledge of these substances.

Aims: To investigate the relationship between decontamination procedures and seizure events caused by venlafaxine overdose and to estimate the time at which 90% of patients would have had their first seizure in the presence and absence of decontamination., Methods: Data were collected from 319 patients who took an overdose of venlafaxine on 436 occasions. Seizures occurred on 24 of 436 occasions (5%). Patients received one of single dose activated charcoal (SDAC), whole bowel irrigation (WBI), a combination of either (SDAC/WBI) or no decontamination. Logistic regression and time to event analysis were used to investigate the influence of dose and decontamination on the probability of seizures and time to 90% (t(90) ) of seizure, respectively., Results: A linear logistic regression model described the data. Simulation from the model showed that the probability of seizure was 0.05 (0.03-0.08), 0.19 (0.09-0.35) and 0.75 (0.30-0.96) at 1000, 5000 and 10 000 mg, respectively (median and 95% credible interval). At the mean dose of 2100 mg the odds ratios (OR) in the presence of SDAC, WBI and SDAC/WBI were 0.48 (0.25-0.89), 0.71 (0.35-1.22) and 0.25 (0.08-0.62), respectively. A modified Gompertz model described the time to seizure events. Simulations from the Gompertz model showed that the t(90) values for first seizure was 26 h and was not affected by dose or decontamination procedure., Conclusion: SDAC/WBI provided greater benefits than the sum of the independent effects of SDAC and WBI. Patients should be observed for at least 24 h for seizures based on the dose and risk of seizure occurring., (© 2011 The Authors. British Journal of Clinical Pharmacology © 2011 The British Pharmacological Society.)

To compare the clinical features of deliberate self-poisoning with venlafaxine and selective serotonin reuptake inhibitors (SSRIs) presenting to the emergency department of an Australian tertiary referral hospital. A retrospective cohort study comparing all 36 patients who presented with venlafaxine self-poisoning with 44 randomly selected patients with SSRI self-poisoning between 1997 and 2006. Patients who had overdosed on venlafaxine were older (mean age 37.4 versus 28.8 years, p ≤ 0.001) and generally exhibited a higher degree of suicidal intent (p ≤ 0.017). Median venlafaxine dose taken was 35 defined daily doses (DDDs) compared with SSRIs 19.4 DDDs. Those who ingested venlafaxine were more likely to become confused (25% versus 0%; p = 0) and have mydriasis (19.4% versus 2%; p ≤ 0.02), than those who took SSRIs. One patient from the venlafaxine group died. Compared with SSRI self-poisoners, patients who deliberately ingested venlafaxine were more likely to exhibit serious suicide intent. They were also more likely to be older, take a higher DDD of the drug, and have confusion and mydriasis. This has implications for management of severely depressed and suicidal patients.

Cyproheptadine (Periactin) is a first-generation antihistamine available in over-the-counter cold medications and is used to treat allergic-type symptoms. Although antihistamines in general have long been known to cause serious side effects, especially when taken in overdose, few reports that specifically address cyproheptadine-related fatalities exist. A 42-year-old healthy female was found dead at her home with no anatomic cause of death and a recent history of suicidal ideations. Toxicology revealed cyproheptadine and citalopram in the femoral postmortem blood at concentrations of 0.49 and 2.3 mg/L, respectively. Vitreous, urine, and bile analysis were also performed, yielding concentrations of < 0.04 and 0.80 mg/L in the vitreous for cyproheptadine and citalopram, respectively; 0.23 and 8.2 mg/L in the urine; and 30.7 and 9.0 mg/L in the bile. The cause of death was determined to be cyproheptadine and citalopram intoxication, and the manner was ruled a suicide. Although cyproheptadine is widely available in the United States and Europe, there are only two published fatalities due to this antihistamine and only one that specifically cites blood and tissue concentrations. Therefore, this case study will be beneficial to the forensic toxicology community by providing additional information regarding postmortem interpretation.

Aims: To assess the impact of the UK Medicines and Healthcare products Regulatory Authority (MHRA) warning in December 2003 not to prescribe selective serotonin reuptake inhibitor (SSRI) antidepressants, except fluoxetine, to under-18-year-olds., Methods: Interrupted time series analysis of prescriptions (UK) and general hospital presentations for nonfatal self-poisoning (three centres in England) for 2000-2006., Results: Following the MHRA warning in December 2003 there were significant decreases in prescribing of SSRI antidepressants (conservative estimate 51%) to young people aged 12-19 years. Surprisingly, this decrease also affected fluoxetine (conservative estimate 20%) and tricyclics (conservative estimate 27%). Nonfatal self-poisoning in this age group following the warning also declined significantly for SSRIs (conservative estimate 44%), but not for fluoxetine, tricyclic antidepressants, or all drugs and other substances. Rates of nonfatal self-harm did not change significantly over the study period., Conclusions: The reduction in both prescribing and self-poisoning with SSRI antidepressants (except fluoxetine) following the MHRA warning is in keeping with reduced availability of these drugs. There was some evidence of substitution from other SSRIs to fluoxetine for use in self-poisoning. Importantly, overall rates of nonfatal self-harm and self-poisoning did not change, indicating no substitution of method or increases in self-injury.

Aims: To investigate serial electrocardiogram (ECG) parameters, haemodynamic changes and arrhythmias following venlafaxine overdose., Methods: The study included 369 venlafaxine overdoses in 273 patients presenting to a toxicology unit where an ECG was available. Demographic information, details of ingestion, haemodynamic effects [heart rate and blood pressure (BP)] and complications (arrhythmias and conduction defects) were obtained. ECG parameters (QT, QRS) were measured manually and analysed by visual inspection, including plotting QT-HR pairs on a QT nomogram., Results: The median ingested dose was 1500 mg [interquartile range (IQR) 600-3000 mg; range 75-13 500 mg). Tachycardia occurred in 54% and mild hypertension (systolic BP >140 mmHg) in 40%. Severe hypertension (systolic BP >180 mmHg) and hypotension (systolic BP <90 mmHg) occurred in 3% and 5%, respectively. No arrhythmias occurred based on continuous telemetry, and conduction defects were found in only seven of 369 admissions; five of these conduction defects were pre-existing abnormalities. In 22 admissions [6%, 95% confidence interval (CI) 4-10] there was an abnormal QT-HR pair, with larger doses being more likely to be associated with an abnormal QT. The median maximum QRS width was 85 ms (IQR 80-90 ms; range 70-145 ms) and the QRS was greater than 120 ms in only 24 admissions (7%, 95% CI 4-10)., Conclusions: Venlafaxine overdose causes only minor abnormalities in the QT and QRS intervals, unlikely to be associated with major arrhythmias, except possibly with large doses.

To our knowledge, the majority of evidence supporting the relationship between the serotonin syndrome and medications that effect 5HT is based on case reports. The justification for taking up this subject has been a fatal outcome of a 21 year-old female following an administration of toxic doses of moclobemide (MAOI) and venlafaxine (SNRI). As a result of complex toxicological investigations including antemortem and postmortem material, antemortem clinical observations and postmortem examinations, the cause of death was identified as overdose with antidepressants--moclobemide and venlafaxine--in the mechanism of the clinically fully developed severe toxic serotonin syndrome. The analysis of a hair strand collected from the victim documented the use of the above-mentioned drugs simultaneously with cocaine in the period of at least 20 months preceding death. The fact is a matter of considerable interest in view of the employed pharmacotherapy, giving rise to suspicion that the woman had not developed the serotonin syndrome during the almost 2-year antemortem period until she took toxic doses of both medications.

Introduction: The safety of antidepressants following overdose is critical because of the high risk of suicide attempts in depressed patients. This study was conducted to decrease the fatality rate of antidepressant overdoses by providing data to shift prescribing toward safer antidepressants., Methods: US poison control data for 2000-2004 were analyzed by 25 antidepressant types. Medical outcome differences were quantified using a hazard index (number of major or fatal outcomes per 1000 reported antidepressant ingestions)., Results: Of 82,802 suicidal single-agent ingestions of identifiable antidepressants approved for use in the US, cases occurred predominantly in females and peaked in teens. Fatal cases peaked at 40 to 49 years of age. Suicidal ingestions of the SSRIs, SNRIs, and other antidepressants peaked in teens, lithium in the twenties, tricyclics and tetracyclics in the thirties, and MAO inhibitors in the forties. There were 40 major or fatal outcomes per 1000 cases. Weighted by antidepressant type, the mean hazard index for the 25 antidepressants was 79 (range: 0 to 292). Amoxapine (292), maprotiline (211), and desipramine (187) had the highest hazard indices. The tricyclic antidepressants, MAO inhibitors, maprotiline, and bupropion were in the more severe half of antidepressants, ranked by hazard index. All SSRIs had low hazard indices. Hazard index and exposure frequency were inversely correlated (R = -0.423, p = 0.035), while hazard index and use of critical care were positively correlated for the 25 antidepressant types (R = 0.797, p < 0.001). Clinical effect profiles for each antidepressant type are presented., Conclusion: Suicidal overdose severity varied considerably by antidepressant type. Prescribing decisions should be informed by regularly updated comparative overdose severity data.

Introduction: Citalopram overdose may produce bradycardia, QT prolongation, and torsades de pointes (TdP). A cardiotoxic metabolite may be responsible for the delayed onset of cardiotoxicity. Although some authorities recommend a minimum of 24 hours of observation following citalopram overdose, a recent analysis suggested that dysrhythmias rarely occur beyond 13 hours post-ingestion. We present a case of citalopram overdose with a substantially delayed onset of cardiac toxicity., Case Report: A 36-year-old woman complained of shakiness, numbness in the arms, and palpitations that began approximately 32 hours after ingesting 50 (20-mg) tablets of citalopram. Her initial vital signs were: blood pressure, 84/44 mmHg; pulse, 102-150/minute; respirations, 17/min; temperature, 99.3 degrees F (37.3 degrees C). Her initial ECG showed sinus rhythm with a prolonged corrected QT interval (572 msec) with paroxysmal, self-limited runs of wide-complex tachycardia that appeared multifocal in nature. Approximately 20 minutes after presentation, she experienced self-terminating TdP, with transient hypotension and loss of consciousness. Her serum citalopram concentration (33 hours post-ingestion) was 477 ng/mL (therapeutic: 40-110 ng/mL); desmethylcitalopram concentration was 123.2 ng/mL (therapeutic: 14-40 ng/mL). She was treated with magnesium and lidocaine, and her corrected QT interval remained abnormal for 24 hours after presentation., Discussion: Citalopram overdose can produce life-threatening cardiac toxicity with a clinical onset that may be delayed beyond a routine observation period of 6 hours. Once the QT interval is prolonged, it seems prudent to prolong the observation period.

Background: Activated charcoal (AC) is commonly used for the routine management of oral drug overdose., Aim: To determine whether the routine use of activated charcoal has an effect on patient outcomes., Design: Randomized controlled unblinded trial., Methods: We recruited all adult patients presenting with an oral overdose at The Canberra Hospital, excluding only transfers, late presenters, those who had ingested drugs not adsorbed by activated charcoal or where administration was contraindicated, and very serious ingestions (at the discretion of the admitting physician). Patients were randomized to either activated charcoal or no decontamination., Results: The trial recruited 327 patients over 16 months. Of 411 presentations, four refused consent, 27 were protocol violations and 53 were excluded from the trial. Only seven were excluded due to the severity of their ingestion. The most common substances ingested were benzodiazepines, paracetamol and selective serotonin reuptake inhibitor antidepressants. More than 80% of patients presented within 4 h following ingestion. There were no differences between AC and no decontamination in terms of length of stay (AC 6.75 h, IQR 4-14 vs. controls 5.5 h, IQR 3-12; p=0.11) or secondary outcomes including vomiting, mortality and intensive care admission., Discussion: Routine administration of charcoal following oral overdose did not significantly influence length of stay or other patient outcomes following oral drug overdose. There were few adverse events. This does not exclude a role in patients who present shortly after ingestion of highly lethal drugs.

The acutely poisoned patient remains a common problem facing doctors working in acute medicine in the United Kingdom and worldwide. This review examines the initial management of the acutely poisoned patient. Aspects of general management are reviewed including immediate interventions, investigations, gastrointestinal decontamination techniques, use of antidotes, methods to increase poison elimination, and psychological assessment. More common and serious poisonings caused by paracetamol, salicylates, opioids, tricyclic antidepressants, selective serotonin reuptake inhibitors, benzodiazepines, non-steroidal anti-inflammatory drugs, and cocaine are discussed in detail. Specific aspects of common paediatric poisonings are reviewed.

Background: Antidepressant prescribing has been increasing in England. Studies in other countries suggest that while this may be associated with reduced suicide rates, it may also be associated with increased fatal poisoning from antidepressant drugs. We therefore conducted an ecological study to assess the association between prescription rates for antidepressants and suicide or fatal antidepressant-related poisoning in England., Methods: The Office for National Statistics provided information on the number of suicides, antidepressant-related poisoning deaths and populations for England between 1993 and 2002. The Department of Health supplied data on prescriptions for all antidepressants dispensed in England. Associations between prescriptions and deaths were assessed using Spearman's rank correlation coefficient., Results: There were 46,747 suicides, 3,987 deaths involving tricyclic antidepressants and 430 involving selective serotonin re-uptake inhibitors and other antidepressants. Increased antidepressant prescribing was statistically associated with a fall in suicide rates (Spearman's rs = -0.73, p = 0.02) and fatal poisoning involving tricyclic antidepressants (rs = -0.64, p = 0.05). In contrast, increased prescribing of selective serotonin re-uptake inhibitors and other antidepressants was statistically associated with an increase in fatal poisoning involving these drugs (rs = 0.99, p < 0.001)., Conclusion: Increased prescribing of antidepressants may indicate improved diagnosis and treatment of depression in primary care. Our analysis suggests that this was accompanied by lower suicide rates. A decrease in poisoning deaths involving tricyclic antidepressants may suggest a change in preference for using serotonin reuptake inhibitors and other antidepressant drugs for high-risk patients. This may also partially explain the increase in deaths involving these drugs. Due to the ecological nature of the design, we cannot say conclusively whether reduced suicide rates are a direct consequence of increased antidepressant prescribing rates. To confirm these associations, individual level data on prescribing and suicide is needed.

Background: Deaths from antidepressants continue to account for a substantial proportion of drug-related deaths., Aims: To investigate the relative toxicity of the major classes of antidepressant drugs, with the specific objective of assessing this in relation to the cause of death; and to analyse the deaths where there were multiple mentions of antidepressant drugs or other psychoactive drugs with antidepressants., Method: Mortality data were collected from the National Programme of Substance Abuse Deaths, and antidepressant prescription data were collected., Results: Most deaths from antidepressant drugs were suicides (80%). Tricyclic antidepressants (TCAs) accounted for more drug mentions than did other antidepressant drugs (12 per million prescriptions). Selective serotonin reuptake inhibitors (SSRIs) were associated with a significantly lower risk of toxicity, but 93% of deaths from SSRIs occurred in combination with other drugs, especially TCAs (24.5%). In 'combination' deaths patients were significantly more likely to have had a history of drug misuse., Conclusions: The efficacy and safety of augmentation therapy with TCAs in SSRI-resistant patients should be monitored carefully, and patients prescribed antidepressants should be screened for drug use/misuse.

Aim: To compare the rates of death per volume of drug dispensed for antidepressants in New Zealand., Methods: Deaths from antidepressant poisonings were identified from the reports of coronial inquiries for New Zealand in 2001. Prescriptions for antidepressant medications were identified from the PharmHouse database from 1 January 2001 to 31 December 2001. The rates of deaths (95% CI) per prescription, tablet/capsule or defined daily dose were calculated for individual antidepressants and classes of antidepressant., Results: There were 200 poisoning deaths recorded in the database for New Zealand in 2001. Antidepressants were involved in 41 deaths, and death was attributed to an antidepressant in 23 cases. There were 5.52 (95% CI 3.85-7.68) deaths per 100 000 prescriptions for tricyclic antidepressants (TCAs) and 2.51 (1.57-3.79) deaths per 100 000 prescriptions for selective serotonin reuptake inhibitors (SSRIs). There was marked variability in rates of death per volume of drug dispensed between individual antidepressants., Conclusions: SSRIs have lower rates of death per volume of drug dispensed than TCAs and there is also variation in these rates within these classes of drugs. Toxicity in overdose should be considered when prescribing antidepressants.

Background: There are difficulties with the diagnosis of serotonin toxicity, particularly with the use of Sternbach's criteria., Aim: To improve the criteria for diagnosing clinically significant serotonin toxicity., Design: Retrospective analysis of prospectively collected data, Methods: We studied all patients admitted to the Hunter Area Toxicology Service (HATS) following an overdose of a serotonergic drug from January 1987 to November 2002 (n = 2222). Main outcomes were: diagnosis of serotonin toxicity by a clinical toxicologist, fulfillment of Sternbach's criteria and treatment with a serotonin receptor (5-HT(2A)) antagonist. A learning dataset of 473 selective serotonin reuptake inhibitor (SSRI)-alone overdoses was used to determine individual clinical features predictive of serotonin toxicity by univariate analysis. Decision rules using CART analysis were developed, and tested on the dataset of all serotonergic overdose admissions., Results: Numerous clinical features were associated with serotonin toxicity, but only clonus (inducible, spontaneous or ocular), agitation, diaphoresis, tremor and hyperreflexia were needed for accurate prediction of serotonin toxicity as diagnosed by a clinical toxicologist. Although the learning dataset did not include patients with life-threatening serotonin toxicity, hypertonicity and maximum temperature > 38 degrees C were universal in such patients; these features were therefore added. Using these seven clinical features, decision rules (the Hunter Serotonin Toxicity Criteria) were developed. These new criteria were simpler, more sensitive (84% vs. 75%) and more specific (97% vs. 96%) than Sternbach's criteria., Discussion: These redefined criteria for serotonin toxicity should be more sensitive to serotonin toxicity and less likely to yield false positives.

Background: Selective serotonin reuptake inhibitors (SSRIs) and venlafaxine have been regarded as less toxic in overdose than tricyclic antidepressants (TCAs). Within the TCAs, dothiepin has greater toxicity. Venlafaxine may be more toxic than SSRIs., Aim: To assess the toxicity in overdose of venlafaxine and SSRIs compared to TCAs, and of dothiepin compared to other TCAs., Design: Cohort study of prospectively collected data from the Hunter area, NSW, Australia., Methods: First admissions with antidepressant deliberate self-poisoning (DSP) (November 1994 to April 2000) were identified; the presence of seizures, life-threatening arrhythmias, coma, serotonin toxicity or ICU admission, and QRS duration were noted., Results: There were 538 admissions, with no deaths. The odds ratio (OR) for seizures with dothiepin vs. other TCAs was 3.4 (95%CI 1.2-9.9). Seizures occurred in 7/51 (14%) venlafaxine overdoses; all patients with seizures consumed > or =900 mg. The OR for seizures vs. TCAs was 4.4 (95%CI 1.4-13.8). Coma was less likely with venlafaxine and SSRIs. SSRIs, but not venlafaxine, were less likely to prolong the QRS to > or =100 ms. ICU admission was less likely for SSRIs. Serotonin toxicity was much more common with venlafaxine and SSRIs., Discussion: Venlafaxine and dothiepin are pro-convulsant in overdose. Venlafaxine is more likely to cause serotonin toxicity, but less likely to cause coma than TCAs. SSRIs are less likely to cause coma, require ICU admission, or prolong the QRS, but are more likely to cause serotonin toxicity. Antidepressants other than TCAs or venlafaxine should be considered in patients at risk of seizure or suicide.

Citalopram, a selective serotonin reuptake inhibitor, is the most frequently prescribed antidepressant in Sweden. To investigate the extent to which citalopram in overdose is found in fatal poisoning cases compared with other drugs, all fatal poisonings in one forensic medicine district in Sweden during the years 1994-1999 were examined. Drugs found in overdose in more than 10 cases were included. The ratio between number of cases with each included drug and prescription of defined daily dose/1,000 inhabitants/day (DDD) was determined. Citalopram was the fourth most frequently found drug in overdose, occurring in 22 (6%) of the 358 fatal poisoning cases, after dextropropoxyphene (DXP), flunitrazepam and nitrazepam, which were present in 111 (31%), 56 (16%) and 31 (9%) cases, respectively. When related to the prescription rate, citalopram was significantly less represented than five of the other seven included drugs, namely DXP, flunitrazepam, nitrazepam, amitriptyline and clomipramine. Propiomazine and zopiclone occurred to the same extent as citalopram. According to the assessments of the forensic physicians, citalopram was the cause of death in five cases (1.4%) and contributed to death in another nine cases (2.5%). It is concluded that citalopram, in spite of its high prescription rate, has not become a drug of importance in fatal poisoning cases. Since, this result may not be generalisable to non-fatal poisoning cases, it is recommended that the prevalence of citalopram in these cases be examined separately.

The case history and toxicological findings of an overdose fatality involving 4-methylthioamphetamine (4-MTA) and 3,4-methylenedioxymethamphetamine (MDMA) are reported along with a description of the analytical method. Detection and quantitation of 4-MTA and MDMA were performed by liquid chromatography-tandem mass spectrometry using phentermine as internal standard. Application of this technique to a variety of matrices allowed an insight in the distribution of 4-MTA. Several blood samples including femoral vein blood (5.23 mg/L), urine (95.5 mg/L), vitreous humor (1.31 mg/L), bile (36.4 mg/L), and numerous tissue samples such as liver (30.8 mg/kg), spleen (4.10 mg/kg), and frontal lobe (31.7 mg/kg) were assayed. These values indicated that 4-MTA could be identified as the cause of this fatality, whereas the concentrations of MDMA, also described, are less important because the concentrations found are lower. This case reports, for the first time, an extensive toxicological analysis of 4-MTA, by which the data presented may shed some light on the distribution of 4-MTA.

Background: It is not clear if the frequency of deliberate self-harm (DSH) is the same in patients taking different pharmacological classes of antidepressant drugs., Aims: To compare the frequency of DSH in patients who had been prescribed a tricyclic antidepressant (TCA) or a selective serotonin reuptake inhibitor (SSRI) prior to the DSH event., Method: This was a prospective study in 2776 consecutive DSH cases attending an accident and emergency department. The incidence of DSH in TCA-treated cases and SSRI-treated cases is expressed as number of DSH events per 10 000 prescriptions of each antidepressant., Results: Significantly more DSH events occurred following the prescription of an SSRI than that of a TCA (P<0.001). The occurrence of DSH was highest with fluoxetine and lowest with amitriptyline., Conclusions: Merely prescribing safer-in-overdose antidepressants is unlikely to reduce the overall morbidity from DSH.

Background: New selective serotonin reuptake inhibitors (SSRIs) are perceived to be much safer in use than older tricyclic antidepressants (TCAs). However, previous assessments of association with fatal toxicity were made too soon after the introduction of the new drugs to permit accurate estimation., Aim: To determine the level of association of antidepressant drugs with fatal poisoning in the treatment of depression., Method: National data for England and Wales for three years (1993 to 1995) for fatal poisonings associated with antidepressants were obtained and, together with national primary care data on prescribing, were used to calculate fatality association by antidepressant drug., Results: There were substantial variations between drugs in the level of association with fatal poisoning. Assuming an average treatment episode lasted three months, one fatality is associated with 11,800 treatment episodes of antidepressant use (95% CI = 11,120 to 12,580) when only single substance fatalities are considered. For SSRIs as a group the association was one in 411,800 (95% CI = 243,300 to 1.34 million) and for TCAs one in 8130 (95% CI = 7650 to 8670). However, for one of the newer TCAs, lofepramine, the single substance fatality rate associated with its use was one in 233,700 (95% CI = 124,500 to 1.89 million), which is not statistically significantly different from the SSRIs (P = 0.35)., Conclusions: Estimated death rates associated with specific antidepressants should be compared with caution because drugs may be used selectively in patients with differing severity of depression. The proportion of these fatalities that could be prevented by switching to safer antidepressants is unclear when so few deaths are recorded as accidental; when there is intent to do self-harm the potential for switching to other means is unknown. However, this approach to relative toxicity may remain the best available since it is unlikely that a randomised trial will ever be conducted with a large enough sample size to obtain experimental data. Fatalities from antidepressant poisoning are very rare but if safety is paramount then lofepramine or an SSRI are justifiable treatment choices.

A simple and sensitive method for the simultaneous analysis of fenfluramine, amphetamine and methamphetamine in whole blood was developed using a headspace-solid phase microextraction (SPME) and derivatization. A 0.5 g whole blood sample, 5 microl d(5)-methamphetamine (50 micrig/ml) as an internal standard, and 0.5 ml sodium hydroxide (1 M) were placed into a 12 ml vial, and sealed rapidly with a silicone septum and an aluminum cap. Immediately after the vial was heated to 70 degrees C in an aluminium block heater, the needle of the SPME device was inserted through the septum of the vial, and the extraction fiber was exposed in the headspace for 15 min. First, heptafluorobutyric anhydride was injected into the injection port of the GC-MS, and the compounds extracted by the fiber were then desorbed and derivatized simultaneously by exposing the fiber in the injection port. The calibration curves, using an internal standard method, demonstrated good linearity throughout the concentration range from 0.01 to 1.0 microg/g. The detection limits of this method were 5.0 ng/g for fenfluramine and methamphetamine, and 10 ng/g for amphetamine. No interferences were found, and the time for analysis was about 30 min for one sample. This method was applied to a suicide case in which the victim ingested fenfluramine. Fenfluramine was detected in the blood sample collected from the victim at the concentration of 7.7 microg/g.

There has been much publicity in the United Kingdom regarding a new phenylethylamine-based compound called 4-methylthioamphetamine (4-MTA), also known as para-methylthioamphetamine (p-MTA), MTA or "Flatliner". Chemically, 4-MTA is an amphetamine derivative and is a non-neurotoxic potent serotonin-releasing agent and reversible inhibitor of rat monoamine oxidase-A. Analysis of postmortem blood and urine specimens in a case implicating 3,4-methylenedioxymethamphetamine revealed the presence of 4-MTA at a concentration of 4.6 mg/L in femoral blood and 87.2 mg/l in the urine. The concentration of 4-MTA in perimortem blood was measured at 4.2 mg/L. This is the first reported case of death involving 4-MTA in the United Kingdom and the first case known to involve 4-MTA only.

There is ongoing debate regarding the relative cost effectiveness of different classes of antidepressants. Although factors such as tolerability and discontinuation rates have been taken into account, there has been little consideration of the cost of overdose. In the current study we examined the cost of antidepressant overdose at four teaching hospitals over a four-week period and found that the cost of selective serotonin reuptake inhibitor overdose was less than half that of tricyclic anti-depressant overdose. The cost of overdose is often ignored and should be considered in future analyses of the cost effectiveness of different antidepressant prescribing policies in primary care.

Well known clinical syndromes can be produced by overdose with more commonly ingested substances such as opiates or tricyclic antidepressants. A case of a much more unusual syndrome presenting to the accident and emergency department resulting from overdose with a combination of tablets is reported. The clinical presentation of serotonin syndrome and its management are described. This resulted from acute ingestion of paroxetine, a selective serotonin reuptake inhibitor, and moclobemide, a monoamine oxidase inhibitor.

Three cases are presented in which death was caused by suicidal intoxication with moclobemide in combination with a selective serotonin reuptake inhibitor. Both antidepressant drug types are considered to be relatively safe with regard to lethal overdose. However, the combination may cause the serotonin syndrome, a condition with a high mortality rate. In one of the cases, there was clinical information consistent with the serotonin syndrome, in the two other cases, there was no information of the clinical course. Postmortem redistribution of the selective monoamine oxidase inhibitor moclobemide was investigated in a rat model. Postmortem concentrations in blood from the vena cava and the heart were found to be in good accordance with antemortem concentrations. Postmortem concentrations in vitreous humour and various tissues were also measured. The apparent volume of distribution was calculated to be 0.95 +/- 0.10 l/kg, which is in the same range as that reported in man.

Objective: To compare the fatal toxicities of antidepressant drugs in 1987-92., Design: Retrospective epidemiological review of prescription data of the Department of Health, Scottish Office Home and Health Department, and Welsh Health Common Services Authority (excluding data from most private general practices and most hospitals), and mortality data from the Office of Population Censuses and Surveys and General Register Office in Scotland., Setting: General practice, England, Scotland, and Wales., Main Outcome Measures: Deaths per million prescriptions and deaths per defined daily dose., Results: 81.6% (1310/1606) of deaths from antidepressant overdose were due to two drugs, amitriptyline and dothiepin. The overall average of deaths per million prescriptions was 30.1. The overall rate for tricyclic drugs was 34.14 (95% confidence interval 32.47 to 38.86; P < 0.001), monoamine oxidase inhibitors 13.48 (6.93 to 22.19; P < 0.001), atypical drugs 6.19 (4.04 to 8.80; P < 0.001), and selective serotonin reuptake inhibitors 2.02 (0.64 to 4.17; P < 0.001). The numbers of deaths per million prescriptions of amoxapine, dothiepin, and amitriptyline were significantly higher than expected, while nine drugs had a significantly lower number of deaths per million prescriptions than expected. Analysis of deaths per defined daily dose showed a similar pattern., Conclusions: Safety in overdose should be considered in risk-benefit and cost-benefit considerations of antidepressants. A switch in prescribing, from drugs with a high number of deaths per million prescriptions to drugs with a low number, could reduce the numbers of deaths from overdose. Although this form of suicide prevention can be implemented easily and immediately, its introduction needs to be considered against the higher costs of some of the newer drugs.