http://medicine.plosjournals.org/perlserv/?request=get-document&doi=10.1371/journal.pmed.0030372&ct=1Antidepressants and Violence: Problems at the Interface of Medicine and Law
David Healy*, Andrew Herxheimer, David B. Menkes
Funding: The authors received no specific funding for this article.
Introduction
In 1989, Joseph Wesbecker shot dead eight people and injured 12 others before killing himself at his place of work in Kentucky. Wesbecker had been taking the selective serotonin reuptake inhibitor (SSRI) antidepressant fluoxetine for four weeks before these homicides, and this led to a legal action against the makers of fluoxetine, Eli Lilly <1>. The case was tried and settled in 1994, and as part of the settlement a number of pharmaceutical company documents about drug-induced activation were released into the public domain. Subsequent legal cases, some of which are outlined below, have further raised the possibility of a link between antidepressant use and violence.
The issue of treatment-related activation has since then been considered primarily in terms of possible increases in the risk of suicide among a subgroup of patients who react adversely to treatment. This possibility has led regulatory authorities to warn doctors about the risk of suicide in the early stages of treatment, at times of changing dosage, and during the withdrawal phase of treatment.
Some regulators, such as the Canadian regulators, have also referred to risks of treatment-induced activation leading to both self-harm and harm to others <2>. The United States labels for all antidepressants as of August 2004 note that “anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric” <3>. Despite these developments, few data are available on the links between antidepressant usage and violence. We here offer new data, review the implications of these data, and summarise a series of medico-legal cases.
This paper focuses on paroxetine primarily because we have access to more illustrative medico-legal case material for this drug than for other antidepressants. Secondly, the manufacturer, GlaxoSmithKline, submitted data on the rates of occurrence of “hostile” episodes on paroxetine for the recent review of antidepressant drugs undertaken by the British regulator <4,5>. It is not clear that the review team obtained comparable data for other antidepressants.
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Discussion
Mechanisms of antidepressant-induced violence
A link between antidepressant use and violence needs a plausible clinical mechanism through which such effects might be realised. There are comparable data on increased rates of suicidal events on active treatment compared to placebo <16,17>. In the case of suicide, several explanations have been offered for the linkage. It is argued that alleviating the motor retardation of depression, the condition being treated, might enable suicides to happen, but this cannot explain the appearance of suicidality in healthy volunteers.
Mechanisms linking antidepressant treatment, rather than the condition, to adverse behavioural outcomes include akathisia, emotional disinhibition, emotional blunting, and manic or psychotic reactions to treatment. There is good evidence that antidepressant treatment can induce problems such as these and a prima facie case that akathisia, emotional blunting, and manic or psychotic reactions might lead to violence...snip
Substantial evidence from SSRI clinical trials shows that these drugs can trigger agitation. Approximately five percent of patients on SSRIs in randomised trials drop out for agitation against 0.5% on placebo. The current data sheets for SSRI antidepressants specify that the drugs can cause akathisia and agitation, and warn about developing suicidality in the early phase of treatment, on treatment discontinuation, and in the wake of a dosage increase during the course of treatment. In the US, these warnings explicitly apply to not only depressed patients but also people being treated for anxiety, smoking cessation, or premenstrual dysphoric disorder. In Canada, warnings specify an increased risk of violence in addition to suicide.
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Case 1
DS was a 60-year-old man with a history of five prior anxiety/depressive episodes. These did not involve suicidality, aggressive behaviour, or other serious disturbance. All prior episodes had resolved within several weeks. In 1990 DS had had an episode of depression, which his doctor treated with fluoxetine. He had a clear adverse reaction to fluoxetine involving agitation, restlessness and possible hallucinations, which worsened over a three-week period despite treatment with trazodone and propranolol that might have been expected to minimise the severity of such a reaction. After fluoxetine was discontinued DS responded rapidly to imipramine.
In 1998, a new family doctor, unaware of this adverse reaction to fluoxetine, prescribed paroxetine 20 mg to DS, for what was diagnosed as an anxiety disorder. Two days later having had, it is believed, two doses of medication, DS using a gun put three bullets each through the heads of his wife, his daughter who was visiting, and his nine-month-old granddaughter before killing himself.
At jury trial in Wyoming in June 2001, instigated by DS' surviving son-in-law, a jury found that paroxetine “can cause some people to become homicidal and/or suicidal” <39>. SmithKline Beecham was deemed 80 percent responsible for the ensuing events <1>.
The documentary evidence included an unpublished company study of incidents of serious aggression in 80 patients, 25 of which involved homicide.Experts for the plaintiff suggested that the mechanism through which paroxetine contributed to these events was probably akathisia or psychosis. A central problem with both akathisia and psychosis in such contexts is that the takers of medications often fail to recognise the fact that the state they are in is drug-induced and that discontinuing treatment can alleviate the symptoms.
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