Use of one class of antidepressant drugs, the SSRIs (selective serotonin reuptake inhibitors), may be associated with severe violence in a small number of individuals say the authors of paper published in PLoS Medicine.

David Healy and David Menkes from Cardiff University, and Andrew Herxheimer from the UK Cochrane Centre, used a variety of sources to look at this association.

The sources used were data on paroxetine presented to the UK Committee on Safety of Medicines Expert Working Group by its maker, GlaxoSmithKline; data from United Kingdom Drug Safety Research Unit (DSRU) prescription-event monitoring studies on paroxetine and fluoxetine; legal cases in which the authors have given evidence; and e-mails from 1,374 patients in response to a BBC TV Panorama programme on paroxetine broadcast in 2002.

The association of antidepressant use and self directed violence, such as suicide, is not new. The authors note that “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” and 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’”.

The current paper in PLoS Medicine focuses on the SSRIs, which are claimed to correct a chemical imbalance in the brain involving a lack of serotonin. Of the SSRIs, paroxetine was primarily studied for two reasons. First, the authors had better access to information about illustrative medico-legal cases for this drug than for other antidepressants. Second, the manufacturer of paroxetine, GlaxoSmithKline, has submitted data on “hostile” episodes associated with paroxetine to the British regulatory authorities.

A summary of placebo controlled trials in children and adults showed that 60 of 9219 (0.65%) patients given paroxetine, compared with 20 of 6,455 given placebo (0.31%) had what was called a “hostility event”.

In their submissions to the Committee on Safety of Medicines Expert Working Group, GlaxoSmithKline reported 44 hostile events in 11,491 patients taking paroxetine in trials comparing paroxetine with other antidepressants (i.e. 0.38% of all patients taking paroxetine experienced a hostile event). In a subset of trials comparing paroxetine with another SSRI, there were 16 hostile events among all 2,418 patients taking paroxetine (0.66%). In healthy volunteer studies, in which paroxetine was given to people who were healthy, hostile events occurred in three of 271 (1.1%) volunteers taking paroxetine, compared with zero in 138 taking placebo. GlaxoSmithKline ascribed these episodes in the healthy volunteers to the fact that the volunteers were confined in a clinical trials centre, although this applied to both the volunteers taking paroxetine and those taking placebo. One other healthy volunteer study had previously reported aggressive behaviour in one volunteer taking sertraline.

In adverse drug event monitoring there were violent events in 56 of 13,741 (0.41%) patients taking paroxetine and 60 in 12,692 patients (0.47%) taking fluoxetine. In the emails from 1,374 patients after the BBC programme the authors report that “Many linked emotional storms and thoughts and acts of violence or self-harm to paroxetine”. Finally, the authors describe 9 illustrative medico legal cases in which they have been involved.

After reviewing the possible mechanisms for the violence associated with SSRIs, the authors conclude that: “The new issues highlighted by these cases need urgent examination jointly by jurists and psychiatrists in all countries where antidepressants are widely used.” However, they caution that “In practice, clinicians need to be aware of the issues, but serious violence on antidepressants is likely to be very rare. When violence is a suspected outcome, every case has to be considered carefully, on the principle that individuals are responsible for their conduct, unless there is clear evidence of compromised function that cannot be otherwise explained.”

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