ANTIDEPRESSANTS AND SUICIDE

On March 22, 2004, the FDA asked the makers of antidepressants to place in the “Warnings” section of their drug’s label a statement that both children and adults should be monitored closely at the beginning of drug therapy, or when a patient’s dosage is increased or decreased, for signs of “worsening depression,” or “emergent suicidality [that] is severe, abrupt in onset, or was not part of the presenting symptoms.” The FDA also stated that health care providers, patients and their families should be warned about the association between these specific antidepressant drugs and: “anxiety, agitation, panic attacks, insomnia, irritability, hostility, impulsivity, akathisia (extreme restlessness), hypomania, and mania[.]”

On October 15, 2004, the FDA issued a Public Health Advisory announcing that it had directed antidepressant drug manufacturers to revise the labeling of their respective antidepressants to include a black box warning that would alert health care providers to an increased risk of suicidality caused by antidepressants in children and adolescents. The FDA acknowledged that: “A causal role for antidepressants in inducing suicidality has been established in pediatric patients.”

After considerable pressure from and negotiations with antidepressant manufacturers, the language for the new black box warnings was finalized in January 2005 and incorporated into antidepressant labels thereafter. The black box warning for antidepressants currently states, inter alia:

Suicidality in Children and Adolescents
Antidepressants increased the risk of suicidal thinking and behavior (suicidality) in short-term studies in children and adolescents with Major Depressive Disorder (MDD) and other psychiatric disorders. Anyone considering the use of Paxil or any other antidepressant in a child or adolescent must balance this risk with the clinical need. Patients who are started on therapy should be observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with prescriber. ... Pooled analyses of short-term (4 to 16 weeks) placebo-controlled trials ... have revealed a greater risk of adverse events representing suicidal thinking or behavior (suicidality) during the first few months of treatment in those receiving antidepressants ...

This labeling change came over a year and a half after the issue was first raised in the UK; over a year after the UK all but banned the drugs for children and adolescents following its review of the clinical trial data, which found a link between the drugs and increased suicidality; several months after one of FDA’s own medical officers observed an association between the drugs and suicidality in clinical trials (all of which had been conducted between 1983 and 2001); after a several-month independent review of the clinical trials by the FDA-contracted "Columbia group"; after two FDA advisory committee meetings spanning over a 3-day period at which 25 of the experts on the FDA advisory panel voted that the data demonstrated a causal relationship between the antidepressants and increased suicidality. (One voted to abstain and one voted against.)

According to one of the FDA advisory panel members (Dr. Thomas B. Newman), the data analyses from the antidepressant clinical trials were "striking" and "such a dramatic result would be expected to occur by chance only 1 time in 20,000 ... The fact that an association emerged from the meta-analysis ... for an outcome that the sponsors of the trials were not looking for, and presumably did not wish to find, was quite convincing."

The catalyst that led both UK and US regulators to examine the risk of suicidality with antidepressants began with Paxil. While examining Paxil clinical trial data in 2003, FDA safety officers noticed that substantially more children on Paxil suffered “emotional lability” compared to placebo. When FDA inquired further into what “emotional lability” meant, it discovered that “almost all of these events related to suicidality” according to an FDA email that would later become part of a congressional investigation of the matter. An FDA official stated in another email that GSK (Paxil’s manufacturer) “has not proposed labeling changes [on Paxil to reflect the discovery], and makes a feeble attempt to dismiss the finding.” This is what began the massive inquiry into antidepressant-induced suicidality, which eventually led to black box warnings.

The FDA is in the process of conducting a similar review of the adult clinical trial database, however, on June 30, 2005, the FDA issued a Public Health Advisory stating:

Several recent scientific publications suggest the possibility of an increased risk for suicidal behavior in adults who are being treated with antidepressant medications ... Adults being treated with antidepressant medications, particularly those being treated for depression, should be watched closely for worsening of depression and for increased suicidal thinking or behavior. Close watching may be especially important early in treatment, or when the dose is changed, either increased or decreased.

Adults whose symptoms worsen while being treated with antidepressant drugs, including an increase in suicidal thinking or behavior, should be evaluated by their health care professional.

Medical Literature related to SSRIs and suicidality
The medical literature is replete with peer-reviewed medical journal articles concerning the relationship between SSRIs, beginning in the early 1990s with Prozac, and an increased risk of suicidality. (For example, Fisher et al. “Postmarketing surveillance by patient self-monitoring: trazadone versus fluoxetine” Journal of Clinical Psychopharmacology 13, 235-242 (1993), which found "a higher incidence of various psychologic/psychiatric adverse clinical events, including delusions and hallucinations, aggression, and suicidal ideation" with Prozac; Jick et al., “Antidepressants and suicide,” British Medical Journal 1995;310:215-218, which found that Prozac was associated with a higher relative risk of suicidality than the other non-SSRI antidepressants studied; an epidemiological study by Donovan et al., “Deliberate Self-Harm and Antidepressant Drugs: Investigation of a Possible Link,” 177 British Journal of Psychiatry, 551, 554 (2000), which found a statistically significant relative risk of 5.5 for all SSRI antidepressants; also by Donovan et al., “The occurrence of suicide following the prescription of antidepressant drugs,” Archives of Suicide Research 5, 181-192, in which the authors reported: "The ratio between the occurrence of suicide and prescription of different classes of antidepressants, particularly tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs), indicated that suicide by any method (violence, gassing, poisoning by ingestion of any substance) was more likely to occur following the prescription of SSRIs than of TCAs.")

According to an article published in 1998 by a Dr. M Marsalek, titled “Do antidepressants increase risk of suicide?” Ceska A Slovenska Psychiatrie 94 (5): 272-81:

Suicidal ideation and behavior can sometimes emerge in persons with obsessive or panic features who take antidepressants or neuroleptics. Typical for such state is rapid development, impulsive and/or obsessive characteristic of suicidal ideation, an independence of the course of depression, severe tension and anxiety, an intense violence of suicidal fantasies and attempts, and their prompt disappearance after the discontinuation of the antidepressant. . . . There is clinical evidence of the link between akathisia and suicidal tendencies. . . .

A 1998 article in European Psychiatry titled “A case of paroxetine-induced akathisia and a review of SSRI-induced akathisia” by Drs. Bonnet-Brilhault, Thibaut and Petit states:

[T]here have been several reports of akathisia associated with other selective serotonin reuptake inhibitors (SSRIs) such as sertraline [Zoloft], and, lately, paroxetine [Paxil]. In addition to the discomfort felt by patients, the most notable secondary complications are non compliance and suicidal ideation or behavior.

The last two editions of the Diagnostic and Statistical Manual of Mental Disorders (DSM), the so-called “bible” of psychiatric diagnoses, even acknowledge the relationship between akathisia and suicidality:

The subjective distress resulting from akathisia is significant and can lead to noncompliance with neuroleptic treatment. Akathisia may be associated with dysphoria, irritability, aggression, or suicide attempts.

The latest version of the DSM, DSM IV TR, discusses the fact that SSRIs, not just neuroleptic drugs, can induce akathisia which, in turn, can induce suicidality.

One of the most extensive studies on the link between SSRIs and the risk of suicide, published recently by Ferguson et al. in the British Medical Journal, involves an analysis of all 702 published SSRI clinical trials. Fergusson et al. “Association between suicide attempts and selective serotonin reuptake inhibitors: systematic review of randomized controlled trials,” British Medical Journal, Vol. 330, 19 February 2005. The authors found a 2.28 times greater risk of suicidal acts on SSRIs compared to placebo, an excess of suicidality that has been apparent since 1988. The authors conclude: “... A significant increase in the odds of suicide attempts ... was observed for patients receiving SSRIs compared with placebo. ... Our systematic review, which included a total of 87,650 patients, documented an association between suicide attempts and the use of SSRIs. We also observed several major methodological limitations in the published trials. A more accurate estimation of risks of suicide could be garnered from investigators fully disclosing all events.”

According to a 2005 Paxil study conducted by researchers at the University of Oslo: “[T]he data strongly suggest that the use of SSRIs is connected with an increased intensity of suicide attempts per year. The two meta-analyses and our contribution taken together make a strong case for the conclusion, at least with a short time perspective, that adults taking antidepressants have an increased risk of suicide attempts.” Aursnes et al., “Suicide attempts in clinical trials with paroxetine randomised against placebo,” BMC Medicine 2005, 3:14, August 22, 2005.

Testimony from experts for antidepressant makers in lawsuits involving antidepressants and suicide acknowledge the relationship between SSRIs and suicidality
Even the drug industry’s own experts do not disagree that SSRIs are associated with suicidality. For instance, Dr. Michael Thase, one of GSK’s experts, testified as follows:

A. There is a relationship between starting antidepressants with a higher risk at least with some subclass of reuptake inhibitors with a broader domain of behavior observation of which suicidality is one of the dimensions; agitation, irritability, hostility are others. My understanding is that the composite pooled across studies establishes this risk at about 2 to 3 percent over and above that of the placebo.

Q. Okay. And is that consistent with your clinical practice? 1

A. Yes, it is. . . .

(Deposition of Dr. Michael Thase at p. 11-12.)

Likewise, another GSK expert, Dr. Charles O’Brien, stated at his deposition: “Any given SSRI might be associated with an activation that maybe, there has been an allegation that it increases suicidality. And I can’t say that doesn’t occur in individual cases because this is something that we’ve known since the 1960s about tricyclics [another class of antidepressants].”

(O’Brien depo p. 76.)

According to a GSK expert, Dr. John Mann, who testified in the Tobin v. SmithKline Beecham trial (a case involving a man who, while taking Paxil, killed his wife, daughter, infant granddaughter and then committed suicide. The jury awarded over $6 million dollars to the plaintiff): “I still think that akathisia has the potential when it is severe of contributing to suicidality and aggression.”
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1 Dr. Thase is an expert in adult psychiatry.

If you, or someone you know, have been the unfortunate victim of this kind of side effect from an antidepressant, please report it immediately to the Federal Food and Drug Administration (“FDA”). This is very important as this is one way pressure can be put on drug companies to fully disclose the adverse side effects of their antidepressants.

Report ADverse Side Effects to MedWatch | Report Adverse Side Effects to Rxisk.org