"In the past, people thought histones were just for packaging DNA," lead investigator Zigang Dong said in a prepared statement. "People believe H2AX plays a role in DNA repair. But we find that if DNA can't be repaired, the cell undergoes apoptosis. The histone H2AX is probably important for both apoptosis and DNA repair."
In this study, Dong and his colleagues exposed cells from the skin of mice to damaging amounts of UV light and found that a form of an enzyme called JNK activates both of the cellular processes that lead to DNA destruction.
In one process, JNK initiates a chain reaction that results in the activation of an enzyme that chops up DNA, the researchers said. In the second process, JNK activates H2AX, which works with the activated enzyme to destroy the DNA. This is the first study to show that activation of H2AX is necessary for apoptosis to occur by means of the DNA-chopping enzyme.
Current practices and research methods tend to exaggerate the benefits and underestimate the risks of suicide posed by the drugs, according to an "analysis and comment" published in the July 8 issue of the British Medical Journal.
"The reason that pharmaceutical companies have been able to claim [that] the science points the other way and [health authorities] have been slow to take action has been because of a misguided appreciation of statistical significance" of suicide, said report author Dr. David Healy, a professor of psychiatry in the North Wales Department of Psychological Medicine at Cardiff University in Bangor, Wales.
Healy, who described SSRIs as an "awfully useful group of drugs," called for reforms to the drug-approval process so health-care providers and consumers get a more complete assessment of a medication's potential benefits and risks.
"Although data submitted to the FDA show an excess of suicides with every antidepressant licensed since 1987 compared with placebo, this simple but crucial finding continues to be obscured," he said. "Companies actually manipulated the data and did it in such a way that [health authorities] were aware of it and didn't correct it."
SSRIs, the class of antidepressants that includes Prozac (fluoxetine) and Paxil (paroxetine), have been the subject of intense controversy in recent years.
In October 2004, the U.S. Food and Drug Administration directed manufacturers of SSRIs to revise their labeling to include a "black box" warning that alerts health-care providers to an increased risk of suicide and suicidal thoughts in children and teens.
In July 2005, the FDA issued a public health advisory that raised the possibility that the risk of suicidality also applied to adults taking SSRIs, after several studies pointed to that possibility.
Meanwhile, the European Medicines Agency recently ruled that children as young as 8 years old can be given Prozac. The ruling added that Prozac should only be given to children with moderate to severe depression who haven't responded to several sessions of psychotherapy. It also said the drug should only be given in small doses and must be used in tandem with counseling.
British health authorities have also declared that all antidepressants except Prozac should not be used by children or teens.
And just last month, a major new study found that SSRIs have actually saved thousands of lives by preventing suicides since they were introduced in 1988.
According to the BMJ report, GlaxoSmithKline, which makes Paxil, recently sent a letter to doctors saying the drug caused a six-fold increase in the risk of suicidal behavior. This was in sharp contrast to a 2004 report by British health authorities, and to previous pronouncements from the company, Healy said.
Attempts by HealthDay to reach GlaxoSmithKline for comment were unsuccessful.
Healy himself performed a meta-analysis of published trials and found that the likely risk of suicide for patients taking SSRIs compared to a placebo was 2.6 -- more than twice the risk. But new trials should be conducted to settle the issue once and for all, he said.
Healy said his main concern now is how this heightened risk could have gone unnoticed and how similar missteps can be avoided in the future.
"These are an awfully useful group of drugs, and I use them," Healy said. "The solution for me and for the people who need them is to know what the risks really are. We need to have access to the raw data and regulators do as well."
Knowing the full picture could mean the difference between life and death, Healy said.
"If we are informed what the risks are, then we don't say, 'it couldn't be the drug,' and increase the dose, which is just the wrong thing to do," he said.
