(Great Neck, NY - October 03, 2007) — Three studies published during the last three weeks have contributed important new facts to the debate about whether depressed teenagers who take antidepressant drugs are at increased risk for contemplating or attempting suicide. Two of the studies were led by NARSAD Investigators.

In 2004, the Food and Drug Administration ordered makers of antidepressants to add “black-box warnings” to their labels, indicating that the drugs were associated with increased risks of suicidal thinking and behavior in young people. Although FDA did not conclude that these drugs caused worsening depression or suicidality, the agency sought to advise health care providers and patients that worsening of symptoms could be due to underlying disease or might be a result of drug therapy.

CDC Study Showed Sudden Increase in Teen Suicides

On September 6th of this year, the government’s Centers for Disease Control (CDC) issued annual statistics on mortality in the U.S. These indicated, to the alarm of many mental health professionals, that the incidence of teen suicide had increased for the first time in years. The period under study happened to be the CDC’s first statistical collection period following the FDA order to re-label antidepressant medications. Some psychiatrists expressed the concern -- which has not been proven -- that this sudden increase in teen suicides may have reflected the warning label’s impact on usage among young patients with major depression. They suspect it may have caused a decline in prescriptions for seriously depressed youth who might have benefited from drug treatment.

CDC statistics indicated the suicide rate for 10- to-24-year-olds increased by 8 percent in 2004, the largest single-year rise in 15 years. In the period from 1990 to 2003, prior to the change in product labeling, the rate of suicide in the age group under study had decreased from 9.48 to 6.78 per 100,000 people, or more than 28 percent. In 2004, it rose from 6.78 to 7.32, according to the CDC’s report.

Combination Therapy Significantly Diminished Suicide Risk, Brought Faster Relief to Teens

Against a backdrop of continuing concern about a possible connection between antidepressant drug treatment and adolescent suicidality, a major study published in the October issue of the Archives of General Psychiatry has commanded great interest. Led by NARSAD Distinguished Investigator John March, M.D., chief of child and adolescent psychiatry at Duke University, the Treatment for Adolescents with Depression Study (TADS), indicated that combination therapy improved depressive symptoms and reduced the level of suicidal thinking and behavior in adolescents.

Funded by the National Institute of Mental Health (NIMH), TADS is a multicenter, randomized clinical trial examining the individual and combined effectiveness in depressed adolescents of the antidepressant fluoxetine (Prozac) and a kind of psychotherapy called cognitive behavior therapy (CBT).

Dr. March and colleagues found that Prozac plus therapy was more effective than medication alone over the course of 36 weeks. The therapy used was a depression-specific treatment designed to create and reinforce positive thought patterns and behavior in the adolescents.
The study’s findings are pertinent to the debate about treating teen depression in two major ways. First, it showed that over a nine-month period, more than eight in 10 young people were either “much better” or “very much better,” regardless of whether they had received only Prozac, only therapy, or both. But, importantly, those who received Prozac showed significant lifting of their depression six weeks earlier than those patients who received only therapy.

Perhaps even more pertinent to the treatment debate, the study revealed that patients who took only Prozac had a significantly higher rate of suicidal thinking than those who received therapy alone or combination therapy. “Suicidal events” were reported in almost 15 percent of the Prozac-only patients (in most instances, not actual attempts but rather suicidal thoughts); but only 6 percent of those who received therapy, alone or in combination with Prozac, reported “suicidal events.”

These results are a powerful argument for combination therapy -- treatment which combines the benefits of Prozac’s much more rapid ameliorative impact on deep depression, and psychotherapy’s seemingly “protective” impact on the risk of suicidal thought, whether this ultimately is shown by scientists to be related or unrelated to the taking of antidepressants like Prozac.

The TADS study included 327 patients between the ages of 12 and 17 with a primary diagnosis of major depressive disorder. At week 12 of the study, depression decreased among all treatment groups, with the greatest reduction occurring in the group receiving combination therapy (71 percent response rate). At 18 weeks, the combination treatment continued to demonstrate superiority to either treatment alone with an 85 percent response rate, compared to 69 percent for Prozac alone and 65 percent for CBT alone. At the conclusion of 36 weeks, combination treatment had the highest response rate at 86 percent compared to 81 percent each for Prozac or CBT.

"While many questions still remain about the safest and most beneficial course of treatment for adolescents, this data provides a significant step forward,” Dr. March said. "It provides an evidence-based option that has been found to improve depression through medication used together with cognitive-behavioral psychotherapy.”

Gene Variants Linked to Suicidal Thinking in Adults During Antidepressant Treatment

On September 27th, a major government-funded study led by a NARSAD Independent Investigator, Francis J. McMahon, M.D., and appearing in the October issue of the American Journal of Psychiatry, shed additional light on the continuing mystery surrounding antidepressants and suicide risk, in this case among depressed adult patients.

Dr. McMahon and colleagues reported that specific variations in two genes are linked to suicidal thinking that sometimes occurs in people taking the most commonly prescribed class of antidepressants. Depending on the particular mix inherited, these versions increased the likelihood of suicidal thoughts from two- to15-fold, the study found. About 1 percent of adult patients were deemed to be at high genetic risk, 41 percent at elevated risk and 58 percent at lower risk.

If confirmed, the findings may hold promise for genetic testing, as more such markers are identified.

Risk increased proportionately if an individual had two as opposed to just one of the suspect gene variants. Both genes are involved in directing the manufacture of proteins that form parts of the brain’s glutamate chemical messenger system, which recent studies suggest is involved in the antidepressant response.

Overall, about 6 percent of 1,915 patients with depression reported in the study that they started to have suicidal thoughts while taking an antidepressant. This rate soared to 36 percent among the few patients who had both of the suspect gene versions; 59 percent of the patients who had suicidal thoughts had at least one of the versions.

Dr. McMahon was joined in this work by Gonzalo Laje, M.D. of the Mood and Anxiety Disorders Program of the National Institute of Health (INIMH), and colleagues at the National Human Genome Research Institute (NHGRI), Mount Sinai School of Medicine, and the University of Texas Southwestern Medical Center.

“These data suggest that genetics may soon help us in our quest to individualize treatments for depression,” said NIMH Director Thomas R. Insel, M.D., a former NARSAD Scientific Council member.

“In the future, we hope that genetic testing will help doctors identify those few patients who are at high risk for suicidal thinking during antidepressant therapy and need close monitoring or alternative treatments,” said Dr. McMahon. “This should help allay concerns for the vast majority of patients. The best way to prevent suicide is to treat depression.”

The study led by Dr. McMahon, called STAR*D (Sequenced Treatment Alternatives for Depression), is the most comprehensive of its kind to date, involving the screening of genetic material from 1,915 adults with major depression. Study participants were treated with the selective serotonin reuptake inhibitor (SSRI) citalopram (Celexa). The researchers looked for associations between self-reports of suicidal thinking and more than 700 locations on 68 suspect genes where letters in the genetic code vary from individual to individual, creating different versions of the same gene.

The researchers found that certain versions of two genes that code for glutamate receptors -- the receiving stations for the neurotransmitter glutamate’s chemical messages -- were more prevalent in patients with suicidal thinking. How the newly identified versions affect the workings of glutamate receptors to confer increased risk remains to be discovered. It’s also not yet known whether the findings generalize to other antidepressants.

One percent of the study participants had a version of the kainate receptor gene, GRIK2, which increased the odds for suicidal thinking more than eight-fold. Forty-one percent of participants had a version of the AMPA receptor gene, GRIA3, which raised the odds nearly two-fold. About one-half of 1 percent of participants had both high-risk gene versions, boosting the odds 15-fold -- but this was the case for only 11 participants, of whom four developed suicidal thinking.

Neither version of the gene was related to self-reported history of suicide attempts. This suggests that the versions are specific to suicidal thoughts that occur during antidepressant treatment, rather than the much more common suicidal thoughts and behavior that occur outside of the treatment setting.

More than 40 percent of those who developed suicidal thoughts lacked either of the two versions, indicating that other genes and environmental factors were also likely involved. But the potential value of predictive testing is increasing as more genes are analyzed.

Also participating in the research were: Drs. Silvia Paddock and Husseini Manji, of NIMH; Dr. A. John Rush, of the University of Texas Southwestern Medical Center; Dr. Alexander Wilson, of NHGRI ; and Dr. Dennis Charney, of Mount Sinai School of Medicine. Dr. Paddock is a NARSAD Young Investigator; Dr. Manji is a member of NARSAD’s Scientific Council and past Independent Investigator; Dr. Rush is a past NARSAD Distinguished Investigator; Dr. Charney is a member of NARSAD’s Scientific Council.

Dr. McMahon’s Admonition About Suicide Risk

Evidence suggests that neither suicidal thoughts, nor the high-risk gene versions, are necessarily related to actual suicide attempts, according to Dr. McMahon. Other studies have shown that the rate of such attempts is higher before antidepressant treatment begins -- and suicide attempts are not always preceded by suicidal thoughts. For example, in the current study, one of the two participants who actually attempted suicide carried high-risk versions of the gene in question, but denied experiencing suicidal thoughts.

Even if suicidal thinking does not predict suicidal behavior, it is associated with a poorer response to antidepressant medication, the researchers say. Only 25 percent of patients with suicidal thinking fully recovered from their depression during the initial phase of the STAR*D trail, compared with 42 percent of patients not affected by such thoughts.

Dr. McMahon and colleagues hope that the newly identified gene variants may prove useful in identifying patients who need closer monitoring, alternative treatments and/or specialty care, while reassuring those for whom antidepressants are appropriate.