Antidepressants and Teenage Suicide Antidepressants and Teenage Suicide: Columbia Experts Clarify Confusion

IN THE MIDST OF THE RECENT CONTROVERSY OVER THE USE OF antidepressants in teenagers, the FDA began examining data from all clinical trials of the drugs in children and immediately ran into a problem that threatened to make the entire examination meaningless.
In one study, the FDA and Columbia reviewers found that a patient who slapped herself in the face was deemed suicidal, but in another study, a 10-year-old's attempt to hang himself with a rope was labeled a personality disorder.
With such vast differences among the studies, "the FDA couldn't make sense of the data," says Kelly Posner, Ph.D., assistant professor of clinical psychology (in psychiatry), "and that may have led to unjustified public health consequences."
In early 2004 the FDA decided that the only way to obtain interpretable data was to reclassify all the potential suicidal events from the 24 trials of nine drugs (including actual attempts, preparatory acts, and thoughts) using a single, consistent classification process. Based on recommendations from suicide researchers, the FDA turned to a group of suicide experts at Columbia and the New York State Psychiatric Institute: Maria Oquendo, M.D., clinical professor of psychiatry; Madelyn Gould, Ph.D., professor of clinical epidemiology (in psychiatry); Barbara Stanley, Ph.D., director of the suicide intervention center at NYSPI; and Dr. Posner. Other contributors were Mark Davies, lecturer in biostatistics at the Mailman School of Public Health and statistical consultant to the work; and data analyst Marjorie Kleinman.
"The NYSPI departments of child psychiatry led by Dr. David Shaffer and neuroscience led by Dr. John Mann are characterized by 20 years of extensive research in suicide, including biological, genetic, epidemiological, and treatment trials in children, teenagers, and adults," Dr. Posner says. "As part of this work, we've developed expertise in adequately measuring suicide variables and then classifying what is a suicide attempt and what is not."
For the antidepressant data, the team created a ratings scale for events based on a definition of suicide attempt as potential self-injury with some intent to die, with the definition consistently applied across all trials. After a training session in the classification scheme, nine internationally recognized suicide experts from outside Columbia reviewed each of the 427 questionable events from the trials.
Despite initial concerns that the case reports would be too sketchy to reach conclusions, the team was able to classify all but nine events that offered too little information. The team uncovered 26 more possibly suicidal events that were initially reported by the pharmaceutical companies as other events, such as accidental injuries. Also, the experts reclassified 45 events originally deemed suicide attempts to other categories.
At an FDA meeting in September 2004, the reclassification was praised by members of the two committees charged with assessing the efficacy and safety of the nine drugs.
"It was a very rigorous examination, very carefully planned. I am impressed with how much they accomplished, and I was somewhat skeptical in our last meeting," said the chairman of the FDA's Psychopharmacologic Drugs Advisory Committee, Wayne Goodman, M.D. "I was not prepared to answer the question [about whether these drugs increase the risk of suicidality in children] at the last meeting, but I am now based upon the reclassification."
Ultimately, the Columbia work contributed to the analyses that led to a new rule requiring manufacturers to add a "black box" warning on drug packaging that describes the increased risk of suicidality in children and adolescents given antidepressant medications.
The risk of suicidality in children now raises a question about why the same effect hasn't been seen in adults. One potential reason for the difference is that adult data were not classified in the same way, Dr. Posner says. The FDA is now asking pharmaceutical companies to reclassify their trial data using Columbia's classification scheme an enormous task given that these trials involved many more patients than the trials with children.
But the project's impact should be much broader and extend beyond the reclassification of already acquired data. "Many times the doctors participating in drug trials don't know the questions to ask to get the appropriate information the first time," Dr. Posner says. "Part of our work involves developing guidelines to help researchers ask the appropriate questions so they can accurately classify suicidal and nonsuicidal events.
"Going forward, hopefully trials will now systematically look for suicide occurrences," she adds. "If you can't identify these events properly, you can't determine if the treatments are safe and effective."
The work is already setting a standard in the field. The FDA's Tom Laughren, M.D., says the work "represents a very substantial effort that has not only helped us to understand these data but will have implications for the field in terms of developing a standard approach to classifying these kinds of data." Susan Conova


Vitamin D in Osteoporosis Vitamin D in Osteoporosis: Patients Don't Get Enough
In an epidemiological study conducted by a P&S researcher and others, more than half of a large group of women treated for osteoporosis had suboptimal levels of vitamin D. The research, presented at the American Society for Bone and Mineral Research meeting in October 2004, suggests that despite routine physician recommendations that women being treated for osteoporosis take over-the-counter vitamin D supplementation, vitamin D inadequacy is still highly prevalent among women with the condition.
Of the more than 10 million people in the United States estimated to have osteoporosis, 80 percent are women. The National Osteoporosis Foundation advises getting recommended Of the more than 10 million people in the United States estimated to have osteoporosis, 80 percent are women. The National Osteoporosis Foundation advises getting recommended daily amounts of vitamin D and calcium as one of the five steps involved in bone health and osteoporosis prevention. Vitamin D, an essential component of osteoporosis therapy, helps ensure that the body absorbs and retains calcium and phosphorus, both critical for building bone.
The cross-sectional observational study examined 1,536 postmenopausal women, averaging age 71, from 61 North American sites between November 2003 and March 2004. Ethel Siris, M.D., the Madeline C. Stabile Professor of Clinical Medicine at P&S and director of the Toni Stabile Center for the Prevention and Treatment of Osteoporosis at New York-Presbyterian Hospital, was on the research team. Most of the study participants were seen in primary care offices, and 84 percent reported good to excellent health.
"While women may know that calcium is an important part of bone health, this research shows that some women on treatment for osteoporosis are unaware of the important role vitamin D plays or are simply not getting adequate amounts as part of their treatment regimen," says Dr. Siris. "Getting enough vitamin D, whether through supplements, proper food choices, or appropriate and careful exposure to sunlight, is vital to managing osteoporosis."
The study showed that prevalence of vitamin D inadequacy was significantly higher in women who took less than 400 international units of vitamin D supplementation daily compared with women who took 400 or more daily (63 percent vs. 45 percent). Although half of the women were not getting enough vitamin D based on their serum vitamin D levels, 66 percent of the women said they had spoken with their physician about the importance of taking vitamin D for bone health.

Scientists Find Surprises in Genome of Legionnaires' Disease Pathogen
Researchers have decoded the genome of Legionella pneumophila, the bacteria responsible for Legionnaires' disease, and have found a few surprises in the bug's 3,000 genes. Legionnaires' disease was first identified in Philadelphia in 1976, after 220 attendees at an American Legion convention were stricken with pneumonia and 34 died. It was soon determined that they were infected with a previously unknown bacteria, L. pneumophila, that had saturated the hotel's air conditioning system. Subsequently, L. pneumophila and related species of Legionella were found in standing water worldwide and are also frequent causes of hospital-acquired pneumonias.
In a report published in the Sept. 24, 2004, issue of Science, a group of researchers led by James J. Russo, Ph.D., associate head of sequencing and chemical biology at the Judith P. Sulzberger Columbia Genome Center; Howard Shuman, Ph.D., professor of microbiology; and Jingyue Ju, Ph.D., associate professor of chemical engineering, and colleagues found several unusual aspects of the bacteria's genome that may lead to new therapies. The genome contains a remarkable number of proteins that pump toxins out of the bacteria, which may account for its survival within plumbing systems, even after treatment with potent biocides. And it possesses a very large number of candidate virulence factors, proteins that may account for its ability to infect and kill human cells.

Researchers Find out Why Dietary Fat Increases Alzheimer's Risk
Researchers uncovered another way dietary fat may increase the risk of getting Alzheimer's, making too much fat a double whammy for the brain's cells. "It's a new way of looking at Alzheimer's disease and it opens up a whole new way to approach the disease therapeutically," says the study's senior author, Neil Shachter, M.D., associate professor of clinical medicine.
Though the connection between fats and Alzheimer's disease initially took researchers by surprise, it's now so accepted that clinical trials are testing whether statins, cholesterollowering drugs, can prevent the disease.
The rationale behind the trials comes from studies that show that cholesterol increases the amount of beta-amyloid, the molecule most researchers believe is the primary culprit in the disease.
In research published in the Sept. 16, 2004, issue of the Journal of Lipid Research, Dr. Shachter found that another component of dietary fat, triglycerides, also increases the amount of beta-amyloid inside cells, but in a different way than cholesterol. Using cultured cells, Dr. Shachter found that triglycerides increase the amount of a molecule called presenilin, which assists in beta-amyloid production. The increase in presenilin level then increases the amount of beta-amyloid in the cell.
A worldwide effort to find drugs that limit the activity of presenilin is already under way, Dr. Shachter says. He suggests his new findings may lead to more effective treatments that rid the cell of excess presenilin altogether, by decreasing fat delivery.

Central Corneal Thickness Impacts Glaucoma Treatment Management
Similar to cholesterol readings for heart disease, measurements of a patient's intraocular pressure (IOP) in the eye are a cornerstone of glaucoma treatment with the clinical goal to get IOP as low as possible to reduce the risk of long-term disease progression and vision loss. However, research has shown that if a patient also has an abnormal central corneal thickness (CCT), the true IOP level may be masked, which may result in under-treatment or over-treatment of glaucoma.
In a new study, P&S researchers used a linear correction scale and a mathematical formula to determine exactly how much of an effect a CCT measurement has on IOP. Results found that CCT has a significant effect on the clinical management of patients with glaucoma and those suspected to have glaucoma, affecting more than half (105) of the 188 patients in the study.
"We were astounded to find that so many of the glaucoma patients in our study needed an IOP adjustment, based on their CCT measurement," says James C. Tsai, M.D., the study's senior author. Dr. Tsai is associate professor of ophthalmology and chief of the glaucoma division at the Edward S. Harkness Eye Institute. "While more research needs to be done to further determine the effects of CCT on clinical management and consequent long-term outcomes, it's clear that CCT should be considered when making glaucoma treatment decisions."
The study was published in the September 2004 issue of Archives of Ophthalmology.

Levodopa May Slow Progression of Parkinson's Disease
Levodopa is the most powerful drug available to treat the symptoms of Parkinson's disease, and almost all patients with the disease will eventually need to take it. A controversy about when it should be started has been eased by a Columbia-led study on the drug's effect on the rate of progression of the disease.
The controversy stems from concern that the medicine might cause further damage to the brain cells that are impaired in the disease. P&S researchers led a team of experts from the Parkinson Study Group to study levodopa's effect. The research, reported in the Dec. 9, 2004, issue of the New England Journal of Medicine, showed that not only does levodopa not appear to worsen the disease, but also that it may actually slow its progression. The clinical trial involved 361 newly diagnosed Parkinson's disease patients at 38 Parkinson Study Group sites across the United States and Canada. The study was a placebo-controlled, doubleblind clinical trial.
Stanley Fahn, M.D., professor of neurology, was the principal investigator of the study. "Although there is still uncertainty on how to interpret the study and further investigation will be necessary to prove levodopa's value beyond reasonable doubt, we found that levodopa did not accelerate the pace of Parkinson disease," says Dr. Fahn. "Now patients can feel more secure about the drug and may wish to start it sooner rather than later."
The results do not prove that levodopa slows the underlying nerve degeneration of Parkinson's disease, and a differently designed clinical study will be necessary. A follow-up study is planned.
The Parkinson Study Group (www.Parkinson-Study-Group.org) is a nonprofit, cooperative group of Parkinson's disease experts from medical centers in the United States and Canada who are dedicated to improving treatment for persons affected by the disease.

Gastric Cancer May Originate from Bone Marrow-Derived Stem Cells
Researchers have found that gastric cancer originates from bone marrow-derived stem cells rather than stomach stem cells, as previously thought. The research, which was conducted in mouse models, was reported in the Nov. 26, 2004, issue of Science.
"This was an unexpected finding, which may lead to a re-evaluation of current assumptions about how all cancers originate," says the study's senior author, Timothy C. Wang, M.D., the Dorothy L. and Daniel H. Silberberg Professor of Medicine and chief of digestive and liver diseases. "The implications of this study may lead to new methods of diagnosis and treatment of many cancers particularly those that have been linked to chronic inflammation such as stomach, esophagus, lung, pancreas, liver, etc."
A common assumption among cancer specialists is that most cancers originate from tissue stem cells for example, the gastric stem cells contained in the lining of the stomach. However, the researchers suspected bone marrow-derived stem cells may contribute to the development or progression of cancer because they are frequently recruited to sites of tissue injury and inflammation, a typical site for cancer development.
Results found that chronic infection with Helicobacter pylori, a bacteria known to cause inflammation and ulcers in the stomach and a known carcinogen, leads to the death of most normal stomach cells. As a result, bone marrow-derived stem cells arrive in numbers to try to repair the site. The cells, which are somewhat prone to undergo transformation, progress over time into stomach cancer cells.
With this clearer understanding of the connection between bone marrow-derived stem cells and stomach cancer, Dr. Wang, who was recruited back to Columbia (he's a 1983 P&S graduate) and the Herbert Irving Comprehensive Cancer Center in 2004, will establish screening models for people at high risk of cancer and work to translate the findings into new treatments that specifically target these cells.

Study Shows Depression Intensifies Through Generations
A new study by P&S and New York State Psychiatric Institute researchers shows that more than half of children whose parents and grandparents suffered from depression have a psychiatric disorder before they reach their early teens, compared with approximately 28 percent of children who develop psychiatric disorders but have no family history of depression.
Researchers found that nearly 60 percent of children in the third generation developed a psychiatric disorder. The study was published in the January 2005 issue of the Archives of General Psychiatry. It is the first study to follow three generations of high-risk families and has taken more than two decades to complete. The researchers began studying 47 first-generation family members in 1982, then interviewed 86 of their children several times as they grew into adulthood. The team has collected data from 161 members of the third generation, whose average age is 12.
Results found that most of the prepubescent grandchildren with a two-generation history of depression developed anxiety disorders that developed into depression as they aged into adolescence. This trend was also found when the researchers followed the children's parents through adolescence and adulthood.
"We have shown that the risk of depression is carried through several generations and that it intensifies as more generations are affected," says the study's lead author, Myrna Weissman, Ph.D., professor of psychiatry and epidemiology and chief of clinical and genetic epidemiology at PI.
Previous studies showed that children of a depressed parent are at greater risk of mood and anxiety disorders, but the Columbia study is the first to illustrate how the risk intensifies across three generations.

ILLUSTRATIONS: CLAUDIA BRANDENBURG

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