University Times

SSRIs, tricyclics safely treat postpartum depression

Two antidepressants commonly used to treat depression in the general population also can effectively and safely treat postpartum depression, according to a study led by the School of Medicine and published in the August issue of the Journal of Clinical Psychopharmacology.

The study is among the first to compare the effectiveness of selective serotonin reuptake inhibitors (SSRIs) and tricyclics, two commonly used classes of antidepressants, in women who experience major depression after childbirth.

Katherine L. Wisner, professor of psychiatry and obstetrics, gynecology and reproductive sciences at the School of Medicine, said, “We’ve been treating postpartum depression based on the assumption that drugs that work for a woman with depression under usual circumstances will work for a woman who experiences depression after giving birth, but there have not been studies that provide scientific proof that this was an effective and safe course of treatment. Treating these women based on that assumption was simply not good enough, and we felt compelled to provide scientific evidence to guide postpartum depression treatment decisions.”

In the study, researchers compared the tricyclic nortriptyline and the SSRI sertraline because both drugs were proven effective in treating general depression in women. In addition, previous studies showed the two drugs were acceptable for use in breastfeeding women. Researchers found 109 women with major depression with postpartum onset at sites in Pittsburgh, Cleveland and Louisville, Ky. They were randomized to receive either nortriptyline or sertraline. A placebo was not used, as researchers felt it would be unethical and dangerous to the mother and her infant to not treat the illness actively.

Using common tools for assessment of depression, the investigators evaluated the women for remission of depressive symptoms at four, eight and 24 weeks. Both groups responded in a similar manner to the medications. By week four, 46 percent of the participants taking sertraline had responded to the medication and 27 percent of them reported having no symptoms, while 56 percent of those taking nortriptyline had responded and 30 percent of them reported having no symptoms. At eight weeks, 56 percent of the participants on sertraline had a reduction of symptoms and 46 percent of them had no symptoms, while of the participants taking nortriptyline 69 percent responded with 48 percent of them reporting no symptoms. Of the 29 participants who remained in the study until 20-24 weeks, 93 percent taking sertraline responded and 73 percent of that group reported having no symptoms, while 100 percent of those taking nortriptyline responded and 79 percent reported having no symptoms. None of these differences was significant by statistical analyses.

Additionally, researchers found that psychosocial functioning improved similarly with use of both drugs. Neither drug proved to be superior to the other in treating aggressive obsessional thoughts. Side-effect burdens were the same, although side effects differed between the drugs. Overall, the majority of women responded to both of the drugs within two to four weeks.

Wisner said, “It’s encouraging to see that these women responded quickly and well to the study medications and that now we have scientific proof on which to base our treatment decisions.”

Co-authors of the study include Barbara H. Hanusa, James M. Perel, Dorothy K.Y. Sit and Eydie Moses-Kolko of Women’s Behavioral Health CARE at Western Psychiatric Institute and Clinic.

The study was funded by the National Institute of Mental Health.

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Lucid & long-lived: Successful aging genes found

A Pitt study published in the September issue of the American Journal of Geriatric Psychiatry and on line at www.AJGPonline.org is one of the first to identify genetic links to cognitive longevity. While previous research shows that genes contribute to long life, this study identified regions of the human genome that contributed, along with lifestyle factors, to reaching age 90 with preserved cognition.

“Successful aging has been defined in many ways; however, we focused on individuals who had reached at least 90 without significant decline in mental capacity,” said lead researcher George S. Zubenko, professor of psychiatry and biological sciences. “While this is a goal that many of us share, such a definition of ‘successful aging’ can be determined objectively and consistently across subjects.”

The study compared the DNA of 100 people age 90 and older who had preserved cognition with that of 100 young adults to identify specific genetic sequences present in older individuals that may be linked to reaching older ages with preserved cognitive abilities, or conversely, specific genetic sequences present in younger individuals (and not present in those over age 90) that may impede successful aging.

Researchers identified nine genetic regions that were associated with successful aging, some of which affected men or women, but not both. The majority of the successful aging or “SAG” regions overlapped with gene locations previously reported to show linkage to susceptibility genes for cardiovascular disorders, psychiatric disorders and the accumulation of tissue damage due to oxidative stress. The results of the study also highlighted the detrimental effects of cigarette smoking, excessive drinking and serious mental disorders on successful aging in both sexes.

“The finding that genetics, lifestyle decision making and their interactions may influence the ability to reach old age with preserved cognition is exciting,” stated Zubenko. “Identifying such genetic and behavioral factors may hold promise for better understanding the aging process.”

Other Pitt co-authors were Hugh B. Hughes III and Wendy N. Zubenko of psychiatry, and Brion S. Maher of the Center for Craniofacial and Dental Genetics.

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HIV research presented at international conference

Several Pitt studies are among the research presented recently in Toronto at the XVI International AIDS Conference, AIDS 2006. Among them are:

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First-line HIV treatments compared

In the first head-to-head comparison between two commonly used HIV treatments, researchers found one triple-drug therapy was significantly more effective at reducing HIV viral load in the blood when used as a first-line treatment. The clinical trial sought to determine from among three different therapies the optimal approach for patients beginning HIV treatment for the first time.

Of the two triple-drug approaches evaluated in the randomized trial, the therapy consisting of two nucleoside reverse transcriptase inhibitors (NRTIs) with efavirenz, a non-nucleoside reverse transcriptase inhibitor (NNRTI), suppressed the virus to undetectable levels in more participants than the three-drug combination of two NRTIs and a protease inhibitor called lopinavir/ritonavir.

A third regimen, efavirenz and lopinavir/ritonavir, performed nearly as well as the three-drug cocktail with efavirenz, suggesting initial therapy need not include NRTIs, a class of drugs that can produce intolerable side effects in some patients.

“Our findings suggest that the efavirenz plus two-NRTI regimen was the best of the three approaches as initial therapy, even in patients with relatively advanced HIV disease,” said Sharon Riddler, assistant professor of medicine in the Division of Infectious Diseases at the School of Medicine, who presented the findings.

“Also, we found that the NRTI-sparing two-drug combination of efavirenz and lopinavir had a similar level of effectiveness to the efavirenz plus two-NRTI regimen. When we started this study, we heard from physicians with concerns about using efavirenz in the absence of NRTIs. Now that we’ve completed the trial, there should be little doubt that patients can benefit from this ‘nuke’-sparing treatment regimen when NRTI side effects are a problem,” she said.

All of the drugs used in the clinical trial are approved for the treatment of HIV. Nucleoside reverse transcriptase inhibitors, or NRTIs, prevent healthy T cells from being infected by blocking a process called reverse transcription that HIV uses to convert its RNA into DNA. By inserting faulty building blocks, HIV can’t copy its DNA. NNRTIs, the non-nucleoside reverse transcriptase inhibitors, target the same mechanism but block the reverse transcriptase enzyme by attaching to a different site than NRTIs. The class of drugs known as protease inhibitors blocks the maturation of proteins that HIV needs to assemble itself into an infectious virus.

John W. Mellors of the School of Medicine also was part of the research team.

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Immunotherapy shows promise

A lab version of boot camp for immune system cells may help patients win their battle against HIV. A Pitt study showed that a therapeutic vaccine loaded with a patient’s own souped-up dendritic cells can rally the immune system to fight the virus.

The key is to modify dendritic cells to get the attention of the killer T cells that find and destroy HIV-infected cells.

Charles R. Rinaldo Jr., professor and chairman of the department of infectious diseases and microbiology at the Graduate School of Public Health (GSPH) and the study’s senior author , said, “Our vaccine, as an immunotherapy, is custom-designed to target the unique virus that has evolved in each individual being treated. A patient’s own dendritic cells together with their unique viral antigens comprise the main elements of the vaccine.”

In the study, white blood cells called monocytes were obtained from both HIV patients and individuals not infected with the virus. The cells were grown into mature dendritic cells in culture with various substances to boost their potency.

Separately, the researchers combined a small amount of the patient’s HIV with their CD4 cells in order to “super infect” them, then inactivated the virus by promoting apoptosis, or programmed cell death.

In their dying state and with trace amounts of viral antigen still present, these CD4 cells were placed in culture with the beefed up dendritic cells. Recognizing the cells as foreign, the dendritic cells processed the antigen. And the dendritic cells presenting the HIV fragments were able to stimulate CD8 or cytotoxic killer T cells when the two cell types were combined.

Results will be incorporated into the protocol for a clinical trial of the vaccine, which is expected to begin later this year.

Other Pitt authors of the study are Zheng Fan of GSPH, and Pawel Kalinski of the School of Medicine.

The research was supported by the National Institute of Allergy and Infectious Diseases.

Homeland Security funds text analysis research

Pitt will receive $2.4 million over the next three years from the U.S. Department of Homeland Security (DHS) to develop techniques for extracting, summarizing and tracking information about events and beliefs from free text.

Pitt is among four University Affiliate Centers (UACs) selected by DHS to conduct research on advanced methods for information analysis. The other members of the Pitt UAC are Cornell University and the University of Utah. Their work will help identify common patterns from numerous sources of information, which may be indicative of potential threats to the nation.

Other centers are at Rutgers University, the University of Illinois at Urbana-Champaign, and the University of Southern California.

Pitt computer science professor and lead researcher Janyce Wiebe said, “The goals of the work will be to identify facts and entities, as well as beliefs and motivations expressed in text and to create new methods for linking events and beliefs across documents, and tracking them over time,” said.

The UACs and their partners will collaborate with the Institute for Discrete Sciences to develop simpler, more efficient software algorithms and architectures for use in a broad range of computing applications.

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Secrets of long life explored

The Graduate School of Public Health (GSPH) is trying to unravel some of the secrets of longevity as one of four sites participating in a study funded by the National Institute on Aging.

Other sites are at Columbia University, Boston University and the University of Southern Denmark.

The five-year $18 million Long Life Family Study (LLFS) seeks to understand why some people live to a very old age and whether families with many long-lived members share common characteristics, behaviors or traits.

Anne B. Newman, professor of epidemiology and medicine at GSPH and one of the principal investigators, said, “We know a lot about some of the factors that contribute to living a longer, healthier life, such as exercise and diet. However, we don’t know all of the factors that impact health and longevity nor do we completely understand how these factors interact. The LLFS is designed to provide us with those types of answers.”

The GSPH team is recruiting up to 250 families with at least two living members who are well over 80 years of age. They also seek to recruit at least one living offspring from these long-lived families.

By examining health-predictive factors in at least two generations, the team hopes to identify any inherited traits that may contribute to longevity.

“We’ll be looking closely at the genetic profiles of our long-lived participants to try to determine the role that specific genes may have played in helping them live so long in relatively good health. Hopefully, we can apply this knowledge to helping the broader community,” said Newman, who also is co-director of GSPH’s Center for Healthy Aging.

Additional information on LLFS is online at www.longlifefamilystudy.org.

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Heinz funds, renames palliative care training program

Pitt’s Institute to Enhance Palliative Care fellowship program will operate under a new name and be supported through a three-year, $300,000 grant from the Heinz Endowments that will prepare medical professionals for careers in palliative medicine.

The fellowship program, to be named in honor of the late Sen. H. John Heinz III, will provide funding during the period leading up to official recognition of palliative medicine as a medical subspecialty. That designation will make the fellowship program eligible for federal funding through the Medicare program.

The goal of palliative care is to relieve both emotional and physical symptoms associated with serious illness while respecting patients’ culture and traditions. The need for training of health care professionals in palliative care has been highlighted in recent reports by the Institute of Medicine, which have stated that training for the rest of the nation’s physicians is not adequate to meet the needs of an aging population that is experiencing more serious chronic disease.

Since 2003, Pitt trainees have been learning to assess and manage the physical, psychological and spiritual suffering experienced by patients and their families. The fellowship stresses communication, ethical and legal decision-making skills, as well as bereavement support and interdisciplinary teamwork associated with patient care.

“The medical profession now recognizes the urgent need to address the palliative care needs of our rapidly aging population, and medical educators are racing to keep up,” said David Barnard, professor of medicine and director of the Institute to Enhance Palliative Care. “The Heinz Endowments’ support for our fellowship program will assure heightened quality and visibility for our efforts.”

Pitt’s program is one of only nine accredited programs in the country that combines patient care experience with clinical research training.

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Gout increases risk of heart attack

People with gout are at increased risk of having a heart attack, according to a School of Medicine study published in the August edition of the journal Arthritis & Rheumatism available online at http://www3.interscience.wiley.com/cgi-bin/jhome/76509746.

Caused by hyperuricemia — a buildup of uric acid in the blood — gout manifests itself as acute arthritis and inflammation of the joints, usually beginning in the knee or foot.

The study shows that among men with no previous history of coronary artery disease, gout is a significant independent risk factor of heart attack.

“Until now this relationship has not been explained by well-known links to renal function, metabolic syndrome, diuretic use and the traditional cardiovascular risk factors,” said Eswar Krishnan, assistant professor of medicine at the School of Medicine, Division of Rheumatology, and principal author of the study.

The study examined data from 12,866 men who were enrolled for a mean of 6.5 years in a primary cardiovascular disease prevention trial. Of 5,337 men with hyperuricemia at the beginning of the study, 1,123 developed gouty arthritis.

There was no statistically significant difference between the groups with regard to cholesterol levels, aspirin use, family history of heart attack or diabetes. However, the group with gout was significantly more likely to have used diuretics and alcohol. Modest yet statistically significant elevations of blood pressure, age, blood glucose and body mass index were observed in the gout group. Subjects in the group with gout were less likely to be current smokers than were those in the group without gout.

During the course of the study, 1,108 heart attacks occurred in the group with gout (10.5 percent) and 990 in the group without gout (8.43 percent).

The study also found a relationship between gout and the risk of heart attack to be present among nonusers of alcohol, diuretics or aspirin and among those who did not have metabolic syndrome, diabetes or obesity.

“The absolute magnitude of the relative risk for the presence of gout was not high. Yet, the odds ratio associated with gout was relatively high compared to other risk factors in this study,” Krishnan said. “Hyperuricemia is well known to be an independent risk factor for atherosclerotic diseases in general and since chronic hyperuricemia is strongly associated with gout, it is not very surprising that an independent coronary risk for the presence of both hyperuricemia and gout was observed.”

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Strategies for coping with illness help in bereavement

An intervention aimed at preventing depression and easing the burden of caring for a relative with dementia also helps prevent complicated grief and depression following the death of the loved one, according to a study led by Pitt researchers.

The findings, published in the August issue of the American Journal of Geriatric Psychiatry, sought to determine which caregivers were at risk for complicated grief and depression after their care-recipients died.

The research unexpectedly found that interventions aimed at helping the caregiver cope while the care-recipient was living also helped the caregiver cope with the recipient’s death, said psychiatry professor Richard Schulz, principal investigator and lead author of the study.

Complicated grief most often occurs after the death of someone in a very close and loving relationship. Key features include disbelief, anger and bitterness over the death, recurrent pangs of painful emotions with intense yearning and longing for the deceased, avoidance of situations and activities that are reminders of the loss, and a preoccupation with thoughts of the loved one, often including distressing, intrusive thoughts related to the death.

Since it is a newly characterized condition, not yet included in the American Psychiatric Association’s Diagnostic and Statistical Manual, little is known about how to treat and prevent complicated grief.

The authors report that the results of this study are the first to demonstrate the effectiveness of interventions including education, skills training and group support on preventing complicated grief and depression after death.

Twenty percent of the caregivers in the study experienced symptoms of complicated grief after their loved ones died. Most of these did not receive the interventions, had depressive symptoms and/or saw the caregiving process as positive, usually because they derived a sense of purpose from the situation, and were most likely to experience severe depression and complicated grief post-death.

“Taking care of a relative with dementia can be very stressful. Most caregivers respond well to their loved one’s death, seeing it as a relief for the patient, which is why we focused on helping during the caregiving process, rather than after,” said Schulz, who is associate director of the University of Pittsburgh Institute on Aging and director of the Center for Social and Urban Research. “Given that in our previous studies we have found that a large number, some 30 percent of caregivers, are still at risk for severe depression after the death of their loved one, it’s encouraging to know that these interventions can help both before and after death.”

The researchers found that reducing caregiver burden, treating depression prior to death and providing supportive psychosocial or skills training caregiver interventions helped the caregivers to better manage with their loved one’s deaths.

Pitt co-authors of the study included Song Zang and Katherine Shear, formerly of Pitt and now at the Columbia School of Social Work.

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RheoGene grants research license for recombinase

RheoGene Inc., a wholly-owned affiliate of UPMC, has granted a nonexclusive research license to Symphogen A/S of Copenhagen to use the Norristown-based biotech company’s gene-targeting AttSite recombinase. The enzyme-based technology is designed to guide gene insertion into specific “hot spots” within the genome, easing the exchange of DNA and aiding in the development of new genetic sequences and cell lines.

Symphogen will use these novel enzymes as part of its effort to pioneer the development and manufacturing of recombinant human polyclonal antibodies. This new class of therapeutic antibodies is designed to mimic the human immune response in key ways that confer advantages over current immunoglobulin and monoclonal antibody therapies.

Financial terms were not disclosed.

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Vitamins, healthy weight reduce risk of preeclampsia

Women who take multivitamins before becoming pregnant and during the first trimester of pregnancy may significantly reduce their risk of developing preeclampsia, a Graduate School of Public Health (GSPH) study published in the American Journal of Epidemiology finds.

Overall, women who used multivitamins regularly showed a 45 percent reduction in preeclampsia risk, according to the study. And results were even more remarkable for women who were not overweight prior to pregnancy.

GSPH assistant professor of epidemiology Lisa Bodnar said, “Our data show that women who are not overweight before pregnancy and who used multivitamins at least once a week before conception and in the first three months of pregnancy reduced their risk of preeclampsia by a striking 72 percent compared to those who didn’t take a multivitamin during this time period. Multivitamin use makes little apparent difference in preeclampsia rates for women who are overweight before pregnancy. Even so, the results suggest that regular multivitamin use in the pre-pregnancy period may help to prevent preeclampsia.”

Also known as toxemia, preeclampsia affects about 7 percent of first pregnancies and is a leading cause of premature delivery and maternal and fetal death. Signs of preeclampsia include high blood pressure, protein in the urine and swelling of the hands and feet. Untreated, the condition may progress to the far more serious eclampsia, which can lead to seizures, coma and death.

Bodnar and her colleagues evaluated data from 1,835 women who were enrolled in Pitt’s Pregnancy Exposures and Preeclampsia Prevention Study between 1997 and 2001.

They found the prevalence of preeclampsia was 4.4 percent for non-multivitamin users and 3.8 percent for those who used multivitamins, with the most significant differences being noted among women who had a body mass index of less than 25. A BMI of 25 is generally considered overweight; a BMI of 30 or above is considered obese.

Because multivitamins contain many nutrients, it is difficult to know exactly how the risk of preeclampsia is reduced, but the study shows that nutrition is a relevant issue in prevention of preeclampsia, Bodnar said.

“Preeclampsia is a potentially devastating condition for mother and baby,” said James M. Roberts, director of the Magee-Womens Research Institute and senior author of the paper. “It may be that taking a multivitamin prior to conception positively influences embryonic implantation, which is a physiologic process known to be abnormal in preeclampsia.”

Researchers are unsure why multivitamin use appears to have no benefit in overweight women.

Other Pitt authors were Gong Tang and Roberta B. Ness, both of GSPH.

Funding for the study was provided by the National Institute of Child Health and Human Development.