Long-Term Antibiotics Reduce COPD Exacerbations, Raise Questions

Long-term use of a macrolide antibiotic may reduce the frequency of exacerbations in patients with moderate to severe chronic obstructive pulmonary disease (COPD) by as much as 35 percent, according to a London-based study.

“Our results show a significant effect of low-dose macrolide therapy, reducing exacerbation frequency and severity with moderate to severe COPD,” wrote lead author of the paper, Terence A. R. Seemungal, Ph.D., and Jadwiga Wedzicha, M.D., principle investigator.
The encouraging news comes on the heels of World COPD Day 2008 and a new report from the Centers for Disease Control and Prevention (CDC) that detailed the rising number of deaths related to COPD. More women than men now die of COPD, and while death rates for men have leveled, the rate is still increasing for women, according to the CDC.

The latest study is the first ever year-long randomized, double-blind, placebo-controlled study of the effects of erythromycin in COPD. The results were published in the first issue for December of the American Journal of Respiratory and Critical Care Medicine, which is published by the American Thoracic Society.

The researchers assessed and followed 109 patients with moderate to severe COPD for a year, after randomly assigning them to receive either a placebo or a twice daily 250 mg dose of erythromycin. The patients recorded their exacerbations and hospitalizations in a daily diary card, and they were assessed using spirometry, sputum testing and blood testing for lung function, bacterial infection and markers of inflammation.

The researchers found that not only did the patients randomized to receive erythromycin have fewer exacerbations, but among the patients studied, 60 percent of the exacerbations that occurred were within the placebo group. While the number of exacerbation-related hospitalizations was small, more than twice as many occurred among the placebo group-14 versus 6. The median duration of exacerbations from onset to resolution of symptoms was 9 days in the erythromycin group and 13 days in the placebo group.

“Our results did not allow us to determine a mechanism for these findings. However based on in-vitro studies we suspect that the mechanism is likely to involve the anti-inflammatory properties of erythromycin,” noted Dr. Seemungal.

While their findings are encouraging, Dr. Seemungal points out that they must be put in context with future findings. Furthermore, the threat of growing antibiotic resistance resulting from widespread prophylactic use of erythromycin is not a trivial concern. “In this scenario, substantial, widespread emergence of macrolide bacterial resistance is virtually foreordained, with attendant reduction in the antimicrobial usefulness of this drug class,” wrote Ken M. Kunisaki, M.D. and Denise E. Niewoehner, M.D., of the Veterans Affairs Medical Center in Minneapolis, in the accompanying editorial. “Balancing benefit against harm could pose a dilemma for which there might be no clear answers.”

Moreover, not all of the study patients were treated with guideline-recommended therapy, such as inhaled corticosteroids or inhaled long-acting bronchodilators, which have been shown to decrease exacerbation frequency. The degree of added benefit of erythromycin over and above standard therapy will require further study.

“Observations that any intervention might decrease the frequency and severity of acute exacerbations in COPD present considerable public health implications,” observed John Heffner, M.D., past president of the ATS. “Exacerbations occur about once a year among patients with moderate to severe COPD and account for more than $30 billion dollars in direct and indirect costs annually in the United States alone.”

“Many patients with advanced COPD receive highly potent, extended spectrum antibiotics during acute exacerbations,” commented Dr. Heffner. “The relative risks of breeding resistance with a long-term preventative use of erythromycin versus more frequent short-term dosing of highly potent antibiotics for acute exacerbations require careful analysis. If future studies demonstrate similar efficacy of prolonged erythromycin therapy, especially if patients are already receiving inhaled steroids and long-acting bronchodilators, the benefits likely will outweigh the risks.”

Caution For Pregnant Women Taking Antibiotics

Two studies published early online and in an upcoming edition of The Lancet find that when antibiotics are given to pregnant women experiencing premature labor, even with intact membranes and no infection, there is an increase in risk of functional impairment and/or cerebral palsy. These unexpected findings are the results of a study of long-term follow-up data from the ORACLE Children’s Study, authored by Dr Sara Kenyon (University of Leicester, UK) and colleagues from the ORACLE study group.Completed in 2001, the original ORACLE I and II trials were designed to see if the antibiotics erythromycin and co-amoxiclav could halt underlying infections in women threatening to give birth prematurely, and therefore delay or prevent premature birth and possibly improve outcomes in the first four weeks of life. The experiment was structured as a factorial randomized design, where mothers received placebo and erythromycin, placebo and co-amoxiclav, both antibiotics, or double-placebo. The ORACLE Children Study I and II were designed to analyze the long-term effects of the antibiotics on the children at 7 years of age that were born to these mothers.

In the ORACLE Children Study II, researchers looked at mothers who had spontaneous premature labor with intact membranes surrounding the unborn children and no obvious infection signs. Seven years after birth, a structured parental questionnaire was used to gather follow-up data on the health status of the children of the 4,221 women who had completed the study. The researchers were able to recover data for 71% (3196) of eligible children. The study revealed that in children whose mothers received erythromycin, there was an increase in functional impairment compared to children of mothers who had not received erythromycin - 42·3% to 38.3%, respectively. This translates to an increase in relative risk of 18% for receiving erythromycin. The researchers found no effect on children whose mothers received Co-amoxiclav - with or without erythromycin - concerning functional impairment.

Further, the investigators discovered that children were more likely to develop cerebral palsy who were born to mothers who had received the antibiotics - an unexpected finding. Specifically, 3.3% of children with mothers who received erythromycin (with or without co-amoxiclav) and 1.7% of children with mothers who did not receive the antibiotic had cerebral palsy. Similar numbers were found for children of mothers given co-amoxiclav (with or without erythromycin) - 3.2% and 1.9% developed cerebral palsy, respectively. For children of mothers given both antibiotics, the risk of cerebral palsy was highest - 4.4% of children had the disease compared to 1.6% of children with mothers who received double placebo. This is a tripling of risk.

The researchers did not conclude that either antibiotic had an effect on the number of deaths, other medical conditions, behavioral patterns, or educational attainment. “The prescription of erythromycin for women in spontaneous preterm labour with intact membranes was associated with an increase in functional impairment among their children at seven years of age. The risk of cerebral palsy was increased by either antibiotic, although the overall risk of this condition was low,” conclude Dr Kenyon and colleagues.

In the ORACLE Children Study I, researchers followed up 4,148 eligible children whose mothers joined the trial with preterm rupture of the membranes without obvious infection signs. Erythromycin is currently the recommended treatment since the original trial found that this antibiotic resulted in reductions in short term neonatal death. Seventy-five percent of eligible children (3,298) were assessed in The Children Study, and the researchers found no differences in functional impairment, behavioral difficulties, medical conditions, or educational achievement with either antibiotic. The researchers conclude that: “The prescription of antibiotics for women with preterm rupture of the membranes seems to have little effect on the health of children at seven years of age.”

Professor Philip J Steer (Chelsea and Westminster Hospital, London, UK) and Dr Alison Bedford Russell (Warwick Medical School and Heart of England NHS Trust, UK) write in an accompanying editorial that: “The lessons to be learned seem clear; contrary to popular opinion (’might as well give them, they don’t do any harm’), antibiotics are not risk-free. There are good reasons not to give them in association with threatened preterm labour unless there is clear evidence of infection. It is vital the practice is not extended by stealth beyond that which is justified by the evidence, and interventions given in pregnancy should always be evaluated with proper long-term follow-up.”

Get Well Soon - Without Antibiotics, UK

Government launches campaign in fight against infections

The latest phase in a campaign to remind the public that antibiotics do not help to treat viral infections such as cough’s, colds and a sore throat was launched today by the Chief Medical Officer for England.

Press adverts and posters will appear in newspapers and magazines from today are aimed at patients and Clinicians and are intended to reduce unnecessary requests for antibiotics from patients. The campaign forms part of the Government’s strategy to tackle the increasing problem antibiotic resistance which could make treatment for common bacterial infections such as pneumonia much more difficult in the future.Chief Medical Officer for England, Sir Liam Donaldson said:
“Antibiotics don’t work on colds, most coughs or sore throats or even the flu. Using antibiotics when they are not necessary will increase resistance to them and make it difficult to treat serious bacterial infections in the future.

“If you are suffering with cold and flu symptoms or a sore throat you should rest, take plenty of fluids and speak to your pharmacist who will advise you on over the counter remedies that are available.”

Antibiotic resistance is a global public health issue in which we all have a part to play in order to keep antibiotics effective. Latest data from the Health Protection Agency shows that resistance to the antibiotic most often used to treat E.Coli increased by 10% between 2001 and 2007. Bacteria will always try to find ways to survive by evolving and developing resistance to antibiotics so we must stay one step ahead of the game.

Notes

– Patients with colds do not normally need medical advice but should consult their doctor if they are worried or if:

- a cough lasts more than three weeks,
- they have shortness of breath or chest pains develop,
- if they already have a chest complaint.

Nanotechnology Used To Probe Effectiveness Of Antibiotics

A group of researchers led by scientists from the London Centre for Nanotechnology, in collaboration with a University of Queensland researcher, have discovered a way of using tiny nano-probes to help understand how an antibiotic is effective against bacteria.

Bacteria such as MRSA (commonly known as Golden Staph) are becoming increasingly resistant to antibiotics, posing a major community health problem.

Professor Matt Cooper, the Australian in the team, has this week joined the Institute for Molecular Bioscience at UQ on a $4 million Australia Fellowship.

Through the fellowship, he will establish a research program in the development of antibiotics and antifungals that are active against drug-resistant pathogens, in particular those responsible for hospital-acquired infections.

“It order to attack this problem we need to understand not only the ways in which bacteria develop and exhibit resistance to antibiotics, but also how new antibiotics can work to kill or slow the growth of resistant bacteria,” Professor Cooper said.

To study antibiotic action, the London team made nano-probes coated with molecules found in bacterial cell walls from normal bacteria and bacteria resistant to antibiotics.

They then added doses of the “last resort” antibiotic, vancomycin, to the system and found that probes from normal bacteria were stressed and changed shape, whereas probes from resistant bacteria were only weakly affected. These bent probes could be detected with a laser, indicating that the antibiotic was applying a force to the surface.

This allowed the researchers to quickly assess the effectiveness of an antibiotic and propose new ways in which antibiotics may be acting to cause the bacteria to burst and die.

“This advance will help us to understand the mode of action of drugs targeted against resistant bacteria, and could also lead to rapid diagnostic tools and novel methods of investigating antibiotic action,” Dr Cooper said.

“There is only a tiny molecular difference between resistant and non-resistant bacteria. We now know that these probes can detect that difference, and can do so within minutes.”

The system was able to detect that it is 1,000 times harder for vancomycin to attach to resistant bacteria than to non-resistant bacteria.

The team are now screening other novel antibiotics with the goal of finding a drug that is able to bind strongly to resistant bacteria and cause substantial structural weaknesses to the cell wall.

University College London researcher Dr Rachel McKendry, who led the team, said the findings had implications for improving the response to the bacteria.

“Investigating both these binding and mechanical influences on the cells’ structure could lead to the development of more powerful and effective antibiotics in future,” Dr McKendry said.

The research was published late last year in the journal Nature Nanotechnology.

The University of Queensland, Brisbane Australia

Researchers Develop Novel Antibiotics That Don’t Trigger Resistance

Bacterial resistance to antibiotics is one of medicine’s most vexing challenges. In a study described in Nature Chemical Biology, researchers from Albert Einstein College of Medicine of Yeshiva University are developing a new generation of antibiotic compounds that do not provoke bacterial resistance. The compounds work against two notorious microbes: Vibrio cholerae, which causes cholera; and E. coli 0157:H7, the food contaminant that each year in the U.S. causes approximately 110,000 illnesses and 50 deaths.

Most antibiotics initially work extremely well, killing more than 99.9% of microbes they target. But through mutation and the selection pressure exerted by the antibiotic, a few bacterial cells inevitably manage to survive, repopulate the bacterial community, and flourish as antibiotic-resistant strains.

Vern L. Schramm, Ph.D., professor and Ruth Merns Chair of Biochemistry at Einstein and senior author of the paper, hypothesized that antibiotics that could reduce the infective functions of bacteria, but not kill them, would minimize the risk that resistance would later develop.

Dr. Schramm’s collaborators at Industrial Research Ltd. earlier reported transition state analogues of an enzyme that interferes with “quorum sensing” the process by which bacteria communicate with each other by producing and detecting signaling molecules known as autoinducers. These autoinducers coordinate bacterial gene expression and regulate processes including virulence that benefit the microbial community. Previous studies had shown that bacterial strains defective in quorum sensing cause less-serious infections.

Rather than killing Vibrio cholerae and E. coli 0157:H7, the researchers aimed to disrupt their ability to communicate via quorum sensing. Their target: A bacterial enzyme, MTAN, that is directly involved in synthesizing the autoinducers crucial to quorum sensing. Their plan: Design a substrate to which MTAN would bind much more tightly than to its natural substrate so tightly, in fact, that the substrate analog permanently “locks up” MTAN and inhibits it from fueling quorum sensing.

To design such a compound, the Schramm lab first formed a picture of an enzyme’s transition state the brief (one-tenth of one-trillionth of a second) period in which a substrate is converted to a different chemical at an enzyme’s catalytic site. (Dr. Schramm has pioneered efforts to synthesize transition state analogs that lock up enzymes of interest. One of these compounds, Forodesine, blocks an enzyme that triggers T-cell malignancies and is currently in a phase IIb pivitol clinical study treating cutaneous T-cell leukemia.)

In the Nature Chemical Biology study, Dr. Schramm and his colleagues tested three transition state analogs against the quorum sensing pathway. All three compounds were highly potent in disrupting quorum sensing in both V. cholerae and E. coli 0157:H7. To see whether the microbes would develop resistance, the researchers tested the analogs on 26 successive generations of both bacterial species. The 26th generations were as sensitive to the antibiotics as the first.

“In our lab, we call these agents everlasting antibiotics,” said Dr. Schramm. He notes that many other aggressive bacterial pathogens S. pneumoniae, N. meningitides, Klebsiella pneumoniae, and Staphylococcus aureus express MTAN and therefore would probably also be susceptible to these inhibitors.

While this study involves three compounds, Dr. Schramm says that his team has now developed more than 20 potent MTAN inhibitors, all of which are expected to be safe for human use: Since MTAN is a bacterial enzyme, blocking it will have no effect on human metabolism.

Other Einstein researchers involved in the study were Jemy Gutierrez, the lead author, Tamara Crowder, Agnes Rinaldo-Matthis, M. C. (Joseph) Ho and Steven C. Almo. The powerful inhibitors were reported in an earlier publication in collaboration with the Carbohydrate Chemistry Team of Industrial Research Ltd., in New Zealand.

The study, “Transition State Analogs of 5′ Methylthioadenosine Nucleosidase Disrupt Quorum Sensing” by Vern L. Schramm et al., appears in the March 8, 2009 online edition of Nature Chemical Biology.

The compounds in this paper have been licensed to Pico Pharmaceuticals, which plans to develop and initiate clinical trials of transition-state analogues. Dr. Schramm is a Pico Pharmaceuticals co-founder and chairman of its scientific advisory board.

About Albert Einstein College of Medicine of Yeshiva University

Albert Einstein College of Medicine of Yeshiva University is one of the nation’s premier centers for research, medical education and clinical investigation. It is the home to some 2,000 faculty members, 750 M.D. students, 350 Ph.D. students (including 125 in combined M.D./Ph.D. programs) and 380 postdoctoral investigators. Last year, Einstein received more than $130 million in support from the NIH. This includes the funding of major research centers at Einstein in diabetes, cancer, liver disease, and AIDS. Other areas where the College of Medicine is concentrating its efforts include developmental brain research, neuroscience, cardiac disease, and initiatives to reduce and eliminate ethnic and racial health disparities. Through its extensive affiliation network involving five hospital centers in the Bronx, Manhattan and Long Island which includes Montefiore Medical Center, The University Hospital and Academic Medical Center for Einstein the College runs one of the largest post-graduate medical training program in the United States, offering approximately 150 residency programs to more than 2,500 physicians in training. For more information, please visit http://www.aecom.yu.edu.

New Research Strives To Understand How Antidepressants May Be Associated With Suicidality

The National Institute of Mental Health (NIMH), part of the National Institutes of Health, is funding five new research projects that will shed light on antidepressant medications, notably selective serotonin reuptake inhibitors (SSRIs), and their association with suicidal thoughts and actions (suicidality).
Studies have shown that most individuals suffering from moderate and severe depression, even those with suicidal thoughts, can substantially benefit from antidepressant medication treatment. However, use of SSRIs in children and adolescents has become controversial. In 2005, the U.S. Food and Drug Administration (FDA) adopted a “black box” warning–the most serious type of warning in prescription drug labeling–for all SSRIs. The notice alerts doctors and patients of the potential for SSRIs to prompt suicidal thinking in children and adolescents, and urges diligent clinical monitoring of individuals of all ages taking the medications. This can be particularly challenging because it is difficult for patients, their family members and practitioners to determine whether suicidal thoughts may be related to the depression, the medication, or both.

“These new, multi-year projects will clarify the connection between SSRI use and suicidality,” said NIMH Director Thomas Insel, M.D. “They will help determine why and how SSRIs may trigger suicidal thinking and behavior in some people but not others, and may lead to new tools that will help us screen for those who are most vulnerable,” he added.

The projects are listed below.

* Kelly Kelleher, M.D., of Columbus Children’s Hospital and the Ohio State University, and Joel Greenhouse, PhD, of Carnegie Mellon University, will build on data initially collected by the FDA to analyze antidepressant medication use and suicidal behavior among youth, adults and older adults. Dr. Kelleher will use new and more sensitive statistical approaches to integrate data from numerous other studies–both randomized and non-experimental–to paint a more complete picture of the relationship between antidepressant medication use and suicidal thoughts or actions.

* Marcia Valenstein, M.D., of the University of Michigan, will examine the records of 994,000 individuals from the U.S. Department of Veterans Affairs National Registry for Depression, Medicare records and the National Death Index to determine what relationships exist between the use of antidepressants and suicide attempts and/or deaths, and use of any concurrent medications or treatments. The study will help determine the relative effectiveness of different depression treatments in reducing suicidal thoughts and actions.

* Wayne Goodman, M.D., of the University of Florida, will investigate if and how SSRIs may induce in some young people an “activation syndrome”–a set of symptoms such as irritability, agitation and mood swings that may lead to suicidal thoughts or actions. He will study this potential syndrome among pediatric patients diagnosed with obsessive compulsive disorder. By focusing on patients with a disorder that is less likely to be associated with suicidality, he will be able to better assess whether SSRIs are related to an actual activation syndrome, and whether suicidality is a component of the syndrome. The study will improve recognition and understanding of the syndrome, and help identify interventions that will reduce the risk of suicide.

* Sebastian Schneeweiss, M.D., of Brigham and Women’s Hospital, will assess critical issues surrounding the safety of antidepressant medication use by comparing several large datasets of SSRI users. He will measure rates of suicidality; identify social and demographic factors that may be associated with SSRI use and suicidality; and examine the impact of FDA actions on use of SSRIs. The study aims to develop and better target prescribing and risk management strategies.

* Prudence Winslow Fisher, PhD., of the New York State Psychiatric Institute, will develop better and more reliable ways of monitoring for adverse reactions to the use of antidepressant medication. The study’s long-term goal is to construct a standardized computer tool for adolescents and parents that could be used to screen for suicidality associated with the use of antidepressant medications.

Antidepressants Associated With Increased Risk For Suicide Attempts, Decreased Risk For Death

Suicidal individuals taking antidepressant medications appear to have an increased risk of additional suicide attempts, but a reduced risk of dying from suicide or any other cause, according to a large Finnish study reported in the December issue of Archives of General Psychiatry, one of the JAMA/Archives journals.Major depression is one of the most important risk factors for suicidal behavior, according to background information in the article. However, medications used to treat depression have also been linked to suicidal attempts and behavior, especially among children and adolescents taking a type of antidepressant known as selective serotonin reuptake inhibitors (SSRIs). The issue is difficult to study because the number of completed suicides is relatively low; an effective study would have to include tens of thousands of patients and last for several years. “Because previous suicide attempts are the most important risk factor for predicting suicide, a large cohort of suicidal patients would be an obvious choice to investigate the association between antidepressant treatment and the risk of suicide,” the authors write.

Jari Tiihonen, M.D., Ph.D., University of Kuopio and Niuvanniemi Hospital, Kuopio, Finland, and colleagues analyzed data from all individuals hospitalized in Finland for suicide attempts between 1997 and 2003. Information about 15,390 hospitalized individuals - including age, sex, location, dates of admission and discharge, number of previous hospitalizations for attempted suicide and antidepressant prescriptions - was gathered through Finnish national registries and databases. The patients were followed for an average of 3.4 years to see if they attempted suicide again, completed suicide or died from another cause.

Among the 7,466 males and 7,924 females in the study, 602 suicides, 7,136 suicide attempts leading to hospitalization and 1,583 deaths were recorded during follow-up. The risk of completed suicide was 9 percent lower among those taking any antidepressants than among those not taking antidepressants. However, the association varied by antidepressant-individuals taking an SSRI known as fluoxetine had a 48 percent lower risk of suicide (6.7 deaths per 1,000 total years that individuals took the drug) compared with those not taking medication (11 deaths per 1,000 years), while those taking venlafaxine hydrochloride, another SSRI, had a 61 percent increased risk (22.5 suicide deaths per 1,000 total years of medication use). The risk of death from any cause was 31 percent to 41 percent lower among those taking antidepressants. Those taking SSRIs had a 61 percent reduced risk of death compared with those taking no antidepressants, a fact that could be attributed to a reduction in deaths related to cardiovascular disease and stroke.

Patients taking any kind of antidepressant had a 36 percent increased risk of a subsequent suicide attempt leading to hospitalization (204.7 per 1,000 total years of taking medications) compared with those taking no antidepressants (106.2 per 1,000 years); a slightly greater increase in risk was observed among those age 10 to 19 years (132.7 per 1,000 years for those taking antidepressants vs. 82.9 for those not taking antidepressants).

Among those who had ever taken antidepressants, current antidepressant use was associated with a 39 percent increase in risk of attempted suicide but a 32 percent decrease in risk of completed suicide and a 49 percent reduced risk of death from any cause. “This opposite type of effect on fatal vs. nonfatal suicidal behavior may be explained by an increased risk of intoxication because of easy availability of means (antidepressant medication), resulting in an increase in nonfatal suicidal behavior, and by a decrease in the incidence of violent and more fatal methods of suicide attempts, such as hanging and shooting,” the authors write.

To Give Or Not To Give Antidepressants To Young People

More and more children are being diagnosed with depression. However, whether or not children should be treated with antidepressants is hotly disputed. You can read a Head to Head - where one person writes in favor, while another writes against, in this week’s issue of The British Medical Journal (BMJ).Yes - Children should be given antidepressants

We should not deny depressed children one of the few evidence-based available treatments, says Andrew Cotgrove, Clinical Director and Consultant in Adolescent Psychiatry at Pine Lodge Young People’s Centre, Chester England.

The most controversial prescribing has been that of SSRIs (selective serotonin reuptake inhibitors) for children. Nevertheless, objective analysis of studies demonstrates a substantial benefit, when compared to a placebo, for some SSRIs. Guidelines recommend their use for young people with depression and OCD (obsessive-compulsive disorder).

Previous research has indicated that the use of SSRIs raises the risk of suicide related events. However, the risk is tiny and can be lessened even further with careful monitoring, Cotgrove writes.

Although cognitive behavioral therapy, interpersonal therapy and family therapy have some effect for young depressed patients, their effects are very small.

Cotgrove explains that disturbing procedural mistakes, exclusion of evidence in the conducting and reporting of some SSRI clinical trials, have justifiably alarmed doctors and members of the public. However, when one reviews the evidence carefully and objectively, the indications are that antidepressants have a role to play in treating young people with depression and OCD.

Young patients and their parents need to be told of the benefits and risks, given advice and support when choosing an evidence-based treatment. If we removed antidepressants as one of the options we would be taking away one of the few potentially effective interventions for these disabling conditions, Cotgrove concludes.

No - Children should not be given antidepressants

Prescribing SSRIs for young people is dangerous, not ethically sound, and poor value for money, writes Sami Timimi, Consultant Child and Adolescent Psychiatrist, Lincolnshire, England.

Timimi explains that as far as childhood depression is concerned, none of the SSRI studies has shown significant benefits over a placebo. Even so, national guidelines indicate the fuoxetine has more benefits than risks for young patients.

However, fluoxetine’s profile is not that different from that of other SSRIs - efficacy is small and there is a potential danger. Timimi does acknowledge that a high placebo response makes it difficult for doctors to accept that SSRIs may be ineffective when faced with a distressed young person.

Timimi adds that a combination of fuzzy reporting and marketing spin have taken precedence over scientific accuracy, which have not helped the situation.

A reason for carrying out the studies in the first place was to validate well established prescribing patterns. It led to a trend which has been hard to undo, in spite of all the evidence. This does not mean we do not reverse it - for that we must, Timimi argues. SSRIs are neither value for money, nor clinically useful, moreover a small but tragic number of deaths may have happened because of their use.

In the majority of childhood cases distress is self limiting and does not need extensive intervention. However, when intervention is needed psychotherapy has shown itself to be effective, Timimi concludes.

Antidepressants Alone: Not For Bipolar Depression

Psychiatrists have cautioned against the use of antidepressants alone in people with bipolar disorders, saying they could worsen a patient’s condition by causing a destabilisation in mood.

Dr Ajeet Singh and Professor Michael Berk, consultant psychiatrists from the University of Melbourne, state in the current edition of Australian Prescriber that the goal of treatment in bipolar disorder is to stabilise mood, and antidepressants may defeat this purpose if they are not taken with other drugs.“Patients may need an antidepressant, but this must be taken with a mood-stabilising drug. Antidepressants place patients at risk of switching to elevated phases of the disorder and rapid cycling patterns,” they say in the article.

Patients should not simply be left on antidepressants long term without review, say the authors, as there is no good evidence of efficacy in the maintenance phase. If symptoms of elevated mood emerge, the patient should have their dose of the antidepressant reduced or stopped.

Dr Singh says that health professionals should consider the diagnosis of bipolar disorder in patients with treatment-resistant or recurrent depression.

The authors also strongly recommend the need for regular review, education, self-monitoring of mood, mood diaries and social-rhythm training to assist with better long-term patient outcomes. Educating patients about lifestyle changes and a close dialogue with relatives and carers is also essential, they say.

“Including family and carers in the management plan is an important aspect of care. Continuity of care, with good communication and rapport between doctor and patient, is particularly important in fostering compliance with treatment,” the article states.

For the complete article visit the Australian Prescriber website http://www.australianprescriber.com.

Daily Use Of Antidepressants And Increased Risk Of Fracture In Older Adults Linked

Daily use of the antidepressant medications known as selective serotonin reuptake inhibitors (SSRIs) by adults 50 years and older is associated with a doubled risk of some fractures, according to a report in the January 22, 2007 issue of Archives of Internal Medicine, one of the JAMA/Archives journals.Depression affects about 10 percent of primary care patients in the United States, according to background information in the article. The use of SSRIs for the treatment of depressive symptoms is widespread due to the medication’s presumed favorable adverse effect profile. Past studies have found the use of these antidepressants to be associated with an increased risk of clinical fragility fracture (fractures due to falling from bed, chair or standing height), but did not reliably examine such factors as falls and bone mineral density, the authors note.

J. Brent Richards, M.D., of McGill University, Montreal, Quebec, and colleagues evaluated 5,008 community-dwelling adults 50 years and older who were followed up for over five years for incident fractures. Researchers examined the relationships between SSRI use, bone mineral density (BMD) and falls. Participants who used the medication at the beginning of the study and at year five were considered to be recurrent users. BMD of the lower spine and hip were measured at the beginning of the study. Patients were then sent a yearly questionnaire to determine if they had experienced clinical fragility fractures and all reported fractures were confirmed radiographically. Other factors such as demographic information, history of falls and medication use were all assessed.

Daily use of SSRIs was reported by 137 participants with an average age of 65.1 years. The researchers found that “daily SSRI use remained associated with a two-fold increased risk of incident clinical fragility fracture even after adjustment for many potential confounding variables.” These fractures occurred at the forearm (40 percent), ankle and foot (21 percent), hip (13 percent), rib (13 percent) femur (9 percent) and back (4 percent). Participants who used SSRIs at the beginning of the study had similar increased risks of fracture to those who used them at follow-up.

During the initial interview, the daily use of SSRIs was associated with an increased risk of falling. The effect was dose-dependent; doubling the daily dose of SSRIs increased the odds of falling 1.5-fold during the previous month. Daily use of SSRIs was also associated with a 4 percent decreased BMD at the total hip and a 2.4 percent decrease at the lumbar spine.

“Our results suggest that BMD and falls may be affected adversely by daily SSRI use but that fracture rates remain elevated despite adjustment for these two risk factors, indicating that other pathways, such as impaired bone quality leading to reduced bone strength, may be of particular relevance,” the authors conclude. “In light of the high rate of SSRI use among the general population, and among elderly persons in particular, further studies that include controlled prospective trials are needed to confirm our findings.”

Cognitive therapy as good as antidepressants, effects last longer

Cognitive therapy to treat moderate to severe depression works just as well as antidepressants, according to an authoritative report appearing today in the Archives of General Psychiatry. The study, conducted by researchers at the University of Pennsylvania and Vanderbilt University, challenges the American Psychiatric Association’s guidelines that antidepressant medications are the only effective treatment for moderately to severely depressed patients.Either form of treatment worked significantly better than a placebo, but the researchers demonstrated that cognitive therapy was more effective than medication at preventing relapses after the end of treatment.

“We believe that cognitive therapy might have more lasting effects because it equips patients with the tools they need to learn how to manage their problems and emotions,” said Robert DeRubeis, professor and chair of Penn’s Department of Psychology. “Pharmaceuticals, while effective, offer no long term cure for the symptoms of depression. For many people, cognitive therapy might prove to be the preferred form of treatment.”

The study, which follows years of debate on the relative merits of cognitive therapy versus medication for more severe forms of depression, is the largest trial yet undertaken on the topic; it involved 240 depressed patients. The patients were randomly placed into groups that received cognitive therapy, antidepressant medication or a placebo. Patients in the antidepressant group, which was twice as large as the other two, were treated with paroxetine (Paxil). Lithium or desipramine was also given, as necessary.

After 16 weeks of treatment, patients in both the medication and cognitive therapy groups showed improvement at about the same rate; however, cognitive therapy patients were less likely to relapse in the two years following the end of treatment. According to the researchers, the return of symptoms might demonstrate that the medication may have blunted the appearance of depression but did not affect underlying disease processes.

“Medication is often an appropriate treatment, but drugs have drawbacks, such as side effects or a diminished efficacy over time,” DeRubeis said. “Patients with depression are often overwhelmed by other factors in their life that pills simply cannot solve. In many cases, cognitive therapy succeeds because it teaches the skills that help people cope.”

The researchers also noted slight differences in the response to treatment between the two testing locations, with cognitive therapy performing better at Penn and medications performing better at Vanderbilt. Researchers surmise that the medication worked so well at the Vanderbilt clinic because more of the patients there were markedly anxious, in addition to being depressed, and the medications used in the research have anti-anxiety properties.

The researchers further believe that cognitive therapy patients might have done better at Penn due to the experience level of the therapists involved. Just as the experience of therapists may be important in cognitive therapy, so, too, can the expertise of prescribing physicians play a role in the success of antidepressant medication treatment. Studies have shown that antidepressant medication dosages are still largely a matter of physicians’ discretion.

“Clearly, cognitive therapy is not for everyone, and its success could depend on variables such as the expertise of the therapist and the patient’s willingness or ability to take the therapy to heart,” DeRubeis said. “The key to establishing any form of treatment is rating its effectiveness in comparison to treatments currently in use, and this study has shown cognitive therapy to be a viable alternative.”

Clinical researchers at the Penn School of Medicine’s Department of Psychiatry involved in the study were Jay D. Amsterdam, Paula R. Young, John P. O’Reardon and Madeline M. Gladis. Vanderbilt researchers include Steven D. Hollon of the Department of Psychology and Richard C. Shelton, Ronald M. Salomon, Margaret L. Lovett, and Laurel L. Brown of the Department of Psychiatry. Contributing author Robert Gallop is with West Chester University’s Department of Mathematics and Applied Statistics.

The work was supported by a grant from the National Institutes of Health. GlaxoSmithKline provided medication and placebos.

Ads for SSRI antidepressants are misleading, say researchers

Consumer ads for a class of antidepressants called SSRIs often claim that depression is due to a chemical imbalance in the brain, and that SSRIs correct this imbalance, but these claims are not supported by scientific evidence, say researchers in PLoS Medicine.
Although scientists in the 1960s suggested that depression may be linked to low brain levels of the chemical serotonin (the so-called “serotonin hypothesis”), contemporary research has failed to confirm the hypothesis, they say.

The researchers–Jeffrey Lacasse, a doctoral candidate at Florida State University and Dr. Jonathan Leo, a neuroanatomy professor at Lake Erie College of Osteopathic Medicine–studied US consumer advertisements for SSRIs from print, television, and the Internet. They found widespread claims that SSRIs restore the serotonin balance of the brain. “Yet there is no such thing as a scientifically established correct ‘balance’ of serotonin,” the authors say.

According to Lacasse and Leo, in the scientific literature it is openly admitted that the serotonin hypothesis remains unconfirmed and that there is “a growing body of medical literature casting doubt on the serotonin hypothesis,” which is not reflected in the consumer ads.

For instance, the widely televised animated Zoloft (setraline) commercials have dramatized a serotonin imbalance and stated, “Prescription Zoloft works to correct this imbalance.” Advertisements for other SSRIs, such as Prozac (fluoxetine), Paxil (paroxetine), and Lexapro (escitalopram), have made similar claims.

In the US, the FDA is responsible for regulating consumer advertisements, and requires that they be based on scientific evidence. Yet, according to Lacasse and Leo, the mismatch between the scientific literature and the SSRI advertisements is “remarkable, and possibly unparalleled.”

And while the Irish equivalent of the FDA, the Irish Medicines Board, recently banned GlaxoSmithKline from claiming in their patient information leaflets that paroxetine (Paxil) corrects a chemical imbalance, the FDA has never taken any similar action on this issue.

Commenting on Lacasse and Leo’s work, Professor David Healy of the North Wales Department of Psychological Medicine, said: “The serotonin theory of depression is comparable to the masturbatory theory of insanity. Both have been depletion theories, both have survived in spite of the evidence, both contain an implicit message as to what people ought to do. In the case of these myths, the key question is whose interests are being served by a widespread promulgation of such views rather than how do we test this theory.”

Dr Joanna Moncrieff, Senior Lecturer in Psychiatry at University College London, said: “It is high time that it was stated clearly that the serotonin imbalance theory of depression is not supported by the scientific evidence or by expert opinion. Through misleading publicity the pharmaceutical industry has helped to ensure that most of the general public is unaware of this.”

Citation: Lacasse JR, Leo J (2005) Serotonin and depression: A disconnect between the advertisements and the scientific literature.
PLoS Med 2(12): e392.

SOURCE: http://www.plosmedicine.org

Pitt Study Of Pregnant Women Shows Antidepressants, Depression May Raise Risk Of Premature Birth

Pregnant women who had untreated major depression in all three trimesters of pregnancy, as well as those who took certain antidepressants, had preterm birth rates exceeding 20 percent, according to a study by University of Pittsburgh School of Medicine researchers published in the March issue of American Journal of Psychiatry. Approximately 10-to-20 percent of women struggle with symptoms of major depression during their pregnancies, but treating it can be complicated. Selective serotonin reuptake inhibitor (SSRI) antidepressants are usually the first line of depression treatment, but can lead to unwanted outcomes such as preterm births if used continuously throughout pregnancy, the findings suggest.

“It is well-known that the prevalence of depression in women is highest during the childbearing years, and treating the symptoms with SSRIs is a common medical therapy,” said Katherine L. Wisner, M.D., M.S., director of the Women’s Behavioral HealthCARE program at Western Psychiatric Institute and Clinic of UPMC, associate investigator at Magee-Womens Research Institute, and professor of psychiatry, obstetrics, gynecology and reproductive sciences and epidemiology at the University of Pittsburgh School of Medicine. “However, given the similarity in outcomes we found for continuous SSRI treatment and continuous depression, it is possible that underlying depressive disorder is a factor in preterm birth among women taking SSRIs.”

Throughout this prospective study, researchers followed 238 women with no, partial, and continuous exposure to either depression or SSRI treatment during pregnancy and compared neonatal outcomes. They found that women exposed to either continuous SSRI treatment, or to continuous depression with no SSRI treatment, had comparable levels of increased risk for preterm birth at 21 percent and 23 percent, respectively. However, women with no exposure to either depression or SSRI medication had lower rates of preterm births, around 6 percent.

The researchers also discovered that either depression or SSRI treatment did not affect the baby’s birth weight or the mother’s weight gain during pregnancy or influence the rate of minor physical birth defects in the infant.

Previous studies have associated both depression and SSRIs with an increased risk for miscarriage. But taking these antidepressants during pregnancy does not greatly increase the overall risk of birth defects, noted Dr. Wisner.

While the results add more evidence linking SSRI treatment to risk of preterm birth, the risk of untreated depression conveys no less risk and suggests that factors independently related to both the disease and its treatment are associated with preterm birth.

“The relationship of preterm birth to depression and SSRI exposure must be clarified through further research,” said Dr. Wisner. “In the meantime, it is recommended that each pregnant woman consult with her doctor to weigh the benefits and risks of depression treatment with antidepressants.”

Co-authors of the study include Dorothy K.Y. Sit, M.D., Barbara H. Hanusa, Ph.D., Eydie L. Moses-Kolko, M.D., Debra L. Bogen, M.D., Diane F. Hunker, R.N., James M. Perel, Ph.D., Sonya Jones-Ivy, M.D., Lisa M. Bodnar, Ph.D., all from WPIC and the University of Pittsburgh Department of Psychiatry; and Lynn T. Singer, Ph.D., from Case Western Reserve University.

This study was supported in part by funding provided by the National Institute of Mental Health.

Western Psychiatric Institute and Clinic (WPIC) is considered to be one of the nation’s foremost university-based psychiatric care facilities and one of the world’s leading centers for research and treatment of mental health disorders. WPIC houses the Department of Psychiatry of the University of Pittsburgh School of Medicine and is the flagship of UPMC Behavioral Health, the psychiatric specialty division of the University of Pittsburgh Medical Center.

Soil Bacteria Work In Similar Way To Antidepressants

UK scientists suggest that a type of friendly bacteria found in soil may affect the brain in a similar way to antidepressants.

Their findings are published in the early online edition of the journal Neuroscience.

Researchers from Bristol University and University College London discovered using laboratory mice, that a “friendly” bacteria commonly found in soil activated brain cells to produce the brain chemical serotonin and altered the mice’s behaviour in a similar way to antidepressants.

They are suggesting this could explain why immune system imbalance could make some people vulnerable to mood disorders like depression.

Lead author, Dr Chris Lowry from Bristol University said, “These studies help us understand how the body communicates with the brain and why a healthy immune system is important for maintaining mental health”.

“They also leave us wondering if we shouldn’t all be spending more time playing in the dirt,” he added.

Dr Lowry and colleagues became interested in the project when they heard that cancer patients treated with the bacterium Mycobacterium vaccae reported increases in their quality of life. They speculated this could be because the bacteria were activating brain cells to release more serotonin.

When they treated mice with Mycobacterium vaccae they found that it did indeed activate a particular group of brain neurons that produce serotonin - in the interfascicular part of the dorsal raphe nucleus (DRI) of the mice, to be precise. They established this by measuring the amount of c-Fos in the area, a biochemical marker whose presence indicates that serotonin releasing neurons have fired.

Serotonin, also known as 5-HT (short for 5-hydroxytryptamine), is found in the gut, brain, nerves and blood of humans and other animals. There are 14 different receptors that bind to serotonin each working a different property of this highly multi-functional chemical messenger.

Apart from having a range of pharmacological actions, serotonin constricts blood vessels, sends messages between cells in the brain and within the central nervous system, regulates secretion of digestive juices, and helps to control the passage of food through the gut.

Different parts of the brain and the body need different levels of serotonin. In the brain for example, the hypothalamus (involved in mood regulation) needs a lot of serotonin while the cortex (involved in many complex processes like thinking, memory, attention, awareness and consciousness) only needs a little.

The brain keeps serotonin levels in balance using at least three mechanisms. One way is by releasing it, a second way is by inactivating it once it is released into the synaptic space between the nerve endings, and the third way is by absorbing it, a process known as “reuptake”.

Low levels of serotonin are linked with a number of disorders including aggression, anxiety, depression, obsessive compulsive disorder (OCD), bipolar disorder, irritable bowel and fibromyalgia.

Antidepressants work by increasing serotonin levels in particular areas of the brain. One type, known as monoamine oxidase (MAO) inhibitors reduce the brain’s ability to inactivate the free serotonin. Another type, called selective serotonin reuptake inhibitors (SSRIs) work by slowing down the reuptake process.

The friendly bacteria in this study appear to be having an antidepressant effect in a third way, by increasing the release of serotonin.Soil Bacteria Work In Similar Way To Antidepressants

Divorce, Antidepressants, Or Weight Gain/Loss Can Add Years To Your Face

Your mother’s wrinkles — or lack there of, may not be the best predictor of how you’ll age. In fact, a new study claims just the opposite. The study, involving identical twins, suggests that despite genetic make-up, certain environmental factors can add years to a person’s perceived age. Results just published on the web-based version of Plastic and Reconstructive Surgery(R), the official medical journal of the American Society of Plastic Surgeons (ASPS), reveal that factors like divorce or the use of antidepressants are the real culprits that can wreak havoc on one’s face.

“A person’s heritage may initially dictate how they age - but if you introduce certain factors into your life, you will certainly age faster. Likewise, if you avoid those factors you can slow down the hands of time,” said ASPS Member Surgeon and study author Bahaman Guyuron, M.D., professor and chairman, department of plastic surgery, University Hospitals Case Medical Center. “In this study, we looked at identical twins because they are genetically programmed to age exactly the same, and in doing so we essentially discovered that, when it comes to your face, it is possible to cheat your biological clock.”

During the study, Dr. Guyuron and his colleagues obtained comprehensive questionnaires and digital images from 186 pairs of identical twins. The images were reviewed by an independent panel, which then recorded the perceived age difference between the siblings.

Results showed that twins who had been divorced appeared nearly 2 years older than their siblings who were married, single or even widowed. Antidepressant use was associated with a significantly older appearance and researchers also found that weight played a major factor too. In those sets of twins who were less than 40 years old, the heavier twin was perceived as being older, while in those groups over 40 years old, the heavier twin appeared younger.

According to Dr. Guyuron, “the presence of stress could be one of the common denominators in those twins who appeared older.” Additionally, researchers suspect that continued relaxation of the facial muscles due to antidepressant use, could account for sagging. And though they do not advocate gaining weight to look younger, researchers note that losing abnormal amounts of weight not only have harmful effects on a person’s health, but on their appearance, too.

“This research is important for two reasons,” Dr. Guyuron said. “First, we have discovered a number of new factors that contribute to aging and second, our findings put science behind the idea that volume replacement rejuvenates the face.”

According to ASPS statistics, there were more than 1.5 million injectable filler procedures performed in 2007.

The American Society of Plastic Surgeons is the largest organization of board-certified plastic surgeons in the world. Representing more than 6,700 physician members, the Society is recognized as a leading authority and information source on cosmetic and reconstructive plastic surgery. ASPS comprises more than 94 percent of all board-certified plastic surgeons in the United States. Founded in 1931, the Society represents physicians certified by The American Board of Plastic Surgery or The Royal College of Physicians and Surgeons of Canada.

American Society of Plastic Surgeons
http://www.plasticsurgery.org