Do antidepressants impair the ability to extinguish fear?

Contact: Rhiannon Bugno Biol.Psych@utsouthwestern.edu 214-648-0880 Elsevier

Answers from a new study in Biological Psychiatry

An interesting new report of animal research published in Biological Psychiatry suggests that common antidepressant medications may impair a form of learning that is important clinically.

Selective serotonin reuptake inhibitors, commonly called SSRIs, are a class of antidepressant widely used to treat depression, as well as a range of anxiety disorders, but the effects of these drugs on learning and memory are poorly understood.

In a previous study, Nesha Burghardt, then a graduate student at New York University, and her colleagues demonstrated that long-term SSRI treatment impairs fear conditioning in rats. As a follow-up, they have now tested the effects of antidepressant treatment on extinction learning in rats using auditory fear conditioning, a model of fear learning that involves the amygdala. The amygdala is a region of the brain vitally important for processing memory and emotion.

They found that long-term, but not short-term, SSRI treatment impairs extinction learning, which is the ability to learn that a conditioned stimulus no longer predicts an aversive event.

“This impairment may have important consequences clinically, since extinction-based exposure therapy is often used to treat anxiety disorders and antidepressants are often administered simultaneously,” said Dr. Burghardt. “Based on our work, medication-induced impairments in extinction learning may actually disrupt the beneficial effects of exposure-therapy.”

This finding is consistent with the results of several clinical studies showing that combined treatment can impede the benefits of exposure therapy or even natural resilience to the impact of traumatic stress at long-term follow-up.

The authors also suggest a mechanism for this effect on fear learning. They reported that the antidepressants decreased the levels of one of the subunits of the NMDA receptor (NR2B) in the amygdala. The NMDA receptor is critically involved in fear-related learning, so these reductions are believed to contribute to the observed effects.

Dr. John Krystal, Editor of Biological Psychiatry, commented, “We know that antidepressants play important roles in the treatment of depression and anxiety disorders. However, it is important to understand the limitations of these medications so that we can improve the effectiveness of the treatment for these disorders.”

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The article is “Chronic Antidepressant Treatment Impairs the Acquisition of Fear Extinction” by Nesha S. Burghardt, Torfi Sigurdsson, Jack M. Gorman, Bruce S. McEwen, and Joseph E. LeDoux (doi: 10.1016/j.biopsych.2012.10.012). The article appears in Biological Psychiatry, Volume 73, Issue 11 (June 1, 2013), published by Elsevier.

Notes for Editors

Full text of the article is available to credentialed journalists upon request; contact Rhiannon Bugno at +1 214 648 0880 or Biol.Psych@utsouthwestern.edu. Journalists wishing to interview the authors may contact Nesha S. Burghardt at nsb2113@columbia.edu.

The authors’ affiliations, and disclosures of financial and conflicts of interests are available in the article.

John H. Krystal, M.D., is Chairman of the Department of Psychiatry at the Yale University School of Medicine and a research psychiatrist at the VA Connecticut Healthcare System. His disclosures of financial and conflicts of interests are available here.

About Biological Psychiatry

Biological Psychiatry is the official journal of the Society of Biological Psychiatry, whose purpose is to promote excellence in scientific research and education in fields that investigate the nature, causes, mechanisms and treatments of disorders of thought, emotion, or behavior. In accord with this mission, this peer-reviewed, rapid-publication, international journal publishes both basic and clinical contributions from all disciplines and research areas relevant to the pathophysiology and treatment of major psychiatric disorders.

The journal publishes novel results of original research which represent an important new lead or significant impact on the field, particularly those addressing genetic and environmental risk factors, neural circuitry and neurochemistry, and important new therapeutic approaches. Reviews and commentaries that focus on topics of current research and interest are also encouraged.

Biological Psychiatry is one of the most selective and highly cited journals in the field of psychiatric neuroscience. It is ranked 5th out of 129 Psychiatry titles and 16th out of 243 Neurosciences titles in the Journal Citations Reports® published by Thomson Reuters. The 2011 Impact Factor score for Biological Psychiatry is 8.283.

About Elsevier

Elsevier is a world-leading publisher of scientific, technical and medical information products and services. The company works in partnership with the global science and health communities to publish more than 2,000 journals, including The Lancet and Cell, and close to 20,000 book titles, including major reference works from Mosby and Saunders. Elsevier’s online solutions include SciVerse ScienceDirect, SciVerse Scopus, Reaxys, MD Consult and Nursing Consult, which enhance the productivity of science and health professionals, and the SciVal suite and MEDai’s Pinpoint Review, which help research and health care institutions deliver better outcomes more cost-effectively.

A global business headquartered in Amsterdam, Elsevier employs 7,000 people worldwide. The company is part of Reed Elsevier Group PLC, a world-leading publisher and information provider, which is jointly owned by Reed Elsevier PLC and Reed Elsevier NV. The ticker symbols are REN (Euronext Amsterdam), REL (London Stock Exchange), RUK and ENL (New York Stock Exchange).

Why your brain tires when exercising : Excess Serotonin shuts down the brain causing fatigue

 

A marathon runner approaches the finishing line, but suddenly the sweaty athlete collapses to the ground. Everyone probably assumes that this is because he has expended all energy in his muscles. What few people know is that it might also be a braking mechanism in the brain which swings into effect and makes us too tired to continue. What may be occurring is what is referred to as ‘central fatigue’.

“Our discovery is helping to shed light on the paradox which has long been the subject of discussion by researchers. We have always known that the neurotransmitter serotonin is released when you exercise, and indeed, it helps us to keep going. However, the answer to what role the substance plays in relation to the fact that we also feel so exhausted we have to stop has been eluding us for years. We can now see it is actually a surplus of serotonin that triggers a braking mechanism in the brain. In other words, serotonin functions as an accelerator but also as a brake when the strain becomes excessive,” says Associate Professor Jean-François Perrier from the Department of Neuroscience and Pharmacology, who has spearheaded the new research.

Help in the battle against doping

Jean-François Perrier hopes that mapping the mechanism that prompts central fatigue will be useful in several ways. Central fatigue is a phenomenon which has been known for about 80 years; it is a sort of tiredness which, instead of affecting the muscles, hits the brain and nervous system. By conducting scientific experiments, it is possible to observe and measure that the brain sends insufficient signals to the muscles to keep going, which in turn means that we are unable to keep performing. This makes the mechanism behind central fatigue an interesting area in the battle against doping, and it is for this reason that Anti Doping Danmark has also helped fund the group’s research.

“In combating the use of doping, it is crucial to identify which methods athletes can use to prevent central fatigue and thereby continue to perform beyond what is naturally possible. And the best way of doing so is to understand the underlying mechanism,” says Jean-François Perrier.

Developing better drugs

The brain communicates with our muscles using so-called motoneurons (see fact box). In several diseases, motoneurons are hyperactive. This is true, for example, of people suffering from spasticity and cerebral palsy, who are unable to control their movements. Jean-François Perrier therefore hopes that, in the long term, this new knowledge can also be used to help develop drugs against these symptoms and to find out more about the effects of antidepressants.

“This new discovery brings us a step closer to finding ways of controlling serotonin. In other words, whether it will have an activating effect or trigger central fatigue. It is all about selectively activating the receptors which serotonin attaches to,” explains Jean-François Perrier.

“For selective serotonin re-uptake inhibitor (SSRI) drugs which are used as antidepressants, we can possibly help explain why those who take the drugs often feel more tired and also become slightly clumsier than other people. What we now know can help us develop better drugs,” concludes Jean-François Perrier.

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The new results have just been published in the renowned scientific journal PNAS. Read the article ‘Serotonin spillover onto the axon initial segment of motoneurons induces central fatigue by inhibiting action potential initiation’. DOI: 10.1073 PNAS article #: 201216150.

CONTACT

Associate Professor Jean-François Perrier Department of Neuroscience and Pharmacology University of Copenhagen Telephone: +45 23 81 27 46 E-mail: Perrier@sund.ku.dk Skype: jfoboulot

Jean-François Perrier will be travelling until March 11. If you cannot reach him by phone, send him an email and he will call you back.

 

Communications Officer

Louise Graa Christensen Faculty of Health and Medical Sciences University of Copenhagen Mobile: +45 24 34 03 22 E-mail: louise.christensen@sund.ku.dk

FACTS

About the research

In addition to Jean-François Perrier, the research team responsible for mapping the braking mechanism includes Florence Cotel and two researchers from the University of Oxford (Stephanie Cragg and Richard Exley). In order to be able to study the motoneurons, the researchers have studied large American turtles. This is because the adult turtle’s spinal marrow, where the motoneurons are found, is accessible to experimentation but also resemble conditions in humans. It is in precisely this respect that that results obtained from  cross-sections of the spinal marrow in turtles, help researchers to understand central fatigue in the nervous system of humans.

Masterful motoneurons

In the human brain there are about 100 billion nerve cells, or neurons. Each neuron consists of a cell body with dendrites and a nerve fiber called the axon, and they communicate with one another via synapses. Nerve cells use nerve impulses to send signals with the axon from the cell body to the nerve ends, which form synapses with the dendrites of the receiving cell.

A special kind of neuron, the motoneurons, are extremely important as they are responsible for ensuring contact between the brain and the muscles. Every time a motoneuron sends impulses to the muscles, it leads to the contraction of the muscle fibres contacted and thus a movement. In order to control the body’s movements, the brain has to be able to control the impulse activity in groups of motoneurons so they are activated in the right sequence and to the right degree. It is here that serotonin plays a role as one of the neurotransmitters which are released from the synapses during the brain’s ingenious control of the motoneurons and thereby our patterns of movement.

Serotonin and central fatigue

Serotonin is well known for being involved in many different human functions: Appetite, sleep, sex and motor control. Serotonin is released as soon as you start moving, and the more you move, the more serotonin is released. In other words, serotonin functions as an accelerator for movement and makes the motoneurons more active. However, when large amounts of serotonin are released, it causes a glut at the synapses through which the neurons communicate. This means that the serotonin starts binding with the receptors lying outside the synapses. Some of these receptors sit at the initial part of the axon, i.e. where nerve impulses are formed. And when the serotonin activates these receptors, the nerve impulse is obstructed, the result being that the muscle contraction is weakened and fatigue occurs

Common antidepressant drugs linked to lactation difficulties in moms

2010 study posted for filing

Contact: Aaron Lohr alohr@endo-society.org 240-482-1380 The Endocrine Society

According to a new study accepted for publication in The Endocrine Society’s Journal of Clinical Endocrinology & Metabolism (JCEM), women taking commonly used forms of antidepressant drugs may experience delayed lactation after giving birth and may need additional support to achieve their breastfeeding goals.

Breastfeeding benefits both infants and mothers in many ways as breast milk is easy to digest and contains antibodies that can protect infants from bacterial and viral infections. The World Health Organization recommends that infants should be exclusively breastfed for the first six months of life. This new study shows that certain common antidepressant drugs may be linked to a common difficulty experienced by new mothers known as delayed secretory activation, defined as a delay in the initiation of full milk secretion.

“The breasts are serotonin-regulated glands, meaning the breasts’ ability to secrete milk at the right time is closely related to the body’s production and regulation of the hormone serotonin,” said Nelson Horseman, PhD, of the University of Cincinnati and co-author of the study. “Common antidepressant drugs like fluoxetine, sertraline and paroxetine are known as selective serotonin reuptake inhibitor (SSRI) drugs and while they can affect mood, emotion and sleep they may also impact serotonin regulation in the breast, placing new mothers at greater risk of a delay in the establishment of a full milk supply.”

In this study, researchers examined the effects of SSRI drugs on lactation using laboratory studies of human and animal cell lines and genetically modified mice. Furthermore, an observational study evaluated the impact of SSRI drugs on the onset of milk production in postpartum women. In this study of 431 postpartum women, median onset of lactation was 85.8 hours postpartum for the SSRI-treated mothers and 69.1 hours for mothers not treated with SSRI drugs. Researchers commonly define delayed secretory activation as occurring later than 72 hours postpartum.

“SSRI drugs are very helpful medications for many moms, so understanding and ameliorating difficulties moms experience can help them achieve their goals for breastfeeding their babies,” said Horseman. “More human research is needed before we can make specific recommendations regarding SSRI use during breastfeeding.”

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Other researchers working on the study include: Aaron Marshall, Laura Hernandez and Karen Gregerson of the University of Cincinnati in Ohio; Laurie Nommsen-Rivers of Cincinnati Children’s Hospital Medical Center in Ohio; Kathryn Dewey of the University of California at Davis; and Caroline Chantry of the University of California Davis Medical Center in Sacramento.

The article, “Serotonin transport and metabolism in the mammary gland modulates secretory activation and involution,” will appear in the February 2010 issue of JCEM.

Founded in 1916, The Endocrine Society is the world’s oldest, largest and most active organization devoted to research on hormones and the clinical practice of endocrinology. Today, The Endocrine Society’s membership consists of over 14,000 scientists, physicians, educators, nurses and students in more than 100 countries. Society members represent all basic, applied, and clinical interests in endocrinology. The Endocrine Society is based in Chevy Chase, Maryland. To learn more about the Society and the field of endocrinology, visit our site at www.endo-society.org.

141st Health Research Report 02 NOV 2012

 

Editors Top Five:

 

1. Study: Flame Retardant ‘Firemaster 550’ Is an Endocrine Disruptor (Major Weight Gain)

2. Feinstein Institute researchers discover that bean used in Chinese food could protect against sepsis

3. Drop in testosterone tied to prostate cancer recurrence

4. Study suggests too much risk associated with SSRI usage and pregnancy

5. Researchers discover watching horror films can help you burn equivalent of a chocolate bar, with The Shining burning most

 

 

 

 

In this issue:

 

1. Task Force Recommends Against Hormone Replacement Therapy for Postmenopausal Women

2. Antibiotics not effective for cough due to ‘common cold’ in children

3. Exercise may trump mental activity in protecting against brain shrinkage

4. Selenium deficiency may cause cardiomyopathy post-gastric bypass

5. Crusty foods may worsen heart problems associated with diabetes

6. New vitamin-based treatment that could reduce muscle degeneration in muscular dystrophy

7. Study: Flame Retardant ‘Firemaster 550’ Is an Endocrine Disruptor (Major Weight Gain)

8. Scripps Research Institute Study Suggests Caution and Further Studies on Drugs Used to Treat Macular Degeneration

9. Researchers develop cocktail of bacteria that eradicates Clostridium difficile infection

10. Feinstein Institute researchers discover that bean used in Chinese food could protect against sepsis

11. Drop in testosterone tied to prostate cancer recurrence

12. Exercise is smart for your heart – and makes you smarter

13. New study reveals that every single junk food meal damages your arteries

14. Common food preservative may slow, even stop tumor growth

15. Study suggests too much risk associated with SSRI usage and pregnancy

16. Men who do exercise produce better quality semen

17. Green tea found to reduce rate of some GI cancers

18. Researchers discover watching horror films can help you burn equivalent of a chocolate bar, with The Shining burning most

Health Research Report

141st Issue Date 02 NOV 2012

Compiled By Ralph Turchiano

www.healthresearchreport.me www.vit.bz

www.youtube.com/vhfilm www.facebook.com/engineeringevil

www.engineeringevil.com

 

Study suggests too much risk associated with SSRI usage and pregnancy: Elevated risk of miscarriage, preterm birth, neonatal health complications and possible longer term neurobehavioral abnormalities, including autism

Contact: Kelly Lawman klawman@bidmc.harvard.edu 617-667-7305 Beth Israel Deaconess Medical Center

Antidepressants should only be prescribed with great caution

BOSTON – Elevated risk of miscarriage, preterm birth, neonatal health complications and possible longer term neurobehavioral abnormalities, including autism, suggest that a class of antidepressants known as selective serotonin reuptake inhibitors (SSRI) should only be prescribed with great caution and with full counseling for women experiencing depression and attempting to get pregnant, say researchers at Beth Israel Deaconess Medical Center, Tufts Medical Center and MetroWest Medical Center.

“Depression and infertility are two complicated conditions that more often than not go hand in hand. And there are no definitive guidelines for treatment,” says lead author Alice Domar, Ph.D, Obstetrics and Gynecology, Beth Israel Deaconess Medical Center and Executive Director of the Domar Center for Mind/Body Health at Boston IVF. “We hope to provide a useful analysis of available data to better inform decisions made by women and the providers who care for them.”

Domar and colleagues conducted a review of published studies evaluating women with depressive symptoms who took antidepressants while pregnant. The results appear online October 31 in the journal Human Reproduction.

“There are three main points that stand out from our review of the scientific studies on this topic,” says senior author Adam Urato, MD, Chairman of Obstetrics and Gynecology at MetroWest Medical Center and a Maternal-Fetal Medicine specialist at Tufts Medical Center. “First, there is clear and concerning evidence of risk with the use of the SSRI antidepressants by pregnant women, evidence that these drugs lead to worsened pregnancy outcomes. Second, there is no evidence of benefit, no evidence that these drugs lead to better outcomes for moms and babies. And third, we feel strongly that patients, obstetrical providers, and the public need to be fully aware of this information.”

Over the last 20 years antidepressant usage has increased 400 percent. Antidepressants are now the most commonly prescribed medication in the United States for people between 18 and 44 years of age, the childbearing years for most women. And as women enter their late 30s and early 40s they are more likely to experience infertility.

“According to the Centers for Disease Control, more than 1 percent of the babies born in the USA each year are the result of an IVF cycle,” write the authors. “And most women will report symptoms of depression during infertility treatment, especially following unsuccessful treatment cycles.”

As many as 11 percent of women undergoing fertility treatment report taking an SSRI to combat depressive symptoms, but Domar and colleagues found no evidence of improved pregnancy outcomes with antidepressant usage, and in fact, found the opposite. They also found plenty of controversy around SSRI efficacy. Many studies found SSRIs to be no more effective or only slightly more effective than placebos in treating depression. “More broadly, there is little evidence of benefit from the antidepressants prescribed for the majority of women of childbearing age–and there is ample evidence of risk,” the authors write.

For starters, there is mounting evidence that SSRIs may decrease pregnancy rates for women undergoing fertility treatment. Additionally, studies consistently show that women using antidepressants experience increased rates of miscarriage. There is also a strong signal of congenital abnormalities, the most noted of which is the association between the use of the antidepressant, Paxil, and cardiac defects. In 2005, this association prompted the FDA to ask Paxil’s manufacturer, GlaxoSmithKline to change Paxil’s risk factor from a C to a D, where a D rating indicates a demonstrated risk to the fetus.

“Preterm birth is, perhaps, the most pressing obstetrical complication,” write the authors. In more than 30 studies, the evidence overwhelmingly points to increased risk for early delivery in women who are taking antidepressants. “This is a significant finding because we know that babies born before 37 weeks are at risk for many short and long-term health problems,” says Urato. “Caring for premature babies adds up to billions of dollars in healthcare expenditures.”

Available data also suggests that antidepressant usage, especially if it extends beyond the first trimester, leads to an increased risk of pregnancy-induced hypertension and preeclampsia. “Given the importance of the hypertensive disorders of pregnancy in terms of maternal and newborn morbidity and mortality, and the widespread use of antidepressants during pregnancy, further investigation into this area will be essential,” write the authors.

Similarly, long-term exposure to SSRIs appears to correspond to an increased incidence of birth weight falling below the 10th percentile, coupled with increased rates of respiratory distress.

The health complications associated with antidepressant usage can be carried into infancy and beyond. A 2006 study showed that infants exposed to antidepressants in utero had a 30 percent risk of Newborn Behavioral Syndrome, most commonly associated with persistent crying, jitteriness and difficulty feeding. In more rare instances the syndrome can produce seizures and breathing difficulties leading to the need for intubation. Studies have also shown delayed motor development in babies and toddlers. And a Kaiser Permanente study showed a “two-fold increased risk of autism spectrum disorders associated with maternal treatment with SSRI antidepressants during the pregnancy, with the strongest effect associated with treatment during the first trimester.”

“There is enough evidence to strongly recommend that great caution be exercised before prescribing SSRI antidepressants to women who are pregnant or who are attempting to get pregnant, whether or not they are undergoing infertility treatment,” says Domar. “We want to stress that depressive symptoms should be taken seriously and should not go untreated prior to or during pregnancy, but there are other options out there that may be as effective, or more effective than SSRIs without all the attendant risks.”

Domar and team looked at studies assessing different treatment modalities for depression in the general population, including psychotherapy, exercise, relaxation training, yoga, acupuncture and nutritional supplements. While many of these options were shown to provide some benefit, psychotherapy, specifically cognitive behavioral therapy (CBT) showed the most promise. “There is overwhelming evidence that CBT is equivalent to antidepressant medication in the treatment of mild to moderate depression and more recent research indicates that it is effective in the treatment of severe depression as well,” write the authors.

A 2008 study showed impressive results for CBT in depressed women undergoing infertility treatments. The results showed that 79 percent of women who received CBT reported a significant decrease in symptoms, compared with 50 percent of women in the medication group.

“These alternative treatment options may not be appropriate for everyone, still we think it’s important for women on an antidepressant who are considering becoming pregnant to have a conversation with their physician about the risks and benefits of continuing to take their medication,” says Domar. “Because at this point in time, with no data to indicate an advantage to taking an SSRI during pregnancy, the research all points to increased risk.”

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In addition to Domar and Urato, other co-authors include: Vasiliki A. Moragianni, MD, MS and David A. Ryley, MD of Beth Israel Deaconess Medical Center and Boston IVF.

Beth Israel Deaconess Medical Center is a patient care, teaching and research affiliate of Harvard Medical School, and currently ranks third in National Institutes of Health funding among independent hospitals nationwide. BIDMC is clinically affiliated with the Joslin Diabetes Center and is a research partner of Dana-Farber/Harvard Cancer Center. BIDMC is the official hospital of the Boston Red Sox. For more information, visit www.bidmc.org.

MetroWest Medical Center is a full-service community teaching hospital system dedicated to meeting the health care needs of the MetroWest region of Massachusetts by providing advanced care with a community touch. The 269-bed health care system — the largest between Worcester and Boston — includes Framingham Union Hospital, Leonard Morse Hospital in Natick, MetroWest HomeCare and Hospice, and The MetroWest Wellness Center, an outpatient diagnostic imaging and rehabilitation center.

Tufts Medical Center is an exceptional, not-for-profit, 415-bed academic medical center that is home to both a full-service hospital for adults and Floating Hospital for Children. Conveniently located in downtown Boston, the Medical Center is the principal teaching hospital for Tufts University School of Medicine. Floating Hospital for Children is the full-service children’s hospital of Tufts Medical Center and the principal pediatric teaching hospital of Tufts University School of Medicine. Tufts Medical Center is affiliated with seven community hospitals and with New England Quality Care Alliance, its community physicians’ network. For more information, please visit www.tuftsmedicalcenter.org.

Antidepressants linked to risk of brain bleeds: antidepressant users were about 40 to 50 percent more likely to suffer bleeding in or around the brain

Thu, 18 Oct 2012 00:18 GMT

Reuters

Oct 18 (Reuters) – People using a common class of antidepressants may have slightly increased odds of suffering bleeding in the brain – though the risk is still very small, according to a Canadian study looking at more than 500,000 people.

The antidepressants are known as selective serotonin reuptake inhibitors (SSRIs) and include widely used drugs like fluoxetine (Prozac), sertraline (Zoloft), citalopram (Celexa) and paroxetine (Paxil.)

The SSRIs have been linked to a risk of stomach bleeding, but studies have come to conflicting findings on whether SSRI users have any higher risk of hemorrhagic strokes, which happen when there is bleeding in or around the brain.

For the study, which appeared in the journal Neurology, researchers pooled the findings from 16 past studies involving more than 500,000 people who were on SSRIs or not.

Overall, antidepressant users were about 40 to 50 percent more likely to suffer bleeding in or around the brain.

But while those numbers might sound big, the risks to any one person would be “extremely low,” said lead researcher Daniel Hackam, an associate professor of medicine at Western University in London, Ontario, Canada.

Based on these figures, he said, there would be one brain hemorrhage for every 10,000 people using an SSRI over one year.

What’s more, the findings do not prove that the antidepressants directly cause brain bleeds. It’s possible, Hackham said, that SSRI users are “sicker” than non-users or have habits that put them at greater stroke risk.

The researchers tried to account for those factors in their calculations, but some of the studies they analyzed lacked key information, such as peoples’s smoking and drinking habits, and whether they had diabetes.

“We can’t infer cause and effect from this,” Hackam said.

On the other hand, there are reasons to believe it’s the medications themselves. For one, the hemorrhage risk seemed greatest in the first months after people started using an SSRI.

There’s also a biological argument. SSRIs seem to make it harder for blood cells called platelets to clump together and form clots – and there can be a big drop in a person’s platelet functions in the first weeks after starting an SSRI, he said.

Still, he stressed that people on the antidepressants should not be alarmed.

“I think that overall, these medications are quite safe,” he added.

But people who are already at increased risk of a brain hemorrhage may need to be careful. That includes people who have had a brain bleed in the past, or are on medications that reduce blood clotting. SOURCE: http://bit.ly/Q5TNI  (Reporting from New York by Amy Norton at Reuters Health; editing by Elaine Lies)

 

http://www.trust.org/alertnet/news/refile-antidepressants-linked-to-risk-of-brain-bleeds-study/

Why Antidepressants Don’t Live Up to the Hype

2009 report posted for filing

By John Cloud Wednesday, May 06, 2009

 

In the ’90s, Americans grew fond of the idea that you can fix depression simply by taking a pill – most famously fluoxetine (better known as Prozac), though fluoxetine is just one of at least seven selective serotonin reuptake inhibitors (SSRIs) that have been prescribed to treat hundreds of millions of people around the world.

 

 

But in the past few years, researchers have challenged the effectiveness of Prozac and other SSRIs in several studies. For instance, a review published in the Journal of Affective Disorders in February attributed 68% of the benefit from antidepressants to the placebo effect. Likewise, a paper published in PLoS Medicine a year earlier suggested that widely used SSRIs, including Prozac, Effexor and Paxil, offer no clinically significant benefit over placebos for patients with moderate or severe depression. Meanwhile, pharmaceutical companies maintain that their research shows that SSRIs are powerful weapons against depression. (Here’s a helpful blog post that summarizes the debate.)

 

 

Now a major new study suggests that both critics and proponents might be right about SSRIs: the drugs can work, but they appear to work best for only a subset of depressed patients – those with a limited range of psychological problems. People whose depression is compounded with, say, substance abuse or a personality disorder may not get much help from SSRIs – which is unfortunate for the 45% to 60% of patients in the U.S. who have been diagnosed with a common mental disorder like depression and also meet the criteria for at least one other disorder, like substance abuse. (Multiple diagnoses are known in medical parlance as comorbidities.)

 

 

The new study, published online in April by the American Journal of Psychiatry, was conducted using data from a large, government-funded trial called Sequenced Treatment Alternatives to Relieve Depression, which usually goes by the moniker STAR*D. The STAR*D project, which collected data from 2001 to 2004 at 41 U.S. psychiatric facilities, was one of the most ambitious efforts ever to understand how best to treat people with major depression. STAR*D participants comprise a powerful research sample because they are highly representative of all depressed Americans. Very few depressed people were excluded from STAR*D; only women who were pregnant, those with seizure disorders and a few others with acute conditions were kept out. All other psychiatric and medical comorbidities were allowed.

 

 

The authors of the new paper, a team of 11 researchers led by University of Pittsburgh professor of epidemiology Stephen Wisniewski, were curious how the STAR*D group would compare with a typical group of patients selected for a run-of-the-mill drug-company trial for a new antidepressant – the very trials on which the Food and Drug Administration bases its decisions regarding new drug approval. Drawing on their own experiences in helping to conduct such trials, which have far more stringent inclusion criteria than the STAR*D group, Wisniewski and his team divided the STAR*D patients into two groups – an “efficacy” sample of patients who would normally be included in a typical Phase III clinical trial for a new antidepressant and a “nonefficacy” sample of patients who would normally be rejected.

 

 

Depressed STAR*D patients who were classified for inclusion had no more than one general medical condition (like, say, heart disease) and no more than one additional primary psychiatric disorder besides depression. All patients with multiple comorbidities – along with anyone whose depression had lasted more than two years – were excluded. Once the authors crunched all the numbers, they found that only 22% of STAR*D patients met entry criteria for a conventional antidepressant trial.

 

 

All the STAR*D patients were taking citalopram, an SSRI marketed in North America as Celexa. Not surprisingly, those who met standard inclusion criteria for a clinical trial had significantly better outcomes on the drug. In the efficacy group, 52% responded to Celexa vs. 40% of the nonefficacy group. Patients in the latter group also took longer to respond and had to be readmitted to psychiatric settings more often. “Thus,” the authors conclude, “current efficacy trials suggest a more optimistic outcome than is likely in practice, and the duration of adequate treatment suggested by data from efficacy trials may be too short.”

 

 

To bolster their findings, the authors cite a smaller 2002 study that arrived at similar results: in that paper, published in the American Journal of Psychiatry, Dr. Mark Zimmerman of Brown University and his colleagues found that of 315 patients with major depressive disorder who sought care, only 29, or 9.2%, met typical criteria for an efficacy trial. Similarly, psychologist Ronald Kessler of Harvard co-authored a 2003 paper in the Journal of the American Medical Association that concluded that most “real world” patients with major depression would be excluded from clinical trials because of comorbidities.

 

 

Such findings help explain why antidepressants haven’t quite lived up to their promise. But the University of Pittsburgh’s Wisniewski, the lead author of the new study, cautions against interpreting the results as an indictment against greedy drug companies eager to exclude difficult patients in order to show better results. “If the population in a [clinical] trial were more representative, that would come at a cost,” he says. Researchers expect a certain number of bad reactions during clinical trials; some of these reactions can cause serious medical problems. If patients enter a trial with multiple complications – if they are, say, not only depressed, but also cocaine-addicted, hypertensive and diabetic – you dramatically increase the chances of adverse side effects. “That’s why trials to determine efficacy are done on a relatively homogeneous population,” Wisniewski says.

 

 

That’s understandable, but the new study does shed light on the limitations of antidepressants. Conducting clinical trials with representative samples would undoubtedly be more complex – and expensive – since patients with multiple risk factors would have to be monitored more carefully. But for a future generation of antidepressants to be truly effective for most patients, more-inclusive trials may be the best answer.

 

http://www.time.com/time/health/article/0,8599,1895672,00.html

Fluoxetine (Prozac) increases aggressive behavior, affects brain development among adolescent hamsters

October 1, 2012

BOSTON, Mass.—Fluoxetine was the first drug approved by the FDA for major depressive disorder (MDD) in children and adolescents, and to this date, it remains one of only two selective serotonin reuptake inhibitors (SSRIs) registered for treatment of MDD in children and adolescents, despite reports that indicate this class of drugs is associated with side effects, such as agitation, hostility and aggression.

SSRIs have been amongst the most widely prescribed medications in psychiatry for over a decade. While there is a wealth of information regarding their effectiveness and safety in adults, considerably less data exists regarding whether they are safe for children.

A study published in Behavioral Neuroscience by Prof. Richard Melloni of Northeastern University shows that repeated administration of a low dose of fluoxetine to adolescent hamsters dramatically increased offensive aggression and altered the development of brain areas directly associated with controlling the aggressive response. “These data show clearly that repeated exposure to fluoxetine during adolescence directly stimulates aggressive responding and alters the normal development of two important brain systems, i.e., the serotonin and vasopressin neural systems, in a fashion consistent with the expression of the highly aggressive behavioral characteristics.”

For over a decade, Prof. Melloni and his team have researched the neural and behavioral consequences of illicit drugs and prescribed medications on the adolescent brain. Importantly, the data collected during the study indicates that clinically relevant doses of fluoxetine, when administered during adolescent development, can dramatically alter the wiring of brain circuits implicated in aggression control.“These data support the notion that interactions between adolescent fluoxetine and the developing vasopressin neural system might underlie fluoxetine-induced aggressive behavior and hint that serotonin, perhaps by acting on vasopressin neurons, may play a more permissive role in this response.”

For more information on this study, please contact: Lori Lennon, Communications Coordinator/Senior Writer, College of Science, Northeastern University, 617/373.7686, 617/680.5129 (cell), l.lennon@neu.edu

Taking Prozac? Don’t drive: Pills raise risk of you having an accident by 70%

By Sophie Borland

PUBLISHED:19:15 EST, 12  September 2012| UPDATED:19:15 EST, 12 September 2012

 

Taking common antidepressants heightens the risk of accidents greatly 

Taking common antidepressants heightens the risk of  accidents greatly

Taking happy pills before driving makes you  more prone to accidents, researchers claim.

They have found that taking common  antidepressants such as Prozac and Seroxat heightens the risk by 70 per  cent.

Even patients who have only been on the pills  for a few hours are far more likely to have a crash if they get behind the  wheel.

Although some manufacturers put warning  notices on boxes telling patients their judgment may be impaired, they don’t  specifically tell them not to drive.

But it is now thought that the same chemical  changes that improve mood among those who take the pills also slows down  reaction times.

Researchers say the study shows that doctors  should be banning patients from getting behind the wheel as soon as they put  them on a course of drugs.

Recently the number prescriptions for  antidepressants have soared and last year nearly 50 million were handed out, a  rise of a quarter in four years.

Campaigners have blamed the economic woes but  also say GPs have become better at diagnosing the illness so are more likely to  hand out the pills.

Researchers from the University of Taiwan  looked at data on 36,000 and compared the likelihood of them having an accident  to whether they were on antidepressants.

They also looked at other drugs including  sleeping pills and antipsychotics which are taken for mental illnesses as well  as dementia.

Collectively all of these drugs are known as  psychotropic medication which means they affect mental activity or  behaviour.

Those taking a common group of  antidepressants known as selective serotonin reuptake inhibitors (SSRIs) which  include Prozac and Seroxat were 72 per cent more at risk.

Careful: It is now thought that the same chemical changes that improve moods also slow down reaction times 

Careful: It is now thought that the same chemical  changes that improve moods also slow down reaction times

Even patients who had only started the course  of drugs that day were 74 per cent more likely to have an accident within 24  hours than those not on medication.

Those on a type of sleeping pills called  benzodiazepines were 56 per cent more at risk of accidents while antipsychotics  increased the likelihood by just 9 per cent.

Lead researcher Hui-Ju Tsai, who is based at  the National Health Research Institutes in Zhunan, Taiwan, said: ‘ Our findings  underscore that people taking these psychotropic drugs should pay increased  attention to their driving performance in order to prevent motor vehicle  accidents.

‘Doctors and pharmacists should choose safer  treatments, provide their patients with accurate information and consider  advising them not to drive while taking certain psychotropic  medications

Read more: http://www.dailymail.co.uk/health/article-2202434/Taking-Prozac-Don-t-drive-Pills-raise-risk-having-accident-70.html#ixzz26Jv7cMR3

Live Vaccination against ( German Measles ) Rubella caused Signifigant Depression up to 10 weeks – Vaccines/ Bacteria Can Alter Mood and Behavior


Mood Disorders

April 30, 2007

Norman Sussman, MD, DFAPA Editor, Primary Psychiatry and Psychiatry Weekly, Professor of Psychiatry, New York University School of Medicine

There is growing interest in a suspected cause of some cases of depression: infection and inflammatory response. New research findings that add to our understanding of the interrelationship of immunology and depression, and the reasons that some currently used antidepressants work, may fundamentally change the way that mood disorders and drug therapies are conceptualized.

There are several unambiguous examples of psychiatric illness being the result of an inflammatory or immune reaction.  Considerable evidence already exists about the Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS), a disorder in which Streptoccal infection triggers an autoimmune response. The antibodies that form against the invading bacteria mistakenly recognize and “attack” certain parts of the brain, causing psychiatric symptoms.

Another notable example of immune-mediated depression is the response of some patients to treatment with Interferon α, who become profoundly depressed and suicidal. Interestingly, onset of depressive symptoms has been shown to be prevented by treatment with antidepressants that work on the serotonin system.

The involvement of immune activation and depressive-like “sickness behavior” symptoms has been suspected for many years. Evidence specifically suggests that patients with major depression exhibit changes in cytokine activity and inflammation. Immune-mediated psychological and neuroendocrine changes were observed following vaccination with live attenuated rubella virus. A subgroup of vulnerable subjects showed a significant virus-induced increase in depressed mood up to 10 weeks following their vaccination. In a related animal study, the investigators also showed that immune activation with a variety of immune challenges induced a “depressive-like syndrome in rodents: anhedonia, anorexia, body weight loess, and reduced exploratory, and social behavior.” Chronic treatment with TCAs or SSRIs attenuated many of the behavioral effects.

A team of English investigators have, for the first time, shown a possible link between administration of a vaccine, peripheral immune activation, psychological and behavioral changes, and the brain serotonin system. The researchers used antigens derived from the bacterium Mycobacterium vaccae, a generally benign and ubiquitous agent found in dirt. After vaccination, they found that the subsequent immune activation was temporally associated with increases in serotonin metabolism within the ventromedial prefrontal cortex. Treatment with the vaccine seemed to alter behavior in mice similarly as is typically seen with antidepressants. This research was initiated following observations that human cancer patients being treated with the bacteria Mycobacterium vaccae unexpectedly reported increases in their quality of life.

The identification of serotonin neurons in the dorsal raphe nucleus that are uniquely responsive to peripheral immune activation raises the possibility that one day there will be a vaccine designed to modulate the immune response which in turn will the prevent the onset or attenuate the symptoms of major depression and other psychiatric disorders

Repsoted at Request

Study: Media perpetuates unsubstantiated chemical imbalance ( Serotonin ) theory of depression

Contact: Jeffrey Lacasse jeffreylacasse@mac.com 850-294-0875 Florida State University

TALLAHASSEE, Fla. — The theory that depression is caused by a chemical imbalance is often presented in the media as fact even though there is little scientific evidence to support it, according to a new study co-authored by a Florida State University visiting lecturer.

Jeffrey Lacasse, an FSU doctoral candidate and visiting lecturer in the College of Social Work, and Jonathan Leo, a neuroanatomy professor at Lincoln Memorial University in Tennessee, found that reporters who included statements in news articles about depression being caused by a chemical imbalance, or a lack of serotonin in the brain, were unable to provide scientific evidence to support those statements.

Lacasse and Leo spent about a year in late 2006 and 2007 monitoring the daily news for articles that included statements about chemical imbalances and contacting the authors to request evidence that supported their statements. Several reporters, psychiatrists and a drug company responded to the researchers’ requests, but Lacasse and Leo said they did not provide documentation that supported the chemical imbalance theory. Their findings were published in the journal Society.

“The media’s presentation of the theory as fact is troublesome because it misrepresents the current status of the theory,” Lacasse said. “For instance, there are few scientists who will rise to its defense, and some prominent psychiatrists publicly acknowledge that the serotonin hypothesis is more metaphor than fact. As the current study documents, when asked for evidence, reporters were unable to cite peer-reviewed primary articles in support of the theory.”

Moreover, the researchers said, several of the responses received from reporters seem to suggest a fundamental misunderstanding of the theory’s scientific status. The “Diagnostic and Statistical Manual of Mental Disorders,” which almost all psychiatrists use to diagnose and treat their patients, clearly states that the cause of depression and anxiety is unknown, according to Lacasse and Leo.

The Society article builds on the pair’s 2005 study, which focused on pharmaceutical advertisements that claim depression is caused by an imbalance of serotonin — an imbalance the drug companies say can be corrected by a class of antidepressants called Selective Serotonin Reuptake Inhibitors (SSRIs).

”The chemical imbalance theory, which was formulated in the 1960s, was based on the observation that mood could be artificially altered with drugs, rather than direct observation of any chemical imbalances,” Leo said. “Since then there has been no direct evidence to confirm the theory and a significant number of findings cast doubt on the theory.”

The researchers said the popularity of the theory is in large part based on the presumed efficacy of the SSRIs, but they say that several large studies now cast doubt on this efficacy. A review of a full set of trial data published in the journal PLoS (Public Library of Science) Medicine last month concluded that much of the perceived efficacy of several of the most common SSRIs was due to the placebo effect. Other studies indicate that for every 10 people who take an SSRI, only one to two people are truly receiving benefit from the medication, according to Lacasse and Leo.

Still, the National Center for Health Statistics found that antidepressants are the most prescribed drugs in the United States, with doctors writing more than 31 million prescriptions in 2005. Both Lacasse and Leo emphasized the importance of patients being given factual information so they can make informed decisions about medications and the role of other potentially useful interventions, such as psychotherapy, exercise or self-help strategies.

*Requested Repost

“Patients might make different choices about the use of medications and possibly use alternative approaches to their distress if they were fully informed,” Lacasse said. “We believe the media can play a positive role by ensuring that their mental health reporting is congruent with scientific literature.”

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Creatine aids women rapidly with major depression

Muscle-building supplement vastly improves reponse time, quality of recovery

(SALT LAKE CITY)—Women battling stubborn major depression may have a surprising new ally in their fight—the muscle-building dietary supplement creatine.

In a new proof-of-concept study, researchers from three South Korean universities and the University of Utah report that women with major depressive disorder (MDD) who augmented their daily antidepressant with 5 grams of creatine responded twice as fast and experienced remission of the illness at twice the rate of women who took the antidepressant alone. The study, published Aug. 3, 2012, in the American Journal of Psychiatry online, means that taking creatine under a doctor’s supervision could provide a relatively inexpensive way for women who haven’t responded well to SSRI (selective serotonin reuptake inhibitor) antidepressants to improve their treatment outcomes.

“If we can get people to feel better more quickly, they’re more likely to stay with treatment and, ultimately, have better outcomes,” says Perry F. Renshaw, M.D., Ph.D., M.B.A, USTAR professor of psychiatry at the U of U medical school and senior author on the study.

If these initial study results are borne out by further, larger trials, the benefits of taking creatine could directly affect many Utahns. The depression incidence in Utah is estimated to be 25 percent higher than the rest of the nation, meaning the state has an even larger proportion of people with the disease. This also brings a huge economic cost to both the state and individuals.

According to numbers recently compiled at the U of U, the state of Utah paid an estimated $214 million in depression-related Medicaid and disability insurance in 2008. Add the costs of inpatient and outpatient treatment, medication, and lost productivity in the workplace, and the total price of depression in Utah reached $1.3 billion in 2008, according to the U estimate. With those large numbers, any treatment that improves outcomes not only could ease the life of thousands of Utah women but also would save millions of dollars.

“There has been a misunderstanding of how crippling and common this disease is in Utah,” says Renshaw, who’s also medical director of the Mental Illness Research, Education and Clinical Center at the Salt Lake City Veterans Affairs Health Care System. “It begs that we understand it better than we do.”

Creatine is an amino acid made in the human liver, kidneys, and pancreas. It also is found in meat and fish. Inside the body it is converted into phosphocreatine and stored in muscle. During high-intensity exercise, phosphocreatine is converted into ATP, an important energy source for cells. For this reason, creatine has become a popular supplement among bodybuilders and athletes who are trying to add muscle mass or improve athletic ability.

How creatine works against depression is not precisely known, but Renshaw and his colleagues suggest that the pro-energetic effect of creatine supplementation, including the making of more phosphocreatine, may contribute to the earlier and greater response to antidepressants.

The eight-week study included 52 South Korean women, ages 19-65, with major depressive disorder. All the women took the antidepressant Lexapro (escitalopram) during the trial. Twenty-five of the women received creatine with the Lexapro and 27 were given a placebo.  Neither the study participants nor the researchers knew who received creatine or placebo. Eight women in the creatine group and five in the placebo group did not finish the trial, leaving a total of 39 participants.

Participants were interviewed at the start of the trial to establish baselines for their depression, and then were checked at two, four, and eight weeks to see how they’d responded to Lexapro plus creatine or Lexapro and a placebo. The researchers used three measures to check the severity of depression, with the primary outcomes being measured by the Hamilton Depression Rating Scale (HDRS), a widely accepted test.

The group that received creatine showed significantly higher improvement rates on the HDRS at two and four weeks (32 percent and 68 percent) compared to the placebo group (3.7 percent and 29 percent). At the end of eight weeks, half of those in the creatine group showed no signs of depression compared with one-quarter in the placebo group. There were no significant adverse side effects associated with creatine.

Antidepressants typically don’t start to work until four to six weeks. But research shows that the sooner an antidepressant begins to work, the better the treatment outcome, and that’s why Renshaw and his colleagues are excited about the results of this first study. “Getting people to feel better faster is the Holy Grail of treating depression,” he says.

Study co-author Tae-Suk Kim, M.D., Ph.D., associate professor of psychiatry at the Catholic University of Korea College of Medicine and visiting associate professor of psychiatry at the U of U, already is recommending creatine for some of his female depression patients.

In prior studies, creatine had been shown to be effective only in female rats. But that shouldn’t rule out testing the supplement in men as well, according to Renshaw.

U of U researchers expect soon to begin another trial to test creatine in adolescent and college-age females who have not responded to SSRI medications. Principal investigator Douglas G. Kondo, M.D., assistant professor of psychiatry, says he is looking for 40 females between the ages of 13-21. Recruitment of participants will begin as soon as the U of U Institutional Review Board approves the study, which is expected in early July.

After the initial eight weeks of treatment, study participants will be offered a six-month extension of close supervision and monitoring by the research team and board-certified child, adolescent, and adult psychiatrist at no charge.

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Those interested in joining the study can call (801) 587-1549; visit the study Web site www.UtahBrain.org; or email Doug.Kondo@hsc.utah.edu.

The first authors on the study are In Kyoon Loo, M.D., Ph.D., professor of the Seoul National University College of Medicine and College of Natural Sciences, Seoul, South Korea, and USTAR research associate professor of psychiatry at the U of U, and Sujung Yoon, M.D., Ph.D., associate professor of psychiatry at the Catholic University of Korea College of Medicine, Seoul, and visiting associate professor of psychiatry at the U of U.

Other authors include Jaeuk Hwang M.D., Ph.D., of the Soonchunhyang University College of Medicine, Seoul; Wangyoun Won, M.D., Catholic University of Korea College of Medicine, Seoul; Jieun E. Kim, M.D., Ph.D., Ewha Womans University Graduate School, Seoul; Sujin Bae, Ph.D., Seoul National University College of Natural Sciences

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.”