Posts tagged antidepressants
Articles and news from the latest research reports.
Single dose of antidepressant changes the brain
A single dose of antidepressant is enough to produce dramatic changes in the functional architecture of the human brain. Brain scans taken of people before and after an acute dose of a commonly prescribed SSRI (serotonin reuptake inhibitor) reveal changes in connectivity within three hours, say researchers who report their observations in the Cell Press journal Current Biology on September 18.
"We were not expecting the SSRI to have such a prominent effect on such a short timescale or for the resulting signal to encompass the entire brain," says Julia Sacher of the Max Planck Institute for Human Cognitive and Brain Sciences.
While SSRIs are among the most widely studied and prescribed form of antidepressants worldwide, it’s still not entirely clear how they work. The drugs are believed to change brain connectivity in important ways, but those effects had generally been thought to take place over a period of weeks, not hours.
The new findings show that changes begin to take place right away. Sacher says what they are seeing in medication-free individuals who had never taken antidepressants before may be an early marker of brain reorganization.
Study participants let their minds wander for about 15 minutes in a brain scanner that measures the oxygenation of blood flow in the brain. The researchers characterized three-dimensional images of each individual’s brain by measuring the number of connections between small blocks known as voxels (comparable to the pixels in an image) and the change in those connections with a single dose of escitalopram (trade name Lexapro).
Their whole-brain network analysis shows that one dose of the SSRI reduces the level of intrinsic connectivity in most parts of the brain. However, Sacher and her colleagues observed an increase in connectivity within two brain regions, specifically the cerebellum and thalamus.
The researchers say the new findings represent an essential first step toward clinical studies in patients suffering from depression. They also plan to compare the functional connectivity signature of brains in recovery and those of patients who fail to respond after weeks of SSRI treatment.
Understanding the differences between the brains of individuals who respond to SSRIs and those who don’t “could help to better predict who will benefit from this kind of antidepressant versus some other form of therapy,” Sacher says. “The hope that we have is that ultimately our work will help to guide better treatment decisions and tailor individualized therapy for patients suffering from depression.”
New study throws into question long-held belief about depression
New evidence puts into doubt the long-standing belief that a deficiency in serotonin — a chemical messenger in the brain — plays a central role in depression. In the journal ACS Chemical Neuroscience, scientists report that mice lacking the ability to make serotonin in their brains (and thus should have been “depressed” by conventional wisdom) did not show depression-like symptoms.
Donald Kuhn and colleagues at the John D. Dingell VA Medical Center and Wayne State University School of Medicine note that depression poses a major public health problem. More than 350 million people suffer from it, according to the World Health Organization, and it is the leading cause of disability across the globe. In the late 1980s, the now well-known antidepressant Prozac was introduced. The drug works mainly by increasing the amounts of one substance in the brain — serotonin. So scientists came to believe that boosting levels of the signaling molecule was the key to solving depression. Based on this idea, many other drugs to treat the condition entered the picture. But now researchers know that 60 to 70 percent of these patients continue to feel depressed, even while taking the drugs. Kuhn’s team set out to study what role, if any, serotonin played in the condition.
To do this, they developed “knockout” mice that lacked the ability to produce serotonin in their brains. The scientists ran a battery of behavioral tests. Interestingly, the mice were compulsive and extremely aggressive, but didn’t show signs of depression-like symptoms. Another surprising finding is that when put under stress, the knockout mice behaved in the same way most of the normal mice did. Also, a subset of the knockout mice responded therapeutically to antidepressant medications in a similar manner to the normal mice. These findings further suggest that serotonin is not a major player in the condition, and different factors must be involved. These results could dramatically alter how the search for new antidepressants moves forward in the future, the researchers conclude.
Low Strength Brain Stimulation May Be Effective for Depression
Brain stimulation treatments, like electroconvulsive therapy (ECT) and transcranial magnetic stimulation (TMS), are often effective for the treatment of depression. Like antidepressant medications, however, they typically have a delayed onset. For example, a patient may receive several weeks of regular ECT treatments before a full response is achieved.
Thus, there is an impetus to develop antidepressant treatments that act to rapidly improve mood.
Low field magnetic stimulation (LFMS) is one such potential new treatment with rapid mood-elevating effects, as reported by researchers at Harvard Medical School and Weill Cornell Medical College.
"LFMS is unlike any current treatment. It uses magnetic fields that are a fraction of the strength but at higher frequency than the electromagnetic fields used in TMS and ECT," explained first author Dr. Michael Rohan.
Indeed, the potential antidepressant properties of LFMS were discovered accidentally, while researchers were conducting an imaging study in healthy volunteers. This led Rohan and his colleagues to conduct a preliminary study in which they identified the imaging parameters that seemed to be causing the antidepressant effect.
They then designed and constructed a portable LFMS device, which delivers a low strength, high frequency, electromagnetic field waveform to the brain. The next step was to test the device in depressed patients, the results of which are published in the current issue of Biological Psychiatry.
A total of 63 currently depressed patients, diagnosed with either major depressive disorder or bipolar disorder, participated in the study and were randomized to receive a single 20-minute treatment of real LFMS or sham LFMS, where the device was on but the electromagnetic fields were inactive. Since neither the patients nor the researchers knew which treatment each person actually received, the true effect of the LFMS could be measured.
An immediate and substantial improvement in mood was observed in the patients who received real LFMS, compared to those who received the sham treatment. There were no reported side effects.
This finding suggests that LFMS may have the potential to provide immediate relief of depressed mood, perhaps even in emergency situations. It also confirms the success of the device’s design.
"The idea that weak electrical stimulation of the brain could produce beneficial effects on depression symptoms is somewhat surprising," said Dr. John Krystal, Editor of Biological Psychiatry. “Yet the data make a compelling case that this safe approach deserves further study.”
Rohan confirmed that additional research is underway to find the best parameters for LFMS use in the clinical treatment of depression. Further research will also be necessary to evaluate the effects of multiple compared to single treatments, and how long the antidepressant effects last following treatment.
Tiny Molecule Could Help Diagnose and Treat Mental Disorders
Scientists “fingerprint” a culprit in depression, anxiety and other mood disorders
According to the World Health Organization, such mood disorders as depression affect some 10% of the world’s population and are associated with a heavy burden of disease. That is why numerous scientists around the world have invested a great deal of effort in understanding these diseases. Yet the molecular and cellular mechanisms that underlie these problems are still only partly understood.
The existing anti-depressants are not good enough: Some 60-70% of patients get no relief from them. For the other 30-40%, that relief is often incomplete, and they must take the drugs for a long period before feeling any effects. In addition, there are many side effects associated with the drugs. New and better drugs are clearly needed, an undertaking that requires, first and foremost, a better understanding of the processes and causes underlying the disorders.
The Weizmann Institute’s Prof. Alon Chen, together with his then PhD student Dr. Orna Issler, investigated the molecular mechanisms of the brain’s serotonin system, which, when misregulated, is involved in depression and anxiety disorders. Chen and his colleagues researched the role of microRNA molecules (small, non-coding RNA molecules that regulate various cellular activities) in the nerve cells that produce serotonin. They succeeded in identifying, for the first time, the unique “fingerprints” of a microRNA molecule that acts on the serotonin-producing nerve cells. Combining bioinformatics methods with experiments, the researchers found a connection between this particular microRNA, (miR135), and two proteins that play a key role in serotonin production and the regulation of its activities. The findings appeared today in Neuron.
The scientists noted that in the area of the brain containing the serotonin-producing nerve cells, miR135 levels increased when antidepressant compounds were introduced. Mice that were genetically engineered to produce higher-than-average amounts of the microRNA were more resistant to constant stress: They did not develop any of the behaviors associated with chronic stress, such as anxiety or depression, which would normally appear. In contrast, mice that expressed low levels of miR135 exhibited more of these behaviors; in addition, their response to antidepressants was weaker. In other words, the brain needs the proper miR135 levels – low enough to enable a healthy stress response and high enough to avoid depression or anxiety disorders and to respond to serotonin-boosting antidepressants. When this idea was tested on human blood samples, the researchers found that subjects who suffered from depression had unusually low miR135 levels in their blood. On closer inspection, the scientists discovered that the three genes involved in producing miR135 are located in areas of the genome that are known to be associated with risk factors for bipolar mood disorders.
These findings suggest that miR135 could be a useful therapeutic molecule – both as a blood test for depression and related disorders, and as a target whose levels might be raised in patients. Yeda Research and Development Co. Ltd., the technology transfer arm of the Weizmann Institute, has applied for a patent connected to these findings and recently licensed the rights to miCure Therapeutics to develop a drug and diagnostic method. After completing preclinical trials, the company hopes to begin clinical trials in humans.
A tiny molecule may help battle depression
Levels of a small molecule found only in humans and in other primates are lower in the brains of depressed individuals, according to researchers at McGill University and the Douglas Institute. This discovery may hold a key to improving treatment options for those who suffer from depression.
Depression is a common cause of disability, and while viable medications exist to treat it, finding the right medication for individual patients often amounts to trial and error for the physician. In a new study to be published in the journal Nature Medicine, Dr. Gustavo Turecki, a psychiatrist at the Douglas and professor in the Faculty of Medicine, Department of Psychiatry at McGill, together with his team, discovered that the levels of a tiny molecule, miR-1202, may provide a marker for depression and help detect individuals who are likely to respond to antidepressant treatment.
“Using samples from the Douglas Bell-Canada Brain Bank, we examined brain tissues from individuals who were depressed and compared them with brain tissues from psychiatrically healthy individuals, says Turecki, who is also Director of the McGill Group for Suicide Studies, “We identified this molecule, a microRNA known as miR-1202, only found in humans and primates and discovered that it regulates an important receptor of the neurotransmitter glutamate”.
The team conducted a number of experiments that showed that antidepressants change the levels of this microRNA. “In our clinical trials with living depressed individuals treated with citalopram, a commonly prescribed antidepressant, we found lower levels in depressed individuals compared to the non-depressed individuals before treatment,” says Turecki. “Clearly, microRNA miR-1202 increased as the treatment worked and individuals no longer felt depressed.”
Antidepressant drugs are the most common treatment for depressive episodes, and are among the most prescribed medications in North America. “Although antidepressants are clearly effective, there is variability in how individuals respond to antidepressant treatment,” says Turecki, “We found that miR-1202 is different in individuals with depression and particularly, among those patients who eventually will respond to antidepressant treatment”.
The discovery may provide “a potential target for the development of new and more effective antidepressant treatments,” he adds.
(Source: mcgill.ca)
Research shows why ketamine is an effective antidepressant but memantine is not
Ketamine is a fast-acting antidepressant. However, it can create symptoms that mimic psychosis. Therefore, doctors don’t give it to depressed patients. Memantine, a similar drug, does not have psychotomimetic effects, but it also does not appear to alleviate depression. Lisa M. Monteggia of the University of Texas Southwestern Medical Center and her colleagues have determined that these drugs have different effects on neurotransmitter pathways. In particular, ketamine promotes the expression of neurotrophic factors but memantine doesn’t. The research appears in the Proceedings of the National Academy of Sciences.
Antidepressant use in pregnancy may be associated with structural changes in the infant brain
A new study by University of North Carolina at Chapel Hill researchers found that children of depressed mothers treated with a group of antidepressants called selective serotonin reuptake inhibitors (SSRIs) during pregnancy were more likely to develop Chiari type 1 malformations than were children of mothers with no history of depression.
However, the researchers cautioned, doctors treating pregnant women for depression should not change their prescribing practices based on the results of this study.
“Our results can be interpreted two ways,” said Rebecca Knickmeyer, PhD, assistant professor of psychiatry in the UNC School of Medicine and lead author of the study published May 19 in the journal Neuropsychopharmacology. “Either SSRIs increase risk for Chiari type 1 malformations, or other factors associated with SSRI treatment during pregnancy, such as severity of depression itself, increase risk. Additional research into the effects of depression during pregnancy, with and without antidepressant treatment is urgently needed.”
A Chiari type 1 malformation is a condition in which brain tissue in the cerebellum (a part of the brain that controls balance, motor systems, and some cognitive functions) extends into the spinal canal. About 5 percent of children have a Chiari type 1 malformation. Most do not have any problems because of it, but some develop symptoms such as headache and balance problems. In severe cases surgery may be necessary.
The study’s results are based on an analysis of magnetic resonance imaging (MRI) brain scans done on four groups of children at UNC Hospitals. Thirty-three children whose mothers were diagnosed with depression and took SSRI antidepressant medications, such as sertraline and fluoxetine, were compared to 66 children whose mothers had no history of depression. In addition, 30 children whose mothers were diagnosed with depression but did not take SSRIs were compared to 60 children whose mothers had no history of depression.
Eighteen percent of the children whose mothers took SSRIs during pregnancy had Chiari type 1 malformations, compared to 3 percent among children whose mothers had no history of depression. The rate of Chiari type 1 malformations was highest in children whose mothers reported a family history of depression in addition to treatment with SSRIs during pregnancy, suggesting an important role for genes as well as environment. Duration of SSRI exposure and SSRI exposure at conception also appeared to increase risk.
“These results raise many interesting questions, and there are many things we still don’t know,” said study co-author Samantha Meltzer-Brody, MD, MPH, associate professor of psychiatry in the UNC School of Medicine and director of UNC’s Perinatal Psychiatry Program. “For example, we do not know how many of these children will go on to develop symptoms of Chiari type 1 malformations. What we do know is that untreated depression can be very harmful for women and their babies, and so we strongly encourage pregnant women who are being treated for depression to continue with their treatment,” she said.
Knickmeyer said that a decision to use antidepressants during pregnancy must be based on the balance between risks and benefits and that it is critical that health care providers and the public get accurate information on this topic. She also noted that a diagnosis of Chiari Type 1 is often delayed due to the non-specific nature of the symptoms. Thus, it may be valuable for families in this situation to know about the results of this study.
In addition, “Chiari type 1 malformations are somewhat common, but very little is known about what causes them,” said study co-author J. Keith Smith, MD, PhD, professor and vice chair of clinical research in UNC’s Department of Radiology. “Studies like this could give us new insight into that question.”
Preventing Alzheimer’s disease — with an antidepressant
Citalopram, an antidepressant better known by its commercial name Celexa, has a remarkable side effect, a new study has found: In both mice bred to develop Alzheimer’s disease and in healthy human volunteers, the selective serotonin reuptake inhibitor, or SSRI, drives down the production of a protein called beta-amyloid, which in the brains of those with Alzheimer’s clumps together in sticky plaques and is thought to short-circuit the brain’s wiring.
In study participants free of Alzheimer’s disease or any other neuropsychiatric affliction, citalopram was found to reduce the concentration of beta-amyloid in the cerebrospinal fluid (outside of the brain) by 38%. Researchers see that as a clear sign that beta-amyloid protein in the brain, too, declines in those taking the antidepressant.
Depressed? Researchers identify new anti-depressant mechanisms, therapeutic approaches
Researchers at UT Southwestern Medical Center are making breakthroughs that could benefit people suffering from depression.
A team of physician-scientists at UT Southwestern has identified a major mechanism by which ghrelin (a hormone with natural anti-depressant properties) works inside the brain. Simultaneously, the researchers identified a potentially powerful new treatment for depression in the form of a neuroprotective drug known as P7C3.
The study, published online in April’s issue of Molecular Psychiatry, is notable because although a number of anti-depressant drugs and other treatments are available, an estimated one in 10 adults in the U.S. still report depression, according to the Centers for Disease Control and Prevention.
"By investigating the way the so-called ‘hunger hormone’ ghrelin works to limit the extent of depression following long-term exposure to stress, we discovered what could become a brand new class of anti-depressant drugs," said Dr. Jeffrey Zigman, Associate Professor of Internal Medicine and Psychiatry at UT Southwestern, and co-senior author of the study.
Ghrelin, a hormone produced in the stomach and intestines, has several widely known functions, including the ability to stimulate appetite. The latest research builds on a 2008 study led by Dr. Zigman, in which the team discovered that ghrelin exhibited natural anti-depressant effects that manifest when its levels rise as a result of caloric restriction or prolonged psychological stress.
The current findings identify ghrelin’s ability to stimulate adult hippocampal neurogenesis, the formation of new neurons, in animal models. In addition, Dr. Zigman and his colleagues also found that the regenerative process inside the hippocampus – a region of the brain that regulates mood, memory, and complex eating behaviors – is crucial in limiting the severity of depression following prolonged exposure to stress.
"After identifying the mechanism of ghrelin’s anti-depressant actions, we investigated whether increasing this ghrelin effect by directly enhancing hippocampal neurogenesis with the recently reported P7C3 class of neuroprotective compounds would result in even greater anti-depressant behavioral effects," Dr. Zigman said.
The P7C3 compounds were discovered in 2010 by a team of UT Southwestern researchers led by Dr. Steven McKnight, Chair of Biochemistry, Dr. Joseph Ready, Professor of Biochemistry, and Dr. Andrew Pieper, a former UT Southwestern faculty member and co-senior author of the current study. Previous research demonstrated P7C3’s promising neuroprotective abilities in instances of Parkinson’s disease, amyotrophic lateral sclerosis (ALS), and traumatic brain injury. Today, researchers hope that it can have a transformative impact on depression treatment too.
"We found that P7C3 exerted a potent anti-depressant effect via its neurogenesis-promoting properties," said Dr. Pieper, who is now Associate Professor of Neurology and Psychiatry at the University of Iowa Carver College of Medicine. "Also exciting, a highly active P7C3 analog was able to quickly enhance neurogenesis to a much greater level than a wide spectrum of currently marketed anti-depressant drugs."
Based on the study’s behavioral findings, researchers believe that individuals with depression associated with chronic stress or with altered ghrelin levels or ghrelin resistance, as has been described or theorized for conditions such as obesity and anorexia nervosa, might be particularly responsive to treatment with highly neuroprotective drugs, such as the P7C3 compounds.
Future studies will examine the ability to apply these findings to other forms of depression, including the possibility of developing clinical trials aimed at identifying whether or not P7C3 compounds have anti-depressant effects in people with major depression, as predicted. The three main types of depressive disorders include major depression, dysthymia, and bipolar disorder.
Researchers Find Boosting Depression-Causing Mechanisms in the Brain Increases Resilience, Surprisingly
A new study points to a conceptually novel therapeutic strategy for treating depression. Instead of dampening neuron firing found with stress-induced depression, researchers demonstrated for the first time that further activating these neurons opens a new avenue to mimic and promote natural resilience. The findings were so surprising that the research team thinks it may lead to novel targets for naturally acting antidepressants. Results from the study are published online April 18 in the journal Science.
Researchers from the Icahn School of Medicine at Mount Sinai point out that in mice resilient to social defeat stress (a source of constant stress brought about by losing a dispute or from a hostile interaction), their cation channel currents, which pass positive ions in dopamine neurons, are paradoxically elevated to a much greater extent than those of depressed mice and control mice. This led researchers to experimentally increase the current of cation channels with drugs in susceptible mice, those prone to depression, to see whether it would enhance coping and resilience. They found that such boosting of cation channels in dopamine neurons caused the mice to tolerate the increased stress without succumbing to depression-related symptoms, and unexpectedly the hyperactivity of the dopamine neurons was normalized.
Allyson K. Friedman, PhD, Postdoctoral Fellow in Pharmacology and Systems Therapeutics at the Icahn School of Medicine at Mount Sinai, and the study’s lead author said: “To achieve resiliency when under social stress, the brain must perform a complex balancing act in which negative stress-related changes in the brain actively trigger positive changes. But that can only happen once the negative changes reach a tipping point.”
The research team used optogenetics, a combination of laser optics and gene virus transfer, to control firing activity of the dopamine neurons. When light activation or the drug lamotrigine is given to these neurons, it drives the current and neuron firing higher. But at a certain point, it triggers compensatory mechanisms, normalizes neuron firing, and achieves a kind of homeostatic (or balanced) resilience.
"To our surprise, we found that resilient mice, instead of avoiding deleterious changes in the brain, experience further deleterious changes in response to stress, and use them beneficially," said Ming-Hu Han, PhD, at Icahn School of Medicine at Mount Sinai, who leads the study team as senior author.
Drs. Friedman and Han see this counterintuitive finding as stimulating research in a conceptually novel antidepressant strategy. If a drug could enhance coping and resilience by pushing depressed (or susceptible) individuals past the tipping point, it potentially might have fewer side effects, and work as a more naturally acting antidepressant.
Eric Nestler, MD, PhD, at the Icahn School of Medicine at Mount Sinai praised the study. “In this elegant study, Drs. Friedman and Han and their colleagues reveal a highly novel mechanism that controls an individual’s susceptibility or resilience to chronic social stress. The discoveries have important implications for the development of new treatments for depression and other stress-related disorders.”
(Source: mountsinai.org)