Posts tagged depression
Posts tagged depression
In the past three decades, the power of placebos has gone through the roof in treating major depressive disorder. In clinical trials for treating depression over that period of time, researchers have reported significant increases in patient’s response rates to placebos — the simple sugar pills given to patients who think that it may be actual medication.
New research conducted by UCLA psychiatrists helps explain how placebos can have such a powerful effect on depression.
“In short,” said Andrew Leuchter, the study’s first author and a professor of psychiatry at the UCLA Semel Institute for Neuroscience and Human Behavior, “if you think a pill is going to work, it probably will.”
The UCLA researchers examined three forms of treatment. One was supportive care in which a therapist assessed the patient’s risk and symptoms, and provided emotional support and encouragement but refrained from providing solutions to the patient’s issues that might result in specific therapeutic effects. The other two treatments provided the same type of therapy, but patients also received either medication or placebos.
The researchers found that treatment that incorporating either type of pill — real medication or placebo — yielded better outcomes than supportive care alone. Further, the success of the placebo treatment was closely correlated to people’s expectations before they began treatment. Those who believed that medication was likely to help them were much more likely to respond to placebos. Their belief in the effectiveness of medication was not related to the likelihood of benefitting from medication, however.
“Our study indicates that belief in ‘the power of the pill’ uniquely drives the placebo response, while medications are likely to work regardless of patients’ belief in their effectiveness,” Leuchter said.
The study appears in the current online edition of the British Journal of Psychiatry.
At the beginning and end of the study, patients were asked to complete the Hamilton Rating Scale for Depression, giving researchers a quantitative assessment of how their depression levels changed during treatment. Those who received antidepressant medication and supportive care improved an average of 46 percent, patients who received placebos and supportive care improved an average of 36 percent, and those who received supportive care alone improved an average of just 5 percent.
“Interestingly, while we found that medication was more effective than placebo, the difference was modest,” Leuchter said.
The researchers also found that people who received supportive care alone were more likely to discontinue treatment early than those who received pills.
People with major depressive disorder have a persistent low mood, low self-esteem and a loss of pleasure in things they once enjoyed. The disorder can be disabling, and it can affect a person’s family, work or school life, sleeping and eating habits, and overall health.
In the double-blind study, 88 people ages 18 to 65 who had been diagnosed with depression were given eight weeks of treatment. Twenty received supportive care alone, 29 received a placebo with supportive care and 39 received actual medication with supportive care.
The researchers measured the patients’ expectations for how effective they thought medication and general treatment would be, as well as their impressions of the strength of their relationship with the supportive care provider.
“These results suggest a unique role for people’s expectations about their medication in engendering a placebo response,” Leuchter said. “Higher expectations of medication effectiveness predicted an improvement in placebo-treated subjects, and it’s important to note that people’s expectations about how effective a medication may be were already formed before they entered the trial.”
Leuchter said the research indicates that factors such as direct-to-consumer advertising may be shaping peoples’ attitudes about medication. “It may not be an accident that placebo response rates have soared at the same time the pharmaceutical companies are spending $10 billion a year on consumer advertising.”
(Image credit: © Chris Lamphear)
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.
Scientists at Seattle Children’s Research Institute have discovered an area of the brain that could control a person’s motivation to exercise and participate in other rewarding activities – potentially leading to improved treatments for depression.
Dr. Eric Turner, a principal investigator in Seattle Children’s Research Institute’s Center for Integrative Brain Research, together with lead author Dr. Yun-Wei (Toni) Hsu, have discovered that a tiny region of the brain – the dorsal medial habenula – controls the desire to exercise in mice. The structure of the habenula is similar in humans and rodents and these basic functions in mood regulation and motivation are likely to be the same across species.
Exercise is one of the most effective non-pharmacological therapies for depression. Determining that such a specific area of the brain may be responsible for motivation to exercise could help researchers develop more targeted, effective treatments for depression.
“Changes in physical activity and the inability to enjoy rewarding or pleasurable experiences are two hallmarks of major depression,” Turner said. “But the brain pathways responsible for exercise motivation have not been well understood. Now, we can seek ways to manipulate activity within this specific area of the brain without impacting the rest of the brain’s activity.”
Dr. Turner’s study, titled “Role of the Dorsal Medial Habenula in the Regulation of Voluntary Activity, Motor Function, Hedonic State, and Primary Reinforcement,” was published today by the Journal of Neuroscience and funded by the National Institute of Mental Health and National Institute on Drug Abuse. The study used mouse models that were genetically engineered to block signals from the dorsal medial habenula. In the first part of the study, Dr. Turner’s team collaborated with Dr. Horacio de la Iglesia, a professor in University of Washington’s Department of Biology, to show that compared to typical mice, who love to run in their exercise wheels, the genetically engineered mice were lethargic and ran far less. Turner’s genetically engineered mice also lost their preference for sweetened drinking water.
“Without a functioning dorsal medial habenula, the mice became couch potatoes,” Turner said. “They were physically capable of running but appeared unmotivated to do it.”
In a second group of mice, Dr. Turner’s team activated the dorsal medial habenula using optogenetics – a precise laser technology developed in collaboration with the Allen Institute for Brain Science. The mice could “choose” to activate this area of the brain by turning one of two response wheels with their paws. The mice strongly preferred turning the wheel that stimulated the dorsal medial habenula, demonstrating that this area of the brain is tied to rewarding behavior.
Past studies have attributed many different functions to the habenula, but technology was not advanced enough to determine roles of the various subsections of this area of the brain, including the dorsal medial habenula.
“Traditional methods of stimulation could not isolate this part of the brain,” Turner said. “But cutting-edge technology at Seattle Children’s Research Institute makes discoveries like this possible.”
As a professor in the University of Washington Department of Psychiatry and Behavioral Sciences, Dr. Turner treats depression and hopes this research will make a difference in the lives of future patients.
“Working in mental health can be frustrating,” Turner said. “We have not made a lot of progress in developing new treatments. I hope the more we can learn about how the brain functions the more we can help people with all kinds of mental illness.”
New Penn Medicine research shows that neuropsychiatric symptoms such as depression, anxiety and fatigue are more common in newly diagnosed Parkinson’s disease (PD) patients compared to the general population. The study also found that initiation of dopamine replacement therapy, the most common treatment for PD, was associated with increasing frequency of impulse control disorders and excessive daytime sleepiness. The new findings, the first longitudinal study to come out of the Parkinson’s Progression Markers Initiative (PPMI), are published in the August 15, 2014, issue of Neurology®, the medical journal of the American Academy of Neurology.
The PPMI, a landmark, multicenter observational clinical study sponsored by The Michael J. Fox Foundation for Parkinson’s Research, uses a combination of advanced imaging, biologics sampling and behavioral assessments to identify biomarkers of Parkinson’s disease progression. The Penn study, which represents neuropsychiatric and cognitive data from baseline through the first 24 months of follow up, was conducted in collaboration with the Philadelphia VA Medical Center and the University Hospital Donostia in Spain.
The study examined 423 newly diagnosed, untreated Parkinson’s patients and 196 healthy controls at baseline and 281 people with PD at six months. Of these, 261 PD patients and 145 healthy controls were evaluated at 12 months, and 96 PD patients and 83 healthy controls evaluated at 24 months.
PD patients were permitted to begin dopamine therapy at any point after their baseline evaluation.
“We hypothesized that neuropsychiatric symptoms would be common and stable in severity soon after diagnosis and that the initiation of dopamine replacement therapy would modify their natural progression in some way,” says senior author, Daniel Weintraub, MD, associate professor of Psychiatry and Neurology at the Perelman School of Medicine at the University of Pennsylvania and a fellow in Penn’s Institute on Aging.
The Penn team showed that while there was no significant difference between PD patients and healthy controls in the frequency of impulse control disorders, a neuropsychiatric symptom that can lead to compulsive gambling, sexual behavior, eating or spending, 21 percent of newly diagnosed PD patients screened positive for such symptoms at baseline. That percentage did not increase significantly over the 24-month period.
However, six patients who had been on dopamine therapy for more than a year at the 24-month evaluation showed impulse control disorders or related behavior symptoms while no impulse control incident symptoms were reported in PD patients who had not commenced dopamine therapy. Dopamine therapy did help with fatigue, with 33 percent of patients improving their fatigue test score over 24 months compared with only 11 percent of patients not on dopamine therapy.
The investigators also found evidence that depression may be undertreated in early PD patients: Two-thirds of patients who screened positive for depression at any time point were not taking an antidepressant.
PPMI follows volunteers for five years, so investigators plan to expand upon these results, which Weintraub still considers preliminary. “We will more closely look at cognitive changes over time,” he says. “Two years is not a sufficient period of follow up to really look at meaningful cognitive decline.”
The perspective of time is what makes the PPMI such an important initiative, Weintraub points out, since many patients with the disease live for 10 to 20 years following their diagnosis. “It’s really a chance to assess the frequency and characteristics of psychiatric and cognitive symptoms in PD, compare it with healthy controls, and then also look at its evolution over time,” he says. “The hope is that we will be able to continue this work so that we can obtain long-term follow up data on these patients,” says Weintraub.
Depression is known to be a common symptom of Parkinson’s disease, but remains untreated for many patients, according to a new study by Northwestern Medicine investigators in collaboration with the National Parkinson’s Foundation (NPF).
In fact, depression is the most prevalent non-motor symptom of Parkinson’s, a chronic neurodegenerative disorder typically associated with movement dysfunction.
“We confirmed suspicion that depression is a very common symptom in Parkinson’s disease. Nearly a quarter of the people in the study reported symptoms consistent with depression,” said Danny Bega, MD, ’14 GME, instructor in the Ken and Ruth Davee Department of Neurology and first author of the study. “This is important because previous research has determined that depression is a major determinant of overall quality of life.”
Using the NPS’s patient database, the investigators looked at records of more than 7,000 people with Parkinson’s disease. Among those with high levels of depressive symptoms, only one-third had been prescribed antidepressants before the study began, and even fewer saw social workers or mental health professionals for counseling.
The investigators then focused their analysis on the remaining two-thirds of patients with depressive symptoms who were not receiving treatment at the start of the study. Throughout a year of observation, less than 10 percent of them received prescriptions for antidepressants or referrals to counseling. Physicians were most likely to identify depression and advocate treatment for patients with the severest depression scores.
The findings were published in the Journal of Parkinson’s Disease.
“The majority of these patients remained untreated,” said Dr. Bega. “Still, the physician recognition of depression in this population was actually better than previous reports had suggested.”
However, recognition may be lower for the general population of patients with Parkinson’s disease – the patients in this study visited medical centers deemed “Centers of Excellence” by the NPF.
“Physicians must be more vigilant about screening patients for depression as part of a routine assessment of Parkinson’s disease, and the effectiveness of different treatments for depression in this population need to be assessed,” said Dr. Bega.
Children with high everyday levels of a protein released into the blood in response to infection are at greater risk of developing depression and psychosis in adulthood, according to new research which suggests a role for the immune system in mental illness.
The study, published today in JAMA Psychiatry, indicates that mental illness and chronic physical illness such as coronary heart disease and type 2 diabetes may share common biological mechanisms.
When we are exposed to an infection, for example influenza or a stomach bug, our immune system fights back to control and remove the infection. During this process, immune cells flood the blood stream with proteins such as interleukin-6 (IL-6), a tell-tale marker of infection. However, even when we are healthy, our bodies carry trace levels of these proteins – known as ‘inflammatory markers’ – which rise exponentially in response to infection.
Now, researchers have carried out the first ever longitudinal study – a study that follows the same cohort of people over a long period of time – to examine the link between these markers in childhood and subsequent mental illness.
A team of scientists led by the University of Cambridge studied a sample of 4,500 individuals from the Avon Longitudinal Study of Parents and Children – also known as Children of the 90s – taking blood samples at age 9 and following up at age 18 to see if they had experienced episodes of depression or psychosis. The team divided the individuals into three groups, depending on whether their everyday levels of IL-6 were low, medium or high. They found that those children in the ‘high’ group were nearly two times more likely to have experienced depression or psychosis than those in the ‘low’ group.
Dr Golam Khandaker from the Department of Psychiatry at the University of Cambridge, who led the study, says: “Our immune system acts like a thermostat, turned down low most of the time, but cranked up when we have an infection. In some people, the thermostat is always set slightly higher, behaving as if they have a persistent low level infection – these people appear to be at a higher risk of developing depression and psychosis. It’s too early to say whether this association is causal, and we are carrying out additional studies to examine this association further.”
The research indicates that chronic physical illness such as coronary heart disease and type 2 diabetes may share a common mechanism with mental illness. People with depression and schizophrenia are known to have a much higher risk of developing heart disease and diabetes, and elevated levels of IL-6 have previously been shown to increase the risk of heart disease and type 2 diabetes.
Professor Peter Jones, Head of the Department of Psychiatry and senior author of the study, says: “Inflammation may be a common mechanism that influences both our physical and mental health. It is possible that early life adversity and stress lead to persistent increase in levels of IL-6 and other inflammatory markers in our body, which, in turn, increase the risk of a number of chronic physical and mental illness.”
Indeed, low birth weight, a marker of impaired foetal development, is associated with increased everyday levels of inflammatory markers as well as greater risks of heart disease, diabetes, depression and schizophrenia in adults.
This potential common mechanism could help explain why physical exercise and diet, classic ways of reducing risk of heart disease, for example, are also thought to improve mood and help depression. The group is now planning additional studies to confirm whether inflammation is a common link between chronic physical and mental illness.
The research also hints at interesting ways of potentially treating illnesses such as depression: anti-inflammatory drugs. Treatment with anti-inflammatory agents leads to levels of inflammatory markers falling to normal. Previous research has suggested that anti-inflammatory drugs such as aspirin used in conjunction with antipsychotic treatments may be more effective than just the antipsychotics themselves. A multicentre trial is currently underway, into whether the antibiotic minocycline, used for the treatment of acne, can be used to treat lack of enjoyment, social withdrawal, apathy and other so called negative symptoms in schizophrenia. Minocycline is able to penetrate the ‘blood-brain barrier’, a highly selective permeability barrier which protects the central nervous system from potentially harmful substances circulating in our blood.
The ‘blood-brain barrier’ is also at the centre of a potential puzzle raised by research such as today’s research: how can the immune system have an effect in the brain when many inflammatory markers and antibodies cannot penetrate this barrier? Studies in mice suggest that the answer may lie in the vagus nerve, which connects the brain to the abdomen. When activated by inflammatory markers in the gut, it sends a signal to the brain, where immune cells produce proteins such as IL-6, leading to increased metabolism (and hence decreased levels) of the ‘happiness hormone’ serotonin in the brain. Similarly, the signals trigger an increase in toxic chemicals such as nitric oxide, quinolonic acid, and kynurenic acid, which are bad for the functioning of nerve cells.
Researchers from The University of Western Australia have shown that electromagnetic stimulation can alter brain organisation which may make your brain work better.
In results from a study published today in the prestigious Journal of Neuroscience, researchers from The University of Western Australia and the Université Pierre et Marie Curie in France demonstrated that weak sequential electromagnetic pulses (repetitive transcranial magnetic stimulation - or rTMS) on mice can shift abnormal neural connections to more normal locations.
The discovery has important implications for treatment of many nervous system disorders related to abnormal brain organisation such as depression, epilepsy and tinnitus.
To better understand what magnetic stimulation does to the brain Research Associate Professor Jennifer Rodger from UWA’s School of Animal Biology and her colleagues tested a low-intensity version of the therapy - known as low-intensity repetitive transcranial magnetic stimulation (LI-rTMS) - on mice born with abnormal brain organisation.
Lead author, PhD candidate Kalina Makowiecki, said the research demonstrated that even at low intensities, pulsed magnetic stimulation could reduce abnormally located neural connections, shifting them towards their correct locations in the brain.
"This reorganisation is associated with changes in a specific brain chemical, and occurred in several brain regions, across a whole network. Importantly, this structural reorganisation was not seen in the healthy brain or the appropriate connections in the abnormal mice, suggesting that the therapy could have minimal side effects in humans.
"Our findings greatly increase our understanding of the specific cellular and molecular events that occur in the brain during this therapy and have implications for how best to use it in humans to treat disease and improve brain function," Ms Makowiecki said.
Research led by the University of Adelaide has resulted in new insights into clinical depression that demonstrate there cannot be a “one-size-fits-all” approach to treating the disease.
As part of their findings, the researchers have developed a new model for clinical depression that takes into account the dynamic role of the immune system. This neuroimmune interaction results in different phases of depression, and has implications for current treatment practices.
"Depression is much more complex than we have previously understood," says senior author Professor Bernhard Baune, Head of Psychiatry at the University of Adelaide.
"Past research has shown that there are inflammatory mechanisms at work in depression. But in the last 10 years there has been much research into the complexities of how the immune system interacts with brain function, both in healthy brains and in people experiencing depression.
"Unfortunately, much of the research is contradictory - and in asking ourselves why, we undertook a review of all the studies conducted to date on these issues.
"This has led us to the conclusion that there are different immune factors at work in depression depending on the clinical phase of depression, and that the genes for this immune response are switched on and off at different times according to phases.
"What we see in the clinical states of acute depression, relapse, remission, and recovery is a highly complex interaction between inflammatory and other immunological cells, brain cells and systems.
"This new model helps us to overcome the simplistic notion that depression is the same kind of disease for everyone, behaving in the same way regardless of the timing of the disease. We can now see that depression is a much more neurobiologically dynamic disease, and this has many implications for both research and treatment," Professor Baune says.
Professor Baune says clinicians and patients alike should be aware that common treatments for depression may, at times, not work based on this new understanding of neuroimmune phases in the disease.
"We are urging caution on the use of blanket anti-inflammatory medication for the treatment of depression. This treatment may need to be tailored according to the phase of illness a patient is undergoing, and this would require an immune profile of the patient prior to treatment," Professor Baune says.
The results of this study are published in the international journal Progress in Neuro-Psychopharmacology & Biological Psychiatry
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.
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.