Posts tagged depression
Articles and news from the latest research reports.
Dopamine Replacement Therapy Associated with Increase in Impulse Control Disorders Among Early Parkinson’s Disease Patients
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.
(Source: uphs.upenn.edu)
Depression Linked to Parkinson’s Disease
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.
(Source: feinberg.northwestern.edu)
Mind and body: Scientists identify immune system link to mental illness
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.
Could your brain be reprogrammed to work better?
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.
(Source: news.uwa.edu.au)
Phases of clinical depression could affect treatment
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
(Source: adelaide.edu.au)
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.
Researchers identify new compound to treat depression
There is new hope for people suffering from depression. Researchers have identified a compound, hydroxynorketamine (HNK), that may treat symptoms of depression just as effectively and rapidly as ketamine, without the unwanted side effects associated with the psychoactive drug, according to a study in the July issue of Anesthesiology, the official medical journal of the American Society of Anesthesiologists® (ASA®). Interestingly, use of HNK may also serve as a future therapeutic approach for treating neurodegenerative disorders such as Alzheimer’s and Parkinson’s diseases, the authors note.
“The clinical use of ketamine therapy for depression is limited because the drug is administered intravenously and may produce adverse effects such as hallucinations and sedation to the point of anesthesia,” said Irving Wainer, Ph.D., senior investigator with the Intramural Research Program at the National Institute on Aging, Baltimore. “We found that the HNK compound significantly contributes to the anti-depressive effects of ketamine in animals, but doesn’t produce the sedation or anesthesia, which makes HNK an attractive alternative as an antidepressant in humans.”
HNK is one of several different compounds produced when ketamine, an anesthesia medicine-turned-antidepressant, is broken down (metabolized) in the body. Using a rat model, researchers tested HNK to see if the compound alone could produce the same beneficial effects attributed to ketamine without ketamine’s unwanted side effects.
In the study, rats were given intravenous doses of ketamine, HNK and another compound produced by ketamine metabolism known as norketamine. The effect each had on stimulating certain cellular pathways of the rats’ brains was examined after 20, 30 and 60 minutes. Brain tissue from drug-free rats was used as a control.
Researchers found the compound HNK, like ketamine, not only produced potent and rapid antidepressant effects, but also stimulated neuro-regenerative pathways and initiated the regrowth of neurons in rats’ brains. HNK also appears to have several advantages over ketamine in that it is 1,000 times more potent, does not act as an anesthetic agent, and can be taken by mouth, the authors report.
Surprisingly, HNK was also found to reduce the production of D-serine, a chemical found in the body, overproduction of which is associated with neurodegenerative disorders such as Alzheimer’s and Parkinson’s diseases. HNK’s ability to reduce the production of D-serine, while stimulating the regeneration of neuron connections in the brain, may present a potential new therapeutic approach to the treatment of these disorders.
“HNK’s unique properties increase the possibility of the development of a self-administered, daily treatment that works quickly and can be taken at home for a variety of central nervous system diseases,” said Dr. Wainer. “This is a very exciting discovery and we hope that the results of this study will enable future investigations into this potentially therapeutic and important compound.”
Dr. Wainer and several of the study’s authors are listed as co-inventors on a patent application for the use of ketamine compounds in the treatment of bipolar disorder and major depression.
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)
(Image caption: Researchers at Cold Spring Harbor Laboratory have identified the neurons in the brain that determine if a mouse will learn to cope with stress or become depressed. These neurons, located in a region of the brain known as the medial prefrontal cortex (green, left image), become hyperactive in depressed mice (right panel is close-up of left, yellow indicates activation). The team showed that this enhanced activity in fact causes depression.)
Dealing with stress – to cope or to quit?
We all deal with stress differently. For many of us, stress is a great motivator, spurring a renewed sense of vigor to solve life’s problems. But for others, stress triggers depression. We become overwhelmed, paralyzed by hopelessness and defeat. Up to 20% of us will struggle with depression at some point in life, and researchers are actively working to understand how and why this debilitating mental disease develops.
Today, a team of researchers at Cold Spring Harbor Laboratory (CSHL) led by Associate Professor Bo Li reveals a major insight into the neuronal basis of depression. They have identified the group of neurons in the brain that determines how a mouse responds to stress — whether with resilience or defeat.
For years, scientists have relied on brain imaging to look for neuronal changes during depression. They found that a region of the brain known as the medial prefrontal cortex (mPFC) becomes hyperactive in depressed people. This area of the brain is well known to play a role in the control of emotions and behavior, linking our feelings with our actions. But brain scans aren’t able to determine if increased activity in the mPFC causes depression, or if it is simply a byproduct of other neuronal changes.
Dr. Li set out to identify the neuronal changes that underlie depression. In work published today in The Journal of Neuroscience,Li and his team, including Minghui Wang, Ph.D. and Zinaida Perova, Ph.D., used a mouse model for depression, known as “learned helplessness.” They combined this with a genetic trick to mark specific neurons that respond to stress. They discovered that neurons in the mPFC become highly excited in mice that are depressed. These same neurons are weakened in mice that aren’t deterred by stress – what scientists call resilient mice.
But the team still couldn’t be sure that enhanced signaling in the mPFC actually caused depression. To test this, they engineered mice to mimic the neuronal conditions they found in depressed mice. “We artificially enhanced the activity of these neurons using a powerful method known as chemical genetics,” says Li. “The results were remarkable: once-strong and resilient mice became helpless, showing all of the classic signs of depression.”
These results help explain how one promising new treatment for depression works and may lead to improvements in the treatment.
Doctors have had some success with deep brain stimulation (DBS), which suppresses the activity of neurons in a very specific portion of the brain. “We hope that our work will make DBS even more targeted and powerful,” says Li, “and we are working to develop additional strategies based upon the activity of the mPFC to treat depression.”
Next, Li is looking forward to exploring how the neurons in the mPFC become hyperactive in helpless mice. “These active neurons are surrounded by inhibitory neurons,” says Li. “Are the inhibitory neurons failing? Or are the active neurons somehow able to bypass their controls? These are some of the many open questions we are pursuing to understand the how depression develops.”