Posts tagged depression
Posts tagged depression
A drug being studied as a fast-acting mood-lifter restored pleasure-seeking behavior independent of – and ahead of – its other antidepressant effects, in a National Institutes of Health trial. Within 40 minutes after a single infusion of ketamine, treatment-resistant depressed bipolar disorder patients experienced a reversal of a key symptom – loss of interest in pleasurable activities – which lasted up to 14 days. Brain scans traced the agent’s action to boosted activity in areas at the front and deep in the right hemisphere of the brain.
“Our findings help to deconstruct what has traditionally been lumped together as depression,” explained Carlos Zarate, M.D., of the NIH’s National Institute of Mental Health. “We break out a component that responds uniquely to a treatment that works through different brain systems than conventional antidepressants – and link that response to different circuitry than other depression symptoms.”
This approach is consistent with the NIMH’s Research Domain Criteria project, which calls for the study of functions – such as the ability to seek out and experience rewards – and their related brain systems that may identify subgroups of patients in one or multiple disorder categories.
Zarate and colleagues reported on their findings Oct. 14, 2014 in the journal Translational Psychiatry.
Although it’s considered one of two cardinal symptoms of both depression and bipolar disorder, effective treatments have been lacking for loss of the ability to look forward to pleasurable activities, or anhedonia. Long used as an anesthetic and sometimes club drug , ketamine and its mechanism-of-action have lately been the focus of research into a potential new class of rapid-acting antidepressants that can lift mood within hours instead of weeks.
Based on their previous studies, NIMH researchers expected ketamine’s therapeutic action against anhedonia would be traceable – like that for other depression symptoms – to effects on a mid-brain area linked to reward-seeking and that it would follow a similar pattern and time course.
To find out, the researchers infused the drug or a placebo into 36 patients in the depressive phase of bipolar disorder. They then detected any resultant mood changes using rating scales for anhedonia and depression. By isolating scores on anhedonia items from scores on other depression symptom items, the researchers discovered that ketamine was triggering a strong anti-anhedonia effect sooner – and independent of – the other effects.
Levels of anhedonia plummeted within 40 minutes in patients who received ketamine, compared with those who received placebo – and the effect was still detectable in some patients two weeks later. Other depressive symptoms improved within 2 hours. The anti-anhedonic effect remained significant even in the absence of other antidepressant effects, suggesting a unique role for the drug.
Next, the researchers scanned a subset of the ketamine-infused patients, using positron emission tomography (PET), which shows what parts of the brain are active by tracing the destinations of radioactively-tagged glucose – the brain’s fuel. The scans showed that ketamine jump-started activity not in the middle brain area they had expected, but rather in the dorsal (upper) anterior cingulate cortex, near the front middle of the brain and putamen, deep in the right hemisphere.
Boosted activity in these areas may reflect increased motivation towards or ability to anticipate pleasurable experiences, according to the researchers. Depressed patients typically experience problems imagining positive, rewarding experiences – which would be consistent with impaired functioning of this dorsal anterior cingulate cortex circuitry, they said. However, confirmation of these imaging findings must await results of a similar NIMH ketamine trial nearing completion in patients with unipolar major depression.
Other evidence suggests that ketamine’s action in this circuitry is mediated by its effects on the brain’s major excitatory neurotransmitter, glutamate, and downstream effects on a key reward-related chemical messenger, dopamine. The findings add to mounting evidence in support of the antidepressant efficacy of targeting this neurochemical pathway. Ongoing research is exploring, for example, potentially more practical delivery methods for ketamine and related experimental antidepressants, such as a nasal spray .
However, ketamine is not approved by the U.S. Food and Drug Administration as a treatment for depression. It is mostly used in veterinary practice, and abuse can lead to hallucinations, delirium and amnesia.
How gut bacteria ensure a healthy brain – and could play a role in treating depression
One of medicine’s greatest innovations in the 20th century was the development of antibiotics. It transformed our ability to combat disease. But medicine in the 21st century is rethinking its relationship with bacteria and concluding that, far from being uniformly bad for us, many of these organisms are actually essential for our health.
Nowhere is this more apparent than in the human gut, where the microbiome – the collection of bacteria living in the gastrointestinal tract – plays a complex and critical role in the health of its host. The microbiome interacts with and influences organ systems throughout the body, including, as research is revealing, the brain. This discovery has led to a surge of interest in potential gut-based treatments for neuropsychiatric disorders and a new class of studies investigating how the gut and its microbiome affect both healthy and diseased brains.
The microbiome consists of a startlingly massive number of organisms. Nobody knows exactly how many or what type of microbes there might be in and on our bodies, but estimates suggest there may be anywhere from three to 100 times more bacteria in the gut than cells in the human body. The Human Microbiome Project, co-ordinated by the US National Institutes of Health (NIH), seeks to create a comprehensive database of the bacteria residing throughout the gastrointestinal tract and to catalogue their properties.
The lives of the bacteria in our gut are intimately entwined with our immune, endocrine and nervous systems. The relationship goes both ways: the microbiome influences the function of these systems, which in turn alter the activity and composition of the bacterial community. We are starting to unravel this complexity and gain insight into how gut bacteria interface with the rest of the body and, in particular, how they affect the brain.
A mini-stroke may not cause lasting physical damage, but it could increase your risk of developing post-traumatic stress disorder (PTSD), a small, new study suggests.
Almost one-third of patients who suffered a mini-stroke — known as a transient ischemic attack (TIA) — developed symptoms of PTSD, including depression, anxiety and reduced quality of life, the researchers said.
"At the moment, a TIA is seen by doctors as a fairly benign disorder," said study co-author Kathrin Utz, a researcher in the department of neurology at the University of Erlangen-Nuremberg in Germany.
At the 22nd United European Gastroenterology Week (UEG Week 2014) in Vienna, Austria, Professor Sigrid Elsenbruch from the University of Duisburg-Essen in Germany, will be presenting a new study which suggests that depression, but not anxiety, contributes to the abnormal pain processing observed in IBS in a model that addresses central pain inhibition during placebo analgesia. “Our study has shown that patients with IBS are less able to suppress pain signals in the brain coming from the bowel and that depression plays a role herein,” she says. “This study confirms the complex relationship between the gut and the brain and shows that affective disorders may contribute to the development or maintenance of disturbed pain processing in IBS.”
IBS, anxiety and depression
IBS is the most common functional gastrointestinal disorder with prevalence rates of up to 23% reported. The condition is characterised by recurrent abdominal pain or discomfort, in combination with bloating and altered bowel habits (e.g. diarrhoea and/or constipation). Depression and anxiety frequently co-exist with IBS, with a recent study reporting that 38% of IBS patients had clinically-confirmed depression (compared with 6% of healthy controls) and 32% had anxiety (compared with 13% of healthy controls).
“The fact that so many people with IBS have anxiety and depression has led many to speculate that IBS is primarily a psychological, not a physical, disorder,” says Prof. Elsenbruch. “However, the condition is complex and most likely results from an interplay between psychological and biological factors. In fact, we don’t really know whether anxiety and depression result from having IBS or whether they contribute to the development or maintenance of symptoms. In many patients, both possibilities may be true at the same time.”
The “brain–gut” axis in IBS
There has been significant scientific interest in the role of central nervous system mechanisms along the “brain–gut” axis in IBS. Neuroimaging studies have demonstrated that neural processing of visceral stimuli (i.e. stimuli generated from internal organs such as the intestine) is altered in IBS, with many IBS patients showing lowered pain thresholds. In Prof. Elsenbruch’s latest study, painful rectal distensions were performed using a pressure-controlled barostat system in 17 patients with IBS and 17 sex- and age-matched healthy controls. Neural activation in pain-related brain areas was assessed using functional MRI (fMRI) while subjects received sequential intravenous administrations of saline and what they thought was an anti-spasmolytic drug (but was actually a saline placebo), in order to observe activation patterns during a typical placebo pain response.
The fMRI results in the healthy volunteers demonstrated reduced neural activation in pain-related brain areas during both the saline and sham treatment (placebo), indicating significant central pain inhibition. However, there was no such inhibition in the group of IBS patients, suggesting a deficiency in central pain inhibitory mechanisms in IBS. Interestingly, higher depression (but not anxiety) scores on the Hospital Anxiety and Depression Scale (HADS) were associated with reduced central pain inhibition in this study.
“Our findings suggest that patients with IBS do not process visceral pain signals in the same way as healthy people and are unable to suppress pain signals in the brain and, as a result, experience more pain from the same stimuli,” says Prof. Elsenbruch. “The fact that the presence of depression was associated with altered brain responses suggests that depression may contribute to these abnormal pain processes in IBS patients.”
On Star Trek, it is easy to take for granted the incredible ability of futuristic doctors to wave small devices over the heads of both humans and aliens, diagnose their problems through evaluating changes in brain activity or chemistry, and then treat behavior problems by selectively stimulating relevant brain circuits.
While that day is a long way off, transcranial magnetic stimulation (TMS) of the left dorsolateral prefrontal cortex does treat symptoms of depression in humans by placing a relatively small device on a person’s scalp and stimulating brain circuits. However, relatively little is known about how, exactly, TMS produces these beneficial effects.
Some studies have suggested that TMS may modulate atypical interactions between two large-scale neuronal networks, the frontoparietal central executive network (CEN) and the medial prefrontal-medial parietal default mode network (DMN). These two functional networks play important roles in emotion regulation and cognition.
In order to advance our understanding of the underlying antidepressant mechanisms of TMS, Drs. Conor Liston, Marc Dubin, and their colleagues conducted a longitudinal study to test this hypothesis.
The researchers used functional magnetic resonance imaging in 17 currently depressed patients to measure connectivity in the CEN and DMN networks both before and after a 25-day course of TMS. They also compared the connectivity in the depressed patients with a group of 35 healthy volunteers.
TMS normalized depression-related hyperconnectivity between the subgenual cingulate and medial prefrontal areas of the DMN, but did not alter connectivity in the CEN.
Liston, an Assistant Professor at Weill Cornell Medical College, further details their findings, “We found that connectivity within the DMN and between nodes of the DMN and CEN was elevated in depressed individuals compared to healthy volunteers at baseline and normalized after TMS. Additionally, individuals with greater baseline connectivity with subgenual anterior cingulate cortex – an important target for other antidepressant modalities – were more likely to respond to TMS.”
These findings indicate that TMS may act, in part, by selectively regulating network-level connectivity.
Dr. John Krystal, Editor of Biological Psychiatry, comments, “We are a long way from Star Trek, but even the current ability to link brain stimulation treatments for depression to the activity of particular brain circuits strikes me as incredible progress.”
Dubin, also an Assistant Professor at Weill Cornell Medical College, adds, “Our findings may inform future efforts to develop personalized strategies for treating depression with TMS based on the connectivity of an individual’s default mode network. Further, they may help triage to TMS only those patients most likely to respond.”
A study by San Diego State University psychology professor Jean M. Twenge shows Americans are more depressed now than they have been in decades.
Analyzing data from 6.9 million adolescents and adults from all over the country, Twenge found that Americans now report more psychosomatic symptoms of depression, such as trouble sleeping and trouble concentrating, than their counterparts in the 1980s.
“Previous studies found that more people have been treated for depression in recent years, but that could be due to more awareness and less stigma,” said Twenge, the author of “Generation Me: Why Today’s Young Americans are More Confident, Assertive, Entitled — and More Miserable than Ever Before.”
“This study shows an increase in symptoms most people don’t even know are connected to depression, which suggests adolescents and adults really are suffering more.”
Compared to their 1980s counterparts, teens in the 2010s are 38 percent more likely to have trouble remembering, 74 percent more likely to have trouble sleeping and twice as likely to have seen a professional for mental health issues.
College students surveyed were 50 percent more likely to say they feel overwhelmed, and adults were more likely to say their sleep was restless, they had poor appetite and everything was an effort — all classic psychosomatic symptoms of depression.
“Despite all of these symptoms, people are not any more likely to say they are depressed when asked directly, again suggesting that the rise is not based on people being more willing to admit depression,” said Twenge.
The study also found that the suicide rate for teens decreased, though the decline was small compared to the increase in symptoms of depression. With the use of anti-depressant medications doubling over this time period, Twenge speculates that medication may have helped those with the most severe problems but has not reduced increases in other symptoms that, she says, can still cause significant issues.
Twenge’s findings were published in the journal Social Indicators Research, and an updated and revised edition of “Generation Me” is being released today.
Physical exercise has many beneficial effects on human health, including the protection from stress-induced depression. However, until now the mechanisms that mediate this protective effect have been unknown. In a new study in mice, researchers at Karolinska Institutet in Sweden show that exercise training induces changes in skeletal muscle that can purge the blood of a substance that accumulates during stress, and is harmful to the brain. The study is being published in the prestigious journal Cell.
“In neurobiological terms, we actually still don’t know what depression is. Our study represents another piece in the puzzle, since we provide an explanation for the protective biochemical changes induced by physical exercise that prevent the brain from being damaged during stress,” says Mia Lindskog, researcher at the Department of Neuroscience at Karolinska Institutet.
It was known that the protein PGC-1a1 (pronounced PGC-1alpha1) increases in skeletal muscle with exercise, and mediates the beneficial muscle conditioning in connection with physical activity. In this study researchers used a genetically modified mouse with high levels of PGC-1a1 in skeletal muscle that shows many characteristics of well-trained muscles (even without exercising).
These mice, and normal control mice, were exposed to a stressful environment, such as loud noises, flashing lights and reversed circadian rhythm at irregular intervals. After five weeks of mild stress, normal mice had developed depressive behaviour, whereas the genetically modified mice (with well-trained muscle characteristics) had no depressive symptoms.
“Our initial research hypothesis was that trained muscle would produce a substance with beneficial effects on the brain. We actually found the opposite: well-trained muscle produces an enzyme that purges the body of harmful substances. So in this context the muscle’s function is reminiscent of that of the kidney or the liver,” says Jorge Ruas, principal investigator at the Department of Physiology and Pharmacology, Karolinska Institutet.
The researchers discovered that mice with higher levels of PGC-1a1 in muscle also had higher levels of enzymes called KAT. KATs convert a substance formed during stress (kynurenine) into kynurenic acid, a substance that is not able to pass from the blood to the brain. The exact function of kynurenine is not known, but high levels of kynurenine can be measured in patients with mental illness. In this study, the researchers demonstrated that when normal mice were given kynurenine, they displayed depressive behaviour, while mice with increased levels of PGC-1a1 in muscle were not affected. In fact, these animals never show elevated kynurenine levels in their blood since the KAT enzymes in their well-trained muscles quickly convert it to kynurenic acid, resulting in a protective mechanism.
“It’s possible that this work opens up a new pharmacological principle in the treatment of depression, where attempts could be made to influence skeletal muscle function instead of targeting the brain directly. Skeletal muscle appears to have a detoxification effect that, when activated, can protect the brain from insults and related mental illness,” says Jorge Ruas.
Depression is a common psychiatric disorder worldwide. The World Health Organization (WHO) estimates that more than 350 million people are affected.
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.”