Posts tagged depression

12 August 2012

Certain brain regions in people with major depression are smaller and less dense than those of their healthy counterparts. Now, researchers have traced the genetic reasons for this shrinkage.

A series of genes linked to the function of synapses, or the gaps between brain cells crucial for cell-to-cell communication, can be controlled by a single genetic “switch” that appears to be overproduced in the brains of people with depression, a new study finds.

"We show that circuits normally involved in emotion, as well as cognition, are disrupted when this single transcription factor is activated," study researcher Ronald Duman, a professor of psychiatry at Yale University, said in a statement.

Shrinking brain

Brain-imaging studies, post-mortem examinations of human brains and animal studies have all found that in depression, a part of the brain called the dorsolateral prefrontal cortex shrinks. The neurons in this region, which is responsible for complex tasks from memory and sensory integration to the planning of actions, are also smaller and less dense in depressed people compared with healthy people. 

Duman and his colleagues suspected that these neuronal abnormalities would include problems with the synapses, the points where brain cells “talk” to one another. At synapses, neurons release neurotransmitters that are picked up by their neighbors, carrying signals from cell to cell at rapid speed.

The researchers conducted gene profiling on the postmortem brain tissue of both depressed and mentally healthy subjects. They found a range of genes that were significantly less active in depressed people’s dorsolateral prefrontal cortexes, particularly five related to synaptic function: synapsin 1, Rab3A, calmodulin 2, Rab4B and TUBB4.

Synaptic damage

These genes are all involved in either the chemical signaling that occurs at synapses or the cellular recycling and regeneration processes that keep the synapse-system humming.  All five are regulated by a single transcription factor called GATA1, which was overproduced in depressed brains.

The researchers activated GATA1 in the brains of rats and found that the factor decreased the complexity of the long, branchlike projections, or dendrites, of brain cells. These projections are the telephone lines that carry synaptic messages, integrating all the information a cell receives.

Extra GATA1 also increased depression-like behavior in the rats. For example, when given a swimming task, rats with extra GATA1 stayed immobile in the water longer, a signal of despair, than normal-GATA1 rats, the researchers report today (Aug. 12) in the journal Nature Medicine.

The researchers believe the damage could be a result of chronic stress, and they hope the findings lead to new depression treatments.

"We hope that by enhancing synaptic connections, either with novel medications or behavioral therapy, we can develop more effective antidepressant therapies," Duman said.

Source: Live Science

August 3, 2012

Scientists have discovered a biological marker that may help to identify which depressed patients will respond to an experimental, rapid-acting antidepressant. The brain signal, detectable by noninvasive imaging, also holds clues to the agent’s underlying mechanism, which are vital for drug development, say National Institutes of Health researchers. 

Dr. Zarate views subject in MEG scanner from scanner control room.

The signal is among the latest of several such markers, including factors detectable in blood, genetic markers, and a sleep-specific brain wave, recently uncovered by the NIH team and grantee collaborators. They illuminate the workings of the agent, called ketamine, and may hold promise for more personalized treatment.

"These clues help focus the search for the molecular targets of a future generation of medications that will lift depression within hours instead of weeks," explained Carlos Zarate, M.D., of the NIH’s National Institute of Mental Health (NIMH). "The more precisely we understand how this mechanism works, the more narrowly treatment can be targeted to achieve rapid antidepressant effects and avoid undesirable side effects."

Zarate, Brian Cornwell, Ph.D., and NIMH colleagues report on their brain imaging study online in the journal Biological Psychiatry.

Previous research had shown that ketamine can lift symptoms of depression within hours in many patients. But side effects hamper its use as a first-line medication. So researchers are studying its mechanism of action in hopes of developing a safer agent that works similarly.

Ketamine works through a different brain chemical system than conventional antidepressants. It initially blocks a protein on brain neurons, called the NMDA receptor, to which the chemical messenger glutamate binds. However, it is not known if the drug’s rapid antidepressant effects are a direct result of this blockage or of downstream effects triggered by the blockage, as suggested by animal studies.

To tease apart ketamine’s workings, the NIMH team imaged depressed patients’ brain electrical activity with magnetoencephalography (MEG). They monitored spontaneous activity while subjects were at rest, and activity evoked by gentle stimulation of a finger, before and 6.5 hours after an infusion of ketamine.

It was known that by blocking NMDA receptors, ketamine causes an increase in spontaneous electrical signals, or waves, in a particular frequency range in the brain’s cortex, or outer mantle. Hours after ketamine administration— in the timeframe in which ketamine relieves depression — spontaneous electrical activity in people at rest was the same whether or not the drug lifted their depression.

Electrical activity evoked by stimulating a finger, however, was different in the two groups. MEG imaging made it possible to monitor excitability of the somatosensory cortex, the part of the cortex that registers sensory stimulation. Those who responded to ketamine showed an increased response to the finger stimulation, a greater excitability of the neurons in this part of the cortex.

Such a change in excitability is likely to result, not from the immediate effects of blocking the receptor, but from other processes downstream, in the cascade of effects set in motion by NMDA blockade, say the researchers. Evidence points to changes in another type of glutamate receptor, the AMPA receptor, raising questions about whether the blocking of NMDA receptors is even necessary for ketamine’s antidepressant effect. If NMDA blockade is just a trigger, then targeting AMPA receptors may prove a more direct way to effect a lifting of depression.

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Tuesday, July 31, 2012

TAU researchers develop bioactive coating to “camouflage” neutral electrodes

Brain-computer interfaces are at the cutting edge for treatment of neurological and psychological disorder, including Parkinson’s, epilepsy, and depression. Among the most promising advance is deep brain stimulation (DBS) — a method in which a silicon chip implanted under the skin ejects high frequency currents that are transferred to the brain through implanted electrodes that transmit and receive the signals. These technologies require a seamless interaction between the brain and the hardware.

But there’s a catch. Identified as foreign bodies by the immune system, the brain attacks the electrodes and forms a barrier to the brain tissue, making it impossible for the electrodes to communicate with brain activity. So while the initial implantation can diminish symptoms, after a few short years or even months, the efficacy of this therapy begins to wane.

Now Aryeh Taub of Tel Aviv University's School of Psychological Sciences, along with Prof. Matti Mintz, Roni Hogri and Ari Magal of TAU’s School of Psychological Sciences and Prof. Yosi Shacham-Diamand of TAU’s School of Electrical Engineering, has developed a bioactive coating which not only “camouflages” the electrodes in the brain tissue, but actively suppresses the brain’s immune response. By using a protein called an “interleukin (IL)-1 receptor antagonist” to coat the electrodes, the multi-disciplinary team of researchers has found a potential resolution to turn a method for short-term relief into a long-term solution. This development was reported in the Journal of Biomedical Materials Research.

Limiting the immune response

To overcome the creation of the barrier between the tissue and the electrode, the researchers sought to develop a method for placing the electrode in the brain tissue while hiding the electrode from the brain’s immune defenses. Previous research groups have coated the electrodes with various proteins, says Taub, but the TAU team decided to take a different approach by using a protein that is active within the brain itself, thereby suppressing the immune reaction against the electrodes.

In the brain, the IL-1 receptor antagonist is crucial for maintaining physical stability by localizing brain damage, Taub explains. For example, if a person is hit on the head, this protein works to create scarring in specific areas instead of allowing global brain scarring. In other words, it stops the immune system from overreacting. The team’s coating, the first to be developed from this particular protein, not only integrates the electrodes into the brain tissue, but allows them to contribute to normal brain functioning.

In pre-clinical studies with animal models, the researchers found that their coated electrodes perform better than both non-coated and “naïve protein”-coated electrodes that had previously been examined. Measuring the number of damaged cells at the site of implantation, researchers found no apparent difference between the site of electrode implantation and healthy brain tissue elsewhere, Taub says. In addition, evidence suggests that the coated electrodes will be able to function for long periods of time, providing a more stable and long-term treatment option.

Restoring brain function

Approximately 30,000 people worldwide are currently using deep brain stimulation (DBS) to treat neurological or psychological conditions. And DBS is only the beginning. Taub believes that, in the future, an interface with the ability to restore behavioral or motor function lost due to tissue damage is achievable — especially with the help of their new electrode coating.

"We duplicate the function of brain tissue onto a silicon chip and transfer it back to the brain," Taub says, explaining that the electrodes will pick up brain waves and transfer these directly to the chip. "The chip then does the computation that would have been done in the damaged tissue, and feeds the information back into the brain — prompting functions that would have otherwise gotten lost."

Source: Tel Aviv University

26 July 2012

Emotional problems in childhood are common. Approximately 8 to 22 percent of children suffer from anxiety, often combined with other conditions such as depression. However, most existing therapies are not designed to treat coexisting psychological problems and are therefore not very successful in helping children with complex emotional issues.

To develop a more effective treatment for co-occurring youth anxiety and depression, University of Miami psychologist Jill Ehrenreich-May and her collaborator Emily L. Bilek analyzed the efficacy and feasibility of a novel intervention created by the researchers, called Emotion Detectives Treatment Protocol (EDTP). Preliminary findings show a significant reduction in the severity of anxiety and depression after treatment, as reported by the children and their parents.

“We are very excited about the potential of EDTP,” says Ehrenreich-May, associate professor of psychology in the College of Arts and Sciences at UM and principal investigator of the study. “Not only could the protocol better address the needs of youth with commonly co-occurring disorders and symptoms, it may also provide additional benefits to mental health professionals,” she says. “EDTP offers a more unified approach to treatment that, we hope, will allow for an efficient and cost-effective treatment option for clinicians and clients alike.”

Emotion Detectives Treatment Program is an adaptation of two treatment protocols developed for adults and adolescents, the Unified Protocols. The program implements age-appropriate techniques that deliver education about emotions and how to manage them, strategies for evaluating situations, problem-solving skills, behavior activation (a technique to reduce depression), and parent training.

In the study, 22 children ages 7 to 12 with a principal diagnosis of an anxiety disorder and secondary issues of depression participated in a 15-session weekly group therapy of EDTP. Among participants who completed the protocol (18 out of 22), 14 no longer met criteria for an anxiety disorder at post-treatment. Additionally, among participants who were assigned a depressive disorder before treatment (5 out of 22), only one participant continued to meet such criteria at post-treatment.

Unlike results from previous studies, the presence of depressive symptoms did not predict poorer treatment response. The results also show a high percentage of attendance. The findings imply that EDTP may offer a better treatment option for children experiencing anxiety and depression.

“Previous research has shown that depressive symptoms tend to weaken treatment response for anxiety disorders. We were hopeful that a broader, more generalized approach would better address this common co-occurrence,” says Bilek, doctoral candidate in clinical psychology at UM and co-author of the study. “We were not surprised to find that the EDTP had equivalent outcomes for individuals with and without elevated depressive symptoms, but we were certainly pleased to find that this protocol may address this important issue.”

The study, titled “An Open Trial Investigation of a Transdiagnostic Group Treatment for Children with Anxiety and Depressive Symptoms,” is published online ahead of print in the journal Behavior Therapy.

The team is currently recruiting participants for a randomized controlled trial comparing the EDTP to another group treatment protocol for anxiety disorders. For more information, please contact the study coordinators at www.miami.edu/childanxiety.

Source: ScienceBlog

ScienceDaily (July 26, 2012) — In one of the first studies to look at transcranial magnetic stimulation (TMS) in real-world clinical practice settings, researchers at Butler Hospital, along with colleagues across the U.S., confirmed that TMS is an effective treatment for patients with depression who are unable to find symptom relief through antidepressant medications. The study findings are published online in the June 11, 2012 edition of Depression and Anxiety in the Wiley Online Library.

(Credit: Butler Hospital)

Previous analysis of the efficacy of TMS has been provided through more than 30 published trials, yielding generally consistent results supporting the use of TMS to treat depression when medications aren’t sufficient. “Those previous studies were key in laying the groundwork for the FDA to approve the first device for delivery of TMS as a treatment for depression in 2008,” said Linda Carpenter, MD, lead author of the report and chief of the Mood Disorders Program and the Neuromodulation Clinic at Butler Hospital. “Naturalistic studies like ours, which provide scrutiny of real-life patient outcomes when TMS therapy is given in actual clinical practice settings, are the next step in further understanding the effectiveness of TMS. They are also important for informing healthcare policy, particularly in an era when difficult decisions must be made about allocation of scarce resources.”

Carpenter explains that naturalistic studies differ from controlled clinical trials because they permit the inclusion of subjects with a wider range of symptomatology and comorbidity, whereas controlled clinical trials typically have more rigid criteria for inclusion. “As a multisite study collecting naturalistic outcomes from patients in clinics in various regions in the U.S., we were also able to capture effects that might arise from introducing a novel psychiatric treatment modality like TMS in non-research settings,” said Carpenter. In all, the study confirms how well TMS works in diverse settings where TMS is administered to a real-life population of patients with depression that have not found relief through many other available treatments.

The published report summarized data collected from 42 clinical TMS practice sites in the US, and included outcomes from 307 patients with Major Depressive Disorder (MDD) who had persistent symptoms despite the use of antidepressant medication. Change during TMS was assessed using both clinicians’ ratings of overall depression severity and scores on patient self-report depression scales, which require the patient to rate the severity of each symptom on the same standardized scale at the end of each 2-week period. Rates for “response” and “remission” to TMS were calculated based on the same cut-off scores and conventions used for other clinical trials of antidepressant treatments. Fifty-eight percent positive response rate to TMS and 37 percent remission rate were observed.

"The patient outcomes we found in this study demonstrated a response rate similar to controlled clinical trial populations," said Dr. Carpenter, explaining that this new data validates TMS efficacy in treating depression for those who have failed to benefit from antidepressant medications. "Continued research and confirmation of the effectiveness of TMS is important for understanding its place in everyday psychiatric care and to support advocacy for insurance coverage of the treatment." Thanks in part to the advocacy efforts of Dr. Carpenter, TMS was recently approved for coverage by Medicare in New England, and it is also now covered by BCBSRI. "Next steps for TMS research involve enhancing our understanding of how to maintain positive response to TMS over time after the course of therapy ends and learning how to customize the treatment for patients using newer technologies, so TMS can help even more patients."

Source: Science Daily

ScienceDaily (July 11, 2012) — Stanford University School of Medicine scientists have laid bare a novel molecular mechanism responsible for the most important symptom of major depression: anhedonia, the loss of the ability to experience pleasure. While their study was conducted in mice, the brain circuit involved in this newly elucidated pathway is largely identical between rodents and humans, upping the odds that the findings point toward new therapies for depression and other disorders.

Additionally, opinion leaders hailed the study’s inventive methodology, saying it may offer a much sounder approach to testing new antidepressants than the methods now routinely used by drug developers.

While as many as one in six Americans is likely to suffer a major depression in their lifetimes, current medications either are inadequate or eventually stop working in as many as 50 percent of those for whom they’re prescribed.

"This may be because all current medications for depression work via the same mechanisms," said Robert Malenka, MD, PhD, the Nancy Friend Pritzker Professor in Psychiatry and Behavioral Sciences. "They increase levels of one or another of two small molecules that some nerve cells in the brain use to signal one another. To get better treatments, there’s a great need to understand in greater detail the brain biology that underlies depression’s symptoms." The study’s first author is Byung Kook Lim, PhD, a postdoctoral scholar in Malenka’s laboratory.

Malenka is senior author of the new study, published July 12 in Nature, which reveals a novel drug target by showing how a hormone known to affect appetite turns off the brain’s ability to experience pleasure when an animal is stressed. This hormone, melanocortin, signals to an ancient and almost universal apparatus deep in the brain called the reward circuit, which has evolved to guide animals toward resources, behaviors and environments — such as food, sex and warmth — that enhance their prospects for survival.

"This is the first study to suggest that we should look at the role of melanocortin in depression-related syndromes," said Eric Nestler, MD, PhD, professor and chair of neuroscience and director of the Friedman Brain Institute at Mount Sinai School of Medicine in New York. Nestler was not involved in the study but is familiar with its contents.

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ScienceDaily (July 9, 2012) — A hormone with anti-diabetic properties also reduces depression-like symptoms in mice, researchers from the School of Medicine at the UT Health Science Center San Antonio reported July 9.

All types of current antidepressants, including tricyclics and selective serotonin reuptake inhibitors, increase the risk for type 2 diabetes. “The finding offers a novel target for treating depression, and would be especially beneficial for those depressed individuals who have type 2 diabetes or who are at high risk for developing it,” said the study’s senior author, Xin-Yun Lu, Ph.D., associate professor of pharmacology and psychiatry and member of the Barshop Institute for Longevity and Aging Studies at the UT Health Science Center.

The hormone, called adiponectin, is secreted by adipose tissue and sensitizes the body to the action of insulin, a hormone that lowers blood sugar. “We showed that adiponectin levels in plasma are reduced in a chronic social defeat stress model of depression, which correlates with the degree of social aversion,” Dr. Lu said.

Facing Goliath over and over

In the study mice were exposed to 14 days of repeated social defeat stress. Each male mouse was introduced to the home cage of an unfamiliar, aggressive resident mouse for 10 minutes and physically defeated. After the defeat, the resident mouse and the intruder mouse each were housed in half of the cage separated by a perforated plastic divider to allow visual, olfactory and auditory contact for the remainder of the 24-hour period. Mice were exposed to a new resident mouse cage and subjected to social defeat each day. Plasma adiponectin concentrations were determined after the last social defeat session. Defeated mice displayed lower plasma adiponectin levels.

Withdrawal, lost pleasure and helplessness

When adiponectin concentrations were reduced by deleting one allele of the adiponectin gene or by a neutralizing antibody, mice were more susceptible to stress-induced social withdrawal, anhedonia (lost capacity to experience pleasure) and learned helplessness.

Mice that were fed a high-fat diet (60 percent calories from fat) for 16 weeks developed obesity and type 2 diabetes. Administration of adiponectin to these mice and mice of normal weight produced antidepressant-like effects.

Possible innovative approach for depression

"These findings suggest a critical role of adiponectin in the development of depressive-like behaviors and may lead to an innovative therapeutic approach to fight depression," Dr. Lu said.

A novel approach would benefit thousands. “So far, only about half of the patients suffering from major depressive disorders are treated to the point of remission with antidepressant drugs,” Dr. Lu said. “The prevalence of depression in the diabetic population is two to three times higher than in the non-diabetic population. Unfortunately, the use of current antidepressants can worsen the control of diabetic patients. Adiponectin, with its anti-diabetic activity, would serve as an innovative therapeutic target for depression treatments, especially for those individuals with diabetes or prediabetes and perhaps those who fail to respond to currently available antidepressants.”

Source: Science Daily