Posts tagged antidepressants
Articles and news from the latest research reports.
First UK study of ketamine for people with severe depression
The first UK study of the use of ketamine intravenous infusions in people with treatment-resistant depression has been carried out in an NHS clinic by researchers at Oxford Health NHS Foundation Trust and the University of Oxford.
'Ketamine is a promising new antidepressant which works in a different way to existing antidepressants. We wanted to see whether it would be safe if given repeatedly, and whether it would be practical in an NHS setting. We especially wanted to check that repeated infusions didn't cause cognitive problems,' explains principal investigator Dr Rupert McShane, a consultant psychiatrist at Oxford Health and a researcher in Oxford University's Department of Psychiatry.
The researchers confirmed that ketamine has a rapid antidepressant effect in some patients with severe depression who have not responded to other treatments. These are patients suffering from severe depression which may have lasted years despite multiple antidepressants and talking therapies. Although many patients relapsed within a day or two, 29% had benefit which lasted at least three weeks and 15% took over two months to relapse.
Ketamine did not cause cognitive or bladder side effects when given on up to six occasions, although some people did experience other side effects such as anxiety during the infusion or being sick. The team have now given over 400 infusions to 45 patients and are exploring ways to maintain the effect. They report their findings in the Journal of Psychopharmacology. The study was funded by National Institute for Health Research (NIHR) Research for Patient Benefit Programme.
Scientists find a new mechanism underlying depression
The World health Organization calls depression “the leading cause of disability worldwide,” causing more years of disability than cancer, HIV/AIDS, and cardiovascular and respiratory diseases combined. In any given year, 5-7% of the world’s population experiences a major depressive episode, and one in six people will at some point suffer from the disease.
Despite recent progress in understanding depression, scientists still don’t understand the biological mechanisms behind it well enough to deliver effective prevention and therapy. One possible reason is that almost all research focuses on the brain’s neurons, while the involvement of other brain cells has not been thoroughly examined.
Now researchers at the Hebrew University of Jerusalem have shown that changes in one type of non-neuronal brain cells, called microglia, underlie the depressive symptoms brought on by exposure to chronic stress. In experiments with animals, the researchers were able to demonstrate that compounds that alter the functioning of microglia can serve as novel and efficient antidepressant drugs.
The findings were published in Molecular Psychiatry, the premier scientific journal in psychiatry and one of the leading journals in medicine and the neurosciences.
The research was conducted by Prof. Raz Yirmiya, director of the Hebrew University’s Psychoneuroimmunology Laboratory, and his doctoral student Tirzah Kreisel, together with researchers at Prof. Yirmiya’s laboratory and at the University of Colorado in Boulder, USA.
The researchers examined the involvement of microglia brain cells in the development of depression following chronic exposure to stress. Comprising roughly 10% of brain cells, microglia are the representatives of the immune system in the brain; but recent studies have shown that these cells are also involved in physiological processes not directly related to infection and injury, including the response to stress.
The researchers mimicked chronic unpredictable stress in humans — a leading causes of depression — by exposing mice to repeated, unpredictable stressful conditions over a period of 5 weeks. The mice developed behavioral and neurological symptoms mirroring those seen in depressed humans, including a reduction in pleasurable activity and in social interaction, as well as reduced generation of new brain cells (neurogenesis) — an important biological marker of depression.
The researchers found that during the first week of stress exposure, microglia cells undergo a phase of proliferation and activation, reflected by increased size and production of specific inflammatory molecules, after which some microglia begin to die. Following the 5 weeks of stress exposure, this phenomenon led to a reduction in the number of microglia, and to a degenerated appearance of some microglia cells, particularly in a specific region of the brain involved in responding to stress.
When the researchers blocked the initial stress-induced activation of microglia with drugs or genetic manipulation, they were able to stop the subsequent microglia cell death and decline, as well as the depressive symptoms and suppressed neurogenesis. However, these treatments were not effective in “depressed” mice, which were already exposed to the 5-weeks stress period and therefore had lower number of microglia. Based on these findings, the investigators treated the “depressed” mice with drugs that stimulated the microglia and increased their number to a normal level.
Prof. Yirmiya said, “We were able to demonstrate that such microglia-stimulating drugs served as effective and fast-acting antidepressants, producing complete recovery of the depressive-like behavioral symptoms, as well as increasing the neurogenesis to normal levels within a few days of treatment. In addition to the clinical importance of these results, our findings provide the first direct evidence that in addition to neurons, disturbances in the functioning of brain microglia cells have a role in causing psychopathology in general, and depression in particular. This suggests new avenues for drug research, in which microglia stimulators could serve as fast-acting antidepressants in some forms of depressive and stress-related conditions.”
The Hebrew University’s technology transfer company, Yissum, has applied for a patent for the treatment of some forms of depression by several specific microglia-stimulating drugs.
Ketamine acts as antidepressant by boosting serotonin
Ketamine is a potent anesthetic employed in human and veterinary medicine, and sometimes used illegally as a recreational drug. The drug is also a promising candidate for the fast treatment of depression in patients who do not respond to other medications. New research from the RIKEN Center for Life Science Technologies in Japan demonstrates using PET imaging studies on macaque monkeys that ketamine increases the activity of serotoninergic neurons in the brain areas regulating motivation. The researchers conclude that ketamine’s action on serotonin, often called the “feel-good neurotransmitter”, may explain its antidepressant action in humans.
The study, published today in the journal Translational Psychiatry demonstrates that Positron Emission Tomography (PET) molecular imaging studies may be useful in the diagnosis of major depressive disorder in humans, as well as the development of new antidepressants.
Ketamine has recently been shown to have an antidepressant action with short onset and long-term duration in patients suffering from treatment-resistant major depressive disorder, who do not respond to standard medications such as serotonin reuptake inhibitors, monoamine oxidase inhibitors and tricyclic antidepressants. However, the mechanisms underlying ketamine’s action on the depressive brain have remained unclear.
To understand the effects of ketamine on the serotonergic system in the brain, Dr. Hajime Yamanaka and Dr. Hirotaka Onoe, who has pioneered PET imaging on conscious non-human primates, together with an international team, performed a PET study on rhesus monkeys.
The team performed PET imaging studies on four rhesus monkeys with two tracer molecules related to serotonin (5-HT) that bind highly selectively to the serotonin 1B receptor 5-HT1B and the serotonin transporter SERT.
From the analysis of the 3 dimensional images generated by the PET scans, the researchers could infer that ketamine induces an increase in the binding of serotonin to its receptor 5-HT1B in the nucleus accumbens and the ventral pallidum, but a decrease in binding to its transporter SERT in these brain regions. The nucleus accumbens and the ventral pallidum are brain regions associated with motivation and both have been shown to be involved in depression.
In addition, the researchers demonstrate that treatment with NBQX, a drug known to block the anti-depressive effect of ketamine in rodents by selectively blocking the glutamate AMPA receptor, cancels the action of ketamine on 5-HT1B but not on SERT binding.
Taken together, these findings indicate that ketamine may act as an antidepressant by increasing the expression of postsynaptic 5-HT1B receptors, and that this process is mediated by the glutamate AMPA receptor.
A Personal Antidepressant for Every Genome
TAU researchers discover gene that may predict human responses to specific antidepressants
Selective serotonin reuptake inhibitors (SSRIs) are the most commonly prescribed antidepressants, but they don’t work for everyone. What’s more, patients must often try several different SSRI medications, each with a different set of side effects, before finding one that is effective. It takes three to four weeks to see if a particular antidepressant drug works. Meanwhile, patients and their families continue to suffer.
Now researchers at Tel Aviv University have discovered a gene that may reveal whether people are likely to respond well to SSRI antidepressants, both generally and in specific formulations. The new biomarker, once it is validated in clinical trials, could be used to create a genetic test, allowing doctors to provide personalized treatment for depression.
Doctoral students Keren Oved and Ayelet Morag led the research under the guidance of Dr. David Gurwitz of the Department of Molecular Genetics and Biochemistry at TAU’s Sackler Faculty of Medicine and Dr. Noam Shomron of the Department of Cell and Developmental Biology at TAU’s Sackler Faculty of Medicine and Sagol School of Neuroscience. Sackler faculty members Prof. Moshe Rehavi of the Department of Physiology and Pharmacology and Dr. Metsada Pasmnik-Chor of the Bioinformatics Unit were coauthors of the study, published in Translational Psychiatry.
"SSRIs only work for about 60 percent of people with depression," said Dr. Gurwitz. "A drug from other families of antidepressants could be effective for some of the others. We are working to move the treatment of depression from a trial-and-error approach to a best-fit, personalized regimen."
Good news for the depressed
More than 20 million Americans each year suffer from disabling depression that requires clinical intervention. SSRIs such as Prozac, Zoloft, and Celexa are the newest and the most popular medications for treatment. They are thought to work by blocking the reabsorption of the neurotransmitter serotonin in the brain, leaving more of it available to help brain cells send and receive chemical signals, thereby boosting mood. It is not currently known why some people respond to SSRIs better than others.
To find genes that may be behind the brain’s responsiveness to SSRIs, the TAU researchers first applied the SSRI Paroxetine — brand name Paxil — to 80 sets of cells, or “cell lines,” from the National Laboratory for the Genetics of Israeli Populations, a biobank of genetic information about Israeli citizens located at TAU’s Sackler Faculty of Medicine and directed by Dr. Gurwitz. The TAU researchers then analyzed and compared the RNA profiles of the most and least responsive cell lines. A gene called CHL1 was produced at lower levels in the most responsive cell lines and at higher levels in the least responsive cell lines. Using a simple genetic test, doctors could one day use CHL1 as a biomarker to determine whether or not to prescribe SSRIs.
"We want to end up with a blood test that will allow us to tell a patient which drug is best for him," said Oved. "We are at the early stages, working on the cellular level. Next comes testing on animals and people."
Rethinking how antidepressants work
The TAU researchers also wanted to understand why CHL1 levels might predict responsiveness to SSRIs. To this end, they applied Paroxetine to human cell lines for three weeks — the time it takes for a clinical response to SSRIs. They found that Paroxetine caused increased production of the gene ITGB3 — whose protein product is thought to interact with CHL1 to promote the development of new neurons and synapses. The result is the repair of dysfunctional signaling in brain regions controlling mood, which may explain the action of SSRI antidepressants.
This explanation differs from the conventional theory that SSRIs directly relieve depression by inhibiting the reabsorption of the neurotransmitter serotonin in the brain. Dr. Shomron adds that the new explanation resolves the longstanding mystery as to why it takes at least three weeks for SSRIs to ease the symptoms of depression when they begin inhibiting reabsorption after a couple days — the development of neurons and synapses takes weeks, not days.
The TAU researchers are working to confirm their findings on the molecular level and with animal models. Adva Hadar, a master’s student in Dr. Gurwitz’s lab, is using the same approach to find biomarkers for the personalized treatment of Alzheimer’s disease.
(Source: aftau.org)
Studies pinpoint specific brain areas and mechanisms associated with depression and anxiety
Research released today reveals new mechanisms and areas of the brain associated with anxiety and depression, presenting possible targets to understand and treat these debilitating mental illnesses. The findings were presented at Neuroscience 2013, the annual meeting of the Society for Neuroscience and the world’s largest source of emerging news about brain science and health.
More than 350 million people worldwide suffer from clinical depression and between 5 and 25 percent of adults suffer from generalized anxiety, according to the World Health Organization. The resulting emotional and financial costs to people, families, and society are significant. Further, antidepressants are not always effective and often cause severe side effects.
Today’s new findings show that:
- A molecule in the immune system may contribute to depression, suggesting a potential biomarker for the disease (Georgia Hodes, PhD, abstract 542.1, see attached summary).
- Decreasing a chemical signal in the amygdala, a brain area associated with emotional processing, produces antidepressant-like effects in mice (Yann Mineur, PhD, abstract 504, see attached summary).
- MicroRNAs, tiny molecules that alter gene expression, correlate with how mice respond to socially stressful situations that cause depressive-like behavior. The findings may help determine why some people are more likely to suffer from depression than others (Karen Scott, PhD, abstract 731.2, see attached summary).
Other recent findings discussed show that:
- A pathway between two brain regions, the amygdala and the hippocampus, plays a significant role in anxiety. Shutting down this connection can decrease anxiety-like behavior in mice (Ada Felix-Ortiz, MS, presentation 393.01, see attached speaker summary).
- Aversive experiences can change how humans, particularly those with anxiety disorders, perceive stimuli. After a severe negative incident, patients with anxiety disorders over-generalize the experience and have increased emotional responses to subsequent similar situations (Rony Paz, PhD, presentation 295.05, see attached speaker summary).
“Today’s findings represent our rapidly growing understanding of the individual molecules and brain circuits that may contribute to depression and anxiety,” said press conference moderator Lisa Monteggia, PhD, of the University of Texas Southwestern Medical Center, an expert on mechanisms of antidepressant action. “These exciting discoveries represent the potential for significant changes in how we diagnose and treat these illnesses that touch millions.”
Research gives new insight into how antidepressants work in the brain
Research from Oregon Health & Science University’s Vollum Institute, published in the current issue of Nature (1, 2), is giving scientists a never-before-seen view of how nerve cells communicate with each other. That new view can give scientists a better understanding of how antidepressants work in the human brain — and could lead to the development of better antidepressants with few or no side effects.
The article in today’s edition of Nature came from the lab of Eric Gouaux, Ph.D., a senior scientist at OHSU’s Vollum Institute and a Howard Hughes Medical Institute Investigator. The article describes research that gives a better view of the structural biology of a protein that controls communication between nerve cells. The view is obtained through special structural and biochemical methods Gouaux uses to investigate these neural proteins.
The Nature article focuses on the structure of the dopamine transporter, which helps regulate dopamine levels in the brain. Dopamine is an essential neurotransmitter for the human body’s central nervous system; abnormal levels of dopamine are present in a range of neurological disorders, including Parkinson’s disease, drug addiction, depression and schizophrenia. Along with dopamine, the neurotransmitters noradrenaline and serotonin are transported by related transporters, which can be studied with greater accuracy based on the dopamine transporter structure.
The Gouaux lab’s more detailed view of the dopamine transporter structure better reveals how antidepressants act on the transporters and thus do their work.
The more detailed view could help scientists and pharmaceutical companies develop drugs that do a much better job of targeting what they’re trying to target — and not create side effects caused by a broader blast at the brain proteins.
"By learning as much as possible about the structure of the transporter and its complexes with antidepressants, we have laid the foundation for the design of new molecules with better therapeutic profiles and, hopefully, with fewer deleterious side effects," said Gouaux.
Gouaux’s latest dopamine transporter research is also important because it was done using the molecule from fruit flies, a dopamine transporter that is much more similar to those in humans than the bacteria models that previous studies had used.
The dopamine transporter article was one of two articles Gouaux had published in today’s edition of Nature. The other article also dealt with a modified amino acid transporter that mimics the mammalian neurotransmitter transporter proteins targeted by antidepressants. It gives new insights into the pharmacology of four different classes of widely used antidepressants that act on certain transporter proteins, including transporters for dopamine, serotonin and noradrenaline. The second paper in part was validated by findings of the first paper — in how an antidepressant bound itself to a specific transporter.
"What we ended up finding with this research was complementary and mutually reinforcing with the other work — so that was really important," Gouaux said. "And it told us a great deal about how these transporters work and how they interact with the antidepressant molecules."
(Source: ohsu.edu)
Antidepressant drug induces a juvenile-like state in neurons of the prefrontal cortex
For long, brain development and maturation has been thought to be a one-way process, in which plasticity diminishes with age. The possibility that the adult brain can revert to a younger state and regain plasticity has not been considered, often. In a paper appearing on November 4 in the online open-access journal Molecular Brain, Dr. Tsuyoshi Miyakawa and his colleagues from Fujita Health University show that chronic administration of one of the most widely used antidepressants fluoxetine (FLX, which is also known by trade names like Prozac, Sarafem, and Fontex and is a selective serotonin reuptake inhibitor) can induce a juvenile-like state in specific types of neurons in the prefrontal cortex of adult mice.
In their study, FLX-treated adult mice showed reduced expression of parvalbumin and perineuronal nets, which are molecular markers for maturation and are expressed in a certain group of mature neurons in adults, and increased expression of an immature marker, which typically appears in developing juvenile brains, in the prefrontal cortex. These findings suggest the possibility that certain types of adult neurons in the prefrontal cortex can partially regain a youth-like state; the authors termed this as induced-youth or iYouth. These researchers as well as other groups had previously reported similar effects of FLX in the hippocampal dentate gyrus, basolateral amygdala, and visual cortex, which were associated with increased neural plasticity in certain types of neurons. This study is the first to report on “iYouth” in the prefrontal cortex, which is the brain region critically involved in functions such as working memory, decision-making, personality expression, and social behavior, as well as in psychiatric disorders related to deficits in these functions.
Network dysfunction in the prefrontal cortex and limbic system, including the hippocampus and amygdala, is known to be involved in the pathophysiology of depressive disorders. Reversion to a youth-like state may mediate some of the therapeutic effects of FLX by restoring neural plasticity in these regions. On the other hand, some non-preferable aspects of FLX-induced pseudo-youth may play a role in certain behavioral effects associated with FLX treatment, such as aggression, violence, and psychosis, which have recently received attention as adverse effects of FLX. Interestingly, expression of the same molecular markers of maturation, as discussed in this study, has been reported to be decreased in the prefrontal cortex of postmortem brains of patients with schizophrenia. This raises the possibility that some of FLX’s adverse effects may be attributable to iYouth in the same type of neurons in this region. Currently, basic knowledge on this is lacking, and there are several unanswered questions like: What are the molecular and cellular mechanisms underlying iYouth? What are the differences between actual youth and iYouth? Is iYouth good or bad? Future studies to answer these questions could potentially revolutionize the prevention and/or treatment of various neuropsychiatric disorders and aid in improving the quality of life for an aging population.
(Source: eurekalert.org)
Experiments with neutrons at the Technische Universität München (TUM) show that the antidepressant lithium accumulates more strongly in white matter of the brain than in grey matter. This leads to the conclusion that it works differently from synthetic psychotropic drugs. The tissue samples were examined at the Research Neutron Source Heinz Maier-Leibnitz (FRM II) with the aim of developing a better understanding of the effects this substance has on the human psyche.
At present lithium is most popular for its use in rechargeable batteries. But for decades now, lithium has also been used to treat various psychological diseases such as depressions, manias and bipolar disorders. But, the exact biological mode of action in certain brain regions has hardly been understood. It is well known that lithium lightens moods and reduces aggression potential.
Because it is so hard to dose, doctors have been reluctant to prescribe this “universal drug”. Nonetheless, a number of international studies have shown that a higher natural lithium content in drinking water leads to a lower suicide rate in the general population. Lithium accumulates in the brains of untreated people, too. This means that lithium, which has so far been regarded as unimportant, could be an essential trace element for humans.
Lithium detection with neutrons
This is what Josef Lichtinger is studying in his doctoral thesis at the Chair for Hadron and Nuclear Physics (E12) at the Technische Universität München. From the Institute for Forensic Medicine at the Ludwig-Maximilians-Universität Munich (LMU) he received tissue samples taken from patients treated with lithium, untreated patients and healthy test persons. The physicist exposed these to a focused cold neutron beam of greatest intensity at the measuring station for prompt gamma activation analysis at FRM II.
Lithium reacts with neutrons in a very specific manner and decays to a helium and a tritium atom. Using a special detector developed by Josef Lichtinger, traces as low as 0.45 nanograms of lithium per gram of tissue can be measured. “It is impossible to make measurements as precise as those using the neutrons with any other method,” says Jutta Schöpfer, forensic scientist at the LMU in charge of several research projects on lithium distribution in the human body.
Lithium concentrates at the nerve-tracts
Lichtinger’s results are surprising: Only in the samples of a depressive patient treated with lithium did he observe a higher accumulation of lithium in the so-called white matter. This is the area in the brain where nerve tracts run. The lithium content in the neighboring grey matter was 3 to 4 times lower. Lithium accumulation in white matter was not observed in a number of untreated depressive patients. This points to the fact that lithium does not work in the space between nerve cells, like other psychotropic drugs, but within the nerve tracts themselves.
In a next step Josef Lichtinger plans to examine further tissue samples at TUM’s Research Neutron Source in order to confirm and expand his results. The goal is a space-resolved map showing lithium accumulation in the brain of a healthy and a depressive patient. This would allow the universal drug lithium to be prescribed for psychological disorders with greater precision and control. The project is funded by the German Research Foundation (DFG).
Publication:
J. Lichtinger et. al, „Position sensitive measurement of lithium traces in brain tissue with neutrons“, Med. Phys. 40, 023501 (2013)
Researchers Pinpoint Molecular Path that Makes Antidepressants Act Quicker in Mouse Model
Understanding alternate pathways for how mental meds work could lead to faster-acting drug targets
The reasons behind why it often takes people several weeks to feel the effect of newly prescribed antidepressants remains somewhat of a mystery – and likely, a frustration to both patients and physicians.
(Image: Mouse hippocampus expressing the Cre- virus. Credit: Julie Blendy, PhD; Brigitta Gunderson, PhD; Perelman School of Medicine, University of Pennsylvania)
Julie Blendy, PhD, professor of Pharmacology, at the Perelman School of Medicine, University of Pennsylvania; Brigitta Gunderson, PhD, a former postdoctoral fellow in the Blendy lab, and colleagues, have been working to find out why and if there is anything that can be done to shorten the time in which antidepressants kick in.
“Our goal is to find ways for antidepressants to work faster,” says Blendy.
The proteins CREB and CREM are both transcription factors, which bind to specific DNA sequences to control the “reading” of genetic information from DNA to messenger RNA (mRNA). Both CREB and CREM bind to the same 8-base-pair DNA sequence in the cell nucleus. But, the comparative influence of CREM versus CREB on the action of antidepressants is a “big unknown,” says Blendy.
CREB, and CREM to some degree, has been implicated in the pathophysiology of depression, as well as in the efficacy of antidepressants. However, whenever CREB is deleted, CREM is upregulated, further complicating the story.
Therefore, how an antidepressant works on the biochemistry and behavior in a mouse in which the CREB protein is deleted only in the hippocampus versus a wild type mouse in which CREM is overexpressed let the researchers tease out the relative influence of CREB and CREM on the pharmacology of an antidepressant. They saw the same results in each type of mouse line – increased nerve-cell generation in the hippocampus and a quicker response to the antidepressant. Their findings appear in the Journal of Neuroscience.
“This is the first demonstration of CREM within the brain playing a role in behavior, and specifically in behavioral outcomes, following antidepressant treatment,” says Blendy.
A Flood of Neurotransmitters
Antidepressants like SSRIs, NRIs, and older tricyclic drugs work by causing an immediate flood of neurotransmitters like serotonin, norepinephrine, and in some cases dopamine, into the synaptic space. However, it can take three to four weeks for patients to feel changes in mental state. Long-term behavioral effects of the drugs may take longer to manifest themselves, because of the need to activate CREB downstream targets such as BDNF and trkB, or as of yet unidentified targets, which could also be developed as new antidepressant drug targets.
The Penn team compared the behavior of the control, wild-type mice to the CREB mutant mice using a test in which the mouse is trained to eat a treat – Reese’s Pieces, to be exact – in the comfort of their home cage. The treat-loving mice are then placed in a new cage to make them anxious. They are given the treat again, and the time it takes for the mouse to approach the treat is recorded.
Animals that receive no drug treatment take a long time to venture out into the anxious environment to retrieve the treat, however, if given an antidepressant drug for at least three weeks, the time it takes a mouse to get the treat decreases significantly, from about 400 seconds to 100 seconds. In mice in which CREB is deleted or in mice in which CREM is upregulated, this reduction happens in one to two days versus the three weeks seen in wild-type mice.
The accelerated time to approach the treat in mice on the medication was accompanied by an increase in new nerve growth in the hippocampus.
“Our results suggest that activation of CREM may provide a means to accelerate the therapeutic efficacy of current antidepressant treatment,” says Blendy. Upregulation of CREM observed after CREB deletion, appears to functionally compensate for CREB loss at a behavioral level and leads to maintained or increased expression of some CREB target genes. The researchers’ next step is to identify any unique CREM target genes in brain areas such as the hippocampus, which may lead to the development of faster-acting antidepressants.
(Source: uphs.upenn.edu)
![The Search for the Best Depression Treatment
Brain scans, blood samples, and other diagnostic tests could one day direct doctors to the best treatments for depression patients and uncover the biological basis of the condition.
When someone is diagnosed with depression, patient and doctor often begin a long trial-and-error process of testing different treatments. Sometimes they work, sometimes they don’t, so patients may try several options before finding the best one. But in the future, a brain scan, blood test, or some combination could help guide doctors to the best drugs, or lead them to suggest talk therapy.
Recently, Emory University researcher Helen Mayberg reported that a PET scan, a commonly used imaging method, can reveal whether a patient will respond better to an antidepressant or cognitive behavioral therapy. And in May, Medscape reported that David Mischoulon of Massachusetts General Hospital presented findings that the amount of a particular protein in the blood of depression patients could indicate whether a patient would do better by adding a form of folic acid to his or her treatment.
A key goal of such research is to distinguish between causes of depression. “The presence of certain biomarkers might give us a clue whether [a particular patient’s] depression is truly biologically driven, or whether it is depression like sadness over an event,” says Mischoulon. “If we can identify people who have these biological bases, it might suggest these patients might do better with medications, as opposed to psychotherapies or meditation.”
According to the World Health Organization, depression is the leading cause of disability globally. Many people do not seek or do not have access to treatment, and among those who do, fewer than 40 percent of depression patients improve with the first type of treatment they try. The problem is not that treatments like antidepressants and cognitive behavioral therapy don’t work, it’s that no one treatment works for every patient. Researchers from many disciplines, from neuroscience to genomics, are studying this complex disorder, which likely represents many different conditions with unique origins and treatments. Large clinical trials to predict a patient’s response to therapy or drugs based on brain or body biomarkers could improve treatment for future patients and perhaps uncover a clearer understanding of depression’s origins.
“You see now a number of big studies on predictive biomarkers,” says Mayberg, who has pioneered pacemaker-like implants as a treatment for severe cases of depression. She’s also involved in a large study of patients who will be treated with antidepressants or cognitive behavioral therapy based on brain scans. “It’s going to be interesting over the next year or two to see how this plays out,” she says. One question will be whether researchers will be able to identify markers that are both unambiguous but also practical to test. Brain scans may be the best place to start, she says, because they focus on the origin of the condition, but once good biomarkers are identified via brain scan, surrogates found in the blood may provide a simpler and more affordable option.
One challenge for researchers is that depression is probably a conglomeration of many diseases, says Madhukar Trivedi, a University of Texas Southwestern researcher heading a large trial that is trying to distinguish patients who respond better to one type of antidepressant compared to another. “There are a lot of subtypes in depression, so any given marker, whether genetic, protein, imaging, or EEG, ends up accounting for only a small percentage of variance for any group of patients,” says Trivedi.
If these researchers are successful, they could dramatically change how depression is treated and perhaps diagnosed. Doctors in the United States use the Diagnostic and Statistical Manual of Mental Disorders, or DSM, to diagnose depression. The diagnoses are largely based on the collection of symptoms presented or described by patients. In May, the head of the National Institute of Mental Health, Thomas Insel, announced that his institution would focus its research in areas other than the categories presented by the DSM. “Patients with mental disorders deserve better,” he said.
Bruce Cuthbert is heading the NIMH’s project to establish new ways of studying mental illness and potentially to improve future versions of the DSM by more precisely identifying the brain abnormalities in various diseases, including depression. The idea behind the project is to map out the genetic, circuit, and cognitive aspects of mental illness and to focus on individual features of disorders instead of clinical diagnoses. It could provide the information necessary to improve the DSM so that it is based on neuroscience and not just collections of symptoms. “In the future, we might define the disorders differently, or we might not. But this project will provide a framework to look at neural systems and how they operate and how that contributes to disease,” says Cuthbert.
Perhaps more immediately, the NIMH project could help researchers tune clinical trials of drugs to the right patients by focusing on discrete symptoms. For example, anhedonia, the inability to feel pleasure or seek pleasure, is a major symptom of depression, but it is also found in other patients, such as those with schizophrenia. By recruiting patients with measurable anhedonia, drug developers may be more likely to succeed in clinical trials than if they focused only on depression patients, says Cuthbert.
The NIMH project could also help to identify biomarkers of depression. “It could give us a structure to look at the pathology through different markers of the disease,” says Trivedi. “The goal is fantastic, but the proof is going to come in doing it.”](http://40.media.tumblr.com/2cee06d8ba637a69d1ed2f2d29d4c882/tumblr_mr0drrDP3b1rog5d1o1_500.jpg)
The Search for the Best Depression Treatment
Brain scans, blood samples, and other diagnostic tests could one day direct doctors to the best treatments for depression patients and uncover the biological basis of the condition.
When someone is diagnosed with depression, patient and doctor often begin a long trial-and-error process of testing different treatments. Sometimes they work, sometimes they don’t, so patients may try several options before finding the best one. But in the future, a brain scan, blood test, or some combination could help guide doctors to the best drugs, or lead them to suggest talk therapy.
Recently, Emory University researcher Helen Mayberg reported that a PET scan, a commonly used imaging method, can reveal whether a patient will respond better to an antidepressant or cognitive behavioral therapy. And in May, Medscape reported that David Mischoulon of Massachusetts General Hospital presented findings that the amount of a particular protein in the blood of depression patients could indicate whether a patient would do better by adding a form of folic acid to his or her treatment.
A key goal of such research is to distinguish between causes of depression. “The presence of certain biomarkers might give us a clue whether [a particular patient’s] depression is truly biologically driven, or whether it is depression like sadness over an event,” says Mischoulon. “If we can identify people who have these biological bases, it might suggest these patients might do better with medications, as opposed to psychotherapies or meditation.”
According to the World Health Organization, depression is the leading cause of disability globally. Many people do not seek or do not have access to treatment, and among those who do, fewer than 40 percent of depression patients improve with the first type of treatment they try. The problem is not that treatments like antidepressants and cognitive behavioral therapy don’t work, it’s that no one treatment works for every patient. Researchers from many disciplines, from neuroscience to genomics, are studying this complex disorder, which likely represents many different conditions with unique origins and treatments. Large clinical trials to predict a patient’s response to therapy or drugs based on brain or body biomarkers could improve treatment for future patients and perhaps uncover a clearer understanding of depression’s origins.
“You see now a number of big studies on predictive biomarkers,” says Mayberg, who has pioneered pacemaker-like implants as a treatment for severe cases of depression. She’s also involved in a large study of patients who will be treated with antidepressants or cognitive behavioral therapy based on brain scans. “It’s going to be interesting over the next year or two to see how this plays out,” she says. One question will be whether researchers will be able to identify markers that are both unambiguous but also practical to test. Brain scans may be the best place to start, she says, because they focus on the origin of the condition, but once good biomarkers are identified via brain scan, surrogates found in the blood may provide a simpler and more affordable option.
One challenge for researchers is that depression is probably a conglomeration of many diseases, says Madhukar Trivedi, a University of Texas Southwestern researcher heading a large trial that is trying to distinguish patients who respond better to one type of antidepressant compared to another. “There are a lot of subtypes in depression, so any given marker, whether genetic, protein, imaging, or EEG, ends up accounting for only a small percentage of variance for any group of patients,” says Trivedi.
If these researchers are successful, they could dramatically change how depression is treated and perhaps diagnosed. Doctors in the United States use the Diagnostic and Statistical Manual of Mental Disorders, or DSM, to diagnose depression. The diagnoses are largely based on the collection of symptoms presented or described by patients. In May, the head of the National Institute of Mental Health, Thomas Insel, announced that his institution would focus its research in areas other than the categories presented by the DSM. “Patients with mental disorders deserve better,” he said.
Bruce Cuthbert is heading the NIMH’s project to establish new ways of studying mental illness and potentially to improve future versions of the DSM by more precisely identifying the brain abnormalities in various diseases, including depression. The idea behind the project is to map out the genetic, circuit, and cognitive aspects of mental illness and to focus on individual features of disorders instead of clinical diagnoses. It could provide the information necessary to improve the DSM so that it is based on neuroscience and not just collections of symptoms. “In the future, we might define the disorders differently, or we might not. But this project will provide a framework to look at neural systems and how they operate and how that contributes to disease,” says Cuthbert.
Perhaps more immediately, the NIMH project could help researchers tune clinical trials of drugs to the right patients by focusing on discrete symptoms. For example, anhedonia, the inability to feel pleasure or seek pleasure, is a major symptom of depression, but it is also found in other patients, such as those with schizophrenia. By recruiting patients with measurable anhedonia, drug developers may be more likely to succeed in clinical trials than if they focused only on depression patients, says Cuthbert.
The NIMH project could also help to identify biomarkers of depression. “It could give us a structure to look at the pathology through different markers of the disease,” says Trivedi. “The goal is fantastic, but the proof is going to come in doing it.”