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.”

UAB researchers cure type 1 diabetes in dogs

Researchers from the Universitat Autònoma de Barcelona (UAB), led by Fàtima Bosch, have shown for the first time that it is possible to cure diabetes in large animals with a single session of gene therapy. As published this week in Diabetes, the principal journal for research on the disease, after a single gene therapy session, the dogs recover their health and no longer show symptoms of the disease. In some cases, monitoring continued for over four years, with no recurrence of symptoms.

The therapy is minimally invasive. It consists of a single session of various injections in the animal’s rear legs using simple needles that are commonly used in cosmetic treatments. These injections introduce gene therapy vectors, with a dual objective: to express the insulin gene, on the one hand, and that of glucokinase, on the other. Glucokinase is an enzyme that regulates the uptake of glucose from the blood. When both genes act simultaneously they function as a “glucose sensor”, which automatically regulates the uptake of glucose from the blood, thus reducing diabetic hyperglycemia (the excess of blood sugar associated with the disease).

As Fàtima Bosch, the head researcher, points out, “this study is the first to demonstrate a long-term cure for diabetes in a large animal model using gene therapy.”

This same research group had already tested this type of therapy on mice, but the excellent results obtained for the first time with large animals lays the foundations for the clinical translation of this gene therapy approach to veterinary medicine and eventually to diabetic patients.

The study was led by the head of the UAB’s Centre for Animal Biotechnology and Gene Therapy (CBATEG) Fàtima Bosch, and involved the Department of Biochemistry and Molecular Biology of the UAB, the Department of Medicine and Animal Surgery of the UAB, the Faculty of Veterinary Science of the UAB, the Department of Animal Health and Anatomy of the UAB, the Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), the Children’s Hospital of Philadelphia (USA) and the Howard Hughes Medical Institute of Philadelphia (USA).

Stroke Survivors with PTSD More Likely to Avoid Treatment

A new survey of stroke survivors has shown that those with post-traumatic stress disorder (PTSD) are less likely to adhere to treatment regimens that reduce the risk of an additional stroke. Researchers found that 65 percent of stroke survivors with PTSD failed to adhere to treatment, compared with 33 percent of those without PTSD. The survey also suggests that nonadherence in PTSD patients is partly explained by increased ambivalence toward medication. Among stroke survivors with PTSD, approximately one in three (38 percent) had concerns about their medications. Results of the study, led by Columbia University Medical Center researchers, are published today in the British Journal of Health Psychology.

According to data from the American Stroke Association, nearly 795,000 Americans each year suffer a new or recurrent stroke. Stroke is the fourth-leading cause of death and the top cause of disability in the United States. Survivors of strokes are often prescribed treatment regiments, including antiplatelet agents, antihypertensive agents, and statins, which help reduce the risk of subsequent strokes. Previous research has shown that PTSD triggered by medical events—which affects 18 percent of stroke survivors—may impair recovery.

“Unfortunately, too many stroke survivors are not compliant with these regimens, even though we know that adherence to post-stroke treatment regimens is one of the most important components of reducing the risk of a future stroke,” said Ian M. Kronish, MD, MPH, assistant professor of medicine (Center for Behavioral Cardiovascular Health) and one of the study’s authors.

“For those with PTSD, this study shows that concerns about medications are a significant barrier to treatment adherence. Stroke survivors should be assessed for concerns about medications and PTSD symptoms, so that interventions may be introduced as early as possible to get patients back on track to avoid future stroke events.”

Diuretic Drug Offers Latest Hope for Autism Treatment

A drug used for decades to treat high blood pressure and other conditions has shown promise in a small clinical trial for autism. The drug, bumetanide, reduced the overall severity of behavioral symptoms after 3 months of daily treatment. The researchers say that many parents of children who received the drug reported that their children were more “present” and engaged in social interactions after taking it. The new findings are among several recent signs that treatments to address the social deficits at the core of autism may be on the horizon.

Several lines of evidence suggest that autism interferes with the neurotransmitter GABA, which typically puts a damper on neural activity. Bumetanide may enhance the inhibitory effects of GABA, and the drug has been used safely as a diuretic to treat a wide range of heart, lung, and kidney conditions. In the new study, researchers led by Yehezkel Ben-Ari at the Mediterranean Institute of Neurobiology in Marseille, France, recruited 60 autistic children between the ages of 3 and 11 and randomly assigned them to receive either a daily pill of bumetanide or a placebo. (Neither the children’s parents nor the researchers who assessed the children knew who received the actual drug).

As a group, those who got bumetanide improved by 5.6 points on a 60-point scale that’s often used to assess behaviors related to autism, the researchers report today in Translational Psychiatry. That was enough to nudge the group average just under the cutoff for severe autism and into the mild to medium category. The study did not look directly at whether the drug improved all symptoms equally or some more than others. “We have some indications that the symptoms particularly ameliorated with bumetanide are the genuine core symptoms of autism, namely communication and social interactions,” Ben-Ari says. More work will be needed to verify that impression. Ben-Ari says his team is now preparing for a larger, multicenter trial in Europe.

Drug May Offer New Approach to Treating Insomnia

A new drug may bring help for people with insomnia, according to a study published in the November 28, 2012, online issue of Neurology®, the medical journal of the American Academy of Neurology.

The drug, suvorexant, blocks the chemical messengers in the brain called orexins, which regulate wakefulness. Other drugs for insomnia affect different brain receptors.

Taking the drug suvorexant increased the amount of time people spent asleep during the night, according to the study. The study involved 254 people ages 18 to 64 who were in good physical and mental health but had insomnia that was not due to another medical condition.

The participants took either the drug or a placebo for four weeks, then switched to the other treatment for another four weeks. The participants spent the night in a sleep laboratory with their sleep monitored on the first night with each treatment and then again in the fourth week of each treatment.

While taking the drug, participants’ “sleep efficiency,” which reflects the total amount of time they slept during a fixed, eight hour time in bed, improved by 5 to 13 percent compared to those taking the placebo. They also experienced 21 to 37 fewer minutes awake during the night after they had fallen asleep than those who took the placebo. “This study provides evidence that suvorexant may offer a successful alternative strategy for treating insomnia,” said study author W. Joseph Herring, MD, PhD, of North Wales, Penn., Executive Director of Clinical Research with Merck, the maker of suvorexant, and a member of the American Academy of Neurology. “Suvorexant was generally well-tolerated, and there were no serious side effects.”

Herring said larger, longer studies have recently been conducted on suvorexant, along with studies to determine whether the drug could be safe and effective for elderly people, who make up a large percentage of those suffering from insomnia.

Combination of two pharmaceuticals proves effective in the treatment of multiple sclerosis

A new substance class for the treatment of multiple sclerosis and other neurodegenerative diseases now promises increased efficacy paired with fewer side effects. To achieve this, a team of scientists under the leadership of Prof. Gunter Fischer (Max Planck Research Unit for Enzymology of Protein Folding, Halle/Saale, Germany) and Dr. Frank Striggow (German Center for Neurodegenerative Diseases (DZNE)) have combined two already approved pharmaceutical substances with each other using a chemical linker structure. The objectives of this combination are to ensure maximum brain cell protection on the one hand and the suppression of unwanted side effects on the other. The new class of substances has now been registered with the European Patent Office as the DZNE’s first patent in the form of a joint patent application with the Max Planck Research Unit. “The patent approval process can take several years. During this phase we are planning to conclude the pre-clinical development. It is our aim to start with clinical research and development at the earliest possible time. Overall, we have identified substantial therapeutic potential as far as chronic and age-related neurodegenerative diseases are concerned,” comments Dr. Frank Striggow.

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Experimental Drug Improves Memory in Mice with Multiple Sclerosis

Johns Hopkins researchers report the successful use of a form of MRI to identify what appears to be a key biochemical marker for cognitive impairment in the brains of people with multiple sclerosis (MS). In follow-up experiments on mice with a rodent form of MS, researchers were able to use an experimental compound to manipulate that same marker and dramatically improve learning and memory.

Half of people with MS experience learning and memory problems, for which there is no approved treatment, along with movement abnormalities that characterize the debilitating autoimmune disorder.

"We have a potentially novel treatment for cognitive impairment in MS, a devastating condition on the rise that affects at least 400,000 people in the United States," says study leader Adam I. Kaplin, M.D., Ph.D., an assistant professor of psychiatry and behavioral sciences and neurology at the Johns Hopkins University School of Medicine.

Kaplin cautions that the treatment has so far been used only in mouse models of MS and is years away from clinical trials in people.

Nevertheless, he says, the research, described in the Proceedings of the National Academy of Sciences published online on Nov. 19, has the potential to speed development of new drugs to treat cognitive impairment not only in MS patients, but also in patients with Alzheimer’s disease and other neurological conditions.

Mayo Clinic Researchers Develop New Tools to Better Treat ADHD Patients in Early Stages

Mayo Clinic researchers are presenting new findings on the early treatment of child and adolescent attention deficit hyperactivity disorder this week at the American Academy of Childhood and Adolescent Psychiatry annual meeting in San Francisco. They include a method to get better input from parents and teachers of children who are being diagnosed with ADHD for the first time — allowing for more effective treatment upon the first consultation. Researchers also showed how a tool can help clinicians better diagnose and treat children who have both ADHD and oppositional defiance disorder.

(Image credit: Psyc3330 w11, Wikimedia Commons)