Depression Research Leads to Promising Discoveries

Findings add to knowledge about major depressive disorder and uncover ways to speed its diagnosis and treatment.

Researchers at MGH and elsewhere are hard at work looking for ways to ease the distress experienced by people with major depressive disorder (MDD), and some are reporting impressive preliminary results. Among their achievements, scientists have created the first blood test that can quickly and accurately diagnose MDD, and discovered two quick-acting antidepressant drugs whose mechanisms of action differ from those of current antidepressants.

“Scientists are looking for treatments that work more rapidly, that work for a greater number of patients, and that can be individually matched to patients so that people don’t have to go through multiple trials to find a medication that works for them,” says George Papakostas, MD, a researcher and Director of Treatment-Resistant Depression Studies at MGH’s Depression and Clinical Research Program. “The recent developments have been especially exciting, since they address some of these major challenges in depression treatment. There’s no doubt that we are making progress.”

Although still in the early stages, the latest research advances may one day help the estimated 21 million Americans who suffer from depression. As many as 49 percent of these individuals fail to respond to treatment with antidepressant medications or therapy, and continue to suffer symptoms that include chronic feelings of sadness, joylessness, guilt, irritability, hopelessness, fatigue, appetite or sleep disturbances, and thoughts of suicide.

Effective therapies for MDD will not only help people find relief from debilitating psychological problems, but also improve their overall health. People with MDD face a greater likelihood of cognitive decline and an increased incidence of physical symptoms, such as back, joint and muscle pain, headache, digestive and even cardiovascular disease. MDD is also closely linked to substance abuse, and research suggests it may nearly double the risk of mortality from all causes, including accidents and suicide.

Biological test

A team of MGH researchers headed by Dr. Papakostas contributed to progress against MDD when they helped develop the first objective biological test for the disorder. In a small pilot study, the scientists introduced a special blood test designed to detect nine biomarkers associated with MDD, including molecules linked to stress and inflammation. The test was administered to volunteers who had been previously diagnosed with MDD by other means, and it identified MDD with 90 percent accuracy. The test, which will soon be evaluated in larger clinical trials, is expected to speed the process of diagnosing MDD and help in finding effective treatments, Dr. Papakostas says.

“Examining patients’ biological fingerprints will allow us to determine conclusively whether their symptoms are associated with MDD and decide which specific treatment is most likely to relieve their specific type of depression,” he explains.

Innovative drugs

Two experimental drugs that work through the brain’s glutamate chemical messenger system—which plays a role in learning and memory—have produced rapid and dramatic improvement in treatment-resistant MDD patients, without major side effects. In preliminary trials, the drugs appear to be more effective than widely used selective serotonin reuptake inhibitor (SSRI) antidepressants such as Prozac, which target the serotonin and norepinephrine neurotransmitter systems. A single dose of either drug, GLYX-13 or AZD6765, reduces depression in a matter of hours or days, as opposed to a time lag of up to eight weeks between the initiation of treatment and response to treatment that is typical of most current antidepressant therapies.

“These drugs work by blocking receptors for glutamate that become hyperactive in people with MDD,” says Dr. Papakostas. “Blocking these receptors appears to stimulate the repair of connections between brain cells that have been damaged by stress and depression. The new drugs were developed in an attempt to duplicate the impressive antidepressant effects of another drug, ketamine, but without the serious negative side effects such as psychosis and hallucinations that are associated with that compound. The researchers wanted to affect the same receptors in the brain, but not shut them down completely as ketamine does—and they appear to have accomplished that.”

GLYX-13: In early trials, one intravenous infusion of this drug provided relief for patients with treatment-resistant MDD within 24 hours, and its antidepressant effects lasted for about one week—nearly twice the effect size achieved after repeated dosing with other antidepressant drugs over a four- to six-week period. Side effects were mild to moderate, according to a report presented Dec. 6, 2012 before the American College of Neuropsychopharmacology. The compound is in phase II trials at 20 sites in the U.S. to test the effects of repeated doses, and plans are underway to develop an oral version of the drug. GLYX-13 is considered a major breakthrough in depression treatment, although questions remain about its safety, the efficacy of long-term use, whether certain patient populations might fail to respond, and whether stopping use might produce undesirable effects.

AZD6765: In a preliminary trial, AZD6765 reduced depression within as little as 80 minutes in 32 percent of treatment-resistant patients who received it. This experimental drug is delivered by infusion, but lasts only about half an hour, although residual antidepressant effects may continue for two days for some patients. Side effects are minor and include dizziness and nausea. In a report published Dec. 1, 2012 in the online edition of the journal Biological Psychiatry, the researchers recommended further trials to test whether higher dosages and repeated infusions might produce longer-lasting effects.

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