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The activity of a single gene sets in motion some of the brain changes seen in depression, according to a new study. The finding suggests a promising target for potential therapies.

People with major depressive disorder, or major depression, have feelings of sadness, loss, anger or frustration that interfere with daily life for weeks or longer. The symptoms of depression also include memory loss and trouble thinking.

Past studies have found that people with major depression have brains that are physically different from those of non-depressed people. The depressed brain has a smaller prefrontal cortex, a region at the front of the brain that handles emotion and complicated thought. The area also has fewer and smaller neurons (nerve cells) in the depressed brain.

To gain insight into the neural mechanisms at work, a group led by Dr. Ronald Duman of Yale University began with data collected in a previous study. They had done a comparison of postmortem brains from 15 depressed people and 15 non-depressed people who were matched in age, ethnicity and gender. Using DNA microarray chips to analyze the activity of 20,000 genes, the researchers had found numerous genes that were expressed (turned on and off) differently in the brains of depressed people.

For the new study, the team focused specifically on genes related to synapses, the place where signals pass from one neuron to another. The work was funded in part by NIH’s National Institute of Mental Health (NIMH) and National Center for Research Resources (NCRR). The findings were published in the September 2012 issue of Nature Medicine.

Analysis revealed that about 30% of the genes with significantly lower expression in the depressed brains related to some aspect of synapse function. Further experiments found significantly reduced expression for 5 particular genes in the prefrontal cortex of depressed people.

The scientists searched for transcription factors—proteins that bind to the DNA of other genes to turn them on or off—that were capable of regulating the 5 genes. They found one called GATA1 that is expressed significantly more in the brains of people with major depressive disorder. Expression of the Gata1 gene in the prefrontal cortex was also higher in a rat model of depression.

Raising expression of Gata1 in cultured rat neurons decreased the expression of synapse-related genes. It also decreased the number of connections between neurons, supporting the idea that higher Gata1 expression can lead to the changes seen in depressed brains.

The researchers next tested the gene in rats and found that putting extra copies of Gata1 into their brains made them behave as if they were depressed.

“We show that circuits normally involved in emotion, as well as cognition, are disrupted when this single transcription factor is activated,” Duman explains.

These findings may point toward a new target for treatment. “We hope that by enhancing synaptic connections, either with novel medications or behavioral interventions, we can develop more effective antidepressant therapies,” says Duman.

— by Helen Fields

A drug that works through the same brain mechanism as the fast-acting antidepressant ketamine briefly improved treatment-resistant patients’ depression symptoms in minutes, with minimal untoward side effects, in a clinical trial conducted by the National Institutes of Health. The experimental agent, called AZD6765, acts through the brain’s glutamate chemical messenger system.

Existing antidepressants available through prescription, which work through the brain’s serotonin system, take a few weeks to work, imperiling severely depressed patients, who can be at high risk for suicide. Ketamine also works in hours, but its usefulness is limited by its potential for dissociative side-effects, including hallucinations. It is being studied mostly for clues to how it works.

“Our findings serve as a proof of concept that we can tap into an important component of the glutamate pathway to develop a new generation of safe, rapid-acting practical treatments for depression,” said Carlos Zarate, M.D., of the NIH’s National Institute of Mental Health, which conducted the research.

Zarate, and colleagues, reported on their results online Dec. 1, 2012 in the journal Biological Psychiatry.

AZD6765, like ketamine, works by blocking glutamate binding to a protein on the surface of neurons, called the NMDA receptor. It is a less powerful blocker of the NMDA receptor, which may be a reason why it is better tolerated than ketamine.

About 32 percent of 22 treatment-resistant depressed patients infused with ASD6765 showed a clinically meaningful antidepressant response at 80 minutes after infusion that lasted for about half an hour – with residual antidepressant effects lasting two days for some. By contrast, 52 percent of patients receiving ketamine show a comparable response, with effects still detectable at seven days. So a single infusion of ketamine produces more robust and sustained improvement, but most patients continue to experience some symptoms with both drugs.

However, depression rating scores were significantly better among patients who received AZD6765 than in those who received placebos. The researchers deemed this noteworthy, since, on average, these patients had failed to improve in seven past antidepressant trials, and nearly half failed to respond to electroconvulsive therapy (ECT).

The patients reported only minor side effects, such as dizziness and nausea, which were not significantly different from those experienced with the placebo.

Zarate and colleagues say their results warrant further trials with AZD6765, testing whether repeated infusions a few times per week or higher doses might produce longer-lasting results.

Project number: 1ZIAMH002828-10 

Clinical trial number: NCT00986479 

Reference

A Randomized Trial of a Low-Trapping Nonselective N-Methyl-D-Aspartate Channel Blocker in Major Depression.  Zarate CA Jr, Mathews D, Ibrahim L, Chaves JF, Marquardt C, Ukoh I, Jolkovsky L, Brutsche NE, Smith MA, Luckenbaugh DA. Biol Psychiatry. 2012 Nov 30. doi:pii: S0006-3223(12)00941-9. 10.1016/j.biopsych.2012.10.019. [Epub ahead of print] PMID: 23206319

A combination of two antidepressants may not be any more effective in treating chronic major depression than a single antidepressant, according to an NIMH-funded study published online ahead of print May 2, 2011, in theAmerican Journal of Psychiatry.

Background

When treating depression, doctors sometimes prescribe a second antidepressant medication if a patient does not improve after several weeks. Because some antidepressants work for some people and not others, the hope is that adding another one will increase the odds of remission. However, treatment guidelines generally do not recommend adding another medication until it is evident the first one is not working.

Madhukar H. Trivedi, M.D., at the University of Texas Southwestern, and colleagues aimed to determine if combination antidepressant therapy as a first treatment step might produce a higher remission rate among people with chronic major depression. In the Combining Medications to Enhance Depression Outcomes (CO-MED) trial, 665 adult participants from several sites around the country were randomly assigned to one of three antidepressant combinations:

• Escitalopram plus placebo
• Buproprion sustained release plus escitalopram
• Venlafaxine plus mirtazapine

Although participants did not know which treatments they were receiving, clinicians were aware of their patients’ treatment assignments so that they could adjust doses as necessary to manage symptoms and side effects. The measurement of primary outcome was based on a self-reporting scale called the Quick Inventory of Depressive Symptoms.

Results of the Study

After three months, remission rates among the three groups all were around 38 percent. After seven months, remission rates continued to be similar among the three treatment groups and averaged around 45 percent. However, the venlafaxine plus mirtazapine combination was associated with a higher risk for side effects and serious adverse events compared to the other treatment options.

Significance

Despite other research suggesting combination antidepressant treatment may work better than a single medication, neither of the combination therapies in this trial appeared to be more effective than the single medication plus placebo. The researchers suggest that the chronic nature of participants’ major depression may be associated with lower remission rates. They also noted that dosage differences may account for the difference in outcomes compared to other studies.

What’s Next

Further evaluation is needed to determine if other drug combinations may affect remission rates differently. Results also highlight the need to evaluate biological markers as a means of personalizing treatment and possibly improving remission rates in major depression.

Reference

Rush AJ, Trivedi MH, Stewart JW, Nierenberg AA, Fava M, Kurian BT, Warden D, Morris DW, Luther JF, Husain MM, Cook IA, Shelton RC, Lesser IM, Kornstein SG, Wisniewski SR. Combining medications to enhance depression outcomes (CO-MED): Acute and long-term outcomes: a single-blind randomized study. Journal of American Psychiatry. online ahead of print May 2, 2011.

Mental health experts are calling for a greater world focus on improving access to care and treatment for mental, neurological, and substance use (MNS) disorders, as well as increasing discoveries in research that will enable this goal to be met.

The Grand Challenges in Global Mental Health Initiative , led by the National Institutes of Health and the Global Alliance for Chronic Diseases, has identified the top 40 barriers to better mental health around the world. Similar to past grand challenges, which focused on infectious diseases and chronic, noncommunicable diseases, this initiative seeks to build a community of funders dedicated to supporting research that will significantly improve the lives of people living with MNS disorders within the next 10 years.

Twenty-five of the specific challenges and the process used to derive them are described in an article that will be published on July 7, 2011, in the journal Nature.

“Participating in global mental health research is an enormous opportunity, a means to accelerate advances in mental health care for the diverse U.S. population, as well as an extension of our vision of a world where mental illnesses are prevented and cured,” said Thomas R. Insel, M.D., director of the National Institute of Mental Health (NIMH), the NIH institute heading this effort.

According to the paper’s authors, the disorders targeted by the Grand Challenges in Global Mental Health—for example, schizophrenia, depression, epilepsy, dementia, and alcohol dependence—collectively account for more years of life lost to poor health, disability, or early death than either cardiovascular disease or cancer. Yet, compared to illnesses like cardiovascular disease and cancer, there are far fewer effective treatments or preventive methods. In addition, interventions are not widely available to those who need them most.

In recognizing the need to address this imbalance, Pamela Collins, M.D., M.P.H., of the NIMH Office for Research on Disparities and Global Mental Health, and colleagues assembled an international panel of experts to identify research priorities using the Delphi method, a widely accepted consensus-building tool. The panel consisted of 422 experts in fields such as neuroscience, basic behavioral science, mental health services, and epidemiology, and represented more than 60 countries.

Over the course of two months, NIMH staff pared the panel’s initial list of 1,565 challenges down to 154, with input from a scientific advisory board. From this list, the expert panel selected the top 40, of which the top five challenges identified after the third and final round of ranking are:

• Integrate screening and core packages of services into routine primary health care
• Reduce the cost and improve the supply of effective medications
• Improve children’s access to evidence-based care by trained health providers in low- and middle-income countries
• Provide effective and affordable community-based care and rehabilitation
• Strengthen the mental health component in the training of all health care personnel.

These top five challenges were ranked according to the ability to reduce the burden of disease, ability to reduce inequalities in health and health care, length of time until results can be observed, and the ability for the topic to be researched effectively.

“Addressing these challenges could have far-reaching effects, including increasing access to services and ultimately, reducing the treatment gap associated with these disorders,” said Dr. Collins.

The Grand Challenges in Global Mental Health Initiative is led by NIMH and the Global Alliance for Chronic Diseases, in partnership with the Wellcome Trust, the McLaughlin-Rotman Centre for Global Health, and the London School of Hygiene and Tropical Medicine. Other NIH components participating in the Grand Challenges in Global Mental Health include the Fogarty International Center; the National Heart, Lung, and Blood Institute; and the National Institute of Neurological Disorders and Stroke.

Reference

Collins PY, Patel V, Joestl SS, March D, Insel TR, Daar A, on behalf of the Grand Challenges in Global Mental Health Scientific Advisory Board and Executive Committee. Grand Challenges in Global Mental Health. Nature. 2011 July 7. 474(7354):pp.

About the National Institute of Mental Health (NIMH): The mission of the NIMH is to transform the understanding and treatment of mental illnesses through basic and clinical research, paving the way for prevention, recovery and cure. For more information, visit the NIMH website.

About the National Institutes of Health (NIH): NIH, the nation’s medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit theNIH website .