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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 .

Patients experiencing cardiovascular or metabolic side effects while taking an antipsychotic medication may fare better if they switch to a different medication provided they are closely monitored, according to an NIMH-funded study. The study was published online ahead of print July 18, 2011, in the American Journal of Psychiatry.

Antipsychotic medications can effectively treat psychotic symptoms among people with schizophrenia or related disorders. However, the medications, especially some of those that are most commonly used, are associated with serious metabolic side effects that can lead to heart disease or diabetes. Even when patients do experience these side effects, doctors are often reluctant to change a patient’s medication regimen if the patient’s psychotic symptoms are controlled by the existing medication.

“Treating the symptoms of schizophrenia is a delicate balancing act between risks and benefits,” said National Institute of Mental Health Director Thomas R. Insel, M.D. “The possible benefits of switching medications to reduce metabolic risks must be carefully weighed against the potential risk of symptom relapse or medication failure.”

Scott Stroup, M.D., of Columbia University and colleagues aimed to determine if a medication switch could be made safely and without sacrificing clinical stability. For the Comparison of Antipsychotics for Metabolic Problems (CAMP) study, they enrolled 215 patients from 27 clinical sites whose psychotic symptoms were stabilized on one of three frequently used antipsychotics (olanzapine, quetiapine or risperidone) but were experiencing serious metabolic side effects such as weight gain and high cholesterol levels. Half of the patients were assigned to stay on their current medication, while the other half were switched to aripiprazole, another antipsychotic that is generally associated with fewer metabolic risks. All of the participants received a behavioral intervention that included a diet and exercise program designed to reduce the risk of cardiovascular disease.

After 24 weeks, the researchers found that those who switched to aripiprazole had improved cholesterol levels and other metabolic factors, and lost more weight (average of 8 lbs) than those who stayed on their original medication (average of 1.5 lbs). Those who switched also did not experience any more illness relapses or worsening of psychotic symptoms compared to those who stayed on their original medication. However, those who switched to aripiprazole were more likely to discontinue the new medication compared to those who stayed on their original medication. Almost 44 percent of those who switched discontinued the aripiprazole compared to 24.5 percent of those who were assigned to stay on their current medication.

The authors suggest that the high discontinuation rate for switchers may have been related to the fact that the study was open label, meaning both the patient and the clinician knew what drug the patient was taking. Some patients who were switched may have felt uncomfortable changing from a medication they knew worked for them, and therefore stopped the new medication. In addition, because clinicians were encouraged to closely monitor and intervene before a patient experienced severe problems, many may have discontinued aripiprazole when the clinician first determined that the patient was having difficulties, but before full-blown treatment failure occurred.

“For patients whose symptoms are stabilized but who are overweight or experiencing other metabolic problems, clinicians may want to consider switching to a medication that is less likely to cause metabolic problems. However, because switching is not always successful, clinicians must monitor patients carefully to avoid illness exacerbation,” said Dr. Stroup. “If switching medications is not an option, then adding a medication like metformin or a statin could help reduce cardiovascular risks while maintaining symptom stability,” he concluded. He also noted that the study’s behavioral intervention that focused on improved diet and exercise habits benefited even those who did not switch medications.

Reference

Stroup TS, McEvoy JP, Ring KD, Hamer RH, LaVange LM, Swartz MS, Rosenheck RA, Perkins DO, Nussbaum AM, Lieberman JA. Comparison of antipsychotics for metabolic problems (CAMP):a randomized trial examining the effectiveness of switching from olanzapine, quetiapine, or risperidone to aripiprazole to reduce metabolic risk. American Journal of Psychiatry. Online ahead of print July 18, 2011.

A widely used suicide screening tool can help determine who is most at risk for suicide by pinpointing the threshold at which a person’s suicidal thinking is severe enough to warrant professional intervention, according to a recent study published online ahead of print November 8, 2011, in the American Journal of Psychiatry.

Background

Developing effective suicide prevention strategies is a priority of theAction Alliance for Suicide Prevention , a public-private partnership developed to advance the national strategy for suicide prevention. One of its main goals is to more efficiently identify those at risk so as to better target intervention. Standardized, reliable screening tools are needed to achieve that.

The Columbia-Suicide Severity Rating Scale (C-SSRS) was developed by a team of researchers from Columbia University, the University of Pennsylvania and the University of Pittsburgh to be used as part of the NIMH-funded Treatment of Adolescent Suicide Attempters (TASA) study. It was developed to meet the need for tracking changes in a person’s suicidal thinking and behavior over time, and to determine who is most at risk. The scale addresses the full range of suicidal behavior and thinking, but includes only the most essential, evidence-based items required for thorough assessment. The scale is now widely used for assessing suicidal thinking and behavior across research and practice in both psychiatric and non-psychiatric settings. It is used domestically and internationally by numerous stakeholders such as first responders (e.g., police, EMTs, fire departments), the U.S. Army, National Guards, prisons, hospitals, schools, and judicial systems to better identify those in need and to direct limited resources.

In this current analysis, Kelly Posner Ph.D., of Columbia University, and colleagues compared the C-SSRS to other similar measures, all of which were administered in three separate studies that featured teens who had attempted suicide or adults presenting to emergency rooms with psychiatric problems. They aimed to determine the scale’s validity, reliability and internal consistency, compared to the other measures.

Results of the Study

The researchers found that compared to other measures, the C-SSRS could reliably predict a potential suicide attempt in those who had previously attempted suicide. It also was able to determine clinically meaningful points at which a person may be at risk for an impending suicide attempt, something that other scales have been unable to consistently determine. According to the researchers, this type of predictive information can more precisely identify who needs the most help and when, while saving time and money by not having to refer people for treatment who are not at imminent risk.

Significance

This was the first major study showing how well the C-SSRS works with regard to identifying those most at risk for suicidal behavior. It was able to show, for the first time, that behaviors beyond previous suicide attempts—such as self-injury or making preparations for an attempt—may be used as predictors of subsequent suicide attempts.

What’s Next

Because the studies used in this analysis were not widely representative, additional research is needed to replicate the findings among diverse community samples.

Reference

Posner K, Brown GK, Stanley B, Brent DA, Yershova KV, Oquendo MA, Currier GW, Melvin GA, Greenhill L, Shen S, Mann JJ. The Columbia-Suicide Severity Rating Scale: Initial Validity and Internal Consistency Findings from Three Multisite Studies with Adolescents and Adults. American Journal of Psychiatry. Online ahead of print Nov 8,2011.

People with treatment-resistant bipolar disorder experienced relief from symptoms of depression in as little as 40 minutes after an intravenous dose of the anesthetic medication ketamine in a preliminary study; while the patient group was small, this work adds to evidence that compounds in the class to which ketamine belongs have potential as rapid and effective medications for depression, including bipolar depression. The potential for side-effects makes ketamine an impractical drug for standard use, but it provides a way to test this approach for developing novel treatments that act more rapidly than existing ones.

Background

Bipolar disorder (BD) is a potentially debilitating illness marked by severe swings in mood, energy, and behavior. Episodes of depression alternate with spells of mania but depressive episodes tend to be more frequent and longer-lasting and the depression is difficult to treat. BD is usually treated with mood stabilizing medications such as lithium, valproate, carbamazepine or other medications with the goal of preventing mood episode relapse. Antidepressant medications are often used in addition to a mood stabilizer for depressive episodes, but antidepressants typically take weeks to have an effect and many patients do not respond adequately to existing medications.

Previous research has suggested that a disruption of signaling between neurons involving the neurotransmitter glutamate is likely to play a role in depression. The anesthetic medication ketamine shuts down one class of receptor for glutamate (NMDA receptors).

This Study

Eighteen people with BD participated in this study of ketamine. All received maintenance treatment with a mood stabilizer medication during the study. All had previously been unsuccessfully treated with at least one antidepressant medication and a mood stabilizer; the average number of medications they had tried unsuccessfully was seven.

In the first phase of the study, each person was randomly assigned to receive a single dose of either intravenous ketamine or placebo (saline). After two weeks, treatment was switched, so those initially receiving ketamine received placebo, and vice versa. Neither patients nor those treating them were told whether they were receiving ketamine or placebo. Investigators used standard surveys of depression symptoms to assess the effect of medication.

Within 40 minutes, 9 of 16 (56 percent) patients receiving ketamine had at least a 50 percent reduction in symptoms, and 2 of 16 (13 percent) became nearly symptom-free. The response to ketamine lasted an average of about a week. By contrast, no patients receiving placebo had declines in symptoms close to the magnitude seen with ketamine within the first 3 days.

Significance

In this study, carried out by scientists Nancy Diazgranados, Carlos Zarate, Jr., and colleagues at the Experimental Therapeutics & Pathophysiology Branch of NIMH’s intramural research program, a single intravenous dose of ketamine brought relief from depression in severely treatment resistant patients with BD, in over half of them within 40 minutes. This study supports a previous one by the same group in which they also found a rapid antidepressant effect in patients with treatment-resistant major depression (unipolar). (NIMH press release, August 7, 2006). The authors note that the rapid antidepressant response observed in these two different disorders (major depressive disorder and bipolar disorder) highlights the importance of the NMDA receptor in developing treatments with a rapid onset of action.

The work adds to the evidence of the potential of medications targeting the glutamate system for rapid relief from depression, even in cases of people who have failed to respond to other existing therapies. Rapid and effective treatment of depression is an urgent public health need. BD can be disabling—nearly all the patients in this study were unemployed as a result of the severity of their illness. BD is among the psychiatric disorders with the highest risk of suicide.

Continuing research is focusing on developing NMDA-targeting medications that are suitable for clinical use; and investigating the use of this class of drugs for long-term maintenance of the rapid antidepressant effect seen in this study.

Reference

Diazgranados, N., Ibrahim, L., Brutsche, N.E., Newberg, A., Kronstein, P., Khalife, S., Kammerer, W. A., Quezado, Z., Luckenbaugh, D.A., Salvadore, G., Machado-Vieira, R., Manji, H.K., and Zarate, C. A randomized add-on trial of an N-methyl-D-aspartate antagonist in treatment-resistant bipolar depression. Archives of General Psychiatry2010;67(8):793-802.

GLYX-13, a molecular cousin to ketamine, induces similar antidepressant results without the street drug side effects, reported a preclinical study funded by the National Institute of Mental Health (NIMH) that was published last month inNeuropsychopharmacology.

Background

Major depression affects about 10 percent of the adult population and is the second leading cause of disability in U.S. adults, according to the World Health Organization. Despite the availability of several different classes of antidepressant drugs such as selective serotonin reuptake inhibitors(SSRIs), 30 to 40 percent of adults are unresponsive to these medications. Moreover, SSRIs typically take weeks to work, which increases the risk for suicide.

Enter NMDA (N-methyl-D-aspartate) receptor modulators. In the 1970s, researchers linked the receptors to learning and memory. Biotech and pharmaceutical companies in the 1980s attempted to apply chemical blockers to these receptors as a means to prevent stroke. But blocking these receptors led to the opposite effect—–the rise of cardiovascular disease. Research in the field dampened until a glutamate receptor antagonist already approved for anesthesia, and known on the streets as “Special K”, ketamine, made headlines in the early 2000s. Human clinical studies demonstrated that ketamine can ward off major and bipolar depressive symptoms within 2 hours of administration and last for several days. Ketamine is fraught with serious side effects including excessive sleepiness, hallucinations, and substance abuse behavior.

“Ketamine lit the field back up,“ said Joseph Moskal, Ph.D., a molecular neurobiologist at Northwestern University and senior study author. “Our drug, GLYX-13, is very different. It does not block the receptor ion channel, which may account for why it doesn’t have the same side effects.”

Moskal’s journey with GLYX-13 came about from his earlier days as a Senior Staff Fellow in NIMH’s Intramural Research Program . While at NIMH, he created specific molecules, monoclonal antibodies, to use as new probes to understand pathways of learning and memory. Some of the antibodies he created were for NMDA receptors. When he moved to Northwestern University, Moskal converted the antibodies to small protein molecules. Comprised of only four amino acids, GLYX-13 is one of these molecules.

Previous electrophysiological and conditioning studies had suggested that GLYX-13, unlike ketamine, enhanced memory and learning in rats, particularly in the brain’s memory hub or hippocampus. GLYX-13 also produced analgesic effects. Using several rat behavioral and molecular experiments, Moskal’s research team tested four compounds: GLYX-13, an inactive, “scrambled” version of GLYX-13 that had its amino acids rearranged, ketamine, and the SSRI fluoxetine.

Results of the Study

GLYX-13 and ketamine produced rapid acting (1 hour) and long-lasting (24 hour) antidepressant-like effects in the rats. Fluoxetine, an SSRI that typically takes from 2–4 weeks to show efficacy in humans, did not produce a rapid antidepressant effect in this study. As expected, the scrambled GLYX-13 showed no antidepressant-like effects at all. The researchers observed none of the aforementioned side effects of ketamine in the GLYX-13–treated rats.

Protein studies indicated an increase in the hippocampus of the NMDA receptor NR2B and a receptor for the chemical messenger glutamate called AMPA. Electrophysiology studies in this brain region showed that GLYX-13 and ketamine promoted long-lasting signal transmission in neurons, known as long-term potentiation/synaptic plasticity. This phenomenon is essential in learning and memory. The researchers propose how GLYX-13 works: GLYX-13 triggers NR2B receptor activation that leads to intracellular calcium influx and the expression of AMPA, which then is responsible for increased communication between neurons.

These results are consistent with data from a recent Phase 2 clinical trial, in which a single administration of GLYX-13 produced statistically significant reductions in depression scores in patients who had failed treatment with current antidepressants. The reductions were evident within 24 hours and persisted for an average of 7 days. After a single dose of GLYX-13, the drug’s antidepressant efficacy nearly doubled that seen with most conventional antidepressants after 4–6 weeks of dosing. GLYX-13 was well tolerated and it did not produce any of the schizophrenia-like effects associated with other NMDA receptor modulating agents.

Significance

NMDA receptors need a molecule each of the amino acid chemical messengers glutamate and glycine to become activated. Moskal speculates that GLYX-13 either directly binds to the glycine site on the NMDA receptor or indirectly modulates how glycine works with the receptor. Resulting activation of more NMDA and AMPA receptors leads to an increase in memory, learning—and antidepressant effects. By contrast, ketamine only blocks the NMDA receptor, but also increases the activity of the AMPA receptor. Knowledge of these mechanisms could lead to the development of more effective antidepressants.

What’s Next

GLYX-13 is now being tested in a Phase 2 repeated dose antidepressant trial, where Moskal and his colleagues at Naurex, Inc., a biotechnology company he founded, hope to find in humans the optimal dosing for the drug. They also want to see if this molecule, and others like it, regulate other NMDA receptor subtypes—there are over 20 of them—and whether it will work on other disorders, such as schizophrenia, attention-deficit hyperactivity disorder, and autism.

“One could call NMDA modulators such as GLYX-13 ‘comeback kids,’” said Moskal. “A toolkit that I developed in 1983 is now setting the stage in 2013 for the development of possible new therapeutics that may provide individuals suffering from depression with a valuable new treatment option.”

Reference

Burgdorf J, Zhang X-l, Nicholson KL, Balster RL, Leander JD, Stanton PK, Gross AL, Kroes RA, Moskal JR. GLYX-13, a NMDA Receptor Glycine-Site Functional Partial Agonist, Induces Antidepressant-Like Effects Without Ketamine-Like Side Effects.Neuropsychopharmacology , April 2013. 38:729–742.

Note: This is an updated version of the science update that first appeared on May 23, 2013.