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Treatment-resistant Depression:Glutamate, Stress Hormones, and their Role in the Regeneration of Neurons

Treatment-resistant Depression
Reported by
Pablo Ariel

Posted April 22, 2013


The standard of care for clinical depression has significant limitations: traditional drugs that focus on monoamine neurotransmitters can take several weeks to be effective, and many patients never respond to any form of treatment. Several clinical trials have demonstrated strikingly better outcomes using the anesthetic ketamine to treat depression. Notably, a single application can have rapid and lasting antidepressant effects in patients who do not respond to other treatments. Because ketamine is an antagonist of NMDA-type glutamate receptors, research is focused on the role of glutamate neurotransmission in depression and on drug development that targets the glutamatergic system. The March 25, 2013, meeting of the Academy's Biochemical Pharmacology Discussion Group, Treatment-resistant Depression: Glutamate, Stress Hormones, and their Role in the Regeneration of Neurons, presented this new research and the avenues it is opening for the treatment of depression.

Harald Murck from Covance Neuroscience Medical and Scientific Services opened the meeting by providing a historical context for recent results. Since the 1960s, the treatment of depression has been based on drugs that affect monoamine neurotransmitters such as serotonin selective reuptake inhibitors (SSRIs). Recent interest in glutamate was sparked by clinical trials in the last decade demonstrating the antidepressant effects of ketamine. Murck highlighted the need to integrate data from successful clinical trials with research into the mechanisms of action of new drugs to provide a foundation for more targeted drug development and new animal models of depression.

Carlos A. Zarate from the National Institute of Mental Health at the NIH emphasized the acute need for new drugs to treat depression, pointing to both the low efficacy and slow onset of current treatments. Slow onset is a serious problem in depressed patients at risk for suicide; therefore, the goal is to develop fast-acting drugs for early and lasting interventions, which would diminish the severity and the duration of depressive episodes. Human biomarkers that could predict a patient's response to antidepressants would aid in the design of rational treatments. Candidates for these markers include signatures of brain activity in areas involved in emotional or cognitive memory encoding, processes that can be affected in depression. These markers could also improve the efficiency of clinical trials by stratifying patient populations according to their predicted sensitivity to particular treatments.

A single dose of ketamine has rapid and lasting antidepressant effects in patients with major depression or bipolar disorder. The Hamilton Rating Scale for Depression (HRSD) is a questionnaire used to evaluate the severity of patients' depression. Less than two hours after ketamine application, HRSD scores decreased significantly, and the effect lasted for several days. (Image courtesy of Carlos A. Zarate)

There is a convincing body of work establishing ketamine as a fast-acting, strong, and long-lasting antidepressant, even in patients who are resistant to other treatments, said Zarate. He also noted its anti-suicidal effects, which are evident less than an hour after application and can last up to three days. Zarate presented brain imaging studies that found correlations between activity in specific areas of the brain, such as the anterior cingulate cortex, and the antidepressant effects of ketamine. These results will help identify the brain circuits ketamine acts on and may provide direction for developing biomarkers that predict a patient's response to antidepressants.

Ronald S. Duman from Yale University School of Medicine reviewed work with animal models that pinpoints the mechanisms underlying ketamine's rapid action. It is well documented that repetitive stress can lead to depression in humans. Rodents develop depressive behaviors when subjected to chronic unpredictable stress and exhibit a loss of synapses in the prefrontal cortex, where post-mortem brain tissue from depressed patients shows a similar decrease in neuronal connections. In animal models ketamine rapidly reverses depression symptoms and restores synapses.

The rapid synaptogenic action of ketamine is thought to be critical to its efficacy as an antidepressant. When applied, ketamine is thought to block NMDA receptors at inhibitory synapses, leading to decreased inhibition of excitatory neurons and a transient burst of glutamate release at excitatory synapses. Glutamate causes target neurons to release brain-derived neurotrophic factor (BDNF) and activates the mammalian target of rapamycin (mTOR) pathway, both of which are necessary for synaptogenesis. Recent studies in humans have confirmed the importance of BDNF release and mTOR activation in depression. A quarter of the human population exhibits a single nucleotide polymorphism in BDNF that inhibits the release of BDNF in response to neural activity; depressed patients with this variant showed a smaller therapeutic response to ketamine treatment. A recent study also showed decreased mTOR levels in post-mortem prefrontal cortex tissue from depressed patients.

Ketamine application leads to an increase in the number of spines, the sites of excitatory connections between neurons. This increased connectivity can reverse lower synapse numbers in depression and is thought to be critical for the antidepressant action of ketamine. (Image courtesy of Ronald S. Duman)

Jorge Quiroz from Roche presented drug development efforts at the company. He emphasized that a third of patients with clinical depression do not respond to any available treatment, highlighting once more the need for new therapeutic options. He described two new drugs in the development pipeline at Roche—negative allosteric modulators targeting metabotropic glutamate receptor subtypes 2 and 5 (mGluR2 and mGluR5), respectively. When they bind to glutamate receptors, these drugs modulate glutamatergic throughput and downstream second signaling cascades within pre- and postsynaptic neurons. In multiple animal models of depression-like symptoms, under acute and chronic administration, both modulators showed robust antidepressant effects. The mGluR2 negative allosteric modulator also produced cognitive enhancements in several animal models. Both drugs have undergone phase I studies in healthy volunteers and are now in phase II. They are being tested at various doses in patients with inadequate response to SSRI/SNRI treatment. This research represents a promising new pharmacological approach for patients with treatment-resistant depression.

Simone B. Sartori from the University of Innsbruck in Austria focused on a new rodent model that demonstrates how low dietary magnesium may contribute to depression. This work is related to the general focus on glutamate because magnesium is critical to the action of the NMDA receptor. This receptor is an ion channel that is typically blocked by Mg2+ such that glutamate binding is not sufficient to open it. The target neuron's membrane must be depolarized when glutamate binds to the NMDA receptor; depolarization removes the Mg2+ blocking the channel, leaving the pore open for Na+ and Ca2+ to enter and K+ to leave the postsynaptic neuron. Thus, reducing the synaptic concentration of Mg2+ leads to hyperactivation of NMDA receptors.

Sartori presented data showing that mice fed a low-magnesium diet present depression-related behaviors and heightened anxiety; interestingly, Mg2+ concentration in the brains of depressed patients is lower than normal. Administering ketamine to magnesium-deficient mice reverses the depressive behavior. Adding magnesium to the diet can elicit antidepressant effects in animals that show depression-like symptoms, and studies suggest this may also be the case in humans. The magnesium-deficient animal model is a promising basis for testing candidate drugs and the molecular underpinnings of depression.

Sartori's results on magnesium supplementation in the diet segued nicely into the final talk of the day by Guosong Liu from Tsinghua University in China, who focused on the potential cognitive-enhancing effects of magnesium supplementation. To achieve significant increases in brain Mg2+, Liu's laboratory designed an enhanced Mg2+-carrying compound with improved absorption characteristics. In mice, this compound increased brain Mg2+ concentration and enhanced synaptic density and plasticity in the prefrontal cortex and hippocampus. Furthermore, the mice had specific improvements in memory retention in various tasks, antidepressant responses, and less anxiety-like behaviors. Liu is leading clinical trials to test the effects of dietary magnesium supplementation in humans. Preliminary results suggest that magnesium enhances cognitive abilities.

Brain circuits maintain a balance between synapse strength and synapse number such that total connection strength is constant. Young brains tend to have many synapses, but each one is rather weak; in contrast, older brains have fewer, yet stronger, synapses. Increasing the brain's Mg2+ concentration leads to more synapses. Thus, Mg2+ leads to a rejuvenation of the brain, returning it to a state with high numbers of weak synapses, explained Liu. Increasing the Mg2+ concentration also causes a homeostatic increase in the number of NMDA receptors at each synapse, so although connection strength under baseline conditions is the same (NMDA receptors are blocked with Mg2+), during bursts of neuronal firing more receptors can open to produce stronger responses. These changes may underlie the increased synaptic plasticity in specific brain regions as well as the cognitive enhancements seen with magnesium supplementation.

Use the tab above to find multimedia from this event.

Presentations available from:
Ronald S. Duman, PhD (Yale University School of Medicine)
Guosong Liu, MD, PhD (Tsinghua University, China)
Jorge Quiroz, MD (Roche)
Harald Murck, MD, PhD (Covance Neuroscience Medical and Scientific Services)
Simone B. Sartori, PhD (University of Innsbruck, Austria)
Carlos A. Zarate, MD (National Institute of Mental Health, NIH)

The Biochemical Pharmacology Discussion Group is proudly supported by

  • American Chemical Society
  • Boehringer Ingelheim
  • Pfizer

Mission Partner support for the Frontiers of Science program provided by Pfizer

Journal Articles

Aan Het Rot M, Zarate CA Jr, Charney DS, Mathew SJ. Ketamine for depression: where do we go from here? Biol Psychiatry. 2012;72(7):537-47.

Carlson PJ, Diazgranados N, Nugent AC, et al. Neural correlates of rapid antidepressant response to ketamine in treatment-resistant unipolar depression: a preliminary positron emission tomography study. Biol Psychiatry. 2013. [Epub ahead of print]

Cornwell BR, Salvadore G, Furey M, et al. Synaptic potentiation is critical for rapid antidepressant response to ketamine in treatment-resistant major depression. Biol Psychiatry. 2012;72(7):555-61.

Duman RS, Aghajanian GK. Synaptic dysfunction in depression: potential therapeutic targets. Science. 2012;338(6103):68-72.

Duman RS, Li N. A neurotrophic hypothesis of depression: role of synaptogenesis in the actions of NMDA receptor antagonists. Philos Trans R Soc Lond B Biol Sci. 2012;367(1601):2475-84.

Duman RS, Li N, Liu RJ, Duric V, Aghajanian G. Signaling pathways underlying the rapid antidepressant actions of ketamine. Neuropharmacology. 2012;62(1):35-41.

Duman RS, Voleti B. Signaling pathways underlying the pathophysiology and treatment of depression: novel mechanisms for rapid-acting agents. Trends Neurosci. 2012;35(1):47-56.

Duric V, Banasr M, Stockmeier CA, et al. Altered expression of synapse and glutamate related genes in post-mortem hippocampus of depressed subjects. Int J Neuropsychopharmacol. 2013;16(1):69-82.

Dwyer JM, Duman RS. Activation of mammalian target of rapamycin and synaptogenesis: role in the actions of rapid-acting antidepressants. Biol Psychiatry. 2013. [Epub ahead of print]

Held K, Antonijevic IA, Künzel H, et al. Oral Mg2+ supplementation reverses age-related neuroendocrine and sleep EEG changes in humans. Pharmacopsychiatry. 2002;35(4):135-43.

Kang HJ, Voleti B, Hajszan T, et al. Decreased expression of synapse-related genes and loss of synapses in major depressive disorder. Nat Med. 2012;18(9):1413-7.

Laje G, Lally N, Mathews D, et al. Brain-derived neurotrophic factor Val66Met polymorphism and antidepressant efficacy of ketamine in depressed patients. Biol Psychiatry. 2012;72(11):e27-8.

Li N, Lee B, Liu RJ, et al. mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science. 2010;329(5994):959-64.

Li N, Liu RJ, Dwyer JM. Glutamate N-methyl-D-aspartate receptor antagonists rapidly reverse behavioral and synaptic deficits caused by chronic stress exposure. Biol Psychiatry. 2011;69(8):754-61.

Licznerski P, Duman RS. Remodeling of axo-spinous synapses in the pathophysiology and treatment of depression. Neuroscience. 2012. [Epub ahead of print]

Liu RJ, Lee FS, Li XY, et al. Brain-derived neurotrophic factor Val66Met allele impairs basal and ketamine-stimulated synaptogenesis in prefrontal cortex. Biol Psychiatry. 2012;71(11):996-1005.

Machado-Vieira R, Ibrahim L, Henter ID, Zarate CA Jr. Novel glutamatergic agents for major depressive disorder and bipolar disorder. Pharmacol Biochem Behav. 2012;100(4):678-87.

Mathews DC, Henter ID, Zarate CA. Targeting the glutamatergic system to treat major depressive disorder: rationale and progress to date. Drugs. 2012;72(10):1313-33.

Müller HK, Wegener G, Liebenberg N, Zarate CA Jr, Popoli M, Elfving B. Ketamine regulates the presynaptic release machinery in the hippocampus. J Psychiatr Res. 2013. [Epub ahead of print]

Murck H. Ketamine, magnesium and major depression: From pharmacology to pathophysiology and back. J Psychiatr Res. 2013. [Epub ahead of print]

Murck H. Magnesium and affective disorders. Nutr Neurosci. 2002;5(6):375-89.

Murck H, Steiger A. Mg2+ reduces ACTH secretion and enhances spindle power without changing delta power during sleep in men: Possible therapeutic implications. Psychopharmacology (Berl). 1998;137(3):247-52.

Murck H, Schubert MI, Schmid D, Schüssler P, Steiger A, Auer DP. The glutamatergic system and its relation to the clinical effect of therapeutic-sleep deprivation in depression—an MR spectroscopy study. J Psychiatr Res. 2009;43(3):1755-80.

Singewald N, Sinner C, Hetzenauer A, Sartori SB, Murck H. Magnesium-deficient diet alters depression- and anxiety-related behavior in mice—influence of desipramine and Hypericum perforatum extract. Neuropharmacology. 2004;47(8):1189-97.

Slutsky I, Abumaria N, Wu LJ, et al. Enhancement of learning and memory by elevating brain magnesium. Neuron. 2010;65(2):165-77.

Zarate CA Jr, Brutsche N, Laje G, et al. Relationship of ketamine's plasma metabolites with response, diagnosis, and side effects in major depression. Biol Psychiatry. 2012;72(4):331-8.

Zarate C Jr, Machado-Vieira R, Henter I, Ibrahim L, Diazgranados N, Salvadore G. Glutamatergic modulators: the future of treating mood disorders? Harv Rev Psychiatry. 2010;18(5):293-303.


Robert Martone

Covance Biomarker Center of Excellence
e-mail | website | publications

Robert Martone is the neuroscience therapeutic area lead for the Covance Biomarker Center of Excellence. He has expertise in both small molecule and protein therapeutics and extensive experience in the pharmaceutical industry leading neuroscience drug discovery and technology teams from target identification through clinical trials. He also has several years of academic research experience in molecular neurobiology, with a focus on the molecular genetics of familial neuropathies and CNS tumor biomarker development.

Harald Murck, MD, PhD

Covance Neuroscience Medical and Scientific Services
e-mail | website | publications

Harald Murck studied physics and medicine at Philipps University of Marburg and Georg-August University in Göttingen, Germany. He completed training in psychiatry at the Max Planck Institute of Psychiatry in Munich. He has over 12 years of large and small pharmaceutical experience in clinical research, medical affairs, and translational medicine and is senior medical director at Covance Neuroscience Medical and Scientific Services and an associate professor at Philipps University of Marburg. He has authored or co-authored several articles related to glutamatergic mechanisms of depression.

Jennifer Henry, PhD

The New York Academy of Sciences

Jennifer Henry is the director of Life Sciences at the New York Academy of Sciences. Henry joined the Academy in 2009, before which she was a publishing manager in the Academic Journals division at Nature Publishing Group. She also has eight years of direct editorial experience as editor of Functional Plant Biology for CSIRO Publishing in Australia. She received her PhD in plant molecular biology from the University of Melbourne, specializing in the genetic engineering of transgenic crops. As director of Life Sciences, she is responsible for developing scientific symposia across a range of life sciences, including biochemical pharmacology, neuroscience, systems biology, genome integrity, infectious diseases and microbiology. She also generates alliances with organizations interested in developing programmatic content.


Ronald S. Duman, PhD

Yale University School of Medicine
e-mail | website | publications

Ronald S. Duman is a professor of psychiatry and neurobiology, director of the Abraham Ribicoff Research Facilities, and the Elizabeth Mears and House Jameson professor of psychiatry at Yale University School of Medicine. Studies from Duman's laboratory have contributed to the characterization of the molecular and cellular actions of antidepressants and stress, providing the basis for a neurotrophic hypothesis of depression. Recent studies also demonstrate that the rapid antidepressant actions of NMDA-receptor antagonists are dependent on synaptogenesis and new protein synthesis. These findings represent major advances in our understanding of the effects of antidepressants and provide a framework for the development of novel therapeutic agents.

Guosong Liu, MD, PhD

Tsinghua University, China
e-mail | website | publications

Guosong Liu is a professor of neuroscience at Tsinghua University in China. He received his PhD in physiological science from the University of California, Los Angeles, and completed postdoctoral training at Stanford University. He held a faculty position at Picower Institute of Learning and Memory in the Department of Brain and Cognitive Science at MIT before moving to Tsinghua University in 2006. Liu is the founder of Magceutics Inc., a biotechnology company that is developing novel anti-brain-aging therapy. Liu's research at Tsinghua University focuses on deciphering organization principles that regulate synapse density in the brain under physiological and pathological conditions. He aims to generate new strategies for designing molecular targets for treating neurodegeneration and psychiatric disorders.

Jorge Quiroz, MD

e-mail | website | publications

Jorge Quiroz is head of psychiatry in neuroscience translational medicine at Hoffmann-La Roche. He received an MD from the Pontifical Catholic University of Chile and completed postgraduate training at the Laboratory of Molecular Pathophysiology at the National Institute of Mental Health. His research focused on clinical research and magnetic resonance spectroscopy (MRS) in populations with severe mood disorders resistant to conventional pharmacological treatments. Quiroz worked for Johnson & Johnson Pharmaceutical Research and Development studying the treatment of bipolar disorder before joining Roche, where he focuses on the development of novel interventions for treatment-resistant forms of major depression, particularly targeting pre- and postsynaptic metabotropic glutamatergic receptors.

Simone B. Sartori, PhD

University of Innsbruck, Austria
e-mail | website | publications

Simone B. Sartori holds a PhD in pharmacy from the University of Innsbruck in Austria, where she also completed postdoctoral research. She had previously worked on the pharmacology of neurotransmitters as a research assistant in the Department of Pharmacology at the University of Oxford, UK. She joined the staff of the Department of Pharmacology and Toxicology at the University of Innsbruck in 2009. Sartori's research has focused on the pathophysiology and pharmacology of various CNS transmitters, particularly neuropeptides and the glutamate system, to find novel strategies for the treatment of mood and anxiety disorders.

Carlos A. Zarate, MD

National Institute of Mental Health, NIH
e-mail | website | publications

Carlos A. Zarate is chief of the Experimental Therapeutics & Pathophysiology Branch of the Section on Neurobiology and Treatment of Mood and Anxiety Disorders at the National Institute of Mental Health. Zarate completed his residency training in psychiatry at the Massachusetts Mental Health Center/Brockton VAMC division. He completed a fellowship in clinical psychopharmacology at McLean Hospital of the Consolidated Department of Psychiatry at Harvard Medical School and remained on staff at McLean Hospital as the director of the Bipolar and Psychotic Disorders Outpatient Services and director of the New and Experimental Clinic. Zarate's research focuses on the pathophysiology and development of novel therapeutics for treatment-resistant mood disorders, as well as the study of biomarkers and neural correlates of treatment response.

Pablo Ariel

Pablo Ariel is a postdoctoral scientist in neuroscience at Columbia University, where he is developing tools to shut down specific brain circuits in behaving animals. Originally from Argentina, he now lives in New York City with his wife, who is also a scientist.


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The Biochemical Pharmacology Discussion Group is proudly supported by

  • American Chemical Society
  • Boehringer Ingelheim
  • Pfizer

Mission Partner support for the Frontiers of Science program provided by Pfizer