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

Overview

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.

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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)

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