People with depression have dozens of antidepressants to choose from—but none is a cure-all. Just one-third of patients experience full remission of symptoms after initial treatment. Worse, it may take six weeks or longer even to get that far.
“We can take care of malignant hypertension in minutes or hours. Why do we have wait weeks with depression?” asked Carlos Zarate, of the National Institute of Mental Health (NIMH).
At the recent symposium at the New York Academy of Sciences where Zarate raised this question, he and other speakers presented research suggesting potential ways to rapidly and effectively relieve the symptoms of depression.
All the antidepressants developed over the past half-century aim at the same few neurotransmitters—the monoamines serotonin, norepinephrine, and dopamine—which apparently go awry in depression.
The new work looks elsewhere. Glutamate, the major excitatory neurotransmitter, is far more ubiquitous than any of the monoamines. It is present in 80 percent of neurons, where it amplifies synaptic signals, and appears central to learning, memory, and neuroplasticity.
Research suggests glutamate may have a role in mood disorders, including abnormal levels of the neurotransmitter in certain brain regions of people with depression. And there is clear evidence that structural remodeling, a process that depends on glutamate, is impaired in the disorder.
Glutamate's actions are mediated through a complex array of pre- and postsynaptic receptors. In an introductory presentation, Jorge Quiroz of Hoffman-LaRoche gave an overview of his pharmaceutical company's research into the antidepressant possibilities of compounds modulating several of these receptor subtypes.
Among the most promising: investigational drugs targeting mGlu2 and mGlu5 receptors, now in phase II clinical trials.
But the most dramatic indication that the glutamatergic system might be a pathway to effective antidepressant treatment comes from ketamine, a drug already in use as an anesthetic that blocks the N-methyl-D-aspartate (NMDA) receptor, a keystone of the system. The bulk of the afternoon’s presentations traced the implications of experience with this drug.
Zarate summarized more than a decade of research that has documented swift, thorough relief of symptoms in people whose depression had not responded to conventional treatments. This includes NIMH research that enrolled patients with a 30 year history of depression, whose current episode had lasted three years or longer, and who had failed at least seven antidepressant trials. Half had not improved with electroconvulsive therapy, and half had attempted suicide.
After a single infusion of ketamine, "there was an antidepressant effect within a couple of hours," Zarate said. In one-third of patients, symptoms had eased by the end of the day. Four placebo-controlled studies have shown similar results. And people with bipolar depression have fared similarly, without the risk of mania associated with conventional antidepressants.
Of particular importance is the effect on suicidality, which is frequent in depression and often worsens in the early days of conventional antidepressant therapy. In one study, Zarate said, suicidal thinking was substantially reduced within 40 minutes of ketamine infusion. He described ketamine as "the paradigm of a new generation of treatments" for depression.
The drug itself would be challenging to use clinically: Its side effects include transient dissociative and psychotic phenomena (as “special K,” ketamine is a recreational drug), and its antidepressant effects dissipate within a week. But these findings have fueled hopes of finding an effective antidepressant along the glutamatergic pathway, Zarate said, and the search is on for compounds that may act like ketamine but without its drawbacks. NIMH researchers are also examining the biological details of the ketamine response for biomarkers that would support this research.
Behind the scenes
Ronald Duman, of Yale University School of Medicine, described research suggesting how ketamine (and by implication, other glutamatergic drugs) might achieve antidepressant effects by promoting synaptogenesis.
Depression seems to be accompanied by diminished prefrontal cortex and hippocampal volume and reduced numbers of synapses, particularly in the dorsolateral prefrontal region. In rodent models of depression following chronic mild stress, changes in these areas include loss of synaptic spinal density and function, and altered spinal shape.
“Considering that these synapses can undergo rapid remodeling in response to neuronal activity, there is the interesting possibility that such deficits can be reversed,” Duman said.
Studies with rodents have found, in fact, that a single dose of ketamine causes significant increases in synaptic spinal density, a shift toward more mature spinal shape, and enhanced synaptic function. Along with these changes come reduced depression-related behavior, in the rodents.
“The idea is that glutamate recruits the kind of synaptic machinery that induces a long-term potentiation (LTP)-like synaptogenesis response,” said Duman. “There is convincing evidence that ketamine induces a burst of glutamate…. extracellular glutamate increases in 30-60 minutes [during ketamine infusion], going back down in two hours.”
This mechanism “is probably really important for the fact that ketamine doesn’t produce lasting toxic effects,” he said. “The activation of pathways induced by the burst of glutamate is very rapid, but transient. You don’t have dissociative, psychotic effects after the infusion is finished, but it sets a synaptogenic event in motion that is relatively long-lasting.”
Research into the cellular process behind ketamine-induced synaptogenesis suggests a role for mTOR (mammalian target of rapamycin), an enzyme that regulates cell growth and, in particular, induces synaptic proteins, Duman said. One dose of ketamine activates mTOR signaling in a temporal pattern that corresponds to the glutamate increase. The introduction of rapamycin, which inhibits mTOR, apparently blocks increases in spine number and function associated with ketamine, along with its amelioration of depression-related behaviors,
Brain-derived neurotrophic factor (BDNF), known to be important in synaptogenesis, is another likely part of the ketamine response pathway. Duman reported research showing that in mice genetically modified to blunt BDNF release, ketamine failed to increase spinal number or produce anti-depressant behavioral changes. Infusing a BDNF antibody had a similar effect.
These and other insights into ketamine biology could help researchers find ways to stabilize the drug’s synaptogenic effects and sustain its clinical efficacy, and aid the search for novel agents, Duman said.
A role for magnesium
Other presenters at the symposium suggested that magnesium may be involved in glutamatergic antidepressant effects.
Simone Sartori, of the University of Innsbruck, Austria, noted the electrolyte’s role in glutamate regulation; Mg2+ blocks the NMDA receptor, and the receptor’s activity is greatly increased in a Mg2+ free solution. NMDA receptor activation, in turn, increases production of nitric oxide, which is linked to cell atrophy, reduced BDNF production, and depression. Although studies have been contradictory, there is some evidence of reduced plasma and/or brain levels of Mg in people with depression, she said.
Animal studies support a depression-Mg link, Sartori said: Increased basal body temperature (which is also described in patients with depression) in Mg-deficient mice, and depression-like behaviors like behavioral despair, passive coping, and anhedonia. She and her colleagues found evidence for increased neuronal activation in the amygdala and part of the hypothalamus-pituitary-adrenal stress axis (regions involved in depression and anxiety) after emotional challenge in Mg-deficient mice.
Chronic treatment with conventional antidepressants reduced depression-like behavior in magnesium-deficient animals—as did a single ketamine injection. Such findings suggest that magnesium deficiency could offer “a useful model for testing novel drugs for depression,” Sartori said.
Although a therapeutic role for magnesium supplementation in human depression is unclear, some studies have shown positive effects, especially in depressed elderly individuals with type 2 diabetes, she said.
Research presented by Guosong Liu of Tsinghua University, Beijing, China, supports the feasibility of such an approach. Work in his laboratory and elsewhere has found increased glutamatergic synaptic density at optimal brain magnesium levels. The region-specific distribution of these changes—enhanced plasticity in the prefrontal cortex and hippocampus, but not in the amygdala—would accord with antidepressant and antianxiety effects, he said.
Magnesium deficiency is widespread in the United States, Liu observed.
The poor bioavailability of most magnesium compounds, particularly in the brain, limits the therapeutic potential of conventional supplementation, he said. But the compound magnesium threonate has been shown to increase brain magnesium levels in rodents, and to ameliorate anxiety- and depression-like behaviors.
Liu and Magceutics, a company he founded, hold a patent for L-magnesium threonate.
A clinical trial of supplementation with the compound is currently underway, he said.