Another Blocker of Glutamate Receptor Function with Rapid Antidepressant Effects
glutamate
Certain drugs such as ketamine and memantine that work by blocking activity at the NMDA receptor for the excitatory neurotransmitter glutamate have antidepressant effects. D-cycloserine is a drug that has a related mechanism and is being studied as an antidepressant. At high doses the drug acts as an antagonist at the glycine site of the NMDA receptor, blocking glycine’s ability to facilitate glutamate transmission through the receptor.
Joshua Kantrowitz, a researcher at Columbia University, reported at a recent scientific meeting that the rapid-onset antidepressant effects of D-cycloserine could be maintained for eight weeks. Similar findings were published in the Archives of General Psychiatry in 2010 and were reported in another study by Uriel Heresco-Levy in a 2013 article in the Journal of Neuropsychopharmacology.
Glutamate is the major excitatory neurotransmitter in the brain and is important for the development of long-term memory. However, glutamate overactivity may contribute to depression. Decreasing this overactivity (with ketamine, memantine, or D-cycloserine) may produce antidepressant effects.
Finding Treatments That Work For Each Patient
At a recent scientific meeting, researcher Andrew H. Miller presented data on infliximab, an inhibitor of the inflammatory cytokine TNF alpha that is used to treat rheumatoid arthritis and is being explored for the treatment of depression. As previously reported in BNN Volume 16, Issue 2 from 2012, the drug was not effective overall among the depressed patients, but in a subgroup of patients with high levels of the inflammatory marker CRP, infliximab was highly effective. Miller emphasized that patients do not fail to respond to treatments; it is doctors who fail, or drugs that fail. He explained that there is tremendous heterogeneity in people’s illnesses, and doctors must get better at sorting out what treatments will work for each patient, striving toward personalized therapeutics.
There are many clinical correlates or predictors of nonresponse to antidepressants used in unipolar depression. These include inflammation, obesity, stress in childhood, anxiety disorder comorbidity, substance abuse comorbidity, and medical comorbidity.
Editor’s Note: How do we doctors target these clinical correlates of illness for better therapeutic effects? We are just starting to learn, and until we identify good markers for predicting illness, the best we can do is carry out carefully sequenced clinical trials of medications and therapies with different mechanisms of action.
Patients can assist their physicians and clinicians by engaging in precise, preferably nightly charting of their mood, functioning, medications, life events, side effects, and other symptoms such as anxiety on a personal calendar. Several of these are available for free download, and there are other longitudinal screening instruments, such as the website and app What’s My M3.
A good personal response to a novel treatment or a poor response to an Federal Drug Administration–approved treatment trumps anything that is written in the research literature. The best way to achieve the best outcome is to engage in excellent monitoring of symptoms and side effects that can guide the next steps in therapeutics.
Therapeutic Potential of Neurosteroids
Neurosteroids have shown promise in the treatment of anxiety and depression.
Allopregnanolone, a natural metabolite of the gondal steroid progesterone, is a neurosteroid that acts as a positive modulator of synaptic and extrasynaptic GABA-A receptors and exerts effects without the development of tolerance.
Researcher Mike Rogawski at the University of California, Davis developed an intravenous formulation of allopregnanolone that is being studied as a treatment for traumatic brain injury. The formulation was provided on an emergency use basis to stop treatment-resistant status epilepticus (non-stop seizures) in patients in intensive care who had been unresponsive to all medications and were placed in a barbiturate coma. When barbiturates were stopped, their seizures returned. All four intensive care patients who were treated with allopregnanolone had their status epilepticus cease and were able to go home. This included a 23-year-old who had been hospitalized with refractory status epilepticus for over 90 days.
BDNF in Learning and Memory
Brain-derived neurotrophic factor (BDNF) is involved in various aspects of learning and memory. The DNA for BDNF contains nine different regulatory sites, each of which is involved in different aspects of learning. Researcher Keri Martinovich studied each site by selectively knocking each one out with a genetic manipulation. She found that blocking the e1 site increased acquisition of new learning and recall in mice, while e2 did the opposite. Blockade of e4 had no effect on these memory functions but markedly blocked the process of extinction, which involves a different kind of new learning.
A mouse that learned to associate a particular cue with a shock (a process known as conditioned fear) will stop reacting to the cue after it is presented many times without a shock. This learning that the cue is no longer associated with the shock is referred to as extinction. The animals with e4 blocked in their BDNF did not develop the new extinction learning, and continued to react to the cue as if it were still associated with the shock.
Editor’s Note: These data may have clinical relevance for humans. The anticonvulsant valproate (trade name Depakote), a histone deacetylase inhibitor, selectively increases the e4 promoter site of BDNF and facilitates extinction of conditioned fear, according to research by Tim Bredy et al. published in 2010.
Clinical trails should examine whether valproate could enhance fear extinction in patients with post-traumatic stress disorder (PTSD).
Types of Epigenetic Modifications
We sometimes refer to epigenetics, a process by which the environment impacts not your inherited genes (based on the DNA nucleotides that encode amino acids to be sequenced in the production of proteins), but how easy it is to activate gene transcription or repress gene transcription.
There are various epigenetic modifications that can occur. Sometimes acetyl or methyl groups are added to DNA or the histones around which DNA is wound.
1. DNA Methylation (usually repressive)
2. Histone Methylation (usually repressive)
3. Histone Acetylation (usually activating)
4. DNA hydroxymethylation
5. Micro RNAs (si-mRNA) (repressing or activating)
6. Nucleosome remodeling by chromatin regulatory enzymes. If the histone spools around which DNA is wrapped are moved further apart, this is activating. If the histones are moved closer together, this is repressing.
Transgenerational Transmission of PTSD
At a recent scientific meeting, Rachael Yehada showed that PTSD-like traits could be passed transgenerationally. Mothers in New York City who were pregnant on September 11, 2001 and developed post-traumatic stress disorder (PTSD) produced children with low cortisol in their blood (a sign of PTSD). If the fathers had PTSD during the mother’s pregnancy, the children had high cortisol.
These gender-related findings have some parallels in studies of rodents. When a rat pup is separated from its mother for 15 minutes, the mother is overjoyed to see the pup return and licks and grooms it excessively. This maternal overprotection yields an animal with lifelong low cortisol through an epigenetic process. The glucocorticoid receptor gives a feedback message to suppress cortisol, and glucocorticoid receptors are increased in the pups’ brains because of lower methylation of the DNA promoter for glucocorticoid receptors.
If a father has PTSD, there is more methylation of the promoter for glucocorticoid receptors and less expression of them in the forebrain. There is also less feedback suppression of cortisol and the baby exhibits high cortisol.
The methylation of the glucocorticoid receptors in the offspring’s white blood cells is highly correlated (r=0.57, p<0.005, n=23) with methylation in the parent’s white blood cells.
