A vexing problem in psychiatry has been that intense suicidal feelings must be countered within minutes, and traditional antidepressant drugs like Prozac take weeks to work.
The good news is that, after decades of work, scientists are zooming in on the precise areas and chemical pathways in the brain that control emotion, and that malfunction to cause severe depression. As understanding of the central mechanisms grows, researchers are identifying targeted drugs that work faster and faster.
Specifically, drugs that target the brain signaling chemical glutamate within nerve networks now work quickly enough to be useful in patients on suicide watch in emergency rooms.
A recent article by our Bob Shepherd talked about how Richard Shelton, M.D., professor in the UAB
Department of Psychiatry, Division of Behavioral Neurobiology, is leading
clinical trials at UAB that look to combat intense, immediate depression with drugs that alter glutamate signaling.
Among the drugs is ketamine, an anesthetic used since the 1970s to put people to sleep during surgery, but increasingly recognized as useful against depression at lower doses. Work with ketamine set the stage for the precision design of newer glutamate-targeting drugs like Glyx-13, also being tested here because it works like ketamine but may have fewer side effects. Dr. Shelton sat down with The Mix to talk about how his field is unraveling the mechanisms of depression.
Show notes for the podcast
1:25 We have long heard about how depression may be caused by problems with nerve pathway signaling chemicals like serotonin, norepinephrine and dopamine. Older drugs that target serotonin include Prozac, Luvox, Paxil and Celexa. Wellbutrin blocks influences dopamine and norepinephrine signalling, while Cymbalta, Effexor, and Remeron affect both norepinephrine and serotonin. A growing research focus in recent years, however, has been on glutamate and the mechanisms by which it interacts with nerve cells. They all appear to influence depression, but which one operates at the heart of the matter?
1:35 Over twenty years, first in animal studies and then in human studies, it became clear that ketamine blocks the interaction between glutamate and a protein receptor on nerve cells called NMDA, which stands for N-methyl-D-aspartate. When glutamate docks into a receptor like NMDA, like a key into a lock, it changes shape such that a biochemical message is passed on inside the nerve cells to create a strong and very quick anti-depressive effect.
2:25 Dr. Shelton leads a first-of-its kind clinical study in that its seeks to test whether or not ketamine can help people with depression so severe they have come to a hospital emergency room to report a strong urge to kill themselves.
4:07 Glutamate is one example of a neurotransmitter, a chemical released from one nerve cell in signaling pathway that floats across space to the next nerve cell to trigger reactions that pass on the message. They regulate not only the passing on of messages but also the growth and connection of nerve cell networks that control, among other things, emotion.
4:53 As is the case with many cellular mechanisms, the binding of glutamate to NMDA opens a channel in the outer membrane of a nerve cell. In through this channel flow charged calcium ions that act like an electric switch kicking on cell processes.
Note: As I understand it (disclaimer), cell signalling is based in part on atomic theory, where atoms are among the basic units making up all matter, and these in turn are made up of electrons, protons and neutrons. Atoms with more positively charged protons have an overall positive charge; those with more electrons carry a negative charge. Whatever charge is (it is undefined), like charges repel and opposites attract, and pulling apart two particles attracted to each other (separation of charge) creates potential energy that can be put to work. Cells have harnessed charge to drive life processes by pumping charged molecules into or out of cells. The buildup of charged particles on one side of a cell membrane means those particles will rush back if given the chance. That chance comes, under carefully regulated circumstances, with the opening of channel proteins that enable charged particle flow.
5:03 Precise regulation of calcium entry into nerve cells is extremely important because calcium signaling has a great many functions throughout the cell, and the glutamate/NMDA partnership regulates the flow. Studies over many years have revealed that when calcium ions flow through NDMA, it shuts down the stimulation of nerve cells to sprout outgrowths that connect them to other nerve cells. These connections are regulatory in nature, helping cells act in concert to better regulate complex processes like the formation of emotions.
5:44 Depression associated with suicide happens when such processes are no longer regulated properly and run out of control thanks to an abnormally low number of connections between nerve cells. Nerve cells start sprouting connections the minute you block glutamate signaling and calcium influx through the NMDA receptor channel with a drug like ketamine, said Shelton.
6:08 High doses of ketamine just put people to sleep. At low doses, Shelton said, it acts as a strong antidepressant within about 15 minutes. A person in terrible distress will not be helped by older antidepressant drug classes like the selective serotonin re-uptake inhibitors that take weeks before they start to work.
7:02 Calcium flow into cells regulates the activity of enzymes and groups of cooperating proteins called complexes. Among the calcium-regulated complexes is nerve cells is MTOR, which calcium shuts down. Among MTOR's functions is to encourage the growth of connections between nerve cells. Ketamine blocks calcium influx, thus preserving the ability of nerve cells to form networks.
8:16 Ketamine is given to patients by infusion, where the medication is delivered via an intravenous line directly into the bloodstream, which leads to a rapid effect. In a typical setting, patients receive ketamine in a higher dose given over 40 minutes of infusion. In the emergency room scenarios seen in Shelton's clinical trials, where a patient is in extreme crisis, his team has been testing whether or now a lower dose given over five minutes can avert suicidal urges.
9:11 The current study by Shelton and colleagues seeks to confirm that treatment with ketamine, if physicians do nothing else, protects patients against sever depression and suicidal urges for five to seven days. Specifically, the current study is looking at what happens when you give the infusion ketamine, and then let physicians take whatever next steps they think best as continuing treatment (counseling, other drugs, etc.). Initial evidence suggest that the combination of ketamine and the physician's choice for continuing treatment sustains the benefit of the ketamine even longer.
10:17 Another study led by Shelton is looking at whether or giving patients a series of ketamine infusions can maintain the protection against severe depression over a period of months.
11:32 It has become clear, said Shelton, that traditional antidepressants act though changing the activity of serotonin and norepipinephrine produce antidipressent effects slowly, and that most people taking them get better but never fully well. Another set of patients gets better but then relapses. Ultimately, these older approaches are not ideal for controlling the emotional state because their effect is indirect and incomplete.
12:16 Researchers believe that somewhere in signaling pathways downstream of serotonin and norepinephrine there is the central set of mechanisms in control of depression that all antidepressant drugs must act on, the mechanism that controls the formation of connections between nerve cells.
12:45 Shelton believes this central mechanism is closely related to the action of glutamate, which comes with about with the blockage of NDMA receptor signalling via ketamine. The effect of drugs that adjust glutamate activity is stronger, faster and more sustainable than the effect of traditional antidepressant treatments. .
13:13 Researchers seek to catch patients in the emergency room, and then prevent them from again becoming acutely depressed again through a series of interventions. They also need new solutions for patients that are chronically depressed and for whom many treatments have failed.
15:02 In the past, and at its traditional dose as an anesthetic, ketamine has been identified as a drug of abuse. A heavy dose puts people to sleep. A lighter, pre-anethesia dose makes people hallucinate. The lower dose used in the current study should not create euphoria or hallucinations. Still, a drug like ketamine is best administered in a clinic, said Shelton, versus sending it home with people.
16:56 A third trial underway at UAB is testing a compound called Glyx-13, produced by Naurex, Inc. Glyx-13 may produce similar results as ketamine by blocking an amino acid called glycine, which works in tandem with glutamate. Glycine regulates glutamate signaling, so it is like an added layer of fine-tuning. When glycine and glutamate bind to NMDA together, the calcium ion channel opens widely. Blocking glutamate with ketamine can reduce the release of calcium. Blocking glycine with Glyx-13 may achieve the same result, but more subtly and with fewer side effects.
