We’ve talked about ketamine’s rapid antidepressant effects. Last month we talked about the role of dissociation in ketamine’s antidepressant benefits. Neuroscientists are studying ketamine to find out WHY it provides such rapid antidepressant results. They’re hoping they can determine what exactly ketamine does in the brain, and whether they can isolate that action from the side effects without losing its extraordinary effectiveness. It’s a long road (rife with trials!), but they soldier on… hoping to make new medications that could become more available to more people. So let’s follow this team of neuroscientists through their quest over nearly 2 decades so far, to see what makes ketamine work.
A team of researchers, led by Lisa Monteggia, Ph.D., have studied this question for 18 years. Beginning in 2003, she and her team were interested in what makes antidepressants work. At the time, they knew that neurons released the neurotransmitter serotonin to keep the mood stable. Therefore, if the serotonin level was “low,” that was the cause of depression. (Or so they thought.)
A lot of antidepressant medicines at that time were designed to increase serotonin availability. (They worked to prevent serotonin from being taken back up by the releasing neuron, and to keep it around in the synapse.)
However, Dr. Monteggia’s team saw a problem with that whole explanation because those antidepressants (SSRIs and SNRIs–serotonin reuptake inhibitors and serotonin norepinephrine reuptake inhibitors) took weeks to relieve depressive symptoms — when the meds worked. So they realized other things must be going on at the same time, since serotonin alone wasn’t the key element.
Next, her team identified an important aspect of neuronal signaling, as well as something vital for antidepressant effects… and that was brain-derived neurotrophic factor (BDNF).
A variation of the gene that “tells” cells to make BDNF contains an error or oddity that can change what the gene and the BDNF do. And that’s significant. Because further studies showed that people who have this “odd” gene, can have a reduced, dampened effect from antidepressants.
Hmmm..!!
Now don’t miss this next part of her story: As her team was studying this weird anomaly, another team (remember research was going on globally!) published their work about the ketamine, an anesthesia agent that can produce rapid antidepressant effects when given at a low dose — too low for it to produce anesthesia.
Ketamine already had a reputation for abuse when taken in moderate to higher doses.
But this finding was so important! That at a low dose, ketamine can effectively sweep away symptoms in someone who has severely treatment resistant depression. Basically, someone who has not been helped by anything else they’ve tried for their depression.
So this really charged up Dr. Monteggia and her research team. They committed to learning all they could about ketamine. And they say they want to use it as a Rosetta Stone, so to speak. In other words, they want to use low dose ketamine as the key to understanding rapid acting antidepressant action. Why? Because maybe understanding the mechanisms of action of ketamine could fuel the development of new antidepressants without side effects… Ah!
For one thing, it may hopefully show us how effective antidepressants work. (Actually work, not how we assume or think they work.) To learn the actual mechanism behind effectiveness; as in, something we haven’t yet seen or identified.
The other is that ketamine is known to impact a specific protein in the brain…the NMDA receptor. This receptor is found embedded on certain neurons — a lot of neurons!!
The team confirmed that ketamine blocks the NMDA receptor. In addition, ketamine has specific effects on a certain signaling pathway, and when they blocked that pathway, ketamine didn’t work.
Ok…the process of elimination.
But let’s see what else they learned.
Here’s one exciting thing … and we count on it with ketamine treatment. They were able to show that when ketamine blocks the NMDA receptor which affects signaling…it produces a series of downstream effects which trigger a special form of neuroplasticity in the brain cells.
Neuroplasticity is the ability of the connections (or synapses) between the brain cells to change their strength. So ketamine helps those synapses change their strength in new and unexpected ways.
The team has tested other medications to see if they act like ketamine. (For instance, memantine is similar to ketamine in some ways, and it does block the NMDA receptor, but it goes about it in a different way. So interesting, though: despite all that, it does not have the same effect on signaling as ketamine, nor does it trigger this novel type of plasticity that ketamine does.)
They only see this specific type of plasticity with rapid antidepressant action. Eureka!!
(OK, so we’re a little excited here. I know.)
So it occurred to them that perhaps this special form of plasticity may actually be an integral part of rapid antidepressant action.…? And they wonder whether this type of neuroplasticity plays a role in “healing” depression, and demonstrates what makes antidepressants work … Not sure yet.
But here’s something to keep in mind: some experts in the field of neuroscience call ketamine a “dirty” drug.
Don’t panic!
When they say that, they don’t mean it’s grimy. They mean that it works in many ways to affect many parts of the brain — it doesn’t do just one thing that explains definitively how it relieves depression. If they could develop a drug that targeted the absolute biologic mechanisms that are specifically involved in depression, bipolar depression, PTSD, suicidal thoughts, and the rest, that would be a breakthrough!
So ketamine emerged as a treatment for psychiatric disorders — quite by surprise.
This team of researchers believe that ketamine’s actions are especially important in the hippocampus. They believe that after ketamine affects brain cells in the hippocampus, changes flow back to the prefrontal cortex (this part of the brain is behind your forehead) and other areas.
So they’re hoping they can follow the path of those changes backward…from hippocampus to prefrontal cortex to other area. The more they learn, the closer they may come to understand rapid acting antidepressants better.
They believe that blocking NMDA receptors results in that novel neuroplasticity and call it “homeostatic” neuroplasticity. This is a different form of plasticity than the one involved in learning.
And as they continue forward with these experiments, studying homeostatic plasticity, which they believe is at the core of what makes ketamine work as an antidepressant, then they can work with other, perhaps newer, medications that do the same thing…to find more and better options.
Meanwhile, we do have IV ketamine treatment. And people often experience remission with it. So we’ll keep using it, and celebrating your joy, freedom…and hope.
At Innovative Psychiatry, we happily work with you in hopes you’ll achieve remission with IV ketamine treatment. We’ll joyfully welcome you for your treatment, and you’ll receive that treatment in a safe environment with clean, pure air. Sanitized to 99.99%. We take every precaution, like our intense plasma cell technology, to keep our environment here safe for you.
Innovative. Super modern. Seeking the best.
For you.
IV ketamine treatment is just like that in our hands: innovative, supermodern, seeking your best self. Is it for everyone? Does it make everyone better? Sadly no. Which is why we’re so grateful that there are teams of researchers…around the world…who won’t give up, who seek more options and even better ones, for all of us.
If you struggle with the kinds of disorders we’ve talked about, and treatments haven’t helped, call us.
We’ll set an appointment to help you know whether you might be a likely candidate for this extraordinary treatment. Your rewarding and fulfilling life lies ahead.
We look forward to meeting you.
To the restoration of your best self,
