Ketamine: What’s Dose Got To Do With It?

Ketamine’s Power Against Depression

We’ve talked before about how ketamine works through a variety of actions to relieve depression in people with Major Depressive Disorder (MDD).

Like the hero in an epic movie, ketamine treatment works in several brain areas at once to improve brain functioning. It triggers a cascade of actions that repair, restore order, and create peace once again.

We know that ketamine turns on mRNA which switches DNA “on” to turbo boost brain-derived-neurotrophic-factor (BDNF). BDNF, in turn, serves as an ultra-rich compost to speed up the dense growth of synapses, dendrites, and dendritic spines to rebuild a superhighway of infrastructure in the brain for signals to move rapidly from cell to cell and deep into the brain.

This is AMAZING.

And there’s more…

While this is happening, there are lazy little G proteins piled high on lipid rafts in the neuronal cell membranes — and they’re needed to enhance signaling along these dense pathways. But they can’t do their job because they’re just piled on those rafts … and unable to operate.

Ketamine, like a proverbial grade school hall monitor, quickly causes these G proteins to slide off those lipid rafts, get into place, and get back to work with their signal transmission job.

The result of all this is a brain that’s communicating at lightning speed again within hours, rather than weeks or months.

Genetic Tests

We’ve talked before about tests that help indicate whether a person is likely to respond to ketamine or not.

One of these tests checks a certain genetic biomarker that signals a person’s likelihood to respond to ketamine treatment. It’s a certain allele, which is one of two more forms of a gene that can arise on the chromosome for BDNF.

The alleles are called Val and Met. You can be a Val/Val, a Val/Met, or a Met/Met for BDNF.

It’s the Met allele that seemed to impede the antidepressant effect of ketamine treatment for depression, anxiety, bipolar disorder, PTSD, OCD and suicidal thinking. Early on, it was reported that those with the Met/Met alleles were least likely to respond to ketamine treatment, and those with Val/Val were most likely.  (Those with Val/Met fell in between.)

However, we’ve noticed in our practice that sometimes our patients who don’t have the Val/Val alleles, and don’t seem to respond to ketamine rapidly, tell us weeks or months later that they’re feeling so much better, and are enjoying their lives again.  Hmmmm …

What Causes the Delay?

That made us wonder what made the difference …?  Why were some of those specific patients enjoying a delayed, but just as robust, response to ketamine treatment…?

So … a new study shines a light on this mystery. (Science is so fantastic!)

A team of researchers from Taiwan and the US has found evidence that ketamine’s antidepressant effects are related to the size of the dose given.

And, importantly, evidence that Met carriers respond to ketamine.

First Study to Explore Ketamine with Taiwanese Subjects

The researchers conducted an elegant double-blind placebo-controlled study of 71 Taiwanese adults who received one ketamine infusion.

Neuroscientists believe ketamine treatment’s effectiveness as an antidepressant depends, in part, on the BDNF gene.

An important fact is that Chinese people typically have at least one copy of the less responsive BDNF allele, Met.

So in testing the effectiveness of ketamine treatment for these Taiwanese participants, the researchers were testing whether ketamine relieves depression in people with the Val/Met allele, and also whether the size of ketamine’s dose determines effectiveness.

Huge. AND exciting.

Ketamine: What’s dose got to do with it?

This was the first study to compare the effectiveness of two different doses of ketamine — 0.2 mg/kg and 0.5 mg/kg.

The researchers genotyped the participants and confirmed that the Met allele is the predominant BDNF gene in this specific group of people — they were Val/Met or Met/Met. In European descendants, the BDNF gene alleles most often seen are the Val/Val pair.

Another factor they explored was whether ketamine’s effectiveness varied depending on the severity of the patient’s depression.

Size of Dose Determined Effectiveness

All in all, they learned that lower doses of ketamine, such as 0.2 mg/kg, weren’t effective at all. (Good to know, because we’ve never used doses this low.)

So if you’re asking, “Ketamine: What’s dose got to do with effective depression treatment…?” you now know that tiny doses under 0.5mg/kg are too low to treat depression and other psychiatric mood disorders.

Only the higher dose, 0.5 mg/kg, was effective, which validates the current most commonly used starting dose, and the starting dose that we use, too.

Also, when they evaluated ketamine’s effectiveness in those with mild depression, they found it really wasn’t effective. (We’ll get back to this later.)

But it was remarkably effective in those with moderate to severe depression.

So, we know that ketamine is effective in people with moderate-to-severe and treatment-resistant depression. And we know it can be effective in people with the Met allele for BDNF — as well as in people with the Val allele, of course. All you Mets, take heart.

Questions That Need Answers

But there’s so much more to be explored.

More studies — for instance, to determine how ketamine infusions could be used to help you if you have mild depression. Using a different dose, different intervals…? 

Don’t you wonder… what if a study were performed among subjects from an equal distribution of multiple BDNF gene variants… if we could learn more about what role the Val and Met alleles play in fast response or delayed response to IV ketamine treatment? 

Or whether a higher dose than 0.5 is needed for those with the Met allele? Or a longer infusion? Maybe a longer series like 9 infusions instead of 6? 

The more we learn, the more we can hopefully bring relief and remission. Relief and remission to adults and adolescents with suicidal thoughts, anxiety, depression, bipolar disorder, social anxiety, PTSD, OCD, and substance use disorders.

Exciting, isn’t it?

If you suffer from depression, anxiety, bipolar disorder, social anxiety, PTSD, OCD, suicidal thinking, or substance use disorders, there’s hope. At Innovative Psychiatry, most of those we treat with IV ketamine achieve remarkable improvement — as in remission — from their symptoms.

We use the most precise state-of-the-art methods of administration. We provide a thorough psychiatric evaluation of our patients’ needs and progress.

And we see people get better every day.

If you’re suffering from symptoms that haven’t responded to other treatments — or if you’re just tired of side effects that never end — call us, or send us a note here. You can feel better, with a new initiative, motivation, and joy. Soon.

To the restoration of your best self,

Lori Calabrese, MD