Episode 01: Neuroplasticity, Depression and Psychedelics
Dr. Sidney Kennedy:
I’m Dr. Sid Kennedy I’m the director of the Canadian Biomarker Integrated Network in Depression otherwise known as CAN-BIND. And CAN-BIND is a program sponsored by the Ontario Brain Institute and we’re one of a number of integrated discovery programs, in our case focusing on depression. And very specifically some of the work that we want to do is to help make better choices for the right treatment for an individual at a given time in his or her illness. So we really want to understand the innovation, some of the exciting new developments that are taking place.
Welcome to the CAN-BIND podcast.
Dr. Wegdan Rashad:
Thanks for the great introduction, Dr. Kennedy. Hello and welcome to the CAN-BIND podcast! I’m your host, Dr. Wegdan Rashad, and I am very excited about the launch of our first episode in this podcast series.
We are all going through some challenging times with the COVID-19 pandemic, and more than ever our mental health is of priority. We hope you are in good health and good spirits. Today our episode is not about the pandemic, however, it is very relevant to mental health and in particular depression research.
In today’s podcast, we interview Dr. Gregor Hasler, Professor, and Chair of Psychiatry at the University of Freiburg in Switzerland. Now Dr. Hasler’s primary interests are in mood disorders, neuroplasticity, and psychedelics and in February 2020, he joined us in Toronto to discuss some of his work and how it overlaps with CAN-BIND’s research.
Dr. Hasler has written two books entitled, “Resilience: The We Factor” and another one on the gut-brain connection and its relation to mental health.
Alright so let’s dive in! I have mentioned the term neuroplasticity a minute ago and before we start asking questions, I think it makes sense to define what neuroplasticity actually is. Basically, neuroplasticity can be defined as the ability of the brain to adapt in response to changes in the environment. It involves coming up with cognitive strategies to successfully cope with new challenges. And looking at our current times, it takes neuroplasticity for us to adapt and cope with the changes happening in our world due to COVID-19 for example. Our brains have different neuroplastic abilities…and so I asked Dr. Hasler about how we might measure neuroplasticity, especially in cases where neuroplasticity might be compromised.
Dr. Gregor Hasler:
Yeah, that is a good question. How do you really measure this neuroplasticity? and I mean from a clinical standpoint you see that these people have problems with flexibility sometimes when we say stress intolerance this means a lack of neuroplasticity. There is a new situation, new challenge, maybe a divorce or you’re fired from a job and you have to find a new one and then you see that their neuroplastic capacity is reduced so instead of looking ahead and doing something new they’re stuck in the old thing and lose interest and see the world very pessimistically.
The other thing is the personality dimension openness. People are interested in new things; if you have a time curve they see themselves not at the end like at the burn out of something but neuroplasticity means you’re at the beginning of your timescale and so you are looking in the future because your brain is open to new things.
So you mentioned that adapting to changing situations involves neuroplasticity and also openness which is a personality dimension. If we are open to experiences, we are more likely to adapt to a changing landscape. Right? I’m really curious about what actually goes on in the brain that allows us to flexibly adapt to change?
Neuroplasticity is extremely complex but certainly, the glutamate system is importantly involved and one thing is at the level of the receptors like how much AMPA receptor we have, how much NMDA receptor, the transformation of these receptors or composition of these receptors. And then you have all of the electrophysiological measures like long term potentiation or long term depression. So there are many things involved and many things we don’t know exactly but certainly in depression what we have showed that you have a lack of glutamate. Basically, the glial cells have problems to re-uptake glutamate with this you have a lack of a fine-tuning of this system and this certainly leads to also clinical lack of neuroplasticity.
So we have the glutamate system and its receptors (NMDA and AMPA) and then you mentioned long-term potentiation and long-term depression. I have a personal interest in long term potentiation or LTP for short, which is basically the process by which synapses in the brain establish really strong, long-lasting friendships with each other as a result of firing together…well, maybe not exactly friendships…but powerful signal transmissions that allow us to learn and store memories. Dr. Hasler shed some light on the idea that problems with the fine-tuning of the glutamate system, could explain why some individuals may show a lack in neuroplasticity.
Now, I did read that ketamine acts on the glutamate receptors AND possibly allows for better neuroplasticity. Could you tell us more, Dr. Hasler?
Exactly, one is certainly what we know for example now is if you put glutamate and we also show we give ketamine then you have an increase in brain-derived neurotrophic factor (BDNF) that’s just one example but the other is that with too much glutamate, it may be toxic and maybe ketamine is counteracting this toxicity so it is certainly doing many things. We also know the mTOR pathway so all the pathways in the cell that can stimulate via ketamine.
Aha! So ketamine may increase BDNF or brain-derived neurotrophic factor, counteract glutamate toxicity and also act on the mTOR pathway. By the way, the mTOR pathway is a central regulator of our metabolism and cell physiology. It helps keep our cells in tip-top shape and when it becomes dysregulated we can be affected with conditions like with diabetes, depression, and certain cancers.
I think it’s quite an important discovery that a very low dose of ketamine can have antidepressant properties through a mechanism that’s different from the serotonin, and dopamine, norepinephrine pathways. That’s really intriguing because ketamine works with the glutamate system and the glutamate system certainly is a core system when it comes to neuroplasticity or learning etc. It’s certainly part of the glutamate system so early on. The other thing that’s interesting is that you have methods, for example, I use magnetic resonance spectroscopy, where you can measure total glutamate concentration in the brain and you could show many years ago that the content is reduced in severe depression.
Now ketamine and its chemical cousin, esketamine are agents which have gained a lot of attention from the psychiatric clinical and research community in the past years. In fact, ketamine and esketamine can now be administered by health care professionals to manage some cases of treatment-resistant depression and it has been shown to have rapid anti-suicide effects as well.
Ketamine is easily eliminated from the body so you give it and you see some acute effects but there is really something special about it that then you still have after a week or 10 days an antidepressant effect although the drug is not really present. Clearly, something in the brain is changing; you can call it neuroplastic. So it’s doing something with the brain not with a very long effect but at least about 7-10 days. We are now looking at psychedelics like in Switzerland I’m involved in a treatment with LSD where we may have a long-term effect which may last, we don’t know more than these two weeks.
For ketamine, maybe several weeks a month. We also know at the clinical level that these drugs in some patients increases the dimension openness so after, they’re more open and see themselves in different ways or they will see the future in different ways. So that is really exciting and I think now we are in a very exciting phase of research where we can think what to do with these effects because I think if you just give them and life is not changing and nothing happens this neuroplasticity may be lost so it is like window of opportunity and we are trying and with ketamine before and now with LSD to combine it with psychotherapy to see how to get the best out of of this drug effects.
Wow, this is very interesting. So Dr. Hasler’s work indicates that LSD increases neuroplasticity and openness but, if things remain unchanged for the patient…then perhaps those effects won’t be as beneficial…so what his research is focused on is to administer psychotherapy combined with LSD.
Dr. Sidney Kennedy joins in the conversation and asks about some interesting specifics.
So some people will talk about being with a person for six to eight hours in the context of psilocybin or LSD; do you do psychological interventions during the course of the six to eight hours? or do you see it as being, for example the next day? or over a longer duration?
The patient is like the pilot of the plane, and if he is happy with himself or herself that’s okay, I’m just there ready. Usually, there is some treatment going on during the sessions, because the patient has come up with something. Certainly, we don’t discuss it to the end or so, but you take it up and I do my notes, then I get prepared in a way for future sessions. You are doing this big session for so many hours, and then you have weekly sessions to integrate all of this information.
Do we have any imaging that will essentially support neuroplasticity in the context of the LSD session for example?
There is one new measure in functional imaging that’s entropic measures, it involves various mathematical approaches. There you see that entropy increases through the use of LSD. There are other approaches where we look at connectivity, you see brain regions are connected that were not connected before. It’s all the beginning and we don’t know exactly how these functional imaging measures relate to real brain function and structure. We have to come up with better measurements of neuroplasticity.
What are some of the concerns with the use of psychedelics to treat depression?
We have a problem with addiction which is really very rare because we use a very low dose, but something we have seen is some somatic side effects like increased blood pressure. With LSD I think there we have to really handpick the patients. We don’t know what’ll happen if the patient is not ready for this experience or there could be a potential of abuse. We know from the 60s that there has been abuse, so we have to take these very seriously and come up with new regulations or guidelines on how to do it in a very safe way. Certainly, for example, compared to previously we have lower doses and a less stimulating setting. So we say the patient is really the pilot in the plane and we are just the flight attendants and that is a different approach. And you have music, so you place more emphasis on this experience, and then you kind of help the patient integrate these new wishes or new force of neuroplasticity.
I also have to say that neuroplasticity is not always a good thing, in depression it goes down because we have a lot of extremely adverse environments. When there’s an increase in neuroplasticity you have to combine it with helpful, constructive, and positive experiences.
So meanwhile the risk of substance abuse is present…Dr. Hasler suggests that the use of psychedelics in a controlled, safe, and well-equipped environment, for some patients this experience can be of great potential.
Now I understand that some treatments may work for some individuals and not for others, could there be a way to subtype or identify biomarkers to predict how responsive someone might be to a certain treatment?
That is a very good question. For each treatment you may need different biomarkers and what we showed in our data is that with ketamine, the subgroup it works in really in a very high psychological level, you know, a sense of self-acceptance, of self-esteem, is very high level that is different from other antidepressants and I see there may be a sub-typing. It’s really this increased neuroplasticity good for people who are rigid. But you have some depressed patients that have more magical thinking, they see too many options, the world is full of opportunities but they don’t know how to select, I think they may not be the ideal patients, but it’s certainly interesting. Maybe biological markers could be related to neuroplasticity but it is also maybe this kind of psychological profiling where certain people benefit more than others.
So from my understanding agents like ketamine and psychedelics might be- based on psychological profiling mind you- be more effective for individuals who are with depression and are sort of mentally stuck, or have great difficulties with adapting flexibly. Dr. Kennedy joins the conversation and brings up early childhood trauma.
Early childhood trauma is almost always identified as being more prevalent in people with depression and with other disorders, and yet we haven’t really been able to define a subtype where we could identify a particular treatment that might be advantageous. I was thinking of your resilience work. I wonder if you have thought much about linking some of the resilience issues to some of early trauma for example?
I think there are some findings that at least people who report such a history of trauma would benefit a lot from psychotherapy more so than people who don’t report such a history. At least that is an important finding that I am using in clinical practice, so if there is trauma I think psychotherapy is very important. Certainly, we have problems, that we know there is a lot of reporting bias, so we don’t know how real, it’s hard work, but if those are not reporting or if they just forgot, it has a lot to do with the memory with memory process and I am just conducting one study in this respect where we are looking look at genes influencing reporting. I think it’s very complex, but there I see in the future a lot of potential to really understand these traumatic events. Also, the processing of traumatic events with respect to neuroplasticity and all treatments like ketamine and psychedelics.
Depression and the guts. Did you know that our gastrointestinal system is sometimes referred to as the ‘second brain?’ The relationship between our gut bacteria and our brain is on the frontiers in neuroscience now. There is a lot of literature out there to show that mental health conditions like depression, anxiety, and even autism are associated with our gut bacteria. We also have Dr. Jane Foster, who leads the CAN-BIND platform that is devoted to studying the gut-brain axis and boy am I looking forward to a whole podcast episode about this sometime soon, so stay tuned for that.
I asked Dr. Hasler about this gut-brain axis in his research.
There is now new data that for example, the microbiome could really influence depressive symptoms. That the microbiome is a bit disturbed in depression is not an extremely exciting finding, but what is really amazing is that if you take out some of these gut bacteria from depressed patients and you put them into rodents, they also get depressed phenotypes. I think this is really a new understanding, where we thought it is psychosomatic; it is always the brain first and then you have the problems here but would be a completely new dimension that could be first in the gut and then in the brain. We see that in Parkinson’s disease and multiple sclerosis, they all discovered that in these disorders may start in the gut. This may also be true for depression so that’s a very promising field
There seems to be this bilateral relationship between mood and gut. So for instance, when we’re anxious we might feel our stomach uncomfortable…and vice versa, having a gut condition may very well affect or exacerbate a certain mental state. What do you think?
Exactly, just if you looked at the biology, for example, it’s the vagus nerve, and 80% of inflammation goes from the gut to the brain. We think how many hormones the gut has, there are dozens of hormones produced way more than in the other direction. Or you see 80% of the immune system is kind of around or close to the gut. We know that the immune system cytokines have a very strong effect on the brain and on social behaviour and mood. And certainly, in evolution, the gut was first and out of the gut-brain, the other brain developed so there’s certainly a lot of connections from the gut to the brain.
Excellent! And that’s about it for today’s podcast. We hope you learned something new and enjoyed this rich discussion. To keep up to date on our research and content, please visit our website, canbind.ca and follow us on social media, just search “The CAN-BIND Program” on Twitter and Facebook and we will see you there!
Tune in for the next episode which will discuss exciting research on ketamine and ECT as well as a personal experience from one of our study participants.
Special thanks to Dr. Gregor Hasler, Dr. Sidney Kennedy, the rest of the CAN-BIND family, and the audio editor, Damien Murphy.
Thank you for listening and until the next episode, goodbye!
Hasler, G. (2019). Toward specific ways to combine ketamine and psychotherapy in treating depression. CNS spectrums, 1-3.
Breit, S., Kupferberg, A., Rogler, G., & Hasler, G. (2018). Vagus nerve as modulator of the brain–gut axis in psychiatric and inflammatory disorders. Frontiers in psychiatry, 9, 44.