BDNF and Depression

I've written a bunch of posts in the past on serotonin, the serotonin theory of depression (and why it's probably wrong), and some stuff on current antidepressant treatments. And I even talked before a little bit about the serotonin theory vs the BDNF theory. But I've never really COVERED what the BDNF theory IS and how it works. And then I saw this paper, and here's my opportunity!

But I have to warn you, this is a LOTTA paper. But it's ok, the point is good. ONWARD.

ResearchBlogging.org Schmidt and Duman. "Peripheral BDNF Produces Antidepressant-Like Effects in Cellular and Behavioral Models" Neuropsychopharmacology, 2010.


(Source)

So what IS BDNF? And what's it got to do with depression? Let's take it from the top. BDNF stands for Brain Derived Neurotropihc Factor, and is part of cascade of proteins, produced in the brain, that promotes neuron growth and stops neurons from dying. It doesn't act alone, of course, but it's a highly useful little dude.

Here we might pause and say "neuron growth?! Wut?!" I don't know about you all, but when Sci was raised in her little public school system, she was told that we were born with all the neurons we would ever have, and that we would produce no more. But now we know that that isn't true. In fact, you produce new neurons throughout your lifetime, in two major areas of the brain, the subventricular zone and the subgranular zone. The subgranular zone is what we are concerned with right now. This is a region of the hippocampus (an area of the brain associated with learning, memory, and depression), and is found roughly here:


(Source)

On the left is a human brain, on the right is a rat brain, and you can see how the hippocampus (in blue) is positioned in both species.

I'm sure you all knew that the hippocampus is associated with learning and memory, but it is ALSO associated with depression. Or, more specifically, with antidepressants. We used to think that antidepressants worked because they increased the neurotransmitter serotonin in the brain. But there was a disconnect between the way the drugs were supposed to work and the onset of the actual antidepressant effects. Traditional antidepressants like Prozac produce peak serotonin levels in the brain in within about 6-8 hours. But the antidepressant effects take longer. WAY longer, up to several weeks. So if the increases in serotonin themselves weren't causing the antidepressant effects, what was?

Well, it turns out that, if you treat an animal with a drug like Prozac for a few weeks, long enough to get a clinical effect in humans, you also get neurogenesis in the hippocampus, along with increases in BDNF. So the idea is that, somehow, antidepressants increase BDNF, which helps to increase neurogenesis, and this produces antidepressant effects.

There are other studies to support this. For example, stress and increases in the stress hormone corticosterone will cause DECREASES in BDNF, and decreases in neurogenesis, and stress itself is associated with the development of major depressive disorder. Not only that, but PEOPLE with depression actually show lower levels of BDNF in their blood than people without.

So with information that BDNF promotes neurogenesis, and stress causes low BDNF, and is associated with depressive behaviors...well, what does BDNF itself do? Scientists have tried putting BDNF directly into the hippocampus of rodents, and gotten increases in neurogenesis and antidepressant effects. But most patients wouldn't really want people all putting drugs directly into their hippocampus. So this study aimed to see if they could get antidepressant effects of BDNF, just giving it in the periphery of the body rather than the brain. Even though it's "brain derived" BDNF is in fact found all over the body, so maybe treatment there could produce effects.

But BDNF has a REALLY short activity period. REALLY short. Giving it as an injection or a pill every day wasn't going to work. So they used a nifty little gadget called an osmotic minipump. You pump these little pumps, filled with drug mixture or saline, under an animal's skin, and it'll just hang out there, with very little pain or irritation to the animal, for as long as you need. In this case, they treated the animals for two weeks with BDNF. The two week treatment is important, because antidepressant effects with normal antidepressants like Prozac normally require THREE weeks. If you can get effects in two weeks (or less than that!) it'd be better than what we have now. In this case, while they looked for the final studies at the end of two weeks, they ran behavioral tests after the FIRST week, to see if the antidepressant effect could come on that quickly.

So they treated the mice, and put them through their paces.

Up here you can see the first set of behavioral tests. The one on the far left is the forced swim test, where you look at what scientists like to call measures of "coping". Basically, you lower a mouse into a bowl of water where its feet can touch the ground. Mice are good swimmers and for a few minutes it will scrabble valiantly against the walls and swim around, trying to find a way out. When it realizes there IS no way out, the animal will stop swimming and float. We call the swimming 'active coping' and the floating 'passive coping'. We know that antidepressants decrease passive coping (floating) and increase active coping (swimming and climbing), and scientists usually take this as a sign of antidepressant activity. The forced swim test is a VERY common screen for antidepressant drugs. You can see in the graph on the far left that the animals who got either saline or the lowest dose of BDNF floated for between 250-300 seconds, while the animals that were being treated with the two highest doses floated a lot less.

The middle graph shows similar effects in a test for antidepressant activity called novelty induced hypophagia (NIH). This test, and the one on the far right (Chronic mild stress, which I'll get to in a minute) are important because they measure the effects of CHRONIC antidepressant treatment, while the forced swim test usually measures the effects of a single injection (though it can also work for chronic treatment as we saw here).

Anyway, NIH test tests to see how long it takes an animal to approach a tasty food in a novel environment. Antidepressants make them approach it faster. Think of it like this: every day, you come home from work or school or whatevs and I give you a tasty cake. You get cake every day, and pretty soon, you come home from work every day being like "WHERE IS MY CAKE!!?!?!" Then, on the last day, I throw you out in the middle of the ocean on a life raft, with the cake. Presumably you'd be a bit more worried about being on a raft in the middle of the ocean, and it would take a little while to get to your cake. With mice, it's just like that, only with something mice find tasty, like peanut butter chips or Froot Loops. You can see that the mice take a lot longer to approach the tasty food in the novel environment, and treatment with the higher doses of BDNF actually decreases how long they take, which is interpreted as both antidepressant and an antianxiety response.

Finally, on the far right up there we have chronic mild stress. This involves treating the animals for a while with...chronic mild stress. This varies so the animals don't get too used to it, but involves some mixture of chilly rooms, strobe lights, rock and roll music, rocking the animals back and forth, and other little things designed to discomfit the animals. After chronic mild stress animals show signs of depression, like drinking less tasty sugary drink when given the opportunity. You can see there that treatment with BDNF made them drink more sugar water after stress than when they didn't get treated (though they still didn't do as well as unstressed animals).

This figure shows the effects of chronic BDNF (I think they picked the middle dose as the best one) on measures of anxiety. Both the elevated plus maze and the open field test work in the same way. Mice like the dark and nice covered tight corners. Light and open spaces stress them out. So how much they will go in to a lighted area or an open area is a measure of anxiety. You can see that BDNF helped with anxiety in the elevated plus maze, but didn't show any difference in the open field. The authors say maybe this is because the open field is less stressful, but it's hard to tell. These tests are VERY sensitive, and honestly it could have been anything.

So ALL these graphs put together basically show that chronic BDNF treatment produces antidepressant-like (we always have to say antidepressant-like until we've seen it in a human) effects. And the cool thing is that they saw these effects after only a WEEK of treatment, rather than the usual THREE WEEKS required for most antidepressants.

And behavioral tests are fine, but what about neurogenesis? After all, antidepressants produce neurogenesis, right?

Well, so does this:

These graphs show increases in neurogenesis and survival. You can see that while the drug treatment had no effect on neurogenesis (it didn't help produce MORE neurons), it DID have an effect on survival. Normally, there is turnover of produced neurons, with some of them dying off. Giving BDNF prevented that, so allowed more neurons to stay around. So while it's not producing neurogenesis, it has a similar effect (though I think it could possibly have produced neurogenesis itself if maybe they had given it longer).

Other experiments they did in this study confirmed that BDNF was working through specific cellular machinery specific to BDNF, and not through other ways (this included differences in cellular machinery with names like pCREB and ERK), but the finding is clear, giving BDNF produced antidepressant effects in stressed mice, and helped neurogenesis by increasing cell survival. This means that drugs which target BDNF, rather than the antidepressants we have now which target serotonin, could be used to maybe combat depression (though whether this is specific to stressed individuals, who can say). Not only that, it may also means that we can use blood levels of BDNF to measure depression in people (though I am personally not to sure about this, there have been mixed findings on this one).

Now, I would like to point out that none of this PROVES that low levels of BDNF cause depression. In fact, decreasing BDNF artificially in animals doesn't itself cause changes in the depressive behaviors I described above (though it makes them more susceptible to stress). So the reality may be that low levels of BDNF and decreases in neurogenesis may be only part of the problem, or may be a symptom rather than the problem itself. But just because it's not the cause, doesn't mean we can't use advances in the study of BDNF to try and find new treatments. And now that we know that BDNF itself can be administered and have antidepressant effects in animals, perhaps we can use that knowledge to make new drugs which target BDNF, producing better antidepressant effects than what we have now. Sure, BDNF right now can't be taken as a pill, but you'd be amazed at the stuff we can come up with.

Schmidt HD, & Duman RS (2010). Peripheral BDNF Produces Antidepressant-Like Effects in Cellular and Behavioral Models. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology PMID: 21085113

27 responses so far

  • MS4 says:

    Nice piece on the BDNF theory. I just wanted to mention that there's literature suggesting a positive correlation between exercise and BDNF levels. Thus, there's an endogenous way to increase one's BDNF levels, which would be great rather using a pharmcological way to effect levels (There's also lot of literature showing that exercise does help mental health, so it kind of does make sense).

  • [...] Exercising regularly, your brain builds up reserves of BDNF, helping neurons to branch out, joining together, forming new [...]

  • Steven Linder says:

    Although BDNF itself is not directly pharmacologically useful, I have tried
    an admittantly dubious quality Noopept in 10 mg/day doses for three days.

    It was the first time in eight years since three brain and spine surgeries that
    I felt aware.

    After the third day of the test, I felt chills and unable to continue the experiment.

    China origin. Pretty dirty with precursor/by products impurities.

    Hence the notion, "let the buyer beware".

    While it lasted, it was wonderful.

  • Altostrata says:

    1) None of the drug studies compare drug-stimulated neurogenesis with, say, that stimulated by walking or having a good time with friends. It may be more, it may be less, it may be noise in the monitoring apparatus.

    2) The emotional world of mice in a forced-swim test or any test in a mouse study may be a far cry from human emotion. The mouse studies can be regarded as only metaphorical. The entire history of mouse studies in psychiatry may indicate absolutely nothing germane to humans, unless what you want is to find a way to get mice to paddle longer.

    3) There is no functional correlate for a brain region with size increased by neurogenesis. It may not mean anything.

    4) Neuroimaging itself is suspect. See The dilemma of weak neuroimaging papers by Daniel Bor http://www.danielbor.com/dilemma-weak-neuroimaging/

    5) Biopsychiatry, keep on looking. This particular fad is probably as valid as the "chemical imbalance" theory.

  • [...] of the disease, but it’s only recently that researchers are entertaining the possibility that low BDNF and depression could be causally related. And indeed – antidepressants actually increase BDNF signaling and synthesis in the [...]

  • [...] of the disease, but it’s only recently that researchers are entertaining the possibility that low BDNF and depression could be causally related. And indeed – antidepressants actually increase BDNF signaling and synthesis in the [...]

  • [...] of the disease, but it’s only recently that researchers are entertaining the possibility that low BDNF and depression could be causally related. And indeed – antidepressants actually increase BDNF signaling and synthesis in the hippocampus [...]

  • Philip Jacobs says:

    Forgive me my foolishness but if the stress hormone 'corticosterone' causes a decrease in BDNF, wouldn't the logical conclusion be to reduce stress levels. I mean, we are saying that stress impairs the survival (if not the genesis) of new neurons, are we not? I mean, it's all very interesting and a lot of people have obviously put in a lot of work but, fundamentally, should we be relying on drugs to keep us from jumping under the next train? Are we not attacking the problem from the wrong end? Of course, you may well be able to get people 'functioning' again but you are only fighting the symptoms and not the causes.

    Apparently, I have been suffering from at least three different types of depression - as well as a mild personality disorder and various phobias for most of my life. I have taken three different SSRIs over the last few years and, apart from impairing my ability to orgasm, they have had absolutely no effect on me whatsoever. However, my own experience and the experience of the numerous fellow sufferers I have met along the way has led me more and more to the conclusion that is the perceived lack of meaningful engagement with the world around us (alienation), constant financial and socio-hierarchical insecurity and the constant pressure of having to perform and compete at the highest possible level in order to justify one's own existence.

    In a few year's time, they will, no doubt, find a drug that can directly stimulate neuron growth. Perhaps this will work so well that we will all eventually be able to get back to destroying the planet and everything that is worth living for -- but this time with a smile on our faces.

    In my opinion, depression is just a symptom of a disease called Capitalism.

  • [...] prévios, alguns deles realizados pelo próprio grupo Ronald S. Duman, da Universidade de Yale, já haviam mostrado que a [...]

  • Charles says:

    Philip Jacobs, you've got it exactly right. I commend you sir

  • Simon says:

    Philip Jacobs, although Capitalism isn't the perfect system, and there will never be because economic systems don't count for the human element, it's still without doubt the best system that we've got at the moment. Without it, you wouldn't even be able to buy your computer (produced by a multi-national company in the third world, oh the irony) just to sit here and write about how much you hate Capitalism. Ask the survivors of the USSR, the people of Eastern Europe, Cambodia, China, North Korea etc. what they think about the alternative because most unlikely like you they've all experienced it in reality, including myself. Oh and by the way, the walls they built around their countries was not supposed to keep outsiders from going into the country, it was meant to keep the inhabitants imprisoned from escaping to surrounding Capitalistic countries. Have you ever been to Cuba? There's a reason why people risk their lives riding cardboard boxes to Florida.

    But I'm not writing this just to debate politics.
    Of course, you are still right on at least one thing - that we are attacking the problem from the wrong end. But you are doing it too! Rather than trying to solve the problem of "jumping under the next train" by saying that trains shouldn't be allowed to exist in the first place, maybe the solution to the problem is rather to learn how to adapt and to educate ourselves on how to gain the maximal potential of our lives by embracing science and make our consciously choices based on knowledge. It's a part of evolution to learn how to adapt. Time is both our enemy and friend here. Life is not about waiting for a storm to pass, it's about learning how to dance in the rain. There are plenty of people in Africa who live in a lot worse socio-economical situation than I guess you are in, yet they are happy and don't feel depressed. Thinking that everyone else feels exactly like you, given that you apply the same socio-economical conditions that you are in as for everyone else, is only being very ignorant and narrow-minded. We are all individuals and some people learn how to adapt faster than others, some don't at all. A part of it is genetic of course, but we still make plenty of choices that affects our lives everyday. Life is not fully deterministic.

    From my point of view nature doesn't recognize good or evil, only balance and imbalance. So, the solution is to find what balance is best for your life in terms of exercise, physical and mental stimulation. These are all factors which are scientifically well-documented to regulate your well-being and mood, and can also be one of the causes of depression. Personally, I can apply it all to myself. When I was in school, I spent my time in a good environment consisting of a daily balanced level of physical and mental stimulation. I did not feel depressed back then at all. After I graduated, I was in the best days of my life, I did everything I wanted to do such as traveling to other countries, party with my friends, meet new people and do whatever I wanted to do. But after experiencing all that, I started to isolate myself from the rest of the world, stop exercising, stop doing things and learning new stuff, just sitting home alone every day and doing nothing but philosophizing all the time whilst I slowly started to fulfill all possible factors necessary for an anxious panic-attack.

    If you want to know what happened after that, this is my story and my way of dealing with it:
    One ordinary day when I was going to jump into my car for a drive, a simple thought hit me: "What is reality?" and then, boom, it all happened so fast. Months of anxiety that had been slowly built up inside of me, without even being aware of it, just exploded inside of me like a volcano. I had never ever experienced such a fear in my life before, feeling extreme derealization and depersonalization. All I could ever think of was disturbing thoughts about the universe, life & death, eternity, existence and nothingness. I personally felt so hopeless and overwhelmingly sad, that I got traumatized and cried nonstop for a week, thinking that I had gone totally insane. It took me many months of living in this hell until I started researching and discover what actually might be the the root and cause of the problem. I gained more knowledge about the subject by reading stories about other people who have had it and also had been cured. I took a good look at my own situation in life and analyzed the previous months before it all happened, and I did not get surprised at all since it was so obvious that living in a lifestyle like that, given time, would make anyone go out of their mind. My lifestyle had made me much more vulnerable to anxiety and lowered my mental resilience. I remember one time in my early age when I was in school, I had thought about the meaning of life and started to question existence but I did not get emotional about it at all even if the concept was still the same. I just said "I don't know" and that answer was fine by me at that time, then I just ignored it and carried on living my life as normal. The reason behind this was obviously because I had a much stronger mental resilience at that point in time. Why? Because I had good social, mental and physical stimulation from school, so my brain had built up a strong resilience to think objectively and logical.

    After discovering that it was just all of the anxiety that I had built up during the previous months consisting of total isolation, no exercise and poor stimulation, I could breathe out knowing that I was not screwed for life. Just like everything that has a beginning has an end. From that point I became more optimistic and started to really dig into the subject. I discovered, among many other things about the brain, that the cause and solution to the problem was based on neuroplasticity. The brain is not hard-wired to work in a specific way, it's structure is actually changing all the time given certain conditions: environment, physical and mental stimulation. The brain is always adapting to get better at the things you are doing. However, this goes in both ways - positive and negative. When I first read and discovered about the theory of BDNF, I immediately felt that it totally made sense and it explained a lot of the stuff that I had stumbled upon during the time I was researching about neuroplasticity. The theory that serotonin is the cause of the problem is outdated and has many flaws in it such as why it takes many weeks before an effect to take place even though the levels of serotonin is peaking just hours after the first pill has been taken, why low levels of serotonin doesn't always make a person depressed etc. It's just like aspirin takes away syndromes such as headache but the reason why you have a headache is not because you have a lack of aspirin. It makes sense. Though, serotonin seems to play a part in the situation but recent scientific evidence shows that it's because it stimulates neurogenesis in the hippocampus (which promotes positive neuroplasticity) and that's why it takes weeks before the effect arrives. So, when I discovered this, that it's neurogenesis in the hippocampus that regulates if you are depressed or not, what regulates neurogenesis? That's when BDNF came into the picture. The protein, BDNF, is what regulates the neurogenesis in the hippocampus. So, since it's pointed out that BDNF has a very short lifespan, what can I do to make the levels naturally higher? What stimulates BDNF without having to take anti-depressants? After some research, I found out that through plenty of scientific studies that 1. Exercise and physical stimulation 2. Diet and 3. Mental stimulation, is what stimulates BDNF. Fascinating, isn't it? That such a complicated problem can sometimes be solved just by doing such simple things mother nature wanted you to do in the first place.

    So, at the moment I'm trying to increase the levels of BDNF so I can get my memory back, feel better and become stronger as a person.
    I found out that:

    * Drinking a few cups of green tea every day,

    * Eating healthy food (brain food, foods that stimulates BDNF such as blueberries etc; no processed junk food or sugary drinks) every day,

    * Exercising (by running and training your strength/agility) every day,

    * Meditating (twice a 20-30 min) every day,

    * Learning new stuff (how to play a new instrument, reading books, studying science, solve Sudoku, doing things that promote logical thinking such as maths etc.) every day,

    * Getting Social interaction (Important to be in real life and NOT over the Internet, meeting new people, doing things together, have fun and laugh, have sex etc.) every day,

    * Being in a good environment (clean room, comfortable clothes, shower every 2nd day, clean your bed every 3-4th day, not sitting in front of your computer all the time etc.) every day,

    * Therapy (by learning how to think positively about things even in bad situations, read the Charles Linden method, train by yourself or with a friend that you can trust, a real therapist just steals your money by literally doing almost nothing but talking bullshit about some things you could have easily read about on the internet by yourself) every day, and

    * Not taking any drugs or medication at all (NO stupid anti-depressants what so ever because they give you nasty side-effects, the only thing you should take is natural supplements such as Fish Oil, Vitamins and Chamomile tea if you have trouble sleeping at night, try to avoid alcohol if you can't handle it because it can make your anxiety skyrocket the day after).

    Even if you do this for some weeks and feel that it doesn't cure it 100%, don't give up, just continue doing it! It takes a long time before positive neuroplasticity to happen, it could take months and even years depending on how effective it is. For me, it took about 5-6 months of negative neuroplasticity to get a panic-attack. During this time, I was isolated every day from social interactions, I was lying in my bed every day with my computer doing absolute nothing to stimulate myself either physically or mentally except playing computer games, I never had sex, I never visited or hung out with friends, I never exercised, I ate bad food, I philosophized about deep shit, I smoked cigarettes (but had quit right before I had the panic-attack) and I even tried marijuana some times. The worst part was that I was just living for the sake of existing, nothing more, I had zero goals in my life and no self-esteem to do anything at all.

    It's been almost 5 months since I had the first panic-attack but since then I've experienced numerous different symptoms. In the beginning, I had frequent panic-attacks with total derealization and depersonalization, anxiety by the time I woke up until I went to sleep, struggling with deep thoughts about existence, eternity, nothingness, reality, solipsism etc; dizziness, confusion, headaches, impaired short-term memory and no long-term memory of things that happened after the first panic-attack at all, fear of madness, insomnia, hypochondria, bad perception of time, severe depression etc.

    Now, I don't have any panic-attacks anymore, I only have dizziness/confusion, bad perception of time, impaired short-term memory and long-term memory sometimes although that I totally feel an improvement by every week that is passing by. It has totally been better since the time I had my first panic-attack and a big part of it is that I have gained huge knowledge about the science behind it, understanding the cause and solution of it so I can breathe out and learn to let go of things, and that I now have a much more positive optimistic attitude towards the future that I will be the awesome person that I once was.

    I really hope someone experiencing the same things as I did reads this text and gets helped. Who ever you might be, don't worry, it will be fine again like it once was. It's just anxiety, nothing else.

    • Mark says:

      Thanks Simon, setting politics aside that was a great comment.
      You ended by saying that you hoped that someone who was reading that and was experiencing the same things could get help. Well I am that person. I read what you have written and felt like I was reading about myself.
      Is there some way that I can contact you, perhaps via email? I'd really love to have the opportunity to talk to you about your experiences and get your opinion on some of my own ideas. I don't know if its possible to post email addresses in here, I know that some sites have restrictions but I'll try adding mine anyway. If you get it can you drop me a line? FeedFastFeast@hotmail.co.uk

    • Sarah says:

      Hey Simon. Am somewhat behind you on this one - exercise has never worked for me, probably because the area where I live has poor air quality and this is said to off-set BDNF benefits - and I got so anxious about my diet that that also failed!

      Hopefully, I am getting a better understanding which will help me to avoid these offsets but would love to hear whether things are continuing to improve for you by using these methods?

      My email is pomphret@hotmail.co.uk.

      Many thanks - Sarah

  • Rebecca Turp says:

    Who conducted the studies with the rats, would love to know for a research paper :)

    • scicurious says:

      The citation to the paper is at the top of the post: Schmidt and Duman. "Peripheral BDNF Produces Antidepressant-Like Effects in Cellular and Behavioral Models" Neuropsychopharmacology, 2010.

  • k.j. says:

    I think resveratrol (found in red wine) increases BDNF.

  • Sarah Jones says:

    Do you have any update about this study ?

  • Petr Melnikov says:

    Do you admit that BDNF levels may be higher in depression and AD?

  • Petr Melnikov says:

    Do you admit BDNF levels being higher in depression and AD?

  • […] that BDNF aids in the survival of neurons by assuming a role in their maturation, and maintenance (http://scientopia.org/blogs/scicurious/2010/12/13/bdnf-and-depression/). Well with the low levels of BDNF that results in individuals who are depressed, serotonergic […]

  • […] and one more benefit from BDNF: it counteracts depression. The folks over at Neurotic Physiology are good enough to explain how that […]

  • […] and one more benefit from BDNF: it counteracts depression. The folks over at Neurotic Physiology are good enough to explain how that […]

  • […] and one more benefit from BDNF: it counteracts depression. The folks over at Neurotic Physiology are good enough to explain how that […]

  • […] of the disease, but it’s only recently that researchers are entertaining the possibility that low BDNF and depression could be causally related. And indeed – antidepressants actually increase BDNF signaling and synthesis in the hippocampus […]

  • […] of neurological disorders in humans, including severe depression. Lower BDNF levels have also been linked to depression in humans, so these results indicate that TMS may beneficially change the brain’s workings at […]