Saturday, December 3, 2011

Beyond the Chemical Imbalance Part 2

Love the new song from the new album by the Black Keys:  Lonely Boy (from El Camino)   I know this guy's video will get slashed soon enough, but for now… enjoy!  The Black Keys said Lonely Boy is a departure from their typical style, as it is up-tempo.  I wish they would do more like this one!

Are you peppy yet?  You ought to be, because we are going to dive back in to this paper (sent to me by Jamie some weeks ago):  Beyond the serotonin hypothesis: Mitochondria, inflammation, and neurodegeneration in major depression and affective spectrum disorders.

There's all this talk about pathogenesis, chickens, and eggs.  Well, I know where it ends.  We chase the trail back to the beginnings (is it abuse?  temperament? soda?  ho-hos?  winter? rancid vegetable oil?  bad reality TV?  the jury is still out).

But here is where it ends.  Ground zero.  Ratty neurons, smoking mitochondria, and brain damage.  Inflammation.

Inflammation is the term for the complex biological response of tissues to harmful stimuli, such as pathogens, damages cells, or irritants.  Inflammation is a protective attempt by the organism to remove the injurious stimuli as well as initiate the healing process for the tissue.
I knew there was a reason I liked this paper so much.  Two sentences of real wisdom.   The paper continues on to talk about cell death, mitochondria, and the cell "executioners" called capases.  They are cysteine proteases that bring it when a cell needs offing.  These are the cellular equivalent of the Necro-whatevers from Chronicles of Riddick.   Overproduction of reactive oxygen species by shoddy, inefficiently-acting mitochondria is a central feature of neuron cell death.   The tricky wicket is that mitochondrial dysfunction and cell death leads to more inflammation, dysfunction, and cell death.

The presence of an inflammatory response in major depression… is evidenced by, amongst other things, increased plasma levels of pro-inflammatory cytokines and acute phase reactants, oxidative damage to red blood cell membranes and serum phospholipids, and lowered serum zinc.
Pro-inflammatory cytokines can induce depression in 70% of people treated with such agents.  Elevations of cytokines have been reported in depression, anxiety, fibromyalgia, migraines, IBS, chronic fatigue syndrome, diabetes, autoimmune arthritis… of course, says any doctor.  The so-called "mitochondrial cocktail" can improve mitochondrial function after a few months and includes the following:  CoQ10, riboflavin, and at least one additional antioxidant (vit C, E, or alpha lipoic acid), and l-carnitine or creatine.

Older school psychopharmacologists will try the following:

Tricyclic antidepressants - they act as classical mitochondrial decouplers by hindering ATP synthesis and enhance ATPase activity.  They tend to change how mitochondria function in a neuroprotective way.

SSRIs: some seem to be toxic to mitochondria at large doses, but protective at lower doses.  In animal models, all antidepressants attenuate inflammation-induced brain cytokine production and prevent the development of depression induced by high dose interferon.  In fact, antidepressants seem to have this effect regardless of mechanism (SSRI, tricyclic, lithium) - which is a major argument against the monoamine theory of depression.

Lithium: seems to enhance mitochondrial function in humans and rats.  Long-term is even better than short-term.  Lithium is the favored medicine of the gray-haired psychopharmacologist.  Between the neuroprotective effects and the anti-suicide benefit, you might expect people to encourage lithium to be in the water

Shock therapy:  Yes, it is still around.  Frankly, there is no faster treatment for depression and it works in refractory cases, thus is often a lifesaver.  It has terrible side effects, there's no denying it.  And it seems to increase the mitochondrial efficiency in rats.

Up to 50% of patients with major depression are unresponsive to medications… here is a poem from old Egyptian papyrus (from the anchor paper)

Disease has sneaked into me.  I feel my limbs heavy.  I no longer know my own body.  Should the master physician come to me… My heart is not revived by his medicines. 


  1. Emily,
    I love the old Egyptian quote! Its such a poetic description of depression. I love the verb sneaked and that the patient is a stranger to himself and that he feels like he cannot be helped. It really captures something about the experience.

  2. What are the terrible side effects of EST, other than memory loss? I know memory loss is not a great thing, but my understanding is that it is generally limited to the past few hours to days prior to the therapy while sparing memories older than a week. I guess this isn't great, but if the past week was spent in a state of major depression, what's to mourn with the loss of those memories?

  3. "Inflammation is a protective attempt by the organism to remove the injurious stimuli as well as initiate the healing process for the tissue."

    So some degree of inflammation's good for us?

    I read Dr. Mark Crislip at Science-Based Medicine a few days ago. He said that he usually makes no attempt to reduce fever caused by infection. In other words, no Tyelenol, ibuprofen, or aspirin. The fever's part of a mechanism to help fight infection. I bet inflammation plays a role in causing most fevers. BTW, Crislip is an infectious disease specialist.

    That's not the first time I've heard the healthy fever hypothesis from an infectious disease docter. It doesn't go over very well with hospital-based nurses when they page me at 2 AM with a fever of 103 F.

    I wonder how often we try to fight inflammation, whereas we should let it run its course.

  4. This looks interesting:
    A complex dietary supplement augments spatial learning, brain mass, and mitochondrial electron transport chain activity in aging mice.

    I had problems to post a comment.

  5. hi Emily. many of us have called BS on the general monoamine theory of depression.

    some of your readers may get something out of this...

    all the best. Shel

  6. Great post! It has opened up a whole new perspective on inflammation (one of my new interests) thanks to your lithium rabbit hole link.

    Being a psychiatric nurse, I find this particularly interesting and hope to share it with the few open minded psychiatrists I know.

  7. I was interested to see the ingredients in this 'mitochondrial cocktail', as I believe the progress I've been making in the past couple years with fighting depression does come down to improvements in my mitochondria. In fact it seems I'm now taking all of the compounds in that list, although I'm not sure if the dosages are always sufficient, and CoQ10 is a very recent addition. For me, avoiding even small quantities of gluten also seems to be critical. It's possible that B-vitamin deficiency played a large part, probably brought on by absorption issues resulting from the gluten sensitivity.

    This interesting video of Dr. Terry Wahls was linked today on MDA:

    She talks about eating a hunter-gatherer diet to improve mitochondrial function, and specifically mentions CoQ10, creatine and omega 3 (also sulphur, iodine, other B vitamins, and I'm sure D has something to do with it as well). It seems to me like the study of mitochondrial breakdowns and insufficiencies is about the take off.

  8. Necro-whatevers!? You’re funny Emily! But if I recall it properly, the Necromongers were conquerors, not executioners.

  9. Aaron, the main side effect is the memory loss, which can be permanent. Though I've had several patients whose lives have probably been saved by ECT, they are all ambivalent or negative about the experience - their families far less so, as they saw how desperately depressed and suicidal they were at the time, and as you mentioned, the patients tend to forget due to the procedure.

    Steve - When my kids have a fever, I never treat it unless they are also in pain or it significantly interferes with their sleep, or if it tops 104 (which happened when my oldest had roseola). I tend to put inflammation in a bad light, but we are all here today because of it! It's definitely a goldilocks sort of thing.

    Ned - Don't they sweep up all the people and blow up the planets along with anyone who refuses to come? I wasn't paying too much attention to that movie - Pitch Black was pretty good, though.

  10. Aa music fan, I can say that TCA's seem to be terrible drugs as Nick Drake overdosed on them. They have a very narrow margin of efficacy/toxicity. Dr. Deans, have you ever thought of doing a series on mental illness and the predilection for artistic achievement. There is a lot of speculation in this regard, and lot of people think artists are crazy or the drugs make them crazy, but what do you think? Is it just a popular mythology? Is there a basis to it? Could it have a evolutionary take as it relates to the origins of music, religion, art, shamanism? You think this is too far a stretch?

  11. Neurometabolic mechanisms for memory enhancement and neuroprotection of methylene blue.

  12. Low dose ketamine works just about as fast as ECT (within hours), without as much memory impairment and without as much stigma. It is also less scary to pop one pill than to be sedated and shocked. I think the main barrier to acceptance of ketamine is that it is also a drug of abuse. Any evidence that ketamine works through mitochondria?

  13. I have a few posts on ketamine. It works but only temporarily - literally a few days to a week, and it seems to become ineffective in short order. ECT can last for a long time. Ketamine is being investigated but its usefulness is somewhat limited.

  14. Great post!

    And I think ketamine has the potential to be addictive, unlike other psychedelic drugs. I know it has been used with some apparent sucess in treating alcoholism and heroin addiction. I saw some studies on MAPS website

  15. "I wonder how often we try to fight inflammation, whereas we should let it run its course."
    I suspect that inflammation will become to the 21st century, what cholesterol was to the 20th. ie: A marker for an underlying issue, rather than the cause of the issue itself. I feel that we need to figure out what is causing the inflammation rather than just fighting it.

  16. Pete - the high powered anti-inflammatory drugs that would kill TNFalpha, for example, tested for sepsis were always disasters as far as I know. The inflammation fascinates me because it is a similar mechanism to all diseases of civilization, suggesting perhaps similar environmental causes and a different way of looking at treatment which is what I explore, obviously. But my prescriptions will never make anyone a billion dollars, to be sure.

  17. I love that movie! and damn it, someone beat me to methylene blue.

  18. Terry Wahls also says that she's done a clinical trial testing her diet and she's going to present the "breathtaking" results. That's really interesting

  19. Just came to mind: if I'm not mistaken, the Egyptians ate mostly bread and beer.

    Just a thought...

  20. Terry Wahls abstract

    Philip Thackray

  21. doctor_ostric you can search for low latency inhibition.

    I don´t have the articles I read at hand but here is on related:

  22. Hi Emily,

    Sorry, but it's not clear to me whether TCA's are a good thing or not. My doc has me on 25mg of Amitriptyline to help with my out of control migraines (not working btw). He is big into inflammation and has me taking many things to do reduce it including the Ami.


  23. Gary Wenk, professor of Psychology and Neuroscience at The Ohio State University. Low doses of marijuana seem to stimulate the brain in positive ways (inflammation). Coffee acts as another stimulant that is proving helpful (neuroprotectant).

  24. Ketamine is addictive in the same way massage therapy is addictive. In my experience many illegal plant and synthetic compounds are contextually necessary nutrients.

  25. Its anandamide-that is the answer.

  26. Dr. Dean, have you ever considered a behavioral economic model of depression?

    Basically, I model mood as the temporally-discounted net rate of intake of reinforcement, which ultimately means the net rate of intake of resources perceived to enhance inclusive fitness. It is the ultimate currency into which all perceived gains and losses are converted.

    The lower mood gets, the less behavioral investment the brain wants to make, given the perceived increasing scarcity of net reward.

    To make matters worse, loss aversion increases as mood decreases, with the subjective value of gains and losses increasing, but losses more rapidly than gains. Hence, there is a behavioral economic trap, with the irony that though each unit of reward is more highly valued(needed), there is less net motivation to obtain it. This is the crux of depression, from this perspective.

    Why increasing loss/cost aversion? Because any prospective gain or loss of an absolute magnitude looms larger relatively, as a percentage of perceived resources available, as those perceived resources dwindle.

    Hence, it's possible that the mechanisms you cite here are merely those by which evolution facilitates the important, non-pathological behavioral economic function of conservation of available resources in scarce environments.

    In this framework, inflammation may get worse with decreasing mood, as a function of increasing risk/loss aversion and a shift of immune system resources toward more immediate threats, given that lower resource states would mean a lower average life span.

    Reward-wise, the depressed brain would thus seek only more profitable rewards, just as a company with lower revenue and profits focuses more on its more profitable operations, sometimes shutting down less profitable ones.

    Consider common shifts in behavior when people are depressed, such as increased appetite for high calorie foods(comfort foods), sex, and generally more immediate gratification.

  27. However, from this perspective, and there are other factors outside of this model to consider, depression can easily lead to less food consumption on average, depending on the relative average costs in terms of effort, money, social consequences, etc. of obtaining and consuming food, sex, etc.. In fact, it is well-known that depressed rats, for example, are less likely to walk across a cage to eat when depressed, but consume more on average than non-depressed rats when the food is placed right in front of them.

    The depressed brain, this perspective argues, often causes at least one of two things to happen, though they aren't necessarily mutually exclusive. One is that a higher quantity, lower quality reproductive strategy is opted for. Young girls with high stress levels tend to enter puberty earlier, have more sexual partners and earlier sex, and are more likely to abuse and neglect their children(the more children, the lower the value of each, especially when resources are scarce. Depressed mothers are even more likely to play favorites, fitting the pattern of shifting to more profitable rewards above).

    The other thing that is fairly common with major depressive disorder, is the phenomenon of suicidal ideations. While people can certainly commit suicide for abstract reasons, this perspective suggests that the sometimes uncontrollable urge to do so is essentially a triggered kind selection program. In other words, given a low resource intake, and depending on the situation the family is perceived to be in resource-wise, it sometimes makes sense to commit suicide to leave more scarce resources to genetic relatives perceived as more fit.

    There is much more to this perspective and plenty of evidence, which can be discussed if you're interested. I know this comment comes late in the discussion, but I just found your blog.

    By the way, I also model emotional responses within the same framework. Anger, for example, is a response to an outcome that's worse than expected.

    Since expectations and the relative(subjective) value of a given outcome determine behavioral investment, when an outcome falls short, there is necessarily a loss and the expectation was necessarily unrealistic.

    The classic textbook example is a person attacking a soda machine after it steals their money.

    Given the framework for mood above, it would make sense for anger to be more severe when mood is lower, since the marginal value of each unit of reward increases.


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