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May 9
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“Pain or suffering of any kind, if long continued,
causes depression and lessens the power of
action; yet it is well adapted to make a
creature guard itself against any great or
sudden evil.”
The Life and Letters of Charles Darwin,
Charles Darwin, 1887

This is a bit of a dangerous post, but so is depression.

The post is largely based on Nesse 2000, ‘Is Depression an Adaptation?’, which I heavily quote from.

Take home message if you don’t have time to read all the article:

Some negative and passive aspects of depression may be
useful because they inhibit dangerous or wasteful actions in situations
characterized by committed pursuit of an unreachable goal,
temptations to challenge authority, insufficient internal reserves to allow
action without damage, or lack of a viable life strategy.

Though, the author also points out that many depressions are disease states - so the notion that depression is an adaptive response might only be a subset of the range of potential depressions.

Continue to read to learn the more fleshed out idea:

I think most of us can agree that depression causes an immense level of suffering, for the person undergoing to depression, but also for the rest of the people close to the depressed. However, with such a large percentage of the population (see depression’s cost to the individual and society) experiencing this malady one might wonder if depression has a ‘function’. And this point Darwin was trying to convey in the opening quote of this piece.

Okay, if we are going to entertain this notion we must still wonder what could possibly( be the function of depression?

Nesse, offers a number of possibilities but emphasizes the idea that depression may play a role in drastically reducing motivation for unreachable goals.

If a commitment to pursue a goal encounters an obstacle, efforts increase and become aggressive. If the obstacle cannot be overcome, low mood helps to disengage the commitment
and end the cycle. If the individual cannot disengage, low mood escalates. Klinger concludes, “depression is ordinarily, therefore, a normal, adaptive part of disengaging oneself from an incentive.”56(p21).

If failure to reach a goal might induce depression to ‘encourage’ the organism to stop pursuing a particular goal (that is unobtainable), then one might surmise that those seeking the highest goals might suffer more depression in an attempt by the system to alter the pursuit of lofty goals.

Clinicians have long noted that depression is common in people who
are pursuing unreachable goals.47,48 “Failure to yield” may be an example,
in the status competition domain, of this more general situation.
When current life plans are not working, the distress and lack of motivation
that characterize depression may motivate planning and reassessment49
or escape, even by suicide.50

To bring in some neuroeconomic aspects to shine light on this problem one needs to think of the commitment of resources (time and energy) in pursuit of a goal with payoff X. Obviously the loftier the goal the greater potential reward, but also the probability is lower. However, if feedback with the environment is indicating that this goal is unobtainable for a particular individual there is a need for a signal to stop pursuing this ‘unprofitable’ wager.

In the article Nesse quotes Wender and Klein:

. . . biologically based self-esteem— and mood in general—seems to us to
have evolutionary utility . . . If one is subject to a series of defeats, it pays to
adopt a conservative game plan of sitting back and waiting and letting others
take the risks. Such waiting would be fostered by a pessimistic outlook.
Similarly if one is raking in the chips of life, it pays to adopt an expansive risk
taking approach, and thus maximize access to scarce resources.73(p204)

This starts becoming interesting and I would like to refer you to a couple articles I have written about optimism and hope (The neuroscience of hope, optimism is good for your health, is the glass half full or half empty: rACC brain activation, are organisms by nature optimists?).

This line of thinking suggests that depending on your probability of success one needs to appropriately adjust your ratio of optimism/pessimism. Of course this just makes common sense that we adjust our behavior based on probability of success, however the question is does depression play a role in adjusting your ‘attitude’, your goals?

Going back to Darwin, one needs to think of how something that seems so hideous like depression would actually improve ‘fitness’ (fitness defined as reproductive success - passing on the genes). If depression reduces the pursuit of an unobtainable goal, and forces a reassessment of the persons overall situation, and an eventual choosing of a goal that will result in a payoff then this could increase the person’s fitness level - then maybe depression could improve the individuals fitness.

I will give an example. Take a 21 year old person who moves to Paris (or Prague, etc) to become an artist (just to take a well know dream/pursuit) for that is their passion. They have an incredible level of drive and determination. This person does whatever is needed to pursue their goal of becoming an artist. Of course it is difficult, as is becoming an actor, athlete, etc. Despite the dogged determination this person has had very little success when nearing their 29th birthday. They might continue to pursue their goal, supplementing their income with low-income, temporary work like they have been doing for the last 8 years. But their reproductive fitness in the culture is low - they are not considered a ‘good catch’ due to the uncertainty of their future, and total lack of success (money or otherwise). Now if the person becomes depressed because of their lack of success and lose all motivation to create their art, this might induce them to give up on their dream. Having abandoned their dream they start a normal job, say based somewhat on their background, as a graphic designer for computer games. The person doesn’t consider themselves an artist for they do not get to draw what they want, but instead what they are told. But the person becomes gainfully employed and his reproductive fitness increases.

However, since depression inhibits all activity then it might just contribute the person to staying in their current situation. If you are stuck in a well and depressed then you don’t have the mental energy to attempt climbing out. This would be a bit of a paradox to the potential adaptive advantage of depression. Nesse then argues that a quick dropping of a dream and a mad rush of to a new un-thought out pursuit would also be disadvantageous.

When depression is instead seen as a state shaped to cope with unpropitious
situations, it is clear how it could be useful, both to decrease investment
in the current unsatisfying life enterprise and also to prevent
the premature pursuit of alternatives. Failure to disengage can
cause depression, and depression can make it harder to disengage. This
may explain why the low-mood system is so prone to getting stuck in
positive feedback loops.88-91 Mood dysregulation may now be so prevalent
because we are bereft of kin, beliefs, and rituals that routinely extracted
our ancestors from such cycles.92

Nesse suggests that he conundrum of depression resulting from failure in life is resolved by accepting the reality of the individual’s life situation. And then the person moves on by giving up on the unlikely probability of their former goal. How this exactly happens was less clear to me. However, what was clear is that if the person fails to disengage then ‘serious pathology‘ is likely to occur.

Earlier in Nesse article he uses the example of an animal behavioral choices while foraging a food patch.

As the food in a patch is depleted, organisms give up on that patch at close to
the optimal time, namely, when the rate of return in the current patch declines
below the average rate of return over all patches. If the overall
rate of return from all patches drops below the cost, foraging stops.

Nesse then returns to this theme when discussing the neuroeconomics of the choice of people when it is apparent they need to move on. Changing your goal engagement is considerably more difficult than simply jumping to the next food patch because of the emotional investment in these various goals.

At least as important as the risks and costs of making a
change is the threat to the person’s identity, reputation, and sense of a
secure place in a social network and the cosmos.

At the end of his paper Nesse offers a few testable hypotheses, which are interesting.

The simplest untested prediction is that depression should be
common in people who are unable to disengage from unreachable goals.
Graduate students who are failing and faculty who are unlikely to make
tenure are obvious candidates for study, but other situations are far
more common: unrequited love, inability to get work, pursuing an elusive
large life goal….

Ability to repress such wishes should prevent depression.

Finally, Nesse wonders about the possibility that foraging/feeding patterns may be linked with the behavior of depression.

If the brain mechanisms that regulate foraging are related to those that mediate depression, then antidepressants should change the duration of foraging time in a depleted patch and the willingness to exert effort even when the net rate of return is negative. They might also change preferences for working hard for a large intermittent reward vs easily getting small, frequent rewards. If low mood is an active coordinated state, then the brain mechanisms that mediate it can be blocked at different points, so antidepressants should be effective via multiple mechanisms.

I find this last point particularly intriguing as I have written previously about the relationship between antidepressants and antipsychotic use, increase levels of ghrelin, and subsequent weight gain.

Take home message:

I guess one needs to know when to hold them, and when to fold them. In specific situations depression may be a signal emanating from your system to give up. The trick is not to give up on life, but rather only give up on the specific unobtainable goal. But on the other side of the coin, ‘what if life without a dream’.

I do not know if a subset of depressions is an evolved adaptive response to stop us from chasing after fruitless endeavors (empty food patches), but it does provide food for thought.

(some of Nesse’s followup papers: Nesse 2004Keller and Nesse, 2005, Keller and Nesse 2006, Nesse and Ellsworth 2009.)

Feb 11

Thursday, February 12th is the 200th anniversary of Darwin’s birth. Additionally, this year is the 150th year anniversary of the release of his epoch changing book: “On the origin of species by means of natural selection, or the preservation of favoured races in the struggle for life”. I linked to a Google’s digitized version (yes I know it is not really Google’s version) of Darwin’s book.

I ashamedly admit while I have studied and read a great deal about evolution (from a very wide variety of sources and angles) I have not read Darwin’s original work. Being the bicentenial of his birthday and 150th anniversary of his most famous work I have decided no time like the present to finely read On the origin of species…. Maybe this would be an interesting choice for a book club - if any of you are invovled in one.

Jun 17

An example of how it is hard to hack a hacked system follows.

Previously I mentioned a quote from Francis Crick (1962 Nobel prize winner for the co-discovery of the structure of DNA (1953)) that biology is a hacked together system rather than engineered from the ground up. This general idea makes sense at an evolutionary level – one tweak, or system, was hay-wired on top of the next for whatever evolutionary gain. Hence, the system is a hacked, ad-hoc assembly that works very well for its appropriate environment, but not easy to reverse engineer.

The great hope of health science is through the intervention of a drug (usually acting by a single mechanism) to alter the biological system to cure, or treat, various diseases. Now it is an open question with all the redundancy and irregular and/or overlapping systems how effective this paradigm can be.

For example purpose, one biological problem that is getting an increasing level of interest is in the general health field of improving the overall health of humans, which can lead to increased longevity or just an increase of health in aged humans – instead of a life with chronic illness and constant health challenges.

Calorie restriction (CR) in its various forms has proven to improve the health and extend the lifespan of numerous organisms. However, many people correctly argue that is unreasonable to expect a significant percentage of the human population to adopt such ‘will power’ driven diets (just have to look at the obesity epidemic to see the logic of this argument). Therefore, there is a large search for calorie restriction mimetics (CRM) to produce the same effects. So like other health scientists, these scientist are looking for a pill to treat the masses, and in this particular case they want to produce the same effect as CR.

Resveratrol (found in wine) is the great hope, which I have covered previously . The main proposed mechanism of resveratrol is to increase the protein Sirt1, (sirt1 is one member of the sirtuin family of proteins) which is reported to be increased with CR in many tissues. Ouborous has a couple of very good posts on resveratrol and sirtuins .

David Sinclair – one of the two big guns in the resveratrol/sirtuin field who co-founded Sirtris Pharmaceuticals, made big news recently when the company was bought by GlaxoSmithKline for 720 million dollars (meaning a stock price of $ 22.50, which is a nice tidy sum over the closing price of $ 12.23 – as of April 23, 2008 - just before the deal). What David Sinclair and company has developed (and GlaxoSmithKline bought, bet on) are potent inducers of Sirt proteins (potential calorie restriction mimetic). David believes when his drug hits the market in 4 or 5 years for diabetes that his pills will only cost 3 or 4 dollars each, and once it comes off-patent only pennies. Alright - a cheap calorie restriction mimietic is coming down the pipeline.

Now what is interesting is a new Sirt1 paper by the other big leader in the field of resveratrol/sirtuin and longevity, Guarente (former supervisor of Sinclair) was recently published. Normally it is thought that CR increases Sirt1 expression (at least protein level and activity, not necessarily at the mRNA level) and this is what Guarente’s group found in the muscle and fat tissue of CR animals. However, in the liver they found lower levels of Sirt1 compared to the control fed group. Therefore, a pill that systemically increases sirtuin levels in all tissues might not produce the same effects as CR – and could even potentially produce some opposite effects of CR. High calorie diets in this study increased Sirt1 levels in the liver. The final line in the abstract is: “Our findings suggest that designing CR mimetics that target Sirt1 to provide uniform systemic benefits may be more complex than currently imagined.”

I think this statement is a caution to the biological field in general and obviously the Sirt1/Resveratrol field specifically.

This example might point out why when you want to hack a hacked system that you need to worry about the devils in the details, and why relatively simple (CR), but highly effective global results (increased lifespan, etc) might not be so easily addressed by a single magic bullet.

I don’t want to sound like a broken record (and I will get off this topic tomorrow), but like yesterday you can wait 4 or 5 years for a pill to produce overall health benefits (that may not work as well as we expect - see above), or do something today to improve your health. None of us are getting any younger, as I understand how time works. Go and try something novel today, go exercise, go light on your lunch today, go learn something new.