Thursday, May 3, 2012

Depression, Antidepressants, and the Endocrine System

It's all connected.  I know it, you know it.  Hormones and mood and the brain and inflammation… precisely how and precisely what to do about it?  Well, that is surely the sticking point.

Santigold: LES Artistes (right click to open in new tab)

I'm working from a paper today (as always) but it is not the world's greatest paper (1).  A small study hardly worth mentioning, but the discussion and conclusions have some interest.  So put your mind in an open frame but don't believe too much what you are reading.

Depression.  Not just a state of mind, really.  Can I tell you how common it is for someone to come in to see me, having just experienced a major loss (job or death in the family) and tell me: "My antidepressant isn't working.  I'm really sad."

I don't know why it is we are blessed and cursed with emotions.  There's some good explanation about how hominids survived via groupings and attachment and all that.  We are left with the baggage, as it were.  We love.  We hate.  We murder, and we grieve.  Sometimes if you sit outside and let the humid air in through your nose and watch the leaves flicker in the wind you can forget all that for a moment, and just exist, where dying is tomorrow, or yesterday, and not important.  Outside of the moment we are left with hopes, ambitions, failures, and loss.

My 9th grade biology teacher, Mr. Turner (who abandonned the profession to become a forest ranger) said to us once:  "Evolution is a fact.  Deal with it."

We have a hormonal system to deal with trauma of all kinds.  Emotional, physicical, present, past.  The lack of differentiation is the problem, frankly.  But it is what it is.  And folks suffering from  major depressive episode frequently have activation of the hypothalamic-pituitary-adrenal axis along with an increase in insulin resistance and increased accumulation of visceral fat.  Things go to hell in a handbasket pretty quickly.  There are elevations in inflammatory cytokines, not just in the brain, but all over the body.

In the traditional medical model, we add antidepressants to the mix.  I know there is no such thing as a serotonin or norepinephrine deficiency but bear with me.   Long ago, the tricyclics, which can indeed improve depression symptoms but result in an increase in body weight and possible worsening of diabetes.  The newer agents of SSRIs (prozac and the like) are actually associated with an improvement in glycemic control.

(Classical music, some of the best ever: Beethoven: Symphony No 7, II)  Classical not your drug of choice?  Sleigh Bells, Comeback Kid, ads up front.  Sorry about that.)

Weirdly, the old fashioned antidepressants who cause weight gain and dry mouth are known to decrease cortisol, whereas the new ones with fewer weight gain side effect have no immediate effects on the HPA axis.  (The wizened psychiatrists who sit in the front row of grand rounds always bemoan the lack of use of the old fashioned antidepressants in favor of the SSRIs.  But no one wants to be fat and dry-mouthed, not to mention the death in overdose so possible with the tricyclics).

Wht could be going on?  Cortisol from stress centrally increasing craving for high-caloric, palatable food… and increasing the secretion of resistin, an adipokine that causes decreased insulin sensitivity and an increase in fat storage and diabetes? In rats that is probably true.  In humans?  Not so clear.

Resistin is typiclly released in rats due to inflammatory and obesigenic influences.  But what about adiponectin, the supposedly antiinflammatory and anti-obesity hormone release in humans in response to stress or excess sugar… In humans, adiponectin is higher in women than in men, and are reduced in obesity and insulin resistance.

In the small study in the paper I've linked, free cortisol levels (STRESS) were strongly associated with levles of resisin in depressed patients.  In follow up, those who were on medicine and had decreased symptoms also had decreased levels of resistin.  There were no changes in hormone levels for those who did not improve on antidepressant treatment.  BMI was correlated with resistin also.

What do we learn?  Depression = increased cortisol secretion = increased resisitin = increased obesity.  Direct or indirect mechanisms may be unknown.  In mice, increased resistin increases fasting glucose in insulin resistance.  This may be true in depressed humans and may explain the link between depression and diabetes.  We don't know for sure.

Adiponectin concentrations didn't change during the six weeks of measurements of these depressed patients on or off antidepressants.  Only resistin measurements were statistically significant.

The endocrine system is always a bit of an investment in reading, and it doesn't always deliver.  That's why we read the Hunger Games Trilogy instead of books about the thyroid.  I get it.  Peeta v. Gale is more interesting than resistin and adiponectin.  That's not hard to understand.  We're human, after all.  We love, we hate.  We let go, we give in.


  1. Saturated fat in the diet enhances adiponectin, at least in this model

    "Furthermore, treatment of rat 3T3-L1 adipocytes with saturated fatty acids (palmitic or stearic acids) in the presence of ethanol increased secretion of adiponectin and enhanced activity of a mouse adiponectin promoter. In conclusion, the protective action of saturated fat against the development of alcoholic fatty liver in mice is partially mediated through induction of adiponectin."

    I suspect that fattening effect of low-fat diets has almost as much to do with the loss of a protective, antiinflammatory effect from animal fats (including vitamins and EFAs) as it has to do with the uniquely fattening effect of carbohydrate.

  2. Sometimes it just seems like this whole inquiry into depression and other similar "disorders" is just a waste of time, or a misnomer. Take a person and throw them up on stage in front of a hundred people. Of course their resistin and cortisol and whatever else is going to be elevated compared to baseline, and I bet they'll even have symptoms of anxiety--So if going in front of tons of people causes this unpleasant jazz to occur, get off the stage! I don't think the solution is to become a forest ranger, though that could be fun. It's not depression we're treating with these meds, its our body's resistance to such an uncomfortable existence. The kind where we deprive ourselves of sleep, of good nutrition, and expose ourselves to stress and every synonym of it every single day. We're not providing treatments for illnesses, we're just selling very specific anodynes.

    1. There's no question that is a major drawback (and, ultimately, a fatal one) to research based on DSMIV classifications. However, certain symptom complexes are well characteized, well understood, and linked to certain consistent changes in brain metabolism. At NIMH they are beginning to do research from the ground up, using these brain findings.

  3. Really liked this piece. Poetry and information all at once!

  4. Hi, interesting post as always.

    Just to let you know that there's some part missing where it says:

    "Things go to hell in a handbasket pretty quickly. There are elevations in inflammaory"

    Oh, and isn't there the type of depression with decreased output of cortisol (and catecholamines)?

    1. Thanks. As always I'm doing too many things at once to properly edit these things sometimes. Coristol increases and decreases are dependent upon the context of how they are measured. Sometimes there are no changes except the timing, as in some folks with SAD.

  5. Re the Beethoven, it's supposed to be allegretto but is typically played slower, this one is about 70 bpm by my reckoning, probably to make it more poignant. Wagner said something about it being impossible not to dance to the second movement so he was probably accustomed to hearing it at a faster pace.

    1. It's funny, I think this rendition is even a bit faster than I am used to hearing it.

  6. This paragraph is not complete:

    We have a hormonal system to deal with trauma of all kinds. (...) quickly. There are elevations in inflammaory

    I really like your blog by the way.

  7. If you read Berlioz' autobiography (for anyone interested in classical music and/or functional madness) you'll realise that conductors took incredible liberties with the works of dead composers until relatively recently.
    In Berlioz' day, most conductors had no qualms about subtituting theiir own compositions for sections of Mozart or Beethoven they thought could be bettered.
    Purism is a modern idea.

  8. Have you read this article Emily? If you have an opinion please comment. Thanks.

    Primum Non Nocere: An Evolutionary Analysis of Whether Antidepressants Do More Harm than Good
    Paul W. Andrews,1,2* J. Anderson Thomson, Jr.,3,4 Ananda Amstadter,2 and Michael C. Neale2

  9. Hey, I just read this post and wanted to point out that SSRIs are very much associated with weight gain also - not just tricyclics. I love your writing!

  10. Many off-label or recreational drugs can produce an antidepressant effect, but their use is controversial. Opioids were used to treat major depression until the late 1950s.Amphetamines were used until the mid-1960s.Scant research on the use of opioids limit their use for the treatment of depression, whereas amphetamines have found a thriving market for conditions as widely arrayed as attention deficit disorder, narcolepsy, and obesity, and continue to be studied for myriad applications.


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