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.

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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.