Depression - Beyond the Chemical Imbalance (Part 1)

Today we go back to the basics of depression.  Borodin's Nocturne (right click to open in new tab).

I would say there are three main theories held by the general public about the causes of depression:

1) Bootstrap theory:  you are a lazy good-for-nothing who just needs to snap out of it and get up and get yourself better.

2) Trauma theory: too much stress, death, trauma, etc.

3) The chemical imbalance:  You have an SSRI deficiency and your serotonin needs to be regulated (see this memorable old zoloft commercial)

Of course, I don't subscribe to any of these theories entirely, though there are elements to each of them that hold a kernel of truth - my belief and one that is largely supported by the literature is that stress and genetic susceptibility leads to depressive symptoms, which are mediated by inflammatory means in the brain.  And certainly if one is capable, getting up and getting out and exercising and eating right can be very helpful, but sometimes asking a depressed person to wake up early and exercise is like asking someone with a broken ankle to go for a run.  The frontal lobe isn't firing on all cylinders.  There's no motivation, no zazz.

The scientifically minded probably are most familiar with theory number three.  In medical terms, the "chemical imbalance" theory is called the "monoamine hypothesis" of depression.  The monoamine theory is (I would say) largely accepted by doctors of a certain age (even psychiatrists), but it holds about as much water as the carbohydrate-insulin theory of obesity.  Back in the day there was a medication for blood pressure called reserpine.  Among other things it depletes the brain of serotonin, and does indeed tend to cause depression (it is rarely used nowadays).

The first antidepressant, a drug used to treat tuberculosis, was found serendipitously.  One of its actions was to change the concentrations of monoamines (such as serotonin and norepinephrine) in the synapse between nerves.   And thus, the monoamine hypothesis of depression was born along with a billion dollar antidepressant industry.  All the antidepressants affect the monoamines one way or another, and they work… if you are lucky, often with side effects, and maybe they protect your brain during one episode of depression, but they don't seem to protect you from the next episode if you go off the medicine when you feel better (talk therapy when compared to medicines seems to have more long term benefit, not surprisingly).

Along the way, the monoamine theory picked up a bunch of other diseases (called the affective spectrum disorders) including major depressive disorder's anxious twin, generalized anxiety disorder, migraines, irritable bowel syndrome, bipolar disorders, social phobia, PTSD, OCD fibromyalgia, and chronic fatigue syndrome among others (1).  All of these diseases have been shown to respond (somewhat) to three or more different classes of antidepressant medication.

Problem is, when you measure serotonin in depressed people, the levels are often all over the map.  In fact, low serotonin doesn't really correlate with depression very well at all, though low serotonin in the central nervous system does correlate with suicide, violence, and insomnia.   Brain researchers quickly figured out that the monoamine hypothesis has some pretty big holes, and the mechanism of antidepressants is not about increasing serotonin and other monoamines in the synapse but rather changing the efficiency with which monoamine signals are transmitted.

Instead, the current literature-supported theory of the brain pathology of depression and the other affective spectrum disorders leads us to two things going awry - the immune system (inflammation) and mitochondrial dysfunction.

How messy is the study of depression?  Consider these facts - if we look at the modern criteria, the classic unipolar major depression is a smallish subset of the whole.  31-62% of people with depression have symptoms of "atypical depression" (leaden feelings in the arms and legs, increased appetite, increased sleep, as opposed to the classic weight loss and insomnia).  64-72% of those with atypical depression meet criteria for bipolar spectrum disorders.  Depressive disorders are often comorbid with ADHD, anxiety, and substance abuse disorders.  You can see if we try to study a group of patients with "major depressive disorder" by criteria that represents the typical clinical outpatient, we will get a mix of people with various complicating neuropsych problems, and any studies of so-called "pure" major depressive disorders where other problems are excluded (which is typical for pharmaceutical studies) will not necessarily be generalizable to the actual population.

Add in frequent comorbid medical conditions, and you have a whole soup of pathology.  92% of depressed inpatients have pain, typically headaches or muscle aches.  Irritable bowel and migraines are often found, along with metabolic syndrome, pre-diabetes and diabetes, and obesity.

However, rather than be taken aback by the complexities, theories of mitochondrial dysfunction and inflammation can scoop up the entire variable pathology (which makes these theories very pleasing to me).

So let's start with mitochondria.  As we know, these are the energy factories of the cells, and their primary mission is to make the cellular equivalent of gasoline, ATP.  Problems with the mitochondria tend to show up as symptoms with the most energetically hungry cells of the muscle and nerves.   Nutritionally, CoQ10, carnitine, B-vitamin, and selenium deficiencies can also cause mitochondrial dysfunction directly.  Mitochondria desperately need these micronutrients to do their work efficiently.

Symptoms of mitochondrial dysfunction can be non-specific, but the cognitive symptoms are very similar to those found in depression, including impairments in attention and executive function and memory.  Tellingly, in families with known genetic problems with mitochondria, the symptoms worsen around times of stress - overwork, fasting, over-exercise, and environmental temperature extremes.  Children with mitochondrial disorders are more likely to be depressed than control children, and among adults, folks with known mitochondrial disorders are more likely to have depression, chronic fatigue, major depressive disorders, bipolar disorder, and panic disorder than the general population.

But all of that is the typical chicken and egg clinical stuff.  Maybe people with genetic mitochondrial problems have a lot of stress, and are thus more depressed.  What's the biochemical evidence for mitochondrial dysfunction in major depressive disorders (and bipolar disorder)?  Autopsies show all sorts of interesting problems with mitochondrial proteins, unusual mitochondrial DNA mutations, and poor mitochondrial complex activity (2).  ATP production rates and respiratory chain enzyme ratios seem to be decreased in the muscle of biopsied patients with major depressive disorder and pain.  In fact, several studies have shown that patients with a high degree of somatic complaints (typically muscle aches) have much lower ATP production than average in the muscle.  In chronic fatigue patients, some similar abnormalities have been found.

And finally, in some mouse models of mitochondrial dysfunction, the mice have bipolar-like symptoms and altered levels and turnover of the monoamines.  The researchers worked out that the mitochondrial dysfunction was the cause of the monoamine depletion, leading to the mouse mood disorders.

So mitochondrial problems (which can be brought about genetically, but also by micronutrient deficiencies) can cause oxidative stress, and eventually lead to nerve damage and psychiatric symptoms.  More on the specifics of this pathology and the role of inflammation in the next post.