Depression is most certainly a biological disease.  Somewhere among the stress and trauma and deficits in coping skills and negative self-talk and genetic predisposition is the molecular basis of why the brain is struggling.

I'll begin by describing the immune system. It's complicated. Imagine an A-list party with all sorts of different security checks and bouncers. There are guys on the perimeter keeping the unwashed masses out, then there are guards on the inside keeping an eye on the elite, and maybe even spies working the crowd, searching for any crashers. The different security forces of our immune system have different names and duties, too. There are the B cells which work via little protein tags called antibodies (known as the "humoral immune system.") Then there are the natural killer cells, hungry macrophages, and other elite shock troops. Finally, you have the cell-mediated immunity, primarily the T cells, who run around messing with anyone who looks like he doesn't belong.

There are several inflammatory cytokines that are biologic markers of depression, among them, high levels of IL-6, IL-2, and TNFalpha. These naturally produced chemicals  (among many more, such as IL-12, interferon gamma, and biomarker neopterin) activate and prime the T cells, who then go out and do their killing. Therefore inflammation means, in a nutshell, that the body's security forces are out there.  There is very intriguing biologic evidence that the cell-mediated part of our inflammatory reaction is the major cause of the symptoms of depression (1).  A number of intriguing papers have been published by a Belgian researcher, Dr. Michael Maes.

Out-of-whack cell-mediated immunity has been implicated in lupus, diabetes mellitus, schizophrenia, rheumatoid arthritis, several cancers, multiple sclerosis, and Grave's disease. But Maes has been able to link various participants in cell mediated immunity to many of the major symptoms of depression, including the "vegetative" symptoms (poor sleep, poor eating), the somatic symptoms (increased worry about illness and increased aches and pains), and the decreases of neurotransmitters serotonin and norepinephrine. He links it to the alterations in the HPA axis, which is the major hormonal regulator in the body. Not to mention the actual inflammation in the hippocampus (the center of depression in the brain) itself. To put it simply, Maes has described the complex biochemical mechanisms of depression using a single overriding, reasonable, and realistic theory of cell-mediated immunity. This is like learning the beautiful ins and outs of how too much fructose causes metabolic syndrome. In a word, awesome.

Maes and other researchers start by measuring a T-cell activating cytokine called sIL-2R. This little bugger is higher in the blood and CNS of people with cerebral lupus, depression, and mania. The worse the symptoms, the higher the levels, and the levels fall when the depression, lupus, and mania symptoms go into remission. Pretty telling. Other markers of cell-mediated immunity (soluble CD8 antigen and other T-cell surface markers, and levels of interferon gamma) follow a similar pattern.

One interesting tidbit - a lot of inflammatory disorders respond to steroids, which suppress the immune response. Asthma, multiple sclerosis, inflammatory bowel. Depression will often get worse with steroids, and Maes figures that's because depression is driven primarily by the T-cells, which are steroid-resistant compared to other parts of the immune response. In case you were wondering.

But let's get back to the actual mechanisms. Check out this link for a very useful diagram. Inflammation causes our body to preferentially make tryptophan, the precursor to serotonin, into kynurenic and xanthurenic acid. Not only does this mean we have less happy, relaxing serotonin around, but kynuretic has the tendency to make us anxious and depressed all on its own. More specifically, T helper cells and indoleamine 2,3-dioxegenase (IDO), parts of our cell-mediated immune response, lower our serotonin levels and make us depressed. This mechanism is true of bipolar depression, major depression, adolescent depression, depression in heart failure patients... you name it, and IDO is smacking down our serotonin. Interferon alpha treatment for hepatitis C or multiple sclerosis will activate the very same mechanism to make us depressed. In animal models, specific cell-mediated immune activation causes lack of interest and changes and sleep and appetite consistent with the similar human symptoms of depression.

Antidepressants work by suppressing the cell-mediated immune response in specific ways. All major classes of antidepressants have been shown to have this effect in various models - tricyclics, SSRIs, SNRIs - they block the production of IL-6 and TNF alpha in immune cells, and also block a number of other acute inflammatory phase proteins, such as C-reactive protein and haptoglobin. Antidepressants are anti-inflammatory, and never-treated depressed individuals will have much higher markers of inflammation than those who are treated. While there are several studies of neuroimaging showing similar changes in metabolism of the brain with response to antidepressants or psychotherapy, I found only one that specifically measured psychotherapy and inflammation, from 2009 in depressed cancer patients. I was also able to find this study of yoga reducing C-reactive protein, IL-6 and other markers of inflammation. I think it makes sense to assume that any successful treatment of depression will be anti-inflammatory. Dance Dance Revolution did not reduce inflammatory markers in obese kids, however. Who knew?

Mood stabilizers, such a lithium and depakote, also affect the ratios of key inflammatory cytokines. Like the antidepressants, they suppress the cell-mediated immune response in specific ways that affect neurotoxicity and neuroplasticity.  And recent genetic findings have lent support to this theory of inflammation leading to depression.

I wish we had more evidence-based lifestyle and dietary trials for psychiatric disorders. Not just (probably biased) studies of medications and a few of psychotherapy, and not just a bunch of epidemiological studies. What if we knew for certain that dietary changes could could stop the inflammation in the first place? If I'm right about my paleolithic-style approach, then I could actually prescribe grass-fed steak (not currently FDA-approved) and wild-caught alaskan salmon.  

I wrote a recent post for Mark's Daily Apple about micronutrients, food intake, and brain energetics, where the comments were overwhelmingly positive and noted a number of positive mental changes that happened upon adoption of an evolutionary-style diet.  This is hardly a scientific sample, but it is encouraging.  

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