If We Had This Drug, I Would Be on It

One of the largest studies on the reduction of chronic disease risk and mortality was recently published in The Lancet.  The study looked at the use of a particular treatment and the reduction of cardiovascular disease risk, stroke risk, as well as the risks of cardiovascular, non-cardiovascular and overall mortality.  The study was very comprehensive involving 135,335 individuals aged 35 to 70 years without cardiovascular disease from 613 communities in 18 low-income, middle-income, and high-income countries in seven geographical regions: North America and Europe, South America, The Middle East, South Asia, China, Southeast Asia, and Africa.

The results shown to the left were fairly striking with the treatment reducing the risks uniformly for all of the followed measures.  The vertical black line is the risk in the non-treatment group.  That is arbitrarily called “1” in a comparative study.

The graphic shows the risk reductions circled in red compared to those not taking the treatment regularly.  The red line shows the risk reduction to 0.7 which means a 30% reduction.  For cardiovascular events (CV disease) the reductions were all about 20%.  The mortality reductions were more dramatic, all being more than 30%.

The conclusion is that this treatment resulted in broad reductions in disease rates and deaths for the leading cause in developed and less developed countries.  The results occurred regardless of age, income status or country of residence.

Participation in this treatment would not take much persuasion if this drug existed, was widely available and relatively inexpensive.  While it meets all of those criteria, it has been and continues to be a hard sell to the population at large.  This is because the “drug” used in the study was actually “more than 3 servings per day of fruits, vegetables and legumes”. 

To give some perspective on these results, the results of similar clinical trials using statin drugs on total cardiovascular mortality have found risk reductions varying between 0 and 12%.  Seems like one could do twice as much just by eating enough fruits and vegetables daily.

The irony of all of this is that virtually every guideline out there supports this “therapy”, yet the minority of the population follow this in practice.  The breakdown seems to occur for many reasons.  Medical practice has become largely “this drug for that problem” with insufficient time spent or emphasis on implementing this very effective prevention.  This is driven by time restraints in patient care, patients preferring a pill over lifestyle change, and intense pharmaceutical advertising biasing opinions.

The bottom line is that you can’t fight data and in this case, it is convincing.  We are in the era of chronic lifestyle related disease and the biggest piece of lifestyle appears to be diet.

How Are Food Sensitivities and Depression Linked?

Food sensitivities or immune reactions to food have been linked to triggering several neurologic and psychiatric disorders.  This is caused by a couple of different mechanisms involving activation of the immune system.  The first is activation of a portion of the immune system called the innate immune system.  The system is the first part of the immune system to respond to challenge, and it activates systemic inflammation.  Much of how bad someone feels when they have the flu is inflammatory activation by the innate immune system.

About 1 in 10 persons will develop an innate immune response against a particular peptide in food, a problem called a foodsensitivity.  The immune system initiates an inflammatory response each time it detects the presence of that particular food peptide. 

Messengers called cytokines that activate inflammation also activate the more specialized part of the immune system called the acquired immune system.  One of its primary jobs is to produce antibodies against whatever has been perceived to be triggering the immune reaction.  Often this reaction can begin to make mistakes when it is chronically activated generating “cross-reactivity” where antibodies made against food molecules such as gluten begin to cause an attack against similarly appearing structures in the brain.

Studies have linked gluten triggered antibody reactions against brain structures in some seizures, neuropathy, migraine and cognitive impairment.  More recently the expanded knowledge of these reactions has suggested links between food reactions and two of the most common brain/mood disorders, anxiety and depression.

Typically, celiac disease is used as the model to test cross-reactivity between a food peptide and molecules in the nervous system.  Celiac disease is a cross-reactivity where antibodies against gluten begin to react with a peptide in the small intestinal lining destroying that structure.  This cross-reactivity can expand to structures in skin, glands and other areas including the nervous system.

A new study used this celiac disease model to look at nervous system involvement that may be associated with depression.  Patients with established celiac disease were examined with transcranial magnetic stimulation (TMS) which allows accurate measurement of the excitability of the brain.  All patients also completed a standardized test for depression, the Hamilton Depression Rating Scale (HDRS).  At the beginning of the trial 60% of the patients had positive depression scales.

A previous study performed by these researchers using TMS demonstrated that the celiac patients had abnormal balance between brain activation and inhibition.  The “balance” in brain response comes from the signal from one neuron to the next being “toned” by both inhibitory and excitatory interneurons.  These interneurons express neurotransmitters that turn up (excitatory) or turn down (inhibitory) the amount of signaling between neurons much like dimmer switches.

Normal information processing in the brain involves excitatory signals involved in the desired process at any moment combined with the inhibition of others that would take the desired function “off track”.

All subjects were asked to follow a gluten free diet.  Sixteen months later the TMS and the HDRS were redone.  There was actually a small reduction in the imbalance in brain activation.  In contrast, the depression scale showed active depression in only 8%, down from the original 60%.

The altered pattern of brain activation was the result of improved control of the inhibiting neurons that used the neurotransmitter GABA to produce the inhibition.  Research has indicated a high rate of cross-reactivity between gluten and casein, a peptide in dairy, antibodies with the enzyme GAD which is responsible for the production of GABA in the brain.  The antibody destruction of that enzyme appears to result in the abnormal pattern of brain activation.

This study brings up several points about the relationship between food sensitivities and depression.  The first is that once the food sensitivity is diagnosed, avoiding the triggering food improves the depression.  The second point is that the brain does not recover a normal activation pattern simply from avoiding the initial food trigger. 

The researchers discussed the failure of the brain to completely normalize its activation pattern.  The subjects were an average of 39 years of age.  Their immune reaction against gluten had been present for many years.  While the chemical stimulus to the brain which altered its activation pattern was removed, the abnormal brain pattern had likely become “learned”.

All learning comes through repeated stimuli to the brain resulting in neurons developing preferred connections and activation patterns.  We now know that when this has occurred with an abnormal activation pattern such as stress, the brain eventually “learns” that preferred pattern.  At this point in time techniques such as neurofeedback which is EEG guided brain training must be used to re-train the brain back into a more normal pattern.

For many the best outcome with depression will result from finding the original trigger such as a food sensitivity but then restoring normal brain activation patterns with neurofeedback.