New Targets for Anti-Depressants?

This post is very long (3850 words) and very difficult. It is a preliminary investigation of the idea that depression arises from chronic sustained arousal leading to amine depletion and various other physiological changes.

This news release from Science Daily highlights a new pharmacological approach to treating depression. The nutshell is this: there is a class of proteins in our brains called RGS proteins which inhibit the signalling of various neurotransmitters. By manipulating the RGS protein that inhibits serotonin signalling we can treat depression. Most current anti-depressant drugs attempt to increase the levels of serotonin or norepinephrine. Unfortunately there are now some studies emerging which indicate these current anti-depressants can increase the risk to develop a range of disorders, from kidney problems to cataracts. Generally the risk profiles are low but given the very widespread use of anti-depressants it could constitute a considerable public health cost. Which raises an interesting question: if we place our faith in these statistical analyses then is the government entitled to extract an "pharmaceutical externality tax" to address the health risks and subsequent costs associated with drug side effectss? Yeah, like that'll ever happen. We'll develop a new class of anti-depressants, and wait 30 years before we know about the associated risks ... .



My unalloyed cynicism aside, what caught my interest about this research is the reference to RGS proteins. It reminded me I read in 1999:

Article: 

Upregulation of RGS7 may contribute to tumor necrosis factor-induced changes in central nervous function

Journal: NATURE MEDICINE • VOLUME 5 • NUMBER 8 • AUGUST 1999

Conquering Depression

Over at SkepticLawyer Legal Eagle has commented on the prevalence of depression in the legal profession. As noted in her post there are many obvious reasons for those in the legal profession experiencing such high rates of depression. Her post prompted me to go over some old data I had read long ago.

Understanding the physiology of depression very much remains a work in progress. In this post I provide a cursory introduction to the these problems.

There are many types of depression.

Dysthymia: a mild form of depression that is very common
Major Depression: less common but much more disabling, major depression is now being perceived as a risk factor for the following conditions:

• heart disease
• dementia in latter life
• cancer
• Gut problems like Irritable Bowel Syndrome
• mild cognitive impairment

Bipolar Disorder: a condition where the individual swings from manic states to intense depression
Cyclothymia: a milder form of bipolar disorder that is frequently misdiagnosed as depression.
SAD: Seasonal Affective Disorder: strangely enough while SAD is usually associated with depression onset with winter, it can also occur with the onset of summer; though the latter is much rarer.
Post partum Depression: a condition experienced by mothers shortly after giving birth.
psychotic depression: depression so severe the individual becomes psychotic
Atypical Depression: where the individual is not necessarily melancholic but demonstrates lack of motivation and anhedonia(lack of pleasure in activities that formerly provided pleasure). People with atypical depression often over eat, tend to be tired all the time, and are often overly sensitive about rejection from others.

Note: The definitions of depression types can vary over time and from place to place.

As the foregoing demonstrates "depression" is a highly variable condition that can manifest itself in a wide variety of ways. It is hardly surprising that trying to understand the physiology of depression remains a work in progress. One obvious problem is that how depression is diagnosed can vary widely from country to country and from clinician to clinician. At the clinical level the issues are very difficult to address. One patient may actually be in a state of major depression but their self reports might be more indicative of dysthymia. More commonly, patients reporting symptoms of depression are cyclothymes. So have mercy on the clinicians, they face a daunting task.

Fortunately recent research may have stumbled upon a "final common pathway" that proffers the potential for better clinical interventions in the years to come. If you have taken anti-depressants you may have experienced what a great many people experience: it can take quite some experimenting to find the anti-depressant that works for you. This can be very frustrating but with ongoing research there is increasing hope for better treatments.

The recent breakthrough I am referring too is the claim that the final common pathway for the successful treatment of depression may well be the re-invigoration of both neurogenesis(new neurons being produced) and gliogenesis. The latter term refers to the "support" cells of the brain, glia. Neurons are amongst the busiest cells in the body and have a specialised network of supporting cells to both nourish and protect them. This is especially crucial for neurons because while new neurons can be produced these can only be produced in relatively small numbers.

It has long been recognised that depression is strongly associated with changes in the endocrine and immunological axes. In 1960's it was hoped that glucocorticoid resistance would prove to be a reliable biological marker of major depression. No such luck, at best 40% of individuals with major depression will exhibit glucocorticoid resistance. Sadly though this was an important clue that was overlooked. Most turned their attention to the amines and for many years the predominant focus was on serotonin and norepinephrine. Fortunately though some researchers maintained a different focus.

Horrobin and Bennett wrote a fascinating paper in 1999 that highlighted some intriguing relationships between psychiatric disorders and immune regulation. When I first read this paper I told my collaborator that "their theory is for s*&t". I have come to rue that arrogant criticism. Their paper was prescient in that it paved the way for a biologically based understanding of how fatty acids, in particular the omega 3 - omega 6 balance in our diets, can have significant implications for our cerebral health and propensity towards depression. It is now well established that omega 3 supplements or boosting fish intake can serve as a valuable adjunct treatment in depression.

Other researchers kept up the good work. In particular, this striking study from Capuron & Dantzer, made no apologies for demanding a new approach towards understanding depression. Recent genetic research indicating that polymorphisms for inflammation related genes are very strong indicators for the propensity towards depression have vindicated this approach.

This post is already too long so I'll cut to the chase.

• Glucocorticoids, induced by psychological stress and other stressors, inhibit growth factors.
• A key growth factor that regulates neurogenesis is Brain Derived Neurotrophic Factor(BDNF). This is particularly important in the hippocampus.
• Ongoing stress initiates inflammatory mediators which in turn induce the expression of nitric oxide.
• While nitric oxide is an important component of neural activity excess nitric oxide inhibits BDNF production.
• Because the hippocampus can modulate the stress response, ongoing loss of neurogenesis in the hippocampus can cause a vicious positive feedback loop; thereby increasing the stress response and the expression of inflammatory mediators.
• If, as is common today, there is an excess of omega 6 fatty acid relative to omega 3 intake, this will exacerbate the inflammatory response.
• Most antidepressant drugs are agonists(increasing the levels of) serotonin and norepinephrine. Activation of some serotonin receptors increases BDNF production and increased norepinephrine appears to lower the expression of inflammatory mediators in the brain.
• Increasing BDNF re-commences neurogenesis and helps pave the way for recovery.

What are the Important Lessons Here?

• Manage Stress! An uncontrolled stress response is the most common cause of depression. In our fast paced world all of us are exposed to real and potential stressors. This is one reason why meditation has been found to be useful in helping those with depression. Also, learn the relaxation response.
• Kill the ANTs: Automatic Negative Thoughts. We all have these little creatures in our skulls and they can be very irritating. Cognitive Behavioral Therapy can be very useful in exterminating the little blighters. Initially though try and develop the habit of suppressing these thoughts. That can take time but the benefits will last you a lifetime. It may even save your life.
• Maintain good sleep habits. One of the first warning signs of looming depression is insomnia. This can constitute a vicious cycle because loss of sleep increases the expression of inflammatory mediators. In fact loss of sleep and chronic circadian disruption can often by the final insult that casts us into a deep depression.
• Boost your intake of fish and consider taking fish oil supplements. Additionally, have a careful look at your diet and if necessary improve it.
• Where possible enjoy the sunshine for short periods each day. Sunshine is essential for vitamin D production and there is now a strong body of evidence indicating that maintaining a strong vitamin D status is not only important for the bones but also confers protection against many cancers, excessive systemic inflammation, and reducing the risk of dementias. Sunshine also gives a slight boost to serotonin production hence its association with being happy and the converse, "gloomy days". Early morning sunlight exposure is also important in maintaining circadian stability which aids sleep and promotes general well being.
  
• Be realistic. Some evidence indicates that those who consistently experience depression expect too much of themselves. You are only here once so enjoy it. Being happy is much more important than being productive or being special. Look at how many celebrities end up in rehab or with serious drug problems. Remember this: Work has its place and its place is not to replace living.
• Don't surround yourself with negative people. Most people are kind and generous of spirit so why bother with those who want to put you down or always criticize you?
• Remember this: Life is not a problem to be solved but a reality to experienced. (Van der Leuww)
• If at first you don't succeed so bloody what!? Have a rest and remember: If you reach for the stars at least you won't end up with a handful of mud. (Og Mandino, University of Success) Success is great, happiness is greater.
• Remember: All sunshine makes a desert(Arab proverb). We all go through trying times and many of us will experience depression. Tackle depression before it tackles you.
• Antidepressant drugs are one of the great breakthroughs in medicine. Don't be afraid to use these to help you recover but try not to become reliant upon these drugs. When you feel yourself becoming depressed don't dig yourself so deep that you can't see the sun.
• Remember: Man is most nearly himself when he achieves the seriousness of a child at play. (Heraclitus) Granted it is not always possible to like a child at play but aiming for that is much better than taking life so seriously that we completely lose our playful nature.