Tuesday, June 8, 2010

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:

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

There is a fascinating little set of linkages here. Over recent years research has elucidated that depression is not just about a wayward CNS. There is a host of physiological changes occurring. Depression is not a state of mind it is a state of physiology. Endocrine and immunologic changes often seen in depression are indicative of excessive activation, somewhat paradoxical given the usual connotations that go with the word "depression".

In the 1960s, during that decade when psychology and psychiatry headed in directions ranging from the madness of MK Ultra to Dr. Spock to frontal lobotomies, there were some people doing some interesting work; as opposed to the greater mass propagating enough psychobabble to bring down a civilisation. As this blog link illustrates, a great deal of what passes for psychology research exemplifies Carl Sagan's intent when he stated science was holding a candle in the dark. Unfortunately it appears too many psychologists have forgotten to light the candle. In spite of the psychobabble psychology has made some very important contributions to our society. It has helped us enormously, make no mistake about that. But whether or not psychology provides genuine models of human behavior is an entirely different question. My personal conviction is that it is intrinsically impossible to create a comprehensive theory of human behavior. We don't need a comprehensive theory, we should avoid thinking like that. We should focus our attention on specific behaviors, not unified theories of behavior.

Decades of study into depression have indicated we may never develop an unambiguous set of correlates between depressive behavior and physiological parameters. I will only address the nature of depression in general terms. At the bottom of all this though there lies a fundamental problem with attempts to link the reported state of depression with physiological parameters. Apart from the problems inherent in verbal reporting, I find it conceivable that an individual can experience a state of depression that is not paralleled with any specific physiological state. I wonder if the term "biologic depression" is a category contradiction. That's about as close as I would like to get to "Popper's World 3" and I'm still wrestling with it.

One of the most significant findings in the 1960's was that up to 40% of people reporting with major depressive disorder exhibited glucocorticoid resistance. This is a condition that arises from chronic high expression of cortisol, the key stress hormone that participates in an large array of physiological and cellular processes. Cortisol is an arousal hormone, it begins to fall in the evening to help sleep onset and from the early hours of morning it begins to climb, thereby providing you with energy reserves to start the day; though in my case there is typically barely enough energy to make that first cup of coffee; which has an arousal effect in part mediated by boosting the adrenal cortices where cortisol is made, the other big part being that caffeine impacts on adenosine A2A receptors thereby helping maintaining dopamine levels which is very important for arousal.

The odd thing that emerges out of this is that while cortisol expression is typically associated with immuno-suppression, it might be more accurate to assert that cortisol suppresses the adaptive arm of the immune system thereby limiting immunological responses to new pathogen challenges. Even that generalises too much because sustained high cortisol expression will do a good job at knocking out macrophages and Natural Killer cells, which are key components in the innate immune response and Natural Killer cells do play a fundamental role in identifying and eliminating potentially carcinogenic cells. So it is not surprising that sustained bouts of depression are associated with increased cancer risk.

What does appear to be happening, as this abstract highlights, is that in some sense the immune system is also expressing excessive activation of certain kind, often referred to as Th 1 mediated inflammation. "Th 1" refers to the type of immune cells that express the molecules which drive inflammation, the molecules being interleukin 1, tumour necrosis factor, interleukin 6, interleukin 12, interleukin 17, GM-CSF, histamine, IFN ... . There must be more and I don't pretend to understand this staggering array of agents involved in all these processes. Nonetheless, trends emerge, patterns of activation appear to make sense, so there remains hope that at some point in the future someone somewhere will help us out of this conceptual bedevilment.

Inflammation is an arousal state of the organism. It is absolutely essential in relation to immunological responses because inflammation is a preparatory response that allows the body to quickly respond to any potential injury. Inflammation has a role to play and that role is limited to restricted tissue areas(typically those tissues under stress) and typically of short duration(hours, or days while waiting for a sufficient immunological cellular response to the pathogen emerge). What happens in depression is sustained states of elevated expression of pro-inflammatory cytokines. Systemic inflammation ensues, and this has implications for cardiovascular and cerebral health. In this state there is even a tendency towards increased blood viscosity, a preparatory strategy in case of hemorrhage, but as an ongoing state it increases blood vessel wall damage, increases the risk of athersclerotic lesions, impairs blood supply to the brain and probably the retina, and increases the risk of occlusive stroke and a heart attack. So it is not surprising that chronic longstanding depression is associated with coronary artery disease and cancer.

The above risks will only arise after several hours of this "permissive period" being present, it will take that long before changed state represents any intrinsic threat to the organism. Even then the risk is small, it is only with sustained elevation of pro-inflammatory cytokines and cortisol, over days, weeks and months, that the risks take on real world significance. Keep in mind here that what I am referring too is the physiological state not the psychological state. While elevated cortisol and pro-inflammatory cytokines can and do influence cognition and behavior we are often unaware of these influences and have little if any control over these influences. There are studies which indicate that even relatively small increases in the expression of some pro-inflammatory cytokines has measurable impacts on cognition.

Glucocorticoid resistance markedly increases the likelihood of systemic inflammation because glucocorticoids play a very important role in providing negative feedback that helps prevent inflammatory overshoot. Thus:
 HPA axis hyperactivity is a marker of glucocorticoid resistance, implying ineffective action of glucocorticoid hormones on target tissues, which could lead to immune activation; and, equally, inflammation could stimulate HPA axis activity via both a direct action of cytokines on the brain and by inducing glucocorticoid resistance. In addition, increased levels of pro-inflammatory cytokines also induce the production of neurotoxic end products of the tryptophan-kynurenine pathway.
Chronic inflammatory changes in the presence of glucocorticoid resistance may represent a common feature that could be responsible for the enhanced vulnerability of depressed patients to develop neurodegenerative changes later in life. 
So with respect to the immune and endocrine functions we find that a state of chronic arousal is often present in those reporting depression. Now we need a time related perspective on this issue of arousal and that is where my empirical problems began long ago.

I had been looking for data on the physiological states preceding depression. (We do such studies for many other pathologies.) We have mountains of good physiological measurements in the time of depression(and after) but it seems there has been very little attention to examining the preceding physiological states. For example, for how long must glucocorticoids be elevated until glucocorticoid resistance becomes established? Given that minor spikes in interleukin 1, a major inflammatory driver, may help in some types of memory consolidation, particularly fearful memories, at what point does sustained immune mediated inflammation lead to the cerebral atrophy so common in major depression? Perhaps in these days such data is available but I don't think so. This is empirical vacuum here that needs to be filled.

Given the current data on physiological states during depression I suspect that prior to depression onset a whole raft of physiological changes have been occurring that arise from persistent arousal driving its deleterious effects primarily through sustained HPA axis stress hyperactivation. This list is not complete because I know I'm too ignorant but it helps create the picture:

  1. Pro-inflammatory cytokines have the effect of preventing the production of serotonin. As noted in the earlier abstract instead of serotonin production being maintained at appropriate levels the metabolic pathway is directed to the production of neurotoxic endproducts, thereby increasing cerebral inflammation. As to why this occurs I can only speculate but it is a widely accepted speculation. Arousal = potential danger = get ready for action = pathogens may attack. Many bacteria require serotonin so one ancient immunological response was to release a compound(IDO) which prevents serotonin production. Hmmm, still not sure that makes sense but moving on .... . Take the lesson, "why" questions are very dangerous!
  2. Glucocorticoids impair neurogenesis. The hippocampus is a key recipient of neural stem cells and many studies report reduced hippocampal volumes in depression. As I stated earlier, many anti-depressants appear to have neurogenesis as one of the central effects. Loss of hippocampal volume may lead to excessive activation of the stress response axis, a vicious cycle can ensue here.
  3. I just found this study, very nice for me because I had MAOs in mind and this study touches on the time perspective issue and highlights the complexity of all this stuff. Here is a news release on that study. MA
  4. O = monoamine oxidase. These enzymes break down the neurotransmitters dopamine, norepinephrine, and serotonin, plus many others but these are not directly relevant for us. People with depression often have elevated MAOs, the implication being the above neurotransmitters are being degraded at a higher rate than those without depression. In this study it was found that even when on anti-depressants many depressed patients still had high levels of MAOs. Interestingly, those patients whose MAO levels did not stabilise were at greater risk for recurrent depression. There is a double whammy effect going on here. Not only will high MAO levels reduce availability of those neurotransmitters but the breakdown generates toxic byproducts, again leading to increased inflammation. Incidentally, a good MAO inhibitor like selegiline is a very good idea for aging brains. Doctors rarely prescribe MAOs now because of potentially dangerous side effects but MAO inhibitors like selegiline largely eliminate this risk.
  5. An infusion of PGE1, a potent anti-inflammatory prostaglandin, can also induce rapid amelioration of depressive symptoms in depression. This finding, together with the BDNF findings, and the remarkably rapid lifting of depression from electroshock therapy, remain mysterious. This whole realm needs a separate investigation and cannot be fully addressed here. My assumption at this point, particularly given that epileptics with temporal lobe or limbic epilepsy are immuno compromised, is that the common feature of all these phenomena is a rapid reduction in the production of pro-inflammatory cytokines. 
  6. One of the most common problems in depression, or even long before the condition actually arises, is circadian disruption. To put this in perspective, chronic circadian disruption even in the absence of sleep deprivation can induce cognitive changes and some degree of cerebral atrophy. Shift work studies reveal time and again that constantly changing sleep patterns can induce a wide range of health problems ranging from depression to cancer. Again the inflammatory markers rise, and with sleep deprivation inflammatory markers rise again. Why does insomnia figure so prominently in depression: "racing brain". Can't stop that damned racket upstairs? Need to extinguish those thoughts ...  

As luck would have it, just last week I came across a news item relating to extinction but very relevant to this issue of arousal in depression. Yes, fortune favours the prepared mind.

This news article relates to a growth factor that is a major player in depression. The article cites how administration of Brain Derived Neurotrophic Factor(BDNF) into the infralimbic prefrontal cortices of mice allowed extinction to occur. "Extinction" refers to an organism ceasing to respond to a stimulus. BDNF is typically associated with synaptic strengthening so it seems somewhat odd that it could allow extinction to occur. This reminded me of an interesting fMRI study on depression that was done at the turn of the century. In this study they administered anti-depressants to depressed patients and then measured the amount of activity occurring in the hippocampus, a region of the CNS that can shrink with sustained depression. The results were that in those that responded to the anti-depressant, there was decreased activity in the hippocampus. No more racing brain! This is, or at least appears to be, consistent with decreased arousal.

Animal studies have indicated that infusion of BDNF into the hippocampus can quickly alleviate depressive symptoms. BDNF also plays an important role in neurogenesis and the hippocampus is a major recipient of neural stem cells. A view emerging from the literature is that many anti-depressants encourage neurogenesis, it may even be a necessary though I doubt sufficient requirement for anti-depressant efficacy. Anti-depressants have also been demonstrated to down regulate the HPA stress response axis, thereby reducing the production of glucocorticoids, in particular cortisol, and anti-depressants do reduce the production the pro-inflammatory cytokines. As to exactly how anti-depressants mediate all these effects, at present we cannot understand this.

This finding about BDNF suggests that in depression it is not only neurogenesis that BDNF is relevant but also that it is relevant in generating sufficient extinction, particularly of fear responses(for information on that read the previous link). Fear induces arousal. What is a common feature of depression? "Racing brain", where an endless stream of thinking continues and we can't stop it. No extinction.

Some  months ago a headline popped up that I didn't even bother to read. The headline stated that anti-depressants change peoples' personality. Well der, isn't that the point!? By what naive dichotomy could one assume that the ongoing administration of anti-depressants and the multiple physiological effects these drugs have would not in some way change the person? I didn't read the item because it just seemed obvious that one of the most important things any person suffering from depression can do is become less neurotic. So now I check and what do I find:

“It looks like a lot of what gives people relief is that they’re feeling whatever the opposite of neuroticism is. Getting better very solidly seems to predict a longer period before the next episode. That argues against the notion that these medications are just band-aids [that] get people through.”
There are still people who think anti-depressants are bad drugs. Bollocks. These drugs have their place in modern society and that may say more about modern society than the individuals taking those drugs. Hard call. However I can't tolerate the suggestion that we should adopt a strategy of long term anti-depressant usage to change peoples' personalities. It seems to be a rather dangerous and expensive way to make people happy. It is also a hopelessly deluded strategy. It reduces depression to a physiological state and largely ignores the role of environmental contingencies which so obviously play a fundamental role in the etiology of depression and the dynamics of physiological states. Given that a recent study claimed that the use of anti-depressants in the elderly has resulted in 22,000 cases of cataract in the USA do we really wish to contemplate the public health implications of increasing numbers of people taking anti-depressants for many years if not continuously? There is a better way. Every morning when you wake read this:
Keep your face to the sun and you cannot see the shadows. 
Helen Keller. 
Where is all this neuroticism coming from? Depression is widespread. I've been depressed but then I've been through some shit that if it didn't leave me depressed I'd have to consider the possibility I was so sociopathic as to be incapable of empathising with myself. Perhaps the majority of people go through at least one period in their lives where they could be classed as suffering major depression. While the drugs certainly do help with major depression, a recent meta-analysis concluded that the drugs appeared to be of little if any benefit for mild to moderate depression. Just because a person is suffering from major depression doesn't mean they need an anti-depressant. The current tendency to address the problem of depression as a physiologically driven pathology reflects a persistent epistemological bias to the effect that we can easily fail to appreciate the causal power inherent in environmental contingencies and in particular behavioral approaches to treating depression. This may be a whimsical accusation but I wonder if it is instructive that we label drugs to treat depression as "anti-depressants" and other modalities to treat depression as "adjunct treatment".

Over recent years these adjunct treatment possibilities for depression have attracted increasing attention both at the research and clinical levels. For example, some studies have found these therapies can be as equally effective as anti-depressants. Here are some extracts from the relevant news releases:

  1. In a study, published in the Journal of Consulting and Clinical Psychology, MBCT proved as effective as maintenance anti-depressants in preventing a relapse and more effective in enhancing peoples' quality of life. The study also showed MBCT to be as cost-effective as prescription drugs in helping people with a history of depression stay well in the longer-term. Abstract can be read here
  2. Studies on anxiety related disorders indicate that cogntive behavioral therapy can induce brain changes and produce good clinical results. A good full text review article can found here
  3. For the first time, researchers have mapped what happens in the brain when a patient recovers from depression using cognitive behavioral therapy, a common form of psychological treatment aimed at breaking the bad habits of thought that bring people low. The changes in the pattern of brain activity are quite different from those observed when patients recover with antidepressant drugs, and in some areas, even opposite, according to findings reported yesterday.
  4. Cognitive therapy to treat moderate to severe depression works just as well as antidepressants, according to an authoritative report appearing today in the Archives of General Psychiatry. The study, conducted by researchers at the University of Pennsylvania and Vanderbilt University, challenges the American Psychiatric Association's guidelines that antidepressant medications are the only effective treatment for moderately to severely depressed patients. 
  5. Exercise has been found useful in the treatment of mild depression. Animal studies reveal that running stimulates neurogenesis and BDNF production. Causal factors currently unknown, I'm speculating that the exercise increases the number of glucocorticoid receptors in skeletal muscle thereby reducing the CORT loading on the relevant immunological and CNS cells, thereby allowing CORT to again suppress the production of inflammatory mediators because there is a transcriptional mutual antagonism between glucocorticoid receptors and the ikb-ikk-NFkB, the latter being a critical requirement for inflammatory cytokine production. 


We have all heard about meditation. Zazen, a Zen form of meditation that is heaven for masochists, has been largely discarded. Insight meditation, often associated with the Theravada school of Buddhism, appears to be the most beneficial. Meditation can clearly improve our mood. How is this so? Earlier findings provide some clues. Meditation practice increases our ability to ignore unwanted distractions. Remind you of extinction? For an excellent paper on mental restoration, meditation I recommend the following:

Meditation, Restoration, and the Management of Mental Fatigue

Stephen Kaplan
University of Michigan
An analysis of the underlying similarities between the Eastern meditation tradition and attention restoration theory (ART) provides a basis for an expanded framework for studying directed attention. The focus of the analysis is the active role the individual can play in the preservation and recovery of the directed attention capacity. Two complementary strategies are presented that can help individuals more effectively manage their attentional resource. One strategy involves avoiding unnecessary costs in terms of expenditure of directed attention. The other involves enhancing the effect of restorative opportunities. Both strategies are hypothesized to be more effective if one gains generic knowledge, self-knowledge, and specific skills. The interplay between a more active form of mental involvement and the more passive approach of meditation appears to have far-reaching ramifications for managing directed attention.

Environment and Behavior, Vol. 33, No. 4, 480-506 (2001)
DOI: 10.1177/00139160121973106


Cognitive Behavioral Therapy has proved equally effective in treating depression. Some studies indicate superior ability to prevent recurrence. Interestingly the changes in brain function are different from anti-depressant treatment, one example of how reported psychological states can vary significantly with the results of neuro-imaging studies.


Exercise  not only helps regulate cortisol production, or at least allow for its absorption into skeletal muscle thereby reducing total CORT loading, exercise also decreases inflammatory mediators, which may well be a consequence of the former. Additionally exercise stimulates BDNF, though again I wonder if this is a downstream effect from the above.

Finally ...

Phew this has been an effort! There are many issues raised that need much deeper investigation. As for the claim of that very first article regarding targeting RGS proteins, this is also a hopelessly deluded strategy. Depression is a condition that occcurs at the interface of the organism and the environment, it is only in that context that it can be fully understood. As I used to comment, trying to understand brain function without reference to the environment is like trying to understand aerodynamics on the moon.

Follow up

GR and MR transcriptional regulators.
GR\Mr and NFkB mutual antagonism.
Wherefore art thou dopamine? Role in driving depression as an arousal agent?


Anonymous said...

Truly excellent analysis of depression... Better than any textbook explanation I've ever read.

John said...

Thanks Anonymous.

There are now some worrying studies on the widespread use of antidepressants. The newer antidepressants raise the risk of lipid isues, obesity, and type 2 diabetes, sometimes the risk increase is large(eg. Mirtazapine).

Worse still a new antidepressant, a melatonin receptor agonists(valdoxan),has such serious cardiac and liver risks it should not be on the market yet I know it is being prescribed in Australia.