Tuesday, April 24, 2012

More Clues to Systemic Inflammation in Mood Disorders

Continuing from the discussion of bipolar disorder and adipokines, There's a lot of intriguing information in various studies about the systemic inflammation found in bipolar disorder.  One of the more interesting papers was done by Kapczinski et al and published in 2011 in Psychiatric Research:  Peripheral biomarkers and illness activity in bipolar disorder.

(Classical today  - Bizet, L'Arlesienne, starting in the middle.  At three minutes is one of my favorite classical lullabies, the Adagietto from the Suite L'Arlesienne.)

The researchers measured a bunch of things in the blood known to be associated with systemic inflammation both in serious disease (blood infections, for example) and in mental illness, including the inflammatory cytokines IL-10, IL-6, TNFalpha, the brain "fertilizer" known to be low in depression and manic episodes, BDNF, and other measures of oxidative stress (which means, imperfectly, that the engines in the cells aren't running efficiently and pumping out some toxic byproducts, causing damage to proteins and fats) and lipid peroxidation such as PCC, TRAP, and TBARS.  There's an awful lot of statistics in the paper, which is always suspicious ;-) but also seems to be a fair way of dealing with a complex set of observational data.

Several groups of people were compared.  A set of healthy controls without any major medical illness or any personal or close family psychiatric history,  known bipolar patients who were currently experiencing normal mood (or "euthymic" as they say in the biz), bipolar patients who were depressed, bipolar patients who were hospitalized for mania, and seriously medically ill patients who were hospitalized in the ICU for infection.  This last group was a "negative control" to see if there were any similarities or differences in the cytokine and measures of stress in the body in the very medically ill compared to the psychiatric patients.

The researchers found that the healthy controls and euthymic bipolar patients were fairly similar.  They also found that the manic and depressed patients (more the manic, who were hospitalized, while the depressed were selected from an outpatient population) had surprising measures of lipid peroxidation, protein damage, and oxidative stress.  These measures in some cases were similar to the medically ill patients who were basically on death's door with sepsis.

The sobering conclusion one could think about is that mood episodes are very stressful and potentially very damaging to the body.  None of these measures were of the cerebrospinal fluid.  Everything was done with a blood draw from the body.  The other conclusion is that folks with known bipolar disorder who were not acutely ill had bounced back to a healthy state, cellularly speaking.  The researchers, most of whom had funding from one pharmaceutical company or another, made the case that aggressive prophylactic treatment of mood disorders was warranted to prevent serious mood episodes.

This argument, along with other evidence from certain longitudinal studies, is used in psychiatry today to promote aggressive pharmacologic treatment.  It is absolutely true that the more mood episodes one has, the more likely one is to have even more episodes in the future, and the harder the future episodes are to get under control.   If these illnesses are pounding your brain and body, decreasing number of manic or depressive episodes via any means necessary would seem to be the logical thing to do.

The problem for a psychiatrist in the field is that we know the studies are stacked in favor of pharmaceuticals.  These issues are discussed at length and in detail in many better blogs than mine (I'll link to the Carlat Psychiatry Blog* as an example).  I'm a psychiatrist, I've seen meds work, I've seen them work and cause major problems, and I've seen them fail miserably.  I've seen EMDR, DBT, neurofeedback, and various forms of behavioral and psychodynamic therapy also work or not (sometimes causing major problems) depending upon the circumstances.  But part of the reason I look at alternatives is because I think there is too much focus on both meds (and talk therapy, in the classic psychiatry circles and in psychology in general) when there are so many other modalities of treatment and lifestyle modification that could also be helpful, and in many cases less likely to cause harm.  What I pull from studies like the one I linked above is that bipolar disorder, like diabetes, deserves a full-bore approach, with support focusing on good nutrition, appropriate sleep and exercise, addressing problems with coping strategies or relationships, and medications when indicated.

Common sense.  Wedded with an understanding of the patient born of time and attention and experience dealing with people.  

*That particular blog article discusses what I found to be a surprising rant by Stephan Stahl, a celebrated and likable psychiatrist who has written several textbooks on pharmacology and runs an education company.  He's a biological psychiatrist and a whiz with meds, but when I read his books I feel a bit empty, because there is so much we do not know about what these medications do in vivo compared to the theory, particulary in the combinations used in common practice today.

Friday, April 20, 2012

Obesity, Systemic Inflammation, and Bipolar Disorder

Mental illness is not invented, and psychiatry is not all in your head.  Today an exploration of the link between bipolar disorder and obesity.  And there is a link, despite the tremendous confounding fact that most of the medicines used to treat bipolar disorder definitely cause obesity, researchers separate out the medication component (and also look at reports from history, prior to medications even being available) to find a strong correlation.  But why, and how?

Cool song: Howler, Back of Your Neck. (right click to open in new tab)

Well, I don't have any definitive answers for you today as to the ultimate cause of bipolar disorder and why it is linked with obesity.  What we do have is a little recent observational study, Increased Levels of Adipokines in Bipolar Disorder that can serve as a handy review of some of our obesity hormones.  

Everyone, I'm assuming, has heard of insulin, and probably leptin.  Leptin is an adipokine, a chemical mediator produced by the fat tissue that can help tell the body how much fat is on board.  Most of you will know that leptin tends to be increased in obese folks, suggesting that obesity may be a function of leptin resistance.  There are other adipokines besides leptin, however, including resistin and and adiponectin.  Adiponectin is of particular interest, because it is known to be anti-inflammatory, the body makes quite a bit of it relative to other hormones, and its levels inversely correlate with obesity in adults.  Leptin is thought to be pro-inflammatory, and may be responsible for the activation of an inflammatory cytokine, TNF-alpha.  Adiponectin will help to decrease the production of TNF-alpha.  So, in general, an obese person will have lower than normal adiponectin and higher than normal leptin, with associated increases in inflammation.

In the study, 30 bipolar (type I) patients were compared with 30 matched (age, BMI, education level, and gender) controls.  All the bipolar patients were on medication (a huge weakness of the study).  Compared to the matched controls, the bipolar patients had higher levels of adiponectin, leptin, and one of the receptors for TNF-alpha.  The kind of medication (as the patients were on several different classes) and medical co-morbities did not correlate with the hormone levels.  Since, again, adiponectin is generally lower in obese individuals, it is interesting that the bipolar patients had higher levels than the controls of the same age, gender, and BMI.  

One previous study of obese bipolar patients showed the same increase in adiponectin.  A study of non-obese depressed bipolar patients had adiponectin levels lower than the controls.  Leptin has been more vigorously studied, and the levels are elevated in some and not in others. The only other study of previously manic but now normal mood patients had the same leptin levels (elevated).  

It's interesting, though we don't quite know what it means.  We get a hint of a large puzzle of a systemic illness, affecting mood, sleep, appetite, thought, immunity, and the adipose tissue.  The connecting process of inflammation is not controversial.  What causes the inflammation… that we don't yet know, and it is likely a confusing combination of factors.  There are a number of papers exploring, for example, peripheral biomarkers and different moods in bipolar disorder, helping us to figure out other pieces of the puzzle.  No one has all the answers. 

Sunday, April 15, 2012

Are You Cool Enough to have a Healthy Immune System?

What is blogging for, anyway?  Posturing on the internets, vying for position, trying to prove to others that we have optimal genetic material in order to further the chances of our offspring.  I'm not a member of a boy band, so I duke it out in my own niche of esoteric intellectuals…

Adagio from Concerto Grosso Op 6. No. 8 in G minor (I could listen to this piece over and over forever, really…)

Why do we build cities, compose music, or make necklaces from the teeth of conquered foes?  Status.

Status means something even besides being able to purchase that Hermes scarf or diamond pendant.  It could mean everything with respect to how our immune system and health functions.  In agricultural times past, aristocrats were often head and shoulders taller than the peasants due to better nutrition.  And it is no accident that a human-species friendly diet will bring about improvement in appearance, and therefore in confidence and status.

Let's get down to the nitty gritty with some primate studies from PNAS.  A high-powered journal self-assured enough to be free access.  Or lowbrow enough for the masses.  You decide.  Social environment is associated with gene regulatory variation in the rhesus macaque immune system.

These guys don't pull punches.  Right at the top of the intro is the following: "In settings in which hierarchies are strongly enforced or subordinates have little social support, low dominance rank can lead to chronic stress, immune compromise, and reproductive dysregulation."

Don't forget that we are the children of all the winners, generation after generation, for millennia.  The joke is on us that evolution is a Red Queen, and we are not compared to the forebears, but to the winners' descendants, decade after decade.   Hierarchy can determine levels of glucocorticoids, serotonergic and dopamine responses, and sex steroid hormone regulation.  These changes exist in the absence of differences in resources available to primates of different ranks, suggesting that rank alone can lead to the physiologic response.

It's not just primates, of course, whose genes and immune system are affected by hierarchy.  Bees and ants and whatnot are heavily affected by gene-expression profiles dependent upon the role the bee is expected to play, workers, reproductive workers, or queens.  While we are not insects, strong ties between diseases and social status probably indicate that status plays a role in our human immune function.

In the study I linked, researchers checked immune function and gene expression of a set of monkeys.  Just by looking at the expression of immune cells (CD4 T cells, CD8 T cells, B cells, and monocytes), they could correctly rank-order the monkeys with 80% accuracy.  Low ranking females have a low proportion of CD8 cells, if you must know.)  Low-ranking monkeys also have a hyperactive hypothalamic-pituitary-adrenal axis (seen in humans under stress as well), and have reduced response to chemical signals to shut down the cortisol response.  The researchers were able to link DNA methylation to monkey dominance as well.  Methylation is how DNA signals are hushed up or not in the process of epigenetics (or changes in gene expression due to environment).

So dominance in monkeys is highly associated with changes in the genome in certain areas, in the endocrine system with stress hormone responses, and in the immune system with inflammatory changes.  Apparently the researchers were able to track shifts in dominance with shifts in these immune and genetic findings, suggesting that the rank comes first, followed by the epigenetic changes.

If the findings can be extrapolated so far as humans, that means there is always a chance to beef up your immune system by becoming more cool.  There's always room for another blog, and more niches of hierarchy to climb every day. Welcome to the 21st century.  

Sunday, April 8, 2012

Fast Food Only Makes Us Happy via the Power of Clowns

Just in time for my Easter dinner of Slim Jims and Mickey Ds (kidding!  I ate grassfed steak and potatoes with spices and kerrygold in honor of Walter Willett) comes this downer of a news article:  Link Between Fast Food and Depression Confirmed.

That science daily piece is based upon a study newly published in Public Health Nutrition, Fast-food and commercial baked goods consumption and the risk of depression.  Now Public Health Nutrition sounds like one of those buttoned-up nutrition journals filled with good intentions and soy, so let's see what the quality of the work is, shall we?

All right, so this is a revisit of the SUN study.  I'm pretty sure I have some SUN study stuff around here somewhere, oh, here.   Basically it is an epidemiological visit to sunny Spain, where nearly 9000 university graduates were followed for about 6 years, answering questions about diet and subsequent health.

And guess what?  If you fill your plate with empty industrial fast food calories (weirdly, they call fast food "sausages, pizza, and hamburgers" in this study, which certainly can be fast food, but also not so fast…) and "commercial baked goods" including "muffins, doughnuts, croissants, and other commercial baked goods."  Okay.  Though I've probably eaten more homemade muffins than commercial ones, can't ever remembering making my own doughnuts or croissants, so they've got me there.

So all the folks did not have diagnosed depression at baseline, and over the years, several hundred began taking antidepressants or were diagnosed with clinical depression by their doctors.  And, three guesses as to how diet correlated with the diagnoses????

That's right, a linear, dose-dependent correlation between the amount of "fast food" at baseline and depression.    The "fast food and commercial baked goods" eaters were more likely to be young, and more likely to not eat other, more delectable foods, such as olive oil, fish, nuts, and vegetables (*cough* Mediterranean diet *cough*).  The fast food shovelers were also more likely to smoke and to work more than 45 hours a week (not recommended!).

If you recall, all those studies listing relative risk of whatever (such as every statin study ever written) are all hiding something.  In general you end up with headlines such as "A 49% increase of DEATH DEATH DEATH" but in actuality the risk of death goes from 1% to 1.49% which is hardly exciting.  I had to edit this next part after Jonathon's comment because I carelessly reported the numbers incorrectly the first time around.  I have several excuses having to do with poor time management and sleep deprivation, but no good excuses because I am not typically so careless… anyway, the percentage of change of the magnitude of the association varied as we went farther and farther from the original dietary measurement, discounting all the folks who had been diagnosed in the months prior to the last measurement of depression… these variations were from 1% or so to 14% or so for commercial baked goods.  The absolute numbers were 493/8964 people diagnosed with depression, or about 5% (this number is low compared to the general population, but many folks were excluded from the sample due to already having a diagnosis of depression prior to the study, which skewed this sample toward healthier folks with later onset of depression symptoms).  The hazard ratios aren't that impressive, but the trend is linear and significant for the fast food consumption.

The discussion is also interesting. The authors suggest that those who eat more fast food and baked goods have a higher trans fat consumption (likely true), and therefore poorer glucose control and poor glucose control (staggered they mention trans fats and not saturated fats here!!  Do these folks actually read the nutrition literature?) Then, even more surprisingly, the authors have a cogent discussion of how  high glycemic carbohydrates (found in abundance in commercial baked goods) will increase plasma tryptophan and increase serotonin uptake into the brain and thus decrease depressive symptoms (blah blah blah)… but these effects seem to have been studied only short term, and that long term, inflammation and pro-inflammatory cytokines are more associated with fast food-style diets and these are more likely to be important to longer term depression.

Phew, I was beginning to think these researchers were way too sensible when they went into a discussion of how high-fat, ketogenic diets can disrupt cognition (pray tell me how likely it is a fast food diet is highly ketogenic?)

And, let's not pull punches on the major weakness of this study.  Diets were only assessed at baseline, and follow up occurred up to 8 years later.  That's a lot of unknown eating to account for.  I also thought the previous study of trans fats wasn't that helpful because it seemed that college graduates in Spain didn't have that much variation in how they ate.  Meaning hardly anyone ate that much vegetable oil, and trans fats were mostly from dairy, as opposed to an American sample, where trans fats can make up a scary percentage of calories.

Still, correlations being what they are, if you are the sort of person to be quaffing from the drive-thru, you are also apparently far more likely to be the sort of person to be diagnosed with a clinical depression.  Confounders galore, but there you have it.  Now, back to my Slim Jims.

Saturday, April 7, 2012

Stress Kills via Inflammation (Possibly)

What a week.  And more busy weeks to come.  I've been neglecting the blog and have only now moderated several days worth of comments, so they have been published now if you were waiting.  I'm starting to feel a bit Kurt Harrisy about comments over time, but for now I am leaving them open.  For the most part things aren't too rambunctious, but I am more easily annoyed these days.  Maybe wiser?  (Not likely).

I am getting more and more requests if I know any other evo med/nutritionally interested psychiatrists around.  Folks are asking from Atlanta to Vienna.  At the moment I know of four, including myself.  Three of us are in New England and one, Ann Childers MD, in Oregon.  My only advice is to keep checking Primal Docs and the Paleo Physician's Network.  The three other psychiatrists I know of seem to be excellent, well-trained, and careful folks, for what it is worth.  If other psychiatrists want to drop me comment (I can see it and not publish it if you ask), I'm more than happy to keep a list and to ask ahead of time if you want your name released to an interested party.  We are also working on a forum for doctors to share case studies, experience, and documentation, so let me know if that would interest any physicians out there (again, can leave a public comment, or leave a comment with a note not to publish if you want to remain incognito).

Love this song (all the songs I like when I first hear them end up being advertisements for Apple.  They should hire me to spot music for them, for sure…) Come Home by Chappo (right click to open in new tab).

Now, science.  Overshadowed by events and personalities sometimes.  I'm a psychiatrist.  I'm used to that sort of thing, but it doesn't mean it is particularly fun for me.  Perhaps it is less fun, as it feels more like work.  But the journals march on, and it is finally spring here.  Lifetime exposure to chronic psychological stress is associated with elevated inflammation in the Heart and Soul Study.

(It is so uncool to post links to Elsevier nowadays, but they have my favorite journal hostage so what can we do?  Ethics only take us so far, and then we have to write a Graham Greene novel, but we are still left with what to do.  This issue is the eternal crux of clinical medicine.  My patient does not walk out of the files of a clinical trial, where all sorts of comorbitities are excluded, but my patient still has clinical depression and still wants some reasonable advice…)

I like the Heart and Soul Study.  They are on my wavelength.  The methods are solid.  All the subjects have a history of some sort of cardiovascular disease, which is important (and they are mostly male, derived mostly from the VA, so keep that in mind).  And here they have looked into people's history of psychologic stress, measured their inflammatory cytokines, and hypothesize a connection.  The connection is confirmed by many other studies linking a history of trauma (all sorts) to elevations in cytokines.

The DL is that stress is linked to bad cytokines (IL-6, TNF alpha, C reactive protein, etc.) and that stress is linked to PTSD and Major Depressive Disorder and anxiety disorders which are also linked to the bad cytokines… as is cardiovascular disease, even in psychologically healthy individuals.  In addition, there are harmful behaviors which increase the inflammatory cytokines (substance abuse, smoking), and ameliorating behaviors that decrease them (exercise, meditation, sleep) less likely to be adhered to by those who have undergone inordinate psychological stress.

Where the rubber meets the road is that higher lifetime trauma was associated with higher levels of inflammatory cytokines at baseline and 5 years later.  When the researchers controlled for psychological symptoms of the trauma (for example, PTSD or a clinical depression), the relationship held, meaning those who had undergone trauma had elevations of inflammation even if their behavior and coping seemed more normal by psychiatric diagnostic standards.  In these folks with pre-existing cardiovascular disease, higher inflammation is associated with greater risk of death and complication.

Maybe I should leave off and move to Hawaii after all...