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.


  1. Interesting, but I wonder if they considered the possible untoward biological effects of medication in the unwell group (eg http://bit.ly/JB6FbA) as explaining the difference rather than the primary underlying disorder.

  2. All of the bipolar patients were on medication, including the euthymic patients. And the medication was from several different classes.

  3. http://www.ncbi.nlm.nih.gov/pubmed/19303978

  4. Dr. Emily,
    I Just happened acrossed this article today in my professional journal and wanted to share. Abstract from the April Journal of Nuclear Medicine:
    While below is a link to an article and not the study, you need a subscription to the journal to get the full text(which I have in hard copy at home.)I'm a nuclear medicine tech and I think NM/PET scanning is going to unlock a lot of truths and prove some things the medical world has been in denial about. I'm not sure how many non-imaging professionals look to our imaging journals for info, so I thought I would pass this gem along.

  5. Regarding medication´s side effects, do you know why SSRIs and some stimulants cause/aggravate ear problems like tinnitus and what to do about it?

  6. @Dr Kruse

    Adiponectin is one of those things that has a reputation for being "good" which actually isn't and is misunderstood by medicine. Adiponectin does increase insulin sensitivity but this is to promote fattening after starvation; adiponectin also promotes adipogenesis - adipocyte differentiation from preadipocytes. This may be why prior history dieting results in higher refeeding weight and why the weight reduced are so insulin sensitive (congrats you now have many more nutritionally greedy fat cells waiting to be filled up!)

    Adiponectin is the shadow of leptin; leptin increases with nutrition and adiponectin decreases. Leptin promotes adipocyte apoptosis. Leptin is the hormone that promotes generous use of energy (we aren't starving yay!) whereas adiponectin is the hormone that tells your body you ARE STARVING and should probably stop wasting energy. Tiny dieted starved fat cells make no leptin and a lot of adiponectin; centrally adiponectin promotes a thrifty state.

    Perhaps the reason high adiponectin is found in bipolar disorder is because bipolar disorder is an energy utilization disorder expressed centrally, and adiponectin promotes distrubed energy use, which is similar to what low leptin also does (and low leptin is most typically the finding in an untreated unmedicated mentally ill patient who has not been sleeping or eating much).

    It is important also when discussing adipokines and bipolar patients to isolate those patients treated with lithium who have impaired renal function. Renal disease very specifically leads to an abnormal elevation of leptin as well as adiponectin and the elevation of leptin in renal failure is one reason a prominent symptom of renal failure is anorexia/weight loss. If some bipolar patients have a crazy high leptin/adiponectin perhaps it is because their kidney is fcked from lithium use. Generally your melancholic severe depressive, psychotic patient, or manic, will have leptin deficiency and this is probably part of the pathophysiology of mental illness. No leptin because you arent' sleeping and eating = no BDNF and a shit ton of cortisol, and congrats the FBI is now looking for you too!

    Inject leptin into a rodent and stress the crap out of it, it keeps on truckin' meanwhile its litter mates roll over and die nervous system wise.

    Furthermore, leptin is not bad. Leptin is bad if you are a man because it probably means you are really fat and unhealthy but reproductive aged females naturally have a high leptin about 3 times or greater than that of a man. Discussion of leptin seems to constantly overlook the fact this hormone is sexually dimorphic and potentiates female endocrine system (estrogen activity upregulates leptin receptors; leptin increases estrogen production in females; there is a cyclical relationship between the female reproductive system + fat tissue and this is regulated primarily by leptin and estrogen respectively). Leptin is good for brain health similarly to estrogen.

  7. A report at http://www.lareb.nl/Signalen/kwb_2005_4_ssri

    "A possible mechanism, which could explain tinnitus with vascular origin, is that serotonin
    has an effect on vessel tonus regulation. Sachanska examined 24 patients with tinnitus.
    They had serotonin blood values that significantly exceeded the reference ones. In users of
    SSRIs, the presynaptic serotonin reuptake is inhibited, which might result in a higher
    serotonin blood value "

    Maybe tinnitus is an indication that the dose is too high even if it appears to be low or is this related to individual differences in ears?

  8. BDNF is directly tied to progesterone conversion. Leptin is a player their but IL -6 and other cytokines are bigger players in blocking progesterone especially in the brain.