I'm going to start with a little history of psychiatry in America and the DSMIV. Up into the 60s and 70s, psychiatry in America was heavily influenced by psychoanalysis - Freudian stuff (patient is on a couch free-associating, and the therapist is a "blank screen" - theoretically, though it hardly ever worked out like that), primarily because most of the psychoanalysts fled Germany during WWII and set up shop in London and New York and Boston - these places are still hotspots of psychoanalysis today and the center of East Coast academic training in psychiatry. Psychoanalysts spend a lot of time talking about rage and repression and the unconscious and the mind, all very interesting, if you like that sort of thing. But psychoanalysis isn't exactly neuroscience, and when biological correlates to some of the major psychiatric disorders started coming out, psychiatry swung the other direction.
In some respects there is a lot to admire about psychoanalysis as a science - Freud, a Victorian, met his match in a young girl with symptoms of hysteria named Ida (he called her Dora), and he came up with all sorts of Victorian theories about repression and sexuality to explain her symptoms of not being able to speak, and some neurological hand problems. The case is often studied in academic feminism as an example as to why psychoanalytic theory is patriarchal and misogynist. And yes, it certainly was, because that was the prevailing idea of the time. However, it is often missed that the whole reason Freud published Dora was to present a failure of his therapy. He missed the boat, he knew it, as a Victorian he didn't quite understand why. In that respect, Dora is a humble case study and real medical science circa 1901. Now we would get to the brass tacks that Dora at the age of 14 was by her account repeatedly sexually propositioned by the father of the children she babysat, and the children's mother was also the lover of Dora's father. Such a situation would be difficult now - imagine when one could not speak of such things and would not have been believed in any event.
Well. Dora has a lot of dream analysis in it, and maybe that was a Victorian indirect way to get to the truth. In 2011 we prefer more direct methods - saves time. And I certainly prefer to look at much of psychiatric pathology from a neuroscience perspective, as it seems only rational. The analysts will say we have lost the art of listening and all the modern psychiatrist does is shove pills down people's throats. The biologic psychiatrist will say that psychiatric illness has more causes than just mental distress and to ignore those causes is unscientific and unconscionable. The analyst will say the biologist is "mindless," the biologic psychiatrist will say the analyst is "brainless."
The truth of the matter is that we cannot afford to lose our ability to listen to patients - that is the problem in all of medicine at this time, and psychiatrists may be the last bastion of listening. On the other hand, we can't afford to base psychiatric treatment on medical science circa 1901 (I'm being a little unfair here - hardly any analysts are Freudian drive-based anymore, most use a mix of more modern theoretical concepts derived from attachment theory, relational therapy, and even chaos theory). So into the fray between biologic sorts and analytic sorts came the DSMIII and IV. These books were written to be atheoretical. Causes (whether it be genes and inflammation or history of trauma and personality style) are left out, on purpose, I think in part due to the fight between the analysts and the biologic psychiatrists. I came into training rather at the end of this "war" but apparently it raged for decades. (One of my teachers, an analyst, said of another, a biologic psychiatrist, "I don't think he even believes in the unconscious!" Another teacher talked about how he was forced as a resident to give psychoanalysis to actively psychotic individuals in state mental hospitals, and when it didn't work, was blamed for his failure.)
The DSMIV is merely a recipe book of traits. Have the traits, match it up to the diagnosis, and there you go. Mostly it was intended for research - since we don't have lab tests to define psychiatric illness, psychiatrists in one research center needed to be studying the same disorders as in another center - thus a checklist of sorts. And then psychiatrists in the field needed to be talking about the same sort of problem that the researchers were studying treatments for. It all makes perfect sense, but the DSMIV is maddeningly boring and the atheoretical part makes it a lightning rod for critics. Then managed care and insurance and services based on diagnosis came along and the DSMIV became way more important than it should have been.
But the DSMIV is what we have, and there are certain definitions for bipolar disorder. Bipolar I is when you have a manic episode (a period of insomnia, hypersexuality, impulsivity, rapid speech, increased religiosity, irritability, racing thoughts, manic psychosis often with religious delusions or grandiose delusions, increased energy, and euphoria - you don't need all of these to be manic, just enough of them, and to be mania, it needs to be serious enough for you to be psychotic or hospitalized.) Bipolar I people usually have major depressive episodes also, but they don't have to. Some people are only manic.
Then there is Bipolar II, where people tend to be depressed most of the time but occasionally have hypomanic episodes - mostly insomnia, irritability, increased goal-directed behavior, impulsivity, euphoria - but not as serious as a full manic episode. Bipolar II is a little hard to sort from regular depression - most of the people who show up at your clinic will be depressed, and hypomanic symptoms are often forgotten about, even when you ask directly about them.
Neither of these are the same thing as "moody." Being moody and irritable does not make you bipolar, though if you are bipolar, you will likely be more moody and irritable than average during an episode. In a lot of ways, bipolar disorder overlaps (and sometimes exists at the same time with) other disorders - substance abuse, personality disorders, anxiety, depression, ADHD, which makes it all the more controversial.
Bipolar symptoms also tend to be different at different stages in life. Kids will tend to cycle very rapidly between mood states and could hit many in the same day. Adults tend to stick with one for several weeks or more. (Bipolar disorder in kids is a bit controversial - it's called bipolar disorder because the same criteria fit to describe the behaviors, and often kids with bipolar symptoms do grow up to be adults with standard adult bipolar disorder, so it seems to be the same animal. It is also highly genetic. However, every kid with a temper or a bratty streak is not bipolar. Bipolar in kids tends to be very serious - these kids are often kicked out of school (or preschool) for behavior problems.)
In a lot of ways, bipolar disorder is poorly understood.
Which brings me to the paper I'm blogging about today, "An admixture analysis of the age at index episodes in bipolar disorder." In this study, researchers interviewed 390 people with bipolar disorder in Canada about the history of illness, threw a bunch of data into a number cruncher, and came out with some interesting correlates.
First off, people with early onset bipolar disorder (average onset age 18) tended to be more likely to have a family history of bipolar disorder, and more likely to have psychosis, anxiety, suicidal thoughts and behaviors, and a chronic and rapid cycling course, and were more likely to have migraines. People with late onset (usually starting around age 33) disease were more likely to also have diabetes. Typically, bipolar disorder begins with a depressive episode, and often earlier in women than in men (which would match up with women's greater vulnerability to mood disorders in general). I can add further speculation that the later onset bipolar being more associated with diabetes would suggest that it is possibly part of metabolic syndrome in certain vulnerable people. Early onset bipolar disorder may be more it's own animal. I do think in both cases, inflammatory Western diets may be contributory, and there is some (bad epidemiologic) evidence that doesn't dispute that speculation. Also interesting is the connection between bipolar disorders and migraines - both can respond to medications for epilepsy and theoretically from a ketogenic diet.
A modern psychiatrist is hamstrung without time to get a good history and the psychological savvy to establish an excellent rapport with the patient and the understanding of basic human nature - but a modern psychiatrist is also crippled by a lack of knowledge of neuroscience, nutrition, and general medicine. We need to pursue both threads in 2011. It all comes back together for the betterment of everyone.
Showing posts sorted by relevance for query Bipolar. Sort by date Show all posts
Showing posts sorted by relevance for query Bipolar. Sort by date Show all posts
Tuesday, January 4, 2011
Saturday, December 15, 2012
Alternative Therapies and Bipolar Disorder
I will get back to OCD. In the mean time a new paper came out called Nutrient-Based Therapies for Bipolar Disorder, A Systemic Review. And this paper is not written by some press agent working out of the basement of a supplement company. It's the Massachusetts General Hospital bipolar research clinic. I've been in meetings with some of these folks and heard them speak.
Psychiatry in Boston (and the East Coast) is such a funny mix of psychoanalysts and rigidly conservative psychopharmacologists. Apparently on the West Coast things are a little different, with more acceptance of polypharmacy and supplements. But from the center of the most conservative bastion of psychiatry from the 1930s-60s and some of the busiest depression and bipolar pharmaceutical clinical researchers on the planet comes some really cool work with supplements and alternative treatments. I'm a big fan of Neirenberg and Fava over at MGH and their work with alternative therapies. They have open minds and scientific eyes.
Tame Impala: Feels Like We Only Go Backwards
Let's get to it. Bipolar disorder can be difficult to diagnose and more difficult to treat. I try not to judge too much when someone comes to my office with a "bipolar II" diagnosis on the newest, most expensive antipsychotic and a mood stabilizer when they really have depression plus ADHD and/or anxiety symptoms and/or a history of being traumatized. All the diagnoses in the DSM are from the symptom level up, not from the brain pathology down, so things are messy. But despite all that there are plenty of honest-to-goodness bipolar folk who benefit from mood stabilizers… but 54-68% of appropriately treated folks continue to experience subthreshold symptoms, and side effects continue to be a major problem.
Omega 3 fatty acid supplementation may be useful not only for brain health but for physical health. (Of course I personally prefer limiting the omega 6 consumption and eating a nominal amount of cold water oily fish weekly…[practical aside here] one trick is to make tuna salad with 2 cans of light tuna, one can of sardines, celery, pickles, carrot, onion, spices, and your own olive oil mayonnaise (I use the olive oil recipe from Well Fed which is still my favorite "paleo" cookbook, though Eat Like A Dinosaur is great for kid-friendly meals and Primal Blueprint Quick and Easy Meals is also a staple).
Individuals with bipolar disorder are more likely to be obese, less likely to cook their own meals, and more likely to eat sugary foods. And, according to a recent paper (1) looking at the nutrient intake of people with bipolar disorder, they tend to consume food with lower levels of thiamin, riboflavin, folate, phosphorous, zinc, vitamin B6, and vitamin B12 compared to the population norms.
Omega 3 fatty acids work by increasing membrane fluidity and normalizing signal transduction, reducing inflammation, and activate nuclear receptor effects. In bipolar disorder, the first studies were done by Andy Stoll of high doses (around 10g), and over a period of 4 months, there was significantly less depression and higher levels of global functioning. EPA + DHA has the most data, and the amount used in various studies… vary a great deal. ALA (flax oil) was not found to be useful, nor was DHA alone. Mania doesn't seem to be affected, only depression and general functioning symptoms, and the effect sizes are not strong enough and the intervention not studied enough to take in lieu of regular pharmacologic treatment for bipolar disorder. However, as an adjunct, the risks may be very low compared to possible benefits.
Inositol has also been studied several times (but all small sample sizes) in bipolar depression. (See my earlier post for the mechanism.) Again, as an adjunct, it seems to have some promise for depression, but we need larger sample sizes.
Choline might be helpful by improving and increasing the efficiency of brain energetics. The brain is hungry for ATP (the energy currency of the cells), and in many neuropsychiatric disorders including bipolar disorder, energetics seem to be impaired, possibly by inflammation and oxidative damage. Choline is the main reason (along with all those delectable B vitamins and general yummyness) that I think advice to toss out the egg yolks is idiocy. All the randomized controlled studies of choline supplementation in bipolar disorder are small, and of complicated patients (for example, rapid cycling bipolar and cocaine dependence). One small open label trial by Stoll did demonstrate some benefit for mood.
Magnesium deficiency, as I've discussed in the past, is quite common in the general population. Signs of deficiency include irritability, fatigue, insomnia, loss of appetite, mental confusion, and a vulnerability to stress. Magnesium also has some effects on neurotransmission that are similar to mood stabilizers lithium, valproate, and lamotrigine. There are some small studies of manic patients doing much better with adjunctive magnesium added (one was oral magnesium oxide, the other injected magnesium in severely manic patients). There is only onse study of magnesium as a monotherapy, and 40 meq daily did reduce mania in rapid cycling patients.
Chromium (I haven't written anything on chromium yet… should get on that) seems to improve insulin sensitivty in the hypothalamus and affects the monoamine neurotransmitter systems. Enhanced hypothalamic function may increase the release of serotonin, norepinephrine, and melatonin. There are a few studies showing efficacy in unipolar depression, but not atypical depression, and in the one study of bipolar disorder, there were lots of drop outs.
Folic acid has been studied only once in bipolar disorder, in conjunction with valproate (which interferes with folate metabolism). It seemed to be helpful, particularly for cognitive symptoms. There are more positive studies in unipolar depression, and there's no reason to think it wouldn't be helfpul in bipolar depression (though there are reasons to think folic acid might be an inferior supplement to l-methylfolate, they have not had head to head studies in depression as far as I know).
Rapid tryptophan depletion will decrease serotonin levels in the brain. It can be achieved fairly readily using a tryptophan-depleted drink (see this post for more details). In Canada, it is actually approved as adjunctive therapy to lithium in acute mania, and another study of manic patients showed it might be helpful, but 23% of patients couldn't tolerate the drink. L-tryptophan itself also looked like a promising antimanic agent in a small study of 24 patients (12 grams daily, looks like, for two weeks). However, after it was banned by the FDA in 1989, further studies have been lacking.
In general, nutritional supplementation to current therapies may work synergistically with the therapies (such as folate and valproate), and for many therapies (excepting perhaps chromium and rapid tryptophan depletion), the side effects and risks seem lower compared to the conventional therapies or combining conventional therapies, which is often done with resistant cases now. More larger studies of some of these combination effects would be great to help us clinicians in the field have a larger tool kit from which to work. In addition, the nutritional therapies haven't been tested with consistent dosing or in consistent populations to really give us a sense of optimal amounts or usage. Their potential coud be fantastic.
Psychiatry in Boston (and the East Coast) is such a funny mix of psychoanalysts and rigidly conservative psychopharmacologists. Apparently on the West Coast things are a little different, with more acceptance of polypharmacy and supplements. But from the center of the most conservative bastion of psychiatry from the 1930s-60s and some of the busiest depression and bipolar pharmaceutical clinical researchers on the planet comes some really cool work with supplements and alternative treatments. I'm a big fan of Neirenberg and Fava over at MGH and their work with alternative therapies. They have open minds and scientific eyes.
Tame Impala: Feels Like We Only Go Backwards
Let's get to it. Bipolar disorder can be difficult to diagnose and more difficult to treat. I try not to judge too much when someone comes to my office with a "bipolar II" diagnosis on the newest, most expensive antipsychotic and a mood stabilizer when they really have depression plus ADHD and/or anxiety symptoms and/or a history of being traumatized. All the diagnoses in the DSM are from the symptom level up, not from the brain pathology down, so things are messy. But despite all that there are plenty of honest-to-goodness bipolar folk who benefit from mood stabilizers… but 54-68% of appropriately treated folks continue to experience subthreshold symptoms, and side effects continue to be a major problem.
Omega 3 fatty acid supplementation may be useful not only for brain health but for physical health. (Of course I personally prefer limiting the omega 6 consumption and eating a nominal amount of cold water oily fish weekly…[practical aside here] one trick is to make tuna salad with 2 cans of light tuna, one can of sardines, celery, pickles, carrot, onion, spices, and your own olive oil mayonnaise (I use the olive oil recipe from Well Fed which is still my favorite "paleo" cookbook, though Eat Like A Dinosaur is great for kid-friendly meals and Primal Blueprint Quick and Easy Meals is also a staple).
Individuals with bipolar disorder are more likely to be obese, less likely to cook their own meals, and more likely to eat sugary foods. And, according to a recent paper (1) looking at the nutrient intake of people with bipolar disorder, they tend to consume food with lower levels of thiamin, riboflavin, folate, phosphorous, zinc, vitamin B6, and vitamin B12 compared to the population norms.
Omega 3 fatty acids work by increasing membrane fluidity and normalizing signal transduction, reducing inflammation, and activate nuclear receptor effects. In bipolar disorder, the first studies were done by Andy Stoll of high doses (around 10g), and over a period of 4 months, there was significantly less depression and higher levels of global functioning. EPA + DHA has the most data, and the amount used in various studies… vary a great deal. ALA (flax oil) was not found to be useful, nor was DHA alone. Mania doesn't seem to be affected, only depression and general functioning symptoms, and the effect sizes are not strong enough and the intervention not studied enough to take in lieu of regular pharmacologic treatment for bipolar disorder. However, as an adjunct, the risks may be very low compared to possible benefits.
Inositol has also been studied several times (but all small sample sizes) in bipolar depression. (See my earlier post for the mechanism.) Again, as an adjunct, it seems to have some promise for depression, but we need larger sample sizes.
Choline might be helpful by improving and increasing the efficiency of brain energetics. The brain is hungry for ATP (the energy currency of the cells), and in many neuropsychiatric disorders including bipolar disorder, energetics seem to be impaired, possibly by inflammation and oxidative damage. Choline is the main reason (along with all those delectable B vitamins and general yummyness) that I think advice to toss out the egg yolks is idiocy. All the randomized controlled studies of choline supplementation in bipolar disorder are small, and of complicated patients (for example, rapid cycling bipolar and cocaine dependence). One small open label trial by Stoll did demonstrate some benefit for mood.
Magnesium deficiency, as I've discussed in the past, is quite common in the general population. Signs of deficiency include irritability, fatigue, insomnia, loss of appetite, mental confusion, and a vulnerability to stress. Magnesium also has some effects on neurotransmission that are similar to mood stabilizers lithium, valproate, and lamotrigine. There are some small studies of manic patients doing much better with adjunctive magnesium added (one was oral magnesium oxide, the other injected magnesium in severely manic patients). There is only onse study of magnesium as a monotherapy, and 40 meq daily did reduce mania in rapid cycling patients.
Chromium (I haven't written anything on chromium yet… should get on that) seems to improve insulin sensitivty in the hypothalamus and affects the monoamine neurotransmitter systems. Enhanced hypothalamic function may increase the release of serotonin, norepinephrine, and melatonin. There are a few studies showing efficacy in unipolar depression, but not atypical depression, and in the one study of bipolar disorder, there were lots of drop outs.
Folic acid has been studied only once in bipolar disorder, in conjunction with valproate (which interferes with folate metabolism). It seemed to be helpful, particularly for cognitive symptoms. There are more positive studies in unipolar depression, and there's no reason to think it wouldn't be helfpul in bipolar depression (though there are reasons to think folic acid might be an inferior supplement to l-methylfolate, they have not had head to head studies in depression as far as I know).
Rapid tryptophan depletion will decrease serotonin levels in the brain. It can be achieved fairly readily using a tryptophan-depleted drink (see this post for more details). In Canada, it is actually approved as adjunctive therapy to lithium in acute mania, and another study of manic patients showed it might be helpful, but 23% of patients couldn't tolerate the drink. L-tryptophan itself also looked like a promising antimanic agent in a small study of 24 patients (12 grams daily, looks like, for two weeks). However, after it was banned by the FDA in 1989, further studies have been lacking.
In general, nutritional supplementation to current therapies may work synergistically with the therapies (such as folate and valproate), and for many therapies (excepting perhaps chromium and rapid tryptophan depletion), the side effects and risks seem lower compared to the conventional therapies or combining conventional therapies, which is often done with resistant cases now. More larger studies of some of these combination effects would be great to help us clinicians in the field have a larger tool kit from which to work. In addition, the nutritional therapies haven't been tested with consistent dosing or in consistent populations to really give us a sense of optimal amounts or usage. Their potential coud be fantastic.
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.
Friday, November 11, 2011
Evolutionary Psychiatry and Bipolar Disorder
A couple of papers came to my attention this week that relate to what I consider "real" evolutionary psychiatry. That is, what are some evolutionary reasons we might have genes that make us vulnerable to psychiatric disorders. The "real" evolutionary psychology academics consider this discussion to be "Abnormal Psychology," and like all evolutionary psychology, it is somewhat controversial. I actually don't think about the disorders much as evolving in an evolutionary light… I tend to think in terms of the human body and gut and neurons working outside design specs, thus breaking down (that is "my" version of evolutionary psychiatry). But the overlap between one ev psych and another deserves some scrutiny, because certainly I can make the case (and often do, to patients, particularly those with bipolar and ADHD and OCD) that there are elements of these disorders that are quite adaptive to certain situations, as long as the maladaptive parts don't derail everything.
Part of my major hypothesis is that the industrial/digital age and processed, low-nutrient food has brought out more severe and different phenotypes of underlying vulnerabilities, and has also brought out seemingly new illnesses ("atypical depression"). Thus a less destructive phenotype (a mildly paranoid schizotypal person, for example, who will be more creative than the average person, as compared to full-blown schizophrenia, which impairs functioning to a terrible extent) will persist in the population due to selective advantage for certain traits.
My only previous article on "real" evolutionary psychiatry can be found here: The Creative Advantage.
Well. It is fitting the first of the two papers today comes from Medical Hypothesis. Melissa McEwen sent it to me - I think she likes that journal because it is crazy and it makes her laugh. (Here is advice for those aspiring to be published there: The purpose of Medical Hypotheses is to publish interesting theoretical papers. The journal will consider radical, speculative and non-mainstream scientific ideas provided they are coherently expressed.)
I have no publications, myself, though I have assisted in some research efforts. My mentor would like me to cobble something together from all the research I've done for the blog on affective disorders, or something. I never did fancy myself much of an academic… thus never felt the motivation to write anything boring enough to be published in a journal ;-)… however, it would certainly add to my street cred. I don't know that I can write the exotic papers for Medical Hypothesis, however (Melissa sent me a paper previously about some sort of reptile origin theory of illness? I can't remember, but it was hysterical, and it must have slipped through part of the editorial process as it was also mostly incoherent). Back to evolutionary psychiatry!
Evolutionary origin of bipolar disorder - revised (EOBD-R) is the paper in question, by one Julia A. Sherman of Madison, Wisconsin. A quick google search brings up her original EOBD (sans R) from 2002. And as much as I make light of Medical Hypothesis, I do have to admire the originality of the paper, noting that it is wildly speculative and the basic premise is most likely incorrect.
Ms. Sherman connects the dots between the circadian rhythm issues and vulnerability to bipolar disorder (manic episodes are known to peak in the spring time, when the light increases exponentially day by day in extremely northern or southern latitudes.) In a nutshell, the EOBD suggests that bipolar disorder developed as an adaptive trait in the northern temperate zones which had more extreme winters during the ice age. If you were hypomanic all spring and summer, you got a lot of stuff done, and then you could slow down and "hibernate" (be depressed) during the winter and not use much energy. The "R" or revision in question actually brings in the interesting bit of Neanderthal DNA that all of us non-San Bushmen (or otherwise directly derived from Africa without side-stepping through Europe or Asia and coming up close and very personal with other hominids) seem to have. Ms. Sherman thinks that bipolar disorder is a Neanderthal trait.
Hmmm. She brings in the observations of a German psychiatrist from the early 20th century, E. Kretchmer, who noted that folks with bipolar disorder tended to be of a certain "pyknic" constitutional type. They have a "thick trunk, relatively short limbs, and a big head on a short, thick neck." Apparently, several other researchers in the early 20th century, when they were really into measuring heads and body sizes and making silly claims based on the measurements found that manic-depressive patients were more likely to be pyknic (endomorphs), and schizophrenics were more likely to be "leptosomic" (ectomorphs). A much newer study in 2003 also confirmed this finding. Sherman believes it is striking that Neanderthals are also described as having big bellies and short limbs. Interesting. In addition, people of African descent apparently have lower incidence of bipolar disorder in some studies Sherman cites. However, there is no reliable data among truly purely African populations such as the San.
There is more to the paper, but I hit the highlights. I'm not entirely sure what to think. There is no question that bipolar disorder has a seasonal component and that light and dark therapies can be useful. Hypomania, with the extended bursts of drive, energy, and creativity can also be very adaptive. And one can imagine being moderately depressed during a cold, dark winter might keep a small tribe of Neanderthal out of each other's hair, when there might have been nothing much to do anyway. I think the pyknik bit is a little ridiculous - as we know, actually, both schizophrenia and bipolar disorder are related to metabolic syndrome, even in people who have never been on medicines. I also would bet a poodle that there are San bushmen with some bipolar disorder out there, but symptoms might be attenuated by their latitude and hunter-gatherer lifestyle with plenty of socialization and exercise (though they do like those omega 6-filled mongongo nuts), according to my own wildly speculative theorizing…
The second paper is far less... imaginative and was published in the much more staid Journal of Affective Disorders. Creativity and affective temperaments in non-clinical professional artists: An empirical psychometric investigation. These researchers looked at 152 undergraduates in art school (or other creative majors) vs. 152 undergraduates who were in majors predicted to lead to professions "mostly requiring the application of learned rules" (like accounting, I suspect). The students were tested with several standard measures to detect subclinical and clinical manifestation of cyclothymia (a mild variation of bipolar disorder), and also other scales of general health and demographic data. I don't think it will surprise anyone to know that the creative students were significantly more likely to score into the cyclothymic range on these scales.
An interesting quote from the paper:
So it appears that bipolar disorder is linked to creativity, which may have an adaptive advantage. I don't think that is particularly controversial, but it is nice to see more studies on the subject. Now were Neanderthals more creative than homo sapiens? At least in the springtime? That might help Julia Sherman's hypothesis!
Edited to add - a Neanderthal winter love song? By Primitive Radio Gods (right click to open in new tab).
Part of my major hypothesis is that the industrial/digital age and processed, low-nutrient food has brought out more severe and different phenotypes of underlying vulnerabilities, and has also brought out seemingly new illnesses ("atypical depression"). Thus a less destructive phenotype (a mildly paranoid schizotypal person, for example, who will be more creative than the average person, as compared to full-blown schizophrenia, which impairs functioning to a terrible extent) will persist in the population due to selective advantage for certain traits.
My only previous article on "real" evolutionary psychiatry can be found here: The Creative Advantage.
Well. It is fitting the first of the two papers today comes from Medical Hypothesis. Melissa McEwen sent it to me - I think she likes that journal because it is crazy and it makes her laugh. (Here is advice for those aspiring to be published there: The purpose of Medical Hypotheses is to publish interesting theoretical papers. The journal will consider radical, speculative and non-mainstream scientific ideas provided they are coherently expressed.)
I have no publications, myself, though I have assisted in some research efforts. My mentor would like me to cobble something together from all the research I've done for the blog on affective disorders, or something. I never did fancy myself much of an academic… thus never felt the motivation to write anything boring enough to be published in a journal ;-)… however, it would certainly add to my street cred. I don't know that I can write the exotic papers for Medical Hypothesis, however (Melissa sent me a paper previously about some sort of reptile origin theory of illness? I can't remember, but it was hysterical, and it must have slipped through part of the editorial process as it was also mostly incoherent). Back to evolutionary psychiatry!
Evolutionary origin of bipolar disorder - revised (EOBD-R) is the paper in question, by one Julia A. Sherman of Madison, Wisconsin. A quick google search brings up her original EOBD (sans R) from 2002. And as much as I make light of Medical Hypothesis, I do have to admire the originality of the paper, noting that it is wildly speculative and the basic premise is most likely incorrect.
Ms. Sherman connects the dots between the circadian rhythm issues and vulnerability to bipolar disorder (manic episodes are known to peak in the spring time, when the light increases exponentially day by day in extremely northern or southern latitudes.) In a nutshell, the EOBD suggests that bipolar disorder developed as an adaptive trait in the northern temperate zones which had more extreme winters during the ice age. If you were hypomanic all spring and summer, you got a lot of stuff done, and then you could slow down and "hibernate" (be depressed) during the winter and not use much energy. The "R" or revision in question actually brings in the interesting bit of Neanderthal DNA that all of us non-San Bushmen (or otherwise directly derived from Africa without side-stepping through Europe or Asia and coming up close and very personal with other hominids) seem to have. Ms. Sherman thinks that bipolar disorder is a Neanderthal trait.
Hmmm. She brings in the observations of a German psychiatrist from the early 20th century, E. Kretchmer, who noted that folks with bipolar disorder tended to be of a certain "pyknic" constitutional type. They have a "thick trunk, relatively short limbs, and a big head on a short, thick neck." Apparently, several other researchers in the early 20th century, when they were really into measuring heads and body sizes and making silly claims based on the measurements found that manic-depressive patients were more likely to be pyknic (endomorphs), and schizophrenics were more likely to be "leptosomic" (ectomorphs). A much newer study in 2003 also confirmed this finding. Sherman believes it is striking that Neanderthals are also described as having big bellies and short limbs. Interesting. In addition, people of African descent apparently have lower incidence of bipolar disorder in some studies Sherman cites. However, there is no reliable data among truly purely African populations such as the San.
There is more to the paper, but I hit the highlights. I'm not entirely sure what to think. There is no question that bipolar disorder has a seasonal component and that light and dark therapies can be useful. Hypomania, with the extended bursts of drive, energy, and creativity can also be very adaptive. And one can imagine being moderately depressed during a cold, dark winter might keep a small tribe of Neanderthal out of each other's hair, when there might have been nothing much to do anyway. I think the pyknik bit is a little ridiculous - as we know, actually, both schizophrenia and bipolar disorder are related to metabolic syndrome, even in people who have never been on medicines. I also would bet a poodle that there are San bushmen with some bipolar disorder out there, but symptoms might be attenuated by their latitude and hunter-gatherer lifestyle with plenty of socialization and exercise (though they do like those omega 6-filled mongongo nuts), according to my own wildly speculative theorizing…
The second paper is far less... imaginative and was published in the much more staid Journal of Affective Disorders. Creativity and affective temperaments in non-clinical professional artists: An empirical psychometric investigation. These researchers looked at 152 undergraduates in art school (or other creative majors) vs. 152 undergraduates who were in majors predicted to lead to professions "mostly requiring the application of learned rules" (like accounting, I suspect). The students were tested with several standard measures to detect subclinical and clinical manifestation of cyclothymia (a mild variation of bipolar disorder), and also other scales of general health and demographic data. I don't think it will surprise anyone to know that the creative students were significantly more likely to score into the cyclothymic range on these scales.
An interesting quote from the paper:
Positive mood, and happiness in particular, was postulated to fuel creativity. Enhanced positive affect is a feature of both hypomania and mania, which are core symptoms of bipolar disorder and may predispose people within the manic-depression/bipolar disorder spectrum to creativity. By contrast, postulated that depression might provide fresh insights which can be executed into the artistic oeuvre during the energized phases of cyclothymia.
So it appears that bipolar disorder is linked to creativity, which may have an adaptive advantage. I don't think that is particularly controversial, but it is nice to see more studies on the subject. Now were Neanderthals more creative than homo sapiens? At least in the springtime? That might help Julia Sherman's hypothesis!
Edited to add - a Neanderthal winter love song? By Primitive Radio Gods (right click to open in new tab).
Thursday, August 26, 2010
Ketogenic Diets and Bipolar Disorder 1
Bipolar disorder is a challenging illness, with various clinical presentations. In "type one" people struggle with alternating symptoms of mania and depression. In "type two," depression is the primary state, with the occasional rare bit of hypomania. By mania, I mean increased energy, increased sexuality, religion, insomnia, and spending money. It feels great right up until reality comes knocking on the door. Medication has been proven to be helpful in decreasing the number of manic and depressive episodes. Typically, the medications are anti- seizure medicines also, such as depakote, lamotrigine, and carbamazepine.
Most low-carb followers will know that ketogenic (extremely low carb) diets have been used to treat epilepsy for a hundred years. Would the same diets be useful in bipolar disorder (1)?
Now is the time to add a special disclaimer. No ketogenic diet has ever been systematically studied with respect to bipolar disorder. If you have bipolar disorder, please discuss any thoughts you might have from reading this article with your personal physician. The one case study I could find in the literature showed *no* benefit from a ketogenic diet. (4:1:1 fat:protein: carb) Bipolar disorder is an illness I wouldn't want to face alone.
In the literature for epilepsy, patients were encouraged to fast for 12-36 hours to promote ketosis, and then to follow a dietary plan with less than 20 g carbohydrate daily (or even lower, in most research ketogenic diets). In doing so their brains would be flooded with ketones, and most importantly, promote extracellular acidosis. There are several seizure medicines (such as gabapentin) that are no good for bipolar disorder. When scientists look closely, they find that only the seizure medicines that promote a reduced extracellular sodium concentration are helpful in bipolar disorder. Ketosis does exactly that.
It all looks great on paper, but as I mentioned earlier, when well- intentioned doctors tried to use a ketogenic diet to treat resistant bipolar symptoms, they came up with a big zero (2). And while ketogenic diets are definitely safe short term, when ever we begin to talk about treating epilepsy or bipolar disorder, we are talking about long-term strict compliance. No cookies. No bread. One would need to work with a knowledgeable nutritionist, and there are reports of patients on ketogenic diets for epilepsy dying of selenium deficiency (3). (my paleo perspective - you are eschewing your vegetables, eat your organ meats!).
In the next post I will review the case studies above more closely, and delve more deeply into the biochemistry of sodium ions and the NMDA receptor. I know you can hardly wait! (It's here - be sure to check out Ketogenic Diets and Bipolar Disorder 2)
Most low-carb followers will know that ketogenic (extremely low carb) diets have been used to treat epilepsy for a hundred years. Would the same diets be useful in bipolar disorder (1)?
Now is the time to add a special disclaimer. No ketogenic diet has ever been systematically studied with respect to bipolar disorder. If you have bipolar disorder, please discuss any thoughts you might have from reading this article with your personal physician. The one case study I could find in the literature showed *no* benefit from a ketogenic diet. (4:1:1 fat:protein: carb) Bipolar disorder is an illness I wouldn't want to face alone.
In the literature for epilepsy, patients were encouraged to fast for 12-36 hours to promote ketosis, and then to follow a dietary plan with less than 20 g carbohydrate daily (or even lower, in most research ketogenic diets). In doing so their brains would be flooded with ketones, and most importantly, promote extracellular acidosis. There are several seizure medicines (such as gabapentin) that are no good for bipolar disorder. When scientists look closely, they find that only the seizure medicines that promote a reduced extracellular sodium concentration are helpful in bipolar disorder. Ketosis does exactly that.
It all looks great on paper, but as I mentioned earlier, when well- intentioned doctors tried to use a ketogenic diet to treat resistant bipolar symptoms, they came up with a big zero (2). And while ketogenic diets are definitely safe short term, when ever we begin to talk about treating epilepsy or bipolar disorder, we are talking about long-term strict compliance. No cookies. No bread. One would need to work with a knowledgeable nutritionist, and there are reports of patients on ketogenic diets for epilepsy dying of selenium deficiency (3). (my paleo perspective - you are eschewing your vegetables, eat your organ meats!).
In the next post I will review the case studies above more closely, and delve more deeply into the biochemistry of sodium ions and the NMDA receptor. I know you can hardly wait! (It's here - be sure to check out Ketogenic Diets and Bipolar Disorder 2)
Tuesday, February 22, 2011
More on Wheat and Serious Mental Illness
All right. Tuesday. Yesterday at noon local time a big earthquake hit Christchurch, and all of our good wishes are with the people there, especially as one of Evolutionary Psychiatry's best internet friends is Jamie, who lives smack dab in the middle of Christchurch. Here's a link to the New Zealand Red Cross if you would like to lend a hand.
Before disaster struck, Jamie was kind enough to send me a link to a new paper (free full text) about Bipolar Disorder and gluten markers. The paper doesn't give us much, but it does stir up some good ol' murk. So let's investigate. Bipolar disorder is an illness of mania or hypomania plus or minus depressive episodes. Bipolar disorder does not equal "moody" or "irritable," though those can certainly be signs. It's not the disorder unless the symptoms are bad enough to get you into serious trouble. You spend too much, you sleep around too much, you don't sleep, you are more religious, you are grandiose - in cycles. And, of course, it is associated with inflammation and metabolic syndrome (1), diabetes (2) and a "western" style diet.
I have suspicions about those links. I'd bet a monkey that a combination of sugar, trans fats and vegetable oil, and high doses of refined wheat products (as I've mentioned before, the evidence against wheat is circumstantial) are culprits behind metabolic syndrome and diabetes. And maybe a subset of the population suffers at the brain level too and manifests bipolar disorder. Hey, seems as good a theory as any.
Wheat has been investigated on and off over the years as a culprit in schizophrenia. And bipolar disorder and schizophrenia can overlap sometimes in symptoms - while depressed people can be psychotic, a frank manic psychosis will look pretty much the same in the hospital as a schizophrenic psychotic episode, and there may even be some genetic overlaps (3)(4). The new paper that Jamie sent me is the first to study celiac and wheat-associated antibodies in bipolar disorder. In schizophrenia, there is a definite increase in wheat-associated antibodies in the serum (5) and these antibodies aren't the same ones that are seen in celiac disease. Well, with bipolar disorder, seems the same thing is true. Bipolar folks had a significant IgG gliadin reaction compared to controls, but there weren't really differences with respect to tTG and IgA gliadin antibodies which are typically elevated in celiac disease.
Ooh ooh ooh, wheat is BAD. Well, probably, for various reasons. But, of course, I don't necessarily believe that a positive IgG test to gliadin means one has a sensitivity to gliadin. I griped about IgG food sensitivity tests not too terribly long ago. I think a robustly positive IgG test to lots of things means one may have a leaky gut. Gliadin is a pretty darn common thing to eat, so folks with leaky guts may come up positive for gliadin. The most robust evidence in humans I've seen for leaky guts linked to wheat (or maybe casein) consumption was from this nifty study in autism (6), where the kids on the GF/CF diets had pretty tight junctions in their guts, especially compared to the autistic kids and their relatives. Boy, I bet the researchers have really pounced on this diet and mental health link and studied leaky guts in bipolar disorder (7)(9)! Er, no. But, links have been found between major depressive disorder and leaky guts (8 - an interesting enough paper for another day).
Like I said, murk. Best I can consolidate from all this information - it may be that folks with bipolar disorder have gut issues, and gut issues are inflammatory issues, and a higher IgG response to gliadin occurs, and inflammation causes the body to release cytokines and general badness, and those cytokines may predispose the genetically vulnerable to psychosis. Also, there may be particular ick associated with exorphins in wheat being neuroactive. And is it just wheat? There's a paper linking recent onset psychosis and schizophrenia to IgG and IgA antibodies to casein (10). In this study, the severity of psychosis was linked to the level of antibody response to casein (actually, the alpha and kappa subunits moreso than the beta, which is interesting, though first onset psychosis had a robust immune response to the beta subunit).
And I'm not entirely off the wall here, because here is an excerpt of the discussion from paper 10 -
So, lesson number one. Don't have a leaky gut. Lesson number two. If your gut is leaky, best to avoid creepy neuroactive peptides. Lesson number three. There is nothing horribly definitive here, but plenty to study.
Before disaster struck, Jamie was kind enough to send me a link to a new paper (free full text) about Bipolar Disorder and gluten markers. The paper doesn't give us much, but it does stir up some good ol' murk. So let's investigate. Bipolar disorder is an illness of mania or hypomania plus or minus depressive episodes. Bipolar disorder does not equal "moody" or "irritable," though those can certainly be signs. It's not the disorder unless the symptoms are bad enough to get you into serious trouble. You spend too much, you sleep around too much, you don't sleep, you are more religious, you are grandiose - in cycles. And, of course, it is associated with inflammation and metabolic syndrome (1), diabetes (2) and a "western" style diet.
I have suspicions about those links. I'd bet a monkey that a combination of sugar, trans fats and vegetable oil, and high doses of refined wheat products (as I've mentioned before, the evidence against wheat is circumstantial) are culprits behind metabolic syndrome and diabetes. And maybe a subset of the population suffers at the brain level too and manifests bipolar disorder. Hey, seems as good a theory as any.
Wheat has been investigated on and off over the years as a culprit in schizophrenia. And bipolar disorder and schizophrenia can overlap sometimes in symptoms - while depressed people can be psychotic, a frank manic psychosis will look pretty much the same in the hospital as a schizophrenic psychotic episode, and there may even be some genetic overlaps (3)(4). The new paper that Jamie sent me is the first to study celiac and wheat-associated antibodies in bipolar disorder. In schizophrenia, there is a definite increase in wheat-associated antibodies in the serum (5) and these antibodies aren't the same ones that are seen in celiac disease. Well, with bipolar disorder, seems the same thing is true. Bipolar folks had a significant IgG gliadin reaction compared to controls, but there weren't really differences with respect to tTG and IgA gliadin antibodies which are typically elevated in celiac disease.
Ooh ooh ooh, wheat is BAD. Well, probably, for various reasons. But, of course, I don't necessarily believe that a positive IgG test to gliadin means one has a sensitivity to gliadin. I griped about IgG food sensitivity tests not too terribly long ago. I think a robustly positive IgG test to lots of things means one may have a leaky gut. Gliadin is a pretty darn common thing to eat, so folks with leaky guts may come up positive for gliadin. The most robust evidence in humans I've seen for leaky guts linked to wheat (or maybe casein) consumption was from this nifty study in autism (6), where the kids on the GF/CF diets had pretty tight junctions in their guts, especially compared to the autistic kids and their relatives. Boy, I bet the researchers have really pounced on this diet and mental health link and studied leaky guts in bipolar disorder (7)(9)! Er, no. But, links have been found between major depressive disorder and leaky guts (8 - an interesting enough paper for another day).
Like I said, murk. Best I can consolidate from all this information - it may be that folks with bipolar disorder have gut issues, and gut issues are inflammatory issues, and a higher IgG response to gliadin occurs, and inflammation causes the body to release cytokines and general badness, and those cytokines may predispose the genetically vulnerable to psychosis. Also, there may be particular ick associated with exorphins in wheat being neuroactive. And is it just wheat? There's a paper linking recent onset psychosis and schizophrenia to IgG and IgA antibodies to casein (10). In this study, the severity of psychosis was linked to the level of antibody response to casein (actually, the alpha and kappa subunits moreso than the beta, which is interesting, though first onset psychosis had a robust immune response to the beta subunit).
And I'm not entirely off the wall here, because here is an excerpt of the discussion from paper 10 -
We can speculate that a subset of individuals with recent onset psychosis and/or schizophrenia may have cellular junction pathology that allows peptide fragments generated from the digestion of bovine milk to permeate the intestinal tract, and enter the bloodstream... Dohan... hypothesized that the aberrent proteolysis of milk and grain products may produce small neuroactive peptides that can enter into the circulation and ultimately cross the blood-brain barrier.
So, lesson number one. Don't have a leaky gut. Lesson number two. If your gut is leaky, best to avoid creepy neuroactive peptides. Lesson number three. There is nothing horribly definitive here, but plenty to study.
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.
(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.
Monday, October 8, 2012
Ketogenic Diets and Bipolar Disorder: New Case Studies
Researching the viability of ketogenic diets for therapeutic usage was one of the original interests that launched this blog. And while there is growing data for brain cancers and even a Cochran review for the use of ketogenic diets in epilepsy, the bipolar story has always been theoretical.
Churchill: Change (song starts at about 30 secs)
Ketogenic (very low carbohydrate and low protein) diets should work a bit like the mood stabilizer depakote in regulating unstable moods in bipolar disorder, making them an interesting option, should the research pan out. I explore the research and details in this post:
A Dietary Treatment for Bipolar Disorder?
But, as I stated in that article, there were no randomized controlled trials, not even a pilot trial, and the only two case studies I had unearthed had one guy getting psychotic on Atkins induction and another one where a hospitalized bipolar woman showed no benefit (but despite reported enthusiasm and being in an inpatient unit where her food was supposedly entirely controlled, she never acheived ketosis).
But the other day PubMed emailed me a new paper with links to the following article: The ketogenic diet for type II bipolar disorder. Thanks to the good Dr. Eades I was able to see the full text without getting a librarian to request it for me.
And here we have not one, but two rather well documented cases of bipolar II disorder in women, beginning in youth with some hypomania, in one person predictable seasonal depressions in the summer and a bit of mania in the spring. Both women had bad responses (such as suicide attempts and suicidal thoughts) to antidepressant trials and one gained weight on quetiapine. They were tried on lamotrigine, an anticonvulsant and mood stablizer, with okay results (one woman was finally able to maintain a job and be functional). One tried a ketogenic diet to help with some irritable bowel symptoms, the other just wanted to try the diet. One woman ate raw cream, grassfed beef, organic pork, free range chicken, and seafood. The other ate mostly chicken, fish, and coconut oil with 2-3 cups of vegetables a day. Both monitored their urine with ketostix or Ketone Care Test Strips most days for several months, achieving mild to moderate ketosis on most days. Both women eventually discontinued the lamotrigine and reported better symptom control with the diet than with medication.
One woman described her irritability going away and a sense of calm. Also "having my head screwed on straight--well, it's definitely worth giving up pie." She said her symptoms seemed better with a ketone level of 15mg/dl vs 5 mg/dl in the urine. The other woman noted that if she remained gluten-free, she felt much better, even though she had never been diagnosed with celiac disease.
Neither woman had any adverse consequences and they remained stable on the diet for 2-3 years at the time the paper was published.
The paper details how a slight acidosis achieved with a ketogenic diet results in decreased intracellular sodium accumulation, which is the mechanism by which all anticonvulsants which are also mood stabilizers appear to work. In addition, the paper details some possible pitfalls of a ketogenic diet, such as difficulty maintaining it in a world of twinkies and coca-cola, and the risk of kidney stones. The author recommends >2.5 liters a day of fluids and a potassium citrate supplement to alkinilize the urine, which is done routinely in pediatric clinics where ketogenic diets are used for seizures, but may not be be necessary in adults. There is a long-term review of the ketogenic diets in kids (though I'm not a fan of the ingredients in some of the formulas used for tube-feeding some of these kids - soybean oil, soybean oil and more soybean oil) talking about complications over 6 years. Since these kids were often very ill with many other debilitating conditions, it is hard to attribute the complications (sepsis, cardiomyopathy, lipid pneumonia) to the diet itself.
Lipids were measured in one woman from a vegetarian to an omnivorous to a ketogenic diet. As is expected her trigs dropped and her LDL and HDL went up on the ketogenic diet. Total cholesterol to HDL ratio (the best cheap test I know of relating to total LDL particle number, with a lower ratio being better) on the vegetarian diet was 4.47, 3.78 on the omnivorous diet, and 3.74 on the ketogenic diet.
All in all, the paper is a nice illustration of two motivated patients acheiving remission of their bipolar symptoms (which they had dealt with for decades) with a free-living ketogenic diet (and some other supplements, though each woman took different ones, for example, probiotics and omega 3). Two anecdotes isn't a huge amount of data, but it is intriguing, and I would say the time for a randomized controlled trial of ketogenic diets in bipolar disorder is way overdue.
(Final note as I was in a bit of a hurry when I wrote the post at first… I did want to say there is a *lot* about these case study diets that could be therapeutic. No processed food, no sugar, lots of nutrients, lots of omega 3, low in gluten or gluten-free, likely low in histamine. The tracking of the ketones and one women's experience that the 15mg/dl ketone level felt more calming to her along with the sensible biologic mechanism makes the ketosis part plausible, but it is important to note these other possible factors).
Churchill: Change (song starts at about 30 secs)
Ketogenic (very low carbohydrate and low protein) diets should work a bit like the mood stabilizer depakote in regulating unstable moods in bipolar disorder, making them an interesting option, should the research pan out. I explore the research and details in this post:
A Dietary Treatment for Bipolar Disorder?
But, as I stated in that article, there were no randomized controlled trials, not even a pilot trial, and the only two case studies I had unearthed had one guy getting psychotic on Atkins induction and another one where a hospitalized bipolar woman showed no benefit (but despite reported enthusiasm and being in an inpatient unit where her food was supposedly entirely controlled, she never acheived ketosis).
But the other day PubMed emailed me a new paper with links to the following article: The ketogenic diet for type II bipolar disorder. Thanks to the good Dr. Eades I was able to see the full text without getting a librarian to request it for me.
And here we have not one, but two rather well documented cases of bipolar II disorder in women, beginning in youth with some hypomania, in one person predictable seasonal depressions in the summer and a bit of mania in the spring. Both women had bad responses (such as suicide attempts and suicidal thoughts) to antidepressant trials and one gained weight on quetiapine. They were tried on lamotrigine, an anticonvulsant and mood stablizer, with okay results (one woman was finally able to maintain a job and be functional). One tried a ketogenic diet to help with some irritable bowel symptoms, the other just wanted to try the diet. One woman ate raw cream, grassfed beef, organic pork, free range chicken, and seafood. The other ate mostly chicken, fish, and coconut oil with 2-3 cups of vegetables a day. Both monitored their urine with ketostix or Ketone Care Test Strips most days for several months, achieving mild to moderate ketosis on most days. Both women eventually discontinued the lamotrigine and reported better symptom control with the diet than with medication.
One woman described her irritability going away and a sense of calm. Also "having my head screwed on straight--well, it's definitely worth giving up pie." She said her symptoms seemed better with a ketone level of 15mg/dl vs 5 mg/dl in the urine. The other woman noted that if she remained gluten-free, she felt much better, even though she had never been diagnosed with celiac disease.
Neither woman had any adverse consequences and they remained stable on the diet for 2-3 years at the time the paper was published.
The paper details how a slight acidosis achieved with a ketogenic diet results in decreased intracellular sodium accumulation, which is the mechanism by which all anticonvulsants which are also mood stabilizers appear to work. In addition, the paper details some possible pitfalls of a ketogenic diet, such as difficulty maintaining it in a world of twinkies and coca-cola, and the risk of kidney stones. The author recommends >2.5 liters a day of fluids and a potassium citrate supplement to alkinilize the urine, which is done routinely in pediatric clinics where ketogenic diets are used for seizures, but may not be be necessary in adults. There is a long-term review of the ketogenic diets in kids (though I'm not a fan of the ingredients in some of the formulas used for tube-feeding some of these kids - soybean oil, soybean oil and more soybean oil) talking about complications over 6 years. Since these kids were often very ill with many other debilitating conditions, it is hard to attribute the complications (sepsis, cardiomyopathy, lipid pneumonia) to the diet itself.
Lipids were measured in one woman from a vegetarian to an omnivorous to a ketogenic diet. As is expected her trigs dropped and her LDL and HDL went up on the ketogenic diet. Total cholesterol to HDL ratio (the best cheap test I know of relating to total LDL particle number, with a lower ratio being better) on the vegetarian diet was 4.47, 3.78 on the omnivorous diet, and 3.74 on the ketogenic diet.
All in all, the paper is a nice illustration of two motivated patients acheiving remission of their bipolar symptoms (which they had dealt with for decades) with a free-living ketogenic diet (and some other supplements, though each woman took different ones, for example, probiotics and omega 3). Two anecdotes isn't a huge amount of data, but it is intriguing, and I would say the time for a randomized controlled trial of ketogenic diets in bipolar disorder is way overdue.
(Final note as I was in a bit of a hurry when I wrote the post at first… I did want to say there is a *lot* about these case study diets that could be therapeutic. No processed food, no sugar, lots of nutrients, lots of omega 3, low in gluten or gluten-free, likely low in histamine. The tracking of the ketones and one women's experience that the 15mg/dl ketone level felt more calming to her along with the sensible biologic mechanism makes the ketosis part plausible, but it is important to note these other possible factors).
Saturday, January 22, 2011
Chronotherapeutics for Affective Disorders
Little update 3/2/11 - Just found this website with research updates on chronotherapuetics which may be of interest: http://www.chronotherapeutics.org/Index.html
(end little update)
I'm going to spend some more time discussing some nitty gritty, genetics, and biochemistry related to mood disorders (especially), treatments for mood disorders, and circadian rhythm abnormalities. Bet you can't wait! In the mean time, however, I came upon some neat articles (1)(2) about the process of chronotherapeutics. That is, using light therapy, dark therapy, sleep deprivation and sleep phase delay or advance to treat mood disorders, such as depression and bipolar disorder. A little warning - these methods are powerful, quick, and affect the same neurotransmitter systems as psychiatric medications (more on that in a different post), and it is not a good idea to experiment with these all on your lonesome. Let me give you a worst case scenario - you try to treat depression with light therapy or sleep deprivation. Turns out you are bipolar. You get manic, spend $30,000 on a new stereo system, sleep with your boss, and antagonize your friends and relatives, and end up in a hospital after singing opera naked on your rooftop (this is an invented but not entirely unreasonable scenario). So... best to let some loved ones know if you attempt these methods, and if you already have a psychiatric diagnosis, don't attempt these methods without the blessing and observation of your therapist or doctor. In addition, if the methods aren't done quite right, you can very quickly relapse (within 1-2 days).
Most of you will be familiar with the concept of light therapy. Sitting in front of special 10,000 lux light sources on late autumn and winter mornings has been proven to be an effective treatment for seasonal affective disorder, major depressive disorders, and even bipolar depression (if you are careful - injudicious use of light therapy can also bring on mania). The FDA approved lights (such as the ones from this company - this is just the company I typically recommend to patients, I have no relationship to them and receive no monetary or other benefit from them) all have a 30 day money back guarantee, also, which is nice, and some insurance companies will pay for them if you are lucky. The usual method is to sit in front of the lights in the morning for 15-30 minutes, glancing at the light every 30 seconds to a minute or so. You have to do it nearly every day, and it works best if you begin when the seasons change (late September here at 40 degrees north). Light therapy can nearly instantaneously improve seasonal depression, and I've heard tales of trucks of light therapy boxes driving around to small towns in Alaska and reducing the winter suicide rate along the way.
But let's get back to the basics of chronotherapeutics. In general, interventions that lead to sleep phase advance (waking up early and going to sleep early) have an antidepressant effect, and sleep phase delay (going to sleep later and waking up later) will have a depressant (or anti-manic) effect. Also, reinforcing the natural circadian rhythm will tend to help mental illness - at hospitals in Canada (3) and Italy (4), they noticed that patients in sunny or easterly facing rooms were discharged on average 2&1/2 to 3&1/2 days earlier than patients in rooms without much sunlight. (Even more interestingly, the differences were minimal in the winter, but extended to up to 7 days in the autumn). Not surprisingly, all of this has been discovered before by our intrepid ancestors. Classical texts and descriptions of psychiatric wards from 1794 showed that depressed patients were advised to spend time out of doors, and agitated patients were closed up in darkened rooms (5).
One old-fashioned and newly-fashionable method of treating all sorts of depression is sleep deprivation (SD). There is complete sleep-deprivation, which is self-explanatory, and partial sleep-deprivation,which generally involves waking people up for the second half of the night. The only known contraindication to sleep deprivation is epilepsy (I've spent some time on the long-term seizure monitoring units in neurology, and we've been known to elicit seizures for diagnosis via EEG by sleep deprivation (basically, sending the medical students and residents - who were up anyway - to keep the patient awake at all hours) and use of a judicious amount of red wine). SD's efficacy has been reported in major depression, bipolar disorder, depression in schizophrenia and in Parkinson's disease, and post-partum depression. Patients who respond best to sleep deprivation are the same patients who respond best to antidepressant medications - those with a diurnal pattern of mood (typically more depressed in the morning and feeling pretty good by afternoon), low IL-6 levels, and an abnormal dexamethasone suppression test. Light therapy has similarly proved therapeutic (nearly instantly) with depression associated with ADHD, Parkinson's, Alzheimer's, pregnancy, post-natal, and regular depressive disorders.
As with every other method (such as therapy and antidepressants) (except shock therapy, which is up to 90% effective), light therapy and sleep deprivation is at least modestly helpful in 60-70% of cases. However, and interestingly, people with bipolar depression seem more likely to respond to sleep deprivation or light therapy than to standard antidepressant medications, suggesting to me (and truth be told I've read other papers with other evidence for this theory) that genetic issues with the circadian rhythm system is the primary problem leading to the vulnerability to bipolar disorder.Due to the tricky nature of bipolar depression and the risk of switching to mania with antidepressant drugs, some of the most robust data has been shown for chronotherapeutics (sleep deprivation, phase advance, or light therapy) for this condition, and mood stabilizers (which work upon the circadian rhythm proteins) can enhance and continue the initial benefits brought about via chronotherapeutics. The medicine remains useful, as once chronotherapeutics are discontinued (one can't be sleep-deprived forever, for example), the depression can return within a hours of a normal night's sleep. In fact, only 5-10% of the studied bipolar depressed patients remain with a normal mood through chronotherapeutics alone. Repeating the intervention doesn't always help, as people tend to become tolerant to the treatment.
One way of ameliorating the tolerance to chronotherapeutic techniques is to combine them. For example, there is a severely depressed patient with known bipolar disorder in the hospital. Start with a few days of sleep deprivation, then begin phase advance treatment (going to bed early, waking up early) and morning light therapy to retain the benefits over time. Perhaps add in some mood stabilizers to enhance the effect (again, I will go into more specifics as to how mood stabilizers and antidepressants affect, directly, the circadian rhythm system in another post - but to give you a preliminary taste, both serum and PET, SPECT, and fmri data has shown that antidepressants and sleep deprivation/phase delay/light therapy affect the same neurotransmitter system in similar areas of the brain), and we have a recipe for nearly immediate reversal of severe bipolar depression with maintenance of normal mood for the foreseeable future.
An interesting part of the discussion of chronotherapeutics is that the techniques (other than the physical lights of light therapy) cannot be patented. Therefore there is less (short-term) economic motivation for future study (as is the case with most evolutionary medicine ideas). However, in countries with socialized medicine, far-sighted bureaucrats might see the writing on the wall - cheap interventions (such as sticking all the depressed patients in easterly-facing rooms in the autumn) decreasing hospital times saves real taxpayer money very quickly. Days in the hospital equals thousands of dollars. It is that simple.
So if you are depressed, seek light and wakefulness (an old timey depression remedy was to wake up at 3am once a month for those known to be vulnerable to the condition), and if you are manic, seek darkness and low stimuli. Under close supervision, of course.
(end little update)
I'm going to spend some more time discussing some nitty gritty, genetics, and biochemistry related to mood disorders (especially), treatments for mood disorders, and circadian rhythm abnormalities. Bet you can't wait! In the mean time, however, I came upon some neat articles (1)(2) about the process of chronotherapeutics. That is, using light therapy, dark therapy, sleep deprivation and sleep phase delay or advance to treat mood disorders, such as depression and bipolar disorder. A little warning - these methods are powerful, quick, and affect the same neurotransmitter systems as psychiatric medications (more on that in a different post), and it is not a good idea to experiment with these all on your lonesome. Let me give you a worst case scenario - you try to treat depression with light therapy or sleep deprivation. Turns out you are bipolar. You get manic, spend $30,000 on a new stereo system, sleep with your boss, and antagonize your friends and relatives, and end up in a hospital after singing opera naked on your rooftop (this is an invented but not entirely unreasonable scenario). So... best to let some loved ones know if you attempt these methods, and if you already have a psychiatric diagnosis, don't attempt these methods without the blessing and observation of your therapist or doctor. In addition, if the methods aren't done quite right, you can very quickly relapse (within 1-2 days).
Most of you will be familiar with the concept of light therapy. Sitting in front of special 10,000 lux light sources on late autumn and winter mornings has been proven to be an effective treatment for seasonal affective disorder, major depressive disorders, and even bipolar depression (if you are careful - injudicious use of light therapy can also bring on mania). The FDA approved lights (such as the ones from this company - this is just the company I typically recommend to patients, I have no relationship to them and receive no monetary or other benefit from them) all have a 30 day money back guarantee, also, which is nice, and some insurance companies will pay for them if you are lucky. The usual method is to sit in front of the lights in the morning for 15-30 minutes, glancing at the light every 30 seconds to a minute or so. You have to do it nearly every day, and it works best if you begin when the seasons change (late September here at 40 degrees north). Light therapy can nearly instantaneously improve seasonal depression, and I've heard tales of trucks of light therapy boxes driving around to small towns in Alaska and reducing the winter suicide rate along the way.
But let's get back to the basics of chronotherapeutics. In general, interventions that lead to sleep phase advance (waking up early and going to sleep early) have an antidepressant effect, and sleep phase delay (going to sleep later and waking up later) will have a depressant (or anti-manic) effect. Also, reinforcing the natural circadian rhythm will tend to help mental illness - at hospitals in Canada (3) and Italy (4), they noticed that patients in sunny or easterly facing rooms were discharged on average 2&1/2 to 3&1/2 days earlier than patients in rooms without much sunlight. (Even more interestingly, the differences were minimal in the winter, but extended to up to 7 days in the autumn). Not surprisingly, all of this has been discovered before by our intrepid ancestors. Classical texts and descriptions of psychiatric wards from 1794 showed that depressed patients were advised to spend time out of doors, and agitated patients were closed up in darkened rooms (5).
One old-fashioned and newly-fashionable method of treating all sorts of depression is sleep deprivation (SD). There is complete sleep-deprivation, which is self-explanatory, and partial sleep-deprivation,which generally involves waking people up for the second half of the night. The only known contraindication to sleep deprivation is epilepsy (I've spent some time on the long-term seizure monitoring units in neurology, and we've been known to elicit seizures for diagnosis via EEG by sleep deprivation (basically, sending the medical students and residents - who were up anyway - to keep the patient awake at all hours) and use of a judicious amount of red wine). SD's efficacy has been reported in major depression, bipolar disorder, depression in schizophrenia and in Parkinson's disease, and post-partum depression. Patients who respond best to sleep deprivation are the same patients who respond best to antidepressant medications - those with a diurnal pattern of mood (typically more depressed in the morning and feeling pretty good by afternoon), low IL-6 levels, and an abnormal dexamethasone suppression test. Light therapy has similarly proved therapeutic (nearly instantly) with depression associated with ADHD, Parkinson's, Alzheimer's, pregnancy, post-natal, and regular depressive disorders.
As with every other method (such as therapy and antidepressants) (except shock therapy, which is up to 90% effective), light therapy and sleep deprivation is at least modestly helpful in 60-70% of cases. However, and interestingly, people with bipolar depression seem more likely to respond to sleep deprivation or light therapy than to standard antidepressant medications, suggesting to me (and truth be told I've read other papers with other evidence for this theory) that genetic issues with the circadian rhythm system is the primary problem leading to the vulnerability to bipolar disorder.Due to the tricky nature of bipolar depression and the risk of switching to mania with antidepressant drugs, some of the most robust data has been shown for chronotherapeutics (sleep deprivation, phase advance, or light therapy) for this condition, and mood stabilizers (which work upon the circadian rhythm proteins) can enhance and continue the initial benefits brought about via chronotherapeutics. The medicine remains useful, as once chronotherapeutics are discontinued (one can't be sleep-deprived forever, for example), the depression can return within a hours of a normal night's sleep. In fact, only 5-10% of the studied bipolar depressed patients remain with a normal mood through chronotherapeutics alone. Repeating the intervention doesn't always help, as people tend to become tolerant to the treatment.
One way of ameliorating the tolerance to chronotherapeutic techniques is to combine them. For example, there is a severely depressed patient with known bipolar disorder in the hospital. Start with a few days of sleep deprivation, then begin phase advance treatment (going to bed early, waking up early) and morning light therapy to retain the benefits over time. Perhaps add in some mood stabilizers to enhance the effect (again, I will go into more specifics as to how mood stabilizers and antidepressants affect, directly, the circadian rhythm system in another post - but to give you a preliminary taste, both serum and PET, SPECT, and fmri data has shown that antidepressants and sleep deprivation/phase delay/light therapy affect the same neurotransmitter system in similar areas of the brain), and we have a recipe for nearly immediate reversal of severe bipolar depression with maintenance of normal mood for the foreseeable future.
An interesting part of the discussion of chronotherapeutics is that the techniques (other than the physical lights of light therapy) cannot be patented. Therefore there is less (short-term) economic motivation for future study (as is the case with most evolutionary medicine ideas). However, in countries with socialized medicine, far-sighted bureaucrats might see the writing on the wall - cheap interventions (such as sticking all the depressed patients in easterly-facing rooms in the autumn) decreasing hospital times saves real taxpayer money very quickly. Days in the hospital equals thousands of dollars. It is that simple.
So if you are depressed, seek light and wakefulness (an old timey depression remedy was to wake up at 3am once a month for those known to be vulnerable to the condition), and if you are manic, seek darkness and low stimuli. Under close supervision, of course.
Thursday, October 7, 2010
Diet and Mood Disorders
Found two more studies measuring diet pattern and mood disorders!
The first one is Dietary pattern and depressive symptoms in middle age from the British Journal of Psychiatry in 2009 (free full text, go take a look!). This paper is part of the large Whitehall II epidemiological study, where some 10,000 people were screened at baseline (phase 1) for all sorts of demographic characteristics, stress levels, health, lifestyle factors, blood pressure, and some labwork. Every 2&1/2 years or so, the study subjects received a postal questionnaire to fill out (phases 2,4,6,8), and every 5 years a questionnaire and a clinical examination were done (phases 3,5,7). In this paper, the data was taken from 3486 White European participants with data on dietary patterns and all covariates at phase 5 and depression at phase 7. The 175 Black and 331 Asian participants were excluded due to "differences in eating patterns." (!!!)
Dietary "pattern" was determined by a Food Frequency Questionnaire based on the one used in the Nurses Health Study (but changed up to include British sorts of foods - like bangers and mash, or crisps, or yorkshire pudding). Here's a good write-up addressing the (actually rather rigorous, but still hopeless) validity of the FFQ used in the Nurses Health Study. 127 food items were rated according to how often they were consumed - "never or less than once per month" up to "six or more times per day" - the 127 items were divided into 37 groups, and dietary patterns were identified using "principal component analysis" of the 37 groups, and statisticians gleefully addressed the data with graphs and scree plots and tweaks and nudges until a score pops out about each person's diet, falling into "whole foods" or the "processed foods" patterns.
"Whole foods" were diets consisting of vegetables, fruits and fish.
"Processed foods" were diets consisting of "high consumption of sweetened desserts, chocolates, fried food, processed meat, pies, refined grains, high fat dairy products, and condiments."
Depression measures were determined by a 20 question "Center for Epidemiologic Studies Depression Scale." People with a score higher than 15 were considered depressed.
Then the statisticians got a whack at the data again, adjusting for covariates such as age, gender, marital status, employment grade, education, smoking, physical activity, health status (based on clinical findings such as a high hemoglobin A1C (a measure of average blood glucose), blood pressure, being on antidepressants, etc.), a second "GHQ" depression subscale, and a cognitive score based on 65 question test.
Ready for the results yet? What do you think will turn out?
Patients with the highest intake of whole foods were less likely to be depressed (and this association wasn't affected much, actually, by adjusting for all the covariates, which is interesting - suggesting that the association with diet could be as important or more important than all those other covariates.). Patients with a high intake of processed food were much more likely to be depressed.
There is another interesting thing about this study. See, from just the above data, you don't know whether depressed people are too blue to do anything but sit around gorging on meat pies, sugar, and refined grains, or if the diet actually leads to the depression. The depression measures were repeated at phase 5 and phase 7, and when the 427 participants who were depressed at stage 5 were excluded, the data showed that the same people who had crappy diets but were not depressed (yet) at phase 5 were more likely to be depressed at phase 7. In addition, the researchers went back to the phase 3 data, and found no evidence that the dietary patterns in phase 5 were worse for the participants who were depressed at phase 3. These are clues that crappy diet precedes depressive symptoms, not the other way around.
All in all, a rather cool study, considering the limitations of epidemiology.
The second study is hot off the presses - Diet quality in bipolar disorder in a population-based sample of women from the Journal of Affective Disorders (I think this is the November issue - these are the corrected proofs available online before print). The subjects used were women from the Australian Geelong Osteoporosis Study (I blogged about them back in June). 1046 women randomly recruited from compulsory voting roles volunteered for this particular piece of the study. Each of the women were given the gold standard interview for diagnosis of psychiatric disorders - the SCID (non-patient edition). Patients with depression or anxiety were excluded, allowing for patients with bipolar disorder to be compared to those with no current (or lifetime) psychopathology.
Once again, a food frequency questionnaire was used, and the diets were broken up into "traditional" (vegetables, fruit, beef, lamb, fish, whole grains), "western" (meat pies, processed meats, pizza, chips, hamburgers, white bread, sugar, flavored milk drinks, and beer), and "modern" (fruits, salads, fish, yogurt, nuts, beans, tofu, and red wine). Blah blah blah logistic regression analyses and exposure variables were studiously applied and accounted for (can you tell I'm not an epidemiologist?).
Here's an interesting tidbit that I don't remember from the previous paper I blogged about in June - the researchers note that it was the absolute amount of western style foods that seemed to be related to the risk of depression rather than the amount as a proportion of overall energy consumption. Therefore, the researchers examined the data in this grouping as both absolute amounts, percentage of energy, and covariate confounding. Whew.
Bipolar disorder is less common than depressive or anxiety disorders, so only 23 women in the whole study qualified for the diagnosis (there were 332 with depression or anxiety and therefore excluded from this analysis, and 691 without depressive or anxiety disorders). Participants with bipolar disorder were younger and had higher average daily energy intake, though there was no difference in education, BMI, alcohol intake, education, socioeconomic status, smoking, and physical activity compared to those with no psychopathology. (Interesting - bipolar disorder and substance abuse are highly correlated so it is something to keep in mind that these 23 bipolar ladies didn't seem to smoke or drink more than the 691 "normals.")
Now the diet results! Individuals with a "modern" pattern were more likely to have a diagnosis of bipolar disorder, as were individuals with a "western" pattern, before and after adjustments for energy intake. A "traditional" dietary pattern was protective. These data held even when accounting for age.
As in the previous study (which I addressed in the comments in my previous blog post), the diets were also given a total "DQS" or dietary quality score, associated with how close the diets came to the national recommendations for good diets (similar to the USDA recommendations). DQS score of diets had no correlation with bipolar disorder, protective or not protective.
Overall, the authors noted (as I do now!) that the association with depressive, anxiety, and bipolar disorders are similar - a "traditional" diet being protective, and modern and western diets being similarly dismal. My theory is that an individual's response to diet would be based on genetic risk, so the inflammation level related to similar dietary choices would come out as different psychopathology depending on your genes.
The authors of the second study make note of the results of the first study I mentioned above - they think diet is causative, not a choice as a result of specific psychiatric illness. They note systemic inflammation, oxidative stress, and neurotrophin levels as potential explanations of the demonstrated associations between dietary quality and bipolar disorder. I agree. Wholeheartedly.
Eat real food, folks. It won't hurt. And maybe it will help.
The first one is Dietary pattern and depressive symptoms in middle age from the British Journal of Psychiatry in 2009 (free full text, go take a look!). This paper is part of the large Whitehall II epidemiological study, where some 10,000 people were screened at baseline (phase 1) for all sorts of demographic characteristics, stress levels, health, lifestyle factors, blood pressure, and some labwork. Every 2&1/2 years or so, the study subjects received a postal questionnaire to fill out (phases 2,4,6,8), and every 5 years a questionnaire and a clinical examination were done (phases 3,5,7). In this paper, the data was taken from 3486 White European participants with data on dietary patterns and all covariates at phase 5 and depression at phase 7. The 175 Black and 331 Asian participants were excluded due to "differences in eating patterns." (!!!)
Dietary "pattern" was determined by a Food Frequency Questionnaire based on the one used in the Nurses Health Study (but changed up to include British sorts of foods - like bangers and mash, or crisps, or yorkshire pudding). Here's a good write-up addressing the (actually rather rigorous, but still hopeless) validity of the FFQ used in the Nurses Health Study. 127 food items were rated according to how often they were consumed - "never or less than once per month" up to "six or more times per day" - the 127 items were divided into 37 groups, and dietary patterns were identified using "principal component analysis" of the 37 groups, and statisticians gleefully addressed the data with graphs and scree plots and tweaks and nudges until a score pops out about each person's diet, falling into "whole foods" or the "processed foods" patterns.
"Whole foods" were diets consisting of vegetables, fruits and fish.
"Processed foods" were diets consisting of "high consumption of sweetened desserts, chocolates, fried food, processed meat, pies, refined grains, high fat dairy products, and condiments."
Depression measures were determined by a 20 question "Center for Epidemiologic Studies Depression Scale." People with a score higher than 15 were considered depressed.
Then the statisticians got a whack at the data again, adjusting for covariates such as age, gender, marital status, employment grade, education, smoking, physical activity, health status (based on clinical findings such as a high hemoglobin A1C (a measure of average blood glucose), blood pressure, being on antidepressants, etc.), a second "GHQ" depression subscale, and a cognitive score based on 65 question test.
Ready for the results yet? What do you think will turn out?
Patients with the highest intake of whole foods were less likely to be depressed (and this association wasn't affected much, actually, by adjusting for all the covariates, which is interesting - suggesting that the association with diet could be as important or more important than all those other covariates.). Patients with a high intake of processed food were much more likely to be depressed.
There is another interesting thing about this study. See, from just the above data, you don't know whether depressed people are too blue to do anything but sit around gorging on meat pies, sugar, and refined grains, or if the diet actually leads to the depression. The depression measures were repeated at phase 5 and phase 7, and when the 427 participants who were depressed at stage 5 were excluded, the data showed that the same people who had crappy diets but were not depressed (yet) at phase 5 were more likely to be depressed at phase 7. In addition, the researchers went back to the phase 3 data, and found no evidence that the dietary patterns in phase 5 were worse for the participants who were depressed at phase 3. These are clues that crappy diet precedes depressive symptoms, not the other way around.
All in all, a rather cool study, considering the limitations of epidemiology.
The second study is hot off the presses - Diet quality in bipolar disorder in a population-based sample of women from the Journal of Affective Disorders (I think this is the November issue - these are the corrected proofs available online before print). The subjects used were women from the Australian Geelong Osteoporosis Study (I blogged about them back in June). 1046 women randomly recruited from compulsory voting roles volunteered for this particular piece of the study. Each of the women were given the gold standard interview for diagnosis of psychiatric disorders - the SCID (non-patient edition). Patients with depression or anxiety were excluded, allowing for patients with bipolar disorder to be compared to those with no current (or lifetime) psychopathology.
Once again, a food frequency questionnaire was used, and the diets were broken up into "traditional" (vegetables, fruit, beef, lamb, fish, whole grains), "western" (meat pies, processed meats, pizza, chips, hamburgers, white bread, sugar, flavored milk drinks, and beer), and "modern" (fruits, salads, fish, yogurt, nuts, beans, tofu, and red wine). Blah blah blah logistic regression analyses and exposure variables were studiously applied and accounted for (can you tell I'm not an epidemiologist?).
Here's an interesting tidbit that I don't remember from the previous paper I blogged about in June - the researchers note that it was the absolute amount of western style foods that seemed to be related to the risk of depression rather than the amount as a proportion of overall energy consumption. Therefore, the researchers examined the data in this grouping as both absolute amounts, percentage of energy, and covariate confounding. Whew.
Bipolar disorder is less common than depressive or anxiety disorders, so only 23 women in the whole study qualified for the diagnosis (there were 332 with depression or anxiety and therefore excluded from this analysis, and 691 without depressive or anxiety disorders). Participants with bipolar disorder were younger and had higher average daily energy intake, though there was no difference in education, BMI, alcohol intake, education, socioeconomic status, smoking, and physical activity compared to those with no psychopathology. (Interesting - bipolar disorder and substance abuse are highly correlated so it is something to keep in mind that these 23 bipolar ladies didn't seem to smoke or drink more than the 691 "normals.")
Now the diet results! Individuals with a "modern" pattern were more likely to have a diagnosis of bipolar disorder, as were individuals with a "western" pattern, before and after adjustments for energy intake. A "traditional" dietary pattern was protective. These data held even when accounting for age.
As in the previous study (which I addressed in the comments in my previous blog post), the diets were also given a total "DQS" or dietary quality score, associated with how close the diets came to the national recommendations for good diets (similar to the USDA recommendations). DQS score of diets had no correlation with bipolar disorder, protective or not protective.
Overall, the authors noted (as I do now!) that the association with depressive, anxiety, and bipolar disorders are similar - a "traditional" diet being protective, and modern and western diets being similarly dismal. My theory is that an individual's response to diet would be based on genetic risk, so the inflammation level related to similar dietary choices would come out as different psychopathology depending on your genes.
The authors of the second study make note of the results of the first study I mentioned above - they think diet is causative, not a choice as a result of specific psychiatric illness. They note systemic inflammation, oxidative stress, and neurotrophin levels as potential explanations of the demonstrated associations between dietary quality and bipolar disorder. I agree. Wholeheartedly.
Eat real food, folks. It won't hurt. And maybe it will help.
Wednesday, June 22, 2011
The Creative Advantage
One thing I hardly ever do is discuss what most people would consider real "Evolutionary Psychiatry." That is, how do diseases such as schizophrenia or autism, which in their worst forms are obviously so detrimental to evolutionary fitness that they would seem to represent a genetic dead end, continue in the gene pool. It doesn't make much sense at first glance. However, one could postulate that, just as the heterozygote carriers of sickle cell anemia are relatively protected against malaria, having some schizophrenia-risk genes could convey some sort of benefit for close relatives. And one must also consider the possibility that the schizophrenia phenotype is worse now than it may have been for much of human history - with plenty of vitamin D, no wheat (speculatively :-) ) or common modern pathogens, it is possible the schizophrenia may not have developed as fully or been as debilitating.
Given dopamine's role in creativity, motivation, and drive, the suspected genetic advantage of being a relative of a schizophrenic is that you may have a bit of extra dopamine, but not so much it will make you psychotic. Psychotic thought is disjointed and disorganized - creative thought is taking seemingly unrelated or unexpected ideas and bringing them together in a novel way.
Sounds reasonable. But what about the data proving it? Well, there has been a lot of speculation looking back at known geniuses and their psychopathologies. It is felt it is no coincidence that many geniuses were not particularly psychologically healthy. A more recent study selected 30 creative writers at a workshop and compared them to controls - writers had higher rates of affective disorders (several variations of this study have been done with the same results). Studies of bipolar individuals showed they scored higher on scales measuring creativity than folks with unipolar depression or non-creative controls - the bipolar folks scored the same as creative healthy controls.
In Iceland, the histories of 486 male relatives of schizophrenics were investigated - these men were more likely to be prominent historically than the general population, and there was a significant increase in those who were specifically successful in creative endeavors.
But all those studies are small, and many rely on historical records. However, a brand new paper from the British Journal of Psychiatry documents a large, population based study of 300,000 individuals with severe forms of affective disorders or schizophrenia from a large population registry in Sweden, where there is data on hospital admissions, diagnoses, IQ, occupation, and detailed family records as well. The were able to find several tens of thousands of folks with bipolar disorder and schizophrenia, and over two hundred thousand diagnosed with unipolar depression.
The results? People with schizophrenia and bipolar disorder (with the effect stronger in schizophrenia) were more likely to have parents and siblings who were in creative professions. Bipolar patients also were more likely to have creative offspring. The ORs aren't huge - ranging from around 1.2 to 1.6, but the bars don't cross the 1.0 line suggesting a real correlation. There were no strong statistically significant correlations between having a relative with unipolar depression and engaging in creative professions (described as "including scientific and artistic occupations.") As one would expect for a genetic link, as relationships got further away (half-siblings, cousins, etc.) the correlations weakened accordingly.
The reverse sort of "non-creative" correlation was also true - folks with schizophrenia were significantly less likely to have relatives who were accountants and auditors.
And the IQ connection (only measured in men in this Swedish registry) - those in creative professions had a higher IQ on average, however, the IQs of people with schizophrenia, unipolar depression, bipolar depression and their relatives were lower on average than people without any of the three diagnoses. IQ was accounted for in the correlations we talked about in the previous paragraphs and did not weaken the genetic association between creativity and severe psychiatric illness (specifically bipolar disorder and schizophrenia).
Well. That is all very interesting! I might go on to be a real Evolutionary Psychiatrist after all.
Given dopamine's role in creativity, motivation, and drive, the suspected genetic advantage of being a relative of a schizophrenic is that you may have a bit of extra dopamine, but not so much it will make you psychotic. Psychotic thought is disjointed and disorganized - creative thought is taking seemingly unrelated or unexpected ideas and bringing them together in a novel way.
Sounds reasonable. But what about the data proving it? Well, there has been a lot of speculation looking back at known geniuses and their psychopathologies. It is felt it is no coincidence that many geniuses were not particularly psychologically healthy. A more recent study selected 30 creative writers at a workshop and compared them to controls - writers had higher rates of affective disorders (several variations of this study have been done with the same results). Studies of bipolar individuals showed they scored higher on scales measuring creativity than folks with unipolar depression or non-creative controls - the bipolar folks scored the same as creative healthy controls.
In Iceland, the histories of 486 male relatives of schizophrenics were investigated - these men were more likely to be prominent historically than the general population, and there was a significant increase in those who were specifically successful in creative endeavors.
But all those studies are small, and many rely on historical records. However, a brand new paper from the British Journal of Psychiatry documents a large, population based study of 300,000 individuals with severe forms of affective disorders or schizophrenia from a large population registry in Sweden, where there is data on hospital admissions, diagnoses, IQ, occupation, and detailed family records as well. The were able to find several tens of thousands of folks with bipolar disorder and schizophrenia, and over two hundred thousand diagnosed with unipolar depression.
The results? People with schizophrenia and bipolar disorder (with the effect stronger in schizophrenia) were more likely to have parents and siblings who were in creative professions. Bipolar patients also were more likely to have creative offspring. The ORs aren't huge - ranging from around 1.2 to 1.6, but the bars don't cross the 1.0 line suggesting a real correlation. There were no strong statistically significant correlations between having a relative with unipolar depression and engaging in creative professions (described as "including scientific and artistic occupations.") As one would expect for a genetic link, as relationships got further away (half-siblings, cousins, etc.) the correlations weakened accordingly.
The reverse sort of "non-creative" correlation was also true - folks with schizophrenia were significantly less likely to have relatives who were accountants and auditors.
And the IQ connection (only measured in men in this Swedish registry) - those in creative professions had a higher IQ on average, however, the IQs of people with schizophrenia, unipolar depression, bipolar depression and their relatives were lower on average than people without any of the three diagnoses. IQ was accounted for in the correlations we talked about in the previous paragraphs and did not weaken the genetic association between creativity and severe psychiatric illness (specifically bipolar disorder and schizophrenia).
Well. That is all very interesting! I might go on to be a real Evolutionary Psychiatrist after all.
Sunday, November 13, 2011
Is Postpartum Psychosis an Autoimmune Disease?
Here's an article for the "everything is connected" file. Also for "yes, psychiatric disease has biologic underpinnings and is medical illness" file. Also the "inflammation in the wrong place at the wrong time is super-bad" file. And it may be of interest to anyone who has had symptoms of autoimmune disease helped by an anti-inflammatory (paleo-type) diet.
Postpartum psychosis is rare and scary. About 1 in 1000 women become psychotic in the first months after having a baby (though anything up to 12 months after is considered "postpartum" the greatest risk is in the first month). The most typical presentation is one of manic psychosis, with prominent insomnia, irritability, and delusions of grandeur. However, some women will also be depressed and be delusional and suicidal, or even with delusions that lead a women to kill her baby.
Not surprisingly, a prior diagnosis of bipolar disorder is the greatest risk factor for developing postpartum psychosis. However, most women with postpartum psychosis have no history of psychiatric illness at all (1). Often the illness requires hospitalization, and though there are no "consensus treatment guidelines," in almost all cases benzodiazepines (sedative, anti-anxiety meds, such as lorazepam) are used to help stabilize sleep-wake cycles, and in most cases antipsychotics are also used, typically with good effect. If those aren't helping, lithium is added.
Here's another bit of info about pregnancy. The fetus is obviously genetically different than mom, so women develop a depressed immune system during pregnancy, in order to protect the growing beastie from mom's antibodies and killer cells. This is why I was told to studiously avoid unpasturized cheese and raw eggs and deli meat during pregnancy, and why healthy women in the third trimester are much more likely to develop severe complications and die from the flu than women who are not pregnant.
It is well known that in women with a dysfunctional immune system (the autoimmune diseases, such as multiple sclerosis, rheumatoid arthritis, and autoimmune thyroiditis), the autoimmune symptoms are generally greatly ameliorated during pregnancy. However, this time of relatively low autoimmune symptoms is followed in the post-partum period by a "rebound" with greatly increased symptoms and greater autoantibody titers measured in the serum.
So is post-partum psychosis a symptom of autoimmune disease? Specifically autoimmune thyroid disease, as thyroid disease (both hyper- and hypothyroidism) is well known to cause psychiatric symptoms, even psychosis?
Well, those societies with socialized medicine were able to gather data in such a way as to start to give us an answer to that question. In the Netherlands, all the women in a certain area of the country who developed post-partum psychosis and ended up in the hospital were checked for autoimmune thyroid antibodies and thyroid function upon admission to the hospital. A larger control group of other post-partum women were also checked. Critically, women who were medicated at admission (particularly with lithium) were excluded from the study, as lithium is known to depress thyroid function. All women with a previous history of thyroid disease, bipolar disorder, schizophrenia, or psychosis were excluded. That left a group of 29 women with new-onset post-partum psychosis and 117 controls.
Here is what the researchers found. 5% of post-partum women in the control group had measurable autoimmune thyroid autoantibodies at 4 weeks after delivery, a sign of autoimmune thyroid disease. This is comparable to surveys of a general population of women in the Netherlands. None of them had measurable abnormalities in thyroid function or any symptoms. In contrast, 19% of the post-partum psychosis patients had measurable thyroid autoantibodies at admission (again, prior to receiving any lithium or antipsychotic medication treatment), and half of those women also had measurable thyroid abnormalities. In the following 9 months, 67% of the postpartum psychosis women with autoimmune thyroid antibodies went on to develop measurable thyroid problems (abnormal TSH or free thyroxine). None of the control women did. The odds ratios for these findings were all >2, some as large as 9, which is quite significant, especially considering the size of the sample).
Even though patients with previous bipolar disorder were excluded from this study, the researchers note that the 19% prevalence of autoimmune thyroid antibodies in these psychotic women is similar to the prevalence in women with bipolar disorder (2). And, to really get your noggins going, twin studies of bipolar disorder show that the presence of autoimmune thyroid antibodies are correlated not only to the illness itself, but to the genetic vulnerability to the illness (3).
The researchers in this study strongly recommended that all women with postpartum psychosis be monitored for thyroperoxidase antibodies and thyroid function abnormalities, and furthermore that all women at high risk for postpartum psychosis be monitored before and throughout pregnancy and the postpartum period. Though this was a small observational study, the advice seems very reasonable.
And, as always, we find that "post-partum psychosis" like many psychiatric symptoms is the equivalent of a fever - signaling underlying abnormalities, but not always caused by the flu. Sometimes fevers are caused by different bugs, or cancer, or autoimmune disease. Differentiating the underlying pathology will go a long way to informing our treatments (and helping in prevention) in the future.
Psychiatrists and other doctors reading this article will be interested in one directed more to healthcare professionals about the same study at the MGH Center for Women's Mental Health blog by Ruta Nonacs, MD PhD. Thanks to Dr. Trevisan for the link to the blog post!
Postpartum psychosis is rare and scary. About 1 in 1000 women become psychotic in the first months after having a baby (though anything up to 12 months after is considered "postpartum" the greatest risk is in the first month). The most typical presentation is one of manic psychosis, with prominent insomnia, irritability, and delusions of grandeur. However, some women will also be depressed and be delusional and suicidal, or even with delusions that lead a women to kill her baby.
Not surprisingly, a prior diagnosis of bipolar disorder is the greatest risk factor for developing postpartum psychosis. However, most women with postpartum psychosis have no history of psychiatric illness at all (1). Often the illness requires hospitalization, and though there are no "consensus treatment guidelines," in almost all cases benzodiazepines (sedative, anti-anxiety meds, such as lorazepam) are used to help stabilize sleep-wake cycles, and in most cases antipsychotics are also used, typically with good effect. If those aren't helping, lithium is added.
Here's another bit of info about pregnancy. The fetus is obviously genetically different than mom, so women develop a depressed immune system during pregnancy, in order to protect the growing beastie from mom's antibodies and killer cells. This is why I was told to studiously avoid unpasturized cheese and raw eggs and deli meat during pregnancy, and why healthy women in the third trimester are much more likely to develop severe complications and die from the flu than women who are not pregnant.
It is well known that in women with a dysfunctional immune system (the autoimmune diseases, such as multiple sclerosis, rheumatoid arthritis, and autoimmune thyroiditis), the autoimmune symptoms are generally greatly ameliorated during pregnancy. However, this time of relatively low autoimmune symptoms is followed in the post-partum period by a "rebound" with greatly increased symptoms and greater autoantibody titers measured in the serum.
So is post-partum psychosis a symptom of autoimmune disease? Specifically autoimmune thyroid disease, as thyroid disease (both hyper- and hypothyroidism) is well known to cause psychiatric symptoms, even psychosis?
Well, those societies with socialized medicine were able to gather data in such a way as to start to give us an answer to that question. In the Netherlands, all the women in a certain area of the country who developed post-partum psychosis and ended up in the hospital were checked for autoimmune thyroid antibodies and thyroid function upon admission to the hospital. A larger control group of other post-partum women were also checked. Critically, women who were medicated at admission (particularly with lithium) were excluded from the study, as lithium is known to depress thyroid function. All women with a previous history of thyroid disease, bipolar disorder, schizophrenia, or psychosis were excluded. That left a group of 29 women with new-onset post-partum psychosis and 117 controls.
Here is what the researchers found. 5% of post-partum women in the control group had measurable autoimmune thyroid autoantibodies at 4 weeks after delivery, a sign of autoimmune thyroid disease. This is comparable to surveys of a general population of women in the Netherlands. None of them had measurable abnormalities in thyroid function or any symptoms. In contrast, 19% of the post-partum psychosis patients had measurable thyroid autoantibodies at admission (again, prior to receiving any lithium or antipsychotic medication treatment), and half of those women also had measurable thyroid abnormalities. In the following 9 months, 67% of the postpartum psychosis women with autoimmune thyroid antibodies went on to develop measurable thyroid problems (abnormal TSH or free thyroxine). None of the control women did. The odds ratios for these findings were all >2, some as large as 9, which is quite significant, especially considering the size of the sample).
Even though patients with previous bipolar disorder were excluded from this study, the researchers note that the 19% prevalence of autoimmune thyroid antibodies in these psychotic women is similar to the prevalence in women with bipolar disorder (2). And, to really get your noggins going, twin studies of bipolar disorder show that the presence of autoimmune thyroid antibodies are correlated not only to the illness itself, but to the genetic vulnerability to the illness (3).
The researchers in this study strongly recommended that all women with postpartum psychosis be monitored for thyroperoxidase antibodies and thyroid function abnormalities, and furthermore that all women at high risk for postpartum psychosis be monitored before and throughout pregnancy and the postpartum period. Though this was a small observational study, the advice seems very reasonable.
And, as always, we find that "post-partum psychosis" like many psychiatric symptoms is the equivalent of a fever - signaling underlying abnormalities, but not always caused by the flu. Sometimes fevers are caused by different bugs, or cancer, or autoimmune disease. Differentiating the underlying pathology will go a long way to informing our treatments (and helping in prevention) in the future.
Psychiatrists and other doctors reading this article will be interested in one directed more to healthcare professionals about the same study at the MGH Center for Women's Mental Health blog by Ruta Nonacs, MD PhD. Thanks to Dr. Trevisan for the link to the blog post!
Thursday, August 18, 2011
Do Carbs Make You Crazy?
Perhaps I should be more circumspect in my title. After all, there are several popular ideas out there - one that carbohydrates cause blood sugar spikes and crashes, leading to mood swings and general crankiness. The second is that sugar (that special fructosey form of carb) causes everything from ADHD to delinquency to psychosis to bipolar disorder.
(Music selection - Serenade in E Major (right click to open in new tab) by Dvorak, who happened to write what is widely accepted as the most exalted piece of American classical music, though he is in fact fromCzechoslovakia Bohemia.)
I think pretty much everyone has heard of these ideas - most recently I saw them in an article I linked a little while ago, "How I Overcame Bipolar II (and Saved My Own Life)" by Michael Ellsberg. Here is a quote from the article:
Then we have the opposite side of the argument, personified by rodent and women's health researcher Judith Wurtman at MIT, and paleo blogger Don Matesz - carbs improve and are essential for good mood, particularly in the case of PMS, atypical depression, and seasonal affective disorder.
What did I learn in psychiatry residency? Well, that the ideas about sugar causing ADHD were unfounded, and that carbohydrates in general wouldn't be an issue plus or minus unless one had uncontrolled diabetes, in which case, of course, uncontrolled glucose swings could cause all sorts of craziness. Diabetes is one of those conditions we are supposed to rule out before spending 20 hours talking to someone about his or her mother, or prescribing Prozac.
So whom do we believe? Orthomolecular Dr. Hoffman? The Harvard Longwood Psychiatry Residency Training Program? Nora Gedgaudas? Parents who have observed their kids after a party with CAKE and ICE CREAM and FACE-PAINTING FAIRY PRINCESSES? (I'm going to tell you right now that the kids totally spaz out for several hours and then collapse in a twitching exhausted heap of sugar/princess withdrawal. The confounders are many, I must admit).
What have I learned from Gary Taubes and Peter and Kurt? Don't believe anyone. Look it up your own self, and see if it makes sense in the context of physiology and evolution. But y'all know me at this point - let's put aside the issue of metabolic syndrome for a second. Most hunter gatherer societies that I'm aware of ate starch when they could get their hands on it, so it doesn't make sense to me that carbohydrates alone would cause craziness. (We will also leave out alcohol and caffeine which Dr. Hoffman wisely recommends bipolar folks to avoid - both of which will affect SLEEP as well as sugar levels, an obvious confounder in bipolar disorder).
And yet, here on my blog and twitter and elsewhere I've seen reports of folks who feel so much better on VLC diets, and others who feel so much better with zone-ish ratios, and others who do better with more carbohydrates. My own experience (now documented in several podcasts) is that I had hypoglycemia in my late teens and early twenties. Of course, I never got an official diagnosis of hypoglycemia, because that doesn't exist outside the context of diabetes or an insulin overdose or insulin-secreting tumor. If I ate super low fat and high carb, I would get shaky, weak, and cranky about 90 minutes after my last meal. When I called the doctor about it, I was checked for diabetes (negative), and then I was told not to eat like a jerk. (Okay, some days I would eat raspberry fig newtons for lunch and dinner, and I was known to eat an entire package of Peeps from time to time - hey, I was 18.) Eat nuts and avoid sugar, sodas, alcohol, and honey, they told me. Eat snacks. And I was careful from then on out to not be such a jerk about eating and to have snacks - packages of peanuts, apples and string cheese, graham crackers stuffed in my bag - and woe befell anyone in my presence who found me snackless two or three hours after a meal… I don't know how I made it through 7-8 hours of sleep… I personally happen to do better eating a bit more fat, though I'm rarely VLC outside fasting days. I do eat bananas, rice, and potatoes. Yes, it's true.
But what does the literature say? Well, let me begin with a very pleasantly retro article from the halcyon days of 1966, when they believed in hypoglycemia outside of insulin tumors and diabetes - tweeted to me by @ambimorph: Relative Hypoglycemia as a Cause of Neuropsychiatric Illness.
This paper defines "relative hypoglycemia" as my doctor did back in the late 90s - a drop in blood sugar that occurs after eating like a jerk - lots of caffeine or sugar. Apparently the people of the early 20th century suffered from this condition, which was misdiagnosed sometimes as a brain tumor, diabetes, or cerebrovascular problems, but when you stop eating like a jerk and consume some protein, fat, and get rid of the caffeine and alcohol, your symptoms go away.
In 1966 Dr. Salzer found that:
Well. That sounds really bad. It sure does sound like sugar (and caffeine) can make you pretty crazy. And when I (personally) was pregnant, I did suffer from some frank neurologic symptoms related to hypoglycemia (despite the fact that I was eating like Michael Pollan told me to, not like a jerk) - true vertigo, headaches, severe nausea… the thing was, it was all pretty much instantly cured by eating some instant mashed potato flakes. Which is why I know I did not have a brain tumor (not typically responsive to mashed potato therapy). In the modern emergency room we have dextrose IV drips, ginger ale, and instant glucometer measures. I think perhaps that put the end to the mysterious hypoglycemia masking as a brain tumor era of medicine.
Next time… a discussion of carbohydrates and mood, from the literature. And a review of the relationship between blood sugar in mood in folks with diabetes, insulin resistance, and women with PCOS.
(Music selection - Serenade in E Major (right click to open in new tab) by Dvorak, who happened to write what is widely accepted as the most exalted piece of American classical music, though he is in fact from
I think pretty much everyone has heard of these ideas - most recently I saw them in an article I linked a little while ago, "How I Overcame Bipolar II (and Saved My Own Life)" by Michael Ellsberg. Here is a quote from the article:
Dr. Hoffman told me there is mounting clinical evidence linking mood swings to blood sugar issues, and that in his experience bipolar patients respond well to cutting out refined sugar, and coffee and alcohol (which affect blood sugar) from their diets. “You should stop eating refined sugar altogether, and stop drinking alcohol and coffee,” he told me.Apparently, Mr. Ellsberg went to a psychiatrist also:
I asked the psychiatrist I was seeing at the time whether he thought there was any link between nutrition and mental health. He looked at me as though I had just asked whether there was any link between mental health and UFO rectal probes. “There is absolutely no evidence of any link whatsoever between dietary choices and mental health,” he said curtly, and changed the subject.Besides my wacky UFO rectal probe blog, on the paleo mental health side of things we have Nora Gedgaudas, who has just released an updated version of Primal Body, Primal Mind. I have read her book, and though I did not attend her talk at AHS, from my memory of her book and the coverage of that talk, it seems to me she advocates a very low carbohydrate approach, that in effect we are either fat burners or sugar burners, and fat burners are steady and serene, while sugar burners are moody and cranky. (Nora herself! clarifies her very reasonable position in the comments below - in short, her clinical experience has shown her that limiting sugars and starches for most people has been very helpful.)
Then we have the opposite side of the argument, personified by rodent and women's health researcher Judith Wurtman at MIT, and paleo blogger Don Matesz - carbs improve and are essential for good mood, particularly in the case of PMS, atypical depression, and seasonal affective disorder.
What did I learn in psychiatry residency? Well, that the ideas about sugar causing ADHD were unfounded, and that carbohydrates in general wouldn't be an issue plus or minus unless one had uncontrolled diabetes, in which case, of course, uncontrolled glucose swings could cause all sorts of craziness. Diabetes is one of those conditions we are supposed to rule out before spending 20 hours talking to someone about his or her mother, or prescribing Prozac.
So whom do we believe? Orthomolecular Dr. Hoffman? The Harvard Longwood Psychiatry Residency Training Program? Nora Gedgaudas? Parents who have observed their kids after a party with CAKE and ICE CREAM and FACE-PAINTING FAIRY PRINCESSES? (I'm going to tell you right now that the kids totally spaz out for several hours and then collapse in a twitching exhausted heap of sugar/princess withdrawal. The confounders are many, I must admit).
What have I learned from Gary Taubes and Peter and Kurt? Don't believe anyone. Look it up your own self, and see if it makes sense in the context of physiology and evolution. But y'all know me at this point - let's put aside the issue of metabolic syndrome for a second. Most hunter gatherer societies that I'm aware of ate starch when they could get their hands on it, so it doesn't make sense to me that carbohydrates alone would cause craziness. (We will also leave out alcohol and caffeine which Dr. Hoffman wisely recommends bipolar folks to avoid - both of which will affect SLEEP as well as sugar levels, an obvious confounder in bipolar disorder).
And yet, here on my blog and twitter and elsewhere I've seen reports of folks who feel so much better on VLC diets, and others who feel so much better with zone-ish ratios, and others who do better with more carbohydrates. My own experience (now documented in several podcasts) is that I had hypoglycemia in my late teens and early twenties. Of course, I never got an official diagnosis of hypoglycemia, because that doesn't exist outside the context of diabetes or an insulin overdose or insulin-secreting tumor. If I ate super low fat and high carb, I would get shaky, weak, and cranky about 90 minutes after my last meal. When I called the doctor about it, I was checked for diabetes (negative), and then I was told not to eat like a jerk. (Okay, some days I would eat raspberry fig newtons for lunch and dinner, and I was known to eat an entire package of Peeps from time to time - hey, I was 18.) Eat nuts and avoid sugar, sodas, alcohol, and honey, they told me. Eat snacks. And I was careful from then on out to not be such a jerk about eating and to have snacks - packages of peanuts, apples and string cheese, graham crackers stuffed in my bag - and woe befell anyone in my presence who found me snackless two or three hours after a meal… I don't know how I made it through 7-8 hours of sleep… I personally happen to do better eating a bit more fat, though I'm rarely VLC outside fasting days. I do eat bananas, rice, and potatoes. Yes, it's true.
But what does the literature say? Well, let me begin with a very pleasantly retro article from the halcyon days of 1966, when they believed in hypoglycemia outside of insulin tumors and diabetes - tweeted to me by @ambimorph: Relative Hypoglycemia as a Cause of Neuropsychiatric Illness.
This paper defines "relative hypoglycemia" as my doctor did back in the late 90s - a drop in blood sugar that occurs after eating like a jerk - lots of caffeine or sugar. Apparently the people of the early 20th century suffered from this condition, which was misdiagnosed sometimes as a brain tumor, diabetes, or cerebrovascular problems, but when you stop eating like a jerk and consume some protein, fat, and get rid of the caffeine and alcohol, your symptoms go away.
In 1966 Dr. Salzer found that:
…patients with relative hypoglycemia have been diagnosed as having psychoneurotic anxiety, psychoneurotic depression, depressive reactions, schizophrenia, manic-depressive psychosis, psychopathic personality, chronic alcoholism, convulsive disorders, migraine, idiopathic cephalalgia, second cervical root syndrome, neurodermatitis, and even hypertensive cardiovascular disease... Major symptoms from a psychiatric standpoint are depression, insomnia, anxiety, irritability, lack of concentration, crying spells, phobias, forgetfulness, confusion… antisocial behavior, and suicidal tendencies… The major neurological symptoms are headache, dizziness, inward and external tremulousness, numbness, blurred vision, staggering, fainting or blackouts, and muscular twitching...There are also extensive somatic symptoms as follows: exhaustion, fatigue, sweating, anorexia, tachycardia, cold hands and feet, obesity, chronic indigestion, bloating, abdomnial spasm, muscle and joint pains, backache, muscle cramps, colitis, and convulsions.
Well. That sounds really bad. It sure does sound like sugar (and caffeine) can make you pretty crazy. And when I (personally) was pregnant, I did suffer from some frank neurologic symptoms related to hypoglycemia (despite the fact that I was eating like Michael Pollan told me to, not like a jerk) - true vertigo, headaches, severe nausea… the thing was, it was all pretty much instantly cured by eating some instant mashed potato flakes. Which is why I know I did not have a brain tumor (not typically responsive to mashed potato therapy). In the modern emergency room we have dextrose IV drips, ginger ale, and instant glucometer measures. I think perhaps that put the end to the mysterious hypoglycemia masking as a brain tumor era of medicine.
Next time… a discussion of carbohydrates and mood, from the literature. And a review of the relationship between blood sugar in mood in folks with diabetes, insulin resistance, and women with PCOS.
Friday, August 27, 2010
Ketogenic Diets and Bipolar Disorder 2
Yesterday I made a brief introduction to the topic of ketogenic diets and bipolar disorder. Today I want to discuss some of the issues raised in that post a little more thoroughly.
First let's talk a bit about how nerves work. It's pretty cool, really, but involves a little biochem and physics, so bear with me. Now a picture, courtesy the US government and wikipedia:
Nerve impulses and signals travel along the nerve fibers via electricity. How that happens is that the extracellular levels of ions and the intracellular levels of ions are maintained at a very different level. Inside neurons, the sodium concentration is about 10mM, but outside, it is 130mM or more - rather like there are a bunch of balls stored in a container on top of a hill. Open a little door on the side of the container, and the balls come pouring out and down the hill. Potassium is the opposite - levels are very high inside the cells, and quite low outside (1).
Neurons have plasma membranes like other cells in our bodies. Those membranes are somewhat like a tarp that has been oiled on both sides. Charged ions such as sodium and potassium can't get through unless they go through special ion pumps that are located in the cell membranes. The sodium pump, in fact, may use up to 50% of the energy in our brains (2)!
The result of all these shenanigans is that our nerve cell membranes are left somewhat negatively charged (-75 mV, in fact). The neurotransmitters (such as serotonin, norepinephrine, dopamine, acetylcholine, glutamate, GABA, etc.) work by changing these membrane potentials in various ways. Neurotransmitters can open ion channels, allowing sodium to enter the cell and causing a wave of electrical impulse that travels along the neuron. Neat!
When the electrical impulse (or "action potential") reaches the end of the neuron, the "presynaptic terminal," neurotransmitters are released into the space between the nerve cells, called the synapse. At this part of the neuron, calcium is the important ion (though sodium plays a role too). The electrical impulse (originally mediated by sodium at the dendrite) that traveled down the nerve causes extracellular calcium to pour into the cell, which then leads to the release of the neurotransmitters into the synapse, which then can affect communication with the next neuron. Voila! Your neurons have now sent messages to one another. Yee haw. The sodium and calcium membrane potential craziness can be set back to baseline by the transport of potassium, so everything is all set for a new signal to be sent.
It's Friday. I know. But it's important to understand the above to some extent to understand why a ketogenic diet might change the ionic environment in our brains.
Before we get to a ketogenic diet, let's look at lithium, carbamazepine, and valproic acid (depakote), all medications that have anti-seizure and mood stabilizing properties. Lithium is especially interesting, because, if you recall, it looks a lot like sodium, so much so that our kidneys can become confused. Seems our brains can too. In rats treated with lithium, the lithium displaces the intracellular sodium in the neurons, and overall sodium is decreased. The changed sodium gradient may be central to the mood-stabilizing effects of lithium. (You doctors out there will be squinting at me right now - hey, lithium isn't an anti-seizure med! Well, actually, it used to be used as one. Most psychiatrists will know that we can get away with somewhat lower doses of many medicines for mood control than neurologists need for seizures - an exception to this is depakote - sometimes. Lithium can be horribly toxic at levels high enough needed to control seizures, so it is never used for seizures now. But it does have anti-seizure potential.) Carbamazepine is a little mysterious, but one of its effects is to definitely inhibit the voltage-sensitive sodium channels. (Lamotrigine, another anti-seizure and mood stabilizing drug, does something very similar). Valproic acid (depakote) has a whole load of actions, and can increase GABA, making it a pretty good anti-anxiety med. Another thing it does is to decrease the rapid-fire ability of the spazziest neurons, probably by inhibiting the sodium channels.
Get the picture here? All these meds can be life-saving if you have bad bipolar disorder or seizures, but they can all be pretty toxic and have a host of side effects. But all of them work (effectively) as insulators in the brain, decreasing the ability of the neurons to send out out-of whack sodium messages leading to neurotoxic calcium overload. This calcium overload is speculated to be the cause not only of seizures, but also migraines and bipolar symptoms, which is why anti-seizure meds can be used to treat all three conditions.
Enter the ketogenic diet. Ketogenic diets (severely carbohydrate restricted diets) result in ketone bodies (made from fat) being used by the brain as fuel in lieu of glucose. The ketone bodies, acetoacetate and beta-hydroxybutyrate, are acidic. That simply means that there will be extra H+ protons hanging out, compared to a non-ketotic brain. Well, protons can be pumped into neurons in exchange for sodium, acting a little bit like lithium. And a few extra protons outside the cell do all sorts of interesting things, such as reduce the excitability of the neurons and reduce the activity of the excitatory neurotransmitters. Protons seem to block the calcium channels at the NMDA receptors, for example (3). GABA (the inhibitory neurotransmitter and anti-seizure also) is increased in the brain in ketogenic diets, along with many other neurotransmitter changes (4)
Sounds good! Well, some intrepid doctors in Israel had a bipolar patient who didn't respond that well to medication, and after discussion with the patient and family, it was decided to try a ketogenic diet (5). The patient fasted for 48 hours and began what is described as a "classic" ketogenic diet for two weeks. Oddly, she didn't have any urinary ketones. After two weeks, the doctors added MCT oil (coconut maybe? It doesn't specify), which low-carbers will also know can induce a more reliable ketogenic state. The patient was pretty gung-ho on the diet, and the doctors made note that her compliance was good for the month the diet was tried. She showed no clinical improvement, no loss of weight, no urinary ketosis, and no changes in liver function. Seems odd that she wouldn't get ketosis while fasting or on a strict ketogenic diet, but perhaps that's why it didn't work. I'll discuss a second case below.
On the internet, one can find a number of anecdotes about people improving bipolar symptoms with ketogenic or low carb diets. But, as I mentioned yesterday, there are absolutely no systematic scientific studies. The last thing you would want to do is, all on your own, ditch your meds and try a home-made ketogenic diet without anyone's help. Ketogenic diets can have pretty bad side effects - constipation, menstrual irregularities, elevated serum cholesterol (if you care) and triglycerides (not good), hemolytic anemia, elevated liver enzymes, kidney stones, and gall stones. Up to 15% of kids on a ketogenic diet will get changes in the heart conduction which puts them at higher risk for death (again, this was thought to be mediated via selenium deficiency). Valproic acid + ketogenic diet seemed to worsen the side effects (6). Now some of these ketogenic diet studies were done at the height of the low-fat era, and likely designed by some pretty lipophobic nutritionists. And, like Atkins, many of the original ketogenic diets will have no regard for the omega6:omega3 ratio. Here's a case where Atkins made manic psychosis a lot worse - I wonder about that, as arachadonic acid (omega 6 metabolite) administration has also been shown to worsen psychosis. In that case, the patient was on valproic acid also, and that may have been part of the problem. A natural sort of ketogenic diet (think Inuit) would probably have a lot fewer of these complications and side effects.
But it makes you think, doesn't it? Many of our ancestors probably spent many a winter in ketosis, and other times lack of food or long fasts would have brought on brief periods of ketone body use in the brain too. Maybe our brains work better if we spend time in ketosis. Speculation, of course, but not an unimportant question to research further.
First let's talk a bit about how nerves work. It's pretty cool, really, but involves a little biochem and physics, so bear with me. Now a picture, courtesy the US government and wikipedia:
Nerve impulses and signals travel along the nerve fibers via electricity. How that happens is that the extracellular levels of ions and the intracellular levels of ions are maintained at a very different level. Inside neurons, the sodium concentration is about 10mM, but outside, it is 130mM or more - rather like there are a bunch of balls stored in a container on top of a hill. Open a little door on the side of the container, and the balls come pouring out and down the hill. Potassium is the opposite - levels are very high inside the cells, and quite low outside (1).
Neurons have plasma membranes like other cells in our bodies. Those membranes are somewhat like a tarp that has been oiled on both sides. Charged ions such as sodium and potassium can't get through unless they go through special ion pumps that are located in the cell membranes. The sodium pump, in fact, may use up to 50% of the energy in our brains (2)!
The result of all these shenanigans is that our nerve cell membranes are left somewhat negatively charged (-75 mV, in fact). The neurotransmitters (such as serotonin, norepinephrine, dopamine, acetylcholine, glutamate, GABA, etc.) work by changing these membrane potentials in various ways. Neurotransmitters can open ion channels, allowing sodium to enter the cell and causing a wave of electrical impulse that travels along the neuron. Neat!
When the electrical impulse (or "action potential") reaches the end of the neuron, the "presynaptic terminal," neurotransmitters are released into the space between the nerve cells, called the synapse. At this part of the neuron, calcium is the important ion (though sodium plays a role too). The electrical impulse (originally mediated by sodium at the dendrite) that traveled down the nerve causes extracellular calcium to pour into the cell, which then leads to the release of the neurotransmitters into the synapse, which then can affect communication with the next neuron. Voila! Your neurons have now sent messages to one another. Yee haw. The sodium and calcium membrane potential craziness can be set back to baseline by the transport of potassium, so everything is all set for a new signal to be sent.
It's Friday. I know. But it's important to understand the above to some extent to understand why a ketogenic diet might change the ionic environment in our brains.
Before we get to a ketogenic diet, let's look at lithium, carbamazepine, and valproic acid (depakote), all medications that have anti-seizure and mood stabilizing properties. Lithium is especially interesting, because, if you recall, it looks a lot like sodium, so much so that our kidneys can become confused. Seems our brains can too. In rats treated with lithium, the lithium displaces the intracellular sodium in the neurons, and overall sodium is decreased. The changed sodium gradient may be central to the mood-stabilizing effects of lithium. (You doctors out there will be squinting at me right now - hey, lithium isn't an anti-seizure med! Well, actually, it used to be used as one. Most psychiatrists will know that we can get away with somewhat lower doses of many medicines for mood control than neurologists need for seizures - an exception to this is depakote - sometimes. Lithium can be horribly toxic at levels high enough needed to control seizures, so it is never used for seizures now. But it does have anti-seizure potential.) Carbamazepine is a little mysterious, but one of its effects is to definitely inhibit the voltage-sensitive sodium channels. (Lamotrigine, another anti-seizure and mood stabilizing drug, does something very similar). Valproic acid (depakote) has a whole load of actions, and can increase GABA, making it a pretty good anti-anxiety med. Another thing it does is to decrease the rapid-fire ability of the spazziest neurons, probably by inhibiting the sodium channels.
Get the picture here? All these meds can be life-saving if you have bad bipolar disorder or seizures, but they can all be pretty toxic and have a host of side effects. But all of them work (effectively) as insulators in the brain, decreasing the ability of the neurons to send out out-of whack sodium messages leading to neurotoxic calcium overload. This calcium overload is speculated to be the cause not only of seizures, but also migraines and bipolar symptoms, which is why anti-seizure meds can be used to treat all three conditions.
Enter the ketogenic diet. Ketogenic diets (severely carbohydrate restricted diets) result in ketone bodies (made from fat) being used by the brain as fuel in lieu of glucose. The ketone bodies, acetoacetate and beta-hydroxybutyrate, are acidic. That simply means that there will be extra H+ protons hanging out, compared to a non-ketotic brain. Well, protons can be pumped into neurons in exchange for sodium, acting a little bit like lithium. And a few extra protons outside the cell do all sorts of interesting things, such as reduce the excitability of the neurons and reduce the activity of the excitatory neurotransmitters. Protons seem to block the calcium channels at the NMDA receptors, for example (3). GABA (the inhibitory neurotransmitter and anti-seizure also) is increased in the brain in ketogenic diets, along with many other neurotransmitter changes (4)
Sounds good! Well, some intrepid doctors in Israel had a bipolar patient who didn't respond that well to medication, and after discussion with the patient and family, it was decided to try a ketogenic diet (5). The patient fasted for 48 hours and began what is described as a "classic" ketogenic diet for two weeks. Oddly, she didn't have any urinary ketones. After two weeks, the doctors added MCT oil (coconut maybe? It doesn't specify), which low-carbers will also know can induce a more reliable ketogenic state. The patient was pretty gung-ho on the diet, and the doctors made note that her compliance was good for the month the diet was tried. She showed no clinical improvement, no loss of weight, no urinary ketosis, and no changes in liver function. Seems odd that she wouldn't get ketosis while fasting or on a strict ketogenic diet, but perhaps that's why it didn't work. I'll discuss a second case below.
On the internet, one can find a number of anecdotes about people improving bipolar symptoms with ketogenic or low carb diets. But, as I mentioned yesterday, there are absolutely no systematic scientific studies. The last thing you would want to do is, all on your own, ditch your meds and try a home-made ketogenic diet without anyone's help. Ketogenic diets can have pretty bad side effects - constipation, menstrual irregularities, elevated serum cholesterol (if you care) and triglycerides (not good), hemolytic anemia, elevated liver enzymes, kidney stones, and gall stones. Up to 15% of kids on a ketogenic diet will get changes in the heart conduction which puts them at higher risk for death (again, this was thought to be mediated via selenium deficiency). Valproic acid + ketogenic diet seemed to worsen the side effects (6). Now some of these ketogenic diet studies were done at the height of the low-fat era, and likely designed by some pretty lipophobic nutritionists. And, like Atkins, many of the original ketogenic diets will have no regard for the omega6:omega3 ratio. Here's a case where Atkins made manic psychosis a lot worse - I wonder about that, as arachadonic acid (omega 6 metabolite) administration has also been shown to worsen psychosis. In that case, the patient was on valproic acid also, and that may have been part of the problem. A natural sort of ketogenic diet (think Inuit) would probably have a lot fewer of these complications and side effects.
But it makes you think, doesn't it? Many of our ancestors probably spent many a winter in ketosis, and other times lack of food or long fasts would have brought on brief periods of ketone body use in the brain too. Maybe our brains work better if we spend time in ketosis. Speculation, of course, but not an unimportant question to research further.
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