After putting up yesterday's post about the strong link between depression and fructose malabsoprtion in women (and adolescents), my mind continued to spin for a while. And I woke up this morning with more questions. If you haven't read that post, you probably should before diving into this one, as it won't make nearly as much sense without the initial information.
First of all, the estrogen link. The study noted that none of the participants were on prescription medicines except oral contraceptives. Oral contraceptives have widely varying amounts of estrogen, but the study probably would have been too small to have detected a lot of difference. It makes one wonder. They also postulated that fructose malabsorption would make premenstrual dysphoria worse, again using the explanation that estrogen's effect on the liver makes the already low amount of tryptophan made into serotonin even lower. However, progesterone is the more likely culprit in premenstrual dysphoria, and depression is a well-known side effect of progesterone-only birth control methods. Look at the hormone levels in this diagram of the menstrual cycle - while estrogen is higher in the second half of the month, when premenstrual dysphoria is likely to occur, it really only spikes just before ovulation, in the middle of the month. Progesterone is quite low at the beginning, and then rises to steady levels for much of the last part of the cycle, until it drops again. Progesterone is also involved in the metabolism of serotonin and dopamine, so it could all be related.
Secondly - I had no idea that fructose malabsorption was so common. When I've seen notes or mentions of it around the internet, I had a mental note in my head - "rare" - and I must have been thinking of hereditary fructose intolerance, which can cause liver damage and is quite rare. Probably not much was known about fructose malabsorption when I was in medical school, or I would have remembered it. I mean, everyone knows about lactose intolerance, after all. But the fact that fructose malabsorption is so common could explain quite a bit about the increasing prevalence and changing symptoms of depression these days. Sure, the studies were small, but the effects of the carbohydrate malabsorption were quite large, which means that there's a good chance the data is meaningful. A lot of people (men and women) now have signs of "atypical" depression that is characterized by weight gain, fatigue, and prominent carbohydrate cravings. Low levels of serotonin are thought to trigger carbohydrate cravings, as carbohydrate is thought to increase serotonin levels in the brain. An unprecedented change in our Western diets has made high-fructose foods readily available year-round, something that was never possible before industrialization. So we have fructose-malabsorbers with depleted serotonin craving carbs, munching on sugary foods, leading to more cravings, and a vicious cycle ensues. Adolescents may be more vulnerable, as they are probably the most likely to have a free fructose-laden diet.
When I discussed the changes in depression symptoms from classical melancholia to the modern, atypical presentation, I had pointed the finger at the omega 6 fatty acids, which may also be involved. But fructose could be a very common factor - ironically, the fructose which is not absorbed is the problem! I wish I knew how common fructose malabsorption is in ethnic groups besides central Europeans. Forget straight-up zinc deficiency and the exorphins in wheat causing schizophrenia - those are relatively rare and cannot explain the recent huge changes and increases in depression and mental illness. But fructose malabsorption has the potential to be a huge factor for a good many people - if the 1/3 prevalence holds true for the American population, that's 100 million people. Even if it is much higher in those of central European descent, the fact that other ethnic groups have some of it still means millions and millions of people in the U.S. alone.
And now a bit more about fructose malabsorption, also from one of Jad's helpful references, "Fructose Malabsorption and Symptoms of Irritable Bowel Syndrome: Guidelines for Effective Dietary Management."
Fructose is found in three forms in the diet - as free fructose (in fruits, honey, high fructose corn syrup, agave nectar, etc.), as part of the disaccharide sucrose (glucose+fructose), and also as a polymer known as a fructan (found in wheat and some vegetables).
Turns out that the other constituents of our diets affect how well we can absorb fructose too. Glucose helps us absorb fructose, for example, as does the amino acid alanine. In moderate amounts, people with IBS symptoms and fructose malabsoprtion didn't get symptoms when they ate sucrose or balanced fructose/glucose mixes. But in immoderate amounts ("greater than 375 ml of sucrose-sweetened soda" was an example in the paper), even sucrose could cause symptoms.
So what exactly was the recommended diet (which was quite effective for the IBS symptoms, according to the study)?
Patients were advised to avoid the following foods which had an imbalance of fructose compared to glucose:
Apple, pear, guava, melon, mango, papaya, watermelon, star fruit
Honey
Anything with the following major sweetening ingredients: HFCS, corn syrup solids, fructose, and fruit juice concentrate
Also avoid the following foods which have a large fructose load (>3 grams per serving), balanced with sucrose or not:
Most dried fruits, especially apple, apricot, dates, raisins, pear, figs, and prunes
Fruit juice, canned packing juice
Fruit sauces (including tomato paste, chutney, relish, plum sauce, sweet and sour sauce, and BBQ sauce)
High sugar fruits (cherry, grapes, persimmon, lychee, apple, pear, watermelon
Coconut milk and cream (surely they mean sweetened coconut milk and cream - my can of 365 Coconut milk has only 2g of carbohydrate total per serving, and 1g of sugar)
Fortified wines such as sherry and port
> 375 ml of sucrose sweetened soft drink
"excessive intake" of confectionery.
For these items, the patients were advised to substitute apricots, nectarines, peaches, pluma, berries, citrus, ripe banana, and other fruits which have more glucose or equal glucose to fructose. They could also consume glucose powder or glucose-sweetened sports drink to balance out a fructose load. (In this paper, substitution was emphasized rather than avoidance of whole food groups, in order to prevent nutritional deficiencies or some such. One wouldn't want to do something scary like eat more fat in lieu of pasta, high-fructose fruits, and bread after all!).
Now the fructans - the most problematic ones (to be avoided) are:
Flour
White bread
Pasta
Whole-grain breakfast cereal
muffins
crumpets (Australian study!)
crackers
cookies
leeks
jerusalem artichoke
onions (less of a fructan effect than the others)
asparagus (ditto for onions)
(I'm leaving out chicory root and some other rare foods - best you get the paper and see for yourself the complete list)
Again, the patients were encouraged to substitute - rye bread or gluten free bread, gluten-free pasta and rice and crackers, maple syrup, gluten-free cookies, etc. And after 2-40 months on the diet, 77% adhered to the diet most of the time, or frequently. 85% of the adherent folks had substantial improvement in IBS symptoms, whereas 36% of the nonadherers had improvement. As this was a dietary study for IBS sufferers with a positive test for fructose malabsorption, depression scales were not administered. It would have been nice if the researchers threw a couple in there, though, right?
Please check out Jamie's post on FODMAPS for even more information, and paleo-style avoidance of fructose and fructans.
Final food for thought - for most people, the vegetable fructans (jerusalem artichokes, onions, leeks, and asparagus) are thought to aid our health by feeding our bacteria a short-chain fatty acid, butyrate, which somehow decreases the permeability of the gut. One can also get butyrate from eating butter. (edited to say - sorry - meant the opposite - the fructans are transformed from the oligosaccharides to the short chain fatty acids by the good bugs. Thanks Avocado!)
Saturday, August 7, 2010
Friday, August 6, 2010
IBS, Fructose, Depression, Zinc, and Women
Reader Jad left some terrific references in a comment last week, and having printed the papers up (I'm old-fashioned that way), I finally got a chance to look them over.
Whoa.
But before we get to that, right click on this youtube video for an incredible performance of the finale to Britten's "The Young Person's Guide to the Orchestra." If you have three minutes, take the time to watch. If you only have a minute, skip to 1:50, which is the part that always gives me chills. By "incredible performance," I mean this is literally one of the best orchestral renditions I've ever heard of any song. The Berlin Philharmonic hit it out of the park. And check out how good they look! Most of the musicians are middle aged, but I see scarcely a paunch among them - as near as I can tell, this was recorded around 6 months ago. Maybe it's because they are European. I've heard that concert musicians are less prone to chronic metabolic illness, but I've never seen any scientific proof of that.
Jad's papers (1)(2) also take us to Central Europe, where apparently a huge percentage (30-50%) of the population suffers from certain kinds of carbohydrate malabsorption (3). In the fructose variety, the GLUT5 transporter in the small intestine doesn't take up fructose as it should, so lots of undigested fructose floats down to the colon, feeding the bacteria there and leading to bloating, cramping, and diarrhea - basically the symptoms of irritable bowel. It's diagnosed via testing for excess hydrogen in the exhaled breath after a fructose load of 50mg. A similar test can show if someone has lactose intolerance.
Well, the researchers took a hundred or so "otherwise healthy volunteers" who had complained about gastrointestinal distress at a doctor's visit. None were on medication (except oral contraception) or had any signs of chronic or serious illness. They were given a standard scale test for depression (the Beck Depression Inventory) a fructose malabsorption test, then, a week later, a lactose malabsorption test.
Let's cut to the chase - a positive test for fructose malabsorption corresponded to depressed women, but not men. Lactose malabsorption alone didn't matter in either sex, but the 12% of women in the study who were both fructose and lactose malabsorption positive were by far the most depressed. The normal female controls had an average depression score of 7.5 - the combined malabsorption women had an average score of 14.6. That's a huge difference, and the bars hardly overlap at all.
Wow.
Well, why would that be?
Turns out that fructose (and lactose) can react chemically with tryptophan, the amino acid precursor for our important happy chemical, serotonin. The sugars can degrade tryptophan so that there isn't as much available to be absorbed into the body. And, indeed, fructose malabsorbers have lower levels of tryptophan in the serum than normal controls (4). And, hey, turns out they have lower serum zinc and folic acid too! (5)(6).
But why would the symptoms of depression be confined to women? The researchers postulated that estrogen made the big difference. Estrogen activates an enzyme called hepatic tryptophan 2,3 dioxygenase that shifts the metabolism of tryptophan from making serotonin (happy) to making kynurenic (not happy). Women already have lower serum levels of tryptophan than men do (which may be part of the reason why we are more vulnerable to depression in the first place), so screwing up whatever available tryptophan in the diet with fructose may lead to even lower levels, and thus depression.
The researchers couldn't figure out why the combination of fructose and lactose malabsorption was worse than fructose alone - they thought maybe the diarrhea from lactose intolerance would interfere with the absorption of zinc and tryptophan, worsening the fructose situation. Since fructose malabsorption was so common in the population they studied, only a few people had isolated lactose intolerance, and they felt the data set wasn't big enough to figure out the lactose component.
It's also important to note that wheat products contain fructans, which can also cause intestinal problems in fructose malabsorbers. Bread with high fructose corn syrup can be especially problematic.
One more snippet - it seems that fructose malabsorption can affect serum zinc in two ways. First, it seems to interfere with the ability of the intestine to take up zinc in the first place. Second, fructose malabsorption is associated with bacterial overgrowth in the large intestine, which is associated with chronic immune stimulation (shown by higher serum neopterin concentrations)(5). As we know, inflammation likely causes us to sequester our zinc.
1/3 of the Western European population has fructose malabsorption. These Michigan researchers found fructose malabsorption in kids of many ethnic groups. Spanish investigators found in a small study that 71% of the depressed adolescents they studied had sugar intolerance, compared to 15% of controls, and that 28% of their known fructose/lactose malabsorbers had depression, which was a higher rate than expected in that population.
Sounds like yet another excuse to get anyone with depression and IBS off fructose and wheat for a while just to see what happens. Actually, one of the papers above suggested that only half of fructose malabsorbers diagnosed by the hydrogen breath test actually have gastrointestinal symptoms. Heck, let's get everyone off wheat and fructose and see what happens :)
Thanks, Jad!
(please see my next post, Dietary Strategies for Fructose Malabsorption for more information on this topic)
Whoa.
But before we get to that, right click on this youtube video for an incredible performance of the finale to Britten's "The Young Person's Guide to the Orchestra." If you have three minutes, take the time to watch. If you only have a minute, skip to 1:50, which is the part that always gives me chills. By "incredible performance," I mean this is literally one of the best orchestral renditions I've ever heard of any song. The Berlin Philharmonic hit it out of the park. And check out how good they look! Most of the musicians are middle aged, but I see scarcely a paunch among them - as near as I can tell, this was recorded around 6 months ago. Maybe it's because they are European. I've heard that concert musicians are less prone to chronic metabolic illness, but I've never seen any scientific proof of that.
Jad's papers (1)(2) also take us to Central Europe, where apparently a huge percentage (30-50%) of the population suffers from certain kinds of carbohydrate malabsorption (3). In the fructose variety, the GLUT5 transporter in the small intestine doesn't take up fructose as it should, so lots of undigested fructose floats down to the colon, feeding the bacteria there and leading to bloating, cramping, and diarrhea - basically the symptoms of irritable bowel. It's diagnosed via testing for excess hydrogen in the exhaled breath after a fructose load of 50mg. A similar test can show if someone has lactose intolerance.
Well, the researchers took a hundred or so "otherwise healthy volunteers" who had complained about gastrointestinal distress at a doctor's visit. None were on medication (except oral contraception) or had any signs of chronic or serious illness. They were given a standard scale test for depression (the Beck Depression Inventory) a fructose malabsorption test, then, a week later, a lactose malabsorption test.
Let's cut to the chase - a positive test for fructose malabsorption corresponded to depressed women, but not men. Lactose malabsorption alone didn't matter in either sex, but the 12% of women in the study who were both fructose and lactose malabsorption positive were by far the most depressed. The normal female controls had an average depression score of 7.5 - the combined malabsorption women had an average score of 14.6. That's a huge difference, and the bars hardly overlap at all.
Wow.
Well, why would that be?
Turns out that fructose (and lactose) can react chemically with tryptophan, the amino acid precursor for our important happy chemical, serotonin. The sugars can degrade tryptophan so that there isn't as much available to be absorbed into the body. And, indeed, fructose malabsorbers have lower levels of tryptophan in the serum than normal controls (4). And, hey, turns out they have lower serum zinc and folic acid too! (5)(6).
But why would the symptoms of depression be confined to women? The researchers postulated that estrogen made the big difference. Estrogen activates an enzyme called hepatic tryptophan 2,3 dioxygenase that shifts the metabolism of tryptophan from making serotonin (happy) to making kynurenic (not happy). Women already have lower serum levels of tryptophan than men do (which may be part of the reason why we are more vulnerable to depression in the first place), so screwing up whatever available tryptophan in the diet with fructose may lead to even lower levels, and thus depression.
The researchers couldn't figure out why the combination of fructose and lactose malabsorption was worse than fructose alone - they thought maybe the diarrhea from lactose intolerance would interfere with the absorption of zinc and tryptophan, worsening the fructose situation. Since fructose malabsorption was so common in the population they studied, only a few people had isolated lactose intolerance, and they felt the data set wasn't big enough to figure out the lactose component.
It's also important to note that wheat products contain fructans, which can also cause intestinal problems in fructose malabsorbers. Bread with high fructose corn syrup can be especially problematic.
One more snippet - it seems that fructose malabsorption can affect serum zinc in two ways. First, it seems to interfere with the ability of the intestine to take up zinc in the first place. Second, fructose malabsorption is associated with bacterial overgrowth in the large intestine, which is associated with chronic immune stimulation (shown by higher serum neopterin concentrations)(5). As we know, inflammation likely causes us to sequester our zinc.
1/3 of the Western European population has fructose malabsorption. These Michigan researchers found fructose malabsorption in kids of many ethnic groups. Spanish investigators found in a small study that 71% of the depressed adolescents they studied had sugar intolerance, compared to 15% of controls, and that 28% of their known fructose/lactose malabsorbers had depression, which was a higher rate than expected in that population.
Sounds like yet another excuse to get anyone with depression and IBS off fructose and wheat for a while just to see what happens. Actually, one of the papers above suggested that only half of fructose malabsorbers diagnosed by the hydrogen breath test actually have gastrointestinal symptoms. Heck, let's get everyone off wheat and fructose and see what happens :)
Thanks, Jad!
(please see my next post, Dietary Strategies for Fructose Malabsorption for more information on this topic)
Thursday, August 5, 2010
A History of Eating Disorders
The first descriptions of anorexia nervosa in the Western world date from the 12th and 13th centuries, most famously Saint Catherine of Siena (1), who denied herself food as part of a spiritual denial of self. By the sixteenth century, ascetics were considered witches and burned at the stake. There are several other clinical descriptions of "wasting disease" in the 17th-19th century, and in the early 20th century, anorexia was considered an endocrine disorder and treated with pituitary hormones. In 1973, Hilde Bruch published a book with a number of case studies, called Eating Disorders: Obesity, Anorexia Nervosa, And The Person Within
. As the disorder reached public awareness in the 1970s, cases increased, spreading beyond the upper class.
Bulimia (binging and then purging via exercise, vomiting, or laxatives) is first reliably described among some of the wealthy in the Middle Ages, who would vomit during meals so they could consume more (2). (Apparently this behavior did not happen in ancient Rome despite a common conception otherwise (3)). The first clinical paper on bulimia came in 1979 - Bulimia nervosa, an ominous variant of anorexia nervosa.
Everyone agrees that the cases of anorexia and bulimia escalated in the 1970s and 1980s, and though some will say they peaked in that time, the national survey data suggests that bulimia, especially, continues to escalate. While most scholars will point to cultural pressures for thinness, increasing depression and obsessive compulsive behavior, and increased dieting behaviors as precipitants for eating disorders, it is impossible to ignore the fact that the 1970s and 80s is when the rates of obesity in the United States began to increase at an unprecedented rate, and low fat eating began its popular progression through the mainstream.
There is a third eating disorder, binge eating disorder, where periodic food binges are not compensated by restricting or purging behavior. While many obese people eat normally, binge eaters will consume up to tens of thousands of calories in a singe day, entire bags of candy, or dinner from five or six fast food restaurants, one after the other. Again this disorder has been described for centuries, but seems to have escalated only recently (4).
All eating disorders remain relatively rare. Anorexia afflicts about 0.5% of women and 0.1% of men. Bulimia around 1-3% of women (also 0.1% of men), and binge eating disorder 3.3% of women and 0.8% of men (4). Anorexia nervosa remains the most deadly of all psychiatric disorders (5), with a 5-10% death rate within 10 years of developing the symptoms, and an 18-20% death rate within 20 years. Anorexia is endemic in the fashion industry, to the point where models are now being airbrushed to add curves (6).
Eating disorders in adolescents are strongly predicted by the earlier presence of depression, bipolar disorder, and anxiety. The eating disorders also appear to be genetic (7)(8), perhaps related to inherited differences in serotonin receptors.
With the growing prevalence, genetic susceptibility, and correlation with increases in obesity and consumption of industrialized food (not to mention the zinc connection), I can't help but wonder if the eating disorders are yet one more disease of Western civilization, most strongly predicated by our poor diets. I'll keep an eye out on the literature, of course, though much of the natural progression of anorexia can be explained by disordered thinking about body image combined with the process of starvation itself. Given the speculation that a combination of massive quantities of fructose, wheat, and omega 6 fatty acids lead to inflammation, leptin and insulin resistance, and obesity, disordered thinking and restrictive or purging behaviors may be the only ways to remain "skinny" on a standard diet. The cost is high, and borne primarily by our young women.
I've found that a personalized approach, based on treating underlying depression, anxiety, nutritional deficiencies, and teaching that our bodies deserve to be nourished with proper, whole foods can be surprisingly effective. Do eating disorders exist in a population where there is no obesity? I don't know. I imagine they are vanishingly rare.
. As the disorder reached public awareness in the 1970s, cases increased, spreading beyond the upper class. Bulimia (binging and then purging via exercise, vomiting, or laxatives) is first reliably described among some of the wealthy in the Middle Ages, who would vomit during meals so they could consume more (2). (Apparently this behavior did not happen in ancient Rome despite a common conception otherwise (3)). The first clinical paper on bulimia came in 1979 - Bulimia nervosa, an ominous variant of anorexia nervosa.
Everyone agrees that the cases of anorexia and bulimia escalated in the 1970s and 1980s, and though some will say they peaked in that time, the national survey data suggests that bulimia, especially, continues to escalate. While most scholars will point to cultural pressures for thinness, increasing depression and obsessive compulsive behavior, and increased dieting behaviors as precipitants for eating disorders, it is impossible to ignore the fact that the 1970s and 80s is when the rates of obesity in the United States began to increase at an unprecedented rate, and low fat eating began its popular progression through the mainstream.
There is a third eating disorder, binge eating disorder, where periodic food binges are not compensated by restricting or purging behavior. While many obese people eat normally, binge eaters will consume up to tens of thousands of calories in a singe day, entire bags of candy, or dinner from five or six fast food restaurants, one after the other. Again this disorder has been described for centuries, but seems to have escalated only recently (4).
All eating disorders remain relatively rare. Anorexia afflicts about 0.5% of women and 0.1% of men. Bulimia around 1-3% of women (also 0.1% of men), and binge eating disorder 3.3% of women and 0.8% of men (4). Anorexia nervosa remains the most deadly of all psychiatric disorders (5), with a 5-10% death rate within 10 years of developing the symptoms, and an 18-20% death rate within 20 years. Anorexia is endemic in the fashion industry, to the point where models are now being airbrushed to add curves (6).
Eating disorders in adolescents are strongly predicted by the earlier presence of depression, bipolar disorder, and anxiety. The eating disorders also appear to be genetic (7)(8), perhaps related to inherited differences in serotonin receptors.
With the growing prevalence, genetic susceptibility, and correlation with increases in obesity and consumption of industrialized food (not to mention the zinc connection), I can't help but wonder if the eating disorders are yet one more disease of Western civilization, most strongly predicated by our poor diets. I'll keep an eye out on the literature, of course, though much of the natural progression of anorexia can be explained by disordered thinking about body image combined with the process of starvation itself. Given the speculation that a combination of massive quantities of fructose, wheat, and omega 6 fatty acids lead to inflammation, leptin and insulin resistance, and obesity, disordered thinking and restrictive or purging behaviors may be the only ways to remain "skinny" on a standard diet. The cost is high, and borne primarily by our young women.
I've found that a personalized approach, based on treating underlying depression, anxiety, nutritional deficiencies, and teaching that our bodies deserve to be nourished with proper, whole foods can be surprisingly effective. Do eating disorders exist in a population where there is no obesity? I don't know. I imagine they are vanishingly rare.
Tuesday, August 3, 2010
Depression and the B Vitamins
I mentioned before that in psychiatry, we don't have many lab tests. In a standard work-up I might check none, or just a few. If a new patient has seen his primary care doctor within a reasonable amount of time, I might check the thyroid, B12, and folate and be done with it. I used to check vitamin D on everyone, but everyone was low, so now I tell patients to supplement with 2000 IU a day and then I check it (plus calcium) after 3 months.
Why B12 (available from animal foods) and folate? Both are B vitamins involved in nerve health and the formation of the all-important neurotransmitters. B12 deficiency can definitely cause depression along with other nerve damage over time (1)(2). In many years of doing this testing, I've caught several underactive thyroids, a few B12 deficiencies, but no folate deficiencies. Not one. In America, all grain-based food is supplemented with folate. Maybe that's why.
I've never tested for B6. It just wasn't a test we were taught to do, or to look out for. B12 deficiency is pretty common (6% of adults) - we have variable abilities to absorb it from our guts, and some people will need shots in order to keep from being low. B6 deficiency - hadn't even thought about it, really. But it stands to reason that we might need it to keep from being depressed. Recall that the all-important serotonin is made from the amino acid tryptophan. Along the way, we need B6 (and zinc) to help the process. B6 is also required to make other neurotransmitters, dopamine and norepinephrine (see this diagram from the archives of EvMedForum).
Which brings me to this study from June's American Journal of Clinical Nutrition - "Longitudinal association of vitamin B6, folate, and vitamin B12 with depressive symptoms among older adults over time."
Basically, a group in Chicago followed a mixed-race group of older adults for an average of 7 years. Food questionnaires and a 10-item Center for Epidemiologic Studies Depression Scale were administered every three years in about 3500 people aged 65 or older.
Let's stop and take a deep breath for a moment. Because, come on. A food questionnaire every three years? A 10 item scale for depression I've never even heard of, and I'm a psychiatrist? Compare the methods in this study to the Heart and Soul study, another large observational trial. In Heart and Soul, they did a real clinical research diagnostic interview - the gold standard, and they drew blood to get actual lab measures. This study is 3 times as big and maybe that's why they used cheap, crappy measures, but you hardly even know what the data is worth at the end. Two pages of this study describe how they managed to squeeze some so-called information out of it - they used "logistic regression with the generalized estimating equation to model the likelihood over time of a participant becoming depressed," plus some logit link functions, and binomial error structure. I'm sure those are all very sensible things for a statistician to do, but wouldn't it have been better to use a bigger, better scale in the first place? Sigh.
We don't have that many nutritional studies in psychiatry. I feel like I need to look at all of them, even the lousy ones. And this one was published in the premier nutrition journal! (Along with that crazy meat makes you fat study).
Anyway! Somehow, from those once-every-three-year food questionnaires, they figured out which older adults were deficient in B6, folate, and B12. They controlled for things like age, smoking, alcohol, sex, race, education, etc. In the end, high total (food + supplement) intake of B12 and B6 were associated with a decreased likelihood of the development of depression over the study period of 7.2 years. Folate intake didn't seem to have any impact, and the B6 difference was primarily made in the supplementing group. Meaning people with the education and wherewithal to take a multivitamin. Which could be a huge confounder. At least the editorial in the same issue admits that more studies need to be done. And done well.
Why B12 (available from animal foods) and folate? Both are B vitamins involved in nerve health and the formation of the all-important neurotransmitters. B12 deficiency can definitely cause depression along with other nerve damage over time (1)(2). In many years of doing this testing, I've caught several underactive thyroids, a few B12 deficiencies, but no folate deficiencies. Not one. In America, all grain-based food is supplemented with folate. Maybe that's why.
I've never tested for B6. It just wasn't a test we were taught to do, or to look out for. B12 deficiency is pretty common (6% of adults) - we have variable abilities to absorb it from our guts, and some people will need shots in order to keep from being low. B6 deficiency - hadn't even thought about it, really. But it stands to reason that we might need it to keep from being depressed. Recall that the all-important serotonin is made from the amino acid tryptophan. Along the way, we need B6 (and zinc) to help the process. B6 is also required to make other neurotransmitters, dopamine and norepinephrine (see this diagram from the archives of EvMedForum).
Which brings me to this study from June's American Journal of Clinical Nutrition - "Longitudinal association of vitamin B6, folate, and vitamin B12 with depressive symptoms among older adults over time."
Basically, a group in Chicago followed a mixed-race group of older adults for an average of 7 years. Food questionnaires and a 10-item Center for Epidemiologic Studies Depression Scale were administered every three years in about 3500 people aged 65 or older.
Let's stop and take a deep breath for a moment. Because, come on. A food questionnaire every three years? A 10 item scale for depression I've never even heard of, and I'm a psychiatrist? Compare the methods in this study to the Heart and Soul study, another large observational trial. In Heart and Soul, they did a real clinical research diagnostic interview - the gold standard, and they drew blood to get actual lab measures. This study is 3 times as big and maybe that's why they used cheap, crappy measures, but you hardly even know what the data is worth at the end. Two pages of this study describe how they managed to squeeze some so-called information out of it - they used "logistic regression with the generalized estimating equation to model the likelihood over time of a participant becoming depressed," plus some logit link functions, and binomial error structure. I'm sure those are all very sensible things for a statistician to do, but wouldn't it have been better to use a bigger, better scale in the first place? Sigh.
We don't have that many nutritional studies in psychiatry. I feel like I need to look at all of them, even the lousy ones. And this one was published in the premier nutrition journal! (Along with that crazy meat makes you fat study).
Anyway! Somehow, from those once-every-three-year food questionnaires, they figured out which older adults were deficient in B6, folate, and B12. They controlled for things like age, smoking, alcohol, sex, race, education, etc. In the end, high total (food + supplement) intake of B12 and B6 were associated with a decreased likelihood of the development of depression over the study period of 7.2 years. Folate intake didn't seem to have any impact, and the B6 difference was primarily made in the supplementing group. Meaning people with the education and wherewithal to take a multivitamin. Which could be a huge confounder. At least the editorial in the same issue admits that more studies need to be done. And done well.
Sunday, August 1, 2010
Depression crashed your party
I've told you before I like Dr. Maes. Turns out he's been working the depression = inflammation angle for the past twenty years, isolating all the cellular mechanisms while we were all busy getting bored by drug reps peddling their newest serotonin reuptake inhibitors.
Maes is not only brilliant, but cranky. The main page of his website is devoted to accusing a Dr. Dantzer of stealing his ideas, and much of the introduction of this brand new paper harps on the fact that Dowlati's recent major meta-analysis of depression and inflammation left out much of Maes' work. Fortunately Maes' current paper cites 39 of his previous papers - so nothing will be left out here. I've got your back, cranky Belgian depression and inflammation researcher!
I'll begin by describing the immune system. It's complicated. Imagine an A-list party with all sorts of different security checks and bouncers. There are guys on the perimeter keeping the unwashed masses out, then there are guards on the inside keeping an eye on the elite, and maybe even spies working the crowd, searching for any crashers. The different security forces of our immune system have different names and duties, too. There are the B cells which work via little protein tags called antibodies (known as the "humoral immune system.") Then there are the natural killer cells, hungry macrophages, and other elite shock troops. Finally, you have the cell-mediated immunity, primarily the T cells, who run around messing with anyone who looks like he doesn't belong.
In several of the last blog posts, I mentioned high levels of IL-6 and TNFalpha as markers of depression. These inflammatory cytokines (among many more, such as IL-2, IL-12, interferon gamma, and biomarker neopterin) activate and prime the T cells, who then go out and do their killing. Therefore inflammation means, in a nutshell, that the body's security forces are out there, and the cell-mediated part of our inflammatory reaction is the major cause of the symptoms of depression.
Out-of-whack cell-mediated immunity has also been implicated in lupus, diabetes mellitus, schizophrenia, rheumatoid arthritis, several cancers, multiple sclerosis, and Grave's disease. But Maes has been able to link various participants in cell mediated immunity to many of the major symptoms of depression, including the "vegetative" symptoms (poor sleep, poor eating), the somatic symptoms (increased worry about illness and increased aches and pains), and the decreases of neurotransmitters serotonin and norepinephrine. He links it to the alterations in the HPA axis. Not to mention the actual inflammation in the hippocampus itself. To put it simply, Maes has described the complex biochemical mechanisms of depression using a single overriding, reasonable, and realistic theory of cell-mediated immunity. This is like learning the beautiful ins and outs of how too much fructose causes metabolic syndrome. In a word, awesome.
Maes and other researchers start by measuring a T-cell activating cytokine called sIL-2R. This little bugger is higher in the blood and CNS of people with cerebral lupus, depression, and mania. The worse the symptoms, the higher the levels, and the levels fall when the depression, lupus, and mania symptoms go into remission. Pretty telling. Other markers of cell-mediated immunity (soluble CD8 antigen and other T-cell surface markers, and levels of interferon gamma) follow a similar pattern.
One interesting tidbit - a lot of inflammatory disorders respond to steroids, which suppress the immune response. Asthma, multiple sclerosis, inflammatory bowel. Depression will often get worse with steroids, and Maes figures that's because depression is driven primarily by the T-cells, which are steroid-resistant compared to other parts of the immune response. In case you were wondering.
But let's get back to the actual mechanisms. I reviewed one in a previous post (a useful diagram is linked here). Inflammation causes our body to preferentially make tryptophan, the precursor to serotonin, into kynurenic and xanthurenic acid. Not only does this mean we have less happy, relaxing serotonin around, but kynuretic has the tendency to make us anxious and depressed all on its own. More specifically, T helper cells and indoleamine 2,3-dioxegenase (IDO), parts of our cell-mediated immune response, lower our serotonin levels and make us depressed. This mechanism is true of bipolar depression, major depression, adolescent depression, depression in heart failure patients... you name it, and IDO is smacking down our serotonin. Interferon alpha treatment for hepatitis C or multiple sclerosis will activate the very same mechanism to make us depressed. In animal models, specific cell-mediated immune activation causes lack of interest and changes and sleep and appetite consistent with the similar human symptoms of depression.
Antidepressants work by suppressing the cell-mediated immune response in specific ways. All major classes of antidepressants have been shown to have this effect in various models - tricyclics, SSRIs, SNRIs - they block the production of IL-6 and TNF alpha in immune cells, and also block a number of other acute inflammatory phase proteins, such as C-reactive protein and haptoglobin. Antidepressants are anti-inflammatory, and never-treated depressed individuals will have much higher markers of inflammation than those who are treated. While there are several studies of neuroimaging showing similar changes in metabolism of the brain with response to antidepressants or psychotherapy, I found only one that specifically measured psychotherapy and inflammation, from 2009 in depressed cancer patients. I was also able to find this study of yoga reducing C-reactive protein, IL-6 and other markers of inflammation. I think it makes sense to assume that any successful treatment of depression will be anti-inflammatory. Dance Dance Revolution did not reduce inflammatory markers in obese kids, however. Who knew?
Mood stabilizers, such a lithium and depakote, also affect the ratios of key inflammatory cytokines. Like the antidepressants, they suppress the cell-mediated immune response in specific ways that affect neurotoxicity and neuroplasticity.
I wish we had more evidence-based lifestyle and dietary trials for psychiatric disorders. Not just (probably biased) studies of medications and a few of psychotherapy, and not just a bunch of epidemiological studies. What if we knew for certain that dietary changes could could stop the inflammation in the first place? If I'm right about my paleolithic-style approach, then I could actually prescribe grass-fed steak (not currently FDA-approved) in addition to fish oil. Well, I'll keep looking!
Maes is not only brilliant, but cranky. The main page of his website is devoted to accusing a Dr. Dantzer of stealing his ideas, and much of the introduction of this brand new paper harps on the fact that Dowlati's recent major meta-analysis of depression and inflammation left out much of Maes' work. Fortunately Maes' current paper cites 39 of his previous papers - so nothing will be left out here. I've got your back, cranky Belgian depression and inflammation researcher!
I'll begin by describing the immune system. It's complicated. Imagine an A-list party with all sorts of different security checks and bouncers. There are guys on the perimeter keeping the unwashed masses out, then there are guards on the inside keeping an eye on the elite, and maybe even spies working the crowd, searching for any crashers. The different security forces of our immune system have different names and duties, too. There are the B cells which work via little protein tags called antibodies (known as the "humoral immune system.") Then there are the natural killer cells, hungry macrophages, and other elite shock troops. Finally, you have the cell-mediated immunity, primarily the T cells, who run around messing with anyone who looks like he doesn't belong.
In several of the last blog posts, I mentioned high levels of IL-6 and TNFalpha as markers of depression. These inflammatory cytokines (among many more, such as IL-2, IL-12, interferon gamma, and biomarker neopterin) activate and prime the T cells, who then go out and do their killing. Therefore inflammation means, in a nutshell, that the body's security forces are out there, and the cell-mediated part of our inflammatory reaction is the major cause of the symptoms of depression.
Out-of-whack cell-mediated immunity has also been implicated in lupus, diabetes mellitus, schizophrenia, rheumatoid arthritis, several cancers, multiple sclerosis, and Grave's disease. But Maes has been able to link various participants in cell mediated immunity to many of the major symptoms of depression, including the "vegetative" symptoms (poor sleep, poor eating), the somatic symptoms (increased worry about illness and increased aches and pains), and the decreases of neurotransmitters serotonin and norepinephrine. He links it to the alterations in the HPA axis. Not to mention the actual inflammation in the hippocampus itself. To put it simply, Maes has described the complex biochemical mechanisms of depression using a single overriding, reasonable, and realistic theory of cell-mediated immunity. This is like learning the beautiful ins and outs of how too much fructose causes metabolic syndrome. In a word, awesome.
Maes and other researchers start by measuring a T-cell activating cytokine called sIL-2R. This little bugger is higher in the blood and CNS of people with cerebral lupus, depression, and mania. The worse the symptoms, the higher the levels, and the levels fall when the depression, lupus, and mania symptoms go into remission. Pretty telling. Other markers of cell-mediated immunity (soluble CD8 antigen and other T-cell surface markers, and levels of interferon gamma) follow a similar pattern.
One interesting tidbit - a lot of inflammatory disorders respond to steroids, which suppress the immune response. Asthma, multiple sclerosis, inflammatory bowel. Depression will often get worse with steroids, and Maes figures that's because depression is driven primarily by the T-cells, which are steroid-resistant compared to other parts of the immune response. In case you were wondering.
But let's get back to the actual mechanisms. I reviewed one in a previous post (a useful diagram is linked here). Inflammation causes our body to preferentially make tryptophan, the precursor to serotonin, into kynurenic and xanthurenic acid. Not only does this mean we have less happy, relaxing serotonin around, but kynuretic has the tendency to make us anxious and depressed all on its own. More specifically, T helper cells and indoleamine 2,3-dioxegenase (IDO), parts of our cell-mediated immune response, lower our serotonin levels and make us depressed. This mechanism is true of bipolar depression, major depression, adolescent depression, depression in heart failure patients... you name it, and IDO is smacking down our serotonin. Interferon alpha treatment for hepatitis C or multiple sclerosis will activate the very same mechanism to make us depressed. In animal models, specific cell-mediated immune activation causes lack of interest and changes and sleep and appetite consistent with the similar human symptoms of depression.
Antidepressants work by suppressing the cell-mediated immune response in specific ways. All major classes of antidepressants have been shown to have this effect in various models - tricyclics, SSRIs, SNRIs - they block the production of IL-6 and TNF alpha in immune cells, and also block a number of other acute inflammatory phase proteins, such as C-reactive protein and haptoglobin. Antidepressants are anti-inflammatory, and never-treated depressed individuals will have much higher markers of inflammation than those who are treated. While there are several studies of neuroimaging showing similar changes in metabolism of the brain with response to antidepressants or psychotherapy, I found only one that specifically measured psychotherapy and inflammation, from 2009 in depressed cancer patients. I was also able to find this study of yoga reducing C-reactive protein, IL-6 and other markers of inflammation. I think it makes sense to assume that any successful treatment of depression will be anti-inflammatory. Dance Dance Revolution did not reduce inflammatory markers in obese kids, however. Who knew?
Mood stabilizers, such a lithium and depakote, also affect the ratios of key inflammatory cytokines. Like the antidepressants, they suppress the cell-mediated immune response in specific ways that affect neurotoxicity and neuroplasticity.
I wish we had more evidence-based lifestyle and dietary trials for psychiatric disorders. Not just (probably biased) studies of medications and a few of psychotherapy, and not just a bunch of epidemiological studies. What if we knew for certain that dietary changes could could stop the inflammation in the first place? If I'm right about my paleolithic-style approach, then I could actually prescribe grass-fed steak (not currently FDA-approved) in addition to fish oil. Well, I'll keep looking!
Saturday, July 31, 2010
Irritable Bowel
Let's start with a bit of melancholy. I do so love this piece (right click to open in new tab) by Ralph Vaughan Williams. My 10th grade band director, who died in his early sixties of a heart attack, loved RVW too. There's plenty of tragedy in an ordinary life to go around, even now.
Last week when researching the lithium post I pulled another article from the Journal of Lipid Research that looked interesting. Its title: "Marked elevations in pro-inflammatory polyunsaturated fatty acid metabolites in females with irritable bowel syndrome." This article was produced by an Irish group, including a psychiatrist! Amazing what you find in the Journal of Lipid Research.
I see a lot of patients with IBS - basically, uncomfortable flatulence, bloating, constipation, and diarrhea, but no particular cause found. It is highly associated with depression and anxiety, thus my common involvement. And the researchers call IBS a "disorder of the brain-gut axis." But you may not be surprised that low-grade inflammation is suspected to be a predisposing factor, as evidenced by the presence of mast cell mediators (regulators of the cellular immune system) and lymphocytes in the colo-rectal mucosa, and elevations of pro-inflammatory cytokines in the serum of people with IBS.
(Yes. Inflammation. Imagine that.)
The study involved some comparison between people with IBS and normal controls. The IBS sufferers were selected from the gastroenterology clinic. The controls were found off the street, or however. Study participants filled out a few questionnaires and then had some blood taken (and centrifuged) for analysis. Some basic confounders were accounted for (such as smoking).
The findings: 41% of the subjects with IBS (17 out of 41 people) met the criteria for major depressive disorder. No one in the control group of 26 were depressed. The IBS group had a mix of constipation dominant vs. diarrhea dominant vs alternating symptoms.
And the fatty acids? IBS sufferers had lower plasma omega 6 and higher plasma omega 3 than the controls (WHA??? I know, sometimes science surprises - though this trend was not statistically significant), but the levels of arachidonic acid (created from omega 6 fatty acids, and the precursor for a ton of inflammatory cytokines) were significantly elevated compared to controls (p=0.029). The inflammatory cytokines themselves (prostaglandins and leukotrienes, if you must know) were also significantly elevated. There was no correlation between the severity of the symptoms and the elevations of the cytokines. Arachidonic acid does seem to play a role in intestinal permeability, so the researchers did not find its elevation surprising. They made note that diet might not be the only factor predisposing people to an inflammatory state.
It might not all be dietary! It might have to do with other stressful factors in life, and such. Those psychotherapy skills might be useful after all.
Last week when researching the lithium post I pulled another article from the Journal of Lipid Research that looked interesting. Its title: "Marked elevations in pro-inflammatory polyunsaturated fatty acid metabolites in females with irritable bowel syndrome." This article was produced by an Irish group, including a psychiatrist! Amazing what you find in the Journal of Lipid Research.
I see a lot of patients with IBS - basically, uncomfortable flatulence, bloating, constipation, and diarrhea, but no particular cause found. It is highly associated with depression and anxiety, thus my common involvement. And the researchers call IBS a "disorder of the brain-gut axis." But you may not be surprised that low-grade inflammation is suspected to be a predisposing factor, as evidenced by the presence of mast cell mediators (regulators of the cellular immune system) and lymphocytes in the colo-rectal mucosa, and elevations of pro-inflammatory cytokines in the serum of people with IBS.
(Yes. Inflammation. Imagine that.)
The study involved some comparison between people with IBS and normal controls. The IBS sufferers were selected from the gastroenterology clinic. The controls were found off the street, or however. Study participants filled out a few questionnaires and then had some blood taken (and centrifuged) for analysis. Some basic confounders were accounted for (such as smoking).
The findings: 41% of the subjects with IBS (17 out of 41 people) met the criteria for major depressive disorder. No one in the control group of 26 were depressed. The IBS group had a mix of constipation dominant vs. diarrhea dominant vs alternating symptoms.
And the fatty acids? IBS sufferers had lower plasma omega 6 and higher plasma omega 3 than the controls (WHA??? I know, sometimes science surprises - though this trend was not statistically significant), but the levels of arachidonic acid (created from omega 6 fatty acids, and the precursor for a ton of inflammatory cytokines) were significantly elevated compared to controls (p=0.029). The inflammatory cytokines themselves (prostaglandins and leukotrienes, if you must know) were also significantly elevated. There was no correlation between the severity of the symptoms and the elevations of the cytokines. Arachidonic acid does seem to play a role in intestinal permeability, so the researchers did not find its elevation surprising. They made note that diet might not be the only factor predisposing people to an inflammatory state.
It might not all be dietary! It might have to do with other stressful factors in life, and such. Those psychotherapy skills might be useful after all.
Thursday, July 29, 2010
Low Cholesterol and Suicide 2
In my last post on the link between low cholesterol and suicide, I made note of some general trends between low cholesterol, suicide (particularly violent suicide), accidents, and violence, and raised some questions about the safety of cholesterol-lowering drugs. I didn't find any researched link between statin therapy and suicide, though one study showed that a statin reduced the ability of a certain serotonin receptor to do its job (linked below). My takeaway point from the post was that, hey, cholesterol is important and needed in the brain. Obliterating the ability of our liver to make cholesterol may have some untoward mental health side effects.
Since then, I've kept an eye out for more information, and a few interesting snippets have come up. Current Psychiatry has a decent article this month, "Cholesterol, mood, and vascular health. Untangling the relationship."
Some interesting facts from the article:
1) 1/4 of the body's free cholesterol is found in the central nervous system
2) Depleting cholesterol impairs the function of the serotonin 1A receptor and the serotonin 7 receptor, and reduces the ability of the membrane serotonin transporter to do its thing. (Serotonin is made within nerve cells and needs to be transported outside into the synapse between the nerve cells to work. If the transporter isn't functioning, we have a Big Problem).
3)Cholesterol is also needed for forming a nerve synapse (also Important) and making myelin.
4) Cholesterol may be involved in GABA and NMDA receptor signaling, opioid signaling, and the transport of excitatory amino acids.
Just to be crystal clear - low serotonin is associated with violent suicide, impulsive acts, hostility, and aggression. We need plenty of cholesterol in the brain to have all our serotonin machinery work properly. Low cholesterol is also associated with suicide and violence. If you have low cholesterol, of course it does not mean you will be suicidal. Suicide is, fortunately, rare, and will have multiple predisposing causes.
So the paragraph above, with its caveat, brings up an interesting and actionable hypothetical question - does lowering cholesterol with medication predispose you to suicide or violence? The first cholesterol-lowering drugs were not statins. And an early analysis of the primary prevention trials of the non-statins showed a doubling of the risk of violent death or suicide. Oops. (I also linked the J-LIT trial in my previous post, which showed a 3-fold increase in suicide or accidents with statin therapy, though the increase was not statistically significant).
A later case-controlled study showed that statin users had a lower risk of depression than patients on non-statin lipid-lowering drugs. The LIPID study followed 1130 patients on pravastatin for 4 years, and found no changes in (self-reported) anger, impulsivity, anxiety, or depression. Pravastatin doesn't cross the blood-brain barrier very well. Simvastatin, a very commonly used statin, crosses it quite readily - but why this would be important may be interesting. HMG Co-A reductase inhibitors (statins) do most of their work in the liver, after all. But it turns out we have HMG Co-A reductase all sorts of places. These researchers found it in Chinese hamster ovary cells. And in these cells, administration of a statin reduced the ability of the serotonin IA receptor to work. Getting rid of the statin restored the serotonin IA receptor function.
But there's another complication in examining the literature for statin side effects. Some studies excluded patients with psychiatric problems (1). And due to the ability of statins to cause birth defects, many trials have excluded any women of childbearing age. Just something to keep in mind.
We are left with... well, a clinical trial is apparently underway to study the effects if pravastatin, simvastatin, or placebo on mood, sleep and aggression. We still don't know if low cholesterol causes suicide and aggression, or if it is a biomarker of depression. I'm convinced high cholesterol is just a biomarker for heart disease, after all, rather than a cause. Thus the whole question of why treat high cholesterol at all (though the magical anti-inflammatory statin effect may help younger men. With known heart disease.)
My brain needs cholesterol! So does yours.
Since then, I've kept an eye out for more information, and a few interesting snippets have come up. Current Psychiatry has a decent article this month, "Cholesterol, mood, and vascular health. Untangling the relationship."
Some interesting facts from the article:
1) 1/4 of the body's free cholesterol is found in the central nervous system
2) Depleting cholesterol impairs the function of the serotonin 1A receptor and the serotonin 7 receptor, and reduces the ability of the membrane serotonin transporter to do its thing. (Serotonin is made within nerve cells and needs to be transported outside into the synapse between the nerve cells to work. If the transporter isn't functioning, we have a Big Problem).
3)Cholesterol is also needed for forming a nerve synapse (also Important) and making myelin.
4) Cholesterol may be involved in GABA and NMDA receptor signaling, opioid signaling, and the transport of excitatory amino acids.
Just to be crystal clear - low serotonin is associated with violent suicide, impulsive acts, hostility, and aggression. We need plenty of cholesterol in the brain to have all our serotonin machinery work properly. Low cholesterol is also associated with suicide and violence. If you have low cholesterol, of course it does not mean you will be suicidal. Suicide is, fortunately, rare, and will have multiple predisposing causes.
So the paragraph above, with its caveat, brings up an interesting and actionable hypothetical question - does lowering cholesterol with medication predispose you to suicide or violence? The first cholesterol-lowering drugs were not statins. And an early analysis of the primary prevention trials of the non-statins showed a doubling of the risk of violent death or suicide. Oops. (I also linked the J-LIT trial in my previous post, which showed a 3-fold increase in suicide or accidents with statin therapy, though the increase was not statistically significant).
A later case-controlled study showed that statin users had a lower risk of depression than patients on non-statin lipid-lowering drugs. The LIPID study followed 1130 patients on pravastatin for 4 years, and found no changes in (self-reported) anger, impulsivity, anxiety, or depression. Pravastatin doesn't cross the blood-brain barrier very well. Simvastatin, a very commonly used statin, crosses it quite readily - but why this would be important may be interesting. HMG Co-A reductase inhibitors (statins) do most of their work in the liver, after all. But it turns out we have HMG Co-A reductase all sorts of places. These researchers found it in Chinese hamster ovary cells. And in these cells, administration of a statin reduced the ability of the serotonin IA receptor to work. Getting rid of the statin restored the serotonin IA receptor function.
But there's another complication in examining the literature for statin side effects. Some studies excluded patients with psychiatric problems (1). And due to the ability of statins to cause birth defects, many trials have excluded any women of childbearing age. Just something to keep in mind.
We are left with... well, a clinical trial is apparently underway to study the effects if pravastatin, simvastatin, or placebo on mood, sleep and aggression. We still don't know if low cholesterol causes suicide and aggression, or if it is a biomarker of depression. I'm convinced high cholesterol is just a biomarker for heart disease, after all, rather than a cause. Thus the whole question of why treat high cholesterol at all (though the magical anti-inflammatory statin effect may help younger men. With known heart disease.)
My brain needs cholesterol! So does yours.
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