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.
Showing posts with label depression. Show all posts
Showing posts with label depression. Show all posts
Thursday, October 7, 2010
Friday, July 23, 2010
Zinc, Depression, and Everything
Today I will review more specific and up-to-date information about the interplay between zinc and depressive disorders and inflammation. Let's summarize the human evidence thus far (1):
1) Depressed patients in studies have a lower serum zinc level than normal controls.
2) The more depressed the patients are, the lower the zinc level.
3) Low zinc levels in pregnant women are associated with pre- and postpartum depression.
4) Treatment with antidepressants normalizes zinc levels (I've been a little loose with the terminology, I admit, and this finding helps us keep in mind that zinc level can be just a biomarker for depression, not necessarily a cause or effect per se.)
5) Zinc supplementation plus antidepressant therapy can work better for depression than antidepressants alone.
6) Zinc supplementation alone can have antidepressant effects.
Now let's try to clarify a bit more about zinc and the brain. As I noted in my last post, the hippocampus seems to be the most vulnerable to zinc deficiency. The hippocampus is a center of memory, and it also plays a big role in nerve plasticity and repair. Recall that nitric oxide and antidepressants seem to work by increasing the production of brain derived neurotrophic factor in the hippocampus. BDNF is one of many nerve growth factors in the hippocampus, and is part of several different neurochemical pathways which help in nerve recovery, adaptation, and repair.
Scientists have been able to cobble together the following pathway in rat brains: Zinc deficiency leads to decreased zinc in the synapse, which results in an increase in the NMDA receptors (these receptors respond to glutamate, an excitatory neurotransmitter that can be responsible for toxic effects in the brain if there is too much). At the same time, the inhibitory (in this case, neuroprotective) neurotransmitter GABA is decreased, along with BDNF and another nerve growth factor, NGF. The glutamate level in the synapse is higher, so calcium mediated stimulation of the nerves is primed. Do this too much, and you get "excitotoxicity." This same mechanism is thought (in acute vs chronic and in differing areas of the brain) to be responsible for seizures, migraines, dementia, anxiety, depression, and bipolar disorder (and is why pharmaceutical GABA receptor modulators can be effective for certain symptoms of any of those conditions).
Getting down to the real nitty-gritty, Zinc works in conjunction with nearly all of the different membrane signaling and second messenger systems you might have learned about in molecular biology classes. Membrane gated ion channels, p53 signaling, g-proteins, zinc-fingers (obviously) - the whole lot. This is why even though a lot of these different nerve chemicals work via different mechanisms, or multiple mechanisms, zinc can have a hand in all of these up regulating and down regulating events. Zinc is a cog in the machine all along the way.
So there are clear mechanisms by which absolute zinc deficiency can have a hand in all sorts of bad brain syndromes, and vegetarians, dieters, the elderly, those with malabsorption or intestinal issues, and the two billion people on the planet who (due to poverty) pretty much subsist on grains alone (rich in zinc-binding phytates) are all at risk for absolute zinc deficiency.
But robust presumably zinc-replete meat-eaters of a Western diet are at risk for depression, diabetes, dementia, and cardiovascular disease along with the whole diaspora of the Western chronic diseases. I contend (along with many others) that inflammation is the primary driving mechanism behind the whole shebang. Could there be a mechanism by which inflammation could affect brain zinc levels (or vice versa) as a part of the pathway leading from inflammation to bad brain disease?
Wanna put some money on it? Did I mention that pancreatic beta cells in particular run on a lot of zinc-dependent pathways too (2)(3)?
It's common knowledge that zinc supplementation can help ameliorate a cold (at least if you take the zinc within the first day of symptoms (4)), and, as I mentioned in the last post, zinc has a lot to do with mediating our body's immune response. We use zinc to activate the immune pathways that zap viruses (like colds), but zinc can influence the activity of 2000 (yeah, two thousand) different immune transcription factors. The baddest of these factors is NFkappaB. NFkappaB hangs around in the nucleus of immune cells and helps them make all sorts of inflammatory cytokines to fight off the perceived bad guys - good old inflammatory frenemies such as IL-6, IL-2, TNFalpha and many, many more. (Yesterday I noted that zinc deficiency is associated with increased IL-6, and on review of several articles, it seems that high and low zinc is associated high IL-6. It is probably a part of what I discuss in the next paragraph, but I'll look into it more, as a lot of the work is done by the Polish group or Maes, and they seem to cite each other all the time). Zinc not only directly promotes the synthesis of NFkappaB, it helps it get into the nucleus where it can work, and it helps it bind to the DNA to promote inflammation.
It isn't so simple as that. Turns out that zinc also has a hand in down regulating inflammation too! It even activates a protein that helps inactivate NFkappaB. And IL-6, an inflammatory cytokine which needs zinc the be born, will then activate a protein in the liver called metallothionein, a protein that holds on to zinc and keeps it in the liver, so that even if you eat a lot of zinc, it won't be available in your blood or brain for other uses. A lot of biochemical systems are like this - too little zinc (such as in people born without the ability to absorb it (5) and you get immune dysfuntion and vulnerability to infection, as your protective inflammatory response won't work. But if inflammation gets high enough, it has its own down regulating systems (sequestering zinc via IL-6 and metallothionein, for example) that cool things off.
Our inflammatory and fight or flight systems were built for acute insults. Viruses, injury, bacterial invasion, angry lion attacking the camp. When the insults are chronic (unalleviated stress, gallons of inflammatory-promoting omega-6 fatty acids, weird glutens and lectins, chronic depression-causing viral infections such as herpes, borna disease, HIV, or Epstein Barr), the whole system becomes dysregulated. What should be up is down. So zinc ought to be in the central nervous system, helping out with nerve repair and plasticity, and instead it is crusading with NFkappaB or stuck with metallothionein in the liver, and your poor hippocampus is shorting out on glutamate and calcium. Extra zinc might help. As might antidepressants, GABA receptor modulators, and other neuroprotective chemicals. But those are bailing buckets. What we really need is to correct the problem causing the boat to sink. We need to reduce the inflammatory insults in the first place.
There's more. Always more!
1) Depressed patients in studies have a lower serum zinc level than normal controls.
2) The more depressed the patients are, the lower the zinc level.
3) Low zinc levels in pregnant women are associated with pre- and postpartum depression.
4) Treatment with antidepressants normalizes zinc levels (I've been a little loose with the terminology, I admit, and this finding helps us keep in mind that zinc level can be just a biomarker for depression, not necessarily a cause or effect per se.)
5) Zinc supplementation plus antidepressant therapy can work better for depression than antidepressants alone.
6) Zinc supplementation alone can have antidepressant effects.
Now let's try to clarify a bit more about zinc and the brain. As I noted in my last post, the hippocampus seems to be the most vulnerable to zinc deficiency. The hippocampus is a center of memory, and it also plays a big role in nerve plasticity and repair. Recall that nitric oxide and antidepressants seem to work by increasing the production of brain derived neurotrophic factor in the hippocampus. BDNF is one of many nerve growth factors in the hippocampus, and is part of several different neurochemical pathways which help in nerve recovery, adaptation, and repair.
Scientists have been able to cobble together the following pathway in rat brains: Zinc deficiency leads to decreased zinc in the synapse, which results in an increase in the NMDA receptors (these receptors respond to glutamate, an excitatory neurotransmitter that can be responsible for toxic effects in the brain if there is too much). At the same time, the inhibitory (in this case, neuroprotective) neurotransmitter GABA is decreased, along with BDNF and another nerve growth factor, NGF. The glutamate level in the synapse is higher, so calcium mediated stimulation of the nerves is primed. Do this too much, and you get "excitotoxicity." This same mechanism is thought (in acute vs chronic and in differing areas of the brain) to be responsible for seizures, migraines, dementia, anxiety, depression, and bipolar disorder (and is why pharmaceutical GABA receptor modulators can be effective for certain symptoms of any of those conditions).
Getting down to the real nitty-gritty, Zinc works in conjunction with nearly all of the different membrane signaling and second messenger systems you might have learned about in molecular biology classes. Membrane gated ion channels, p53 signaling, g-proteins, zinc-fingers (obviously) - the whole lot. This is why even though a lot of these different nerve chemicals work via different mechanisms, or multiple mechanisms, zinc can have a hand in all of these up regulating and down regulating events. Zinc is a cog in the machine all along the way.
So there are clear mechanisms by which absolute zinc deficiency can have a hand in all sorts of bad brain syndromes, and vegetarians, dieters, the elderly, those with malabsorption or intestinal issues, and the two billion people on the planet who (due to poverty) pretty much subsist on grains alone (rich in zinc-binding phytates) are all at risk for absolute zinc deficiency.
But robust presumably zinc-replete meat-eaters of a Western diet are at risk for depression, diabetes, dementia, and cardiovascular disease along with the whole diaspora of the Western chronic diseases. I contend (along with many others) that inflammation is the primary driving mechanism behind the whole shebang. Could there be a mechanism by which inflammation could affect brain zinc levels (or vice versa) as a part of the pathway leading from inflammation to bad brain disease?
Wanna put some money on it? Did I mention that pancreatic beta cells in particular run on a lot of zinc-dependent pathways too (2)(3)?
It's common knowledge that zinc supplementation can help ameliorate a cold (at least if you take the zinc within the first day of symptoms (4)), and, as I mentioned in the last post, zinc has a lot to do with mediating our body's immune response. We use zinc to activate the immune pathways that zap viruses (like colds), but zinc can influence the activity of 2000 (yeah, two thousand) different immune transcription factors. The baddest of these factors is NFkappaB. NFkappaB hangs around in the nucleus of immune cells and helps them make all sorts of inflammatory cytokines to fight off the perceived bad guys - good old inflammatory frenemies such as IL-6, IL-2, TNFalpha and many, many more. (Yesterday I noted that zinc deficiency is associated with increased IL-6, and on review of several articles, it seems that high and low zinc is associated high IL-6. It is probably a part of what I discuss in the next paragraph, but I'll look into it more, as a lot of the work is done by the Polish group or Maes, and they seem to cite each other all the time). Zinc not only directly promotes the synthesis of NFkappaB, it helps it get into the nucleus where it can work, and it helps it bind to the DNA to promote inflammation.
It isn't so simple as that. Turns out that zinc also has a hand in down regulating inflammation too! It even activates a protein that helps inactivate NFkappaB. And IL-6, an inflammatory cytokine which needs zinc the be born, will then activate a protein in the liver called metallothionein, a protein that holds on to zinc and keeps it in the liver, so that even if you eat a lot of zinc, it won't be available in your blood or brain for other uses. A lot of biochemical systems are like this - too little zinc (such as in people born without the ability to absorb it (5) and you get immune dysfuntion and vulnerability to infection, as your protective inflammatory response won't work. But if inflammation gets high enough, it has its own down regulating systems (sequestering zinc via IL-6 and metallothionein, for example) that cool things off.
Our inflammatory and fight or flight systems were built for acute insults. Viruses, injury, bacterial invasion, angry lion attacking the camp. When the insults are chronic (unalleviated stress, gallons of inflammatory-promoting omega-6 fatty acids, weird glutens and lectins, chronic depression-causing viral infections such as herpes, borna disease, HIV, or Epstein Barr), the whole system becomes dysregulated. What should be up is down. So zinc ought to be in the central nervous system, helping out with nerve repair and plasticity, and instead it is crusading with NFkappaB or stuck with metallothionein in the liver, and your poor hippocampus is shorting out on glutamate and calcium. Extra zinc might help. As might antidepressants, GABA receptor modulators, and other neuroprotective chemicals. But those are bailing buckets. What we really need is to correct the problem causing the boat to sink. We need to reduce the inflammatory insults in the first place.
There's more. Always more!
Thursday, July 22, 2010
Zinc!
When one makes a study of evolutionary medicine-type issues (that is, all chronic Western disease mediated by inflammation and diet and lifestyle so far removed from the life our bodies were designed for), the same nutrients keep popping up again and again. Fish oil is a good example. Yes, for heaven's sakes. I'm taking my fish oil. Shut up about it already.
When examining the small unexplored niche of nutritional evolutionary psychiatry, however, another trace mineral nutrient keeps bobbing to the top. This warrants a post, of course (or two, or three). Yup, no surprises here - I'm talking about zinc.
Let's start with the basics. This first bit of info comes from a rather abruptly titled "Zinc and depression. An update." from Poland in 2005. No cutesy titles in Poland! They get down to business. Good. I'm from Texas. I prefer cute yet vaguely threatening, myself (i.e. "Don't mess with Texas" as an anti-littering campaign - Also, driving out in the hill country, a large sign with scarecrow: "No trespassing. We don't call 911.") Gulp.
Zinc is a trace mineral (like magnesium, iodine, selenium, et al) that is essential for our continued life. Turns out that 300 or more enzymes in our bodies use zinc as a buddy to help them do their thing. DNA replication, protein synthesis, cell division - basic, mondo important, reliant on the presence of zinc. And guess what - the highest amount of zinc in our bodies is found in the brain - specifically in our hippocampus and cerebral cortex. Zinc deficiency can therefore lead to all sorts of unlovely consequences, such as ADHD, depression, alterations in behavior, learning, mental function, and seizures.
Turns out scientists of yore did all sorts of horrible tests on rats to figure out how zinc might be related to depression. Antidepressants seem to increase the ability of zinc to work as an anti-inflammatory agent in rat brains, zinc alone seems to be an antidepressant for rats, and the combination of zinc + small amounts of different classes of antidepressants (TCAs and SSRIs) enhanced the ability of the antidepressants to do their thing (helping the rats swim longer in hopeless situations, for example, or endure being held by their tails. Is reality TV really any different?).
Zinc therapy in rats also increases the amount of BDNF in rat hippocampi. Readers of the archives will note I am a big fan of BDNF in the hippocampus. And zinc reduced the fighting behavior of rats (and prisoners) too!
Yes, humans. Turns out Maes (my new hero - churned out a 62 page article on inflammation and depression this year, which I now have in my hot little hands!) discovered that zinc is low in the serum of humans with depression. Also, that low zinc seems to affect inflammation and immunity. Our T-cells (members of the immune system who hunt and kill infection) don't work well without zinc, and seem to release more inflammatory cytokines (IL-6 and IL-1) with low levels of zinc. Also, one of zinc's special actions is to inhibit the NMDA receptor in the brain. In suicide victims, there seems to be an alteration of zinc's ability to affect the NMDA receptor. (Turns out, BDNF + zinc helps calm down the NMDA receptor, leading to antidepressant effects.) Can zinc supplementation have antidepressant effects in humans? You may not be surprised at this point that the answer is yes (1).
There is more, much, much more to the story of zinc and psychopathology, but for now, let's end with good sources of zinc in our diets. Not surprisingly, the best sources of zinc are protein-rich meats, such as beef, pork, lamb, shellfish (especially oysters), chicken, turkey, etc. Pumpkin seeds are also a good non-meat source, and while grains have zinc, the absorption is strongly affected by the phytic acid in grains (2). Vitamin C, E, and B6 help you absorb zinc also. Seems that people with intestinal problems (celiac disease, inflammatory bowel), vegetarians, those with chronic kidney and liver diseases, alcoholics, and the elderly are most likely to suffer from zinc deficiency (3). Intake of more than 50mg a day (both from diet and from supplements) can lead to improper copper metabolism, altered iron function, reduction of HDL and reduced immune function.
More on zinc to come!
When examining the small unexplored niche of nutritional evolutionary psychiatry, however, another trace mineral nutrient keeps bobbing to the top. This warrants a post, of course (or two, or three). Yup, no surprises here - I'm talking about zinc.
Let's start with the basics. This first bit of info comes from a rather abruptly titled "Zinc and depression. An update." from Poland in 2005. No cutesy titles in Poland! They get down to business. Good. I'm from Texas. I prefer cute yet vaguely threatening, myself (i.e. "Don't mess with Texas" as an anti-littering campaign - Also, driving out in the hill country, a large sign with scarecrow: "No trespassing. We don't call 911.") Gulp.
Zinc is a trace mineral (like magnesium, iodine, selenium, et al) that is essential for our continued life. Turns out that 300 or more enzymes in our bodies use zinc as a buddy to help them do their thing. DNA replication, protein synthesis, cell division - basic, mondo important, reliant on the presence of zinc. And guess what - the highest amount of zinc in our bodies is found in the brain - specifically in our hippocampus and cerebral cortex. Zinc deficiency can therefore lead to all sorts of unlovely consequences, such as ADHD, depression, alterations in behavior, learning, mental function, and seizures.
Turns out scientists of yore did all sorts of horrible tests on rats to figure out how zinc might be related to depression. Antidepressants seem to increase the ability of zinc to work as an anti-inflammatory agent in rat brains, zinc alone seems to be an antidepressant for rats, and the combination of zinc + small amounts of different classes of antidepressants (TCAs and SSRIs) enhanced the ability of the antidepressants to do their thing (helping the rats swim longer in hopeless situations, for example, or endure being held by their tails. Is reality TV really any different?).
Zinc therapy in rats also increases the amount of BDNF in rat hippocampi. Readers of the archives will note I am a big fan of BDNF in the hippocampus. And zinc reduced the fighting behavior of rats (and prisoners) too!
Yes, humans. Turns out Maes (my new hero - churned out a 62 page article on inflammation and depression this year, which I now have in my hot little hands!) discovered that zinc is low in the serum of humans with depression. Also, that low zinc seems to affect inflammation and immunity. Our T-cells (members of the immune system who hunt and kill infection) don't work well without zinc, and seem to release more inflammatory cytokines (IL-6 and IL-1) with low levels of zinc. Also, one of zinc's special actions is to inhibit the NMDA receptor in the brain. In suicide victims, there seems to be an alteration of zinc's ability to affect the NMDA receptor. (Turns out, BDNF + zinc helps calm down the NMDA receptor, leading to antidepressant effects.) Can zinc supplementation have antidepressant effects in humans? You may not be surprised at this point that the answer is yes (1).
There is more, much, much more to the story of zinc and psychopathology, but for now, let's end with good sources of zinc in our diets. Not surprisingly, the best sources of zinc are protein-rich meats, such as beef, pork, lamb, shellfish (especially oysters), chicken, turkey, etc. Pumpkin seeds are also a good non-meat source, and while grains have zinc, the absorption is strongly affected by the phytic acid in grains (2). Vitamin C, E, and B6 help you absorb zinc also. Seems that people with intestinal problems (celiac disease, inflammatory bowel), vegetarians, those with chronic kidney and liver diseases, alcoholics, and the elderly are most likely to suffer from zinc deficiency (3). Intake of more than 50mg a day (both from diet and from supplements) can lead to improper copper metabolism, altered iron function, reduction of HDL and reduced immune function.
More on zinc to come!
Monday, July 12, 2010
D-D-Depression
I was deficient in vitamin D. Of course. I paid attention to the official word about sunshine - it's bad for you. Ultraviolet radiation chops up your skin cell DNA, and with enough scrambled DNA and a bit of bad luck, you will eventually get cancer. There are several major types of skin cancer, but melanoma is the scariest, also, sun gives you wrinkles and age spots and... so I've been putting on sunblock and avoiding the beach except for a few days a year for a least 10 years.
At the same time the dermatologists and women's magazines were scaring us away from the sun, our own fat phobia and a cultural trend of eating less organ meat scared us away from the best dietary sources of some key fat soluble vitamins (A, D, E, and K). We don't want to be low in these vitamins, as they tend to help orchestrate a lot of functions in the body. Vitamin D (which is found in animal fats, but we tend to get about 90% from the sun) in particular seems to be involved in about 10% of the biochemical soupy stuff our body does every day. It has a lot to do with membrane signaling and scavenging up any screwy cells that are starting to go awry (i.e. cancer), and being low in vitamin D seems to put us at hugely increased risk of cancer, including melanoma. And prostate cancer. And breast cancer. And colon cancer. In fact, women diagnosed with breast cancer in the summer and fall have the best prognosis. There are reports of chemotherapy not working as well in the winter. (1)
There are also links to mental health - depression, bipolar disorder, and psychotic disorders (2) have all increased in populations once most people stopped working outside and went to work inside. The elderly with low vitamin D also have much higher rates of depression (3). In this study of bone mineral density and depression, the elderly with poorer bone status were also more depressed (vitamin D was not explicitly stated to be the possible linking factor for both illnesses).
How would vitamin D affect the brain? Vitamin D is involved in the synthesis of the catecholamines (which are highly involved in neurotransmission). Summer sunlight increases brain serotonin levels twice as much as winter sunlight (4). Neurons and glial cells in all kinds of areas of the brain have vitamin D receptors on them, indicating a brain that is hungry to use vitamin D. Some effects in the nervous system include the synthesis of neurotrophic factors (what I call "brain fertilizer"), inhibition of the creation of an enzyme that chews up nitric oxide, and increasing glutathione levels. (See my previous posts for a molecular description of how some of these brain chemicals are thought to be involved in depression). As vitamin D in the periphery is associated with scavenging and cleaning cancer cells, vitamin D in the central nervous system seems to be involved in detoxification and anti-inflammatory pathways (5)(6).
Does supplementation help depression? Well, the first several studies were disappointing. Harris and Dawson Hughes tried treating Seasonal Affective Disorder with 400 IU vitamin D2 daily. Didn't do squat. Of course, D2 is the plant form of vitamin D (the animal form is D3), and 400 IU is a tiny dose anyway. Lansdowne and buddies gave 400 IU and 800 IU of vitamin D3 to healthy subjects in late winter, and found a lightened mood in those receiving the supplements. Hollis gave people with seasonal affective disorder a single 100,000 IU dose of D3, and found it to be more effective than light therapy, and the improvement was statistically correlated with the improvement in serum 25(OH) vitamin D levels. In this intriguing study, young adults were given access to tanning beds on Mondays and Wednesdays. One bed had UV light, and identical bed didn't. On Fridays, the participants were allowed to choose which bed they wanted. 95% of the time, they chose the UV bed, and participants also reported being more relaxed after a UV tan than in the sham bed.
Unfortunately, there is no large, well-designed study of D3 supplementation for depression that I'm aware of. However, there is enough interesting evidence for such a trial to be done, especially in populations that are more likely to be vitamin D deficient, such as the elderly. Like fish oil, vitamin D3 is cheap (about $10 for a three month supply) and readily available. And given the links to other diseases also (heart disease, stroke, osteoporosis, kidney damage, hypertension, you name it (1)), it would seem prudent (and money-saving from a public health standpoint if a lot of cancer is really prevented by adequate supplementation) to test for and treat deficiency in people with psychiatric disorders.
Another issue is that the RDA for vitamin D is woefully small. About 400 IU daily. This is an amount that will keep you from getting rickets, but it's certainly not an optimal amount for humans. I've heard murmurings that the official RDA is going to be increased to 1000 IU daily, and most decent multivitamins will have 1000 IU of vit D already (that's why your multi says "250%" of RDA of cholecalciferol (vit D3), in case you were wondering). The amount in fortified milk is also small, so that one would need to drink a truckload for it to matter much.
So how much vitamin D do we need, and hey, isn't vitamin D a fat soluble vitamin, which means we can store is for a long time, and couldn't we get toxic from high amounts? The answer is - we probably need many times the current RDA for vitamin D to get reasonable serum levels of the stuff, and yes, we can get toxic, but for most people that is not a realistic worry.
According to the Vitamin D Council, a serum level of 50 ng/ml or higher of 25 (OH) vit D3 is optimal. This level is not without controversy, and 35 is accepted by most as the minimal acceptable level. One probably doesn't want to go above 100, though toxicity has only been reported at serum levels higher than 150 (6). You can't get too much vitamin D from the sun - our skin actually destroys excess vitamin D made there after you have enough for the day. A cool regulatory mechanism if ever I heard one. You *could* theoretically get toxicity from combining high amounts of supplementation *and* lots of sunshine. There's a description on the vitamin D council website of one guy who actually did get toxic from supplements - turned out an industrial accident made his particular variety of vitamins (Prolongevity) contain up to 430 times the amount on the label. This guy was taking between 50,000 IU and 2.6 million IU daily for about two years. He recovered (uneventfully) with some medicine and sunscreen.
So how do you know if you have enough vitamin D? Well, if you are a lifeguard in Miami, you're probably fine. If you have very dark skin, unless you are a lifeguard on the equator, you probably need some supplementation. It can take someone with very dark skin about 5-6 times longer in the sun to get enough vitamin D to have adequate levels compared to someone with very pale skin. If you live north of 40 degrees latitude (above New York City), you only have a few weeks in the summer to expose that skin and get the full amounts of vitamin D you need to last you for the year, and you may have to supplement (again, there is controversy about this, especially as very pale people of Northern European ancestry seemed to live to the far north of 40 degrees and had only a few days a year they could possibly get adequate vitamin D from the sun). Anyway, to really know your blood levels of vitamin D, you need to get a blood test. The key level you need to know is 25-OH vitamin D3. If your doctor orders 1,25 OH or just "total vitamin D" you might not get the right number, so make sure you look at the lab slip. If you don't want to go to the doctor, you can go to this website and pay $65 or so for a home testing kit. Unless you live in New York state, where home testing via mailing bloodspot cards is apparently illegal.
So let's say you ordered a home test kit and stabbed your finger and shipped your spot of blood back to the lab and your level comes out to be 31 ng/ml. There's a general rule of thumb that 1000 IU of supplementation daily will increase blood levels by 10 ng/ml. (Use geltabs in oil suspension rather than tablets, unless you are always going to be taking the supplement with some oil/fat.) So let's say we are aiming for 50 - then one could take 2000 IU D3 daily in the morning. If you were already supplementing at 1000 IU (in your multivitamin, for example), you could take an additional 2000 IU daily, and you could skip the additional supplementation on days you spent time in the sun (without suncreen - sunscreen will block the UVB rays that synthesize vitamin D in the skin). Arms and legs exposure for 20 minutes midday in the summertime in Boston about 3-4 times a week would get you a goodly amount (probably around 10,000-12,000 IU with each exposure) if you have pale skin. That kind of exposure is not such a big deal for skin cancer risk, as long as you avoid burning. The farther south you are (until you get to the equator, then reverse!) and the paler you are, the less time you need.
It is standard practice for physicians to treat vitamin D deficiency with 50,000 IU pills once a week for 8-12 weeks, then recheck. Unfortunately, a recent JAMA study of similar treatment in elderly women (admittedly it was 50,000 IU D3 daily for 10 days) resulted in a great increase in the number of fractures. The editorial for the study thought 4000 IU daily was a safer, more physiological amount to treat deficiency, and be sure you are getting adequate calcium too. However, if you supplement with calcium and vitamin D3, as your vitamin D levels become adequate, your absorption of calcium can increase quite a bit (see slides 18-36). Therefore, you may not need as much calcium if you take vitamin D. The recommendations are not set in stone, though. (Our current RDA for calcium may be high simply because we don't get enough vitamin D!) Also, most of the prescription vitamin D doses are D2, not D3, and D2, the plant form, is probably not nearly as effective as the animal-derived form, D3.
Here's yet another thing to watch out for with higher-dose vitamin D3 supplementation. Occasionally, you will unmask some hyperparathyroidism. If someone's parathyroid is working on overdrive, he or she will start to have serum levels of calcium that are way too high, potentiated by the higher doses of vitamin D3. This can be dangerous if it goes undetected, though high calcium levels can be very uncomfortable, with symptoms of muscle twitching, cramping, fatigue, insomnia, depression, thinning hair, high blood pressure, bone pain, kidney stones, headaches, and heart palpitations. Since bone pain, fatigue, depression, and insomnia can be symptoms of low vitamin D3 as well, it is important to realize that if your symptoms get worse with supplementation, you should see your doctor and get a calcium and parathyroid hormone checked. While I personally don't check calcium levels with the initial vitamin D level, I do check it for follow-up ones (I tend to check after three months or so). While home testing is a neat option for the initial level, seeing your doctor about follow up and his or her suggestions for supplementation is a good idea if your level is found to be low.
And what about those other fat soluble vitamins: A, E, and K? It is important that you have enough of each of them, or things can get a bit screwy. For example, in order to create bone, you need adequate vitamin D (at least a level of 20-30), adequate calcium, AND vitamin K2. The best sources are animal fats, particularly the fats from animals that eat their natural diet - grass for cows, or grubs and grains and whatnot for chickens. So pastured chicken egg yolks, and butter and liver from pastured cows. Conventionally-raised eggs can have about 1/20th the vitamins of pastured eggs, and butter from grain-fed cows may have as little as 1/200th as much K2 as pastured butter, so it really does matter what the animals you eat ate. Vitamin A is also found in multivitamins and it is important not to have too much vitamin D3 and too little A, so I've recommended a multivitamin in addition to vit D3 for people who are deficient in serum 25 (OH) vitamin D (and aren't big liver eaters :)).
Strict vegetarians - here's another place you need to be super careful about what you eat, and you might need to choke down some fermented soy products (netto) to get enough Vitamin K2. K2 isn't found in a standard multivitamin (though we can make K1 into K2, if our intestinal flora is happy, which it might not be on a standard American diet - no idea about flora in a vegan diet. Interesting question) and is vital to bone formation and in keeping our arteries resilient. K2 is what warfarin blocks, so don't take it if you are on coumadin for blood clots. (Though why are you at risk for blood clots in the first place? maybe too much omega 6 compared to omega 3??)
So, a key part of good, lasting health is either to get plenty of (safe - no burns!) sun as our ancestors did, or use today's science to get your blood levels of vitamin D where they need to be. Chat with your doctor about it - and check out the Vitamin D Council Website for more information.
At the same time the dermatologists and women's magazines were scaring us away from the sun, our own fat phobia and a cultural trend of eating less organ meat scared us away from the best dietary sources of some key fat soluble vitamins (A, D, E, and K). We don't want to be low in these vitamins, as they tend to help orchestrate a lot of functions in the body. Vitamin D (which is found in animal fats, but we tend to get about 90% from the sun) in particular seems to be involved in about 10% of the biochemical soupy stuff our body does every day. It has a lot to do with membrane signaling and scavenging up any screwy cells that are starting to go awry (i.e. cancer), and being low in vitamin D seems to put us at hugely increased risk of cancer, including melanoma. And prostate cancer. And breast cancer. And colon cancer. In fact, women diagnosed with breast cancer in the summer and fall have the best prognosis. There are reports of chemotherapy not working as well in the winter. (1)
There are also links to mental health - depression, bipolar disorder, and psychotic disorders (2) have all increased in populations once most people stopped working outside and went to work inside. The elderly with low vitamin D also have much higher rates of depression (3). In this study of bone mineral density and depression, the elderly with poorer bone status were also more depressed (vitamin D was not explicitly stated to be the possible linking factor for both illnesses).
How would vitamin D affect the brain? Vitamin D is involved in the synthesis of the catecholamines (which are highly involved in neurotransmission). Summer sunlight increases brain serotonin levels twice as much as winter sunlight (4). Neurons and glial cells in all kinds of areas of the brain have vitamin D receptors on them, indicating a brain that is hungry to use vitamin D. Some effects in the nervous system include the synthesis of neurotrophic factors (what I call "brain fertilizer"), inhibition of the creation of an enzyme that chews up nitric oxide, and increasing glutathione levels. (See my previous posts for a molecular description of how some of these brain chemicals are thought to be involved in depression). As vitamin D in the periphery is associated with scavenging and cleaning cancer cells, vitamin D in the central nervous system seems to be involved in detoxification and anti-inflammatory pathways (5)(6).
Does supplementation help depression? Well, the first several studies were disappointing. Harris and Dawson Hughes tried treating Seasonal Affective Disorder with 400 IU vitamin D2 daily. Didn't do squat. Of course, D2 is the plant form of vitamin D (the animal form is D3), and 400 IU is a tiny dose anyway. Lansdowne and buddies gave 400 IU and 800 IU of vitamin D3 to healthy subjects in late winter, and found a lightened mood in those receiving the supplements. Hollis gave people with seasonal affective disorder a single 100,000 IU dose of D3, and found it to be more effective than light therapy, and the improvement was statistically correlated with the improvement in serum 25(OH) vitamin D levels. In this intriguing study, young adults were given access to tanning beds on Mondays and Wednesdays. One bed had UV light, and identical bed didn't. On Fridays, the participants were allowed to choose which bed they wanted. 95% of the time, they chose the UV bed, and participants also reported being more relaxed after a UV tan than in the sham bed.
Unfortunately, there is no large, well-designed study of D3 supplementation for depression that I'm aware of. However, there is enough interesting evidence for such a trial to be done, especially in populations that are more likely to be vitamin D deficient, such as the elderly. Like fish oil, vitamin D3 is cheap (about $10 for a three month supply) and readily available. And given the links to other diseases also (heart disease, stroke, osteoporosis, kidney damage, hypertension, you name it (1)), it would seem prudent (and money-saving from a public health standpoint if a lot of cancer is really prevented by adequate supplementation) to test for and treat deficiency in people with psychiatric disorders.
Another issue is that the RDA for vitamin D is woefully small. About 400 IU daily. This is an amount that will keep you from getting rickets, but it's certainly not an optimal amount for humans. I've heard murmurings that the official RDA is going to be increased to 1000 IU daily, and most decent multivitamins will have 1000 IU of vit D already (that's why your multi says "250%" of RDA of cholecalciferol (vit D3), in case you were wondering). The amount in fortified milk is also small, so that one would need to drink a truckload for it to matter much.
So how much vitamin D do we need, and hey, isn't vitamin D a fat soluble vitamin, which means we can store is for a long time, and couldn't we get toxic from high amounts? The answer is - we probably need many times the current RDA for vitamin D to get reasonable serum levels of the stuff, and yes, we can get toxic, but for most people that is not a realistic worry.
According to the Vitamin D Council, a serum level of 50 ng/ml or higher of 25 (OH) vit D3 is optimal. This level is not without controversy, and 35 is accepted by most as the minimal acceptable level. One probably doesn't want to go above 100, though toxicity has only been reported at serum levels higher than 150 (6). You can't get too much vitamin D from the sun - our skin actually destroys excess vitamin D made there after you have enough for the day. A cool regulatory mechanism if ever I heard one. You *could* theoretically get toxicity from combining high amounts of supplementation *and* lots of sunshine. There's a description on the vitamin D council website of one guy who actually did get toxic from supplements - turned out an industrial accident made his particular variety of vitamins (Prolongevity) contain up to 430 times the amount on the label. This guy was taking between 50,000 IU and 2.6 million IU daily for about two years. He recovered (uneventfully) with some medicine and sunscreen.
So how do you know if you have enough vitamin D? Well, if you are a lifeguard in Miami, you're probably fine. If you have very dark skin, unless you are a lifeguard on the equator, you probably need some supplementation. It can take someone with very dark skin about 5-6 times longer in the sun to get enough vitamin D to have adequate levels compared to someone with very pale skin. If you live north of 40 degrees latitude (above New York City), you only have a few weeks in the summer to expose that skin and get the full amounts of vitamin D you need to last you for the year, and you may have to supplement (again, there is controversy about this, especially as very pale people of Northern European ancestry seemed to live to the far north of 40 degrees and had only a few days a year they could possibly get adequate vitamin D from the sun). Anyway, to really know your blood levels of vitamin D, you need to get a blood test. The key level you need to know is 25-OH vitamin D3. If your doctor orders 1,25 OH or just "total vitamin D" you might not get the right number, so make sure you look at the lab slip. If you don't want to go to the doctor, you can go to this website and pay $65 or so for a home testing kit. Unless you live in New York state, where home testing via mailing bloodspot cards is apparently illegal.
So let's say you ordered a home test kit and stabbed your finger and shipped your spot of blood back to the lab and your level comes out to be 31 ng/ml. There's a general rule of thumb that 1000 IU of supplementation daily will increase blood levels by 10 ng/ml. (Use geltabs in oil suspension rather than tablets, unless you are always going to be taking the supplement with some oil/fat.) So let's say we are aiming for 50 - then one could take 2000 IU D3 daily in the morning. If you were already supplementing at 1000 IU (in your multivitamin, for example), you could take an additional 2000 IU daily, and you could skip the additional supplementation on days you spent time in the sun (without suncreen - sunscreen will block the UVB rays that synthesize vitamin D in the skin). Arms and legs exposure for 20 minutes midday in the summertime in Boston about 3-4 times a week would get you a goodly amount (probably around 10,000-12,000 IU with each exposure) if you have pale skin. That kind of exposure is not such a big deal for skin cancer risk, as long as you avoid burning. The farther south you are (until you get to the equator, then reverse!) and the paler you are, the less time you need.
It is standard practice for physicians to treat vitamin D deficiency with 50,000 IU pills once a week for 8-12 weeks, then recheck. Unfortunately, a recent JAMA study of similar treatment in elderly women (admittedly it was 50,000 IU D3 daily for 10 days) resulted in a great increase in the number of fractures. The editorial for the study thought 4000 IU daily was a safer, more physiological amount to treat deficiency, and be sure you are getting adequate calcium too. However, if you supplement with calcium and vitamin D3, as your vitamin D levels become adequate, your absorption of calcium can increase quite a bit (see slides 18-36). Therefore, you may not need as much calcium if you take vitamin D. The recommendations are not set in stone, though. (Our current RDA for calcium may be high simply because we don't get enough vitamin D!) Also, most of the prescription vitamin D doses are D2, not D3, and D2, the plant form, is probably not nearly as effective as the animal-derived form, D3.
Here's yet another thing to watch out for with higher-dose vitamin D3 supplementation. Occasionally, you will unmask some hyperparathyroidism. If someone's parathyroid is working on overdrive, he or she will start to have serum levels of calcium that are way too high, potentiated by the higher doses of vitamin D3. This can be dangerous if it goes undetected, though high calcium levels can be very uncomfortable, with symptoms of muscle twitching, cramping, fatigue, insomnia, depression, thinning hair, high blood pressure, bone pain, kidney stones, headaches, and heart palpitations. Since bone pain, fatigue, depression, and insomnia can be symptoms of low vitamin D3 as well, it is important to realize that if your symptoms get worse with supplementation, you should see your doctor and get a calcium and parathyroid hormone checked. While I personally don't check calcium levels with the initial vitamin D level, I do check it for follow-up ones (I tend to check after three months or so). While home testing is a neat option for the initial level, seeing your doctor about follow up and his or her suggestions for supplementation is a good idea if your level is found to be low.
And what about those other fat soluble vitamins: A, E, and K? It is important that you have enough of each of them, or things can get a bit screwy. For example, in order to create bone, you need adequate vitamin D (at least a level of 20-30), adequate calcium, AND vitamin K2. The best sources are animal fats, particularly the fats from animals that eat their natural diet - grass for cows, or grubs and grains and whatnot for chickens. So pastured chicken egg yolks, and butter and liver from pastured cows. Conventionally-raised eggs can have about 1/20th the vitamins of pastured eggs, and butter from grain-fed cows may have as little as 1/200th as much K2 as pastured butter, so it really does matter what the animals you eat ate. Vitamin A is also found in multivitamins and it is important not to have too much vitamin D3 and too little A, so I've recommended a multivitamin in addition to vit D3 for people who are deficient in serum 25 (OH) vitamin D (and aren't big liver eaters :)).
Strict vegetarians - here's another place you need to be super careful about what you eat, and you might need to choke down some fermented soy products (netto) to get enough Vitamin K2. K2 isn't found in a standard multivitamin (though we can make K1 into K2, if our intestinal flora is happy, which it might not be on a standard American diet - no idea about flora in a vegan diet. Interesting question) and is vital to bone formation and in keeping our arteries resilient. K2 is what warfarin blocks, so don't take it if you are on coumadin for blood clots. (Though why are you at risk for blood clots in the first place? maybe too much omega 6 compared to omega 3??)
So, a key part of good, lasting health is either to get plenty of (safe - no burns!) sun as our ancestors did, or use today's science to get your blood levels of vitamin D where they need to be. Chat with your doctor about it - and check out the Vitamin D Council Website for more information.
Saturday, July 3, 2010
Low Cholesterol and Suicide
Low serum cholesterol has been linked in numerous scientific papers to suicide, accidents, and violence (1)(2)(3)(4)(5)(6)(7)... there are a bunch more, but I'm a bit weary of linking! This is why I write a blog, and not a peer-reviewed journal. Anyway, no one knows to this day whether depression, violence, and suicidal risk have a metabolic byproduct of low cholesterol, or whether having low cholesterol will predispose you to suicide out of hand (here's a rather snarky editorial pointing out that fact (8)). Some trials of statins (with the resultant crackerjack drop in cholesterol) will show no effect on suicide (9). A statin skeptic's favorite study, the J-LIT trial, showed deaths by accidents/suicides increased threefold in the group with total cholesterol less than 160 (yes, the p was .09, but that means there is only a 91% chance that finding didn't happen by random happenstance (10)).
Now, why could serum cholesterol have anything to do with the brain and depression? Good question - and the first question to ask in any theory of the brain is do the peripheral levels of something have anything at all to do with the central nervous system amounts of the same thing - so do serum cholesterol levels match up to relative amounts of cholesterol in the brain? They do (11). And cholesterol is important in the brain. Synapses, where brain function goes live, have to have cholesterol to form. Brain signaling is all about membranes, and cell membranes are constructed from fat. Cholesterol and the omega 3 and 6 fatty acids are the most important molecules in the synapse. If your brain fat is significantly different from so-called "normal" fat (which I'll go back to the hunter gatherer paradigm and say an HG's brain is going to have the approximate fat constituents for which we are evolved), the signaling in your brain could be very different too (12). Scientific papers will call this "alterations of membrane fluidity." (13)
So we know that low serum cholesterol is associated with suicide, violence, and accidents. (Another wrench in the works - low serum cholesterol is also associated with low CSF serotonin - which is of course associated with increased violence and suicide! These association studies are enough to make anyone give up and go boar hunting.) But does dietary fat intake have anything to do with depression and suicide? (Remember, serum cholesterol is often a chancy thing to connect to diet, after all.) Well, of 3400 some-odd people in Finland, the omega-3 rich fish consumers (14) had significantly less depression than abstainers, but the finding was more robust among women (no one knows why). In this round-up of 408 suicide attempters and an equal number of controls, there was no difference in saturated fat intake between attempters and controls, but the attempters did report lower fiber and polyunsaturated fat intake.
And, finally, do statins cause depression? I've seen statins cause or exacerbate depression several times in my clinical practice, especially in women. (I've also seen them cause paranoid psychosis a couple of times - twice in women and once a long time ago in a man. The psychosis remitted with withdrawal of the statin). Very striking! But anecdotes aren't clinical trials. This brand new study shows no link, and statins actually seemed to decrease depression in elderly women. This study also shows no link. This study shows that chronic cholesterol depletion via statin use decreases the functioning of the serotonin 1A receptors in humans, by decreasing the ability of the receptor to bind to its friendly neighborhood G proteins and other binding proteins. (The serotonin 1A receptor is more highly associated with anxiety-type symptoms than depression).
Clear as mud! But stepping back to whole health, I never like the idea of "the lower the better, no matter what," which seems to be the prevailing winds of cholesterol treatment right now. Usually, chemicals in the body are important for something, or else they wouldn't be there, and typically, a U-shaped curve emerges, where too little or too much (cholesterol, vitamin D, omega 3s, immunoglobulins, you name it!) is bad for human health. Here's an example of the U-shaped curve from the J-Lit trial (via Hyperlipid), showing increased cardiac death at low and high serum cholesterol levels.
Statins may have their role, but please don't put them in the water. In my opinion, adopt a whole foods, paleo-style diet. Keep yourself in the middle of that U-shaped curve for what our human systems were evolved for. It may help your mood, too, especially if you are a woman who eats fish!
(Follow-up posts: Low Cholesterol and Suicide 2 and Your Brain Needs Cholesterol, Don't Go Too Low)
Now, why could serum cholesterol have anything to do with the brain and depression? Good question - and the first question to ask in any theory of the brain is do the peripheral levels of something have anything at all to do with the central nervous system amounts of the same thing - so do serum cholesterol levels match up to relative amounts of cholesterol in the brain? They do (11). And cholesterol is important in the brain. Synapses, where brain function goes live, have to have cholesterol to form. Brain signaling is all about membranes, and cell membranes are constructed from fat. Cholesterol and the omega 3 and 6 fatty acids are the most important molecules in the synapse. If your brain fat is significantly different from so-called "normal" fat (which I'll go back to the hunter gatherer paradigm and say an HG's brain is going to have the approximate fat constituents for which we are evolved), the signaling in your brain could be very different too (12). Scientific papers will call this "alterations of membrane fluidity." (13)
So we know that low serum cholesterol is associated with suicide, violence, and accidents. (Another wrench in the works - low serum cholesterol is also associated with low CSF serotonin - which is of course associated with increased violence and suicide! These association studies are enough to make anyone give up and go boar hunting.) But does dietary fat intake have anything to do with depression and suicide? (Remember, serum cholesterol is often a chancy thing to connect to diet, after all.) Well, of 3400 some-odd people in Finland, the omega-3 rich fish consumers (14) had significantly less depression than abstainers, but the finding was more robust among women (no one knows why). In this round-up of 408 suicide attempters and an equal number of controls, there was no difference in saturated fat intake between attempters and controls, but the attempters did report lower fiber and polyunsaturated fat intake.
And, finally, do statins cause depression? I've seen statins cause or exacerbate depression several times in my clinical practice, especially in women. (I've also seen them cause paranoid psychosis a couple of times - twice in women and once a long time ago in a man. The psychosis remitted with withdrawal of the statin). Very striking! But anecdotes aren't clinical trials. This brand new study shows no link, and statins actually seemed to decrease depression in elderly women. This study also shows no link. This study shows that chronic cholesterol depletion via statin use decreases the functioning of the serotonin 1A receptors in humans, by decreasing the ability of the receptor to bind to its friendly neighborhood G proteins and other binding proteins. (The serotonin 1A receptor is more highly associated with anxiety-type symptoms than depression).
Clear as mud! But stepping back to whole health, I never like the idea of "the lower the better, no matter what," which seems to be the prevailing winds of cholesterol treatment right now. Usually, chemicals in the body are important for something, or else they wouldn't be there, and typically, a U-shaped curve emerges, where too little or too much (cholesterol, vitamin D, omega 3s, immunoglobulins, you name it!) is bad for human health. Here's an example of the U-shaped curve from the J-Lit trial (via Hyperlipid), showing increased cardiac death at low and high serum cholesterol levels.
Statins may have their role, but please don't put them in the water. In my opinion, adopt a whole foods, paleo-style diet. Keep yourself in the middle of that U-shaped curve for what our human systems were evolved for. It may help your mood, too, especially if you are a woman who eats fish!
(Follow-up posts: Low Cholesterol and Suicide 2 and Your Brain Needs Cholesterol, Don't Go Too Low)
Thursday, June 24, 2010
Diet, Depression, and Anxiety
This post will focus on a single paper, published in March 2010 in the American Journal of Psychiatry: Association of Western and Traditional Diets With Depression and Anxiety in Women. (Thank you to Dr. Hale for pointing out the study). In the introduction, the authors make note that depression and anxiety are highly prevalent with other chronic dietary-related illnesses such as cardiovascular disease, obesity, and type 2 diabetes. At the same time, psychiatry lacks evidence-based prevention and treatment strategies based on dietary modification. That may be for the best, considering what has happened with obesity and type II diabetes over the past 30 years, but that is, in part, why I'm trying to get the information out, blog-wise.
So - the study! Well, these researchers in Australia hijacked an ongoing study, called the "Geelong Osteoporosis Study." Thousands of intrepid women were randomly picked from compulsory voting rolls, and all told, 1046 women ages 20-93 were followed for roughly 10 years for the diet and depression part. Each participant filled out yearly questionnaires about her diet. (Problem number one - imagine I gave you a questionnaire about your usual consumption of 74 foods, 6 alcoholic beverages, and the type of bread, dairy products, and fat spreads you used? How accurate could it be? The researchers say the "comprehensive food frequency questionnaire" was a validated instrument, but one must keep limitations in mind.)
Then, all participants were given a SCID (that's a standard structured clinical interview used to diagnose psychiatric disorders in research), and they looked for current diagnoses of major depressive disorder, dysthymia (a low-grade, ongoing depression), and anxiety disorders. Also, a wide variety of statistical analysis tools were used to account for so-called "covariates" such as socioeconomic status, physical activity, alcohol consumption, and smoking. (Problem number two - which is the major problem with any observational study - one can never really account for all the covariates. For example, people who drink moderate amounts of wine have less heart disease. Wine could be a factor in that. Or perhaps people who drink wine happen to exercise more. Or maybe people who drink wine also have magical hearts. We really don't know. If you take a group of people and force-feed some a glass of wine or two a day, and then tell another group to abstain, then see if there is a difference in heart disease between the two groups, then you have a prospective trial, and that's not the kind of data we're talking about with the current study I'm examining, which is an observational study. We end up with associations and correlations with such studies, which are interesting, but could be meaningless. Tom Naughton brings up this issue and the 2010 US dietary guidelines in this blog post. Don't click that link if you have extremely delicate sensibilities.) The researchers weighed and measured the height of all the participants also.
Results! Everyone's diet was analyzed and segregated into three basic groups - traditional, Western, and modern. Traditional diets were comprised of vegetables, fruit, beef, lamb, fish, and whole grain foods. A Western pattern was associated with meat pies (Australian fast food), processed meats, pizza, chips (I seriously do not know if they mean french fries or potato chips here - Australian readers, help me out!), hamburgers, white bread, sugar, flavored milk drinks, and beer. The "modern" diet consisted of fruits, salads, fish, tofu, beans, nuts, yogurt, and red wine (in other words, the people who read the news reports on all the observational studies out there...).
And the punch line? A traditional dietary pattern "was associated with a lower likelihood of depressive and anxiety disorders."
Traditional fruit, veggie, lamb, beef, fish and whole grain eaters had a 25% lower risk for major chronic disease (cardiovascular disease and cancer) after 10 years. They had 35% reduced odds for having major depression or dysthymia, and 32% reduced odds for anxiety disorders. The "Western" (junk) and "modern" (bean, fish, wine, and tofu) eaters fared about the same, but the Western eaters were slightly more depressed.
So there you have it! Beans and tofu and meat pies are correlated with depression and anxiety! Well, the authors of the study are pretty fair about the limitations of their design in the discussion. The do mention another study and how high-fat, high-sugar diets caused decreased hippocampal BDNF in animals, and that diets high in refined carbohydrates are associated with more inflammation. They also made note that a Mediterranean-style diet (which would roughly correspond to the traditional and modern diets) tends to decrease inflammatory markers.
I wonder what the data would look like without the whole grain eaters? Also, full fat dairy versus low fat dairy. Why do researchers never present the really interesting stuff to a paleolithic diet-inspired psychiatrist?
(A sobering thought is that I may be the only paleolithic-diet inspired psychiatrist).
So - the study! Well, these researchers in Australia hijacked an ongoing study, called the "Geelong Osteoporosis Study." Thousands of intrepid women were randomly picked from compulsory voting rolls, and all told, 1046 women ages 20-93 were followed for roughly 10 years for the diet and depression part. Each participant filled out yearly questionnaires about her diet. (Problem number one - imagine I gave you a questionnaire about your usual consumption of 74 foods, 6 alcoholic beverages, and the type of bread, dairy products, and fat spreads you used? How accurate could it be? The researchers say the "comprehensive food frequency questionnaire" was a validated instrument, but one must keep limitations in mind.)
Then, all participants were given a SCID (that's a standard structured clinical interview used to diagnose psychiatric disorders in research), and they looked for current diagnoses of major depressive disorder, dysthymia (a low-grade, ongoing depression), and anxiety disorders. Also, a wide variety of statistical analysis tools were used to account for so-called "covariates" such as socioeconomic status, physical activity, alcohol consumption, and smoking. (Problem number two - which is the major problem with any observational study - one can never really account for all the covariates. For example, people who drink moderate amounts of wine have less heart disease. Wine could be a factor in that. Or perhaps people who drink wine happen to exercise more. Or maybe people who drink wine also have magical hearts. We really don't know. If you take a group of people and force-feed some a glass of wine or two a day, and then tell another group to abstain, then see if there is a difference in heart disease between the two groups, then you have a prospective trial, and that's not the kind of data we're talking about with the current study I'm examining, which is an observational study. We end up with associations and correlations with such studies, which are interesting, but could be meaningless. Tom Naughton brings up this issue and the 2010 US dietary guidelines in this blog post. Don't click that link if you have extremely delicate sensibilities.) The researchers weighed and measured the height of all the participants also.
Results! Everyone's diet was analyzed and segregated into three basic groups - traditional, Western, and modern. Traditional diets were comprised of vegetables, fruit, beef, lamb, fish, and whole grain foods. A Western pattern was associated with meat pies (Australian fast food), processed meats, pizza, chips (I seriously do not know if they mean french fries or potato chips here - Australian readers, help me out!), hamburgers, white bread, sugar, flavored milk drinks, and beer. The "modern" diet consisted of fruits, salads, fish, tofu, beans, nuts, yogurt, and red wine (in other words, the people who read the news reports on all the observational studies out there...).
And the punch line? A traditional dietary pattern "was associated with a lower likelihood of depressive and anxiety disorders."
Traditional fruit, veggie, lamb, beef, fish and whole grain eaters had a 25% lower risk for major chronic disease (cardiovascular disease and cancer) after 10 years. They had 35% reduced odds for having major depression or dysthymia, and 32% reduced odds for anxiety disorders. The "Western" (junk) and "modern" (bean, fish, wine, and tofu) eaters fared about the same, but the Western eaters were slightly more depressed.
So there you have it! Beans and tofu and meat pies are correlated with depression and anxiety! Well, the authors of the study are pretty fair about the limitations of their design in the discussion. The do mention another study and how high-fat, high-sugar diets caused decreased hippocampal BDNF in animals, and that diets high in refined carbohydrates are associated with more inflammation. They also made note that a Mediterranean-style diet (which would roughly correspond to the traditional and modern diets) tends to decrease inflammatory markers.
I wonder what the data would look like without the whole grain eaters? Also, full fat dairy versus low fat dairy. Why do researchers never present the really interesting stuff to a paleolithic diet-inspired psychiatrist?
(A sobering thought is that I may be the only paleolithic-diet inspired psychiatrist).
Tuesday, June 22, 2010
Depression 2 - Inflammation Boogaloo
It is well known that symptoms of clinical depression are likely mediated by inflammation in the brain. A number of lines of evidence support this idea, including that depressed people, old and young, have elevated levels of certain inflammatory proteins in the plasma and cerebrospinal fluid. Anti-inflammatory agents treat depression, and pharmacologic agents such as interferon-alpha, that cause depression, also lead to increases in the inflammatory proteins IL-6 and TNF-alpha. In addition, when someone who is depressed responds to antidepressant treatment, these same inflammation markers decrease (1). People with generalized inflammatory syndromes (such as acute viral illness, rheumatoid arthritis, insulin resistance, and cardiovascular disease) have higher rates of depression than the general population too. I also notice in my clinic that people who have had bone surgery tend to get depressed for a few weeks after the operation, more so than people who had other kinds of surgery. I always wonder if sawing through the bones releases an enormous wave of inflammatory cytokines.
There are several suspected mechanisms of how this inflammation leads to depression, many of them very cute. Here's one - the amino acid tryptophan is a precursor to Eli Lilly's second favorite neurotransmitter, serotonin*. Turns out that tryptophan is also the precursor to kynurenic. When the inflammatory cascade is activated, more tryptophan is made into kynurenic, which leaves less tryptophan around to make into Eli Lilly's second favorite neurotransmitter, serotonin. And everyone knows that without serotonin, we're unhappy (and angry). SSRIs work, in part, by undermining the effect of the inflammatory cytokines, pushing more tryptophan to be made into serotonin.
Here's another mechanism - inflammatory cytokines also interfere with the regulation of another neurotransmitter, glutamate. Glutamate is an excitatory neurotransmitter that, if left to go wild, can pound our NMDA receptors in the brain and wreak major havoc. No one wants overexcited NMDA receptors, and clinical depression is one among many nasty brain issues that can be caused by overexcitement. Astrocytes, little clean-up cells in the brain, are supposed to mop up excess glutamate to keep it from going nutso on the NMDA. Turns out inflammatory cytokines interfere with the clean-up process (2). The horse tranquilizer (and club drug) ketamine, when administered IV, can eliminate symptoms of severe depression pretty much immediately in some cases (do NOT try this at home) (3). Ketamine helps the astrocytes mop up glutamate, and it is assumed that this is how ketamine instantly cures depression. Unfortunately, the effects of ketamine don't last, otherwise it would be a nifty psychiatrist's tool, indeed.
Finally, inflammatory cytokines also push the brain from a general environment of happy "neuroplasticity" (mediated finally by our old friend, BDNF) towards an environment of neurotoxicity (sounds bad, and it is!).
In my post on vegetable oils, I made note of a popular theory that a relative imbalance between the consumption of anti-inflammatory omega 3 fatty acids (fish oil) and inflammatory omega 6 fatty acids (vegetable oil, such as corn oil) predisposes us to inflammation. The omega 6 fatty acids are the precursors for many of the nasty, depressing cytokines mentioned above (such as IL-6). Well, an absolute flurry of research has been done in this area in the last decade or so, because omega 3 fish oils would be a nifty, low side effect, cheap treatment for depression, if it worked. Some studies have been disappointing (4)(5). However, the largest study yet, hot off the presses, does show benefit (equal to a prescription antidepressant) for those who have depression, but not concurrent anxiety, at a daily dose of 150mg DHA and about 1000mg EPA. (DHA and EPA are fish oil omega 3 fatty acids).
Well, neat! But adding extra omega 3 is just one half of the omega 6/omega 3 balancing act. What if we decreased dietary omega 6 at the same time? Researchers looked at the blood levels and tissue levels of all the different kinds of fatty acid in this recent paper. Turns out that depressed people had higher amounts of omega-6 fatty acids, but the amounts of monounsaturated fats, saturated fats, and omega 3 fats were about the same between depressed and non-depressed individuals. (Other studies showed a decreased amount of omega 3 and an increased amount of omega 6 (6)).
As far as I know, there haven't been any major studies testing both a dietary decrease in omega 6 and supplementation with omega 3 for depression, but it would be an interesting intervention. Dr. Guyenet uses the work of Dr. Lands to make a case that reducing omega 6 PUFAs to less than 4% of calories would be a great way to reduce overall inflammation, and lots of Western disease. Hunter gatherers, such as the Kitavans, consume less than 1% of calories from omega 6 fatty acids. Right now, in the US, about 7% of our calories are omega 6 PUFAs.
In summary - inflammation is depressing! Fish oil may make it better, but avoiding corn/safflower/sunflower/soybean oil (theoretically) makes it all better still, and is the natural state for which we are evolved.
*Eli Lilly's favorite neurotransmitter is, of course, dopamine.
There are several suspected mechanisms of how this inflammation leads to depression, many of them very cute. Here's one - the amino acid tryptophan is a precursor to Eli Lilly's second favorite neurotransmitter, serotonin*. Turns out that tryptophan is also the precursor to kynurenic. When the inflammatory cascade is activated, more tryptophan is made into kynurenic, which leaves less tryptophan around to make into Eli Lilly's second favorite neurotransmitter, serotonin. And everyone knows that without serotonin, we're unhappy (and angry). SSRIs work, in part, by undermining the effect of the inflammatory cytokines, pushing more tryptophan to be made into serotonin.
Here's another mechanism - inflammatory cytokines also interfere with the regulation of another neurotransmitter, glutamate. Glutamate is an excitatory neurotransmitter that, if left to go wild, can pound our NMDA receptors in the brain and wreak major havoc. No one wants overexcited NMDA receptors, and clinical depression is one among many nasty brain issues that can be caused by overexcitement. Astrocytes, little clean-up cells in the brain, are supposed to mop up excess glutamate to keep it from going nutso on the NMDA. Turns out inflammatory cytokines interfere with the clean-up process (2). The horse tranquilizer (and club drug) ketamine, when administered IV, can eliminate symptoms of severe depression pretty much immediately in some cases (do NOT try this at home) (3). Ketamine helps the astrocytes mop up glutamate, and it is assumed that this is how ketamine instantly cures depression. Unfortunately, the effects of ketamine don't last, otherwise it would be a nifty psychiatrist's tool, indeed.
Finally, inflammatory cytokines also push the brain from a general environment of happy "neuroplasticity" (mediated finally by our old friend, BDNF) towards an environment of neurotoxicity (sounds bad, and it is!).
In my post on vegetable oils, I made note of a popular theory that a relative imbalance between the consumption of anti-inflammatory omega 3 fatty acids (fish oil) and inflammatory omega 6 fatty acids (vegetable oil, such as corn oil) predisposes us to inflammation. The omega 6 fatty acids are the precursors for many of the nasty, depressing cytokines mentioned above (such as IL-6). Well, an absolute flurry of research has been done in this area in the last decade or so, because omega 3 fish oils would be a nifty, low side effect, cheap treatment for depression, if it worked. Some studies have been disappointing (4)(5). However, the largest study yet, hot off the presses, does show benefit (equal to a prescription antidepressant) for those who have depression, but not concurrent anxiety, at a daily dose of 150mg DHA and about 1000mg EPA. (DHA and EPA are fish oil omega 3 fatty acids).
Well, neat! But adding extra omega 3 is just one half of the omega 6/omega 3 balancing act. What if we decreased dietary omega 6 at the same time? Researchers looked at the blood levels and tissue levels of all the different kinds of fatty acid in this recent paper. Turns out that depressed people had higher amounts of omega-6 fatty acids, but the amounts of monounsaturated fats, saturated fats, and omega 3 fats were about the same between depressed and non-depressed individuals. (Other studies showed a decreased amount of omega 3 and an increased amount of omega 6 (6)).
As far as I know, there haven't been any major studies testing both a dietary decrease in omega 6 and supplementation with omega 3 for depression, but it would be an interesting intervention. Dr. Guyenet uses the work of Dr. Lands to make a case that reducing omega 6 PUFAs to less than 4% of calories would be a great way to reduce overall inflammation, and lots of Western disease. Hunter gatherers, such as the Kitavans, consume less than 1% of calories from omega 6 fatty acids. Right now, in the US, about 7% of our calories are omega 6 PUFAs.
In summary - inflammation is depressing! Fish oil may make it better, but avoiding corn/safflower/sunflower/soybean oil (theoretically) makes it all better still, and is the natural state for which we are evolved.
*Eli Lilly's favorite neurotransmitter is, of course, dopamine.
Friday, June 18, 2010
Depression 1
I realize this blog is titled "Evolutionary Psychiatry," and I have yet to actually mention much psychiatry. In part because my job is to stick my nose where it doesn't belong, such asking you about your relationship with your father, or smack in the middle of metabolic syndrome and weight loss. In part we began with the paleolithic theories because I wanted to describe a basis of healthy eating, and put out some more information to say I'm not coming completely out of left field, though some of my perspectives aren't exactly conventional (though perhaps they are exceedingly conventional, seeing as how I prefer to eat as my ancestors did). I'm happy to be proven wrong about my ideas and perspectives if I find something that changes my mind along the way.
But let's talk about depression for a bit. It's a blockbuster, after all. In any given year, approximately 9% of the adult population is suffering from major depression or dysthymia (1). Women are afflicted about 2-3 times as often as men, and 10-15% of women will become depressed after having children.
What is depression? Well, one must have a certain number of the following symptoms for a certain period of time - depressed mood, lack of interest, appetite changes (increased or decreased), sleep changes (increased or decreased), a generally negative outlook, suicidal thoughts, feelings of hopelessness, helplessness, worthlessness, poor energy, poor motivation, poor concentration, feelings of guilt... you get the picture. What causes depression? Well, it isn't zoloft deficiency. (That doesn't mean that zoloft won't help...) But it is obviously a combination of factors, including genetic predisposition, adaptive versus maladaptive coping skills, levels of stress, and sometimes biological or iatrogenic (i.e. caused by other medical treatments) factors.
To appropriately treat depressive disorders, one must obviously address all these these factors, and the generally accepted procedure nowadays is to combine a thorough medical work-up, psychotherapy, and medication if needed. In that respect the treatment for depression is extremely similar to the treatment for obesity and diabetes - which involves medical monitoring, nutritional counseling, psychological counseling if needed, and medication if needed.
But what *really* causes depression? Biologically speaking? Having a clinical depression means your brain isn't working as it should, and number of factors have been implicated. Among them serotonin system dysfunction, and problems with norepinephrine regulation. But the heart of the matter may be way down in the hippocampus, where stress may interact with genetic predisposition and other factors to create a deficiency in a brain fertilizer of sorts, brain-derived neurotrophic factor (BDNF). It is thought that antidepressant medication actually helps depression by increasing the production of BDNF.
Well, what else can increase BDNF? What other commonly recommended treatment works just as well for depression as antidepressant medication? Exercise, of course. How would exercise increase BDNF in the hippocampus, of all places? There are a number of ways, but the most interesting to me right now is via nitric oxide. Nitric oxide is a gas we make in our red blood cells, especially during exercise and meditative-type breathing. Nitric oxide does all sorts of happy things in our bodies, including relaxing blood vessels and lowering blood pressure, and it is also necessary for erections in men.
Perhaps I have gone far afield of depression at the moment. We psychiatrists, always getting distracted. (Did you know that impotence is related to diabetes and insulin resistance?) But back to the brain! See, antidepressants have to be absorbed in the GI tract, then the active molecules have to somehow make it to the blood brain barrier, and then find the right part of the brain, where a whole cascade of membrane proteins, second messengers, vitamins, and neurotransmitters have to work in concert to increase the production of BDNF to cause the antidepressant effect. Whew. But good old nitric oxide, it is a tiny little molecule, a gas. It doesn't have to rely on all these other players. It can just float through membranes and bind directly to the promoter region of the gene for BDNF, and help the brain make more.
Great! Everyone go out and get some exercise, or meditate. But wait a minute.
It turns out that depressive disorders are a lot more common in people with type II diabetes, and that people with depressive disorders have a 65% greater chance than unaffected adults of developing diabetes. The correlation is so strong, in fact, that for a while researchers were trying to figure out if antidepressant medication actually caused diabetes. (Don't panic - unless the medicine is also making you gain weight, it is probably not adding to your risk of diabetes). As it turns out, successfully treating the depression doesn't improve the increased risk of diabetes. Hmmm, why would that be? Maybe because something else is causing diabetes and the depression, and zoloft isn't FDA-approved to treat insulin resistance?
Well, what does that have to do with the price of tea? I don't know, not 100%. But I have a sneaking suspicion about several factors. Here's one. You see, insulin resistance is associated with endothelial dysfunction (damage to the inner walls of the blood vessels). This means that nitric oxide isn't able to float through the blood vessels (where it is made) into the cells (where it is used). In a nutshell, the nitric oxide of people with insulin resistance cannot do all the things it needs to do. Such as help with sexual activity, reduce blood pressure, and perhaps, just perhaps, help the spectacular brain fertilizer, BDNF, repair the oxidative and inflammatory damage thought to be characteristic of a depressed brain.
So it turns out that maybe it is important for psychiatrist to know a little something about what causes insulin resistance and diabetes, and what an appropriate and effective dietary intervention might be for the whole metabolic derangement in the first place (hint - it's not a high carbohydrate diet).
But let's talk about depression for a bit. It's a blockbuster, after all. In any given year, approximately 9% of the adult population is suffering from major depression or dysthymia (1). Women are afflicted about 2-3 times as often as men, and 10-15% of women will become depressed after having children.
What is depression? Well, one must have a certain number of the following symptoms for a certain period of time - depressed mood, lack of interest, appetite changes (increased or decreased), sleep changes (increased or decreased), a generally negative outlook, suicidal thoughts, feelings of hopelessness, helplessness, worthlessness, poor energy, poor motivation, poor concentration, feelings of guilt... you get the picture. What causes depression? Well, it isn't zoloft deficiency. (That doesn't mean that zoloft won't help...) But it is obviously a combination of factors, including genetic predisposition, adaptive versus maladaptive coping skills, levels of stress, and sometimes biological or iatrogenic (i.e. caused by other medical treatments) factors.
To appropriately treat depressive disorders, one must obviously address all these these factors, and the generally accepted procedure nowadays is to combine a thorough medical work-up, psychotherapy, and medication if needed. In that respect the treatment for depression is extremely similar to the treatment for obesity and diabetes - which involves medical monitoring, nutritional counseling, psychological counseling if needed, and medication if needed.
But what *really* causes depression? Biologically speaking? Having a clinical depression means your brain isn't working as it should, and number of factors have been implicated. Among them serotonin system dysfunction, and problems with norepinephrine regulation. But the heart of the matter may be way down in the hippocampus, where stress may interact with genetic predisposition and other factors to create a deficiency in a brain fertilizer of sorts, brain-derived neurotrophic factor (BDNF). It is thought that antidepressant medication actually helps depression by increasing the production of BDNF.
Well, what else can increase BDNF? What other commonly recommended treatment works just as well for depression as antidepressant medication? Exercise, of course. How would exercise increase BDNF in the hippocampus, of all places? There are a number of ways, but the most interesting to me right now is via nitric oxide. Nitric oxide is a gas we make in our red blood cells, especially during exercise and meditative-type breathing. Nitric oxide does all sorts of happy things in our bodies, including relaxing blood vessels and lowering blood pressure, and it is also necessary for erections in men.
Perhaps I have gone far afield of depression at the moment. We psychiatrists, always getting distracted. (Did you know that impotence is related to diabetes and insulin resistance?) But back to the brain! See, antidepressants have to be absorbed in the GI tract, then the active molecules have to somehow make it to the blood brain barrier, and then find the right part of the brain, where a whole cascade of membrane proteins, second messengers, vitamins, and neurotransmitters have to work in concert to increase the production of BDNF to cause the antidepressant effect. Whew. But good old nitric oxide, it is a tiny little molecule, a gas. It doesn't have to rely on all these other players. It can just float through membranes and bind directly to the promoter region of the gene for BDNF, and help the brain make more.
Great! Everyone go out and get some exercise, or meditate. But wait a minute.
It turns out that depressive disorders are a lot more common in people with type II diabetes, and that people with depressive disorders have a 65% greater chance than unaffected adults of developing diabetes. The correlation is so strong, in fact, that for a while researchers were trying to figure out if antidepressant medication actually caused diabetes. (Don't panic - unless the medicine is also making you gain weight, it is probably not adding to your risk of diabetes). As it turns out, successfully treating the depression doesn't improve the increased risk of diabetes. Hmmm, why would that be? Maybe because something else is causing diabetes and the depression, and zoloft isn't FDA-approved to treat insulin resistance?
Well, what does that have to do with the price of tea? I don't know, not 100%. But I have a sneaking suspicion about several factors. Here's one. You see, insulin resistance is associated with endothelial dysfunction (damage to the inner walls of the blood vessels). This means that nitric oxide isn't able to float through the blood vessels (where it is made) into the cells (where it is used). In a nutshell, the nitric oxide of people with insulin resistance cannot do all the things it needs to do. Such as help with sexual activity, reduce blood pressure, and perhaps, just perhaps, help the spectacular brain fertilizer, BDNF, repair the oxidative and inflammatory damage thought to be characteristic of a depressed brain.
So it turns out that maybe it is important for psychiatrist to know a little something about what causes insulin resistance and diabetes, and what an appropriate and effective dietary intervention might be for the whole metabolic derangement in the first place (hint - it's not a high carbohydrate diet).
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