Spirituality, Depression, and Recent Events

A brand new post is up over at Psychology Today: Brains, Spirituality, and Depression. It discusses the links between�well, guess. There are some interesting anatomical findings in the brain that correlate with both increased spirituality and a reduced risk of depression, but go read to find out more.

Thanks for comments and donations! I've not always been on top of the comments situation, and given the vagaries of gmail, I can't have my comment-approval gmail open at work�sometimes it takes me a week or two to approve a comment, and some get missed in the avalanche of spam. Excuses excuses�

I'm on track to writing more, though new article/science stuff will probably end up on Psychology Today first to be a more effective use of my time, because I have to blog monthly over there to get paid. :-). Other recent activities include freezing, hiking, a lovely Brazilian steakhouse dinner with Chris Kresser, Mat Lalonde, Sarah Johnson, and Diana Rogers and registering the youngest for�gasp�kindergarten.

Cage The Elephant: Take It or Leave It 

Chris Kresser's book is out, btw! Great addition to the paleo book menagerie. And you might find the author of the Foreward to be familiar.

Too cold unless you are these guys

Meltwater on the ice-covered pond at Stony Brook

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Man of Steel

Hello 2014! This blog post probably makes more sense if you have seen Man of Steel. Seriously, spend $1.50 at redbox. It�s awesome. Though perhaps ethically disappointing. 

I know it has been a long time. Suffice it to say that between some unexpected illnesses and deaths in the extended family, along with the normal life of a family with two working parents and two very active little girls, there was simply no extra time or energy for a little while. There was also a little stutter in my sense of purpose, trying to figure out what it is I am trying to do here. There is a lot more attention from my fellow psychiatrists (the president of the APA follows me on twitter, so all the sudden I feel a little awkward sharing my 140 character opinions and links on the Hunger Games). Far more importantly, I�ve been honored to be selected for a three hour symposium on Evolutionary Psychiatry at the next APA annual meeting in New York City, which is the major meeting of psychiatrists in North America, if not the world.  It�s all very academic and serious. 

Yet the underpinnings of what I am trying to say (and, in this blogosphere, trying to pick out the truth) are so simple it often feels as if there is nothing left. Sleep well. Eat well. Take a break. Be merry-ish. I am not temperamentally designed for ambivalence (except as an appropriate therapy tool), but after three and a half years of blogging the basics are settled, and the tougher subtleties come to the fore. The blog is coming out of infancy and becoming self-aware. A separate consciouness dogging me, and mocking, sometimes. Is there no way to make a difference without being outrageous and unconscionable?

There is a community now, of doctors and people looking for common sense and an active role in their own care. Yet the publicity is centered on the straw-man paleo critics and the ridiculous purveyors of �paleo� brownies and doughnuts. I do see a use for these on some level and I don�t begrudge anyone the right to make a living by selling grain-free garbage, just not with that smarmy stamp of �health� across the top. It�s no better than the American Heart Association approval across the top of cheerios or whatever stupid processed cereal product they decide to endorse (shoot, even the AHA is ambivalent about the grocery store, as I can�t get their grocery store heart check products list to even load at the moment).

 It�s like Christopher Nolan took over my blog and replaced the shining optimism of a summer blockbuster with the dark semi-antihero superhero (spoiler!) who breaks General Zod�s neck in front of the sobbing families in Grand Central Station or the Metropolis equivalent. Yet life is really positive and wonderful, and the kids are doing well, and business is booming.

The ultimate child-like medical journal (no grumpy, scene-stealing, genetically engineered to be two-dimentional Krytponian General Zods allowed) is Medical Hypothesis. The staid and serious need not apply. No question that the glorious and insane ideas unleashed there could spark a revolution in medical treatment. The next generation is inspired, unplanned, and is blessed with the looks of Henry Cavill (he is training at Gym Jones for the MOS sequel, can you confirm this, Dallas?). Maybe. Or maybe it�s all an optimistic waste of time or craziness. You never know until the battle to the death that makes it all clear at the end of the summer blockbuster.  Victoria Prince (with her shiny new MD and PhD in addition to her native awesomeness, not unlike like Natalie Portman in Thor) sent me an article from there about OCD and the gut microbiome.

OCD I�ve always considered to be one of the more �organic� of mental disorders. More neurology, less psychology. Let�s not confuse it with obsessive compulsive tendencies that have led many a med student to success. No, OCD is a heart-breaking disorder, where people get stuck with unwelcome, repetitive, ego-dystonic thoughts and engage in uncomfortable compulsions to relieve the anxiety of those thoughts. Typical thoughts include pedophilia in a teacher who would never dream of harming students, or killing your own children, or stealing, or running over someone, or being contaminated by germs. (Hoarding is thought of as a variant of OCD, but is more responsive to treatments such as stimulants, which typically make OCD worse). Worsening OCD symptoms tend to be caused by pregnancy (even typical post-partum depression symptoms are OCD in nature, worries about the harming the baby, germophobia, etc.) and other stressful life events. It�s horrible but, in my experience, typically amenable to the standard treatment, therapy with an OCD specialist and high doses of SSRIs. Hardly paleo but neither is an appendectomy. Seriously, I�ve had patients who have led shadow lives for decades, bothered by these intrusive thoughts, who tried therapy after therapy, finally convinced to take an appropriate dose of medication who are suddenly free of the obsessions, the compulsions, and the constant mental torture. It�s an awakening. Sol to the native-born Kryptonian. Stretched the metaphor too far? Sorry, you are reading the wrong blog.

But I�ve been interested in the microbiome for a long time. 90% of our personhood are these �other� cells who inhabit us. They communicate with our brain, serve as a major part of our immunity, and regulate our immune response. Right up until the 20^th century (more specifically mostly before 1975) we co-evolved with parasites, certain commensal bacterial, and pseudocommensals. The major autoimmune diseases, such as multiple sclerosis, rheumatoid arthritis, asthma, etc. have increased in incidence and prevalence in the last thirty years (though peaking, in some instances, around 2000, prior to more aggressive anti-autoimmune medical care instituted early). OCD has long been considered a variant of an autoimmune disease (while most of my patients were affected in childhood, I do have a few who became symptomatic in adulthood after infection with lyme disease, herpes, or other neurologic pathogen, plausibly leading to an autoimmune attack on the brain causing chronic OCD symptoms.)

So what does Medical Hypothesis have to say about all this speculation? Both dietary and emotional stress are known to affect the microbial population. And the PANDAS associated with OCD might not be the problem�perhaps it is the antibiotics given to treat the strep infection? Let�s not forget that before antibiotics, people died right and left of scarlet fever and all sorts of bad things. Henry Cavill also struggles with throwing the baby out with the bathwater. Do I reveal myself and save the school bus full of children? [SPOILER] Does Kevin Costner really want me to let those children drown? Good thing the tornado takes away his crazy moral equivalency�

The Medical Hypothesis article calls for the trials of probiotics that we all deserve, except that everyone knows the only hard core way to permanently affect the gut microbiome is via helminth therapy (yes, introducing parasitic worms) or fecal transplant. If we are going to be radical, let�s go radical in a scientific and controlled and meaningful way.

I�m impatient sometimes. And no one wants to wait for everyone to wear blue-blocking glasses, get some general daily activity in already, and save the magic paleo cookies for a few special occasions a year. People want sensibility, convenience, beauty, and fresh air. A glorious man in Antarctica who can fly with his red cape in the light of our young sun. Coconut milk. Roast beast. Fermentation. They want a grumpy, two-dimensional villain, like Zod, or Carbsane, or the Medical Establishment, or the flu vaccine.

I get so many emails that break my heart. Can you help me, I�m sick, my relative is sick.

I have no magic elixirs. I am no Henry Cavill. I can barely keep myself operating sometimes with all the souls currently assigned to my watch. I couldn�t save my young cousin from sarcoma. I can�t save anyone. You have to save yourself.

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Gluten and Schizophrenia Again (with an added splash of Toxo!)

Researchers have been chasing the elusive links between gluten and major mental illness for decades. Despite some hyperbolic coverage in Wheat Belly and slightly more convincing coverage in Grain Brain, there is, so far, quite a bit of smoke, but no fire outside a few case studies. Curt Dohan had quite a few papers back in the day (including this one), and much more recently Faith Dickerson, now armed with antibody titres, could be more precise (including in this paper).

In the last couple years the rather stunning data from the CATIE trial (a very large multi-center study of schizophrenia treatment run by NIMH in the last decade) that schizophrenics were 5X as likely to have anti-tTG antibodies as healthy controls and over 7X the likelihood of having high AGA (antibodies to gliadin) compared to normal controls has made more researchers take notice. Yet on face, all we could really say is, wow, a certain subset of people with schizophrenia sure do have some suspicious antibodies to different wheat proteins, and it is pretty clear that devastating neurological illness can be caused by gluten (dystonias in some people, for example) without the classic celiac gut findings, but is the issue in schizophrenia a leaky gut (thus higher antibody titres to certain food moieties) or the wheat itself, or both? I covered these questions in a bit more detail here.

One major issue with the theory that wheat causes schizophrenia is that schizophrenia seems to have a similar prevalence in gluten and non-gluten eating areas, but since "schizophrenia"is pretty clearly recognized as a final common pathway for a number of different genetic and environmental pathologies, it wouldn't necessarily torpedo the gluten theory. Now, finally, we can test whether gluten-free diets help symptoms in the subset of schizophrenics who have suspicious wheat antibodies. The newest round of researchers, led by Jessica Jackson (along with Alessio Fasano) at the University of Maryland and Emily Severance at Johns Hopkins, are following these leads.

Come A Little Closer: Cage the Elephant

First off, we have "A gluten-free diet in people with schizophrenia and anti-tissue transglutaminase or anti-gliadin antibodies." This paper starts off with discussing the mixed results of previous trials (7 in all) of gluten-free diets in schizophrenia, showing a subset with real improvement (and some with remission, which is an astonishing finding), but many without improvement whatsoever. None of these studies tried to differentiate schizophrenics with or without anti-tTG and AGA, mostly because they were done before these titres were available. The paper makes the distinction that anti-tTG antibodies are more likely to signify celiac disease, whereas AGA is more likely to signify non-celiac gluten sensitivity. In the current paper, exactly two patients with schizophrenia (one woman symptomatic since 1976 and a man symptomatic for the past 8 years) and positive antibody titres (one for anti-tTG and one for AGA) who were stable on medicines but still symptomatic (pretty common) were put in an inpatient unit and observed on a gluten-free diet for two weeks.

The woman had improved concentration and attention (critical, because psychotic symptoms often respond relatively well to medication, but poor executive functioning, attention and concentration are not so responsive, and those deficits keep many people with schizophrenia from being able to function independently). The man had some reduction in psychotic symptoms and increased insight into his condition. Since schizophrenia is a progressive neurodegenerative disease, seeing improvement, particularly in the woman who had been sick since 1976 from a non-medicine intervention in two weeks' time is at the least interesting.

The limitations of this study are profound. Open label, about as tiny as you can get, and obviously taking someone and sticking him or her in an inpatient unit with structure and observation is an intervention all on its own. But the level of improvement was enough that Schizophrenia Research (not the topmost tier of psychiatry journals, but certainly no Medical Hypothesis) published the paper, and it is available free full text on pubmed if you care to click the link above.

The second paper was sent to me by the amazing Victoria Prince (who just finished her last rotations in medical school. Woo hoo!) I love this paper, and I want to give Emily Severance a hug just for the ideas it brings together. She already deserves a hug for the previous paper I discussed in this article: Schizophrenia and the Gut. We know schizophrenia is multitudes, it's complex, it's genetic and environmental and immune-mediated. Ergo: Anti-Gluten Immune Response following Toxoplasma gondii Infection in Mice. (I know, mice.) It's also available free full text over at PLOSone.

Anyway, we already know that folks with schizophrenia have higher levels of gut inflammation (measured by checking antibodies to known infections that get into the system when there is gut inflammation or infections that actively cause gut inflammation, such as our old friend Toxoplasma gondii), and the newer the onset of illness, the more likely you are to find gut inflammation, AND the more antibodies to gluten and casein you have, the more likely you are to have these signs of gut inflammation. So Dr. Severance sought to answer some of the questions raised by this finding. Did the infection cause a gut pathology that allowed neurotoxic food fragments to attack the brain of the genetically susceptible? Were the infections themselves the problem in the brain, and the food antibodies just secondary to the infections? Well, it is difficult (not to say unethical) to do the sorts of experiments you need to answer these questions in humans, but mice can be housed and infected and their little immune systems examined in greater numbers over several generations more readily.

So the researchers took mice and gave them delicious T gondii infected rodent chow (via infected ground up mouse brains!!). They infected some adult mice and a subset of female mice who were then knocked up so they could check the pups for gut inflammation as well�there are a lot of mini-experiments in this paper and I won't explain them all to death here, as the paper is freely available. Anyway, after infection with T gondii, serum antibodies to wheat proteins and complement activation (not a sign of well-bred mice but rather a measure of inflammation) increased in the infected groups but not in the mock-infected or uninfected groups. The anti-wheat antibodies in mouse pups born to the infected moms were also significantly higher than in those born to uninfected mouse moms.

So here we have proof, in mice, that infection with Toxoplasma, a known risk factor for schizophrenia in humans, leads to the generation of anti-gluten antibodies, presumably via a gut inflammatory mechanism. Most importantly, in the mouse pups, the anti-gluten antibodies and infection happen at a time of critical neurodevelopment. Thus the combination of infection and, perhaps, a dietary enhancer (such as, possibly, gluten) could be working in concert to make someone vulnerable to developing schizophrenia later on. The "gut inflammatory" mechanism is vague at this point. In celiac disease in humans (more associated with the anti-tTG antibodies), there is definitely gut damage and permeability. In non-celiac gluten sensitivity (more associated with AGA), there doesn't seem to be frank leakage, but apparently large gluten peptides can cross the border via transcytosis and this may happen more readily if the gut is infected and the immune system is on the case and things�frankly the exact details of gluten and the gut continue to elude us. Check out the last paragraph of this paper (BIG HUGS):

In summary, the models described in this paper provide appropriate experimental tools to examine the impacts of gluten peptides, T. gondii and associated immune activation on brain physiology. As we accumulate more information from analyses of clinical biomarkers, we can adapt these animal models to test the effects of dietary modifications and other types of infections on behavioral endpoints, the pharmacological outcomes of specific antipsychotics on immune system parameters, and the autoimmune response responses triggered by T. gondii infection. Ultimately, we envision a translational system by which we can fully evaluate the interface of environmental perturbation and genetic predisposition as it relates to serious neurodevelopmental disorders such as schizophrenia, bipolar disorder, and autism.

I've never been a very linear person; I tend to absorb and think about things all at once. That's part of what I like about my so-called Evolutionary Psychiatry. We can think about lots of things at once as they impact physiology, immune activation, and genetics. The researchers who also seem to think this way, but can also break down these questions and not leave gaping holes (Severance's previous experiment where she took the trouble to go across the ocean to study gut and immune activation in medication naiive and medicated schizophrenics, taking out a major confounder in most schizophrenia research in the US) are the kinds of thinkers we need who can do good science to work out these big complex tangles. I can't wait for the next papers to come out. In the mean time, there is no clinical guidance. Is it worth checking your schizophrenics for anti-tTG and AGA? What are the risks of recommending a gluten-free diet and what is the likelihood it will be strictly followed in an outpatient setting?

Always, more questions than answers.

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Get Your Sleep On

New post over at Psychology Today about the possible benefits of sleep flushing the brain like a cranberry bog harvest. And some gluten and psychosis and toxoplasma mash-up here in the next couple of days, once I clean the house and get all the candy and mouldering pumpkins put away.

Even Michael Stipe thinks sleep is important in this odd homage to the 7th interval�

Happy Halloween! Don't let the goblins bite.

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More Zinc Nitty Gritty

On the personal front we are going full speed ahead into fall, school, apple picking, corn mazes, and sweater weather. I also decided to participate in a little n=1 experiment of caffeine elimination for 24 days along with Dallas Hartwig, who apparently does an elimination of this sort at least once a year. He drinks quite a bit of coffee and the occasional detox seems prudent. For me, I figured there wouldn't be much difference in my life with or without caffeine. I rarely drink coffee, and a typical day will see me drinking 0-3 cups of tea, most days one. Since I could skip a day of caffeine without even noticing, I imagined there wouldn't be caffeine withdrawal.

I was surprised about 52 hours after my last dose when the classic headache and a combination of irritability and cognitive fog set in. (Withdrawal can begin as early as 12 hours, typically peaks at 48 hours, and can last 2-9 days total). Mine lasted about 6 hours until I went to bed, and it was gone the next morning. Over the next three weeks, I noticed my sleep was improved, muscle tension was noticeably decreased at the end of a clinic day, and I missed caffeine the most on Monday mornings, Wednesday afternoons (not surprising, my longer clinic day), and, unexpectedly, Sunday mornings. For the first week and even into the second I still didn't feel quite as "sharp," though that feeling began to pass a little by the third week. The experiment ends in a couple of days, and I have plans to moderate my caffeine intake a little more than I did before. Maybe 3 days a week instead of most days a week (thinking of those "most missed" times), and probably won't exceed a single cup of tea. All told, I learned some things, and I'm glad I did the experiment. Probably a worthy one for most people to do, as long as the withdrawal isn't too debilitating.

Last week we left off with some review of zinc, before that a bit of a review of the pathophysiology of depressive disorders in the brain. Today I would like to tie that together from the most recent review article and then discuss the overall human clinical data about zinc as an antidepressant.

Damage to the brain in major depression in the hippocampus seems to occur in part due to overstimulation of the NMDA receptors (by glutamate or similar substances). The overstimulation leads to a large influx of calcium molecules into the cells which results in damage to the neurons and can stimulate programmed cell death. Zinc can turn off this cascade to some extent, because it is a non-competitive inhibitor of the NMDA receptor, which means it keeps the receptor from being quite as easily activated. Thus it could potentially decrease the amount of damage done during a period of high stress.

In addition, zinc spurs the production of the brain fertilizer, BDNF, in the hipocampus, leading to recovery, nerve regeneration, and repair. Below is a modified diagram from the review similar to the ones I posted a couple of weeks ago with much of the zinc penciled in (IN COLOR. hah). For more step by step explanation, please go back to my previous post. Click the diagram to make it larger.

So now, the human data, which works better as a list:

1) In healthy humans, zinc levels in the central nervous system and in the serum tend to be equivalent with free passage through the blood brain barrier.

2) A post-mortum study of schizophrenic patients showed 50% reduction in brain zinc (particularly in the hippocampus) compared to controls.

3) In neurodegenerative diseases, reductions in brain zinc tend to be higher than reductions in serum zinc.

4) Numerous studies link lower serum zinc levels to increased depression scores on a rating scale (there is even some linear correlation, making zinc a reasonable candidate as a biomarker for depression).

5) Zinc levels are lower in treatment resistant patients (in some but not all studies).

6) Patients whose depression improves also have recovery of zinc levels.

7) People who are depressed tend to have lower zinc levels and lower zinc intake (eating less meat, fish, and legumes, and I'm assuming oysters), but hospitalized depressed patients fed the same diet as controls also had lower zinc levels than the controls.

8) Intense, competitive, anxious "Type A" personalities tend to excrete more zinc under stress than the more laid back, "Type B" sort of person.

9) Zinc is excreted in hyperactive kids exposed to artificial food dyes but not in kids who weren't hyperactive in a small study.

10) Zinc supplementation can increase testosterone in zinc-deficient men, and low testosterone is associated with depression.

11) In several (small) randomized trials, zinc (25mg) plus an antidepressant elicited a more robust recovery than antidepressnt alone. Similar results have consistently been found in animal models.

Still, more data is needed, and more information is needed about the genetic differences in people in zinc absorption, sequestration, and secretion in healthy and unhealthy states. The upper limit of recommended zinc intake is 40mg daily, the recommended daily allowance is around 11-12. Temporary supplementation of less than the upper limit during a stressful period seems low-risk, but there is still much to learn.

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Zinc at Psych Today

Terribly busy between back to school (both kids now have homework!) and my sister getting married last weekend (which required me to be a bridesmaid and also to supply a few adorable flower girls and some quick cross-country flying and jetlag). Also trying to get in our American Psychiatric Association Annual Meeting abstracts on time�my medical school class starts next week panic yet?

I'm still working on the nitty-gritty of zinc and depression from the last paper, but for a review: Zinc! An Antidepressant? at Psychology Today, so each click supports my research, writing, and the blog.

Appropriate new (amazing) song: Hurricane.

Trying to keep active and getting the girls out of doors as much as possible before the winter closes in. Not enough time for writing and thinking, but as always, those are luxuries, particularly in modern times. Doesn't that seem backwards? It seems to me there should be more time for leisure.

Keep eyes peeled for more on zinc and the pathophysiology of depression.

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Pathophysiology of Depression and Happiness

I'll be on the Creative Live video podcast later today (3pm pacific, 6pm eastern) on the topic of happiness (Dave Asprey invited me to participate, and while he is going into some of the technology he uses to monitor his brain and functioning, I'll be talking about some of the research about happiness and different Eastern and Western perspectives.)

Just going through an amazing review from Neuroscience and Biobehavioral Reviews: Potential roles of zinc in the pathophysiology and treatment of major depressive disorder. I'm going to do an updated zinc post (which is why I pulled the paper), but it does have a terrific and concise review of the biology of depression and, as it happens, happiness. Though this biochemistry will not be part of the talk later today. Suffice it to say (click the diagrams to make them bigger if you like):

So diet provides the amino acid tryptophan, but circumstances can push the metabolism in two directions, toward the neuroprotective, neurogenerative and repair pathway (via serotonin and melatonin) or to the neurotoxic pathway. Stress and inflammation tend to favor the production of kynurenine, which can become quinolinic acid (a potent oxidative agent and neurotoxin) or kynurenic acid (which can go both ways, more on that in a bit).

On the neurotoxic pathway, quinolinic acid triggers the release of glutamate via alpha 7 nicotinic acetylcholine receptors and may also directly stimulate the NMDA receptors. High levels are associated with reduced neuronal growth and repair in the hippocampus of the brain along with markers of neuronal injury. Kynurenic acid, also made from kynurenine, can ameliorate this pathway somewhat by modulating the activity of these alpha 7 nicotinic receptors, but in the wrong amounts kynurenic acid can be neurotoxic as well. In layman's terms you get depressed mood, irritability, suicidal thoughts, memory problems, poor resistance to stress, dysregulated energy metabolism, poor sleep or unrestorative sleep. Poor motivation and reduced concentration. The brain just doesn't function well.

On the bright side you get serotonin and melatonin supporting sleep, appropriate circadian rhythms, appetite and hormonal regulation, and then the effects of reduced excitotoxicity via various receptors and components including 5-HT1A, leading to good memory, good neuronal plasticity (which permits adaptation to new experiences and stimuli), and appropriate levels of brain derived neurotrophic factor and dopamine (some of these are mediated by insulin growth factor 1 by the way) toward neurogenesis and neuroprotection. So here we have good memory, good sleep, regulated energy metabolism, positive outlook, motivation, serenity, and appropriate resiliency to stress.

My apologies for the low tech diagrams, but hey, this is a free blog after all�zinc, by the way, plays a role at almost every level in these pathways. But more on that in a bit!

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