There's been a bit of upheaval at the house...all will be well, but in the mean time, I'm trying to blog more and get some more clicks over at Psychology Today. Clicks support the writing and research I do and they are much appreciated! There's a new post up about ketamine, the noncompetitive inhibitor of the NMDA receptor that, in one single IV infusion, can alleviate a suicidal depression in about 30 minutes. However, the magic doesn't last, and depression comes back after a week or two. Still, the mechanism and understanding of this phenomenon is important to figuring out the physiology underlying depression.
For right now, ketamine is being used experimentally in hospitals and also in some "salvage" clinics where folks who've responded poorly to other treatments pay for to get a short break from depression. Other NMDA receptor antagonists might be useful drug targets for experimentation...but to be honest glutamate has been the holy grail neurotransmitter for several psychiatric disorders (schizophrenia, major depressive disorder, and bipolar disorder among them) for the past 20 years, and I've not seen anything come of it, or anything new in the drug pipeline that has panned out.
The supplement NAC utilizes the glutamate pathway via a somewhat convoluted mechanism. I've seen it work for obsessive thoughts, hair pulling (but never for picking behaviors in general) and, interestingly, bipolar depression when every other treatment has already been tried. There's only one study for bipolar depression, but the trichotillomania efficacy is solid and NAC should be part of the clinical arsenal for that symptom.
Here's the post: The Ketamine Key
And here's a new Lorde song I like a lot: Yellow Flicker Beat
Showing posts sorted by date for query Bipolar. Sort by relevance Show all posts
Showing posts sorted by date for query Bipolar. Sort by relevance Show all posts
Friday, October 24, 2014
Friday, November 1, 2013
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):
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.
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.
Sunday, July 28, 2013
Minerals, OCD, ADHD, and Questions
None other than the amazing Dallas Hartwig sent me a link to this paper about OCD and serum mineral levels a while back. It's hard to know what to make of the paper. In Bangladesh, 48 folks with OCD (mostly men) and matched controls had serum measures of minerals zinc, copper, magnesium, manganese, iron, and calcium taken. And, low and behold, the serum levels of those anti-anxiety metals zinc and magnesium (along with iron) were significantly lower than controls, and calcium and manganese were significantly higher. Copper levels were not significantly different.
And that's all we have. One small study, just an observation, a single measurement. Just a blood measurement too, not cellular or other tissue.
AWOLNation: THISKIDSNOTALRIGHT
The main thing I take away from this study is that we still know so very little about nutritional status, minerals, and psychopathology. There are any number of fMRI and other expensive studies looking at the brain in OCD trying to peer into the metabolism of the brain in OCD, and we can learn from those sorts of studies, but we do tend to forget that these are full-body disorders mediated in part by the stress response, so there are some other systemic and measurable clues as to what is going on in the body.
Zinc, magnesium, and iron do tend to be low in people with certain psychopathology. In ADHD and autism, for example, there are several studies showing increased zinc excretion and decreased zinc levels in the body in kids. If you search individually for iron and OCD links in pubmed, you tend to find case studies of kids with pica (obsessively eating sponges, clay, or the padding from couches or other non-nutrative substances) who turn out to have iron deficiency (typically from previously undiagnosed celiac disease). When the gluten is stopped and the iron is repleted, the pica goes away. Iron also tends to be on the low side in kids with ADHD who have ferritin tested, though this larger study showed no association between iron status in the general population of children and symptoms of ADHD.
Are these cause or effect? Do certain variations in mineral metabolism leave you more vulnerable to psychopathology, or do the symptoms expose you to greater stress so your mineral status is different compared to healthy controls? Certainly in the particular cases of the pica "OCD," there is a clear arrow of causation from celiac disease to iron deficiency to pica symptoms. But in other cases the stress will cause people to excrete more magnesium and zinc, which if they are not repleted could amp up the stress response in general and be a self-perpetuating cycle. In the modern world where we get many minerals from our grains and don't tend to drink mineral water, if soils are depleted of certain minerals (and perhaps higher in others due to different agricultural practices) and the phytates in grains, legumes, and nuts bind some of the minerals, all the sudden it is a lot harder to replete minerals than if our intake was more like the ancestral picture prior to agriculture. Combine chronic modern stress with mineral deficiency with a certain genetic vulnerability to ADHD symptoms, OCD symptoms, other anxiety symptoms, etc. and you now have a lot more psychopathology popping up.
One side of the mineral story is the decreased zinc, magnesium, and iron. The other side is the increase in serum manganese and calcium. At this point it is a bit hard to know what to make of that. In certain folks with schizophrenia, there is a certain type of antioxidant-assisting enzyme called manganese superoxide dismutase that has lower activity, leading to poorer ability to clear the toxic metabolic byproducts and presumably cell damage and neurotoxicity. In ADHD (once again), high serum manganese is fairly consistently seen in children with the disorder when it is measured. The same is also true of children with cognitive disorders and other learning problems. Manganese is found in high concentrations in soybeans, rice, and black beans (in which case the associated phytates would protect one somewhat from absorption…but our modern tendency to eat a lot of different processed "foods" made from the same few grains might make us more vulnerable to certain deficiencies and excesses). Manganese seems to interfere with cell energy metabolism, making it hard to make enough ATP to power the cell.
ADHD is associated with issues with dopamine neurotransmission, and manganese can accumulate in the presynaptic dopaminergic neurons via the dopamine transporter. In high enough concentrations, manganese is absolutely neurotoxic and leads to symptoms similar to Parkinson's disease. Brazilian children with ADHD tended to have high serum manganese prior to being treated with ritalin, which blocks the presynaptic dopamine transporter (therefore increasing dopamine in the synapse). After treatment, the serum manganese levels in these children dropped and presumably there was decreased uptake of manganese into those dopamine neurons.
Calcium's link is even trickier to figure out. Certainly on a synaptic level, calcium flux through membranes is a major "on" switch for neurotransmission. If there is too much calcium flux, you get "excitatory neurotoxicity," and this mechanism is related to migraines, seizures, and probably bipolar disorder. Whether or not higher (but still normal) serum levels of calcium (which, like magnesium, is very tightly hormonally regulated because you can get heart arrhythmias and sudden death if the levels are off) is associated with higher excitatory neurotransmission is unknown to me…hypercalcemia is definitely associated with fatigue, cognitive dysfunction, and irritability, but are high-ish but still normal levels, particularly in certain vulnerable people? I've not seen studies or anything about that, but it is plausible.
Once again, more questions than answers. Typical.
More on minerals
Magnesium and the Brain, The Original Chill Pill
Zinc!
And that's all we have. One small study, just an observation, a single measurement. Just a blood measurement too, not cellular or other tissue.
AWOLNation: THISKIDSNOTALRIGHT
The main thing I take away from this study is that we still know so very little about nutritional status, minerals, and psychopathology. There are any number of fMRI and other expensive studies looking at the brain in OCD trying to peer into the metabolism of the brain in OCD, and we can learn from those sorts of studies, but we do tend to forget that these are full-body disorders mediated in part by the stress response, so there are some other systemic and measurable clues as to what is going on in the body.
Zinc, magnesium, and iron do tend to be low in people with certain psychopathology. In ADHD and autism, for example, there are several studies showing increased zinc excretion and decreased zinc levels in the body in kids. If you search individually for iron and OCD links in pubmed, you tend to find case studies of kids with pica (obsessively eating sponges, clay, or the padding from couches or other non-nutrative substances) who turn out to have iron deficiency (typically from previously undiagnosed celiac disease). When the gluten is stopped and the iron is repleted, the pica goes away. Iron also tends to be on the low side in kids with ADHD who have ferritin tested, though this larger study showed no association between iron status in the general population of children and symptoms of ADHD.
Are these cause or effect? Do certain variations in mineral metabolism leave you more vulnerable to psychopathology, or do the symptoms expose you to greater stress so your mineral status is different compared to healthy controls? Certainly in the particular cases of the pica "OCD," there is a clear arrow of causation from celiac disease to iron deficiency to pica symptoms. But in other cases the stress will cause people to excrete more magnesium and zinc, which if they are not repleted could amp up the stress response in general and be a self-perpetuating cycle. In the modern world where we get many minerals from our grains and don't tend to drink mineral water, if soils are depleted of certain minerals (and perhaps higher in others due to different agricultural practices) and the phytates in grains, legumes, and nuts bind some of the minerals, all the sudden it is a lot harder to replete minerals than if our intake was more like the ancestral picture prior to agriculture. Combine chronic modern stress with mineral deficiency with a certain genetic vulnerability to ADHD symptoms, OCD symptoms, other anxiety symptoms, etc. and you now have a lot more psychopathology popping up.
One side of the mineral story is the decreased zinc, magnesium, and iron. The other side is the increase in serum manganese and calcium. At this point it is a bit hard to know what to make of that. In certain folks with schizophrenia, there is a certain type of antioxidant-assisting enzyme called manganese superoxide dismutase that has lower activity, leading to poorer ability to clear the toxic metabolic byproducts and presumably cell damage and neurotoxicity. In ADHD (once again), high serum manganese is fairly consistently seen in children with the disorder when it is measured. The same is also true of children with cognitive disorders and other learning problems. Manganese is found in high concentrations in soybeans, rice, and black beans (in which case the associated phytates would protect one somewhat from absorption…but our modern tendency to eat a lot of different processed "foods" made from the same few grains might make us more vulnerable to certain deficiencies and excesses). Manganese seems to interfere with cell energy metabolism, making it hard to make enough ATP to power the cell.
ADHD is associated with issues with dopamine neurotransmission, and manganese can accumulate in the presynaptic dopaminergic neurons via the dopamine transporter. In high enough concentrations, manganese is absolutely neurotoxic and leads to symptoms similar to Parkinson's disease. Brazilian children with ADHD tended to have high serum manganese prior to being treated with ritalin, which blocks the presynaptic dopamine transporter (therefore increasing dopamine in the synapse). After treatment, the serum manganese levels in these children dropped and presumably there was decreased uptake of manganese into those dopamine neurons.
Calcium's link is even trickier to figure out. Certainly on a synaptic level, calcium flux through membranes is a major "on" switch for neurotransmission. If there is too much calcium flux, you get "excitatory neurotoxicity," and this mechanism is related to migraines, seizures, and probably bipolar disorder. Whether or not higher (but still normal) serum levels of calcium (which, like magnesium, is very tightly hormonally regulated because you can get heart arrhythmias and sudden death if the levels are off) is associated with higher excitatory neurotransmission is unknown to me…hypercalcemia is definitely associated with fatigue, cognitive dysfunction, and irritability, but are high-ish but still normal levels, particularly in certain vulnerable people? I've not seen studies or anything about that, but it is plausible.
Once again, more questions than answers. Typical.
More on minerals
Magnesium and the Brain, The Original Chill Pill
Zinc!
Tuesday, June 18, 2013
Infection and Psychosis in Schizophrenia
Last year the daughter of one of my patients called me. "Mom is acting really strange. She's being aggressive, and she thinks my Dad is still alive. I don't think she slept last night. Do you think she needs an increase in her medication?"
My patient was a sweet 70 year old woman with a psychosis-heavy bipolar disorder who could get paranoid from time to time, but was never violent, and had been stable on a low dose of medicine for many years. I told her daughter, "If she didn't fall down and hit her head somehow, I think she has a urinary tract infection (UTI). You should take her in to see her primary care doctor if she'll let you. Otherwise, you might need to take her to the ER."
A few hours later, the daughter called me back, quite amazed. "You were right! Her doctor says she has a bad UTI. How did you diagnose that over the phone?"
I'm sure all my psychiatrist/doctor readers were guessing the outcome right away. UTIs rather famously turn into strange behavior in the elderly, particularly in those with dementia. One time when I was on call in the emergency room, we got a consult for new-onset obsessive compulsive disorder in 77 year old. My fellow resident and I exchanged looks and told the emergency room intern to wait for the results of the urinalysis before we were consulted. 77 year olds don't develop OCD out of the blue without something else medical going on. We were correct…she had a urinary tract infection. The "OCD" resolved with antibiotics. The tricky part for doctors is that these UTIs can occur without any of the usual symptoms we are used to hearing about. No incontinence, fever, or urinary urgency. Or sometimes the patient can't tell us about these symptoms.
So we already know that urinary tract infections can cause pretty weird behavior in vulnerable people. Recently Brian Miller, MD from Georgia Health Sciences University wrote an article in Psychiatric Times about his recent study in the Journal of Clinical Psychiatry: "A Prevalence Study of Urinary Tract Infections in Acute Relapse of Schizophrenia." Not only do I have a subscription to JCP, but my academic access should grant me full access, but on a Sunday morning I was unable to get a copy of the full text because JCP's website is HORRIBLE. In desperation I emailed Dr. Miller, and on Monday morning he very kindly sent me not only a copy of the full text article, but also his letter to the editor in Schizophrenia Research. Thank you!
Schizophrenia is associated with hugely increased mortality, and those afflicted die in increased numbers and earlier from almost every major leading cause of death. Heart disease is most famous (blamed on the increased schizophrenic tendency to smoke and to the effects of the medications), but schizophrenics have an 8-fold increased risk of death by pneumonia. Is it from lack of self-care and not being organized enough to go to the doctor for serious medical symptoms? Maybe. That has been the assumption. But recent studies have shown what is no surprise to followers of Evolutionary Psychiatry. Schizophrenia is not just a brain disease, it is a disease of immune function. Schizophrenics have major abnormalities in levels of inflammatory cytokines, C-reactive protein, and reduced neutrophil activity. Neutrophils are a first-line response to inflammation and are vital to keeping us safe from bacterial infection.
Despite all these abnormalities, Dr. Miller notes in his paper that there are NO studies of the prevalence of infection at the time of infection of hospitalization for acute illness relapse in patient with schizophrenia. As all clinical psychiatrists will know, schizophrenics can remain relatively stable for many years, then have terrible relapses of psychotic behavior. Often going off medication or substance abuse is blamed (and may well be responsible). But sometimes something else is going on… and it may well be a bacterial infection. Dr. Miller studied healthy controls and some long-term schizophrenics admitted with acute psychotic relapse. He found that those hospitalized with schizophrenia, men and women, were 29 times as likely as controls to have a urinary tract infection. 35% of subjects in the acute relapse group had serologic/urinalysis evidence of a UTI as opposed to 5% of stable outpatient and 3% of controls.
There are reports of certain antibiotic treatment associate with increased risk of psychosis (cipro and gatifloaxin are known)… is it the antibiotics, or the UTI they were treating? It is well-known that elderly and particularly demented patients are vulnerable to odd behavior caused by urinary tract infections. It is not beyond the realm of possibility that people with schizophrenia are vulnerable to the same pathology.
The time is coming that schizophrenia is recognized as a full-body immune dysregulation disorder, from the gut to the brain to the neutrophils. At that point are the psychiatrists going to be removed from the picture and the allergists and rheumatologists to step forward? We'll see.
Tuesday, March 5, 2013
The Grand Theory
Last week there was a bit of hubbub as a new paper was printed in The Lancet, Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis.
The paper is a dense discussion of the higher maths of a large genome-wide association study. There’s all sorts of statistical wizardry going on with triple pseudocontrols and a number of things that are a bit above my pay grade, with my single statistics class from medical school and my genetics knowledge from the 20th century. But the gist of the paper is the following: after hacking the genome (using variations in genome markers, called SNPs, or “snips” to use the genetic parlance, meaning “genome-wide single nucleotide polymorphisms”) of many tens of thousands of cases and controls for people with autistic spectrum disorders, schizophrenia, bipolar disorder, major depressive disorder, and attention deficit hyperactivity disorder, several gene clusters were found that seemed to increase the risk of ALL FIVE of those disorders. Most of the genes found to increase the risk of these disorders were located within the coding for two L-type voltage-gated calcium channel subunits.
What? Okay, so we know that psychiatric diagnosis is a mess. We have the DSM (soon to be in its 5th iteration) which is basically a recipe list of symptoms. Find enough of your symptoms on the list, and voila, a diagnosis. The DSM is atheoretical ON PURPOSE. They make no pretensions at looking for pathology or brain chemistry issues or whatnot because, for the most part, back in 1980 when the DSMIII came out no one knew what the heck the actual pathology was. The earlier renditions did have some “causes” which led to some gems like the “schizophrenogenic mother,” and so instead of making horrible gaffes, the psychiatrists writing the DSMIII (and IV and V) really strove to see if there were clusters of symptoms that seemed to have some diagnostic validity without venturing into causes at all, so that researchers and clinicians and everyone could more or less speak the same language when talking about patients and trying to come up with evidenced-based treatments. The first MRI was built in 1977, and it’s only been since then (and really, since the invention of functional MRIs, advanced genetics with rapid PCR and PET scans and SPECT scans and the like) that we’ve really been able to see a bit more what is going on in a human brain in a living, thinking subject.
One of the frustrating (and great) things about psychiatry (and, frankly, medicine in general) is that you will almost never see a textbook case of anything. Most of my patients who show up at my office for the first time meet criteria for several diagnoses simultaneously. It’s easier to use symptoms as a benchmark rather than the full diagnoses, though for FDA purposes, treatments are researched based on diagnosis, not symptom. More recently genetic studies have shown links between various diagnoses (most notably, I think, bipolar disorder and schizophrenia, and schizophrenia and autism). While the diagnostic categories are quite clear, sometimes it can be quite difficult in practice to distinguish schizophrenia from bipolar disorder (so much so that there is a midway in between diagnosis called schizoaffective disorder), and many antipsychotic medications are approved for both treating the psychosis of schizophrenia and treating the manic episodes of bipolar disorder.
So what the new paper tells us is that these 5 different disorders of adult and childhood-onset diseases may well all be related. Voltage-gated calcium channels are little places in the cell membrane that decide, based on the voltage of the membrane at the time, whether to let a parade of positively charged calcium ions through the membrane. We need the particular calcium channel subunits coded by the genes found in the study for many brain processes, including functions involved with memory, planning, emotional processing and regulation, and attention. Another one of the calcium channels identified by the study helps other calcium channel subunits be turned on and off, whether by helping them travel to the membrane to set up shop, assist in their regulation by other molecules, or increase their function in other ways.
A commentary on the study published at the same time in The Lancet spoke to the methods used in the study (and some of the weaknesses, geneticists, by all means, pull the papers and have a look). But it also tried to make some sense of the overall picture here. Basically we have many, many interacting factors that convey risk for psychiatric disorders.
Prenatally, we have infectious disease, drugs, alcohol, nicotine, nutritional deficiencies, maternal stress and disease interacting with the genetic make-up of the baby. The postnatal environment of trauma, living conditions, nutrition, disease, etc can effect epigenetic changes which interact with brain plasticity to influence, along with the genetic make-up, disease vulnerability. So someone with an abnormal calcium channel gene in the wrong place at the wrong time (along with some other genetic and environmental issues) will get symptoms of ADHD. Another person (with the same calcium channel gene issue but different other genes, environment, etc.) will end up with schizophrenia. Some with the gene will have no psychiatric disorder at all, I’m sure.
Are we getting closer to upending the DSM? To define disease from the pathology upwards rather from the symptoms down? I hope so.
Sunday, January 27, 2013
Is Schizophrenia an Autoimmune Disease?
Psychopathology and particularly psychosis has had a bit of a research dance with immunology over the past several years. For example, women with post-partum psychosis are more likely than controls to have anti-thyroid antibodies. And folks with schizophrenia and bipolar disorder are more likely to have strange anti-wheat protein antibodies than controls. In the recent, very large CATIE trial, 23.% of those with schizophrenia had IgA anti-AGA antibiodies (anti-gliadin) compared to 3.1% of a comparison group, and 5.4% had high levels of tTG antibodies compared to 0.8% of the comparison group.
Brahms Violin Concerto (very long, really famous bit begins at around minute 35)
No one is sure what these immune reactions mean. But it would be interesting to see how immune modulators might affect psychosis in a clinical trial. In evolutionary medicine, immune and inflammatory modulators could include a dietary intervention, probiotics, or even helminth therapies. To my knowledge, none of these have been applied to schizophrenia or post-partum psychosis in a clinical trial of any kind.
This week, a paper came out in the renamed Archives of General Psychiatry (Now JAMA Psychiatry) linking schizophrenia to a set of autoantibodies. The findings in this paper lend more credence to the idea that a subset of schizophrenia may be caused by an immune attack on the brain. Blood from a group of unmedicated, hospitalized schizophrenics was compared to blood from people admitted with major depressive disorder, borderline personality disorder, and healthy controls.
9.9% of the actuely ill schizophrenics were found to have anti-NMDA receptor antibodies, compared with 2.8% of those with major depressive disorder, 0.4% of controls, and 0 of those with borderline personality disorder. The NMDA receptor (glutamate is the key neurotransmitter at this receptor) is known to be associated with psychotic symptoms. PCP and ketamine are NMDA receptor antagonists that rather famously cause agitation and psychosis.
Now there is already an illness of anti-NMDA receptors called "NMDA-R encephalitis." It affects young women with a rare type of ovarian tumor called a teratoma, and presents with psychosis, agitation, memory problems, and seizures. It tends to progress to problems with the autonomic nervous system (which can control breathing, temperature and blood pressure regulation) and cause a catatonic state. It is treated, like many life-threatening autoimmune conditions, with high dose steroids and plasmaphoresis (or plasma exchange, which can clear the blood of the offending autoantibodies). The autoantibodies in the cases of NMDA-R encephalitis are to a different specific protein subunit of the receptor and tend to be in much higher concentrations than the folks with autoantibodies who had acute schizophrenia, so it is not exactly the same disease. In this trial, however, two of the patients originally diagnosed with schizophrenia were re-diagnosed as NMDA-R encephalitis due to the type of antibodies they had. They also had some intriguing physical symptoms and CNS and blood inflammatory markers that aren't typically found in schizophrenia.
But it is fascinating and needs to be studied in more populations at greater length. Is there a time coming when 10% of our first break psychosis patients might be getting plasma exchange and steroids? Would they be maintained on autoimmune dietary protocols (if effective for blood titres of antibodies) and relatively benign chronic immune modulators (again, just hypothesizing in an exciting sort of way) such as pig whipworm or killed M vaccae?
As always, more questions than answers, but getting one step closer to the bottom of the pathology of mental illness and brain diseases is always interesting, and always gives me hope. And what about the healthy control and the patients with major depressive disorder who had anti-NMDA-R antibodies? Are they more likely to have problems with psychosis or psychopathology? I suppose we will have to wait and see.
Brahms Violin Concerto (very long, really famous bit begins at around minute 35)
No one is sure what these immune reactions mean. But it would be interesting to see how immune modulators might affect psychosis in a clinical trial. In evolutionary medicine, immune and inflammatory modulators could include a dietary intervention, probiotics, or even helminth therapies. To my knowledge, none of these have been applied to schizophrenia or post-partum psychosis in a clinical trial of any kind.
This week, a paper came out in the renamed Archives of General Psychiatry (Now JAMA Psychiatry) linking schizophrenia to a set of autoantibodies. The findings in this paper lend more credence to the idea that a subset of schizophrenia may be caused by an immune attack on the brain. Blood from a group of unmedicated, hospitalized schizophrenics was compared to blood from people admitted with major depressive disorder, borderline personality disorder, and healthy controls.
9.9% of the actuely ill schizophrenics were found to have anti-NMDA receptor antibodies, compared with 2.8% of those with major depressive disorder, 0.4% of controls, and 0 of those with borderline personality disorder. The NMDA receptor (glutamate is the key neurotransmitter at this receptor) is known to be associated with psychotic symptoms. PCP and ketamine are NMDA receptor antagonists that rather famously cause agitation and psychosis.
Now there is already an illness of anti-NMDA receptors called "NMDA-R encephalitis." It affects young women with a rare type of ovarian tumor called a teratoma, and presents with psychosis, agitation, memory problems, and seizures. It tends to progress to problems with the autonomic nervous system (which can control breathing, temperature and blood pressure regulation) and cause a catatonic state. It is treated, like many life-threatening autoimmune conditions, with high dose steroids and plasmaphoresis (or plasma exchange, which can clear the blood of the offending autoantibodies). The autoantibodies in the cases of NMDA-R encephalitis are to a different specific protein subunit of the receptor and tend to be in much higher concentrations than the folks with autoantibodies who had acute schizophrenia, so it is not exactly the same disease. In this trial, however, two of the patients originally diagnosed with schizophrenia were re-diagnosed as NMDA-R encephalitis due to the type of antibodies they had. They also had some intriguing physical symptoms and CNS and blood inflammatory markers that aren't typically found in schizophrenia.
But it is fascinating and needs to be studied in more populations at greater length. Is there a time coming when 10% of our first break psychosis patients might be getting plasma exchange and steroids? Would they be maintained on autoimmune dietary protocols (if effective for blood titres of antibodies) and relatively benign chronic immune modulators (again, just hypothesizing in an exciting sort of way) such as pig whipworm or killed M vaccae?
As always, more questions than answers, but getting one step closer to the bottom of the pathology of mental illness and brain diseases is always interesting, and always gives me hope. And what about the healthy control and the patients with major depressive disorder who had anti-NMDA-R antibodies? Are they more likely to have problems with psychosis or psychopathology? I suppose we will have to wait and see.
Saturday, December 15, 2012
Alternative Therapies and Bipolar Disorder
I will get back to OCD. In the mean time a new paper came out called Nutrient-Based Therapies for Bipolar Disorder, A Systemic Review. And this paper is not written by some press agent working out of the basement of a supplement company. It's the Massachusetts General Hospital bipolar research clinic. I've been in meetings with some of these folks and heard them speak.
Psychiatry in Boston (and the East Coast) is such a funny mix of psychoanalysts and rigidly conservative psychopharmacologists. Apparently on the West Coast things are a little different, with more acceptance of polypharmacy and supplements. But from the center of the most conservative bastion of psychiatry from the 1930s-60s and some of the busiest depression and bipolar pharmaceutical clinical researchers on the planet comes some really cool work with supplements and alternative treatments. I'm a big fan of Neirenberg and Fava over at MGH and their work with alternative therapies. They have open minds and scientific eyes.
Tame Impala: Feels Like We Only Go Backwards
Let's get to it. Bipolar disorder can be difficult to diagnose and more difficult to treat. I try not to judge too much when someone comes to my office with a "bipolar II" diagnosis on the newest, most expensive antipsychotic and a mood stabilizer when they really have depression plus ADHD and/or anxiety symptoms and/or a history of being traumatized. All the diagnoses in the DSM are from the symptom level up, not from the brain pathology down, so things are messy. But despite all that there are plenty of honest-to-goodness bipolar folk who benefit from mood stabilizers… but 54-68% of appropriately treated folks continue to experience subthreshold symptoms, and side effects continue to be a major problem.
Omega 3 fatty acid supplementation may be useful not only for brain health but for physical health. (Of course I personally prefer limiting the omega 6 consumption and eating a nominal amount of cold water oily fish weekly…[practical aside here] one trick is to make tuna salad with 2 cans of light tuna, one can of sardines, celery, pickles, carrot, onion, spices, and your own olive oil mayonnaise (I use the olive oil recipe from Well Fed which is still my favorite "paleo" cookbook, though Eat Like A Dinosaur is great for kid-friendly meals and Primal Blueprint Quick and Easy Meals is also a staple).
Individuals with bipolar disorder are more likely to be obese, less likely to cook their own meals, and more likely to eat sugary foods. And, according to a recent paper (1) looking at the nutrient intake of people with bipolar disorder, they tend to consume food with lower levels of thiamin, riboflavin, folate, phosphorous, zinc, vitamin B6, and vitamin B12 compared to the population norms.
Omega 3 fatty acids work by increasing membrane fluidity and normalizing signal transduction, reducing inflammation, and activate nuclear receptor effects. In bipolar disorder, the first studies were done by Andy Stoll of high doses (around 10g), and over a period of 4 months, there was significantly less depression and higher levels of global functioning. EPA + DHA has the most data, and the amount used in various studies… vary a great deal. ALA (flax oil) was not found to be useful, nor was DHA alone. Mania doesn't seem to be affected, only depression and general functioning symptoms, and the effect sizes are not strong enough and the intervention not studied enough to take in lieu of regular pharmacologic treatment for bipolar disorder. However, as an adjunct, the risks may be very low compared to possible benefits.
Inositol has also been studied several times (but all small sample sizes) in bipolar depression. (See my earlier post for the mechanism.) Again, as an adjunct, it seems to have some promise for depression, but we need larger sample sizes.
Choline might be helpful by improving and increasing the efficiency of brain energetics. The brain is hungry for ATP (the energy currency of the cells), and in many neuropsychiatric disorders including bipolar disorder, energetics seem to be impaired, possibly by inflammation and oxidative damage. Choline is the main reason (along with all those delectable B vitamins and general yummyness) that I think advice to toss out the egg yolks is idiocy. All the randomized controlled studies of choline supplementation in bipolar disorder are small, and of complicated patients (for example, rapid cycling bipolar and cocaine dependence). One small open label trial by Stoll did demonstrate some benefit for mood.
Magnesium deficiency, as I've discussed in the past, is quite common in the general population. Signs of deficiency include irritability, fatigue, insomnia, loss of appetite, mental confusion, and a vulnerability to stress. Magnesium also has some effects on neurotransmission that are similar to mood stabilizers lithium, valproate, and lamotrigine. There are some small studies of manic patients doing much better with adjunctive magnesium added (one was oral magnesium oxide, the other injected magnesium in severely manic patients). There is only onse study of magnesium as a monotherapy, and 40 meq daily did reduce mania in rapid cycling patients.
Chromium (I haven't written anything on chromium yet… should get on that) seems to improve insulin sensitivty in the hypothalamus and affects the monoamine neurotransmitter systems. Enhanced hypothalamic function may increase the release of serotonin, norepinephrine, and melatonin. There are a few studies showing efficacy in unipolar depression, but not atypical depression, and in the one study of bipolar disorder, there were lots of drop outs.
Folic acid has been studied only once in bipolar disorder, in conjunction with valproate (which interferes with folate metabolism). It seemed to be helpful, particularly for cognitive symptoms. There are more positive studies in unipolar depression, and there's no reason to think it wouldn't be helfpul in bipolar depression (though there are reasons to think folic acid might be an inferior supplement to l-methylfolate, they have not had head to head studies in depression as far as I know).
Rapid tryptophan depletion will decrease serotonin levels in the brain. It can be achieved fairly readily using a tryptophan-depleted drink (see this post for more details). In Canada, it is actually approved as adjunctive therapy to lithium in acute mania, and another study of manic patients showed it might be helpful, but 23% of patients couldn't tolerate the drink. L-tryptophan itself also looked like a promising antimanic agent in a small study of 24 patients (12 grams daily, looks like, for two weeks). However, after it was banned by the FDA in 1989, further studies have been lacking.
In general, nutritional supplementation to current therapies may work synergistically with the therapies (such as folate and valproate), and for many therapies (excepting perhaps chromium and rapid tryptophan depletion), the side effects and risks seem lower compared to the conventional therapies or combining conventional therapies, which is often done with resistant cases now. More larger studies of some of these combination effects would be great to help us clinicians in the field have a larger tool kit from which to work. In addition, the nutritional therapies haven't been tested with consistent dosing or in consistent populations to really give us a sense of optimal amounts or usage. Their potential coud be fantastic.
Psychiatry in Boston (and the East Coast) is such a funny mix of psychoanalysts and rigidly conservative psychopharmacologists. Apparently on the West Coast things are a little different, with more acceptance of polypharmacy and supplements. But from the center of the most conservative bastion of psychiatry from the 1930s-60s and some of the busiest depression and bipolar pharmaceutical clinical researchers on the planet comes some really cool work with supplements and alternative treatments. I'm a big fan of Neirenberg and Fava over at MGH and their work with alternative therapies. They have open minds and scientific eyes.
Tame Impala: Feels Like We Only Go Backwards
Let's get to it. Bipolar disorder can be difficult to diagnose and more difficult to treat. I try not to judge too much when someone comes to my office with a "bipolar II" diagnosis on the newest, most expensive antipsychotic and a mood stabilizer when they really have depression plus ADHD and/or anxiety symptoms and/or a history of being traumatized. All the diagnoses in the DSM are from the symptom level up, not from the brain pathology down, so things are messy. But despite all that there are plenty of honest-to-goodness bipolar folk who benefit from mood stabilizers… but 54-68% of appropriately treated folks continue to experience subthreshold symptoms, and side effects continue to be a major problem.
Omega 3 fatty acid supplementation may be useful not only for brain health but for physical health. (Of course I personally prefer limiting the omega 6 consumption and eating a nominal amount of cold water oily fish weekly…[practical aside here] one trick is to make tuna salad with 2 cans of light tuna, one can of sardines, celery, pickles, carrot, onion, spices, and your own olive oil mayonnaise (I use the olive oil recipe from Well Fed which is still my favorite "paleo" cookbook, though Eat Like A Dinosaur is great for kid-friendly meals and Primal Blueprint Quick and Easy Meals is also a staple).
Individuals with bipolar disorder are more likely to be obese, less likely to cook their own meals, and more likely to eat sugary foods. And, according to a recent paper (1) looking at the nutrient intake of people with bipolar disorder, they tend to consume food with lower levels of thiamin, riboflavin, folate, phosphorous, zinc, vitamin B6, and vitamin B12 compared to the population norms.
Omega 3 fatty acids work by increasing membrane fluidity and normalizing signal transduction, reducing inflammation, and activate nuclear receptor effects. In bipolar disorder, the first studies were done by Andy Stoll of high doses (around 10g), and over a period of 4 months, there was significantly less depression and higher levels of global functioning. EPA + DHA has the most data, and the amount used in various studies… vary a great deal. ALA (flax oil) was not found to be useful, nor was DHA alone. Mania doesn't seem to be affected, only depression and general functioning symptoms, and the effect sizes are not strong enough and the intervention not studied enough to take in lieu of regular pharmacologic treatment for bipolar disorder. However, as an adjunct, the risks may be very low compared to possible benefits.
Inositol has also been studied several times (but all small sample sizes) in bipolar depression. (See my earlier post for the mechanism.) Again, as an adjunct, it seems to have some promise for depression, but we need larger sample sizes.
Choline might be helpful by improving and increasing the efficiency of brain energetics. The brain is hungry for ATP (the energy currency of the cells), and in many neuropsychiatric disorders including bipolar disorder, energetics seem to be impaired, possibly by inflammation and oxidative damage. Choline is the main reason (along with all those delectable B vitamins and general yummyness) that I think advice to toss out the egg yolks is idiocy. All the randomized controlled studies of choline supplementation in bipolar disorder are small, and of complicated patients (for example, rapid cycling bipolar and cocaine dependence). One small open label trial by Stoll did demonstrate some benefit for mood.
Magnesium deficiency, as I've discussed in the past, is quite common in the general population. Signs of deficiency include irritability, fatigue, insomnia, loss of appetite, mental confusion, and a vulnerability to stress. Magnesium also has some effects on neurotransmission that are similar to mood stabilizers lithium, valproate, and lamotrigine. There are some small studies of manic patients doing much better with adjunctive magnesium added (one was oral magnesium oxide, the other injected magnesium in severely manic patients). There is only onse study of magnesium as a monotherapy, and 40 meq daily did reduce mania in rapid cycling patients.
Chromium (I haven't written anything on chromium yet… should get on that) seems to improve insulin sensitivty in the hypothalamus and affects the monoamine neurotransmitter systems. Enhanced hypothalamic function may increase the release of serotonin, norepinephrine, and melatonin. There are a few studies showing efficacy in unipolar depression, but not atypical depression, and in the one study of bipolar disorder, there were lots of drop outs.
Folic acid has been studied only once in bipolar disorder, in conjunction with valproate (which interferes with folate metabolism). It seemed to be helpful, particularly for cognitive symptoms. There are more positive studies in unipolar depression, and there's no reason to think it wouldn't be helfpul in bipolar depression (though there are reasons to think folic acid might be an inferior supplement to l-methylfolate, they have not had head to head studies in depression as far as I know).
Rapid tryptophan depletion will decrease serotonin levels in the brain. It can be achieved fairly readily using a tryptophan-depleted drink (see this post for more details). In Canada, it is actually approved as adjunctive therapy to lithium in acute mania, and another study of manic patients showed it might be helpful, but 23% of patients couldn't tolerate the drink. L-tryptophan itself also looked like a promising antimanic agent in a small study of 24 patients (12 grams daily, looks like, for two weeks). However, after it was banned by the FDA in 1989, further studies have been lacking.
In general, nutritional supplementation to current therapies may work synergistically with the therapies (such as folate and valproate), and for many therapies (excepting perhaps chromium and rapid tryptophan depletion), the side effects and risks seem lower compared to the conventional therapies or combining conventional therapies, which is often done with resistant cases now. More larger studies of some of these combination effects would be great to help us clinicians in the field have a larger tool kit from which to work. In addition, the nutritional therapies haven't been tested with consistent dosing or in consistent populations to really give us a sense of optimal amounts or usage. Their potential coud be fantastic.
Sunday, November 11, 2012
B12 Deficiency and Psychosis, A Case Study
I'm a little few and far between here lately. Besides the day job and the children, between my weekly class, natural disasters, and presenting (almost every week, it seems), all my spare time for looking up papers and blogging has been sucked away. I'm eager to engage on another bigger project instead of doing these posts on single papers, and in that vein I'm hopeful to pursue OCD and then a lot of work on eating disorders.
If you are a stranger who has emailed me or commented on a specific clinical issue, I'm sorry, but I can't help you right now. If you have emailed me to follow up about some other issue, give me a week or two to get back to you, please. The presentations are over for the year, at least, with my last one at Xavarian Brothers High School on the disaster that is processed food and the brain. I've already been invited for two more grand rounds in the spring, PaleoFx13, and for a physicians and ancestral health get-together in February. I was invited also to be part of a proposed panel for the American Psychiatric Association on diet and psychiatry, but we have not heard back from the APA about whether it has been accepted. Fingers crossed. So! Very busy and trying to get the word out about all of these interesting intersections between ancestral health and pathology, and mental health so the real academics can do some awesome research and answer some questions for us.
Brahms Symphony No. 3 Poco Allegretto (ad to start. sorry. right click to open in new tab or window)
In the mean time, a search for vegetarian diets and mood brought up this new (free full text) paper which is both interesting and a nice review of B12 deficiency symptoms and signs in general. (The young man was not a vegetarian, by the way).
B12 is an essential vitamin, and in medical school we are taught mainly the neurologic and hematologic (blood) findings of a severe deficiency, which are a particular kind of nerve damage (subacute combined degeneration of the spinal cord which is on pretty much every board exam I ever took), peripheral neuropathy, cognitive problems reminiscent of dementia, and an enlargement and numerical reduction of the red blood cells called "megaloblastic anemia." What I didn't know until psychiatry residency is that psychiatric symptoms can precede all the more obvious medical findings*, and the psychiatric symptoms include irritability, insomnia, confusion, negativism, and impaired attention, and folks with B12 deficiency can be diagnosed with depression, bipolar disorder, panic disorder, dementia, and even psychotic disorders.
B12 is vital for making neurotransmitters, for methylation, and for making DNA, so a deficiency can cause all sorts of issues with the nerves. If caught early on, these issues are largely reversible. Our serum test for B12 is also not as reliable an indicator of B12 available at the tissue level, and for this reason it is recommended that patients with depressive disorders (and I would broaden this recommendation to most psychiatric patients, as occult deficiency can masquerade as many psychiatric disorders) be checked for deficiency and be repleted to a level of at least 400 ng/ml (normal range is 200-1200 in most of the lab ranges I've seen). This recommendation is printed right at the bottom of the lab results from the lab I commonly use, so not terribly controversial, though many of my patients come in at a level in the mid 300s.
We are taught that most people with B12 deficiency have a problem with absorption, not a dietary deficiency. There is a test called the Schilling Test to determine if malabsorption exists, but I've never seen it done in practice (though it is another common board exam question). As it involves a radioactive dose of B12 and 24 hour urine and several stages, I can see why it is not typically done.
In general, practitioners try oral or sublingual B12 at extra doses to try to prop up the levels (which normally works in practice, suggesting that maybe some of us are consuming less B12 than we think, even us non-vegans**), and if that doesn't help or the level is low enough, you start off with B12 shots to bypass the pesky gut. Often the malabsorption is due to something obvious, such as a gastric bypass, so the Schilling Test would probably be a waste of time. I also think it is easier to check for bacterial overgrowth by other (non radioactive) means these days, and since bacterial overgrowth or celiac or some other condition are typically the cause, and gastronenterologists are often pursuing the diagnosis of B12 deficiency, they will tend to look for those causes if oral repletion of B12 fails rather than chase down the Schilling Test. I think that might be enough background, so...
On to the case study! In this paper, a young Turkish man, age 16 (unusual, since most B12 deficiencies are thought to be in the elderly) who is not a vegan presented with one year of complaints of anxiety, weepiness, lethargy, and skipping school. He began to stop sleeping and eating, withdrew from his friends, and spent a lot of time online buying things. Before this change, the young man had been extroverted and active with no previous episodes of compulsive buying or obsessive behavior. He had always had trouble paying attention since at least the second grade, and was described as "fidgety," especially in math class. On mental status exam, the patient had impaired attention and several varieties of hallucinations, including olfactory***, visual, and auditory. He had other symptoms of a major depressive episode, with slow thought and speech, decreased interest, suicidal ideation, and other psychotic symptoms including delusions that others could read his mind ("thought broadcasting") and paranoia that others were thinking and talking about him.
The patient had no history of drug use or use of antipsychotics, toxic screens (including those for heavy metals and pesticide exposure) were negative. On physical exam he had prominent neurologic findings including glossitis (a swollen, discolored tongue), cogwheeling and shoulder rigidity, decreased coordination (specifically with certain muscular movement and ability to correct posture called ataxia.) He had a positive Romberg's sign (stand up, close your eyes and don't fall over) but no other obvious symptoms of peripheral neuropathy (which normally begins with complaints of numbing, tingling, or burning in the hands and feet). In short, he had a lot of neurologic signs that many areas of his brain were, to some extent, shorting out and going offline.
His team did a massive medical work-up, including bone marrow biopsy, MRI, EEG, EMG, HIV testing and other blood testing, almost all of which were normal (including folate and transcobalamine), and he did not have the classic megaloblastic anemia. He did have slightly low hemoglobin and his red blood cell size was on the high end of normal. His serum B12 test was low, at 166 ng/ml (measured twice, fasting). The doctors went further to biopsy his intestines, did not find evidence of celiac, but did find a positive Schilling Test for B12 malabsorption and an overgrowth of H pylori bacteria, which was thought to be the cause of his malabsoprtion. He was treated with antibiotics, daily B12 shots, and a low dose of an antipsychotic, and his symptoms began to improve. In two weeks his psychosis was gone, and many of his worst neurologic symptoms (such as the ataxia) were gone, and his mood, anxiety, and tearfulness were improving. After two weeks of daily injections, his B12 levels were 595. His antipsychotic was discontinued and his shots were changed to once monthly. He was followed closely for the next 6 months and there was no recurrence of the psychiatric symptoms, and his H pylori overgrowth was resolved.
It was thought that the patient may have had a genetic polymorphism called C677T of the MTHFR gene of the folate cycle which is more prevalent in Mediterranean countries, and this genetic change may have caused him not to have the hematologic signs before presenting with a great many neurologic signs. It is also interesting he presented with what are called "extrapyramidal" symptoms (postural problems and rigidity, similar to Parkinson's disease, which is why the doctors were busy looking for pesticide exposure or antipsychotic use) rather than the more common neurologic problems from B12 deficiency (such as peripheral neuropathy) and it may also have been due to genetic differences in his folate cycle machinery. Biochemists and medical folks should read the last paragraph of the case presentation in the paper itself, as it goes into all the gory details and possibilities with respect to cysteine, SAMe, folate, dopamine, and motor neurons.
All in all, this case is a fascinating but rare presentation of what I would call a relatively common vitamin deficiency. I plan to update my previous post on vegetarian diets and mental disorders later today, and get to work on some of the projects…
*I do my best to test all my patients for B12 deficiency at least once. One time, a patient with recurrent and resistant depression along with some peripheral neuropathy symptoms had a low B12 in a laboratory measure, but her primary care doctor refused to write an order for the standard of care, which is B12 shots for a period of time, because she didn't have the megaloblastic anemia. After a very confusing phone call with the primary, I decided to go over his head and order the shots myself, and her peripheral neuropathy symptoms resolved, along with the insomnia and agitation that had accompanied her tough longstanding depression. I still shake my head over that one, because it is a relatively low cost test and a very inexpensive treatment, with possible dire permanent consequences if left untreated.
** I now have several "paleo" patients in my practice, and all of them have had terrific B12 levels (usually in the 600s), I would say about 200 ng/ml above the typical patient, who tends to hover in the 300-400 range. Strict daily multivitamin takers also tend to have robust B12 levels. Anecdotal but interesting.
***general rule of thumb in psychiatry is that olfactory (smell) hallucinations are neurologic from say a seizure or a brain tumor until proven otherwise. They are almost always unpleasant smells of burning rubber or old mouldering flowers or something of that nature.
If you are a stranger who has emailed me or commented on a specific clinical issue, I'm sorry, but I can't help you right now. If you have emailed me to follow up about some other issue, give me a week or two to get back to you, please. The presentations are over for the year, at least, with my last one at Xavarian Brothers High School on the disaster that is processed food and the brain. I've already been invited for two more grand rounds in the spring, PaleoFx13, and for a physicians and ancestral health get-together in February. I was invited also to be part of a proposed panel for the American Psychiatric Association on diet and psychiatry, but we have not heard back from the APA about whether it has been accepted. Fingers crossed. So! Very busy and trying to get the word out about all of these interesting intersections between ancestral health and pathology, and mental health so the real academics can do some awesome research and answer some questions for us.
Brahms Symphony No. 3 Poco Allegretto (ad to start. sorry. right click to open in new tab or window)
In the mean time, a search for vegetarian diets and mood brought up this new (free full text) paper which is both interesting and a nice review of B12 deficiency symptoms and signs in general. (The young man was not a vegetarian, by the way).
B12 is an essential vitamin, and in medical school we are taught mainly the neurologic and hematologic (blood) findings of a severe deficiency, which are a particular kind of nerve damage (subacute combined degeneration of the spinal cord which is on pretty much every board exam I ever took), peripheral neuropathy, cognitive problems reminiscent of dementia, and an enlargement and numerical reduction of the red blood cells called "megaloblastic anemia." What I didn't know until psychiatry residency is that psychiatric symptoms can precede all the more obvious medical findings*, and the psychiatric symptoms include irritability, insomnia, confusion, negativism, and impaired attention, and folks with B12 deficiency can be diagnosed with depression, bipolar disorder, panic disorder, dementia, and even psychotic disorders.
B12 is vital for making neurotransmitters, for methylation, and for making DNA, so a deficiency can cause all sorts of issues with the nerves. If caught early on, these issues are largely reversible. Our serum test for B12 is also not as reliable an indicator of B12 available at the tissue level, and for this reason it is recommended that patients with depressive disorders (and I would broaden this recommendation to most psychiatric patients, as occult deficiency can masquerade as many psychiatric disorders) be checked for deficiency and be repleted to a level of at least 400 ng/ml (normal range is 200-1200 in most of the lab ranges I've seen). This recommendation is printed right at the bottom of the lab results from the lab I commonly use, so not terribly controversial, though many of my patients come in at a level in the mid 300s.
We are taught that most people with B12 deficiency have a problem with absorption, not a dietary deficiency. There is a test called the Schilling Test to determine if malabsorption exists, but I've never seen it done in practice (though it is another common board exam question). As it involves a radioactive dose of B12 and 24 hour urine and several stages, I can see why it is not typically done.
In general, practitioners try oral or sublingual B12 at extra doses to try to prop up the levels (which normally works in practice, suggesting that maybe some of us are consuming less B12 than we think, even us non-vegans**), and if that doesn't help or the level is low enough, you start off with B12 shots to bypass the pesky gut. Often the malabsorption is due to something obvious, such as a gastric bypass, so the Schilling Test would probably be a waste of time. I also think it is easier to check for bacterial overgrowth by other (non radioactive) means these days, and since bacterial overgrowth or celiac or some other condition are typically the cause, and gastronenterologists are often pursuing the diagnosis of B12 deficiency, they will tend to look for those causes if oral repletion of B12 fails rather than chase down the Schilling Test. I think that might be enough background, so...
On to the case study! In this paper, a young Turkish man, age 16 (unusual, since most B12 deficiencies are thought to be in the elderly) who is not a vegan presented with one year of complaints of anxiety, weepiness, lethargy, and skipping school. He began to stop sleeping and eating, withdrew from his friends, and spent a lot of time online buying things. Before this change, the young man had been extroverted and active with no previous episodes of compulsive buying or obsessive behavior. He had always had trouble paying attention since at least the second grade, and was described as "fidgety," especially in math class. On mental status exam, the patient had impaired attention and several varieties of hallucinations, including olfactory***, visual, and auditory. He had other symptoms of a major depressive episode, with slow thought and speech, decreased interest, suicidal ideation, and other psychotic symptoms including delusions that others could read his mind ("thought broadcasting") and paranoia that others were thinking and talking about him.
The patient had no history of drug use or use of antipsychotics, toxic screens (including those for heavy metals and pesticide exposure) were negative. On physical exam he had prominent neurologic findings including glossitis (a swollen, discolored tongue), cogwheeling and shoulder rigidity, decreased coordination (specifically with certain muscular movement and ability to correct posture called ataxia.) He had a positive Romberg's sign (stand up, close your eyes and don't fall over) but no other obvious symptoms of peripheral neuropathy (which normally begins with complaints of numbing, tingling, or burning in the hands and feet). In short, he had a lot of neurologic signs that many areas of his brain were, to some extent, shorting out and going offline.
His team did a massive medical work-up, including bone marrow biopsy, MRI, EEG, EMG, HIV testing and other blood testing, almost all of which were normal (including folate and transcobalamine), and he did not have the classic megaloblastic anemia. He did have slightly low hemoglobin and his red blood cell size was on the high end of normal. His serum B12 test was low, at 166 ng/ml (measured twice, fasting). The doctors went further to biopsy his intestines, did not find evidence of celiac, but did find a positive Schilling Test for B12 malabsorption and an overgrowth of H pylori bacteria, which was thought to be the cause of his malabsoprtion. He was treated with antibiotics, daily B12 shots, and a low dose of an antipsychotic, and his symptoms began to improve. In two weeks his psychosis was gone, and many of his worst neurologic symptoms (such as the ataxia) were gone, and his mood, anxiety, and tearfulness were improving. After two weeks of daily injections, his B12 levels were 595. His antipsychotic was discontinued and his shots were changed to once monthly. He was followed closely for the next 6 months and there was no recurrence of the psychiatric symptoms, and his H pylori overgrowth was resolved.
It was thought that the patient may have had a genetic polymorphism called C677T of the MTHFR gene of the folate cycle which is more prevalent in Mediterranean countries, and this genetic change may have caused him not to have the hematologic signs before presenting with a great many neurologic signs. It is also interesting he presented with what are called "extrapyramidal" symptoms (postural problems and rigidity, similar to Parkinson's disease, which is why the doctors were busy looking for pesticide exposure or antipsychotic use) rather than the more common neurologic problems from B12 deficiency (such as peripheral neuropathy) and it may also have been due to genetic differences in his folate cycle machinery. Biochemists and medical folks should read the last paragraph of the case presentation in the paper itself, as it goes into all the gory details and possibilities with respect to cysteine, SAMe, folate, dopamine, and motor neurons.
All in all, this case is a fascinating but rare presentation of what I would call a relatively common vitamin deficiency. I plan to update my previous post on vegetarian diets and mental disorders later today, and get to work on some of the projects…
*I do my best to test all my patients for B12 deficiency at least once. One time, a patient with recurrent and resistant depression along with some peripheral neuropathy symptoms had a low B12 in a laboratory measure, but her primary care doctor refused to write an order for the standard of care, which is B12 shots for a period of time, because she didn't have the megaloblastic anemia. After a very confusing phone call with the primary, I decided to go over his head and order the shots myself, and her peripheral neuropathy symptoms resolved, along with the insomnia and agitation that had accompanied her tough longstanding depression. I still shake my head over that one, because it is a relatively low cost test and a very inexpensive treatment, with possible dire permanent consequences if left untreated.
** I now have several "paleo" patients in my practice, and all of them have had terrific B12 levels (usually in the 600s), I would say about 200 ng/ml above the typical patient, who tends to hover in the 300-400 range. Strict daily multivitamin takers also tend to have robust B12 levels. Anecdotal but interesting.
***general rule of thumb in psychiatry is that olfactory (smell) hallucinations are neurologic from say a seizure or a brain tumor until proven otherwise. They are almost always unpleasant smells of burning rubber or old mouldering flowers or something of that nature.
Saturday, October 27, 2012
What is Evolutionary Psychiatry?
I am in the midst of a new academic year of talks. Last week I went to the Brigham and Women's Hospital behavioral neurology interest group talk, and last Thursday to Boston University Medical Center Psychiatry Grand Rounds. I do like these academic talks, though naturally the audience is much more skeptical than the Ancestral Health Symposium and PaleoFx folks. Skepticism is good. Keeps me on my toes. At the Brigham Behavioral Neurology group, I had immediate questions involving how long our ancestors lived, how old was the individual who owned the beautiful choppers in the ancient Maori skull when he/she died, and what exactly were the questions asked by Staffan Lindeberg and company to determine that the Kitavan elders didn't seem to have symptoms of dementia.
All important questions! I didn't have answers to as many as I wanted to… but I think I held my own. I do try to make the point that my blog is not about answers, but rather about asking these questions for research in a meaningful way. If the government food plate leads us to "whole grain" sugary honey nut "O" cereal as a big healthy part of our diet, and beautiful nutrient-rich egg yolks are deadly, maybe we should step back and think about that for a moment.
Grand Rounds at Boston Medical Center went well. I thought the talk was received with interest, and I certainly thank Dr. Searl and Dr. Chapman for inviting me to speak. I hope that someone thinks about a research idea…I'm particularly hopeful that we will get more research about fructose malabsorption and depression. We'll see.
Recently I've been hard at work reading an amazing textbook about the immune system and evolution recommended to me by Kurt Harris.
The textbook has quite a bit to say about mental illness, a whole chapter (pages 189-220), which is quite amazing, as most anthropology and hygiene hypothesis tends to avoid mental illness. So much easier to focus on diabetes and obesity and autoimmune disease. All easily marked and tallied. Not so mental illness, defined by the recipe book of symptoms we call the DSMIVTR.
Well. Stress-related psychiatric disorders (which is nearly all of them, when I think about it), particularly depressive and anxiety disorders, are associated with markers of inflammation, particularly raised levels of proinflammatory cytokines. Some of the proinflammatory cytokines (most famously interferon alpha, used to treat hepatitis C) can induce depression in folks with no previous symptoms. Thus it is reasonable to assume that immune dysregulation, that is our immune system a bit out of whack, like an army milling about without clear leadership, could be part of mental illness.
Like autoimmune disease and allergic disorders (athma, hay fever, type I diabetes, multiple sclerosis, and inflammatory bowel diseases such as ulcerative colitis) have been increasing preciptiously in the developed world in recent decades. The "old friends hypothesis" suggests that we are, in effect, missing a major regulator of our immune system that we co-evolved with for thousands upon thousands of generations. That is, three classes of organisms who have lived within us or passed through us, all of our ancestors, until very recently. They are the pseudocommensals, the commensals, and the parasitic worms. (More about the old friends hypothesis in this article.)
The down and dirty of it is that we have several arms of our immune system, kind of like infantry and navy and military intelligence. There are various forms of T helper cells (Th1 and Th2) that secrete inflammatory cytokines to tell which arms of our immune system to come forth and attack. What will tell the Th1 and Th2 cells to back off is a third variety of T cell, called Tregs (short for regulatory T cells). Infection with our "old friends" (such as pinworms, or tapeworms, or the pseudocommensals like soil mycobacteria) seems to cause continuous activation of the Tregs, keeping the Th1 and Th2 cells in check. In effect, these "old friends" organisms have always been there, and have become a part of our immune system. It is no wonder that we have problems when we no longer have the old friends at our disposal.*
Both Th1 and Th2-regulated inflammation have been associated with anxiety and depression. The "pro-inflammatory cytokines" IL-1, IL-2, IL-6, IL-12, TNFalpha, and interferon alpha and gamma. On the Th1 side, IL-6 and IL-1 levels are related to symptoms of depression in cancer patients and others. Downstream agents, such as C reactive protein, cerulosplasmin, and lower levels of zinc and albumin are also associated with depression symptoms. There are also increased levels of neutrophils and complement proteins** seen in acute exacerbations of bipolar disorder and major depressive disorder. Seems that people with increased levels of background inflammation are more susceptible to interferon and IL-2 administration causing depressive symptoms as well.
When we go over to the Th2 side of things (Th2 excess seems to be associated with allergies and hay fever and ulcerative colitis, whereas Th1 excess is associated with other autoimmune diseases such as type I diabetes and crohns), the evidence for specific cytokines is not as clear. However, people with allergies are known to have a greater incidence of depression. 50% of asthma sufferers seem to have clinically significant depression, and allergies are associated with an increased risk of suicide. Asthma is also clearly associated with anxiety (in studies, and also any experienced clinician can tell you… trouble breathing causes great anxiety and worries about future attacks). However, that association begs an important question…is it the immune dysregulation causing both anxiety and asthma, or the asthma symptoms particularly prone to causing anxiety? Until we have a better handle on the Th2 cytokines such as Il-4 (experimental tests are problematic) we may not know.
So, there is an enzyme called IDO, which can act on tryptophan leading to a depletion of serotonin. Inflammation seems to activate IDO, whereas antidepressants (such as SSRIs) seem to deactivate it, which may be the secret to how they might work. In pregnancy, there is a bias toward Th2 and regulatory T cells (thought to prevent immune attack on the growing fetus. Mothers-to-be are in a somewhat immune compromised state, particularly in the third trimester, which can actually decrease the incidence of some autoimmune symptoms during pregnancy). After pregnancy, however, there seem to be a Th1 "bounce back" that can lead to exacerbation of inflammatory disorders and depression. There is increased metabolism of tryptophan and increases in Th1-related cytokines.
The Dead Weather: I Can't Hear You (starts with an ad that can be skipped after a few seconds)
What about the gut and depression? Are raised levels of immune cytokines seen in depression caused by "leaky gut"? Levels of antibodies directed against several gut bacterial species are elevated in people with depression, suggesting leakiness. Leakiness is associated with increased bacterial endotoxin crossing the gut barrier, leading to increases in proinflammatory cytokines, which could plausibly cause depression symptoms. Gut epithelial barrier permeability is highly dependent upon the enteric immune system, and parasites and healthy, normal commensal organisms may help regulate and protect normal gut integrity. It's not a coincidence that Chron's and ulcerative colitis are associated with higher levels of affective disorders.
Depression is also very common in folks with vascular disease (those at high risk for heart attacks and thrombotic strokes). Metabolic syndrome, associated with athersclerosis and heart disease, is also associated with depressive symptoms. Brain-derived neurotrophic factor (a nerve fertilizer of sorts) seems to be diminished in depression and in vascular disease. Levels of BDNF are low before treatment, and seem to rise in response to succesful treatment. Autoimmune diseases such as MS are also noted for low levels of BDNF.
There are a lot of intriguing connections between whole-body immune pathology and depression and anxiety symptoms. Gut and immune dysregulation may be keys to these disorders. It will take more time and more asking the correct questions to find out whether these issues are of fundamental importance or not. Psychiatrists might want to read up on the immune system, however, as a part of continuing medical education.
*there are clear benefits to a hygenic water supply (unless you like cholera for breakfast), not eating dirt, and not having unchecked parasitic infections. Don't go drink untreated pondwater after reading this post. But my guess is that better study of these organisms will lead to safe and ingenious ways to emulate the old friends with much less risk than drinking untreated water and living with hookworms.
** a thorough grounding in immunology is beyond the scope of my post. However, these wikepedia articles can give you a good start.
Monday, October 8, 2012
Ketogenic Diets and Bipolar Disorder: New Case Studies
Researching the viability of ketogenic diets for therapeutic usage was one of the original interests that launched this blog. And while there is growing data for brain cancers and even a Cochran review for the use of ketogenic diets in epilepsy, the bipolar story has always been theoretical.
Churchill: Change (song starts at about 30 secs)
Ketogenic (very low carbohydrate and low protein) diets should work a bit like the mood stabilizer depakote in regulating unstable moods in bipolar disorder, making them an interesting option, should the research pan out. I explore the research and details in this post:
A Dietary Treatment for Bipolar Disorder?
But, as I stated in that article, there were no randomized controlled trials, not even a pilot trial, and the only two case studies I had unearthed had one guy getting psychotic on Atkins induction and another one where a hospitalized bipolar woman showed no benefit (but despite reported enthusiasm and being in an inpatient unit where her food was supposedly entirely controlled, she never acheived ketosis).
But the other day PubMed emailed me a new paper with links to the following article: The ketogenic diet for type II bipolar disorder. Thanks to the good Dr. Eades I was able to see the full text without getting a librarian to request it for me.
And here we have not one, but two rather well documented cases of bipolar II disorder in women, beginning in youth with some hypomania, in one person predictable seasonal depressions in the summer and a bit of mania in the spring. Both women had bad responses (such as suicide attempts and suicidal thoughts) to antidepressant trials and one gained weight on quetiapine. They were tried on lamotrigine, an anticonvulsant and mood stablizer, with okay results (one woman was finally able to maintain a job and be functional). One tried a ketogenic diet to help with some irritable bowel symptoms, the other just wanted to try the diet. One woman ate raw cream, grassfed beef, organic pork, free range chicken, and seafood. The other ate mostly chicken, fish, and coconut oil with 2-3 cups of vegetables a day. Both monitored their urine with ketostix or Ketone Care Test Strips most days for several months, achieving mild to moderate ketosis on most days. Both women eventually discontinued the lamotrigine and reported better symptom control with the diet than with medication.
One woman described her irritability going away and a sense of calm. Also "having my head screwed on straight--well, it's definitely worth giving up pie." She said her symptoms seemed better with a ketone level of 15mg/dl vs 5 mg/dl in the urine. The other woman noted that if she remained gluten-free, she felt much better, even though she had never been diagnosed with celiac disease.
Neither woman had any adverse consequences and they remained stable on the diet for 2-3 years at the time the paper was published.
The paper details how a slight acidosis achieved with a ketogenic diet results in decreased intracellular sodium accumulation, which is the mechanism by which all anticonvulsants which are also mood stabilizers appear to work. In addition, the paper details some possible pitfalls of a ketogenic diet, such as difficulty maintaining it in a world of twinkies and coca-cola, and the risk of kidney stones. The author recommends >2.5 liters a day of fluids and a potassium citrate supplement to alkinilize the urine, which is done routinely in pediatric clinics where ketogenic diets are used for seizures, but may not be be necessary in adults. There is a long-term review of the ketogenic diets in kids (though I'm not a fan of the ingredients in some of the formulas used for tube-feeding some of these kids - soybean oil, soybean oil and more soybean oil) talking about complications over 6 years. Since these kids were often very ill with many other debilitating conditions, it is hard to attribute the complications (sepsis, cardiomyopathy, lipid pneumonia) to the diet itself.
Lipids were measured in one woman from a vegetarian to an omnivorous to a ketogenic diet. As is expected her trigs dropped and her LDL and HDL went up on the ketogenic diet. Total cholesterol to HDL ratio (the best cheap test I know of relating to total LDL particle number, with a lower ratio being better) on the vegetarian diet was 4.47, 3.78 on the omnivorous diet, and 3.74 on the ketogenic diet.
All in all, the paper is a nice illustration of two motivated patients acheiving remission of their bipolar symptoms (which they had dealt with for decades) with a free-living ketogenic diet (and some other supplements, though each woman took different ones, for example, probiotics and omega 3). Two anecdotes isn't a huge amount of data, but it is intriguing, and I would say the time for a randomized controlled trial of ketogenic diets in bipolar disorder is way overdue.
(Final note as I was in a bit of a hurry when I wrote the post at first… I did want to say there is a *lot* about these case study diets that could be therapeutic. No processed food, no sugar, lots of nutrients, lots of omega 3, low in gluten or gluten-free, likely low in histamine. The tracking of the ketones and one women's experience that the 15mg/dl ketone level felt more calming to her along with the sensible biologic mechanism makes the ketosis part plausible, but it is important to note these other possible factors).
Churchill: Change (song starts at about 30 secs)
Ketogenic (very low carbohydrate and low protein) diets should work a bit like the mood stabilizer depakote in regulating unstable moods in bipolar disorder, making them an interesting option, should the research pan out. I explore the research and details in this post:
A Dietary Treatment for Bipolar Disorder?
But, as I stated in that article, there were no randomized controlled trials, not even a pilot trial, and the only two case studies I had unearthed had one guy getting psychotic on Atkins induction and another one where a hospitalized bipolar woman showed no benefit (but despite reported enthusiasm and being in an inpatient unit where her food was supposedly entirely controlled, she never acheived ketosis).
But the other day PubMed emailed me a new paper with links to the following article: The ketogenic diet for type II bipolar disorder. Thanks to the good Dr. Eades I was able to see the full text without getting a librarian to request it for me.
And here we have not one, but two rather well documented cases of bipolar II disorder in women, beginning in youth with some hypomania, in one person predictable seasonal depressions in the summer and a bit of mania in the spring. Both women had bad responses (such as suicide attempts and suicidal thoughts) to antidepressant trials and one gained weight on quetiapine. They were tried on lamotrigine, an anticonvulsant and mood stablizer, with okay results (one woman was finally able to maintain a job and be functional). One tried a ketogenic diet to help with some irritable bowel symptoms, the other just wanted to try the diet. One woman ate raw cream, grassfed beef, organic pork, free range chicken, and seafood. The other ate mostly chicken, fish, and coconut oil with 2-3 cups of vegetables a day. Both monitored their urine with ketostix or Ketone Care Test Strips most days for several months, achieving mild to moderate ketosis on most days. Both women eventually discontinued the lamotrigine and reported better symptom control with the diet than with medication.
One woman described her irritability going away and a sense of calm. Also "having my head screwed on straight--well, it's definitely worth giving up pie." She said her symptoms seemed better with a ketone level of 15mg/dl vs 5 mg/dl in the urine. The other woman noted that if she remained gluten-free, she felt much better, even though she had never been diagnosed with celiac disease.
Neither woman had any adverse consequences and they remained stable on the diet for 2-3 years at the time the paper was published.
The paper details how a slight acidosis achieved with a ketogenic diet results in decreased intracellular sodium accumulation, which is the mechanism by which all anticonvulsants which are also mood stabilizers appear to work. In addition, the paper details some possible pitfalls of a ketogenic diet, such as difficulty maintaining it in a world of twinkies and coca-cola, and the risk of kidney stones. The author recommends >2.5 liters a day of fluids and a potassium citrate supplement to alkinilize the urine, which is done routinely in pediatric clinics where ketogenic diets are used for seizures, but may not be be necessary in adults. There is a long-term review of the ketogenic diets in kids (though I'm not a fan of the ingredients in some of the formulas used for tube-feeding some of these kids - soybean oil, soybean oil and more soybean oil) talking about complications over 6 years. Since these kids were often very ill with many other debilitating conditions, it is hard to attribute the complications (sepsis, cardiomyopathy, lipid pneumonia) to the diet itself.
Lipids were measured in one woman from a vegetarian to an omnivorous to a ketogenic diet. As is expected her trigs dropped and her LDL and HDL went up on the ketogenic diet. Total cholesterol to HDL ratio (the best cheap test I know of relating to total LDL particle number, with a lower ratio being better) on the vegetarian diet was 4.47, 3.78 on the omnivorous diet, and 3.74 on the ketogenic diet.
All in all, the paper is a nice illustration of two motivated patients acheiving remission of their bipolar symptoms (which they had dealt with for decades) with a free-living ketogenic diet (and some other supplements, though each woman took different ones, for example, probiotics and omega 3). Two anecdotes isn't a huge amount of data, but it is intriguing, and I would say the time for a randomized controlled trial of ketogenic diets in bipolar disorder is way overdue.
(Final note as I was in a bit of a hurry when I wrote the post at first… I did want to say there is a *lot* about these case study diets that could be therapeutic. No processed food, no sugar, lots of nutrients, lots of omega 3, low in gluten or gluten-free, likely low in histamine. The tracking of the ketones and one women's experience that the 15mg/dl ketone level felt more calming to her along with the sensible biologic mechanism makes the ketosis part plausible, but it is important to note these other possible factors).
Friday, June 1, 2012
Glutathione: We Loves It (NAC and Autism)
I love twitter. And I'm nearing 10,000 tweets, which is probably diagnostic of something. But twitter is a great way to find articles and studies and things of interest tweeted by others with similar interests. And twitter is how I found this new study from Biological Psychiatry, A Randomized Controlled Pilot Trial of Oral N-Acetylcysteine in Children with Autism. Everyone go follow Cognitie. He's obviously intelligent and good-looking to boot, with lots of cool links and whatnot.
N-acetylcysteine is a supplement I've covered before, in Problems? I Have a NAC for That.
(Phoenix: Armistice. Right click to open in new tab)
A healthy brain is all about balance. One one side we have glutamate, which is the major excitatory neurotransmitter in the central nervous system. Think of glutamate as a charioteer with a whip forcing the horses in your noggin to GO GO GO. We're glad we have glutamate. Without glutamate we'd be dead. But the problem is, glutamate doesn't always know when to stop. That's why we have GABA, the major inhibitory neurotransmitter in the central nervous system. GABA is the groom who takes those horses out to pasture to munch on the green grass and rubs the horses down with a nice brush. In the right balance, you have a winning horse. With too much excitatory action you get a worn-out old nag.
In autistic spectrum disorders, there are a number of lines of evidence pointing to problems with the excitatory/inhibitory balance in the brain. There seem to be increases in expression of RNA for genes in the glutamate pathway, and there are certain genes having to do with the glutamate system that increase the risk for having autism. Glutamate is actually the precursor for GABA, and the enzyme that catalyzes the transformation from one to the other is glutamic acid decarboxylase. Both reduced levels of this enzyme and increased levels of glutamate have been reported in areas of the brain and spinal fluid in some children with autism.
In addition, as I noted in a previous blog post, autism symptoms may be a result of redox imbalance. That is, throughout the body, we have oxidants and antioxidants. We oxidize things to burn them in order to make energy, but we are left with "reactive oxygen species" as part of the burning process. Antioxidants go around and sop up the reactive oxygen species to prevent them from damaging and destabilizing proteins and fats and whatnot. Reactive oxygen species run amok can damage neurons and cause major brain problems.
We're used to thinking of "antioxidants" as vitamins such as C and E. However, the major antioxidants in the body are actually superoxide dismutase, catalase, and glutathione. The glutathione is one of the ways where NAC comes in, because as a supplement it is the best way to replenish gluathione in the liver and the rest of the body.*
(Animal Kingdom: Strange Attractor )
In the brain, the cysteine from N-acetylcysteine activates a glutamate-cysteine antiporter (a type of transporter in and out of a cell that exchanges cysteine for glutamate). Shoving glutamate into the extracellular space in the brain leads to downregulation of glutamate transmission in the central nervous system. So if you have too much glutamate whipping the brain, NAC seems like a mighty useful supplement to take. Therefore, if autism spectrum disorders (and other neurologic and psychiatric disorders) are a result of an excitatory:inhibitory imbalance, with overabundant excitation, NAC will bring the players more into balance.
At the same time, if autism spectrum disorders (and other neurologic and psychiatric disorders) are a result of redox imbalance, with reactive oxygen species terrorizing the delicate neurons, NAC will help the body make plenty of glutathione to help clean up those bad boys.
There's no single cause of austim, but NAC might be a way to kill several birds with one stone, as it were. AND, in the brain the two pathways (excitatory:inhibitory and redox) come together, as glutathione can displace glutamate at its receptor. Another win for NAC, it would seem.**
And, as noted in the excellent editorial in the same issue of Biological Psychiatry, Translating the Rosetta Stone of N-Acetylcysteine, these multiple effects may be why NAC has been shown to be efficacious in trials of so many psychiatric disorders. In the first paper I linked above, a small pilot trial, symptoms of irritability in autism were much improved in 5 kids, minimally improved in 6 kids, no change in 2, and one child got worse (though after the trial and on no NAC the subject had the same symptoms which were eventually found to be due to constipation). In the placebo group, two were much improved, five were minimally improved, five had no change, one was minimally worse, and one was much worse. Postive trials for NAC have also been reported for certain symptoms of schizophrenia, bipolar depression, cocaine craving, smoking cessation, trichotillomania, and gambling. What is also fairly remarkable is a lack of negative studies (established agents for all of these conditions have many negative studies.)
We still don't know if NAC is entirely safe (I wrote some theoretical problems with long-term use in my original blog article), and dietary supplements that aren't pharmaceutical grade might not be as reliable in dose, active ingredient, etc. as prescription medication. On the other hand, we know that prescription medicines aren't entirely safe, and in many cases, we know they have very considerable risks.
It would be nice to have some replication of these studies. As it stands, however, NAC has more of an evidence-base for use trichotillomania than any standard pharmaceutical.
Out of all the supplements, the ones that impress me the most are NAC and magnesium. NAC sure isn't "evolutionary psychiatry," but in this modern world of stress, poor sleep, and inflammatory food, beefing up the glutathione and taming the glutamate seems like a reasonable approach, particularly if you are having devastating symptoms (as in severe autistic disorders).
*Glutathione itself is poorly absorbed as a supplement, and is too large a molecule to be easily absorbed into the cells. Cysteine is the rate-limiting component of the reactions taking glutamate + cysteine to eventually make glutathione. Cysteine itself is not easily absorbed, but the acetylated form, N-acetylcysteine, is. Therefore, if you take n-acetylcysteine, you supply both a necessary precursor for glutathione and a nifty way to mop up excess glutamate. Win-win on that front.
**and another eek! for acetaminophen
N-acetylcysteine is a supplement I've covered before, in Problems? I Have a NAC for That.
(Phoenix: Armistice. Right click to open in new tab)
A healthy brain is all about balance. One one side we have glutamate, which is the major excitatory neurotransmitter in the central nervous system. Think of glutamate as a charioteer with a whip forcing the horses in your noggin to GO GO GO. We're glad we have glutamate. Without glutamate we'd be dead. But the problem is, glutamate doesn't always know when to stop. That's why we have GABA, the major inhibitory neurotransmitter in the central nervous system. GABA is the groom who takes those horses out to pasture to munch on the green grass and rubs the horses down with a nice brush. In the right balance, you have a winning horse. With too much excitatory action you get a worn-out old nag.
In autistic spectrum disorders, there are a number of lines of evidence pointing to problems with the excitatory/inhibitory balance in the brain. There seem to be increases in expression of RNA for genes in the glutamate pathway, and there are certain genes having to do with the glutamate system that increase the risk for having autism. Glutamate is actually the precursor for GABA, and the enzyme that catalyzes the transformation from one to the other is glutamic acid decarboxylase. Both reduced levels of this enzyme and increased levels of glutamate have been reported in areas of the brain and spinal fluid in some children with autism.
In addition, as I noted in a previous blog post, autism symptoms may be a result of redox imbalance. That is, throughout the body, we have oxidants and antioxidants. We oxidize things to burn them in order to make energy, but we are left with "reactive oxygen species" as part of the burning process. Antioxidants go around and sop up the reactive oxygen species to prevent them from damaging and destabilizing proteins and fats and whatnot. Reactive oxygen species run amok can damage neurons and cause major brain problems.
We're used to thinking of "antioxidants" as vitamins such as C and E. However, the major antioxidants in the body are actually superoxide dismutase, catalase, and glutathione. The glutathione is one of the ways where NAC comes in, because as a supplement it is the best way to replenish gluathione in the liver and the rest of the body.*
(Animal Kingdom: Strange Attractor )
In the brain, the cysteine from N-acetylcysteine activates a glutamate-cysteine antiporter (a type of transporter in and out of a cell that exchanges cysteine for glutamate). Shoving glutamate into the extracellular space in the brain leads to downregulation of glutamate transmission in the central nervous system. So if you have too much glutamate whipping the brain, NAC seems like a mighty useful supplement to take. Therefore, if autism spectrum disorders (and other neurologic and psychiatric disorders) are a result of an excitatory:inhibitory imbalance, with overabundant excitation, NAC will bring the players more into balance.
At the same time, if autism spectrum disorders (and other neurologic and psychiatric disorders) are a result of redox imbalance, with reactive oxygen species terrorizing the delicate neurons, NAC will help the body make plenty of glutathione to help clean up those bad boys.
There's no single cause of austim, but NAC might be a way to kill several birds with one stone, as it were. AND, in the brain the two pathways (excitatory:inhibitory and redox) come together, as glutathione can displace glutamate at its receptor. Another win for NAC, it would seem.**
And, as noted in the excellent editorial in the same issue of Biological Psychiatry, Translating the Rosetta Stone of N-Acetylcysteine, these multiple effects may be why NAC has been shown to be efficacious in trials of so many psychiatric disorders. In the first paper I linked above, a small pilot trial, symptoms of irritability in autism were much improved in 5 kids, minimally improved in 6 kids, no change in 2, and one child got worse (though after the trial and on no NAC the subject had the same symptoms which were eventually found to be due to constipation). In the placebo group, two were much improved, five were minimally improved, five had no change, one was minimally worse, and one was much worse. Postive trials for NAC have also been reported for certain symptoms of schizophrenia, bipolar depression, cocaine craving, smoking cessation, trichotillomania, and gambling. What is also fairly remarkable is a lack of negative studies (established agents for all of these conditions have many negative studies.)
We still don't know if NAC is entirely safe (I wrote some theoretical problems with long-term use in my original blog article), and dietary supplements that aren't pharmaceutical grade might not be as reliable in dose, active ingredient, etc. as prescription medication. On the other hand, we know that prescription medicines aren't entirely safe, and in many cases, we know they have very considerable risks.
It would be nice to have some replication of these studies. As it stands, however, NAC has more of an evidence-base for use trichotillomania than any standard pharmaceutical.
Out of all the supplements, the ones that impress me the most are NAC and magnesium. NAC sure isn't "evolutionary psychiatry," but in this modern world of stress, poor sleep, and inflammatory food, beefing up the glutathione and taming the glutamate seems like a reasonable approach, particularly if you are having devastating symptoms (as in severe autistic disorders).
*Glutathione itself is poorly absorbed as a supplement, and is too large a molecule to be easily absorbed into the cells. Cysteine is the rate-limiting component of the reactions taking glutamate + cysteine to eventually make glutathione. Cysteine itself is not easily absorbed, but the acetylated form, N-acetylcysteine, is. Therefore, if you take n-acetylcysteine, you supply both a necessary precursor for glutathione and a nifty way to mop up excess glutamate. Win-win on that front.
**and another eek! for acetaminophen
Saturday, May 12, 2012
Mom's Wheat Sensitivity and Offspring's Schizophrenia Risk
In the midst of all the chaos this week came a very interesting diet/mental illness risk paper. Particularly good because it comes from the premier psychiatry journal (that we in the biz call the "Green Journal" because the cover is… well…anyway): The American Journal of Psychiatry (and looks like the full text is available for free) --- Maternal antibodies to dietary antigens and risk of nonaffective psychosis in offspring.
"Nonaffective psychosis" are psychotic disorders not related to major depressive disorder or bipolar disorder (both of which can cause psychotic symptoms during severe episodes). The most common primary nonaffective psychosis will be schizophrenia, though there are a few other rarer disorders, such as delusional disorder.
Lest we forget who the enemy is, it is inflammation. Yes, our immune system, in the context of our modern lifestyle is often like an group of soldiers armed to the teeth with too much to do on one hand (all these modern epidemics of infections) and too little on the other (wherefore art thou, old friends?). Lest we forget, without inflammation, we will die. Our immune system is necessary, just like an army from time to time.
To put the screws on schizophrenia risk, let's say now, with relative surety, that there is no single cause. Schizophrenia isn't even a single disorder, but rather a variety of disorders with similar enough symptoms to be lumped together by that most imperfect of documents, the DSMIV. But, a few things come up over and over when we look at the suspicious characters, and these things all go back to the immune system (inflammation), genetic risk, and those contributions to the pathology of schizophrenia (ultimately brain damage of a particular kind, a neurodegenerative disease).
Risk factors for developing schizophrenia that I've heard over the years:
Family history
Urban
Advanced paternal age (and to a lesser extent, advanced maternal age)
Infections (particularly toxo and herpes)
Birth in the winter months (could be associated with infections or…)
...Low vitamin D at birth
Complications during pregnancy or birth
Cannabis use, particularly at a young age
(before I forget, it's a beautiful day… Punching in a dream by Naked and Famous)
So we get the usual hodgepodge of genetic risk (family history) plus environmental stress (particularly severe stressors that occur when the brain is forming) = increased risk of developing the disease(es). Ultimately at a certain stage of development (typically late adolescence for men and about 10 years later for women), brain cells begin to die, signals misfire, and we end up with the typical symptoms.
It makes perfect sense that if we have a sensitivity to something in our diet, inflammation will increase, and that risk for all sorts of autoimmune conditions and other chronic diseases will increase. And, as we already know, there is an association between schizophrenia and celiac disease, and schizophrenia and weird wheat antibodies.
So now, the new paper in the Green Journal. It's one of those cool studies that are only possible in Scandanavian countries where you pay 70% of your income in taxes and the government keeps tab on all your health information from birth to death. In this case, the neonatal blood samples of a whole population of folks were collected (everyone in born Sweden since 1975) and a sample of folks later diagnosed with schizophrenia and matched healthy controls were analyzed. IgG antibodies (immune response) to gliadin (from wheat) and casein (from milk) were measured. Newborns have immature immune systems and do not make IgG antibodies. These antibodies must have been made by the mother and passed through the placenta in the late stages of pregnancy to the baby.
Don't all run out and get expensive IgG tests to see if you are "sensitive" to foods. I've never seen anything compelling to show me these tests were a reliable indicator of allergies. Wheat is so commonly eaten that almost anyone with an inflamed or "leaky" gut will have IgG antibodies floating around… however, in this study, it was the 10% of folks who had the highest IgG signal to gliadin whose offspring had increased risk of schizophrenia. IgG antibodies to casein were not linked to any increased risk. If only the 5% of babies with the very highest levels of IgG antibodies to gliadin were consider, the odds ratio of developing schizophrenia later in life jumps to 2.5. Don't get me wrong, the absolute risk will still be pretty low, but any time an odds ratio jumps to >2 one should prick up one's ears as it is an interesting finding. These findings were not attenuated by adjusting for confounders.
In general, a highly positive IgG test to gliadin means you have a risk of having celiac disease (though it is not one of the standard tests, which are typically measures of types of HLA genes, anti tissue transglutaminiase, and IgA to gliadin). Did the moms with the highest IgG in this study have untreated celiac disease, and thus a fully flowered autoimmune disease with all the inflammation on board, affecting mom as well as fetus? Sure, except full blown untreated maternal celiac disease is typically associated with malnutrition and small birth weight, whereas in this study there was no correlation between high anti-gliadin IgG and low birth weight. In addition, while 90% of folks with celiac will have the HLA-DQA*0501 and DQB*0201 alleles, these alelles are not increased among folks with schziphrenia.
All told, once again we have a link between wheat and schizophrenia, one not explained by celiac disease alone. More unveiling of the connection needs to be done.
"Nonaffective psychosis" are psychotic disorders not related to major depressive disorder or bipolar disorder (both of which can cause psychotic symptoms during severe episodes). The most common primary nonaffective psychosis will be schizophrenia, though there are a few other rarer disorders, such as delusional disorder.
Lest we forget who the enemy is, it is inflammation. Yes, our immune system, in the context of our modern lifestyle is often like an group of soldiers armed to the teeth with too much to do on one hand (all these modern epidemics of infections) and too little on the other (wherefore art thou, old friends?). Lest we forget, without inflammation, we will die. Our immune system is necessary, just like an army from time to time.
To put the screws on schizophrenia risk, let's say now, with relative surety, that there is no single cause. Schizophrenia isn't even a single disorder, but rather a variety of disorders with similar enough symptoms to be lumped together by that most imperfect of documents, the DSMIV. But, a few things come up over and over when we look at the suspicious characters, and these things all go back to the immune system (inflammation), genetic risk, and those contributions to the pathology of schizophrenia (ultimately brain damage of a particular kind, a neurodegenerative disease).
Risk factors for developing schizophrenia that I've heard over the years:
Family history
Urban
Advanced paternal age (and to a lesser extent, advanced maternal age)
Infections (particularly toxo and herpes)
Birth in the winter months (could be associated with infections or…)
...Low vitamin D at birth
Complications during pregnancy or birth
Cannabis use, particularly at a young age
(before I forget, it's a beautiful day… Punching in a dream by Naked and Famous)
So we get the usual hodgepodge of genetic risk (family history) plus environmental stress (particularly severe stressors that occur when the brain is forming) = increased risk of developing the disease(es). Ultimately at a certain stage of development (typically late adolescence for men and about 10 years later for women), brain cells begin to die, signals misfire, and we end up with the typical symptoms.
It makes perfect sense that if we have a sensitivity to something in our diet, inflammation will increase, and that risk for all sorts of autoimmune conditions and other chronic diseases will increase. And, as we already know, there is an association between schizophrenia and celiac disease, and schizophrenia and weird wheat antibodies.
So now, the new paper in the Green Journal. It's one of those cool studies that are only possible in Scandanavian countries where you pay 70% of your income in taxes and the government keeps tab on all your health information from birth to death. In this case, the neonatal blood samples of a whole population of folks were collected (everyone in born Sweden since 1975) and a sample of folks later diagnosed with schizophrenia and matched healthy controls were analyzed. IgG antibodies (immune response) to gliadin (from wheat) and casein (from milk) were measured. Newborns have immature immune systems and do not make IgG antibodies. These antibodies must have been made by the mother and passed through the placenta in the late stages of pregnancy to the baby.
Don't all run out and get expensive IgG tests to see if you are "sensitive" to foods. I've never seen anything compelling to show me these tests were a reliable indicator of allergies. Wheat is so commonly eaten that almost anyone with an inflamed or "leaky" gut will have IgG antibodies floating around… however, in this study, it was the 10% of folks who had the highest IgG signal to gliadin whose offspring had increased risk of schizophrenia. IgG antibodies to casein were not linked to any increased risk. If only the 5% of babies with the very highest levels of IgG antibodies to gliadin were consider, the odds ratio of developing schizophrenia later in life jumps to 2.5. Don't get me wrong, the absolute risk will still be pretty low, but any time an odds ratio jumps to >2 one should prick up one's ears as it is an interesting finding. These findings were not attenuated by adjusting for confounders.
In general, a highly positive IgG test to gliadin means you have a risk of having celiac disease (though it is not one of the standard tests, which are typically measures of types of HLA genes, anti tissue transglutaminiase, and IgA to gliadin). Did the moms with the highest IgG in this study have untreated celiac disease, and thus a fully flowered autoimmune disease with all the inflammation on board, affecting mom as well as fetus? Sure, except full blown untreated maternal celiac disease is typically associated with malnutrition and small birth weight, whereas in this study there was no correlation between high anti-gliadin IgG and low birth weight. In addition, while 90% of folks with celiac will have the HLA-DQA*0501 and DQB*0201 alleles, these alelles are not increased among folks with schziphrenia.
All told, once again we have a link between wheat and schizophrenia, one not explained by celiac disease alone. More unveiling of the connection needs to be done.
Tuesday, April 24, 2012
More Clues to Systemic Inflammation in Mood Disorders
Continuing from the discussion of bipolar disorder and adipokines, There's a lot of intriguing information in various studies about the systemic inflammation found in bipolar disorder. One of the more interesting papers was done by Kapczinski et al and published in 2011 in Psychiatric Research: Peripheral biomarkers and illness activity in bipolar disorder.
(Classical today - Bizet, L'Arlesienne, starting in the middle. At three minutes is one of my favorite classical lullabies, the Adagietto from the Suite L'Arlesienne.)
The researchers measured a bunch of things in the blood known to be associated with systemic inflammation both in serious disease (blood infections, for example) and in mental illness, including the inflammatory cytokines IL-10, IL-6, TNFalpha, the brain "fertilizer" known to be low in depression and manic episodes, BDNF, and other measures of oxidative stress (which means, imperfectly, that the engines in the cells aren't running efficiently and pumping out some toxic byproducts, causing damage to proteins and fats) and lipid peroxidation such as PCC, TRAP, and TBARS. There's an awful lot of statistics in the paper, which is always suspicious ;-) but also seems to be a fair way of dealing with a complex set of observational data.
Several groups of people were compared. A set of healthy controls without any major medical illness or any personal or close family psychiatric history, known bipolar patients who were currently experiencing normal mood (or "euthymic" as they say in the biz), bipolar patients who were depressed, bipolar patients who were hospitalized for mania, and seriously medically ill patients who were hospitalized in the ICU for infection. This last group was a "negative control" to see if there were any similarities or differences in the cytokine and measures of stress in the body in the very medically ill compared to the psychiatric patients.
The researchers found that the healthy controls and euthymic bipolar patients were fairly similar. They also found that the manic and depressed patients (more the manic, who were hospitalized, while the depressed were selected from an outpatient population) had surprising measures of lipid peroxidation, protein damage, and oxidative stress. These measures in some cases were similar to the medically ill patients who were basically on death's door with sepsis.
The sobering conclusion one could think about is that mood episodes are very stressful and potentially very damaging to the body. None of these measures were of the cerebrospinal fluid. Everything was done with a blood draw from the body. The other conclusion is that folks with known bipolar disorder who were not acutely ill had bounced back to a healthy state, cellularly speaking. The researchers, most of whom had funding from one pharmaceutical company or another, made the case that aggressive prophylactic treatment of mood disorders was warranted to prevent serious mood episodes.
This argument, along with other evidence from certain longitudinal studies, is used in psychiatry today to promote aggressive pharmacologic treatment. It is absolutely true that the more mood episodes one has, the more likely one is to have even more episodes in the future, and the harder the future episodes are to get under control. If these illnesses are pounding your brain and body, decreasing number of manic or depressive episodes via any means necessary would seem to be the logical thing to do.
The problem for a psychiatrist in the field is that we know the studies are stacked in favor of pharmaceuticals. These issues are discussed at length and in detail in many better blogs than mine (I'll link to the Carlat Psychiatry Blog* as an example). I'm a psychiatrist, I've seen meds work, I've seen them work and cause major problems, and I've seen them fail miserably. I've seen EMDR, DBT, neurofeedback, and various forms of behavioral and psychodynamic therapy also work or not (sometimes causing major problems) depending upon the circumstances. But part of the reason I look at alternatives is because I think there is too much focus on both meds (and talk therapy, in the classic psychiatry circles and in psychology in general) when there are so many other modalities of treatment and lifestyle modification that could also be helpful, and in many cases less likely to cause harm. What I pull from studies like the one I linked above is that bipolar disorder, like diabetes, deserves a full-bore approach, with support focusing on good nutrition, appropriate sleep and exercise, addressing problems with coping strategies or relationships, and medications when indicated.
Common sense. Wedded with an understanding of the patient born of time and attention and experience dealing with people.
*That particular blog article discusses what I found to be a surprising rant by Stephan Stahl, a celebrated and likable psychiatrist who has written several textbooks on pharmacology and runs an education company. He's a biological psychiatrist and a whiz with meds, but when I read his books I feel a bit empty, because there is so much we do not know about what these medications do in vivo compared to the theory, particulary in the combinations used in common practice today.
(Classical today - Bizet, L'Arlesienne, starting in the middle. At three minutes is one of my favorite classical lullabies, the Adagietto from the Suite L'Arlesienne.)
The researchers measured a bunch of things in the blood known to be associated with systemic inflammation both in serious disease (blood infections, for example) and in mental illness, including the inflammatory cytokines IL-10, IL-6, TNFalpha, the brain "fertilizer" known to be low in depression and manic episodes, BDNF, and other measures of oxidative stress (which means, imperfectly, that the engines in the cells aren't running efficiently and pumping out some toxic byproducts, causing damage to proteins and fats) and lipid peroxidation such as PCC, TRAP, and TBARS. There's an awful lot of statistics in the paper, which is always suspicious ;-) but also seems to be a fair way of dealing with a complex set of observational data.
Several groups of people were compared. A set of healthy controls without any major medical illness or any personal or close family psychiatric history, known bipolar patients who were currently experiencing normal mood (or "euthymic" as they say in the biz), bipolar patients who were depressed, bipolar patients who were hospitalized for mania, and seriously medically ill patients who were hospitalized in the ICU for infection. This last group was a "negative control" to see if there were any similarities or differences in the cytokine and measures of stress in the body in the very medically ill compared to the psychiatric patients.
The researchers found that the healthy controls and euthymic bipolar patients were fairly similar. They also found that the manic and depressed patients (more the manic, who were hospitalized, while the depressed were selected from an outpatient population) had surprising measures of lipid peroxidation, protein damage, and oxidative stress. These measures in some cases were similar to the medically ill patients who were basically on death's door with sepsis.
The sobering conclusion one could think about is that mood episodes are very stressful and potentially very damaging to the body. None of these measures were of the cerebrospinal fluid. Everything was done with a blood draw from the body. The other conclusion is that folks with known bipolar disorder who were not acutely ill had bounced back to a healthy state, cellularly speaking. The researchers, most of whom had funding from one pharmaceutical company or another, made the case that aggressive prophylactic treatment of mood disorders was warranted to prevent serious mood episodes.
This argument, along with other evidence from certain longitudinal studies, is used in psychiatry today to promote aggressive pharmacologic treatment. It is absolutely true that the more mood episodes one has, the more likely one is to have even more episodes in the future, and the harder the future episodes are to get under control. If these illnesses are pounding your brain and body, decreasing number of manic or depressive episodes via any means necessary would seem to be the logical thing to do.
The problem for a psychiatrist in the field is that we know the studies are stacked in favor of pharmaceuticals. These issues are discussed at length and in detail in many better blogs than mine (I'll link to the Carlat Psychiatry Blog* as an example). I'm a psychiatrist, I've seen meds work, I've seen them work and cause major problems, and I've seen them fail miserably. I've seen EMDR, DBT, neurofeedback, and various forms of behavioral and psychodynamic therapy also work or not (sometimes causing major problems) depending upon the circumstances. But part of the reason I look at alternatives is because I think there is too much focus on both meds (and talk therapy, in the classic psychiatry circles and in psychology in general) when there are so many other modalities of treatment and lifestyle modification that could also be helpful, and in many cases less likely to cause harm. What I pull from studies like the one I linked above is that bipolar disorder, like diabetes, deserves a full-bore approach, with support focusing on good nutrition, appropriate sleep and exercise, addressing problems with coping strategies or relationships, and medications when indicated.
Common sense. Wedded with an understanding of the patient born of time and attention and experience dealing with people.
*That particular blog article discusses what I found to be a surprising rant by Stephan Stahl, a celebrated and likable psychiatrist who has written several textbooks on pharmacology and runs an education company. He's a biological psychiatrist and a whiz with meds, but when I read his books I feel a bit empty, because there is so much we do not know about what these medications do in vivo compared to the theory, particulary in the combinations used in common practice today.
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