ADHD: Stimulants, Alternative Treatments, and Criminality

Attention Deficit Disorders more than most I feel are diseases of civilization, particularly our hypermodern civilization. Certainly they are inherited, and many folks will show up at my office after a child has been diagnosed with ADHD, telling me, "you know what, I've always had trouble focusing as well." I've even seen old grade school report cards from the seventies, with neat teacher's script: "doesn't pay attention" "moves around too much" "too talkative" and "doesn't live up to potential." Of course there is controversy over the diagnosis, which is clinical, like every psychiatric diagnosis, and I have no doubt that a variety of different genetic and environmental influences on the frontal lobes are all swept together into a wastebasket diagnosis for the purposes of billing…on the other hand, sometimes I think the most good I do with the medicines at my disposal as a practicing psychiatrist is the judicious use of stimulant.

Now more than ever, in our world of 25 different passwords and constant stimulation and distraction, anyone who has a bit of ADHD potential may find himself quite debilitated. As a child where the only job you can have is school, if school is a problem (and school seems increasingly driven by perfect conduct and test scores), life becomes difficult. With classic hyperactive ADHD, if the child isn't the personable class clown, he may find himself ostracized by classmates who don't appreciate his distraction and hyperactive behavior. Many adults will have gone from job to job, rarely successful, and will often have a long track record of broken relationships and disappointments. Back in hunter-gatherer times, ADHD tendencies may have been an advantage, and one aspect of ADHD is to be able to "hyperfocus" during a crisis or on activities in which one has an emotional interest.

5% of the children in the western world meet criteria for ADHD (though in the US, the most recent CDC statistics show an increase in diagnoses from 7% to 9%.)

A recent study (from the New England Journal of Medicine, meaning it is a hot ticket)  made big headlines: Medication for Attention Deficit Hyperactivity Disorder and Criminality (hat tip to Dallas and every major news outlet). This study is one of those "wow socialized medicine with the very large registries makes for interesting data-gathering" sort of studies.

So, the researchers gathered data from 25,656 patients diagnosed with ADHD in Sweden between 2006 and 2009. They checked out the pharmacologic treatment and criminal convictions to compare the rates of convictions while receiving medicine or not receiving medicine. In short, criminal convictions decreased 32% in men and 41% in women if they were taking medication for ADHD compared to times while not taking medication. ADHD has previously been associated with criminality (1)(2), so it makes sense to investigate the circumstances more closely.

But the primary pharmacologic treatment of ADHD is controversial: stimulants. Ritalin and adderall in many, many different formulations. Stimulants are, in fact, much less potent versions of methamphetamines. They act on dopamine receptors (though, as always, it's complicated). What happens to a child's brain and body on stimulants over years and years? What happens if he or she has untreated ADHD and is not on stimulants? Those questions are important, but we don't really have the answers. Of course behavioral modification and accommodation at school also are big parts of appropriate therapy for ADHD.

Numerous studies have shown the short-term efficacy of stimulants in folks diagnosed with ADHD. Long-term it starts to get more murky, and most people discontinue medicines at one point or another (while many grow out of the "hyperactive" part, the inattentive piece often persists for a lifetime). By 36 months of treatment, many of the positive effects seen at 14 months are diminished (3). Questions have been raised as to the risks of stimulants with respect to tolerance, dependence, growth retardation, insomnia, psychosis, abdominal pain, decreased appetite, overprescription, and addiction (though a meta-analysis of studies of stimulants started in childhood show decreased risk of substance abuse later on compared to individuals with ADHD not treated with stimulants). 

In the large Swedish criminality study, the ADHD cases (16,087 men and 9569 women) were each matched with 10 controls according to year of birth, sex, and geographic location at time of diagnosis. Those who were defined as "in treatment" with stimulant medication included those who received at least 2 prescriptions within a 6 month period. 6 month intervals without prescriptions was defined as not receiving medication treatment. The outcome measure was any convicted crime (convictions in Sweden are supposedly independent of mental health diagnoses though a diagnoses may influence sentences). Date of the crime was used for the most part, but if none were recorded, the date of conviction was used. Confounding diagnoses (oppositional defiant disorder, antisocial personality, and substance use disorders) were also accounted for as well as whether or not a conviction would have interrupted medication treatment. In order to address the very obvious confounder that patients who decide to take medications are also perhaps at a point where they are making major changes with their lives, they also adjusted for non-medication treatments and the use of SSRI medication. Criminality was still highly associated with periods of time while not on stimulant medication. There was no long term association between use of stimulants for ADHD in 2006 and criminality in 2009. 

All in all, this is an observational study with the typical limitations, but the results are consistent with previous smaller studies. While there are many influences on ADHD behavior including diet in children, all treatment modalities are worth consideration.

That said, there is an interesting new article in Psychiatric Times by Dr. James Lake reviewing the alternative medicine treatments for ADHD. Up to 50% of families with a child diagnosed with ADHD will try an alternative therapy (typically diet or some sort of vitamin supplement), but supposedly only 10% admit the use of these complimentary treatments to the pediatrician.  

Studies of omega 3 fatty acids have been mixed. The most promising one used high doses (>16 g) of EPA and DHA. French maritime pine bark (Pinus pinaster) extract was effective in a couple of very small studies. Brahmi 50mg twice a day also fared better than placebo in a randomized controlled trial of 36 children. Zinc (up to 150mg daily) has helped in a few trials, and also as an augmentation strategy for stimulants. Iron was also shown to be helpful in children with low ferritin (but who weren't iron deficient by other measures). Carnitine has had mixed results. None of these herbal treatments have nearly as much evidence as the stimulant treatments, and the long term effects for all treatments are unknown. 

"Green play" is also a studied remedy for ADHD. Children who spend more time out of doors playing tend to have fewer symptoms of hyperactivity and inattentiveness (4). This study has some serious limitations, though it is difficult to imagine how more playing outdoors wouldn't be helpful for hyperactive children in particular. 

All told, in this modern world, ADHD can be a huge impairment, though it does have some advantages. I'm all in favor of green play and behavior and dietary modification first, but sometimes further medical interventions are necessary. 

Next up will be OCD!

Inflammation and Depression: Cause or Effect

Longest hiatus ever. We've been out of town, and then there is the business involved in preparing to go out of town and all the stuff piled up to do when you get back into town. I've been wanting to finish up the anxiety and depression chapter from The Hygiene Hypothesis and Darwinian Medicine (I started that chapter with "What is Evolutionary Psychiatry?" a month ago.  So here we are.

The Mighty Mighty Bosstones: The Impression That I Get 

Depression (and anxiety) are associated with multiple markers of inflammation in the body, though a source for inflammation is often not apparent. Mere exposure to psychological stress can cause elevations in pro-inflammatory cytokines, and the ability of stress to drive inflammation is increased in depressed individuals (as measured by levels of IL-6 and DNA binding of NF-kappaB. The most stressed students had larger increases in interferon gamma, IL-1receptor alpha, TNF, and IL-6 than students who were less stressed about an exam in one study. Since there is a truckload of evidence that stress is a major factor mediating depression, here is evidence that the stress causes the inflammation that causes the depression, not the other way around. And yet…

Just the administration of certain cytokines alone (as we've discussed at length before) can cause depression symptoms in humans and animals. Blocking the action of IL-1 in the central nervous system in animals will stop this effect. Humans with a depression syndrome caused by administration of proinflammatory cytokines will also respond to treatment with antidepressant medications. 

There are genetic studies of different families with depression vulnerabilities, and some of the genes implicated are in the inflammatory pathway (such as IL-1and TNF). In addition, folks with a certain type of serotonin (5HT) 1A receptor seem to be more vulnerable to the induction of depression by interferon alpha 2 beta. Interferon alpha will downregulate the production of the 5HT-1A receptor. Both anxiety and depression patients have been showed to have decreased 5HT-1A receptor, and certain folks with a subtype of the receptor are more vulnerable to anxiety and depression, and they also seem to be less responsive to certain antidepressant medications.

Inflammation also seems to impair the function of glucocorticoid receptors. That would explain why people with depression and anxiety seem to have high levels of cortisol, but decreased ability to respond to it in an effective way (so people feel fatigued and overwhelmed rather than energized and capable despite mountains of cortisol running through the body). The term "adrenal fatigue" which I often see in blogs and whatnot is misleading and "glucocorticoid resistance" is much more meaningul.

Anti-inflammatory agents have been shown to help with depression symptoms in certain cases. Usually the research uses fancy-schmancy anti-inflammatories (such as anti-TNF antibodies used in Crohn's disease and psoriasis), but celecoxib has also been shown to have some positive effects on major depressive disorder.

More standard antidepressant medications (of most of the major classes) have been shown to be anti-inflammatory in vivo and in vitro. For example, tricyclic antidepressants, norepinephrine reuptake inhibitors, and SSRIs have all been shownn to reduce the toxin-induced secretion of IFN gamma and IL-10 in a solution of red blood cells exposed to toxin.  In addition, in certain studies, people treated with antidepressants have decreased c-reactive protein levels after treatment, and decreased levels of release of TNF from whole blood samples. Electroshock treatment also decreases TNF in patients with major depression, as does vagus nerve electrode stimulation.

SSRIs in particular could have a direct action on a person's T cells. SSRIs work on the SERT (serotonin transporter). Certain immune cells have SERT and they use it to take up serotonin from mature T cells. The serotonin is eventually transferred to naive T-cells and seems to enhance their activation. This mechanism would explain how SSRIs at least could reduce pro-inflammatory cytokine expression (many of the pro-inflammatory cytokines are released from certain types of T cells). Since genetic polymorophisms in the promotor region of the SERT gene have also been shown to cause increased vulnerability to depression in those exposed to stress, this inflammatory mechanism may be the cause. We will have to look outside the brain to really understand all the systemic vulnerabilities and expressions of depression and anxiety. 

And finally we get to some mechanisms that I've actually discussed previously (the most common and widely accepted mechanisms of how depression goes hand in hand with inflammation, and how antidepressants seem to help when they do). Antidepressant drugs tend to reduce the activity of TDO which metabolizes tryptophan, the dietary precursor to serotonin. This action tends to oppose those of pro-inflammatory cytokines (such as IFN-gamma and IL-1) to increase the catabolism of tryptophan by IDO and of glucocorticoid hormones to increase catabolism of tryptophan by TDO. These medicines seem to increase plasma and brain tryptophan concentrations, and secondarily increased production of serotonin in the brain. Tryptophan and serotonin are also known immune regulators. So, once more, stress hormones and pro-inflammatory cytokines antagonize serotonin, tryptophan, and antidepressant drugs, and vice-versa.

Probiotics, which also seem to have anti-inflammatory effects, have had antidepressant and antianxiety actions in animal studies. The human studies are very few and far between (I reviewed them here and then a later mouse study here). The pseudocommensal M vaccae, which induces T regs and downregulates the chronic inflammatory state has also been shown to (unexpectedly) improve quality of life scores in people receiving it experimentally for asthma or psoriasis.  

There is a very new explosion of research concerning regulatory T cells and depression in animal models and even in human cell lines. The published studies seem to show that there is a type of autoimune dysregulation in depressive disorders and that the same old suspects of pro-inflammatory cytokines mediate the symptoms. Thinking about depression and anxiety as immune disorders helps us to frame a whole health approach for its treatment: anti-inflammatory diet, exercise (in personalized amount and difficulty) counseling, meditation, and appropriate use of different immune modulators (antidepressants are well studied, of course) as more studies come out showing efficacy and safety. 

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.

Autism and Maternal Metabolic Health

I've been sitting on this study for a while. It was published in Pediatrics in May, 2012:

Maternal Metabolic Conditions and Risk for Autism and Other Neurodevelopmental Disorders

In California, many children aged 2-5 between 2003 and 2010 were involved in population based cohorts with the CHARGE study. I've covered a previous paper from this study before…

Captial Cities: Safe and Sound

Diagnoses of children in the cohort were confrimed using standard assessments Information on mothers was ascertained by medical records or a structured interview. The results are not terribly surprising… all metabolic conditions were more common among autism cases than among controls. Odds ratios were about 1.66, which isn't earth-shattering, but is more than 1, and in a large study, at least worth noting.

Currently: 1:110 kids have an autistic spectrum disorder. 1:83 have some other developmental delays. It is known that mothers with gestational diabetes (GD) have babies with more cognitive impairments than children born to mothers without GD. In the CHARGE study, children born to mothers with obesity, gestational diabetes, and hypertension were all followed (as "any metabolic condition").

All told, 28.6% of the autistic children and 34.9% of the children with any developmental delay had a mother with a metabolic condtion compared to 19.4% of controls. Within the autistic spectrum disorder group, children of mothers with diabetes performed worse on an expressive language scale than did children of mothers without diabetes. Given the fact that obesity and diabetes are increasing, we are looking at a worrying trend. The paper did not speculate much as to causation, but generalized inflammation and insulin resistance are the pathogens of interest. It would have been nice if inflammatory markers were measured, but with such a large study, that may be asking too much.

Poorly regulated maternal glucose can result in adverse fetal consequences. Maternal diabetes is due to a number of factors, but I'm sure a modern processed food diet can be counted among them. I know how hard it is to control appetite during pregnancy, even while eating supposedly "real" foods.  Keep to the outside of the grocery store and skip the bakery. Not terribly controversial advice, I would hope!

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.

Them Swoops: Work Around It

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.

Depression: A Cosmetic Cure?

"Fake it until you make it." This phrase, though often met with derision, constitutes some practical advice when dealing with a devastating problem like chronic depression.

There are, at the base of it, two major psychotherapeutic approaches to the treatment of depression. One way to explore relationships and history to find past trauma and metabolize it in order to get through it and better under stand current pain. Another approach is to focus on appropriate lifestyle and coping habits to reduce depression. The phrase "fake it until you make it" speaks to the second "cognitive behavioral" method.* One extreme (but interesting) version of behavioral therapy is called "solutions based" therapy. I learned about it in residency and dabbled a bit with the ideas in practice, but saw it popularized most recently in the scorching (but intolerably paced, plotted, and characterized) "50 Shades" trilogy. Solutions based therapy apparently helped the billionaire hero, but not enough so he could give up his sex dungeon. It takes a co-ed implausibly promoted to senior book editor to do that.

Two Door Cinema Club: Sleep Alone

In any event, solutions-based therapy begins with the "miracle question." Let's say in the middle of the night while you were asleep, a miracle happened and you were cured of depression. How do you know you were cured? What do you feel when you wake up in the morning that is different? How is your energy? What does your face look like when you first see yourself in the mirror? How would your loved ones know you are cured and what would they see? The idea is to focus on those "solutions." If being happy means having energy in the morning and looking at yourself in the mirror and seeing  bright smile, then maybe changing some habits so your sleep improves and grinning at yourself in the mirror can be part of the cure.

There is some neurobiological truth to the smile therapy. The mere act of smiling sends positive signals to the brain and can lift the spirit, while the act of scowling can make you feel immediately grumpier. It's subtle, but give it a try.

Believe it or not, there is some research to suggest that treatment with botox, paralyzing certain muscles to prevent deep scowling, can be an effective antidepressant treatment as well. And no, this treatment is not exactly "evolutionary psychiatry" but I do like to explore novel ways to look at the pathology and treatment of mental illness, and I would say the cosmetic cure qualifies. Even looking at smiling faces makes people happier. Do you think our ancient ancestors were more carefree than we are? More relaxed? More apt to smile? I wish I knew the answer to that question. It's not preserved in the fossil record.

Can butulinum toxin improve mood in depressed patients?

The largest and perhaps most famous trial of resistant depression patients was the STAR*D trial (and I did have the privilege of sitting in on some of the weekly research meetings at MGH while this trials were being conducted).  "Resistant" depression means depression that lingers despite antidepressant treatment. Only 30% of these patients find significant relief from the medication antidepressants that are available, of whatever variety. Nearly 50% of medicated patients discontinue antidepressants within 6 months, though most data suggests that treatment of 9-12 months after remission is most effective.

Other new technologies, such as inserted vagus nerve stimulation (VNS) devices and transcranial magnetic stimulation (TMS) have tried to fill the void in resistant depression treatment. They remain out of reach for most patients as insurance will generally not pay for them. The other treatment for severe resistant depression is electroshock therapy, which tends to be quite effective but has many side effects and can be very disruptive. In truth, the data for resistant depression for most modalities is poor. Not much we've discovered so far will work well, and drug companies don't want to spend millions on a trial that will likely result in failure. To find a new experimental method used in resistant patients is actually rather exciting.

(Lest we get too excited) the study I'm reviewing is merely a pilot trial.  30 people with resistant depression (average duration of 16 years) were randomly assigned to botox injection or saline placebo injection (and by the end 90% of people were able to tell whether or not they got the active agent, which pretty much negates the blinding). The single injection was made into the glabellar region (right at the top of the nose, where forehead scowling lines will center). To try to preserve a bit of experimental blinding at least for the raters for the follow ups, everyone wore a skullcap to cover the forehead. Scale ratings were done via the rather classic Hamilton D 17 item depression scale.  Inclusion into the trial involved full structured clinical interview with a diagnosis of major depressive disorder, which is gold standard. Response to treatment was tracked from week 2 to 16 weeks after the injection.

HAM-D scores improved a whopping 10.1 points in the treatment group in 6 weeks versus 1.7 in the control group. Nonresponse is characterized as a <25% reduction, partial response a 25-50% reduction, and >50% reduction in HAM-D score is considered "remission" and the holy grail of psychiatry in resistant depression treatment. In this trial, partial response in the treatment group was 86.7% vs. 26.7% of the placebo. That's a pretty big deal in resistant depression. Actual depression remission occured in 33.3% of active treatment vs. 13.3% of placebo which was not statistically significant given the small sample size. Let me put it thusly:

In this little study, a single botox injection was a bit better than the classic antidepressants and really blows the expensive and/or invasive TMS or VNS treatments out of the water. The only side effect reported was a mild short-term headache. Antidepressants tend to cause sexual dysfunction and/or weight gain or stomach upset or sweating or a number of other issues, and botox needs to be repeated only every 4 months or so, rather than daily pills.

There are a lot of limitations in this study. It was small. Mostly women. Mostly the melancholic subtype of resistant depression (which can actually be easier to treat). Most of the patients guessed correctly whether they were in the treatment group or not, so blinding was a huge issue. But the theory is that the more positive facial expressions after botox treatment deliver positive neurofeedback, improving mood, and causing the treatment effect.

But, as a psychiatrist, the most exciting procedure I tend to perform on patients is checking blood pressure. It might be nice to inject some botox now and again. I'm a terrible evolutionary psychiatrist, when it comes down to it.

*In actuality, most therapists in practice combine the two methods, and a manualized and studied version of that is called short-term dynamic psychotherapy, the textbook of which was written by one of my teachers in residency, Leigh McCullough, PhD. I was saddened to learn she died of ALS earlier this year.

Omega 3, the Elderly, and Getting It Right

New study seen on twitter (as I see most cool stuff, partly because I can't really bear facebook and am pretty bad about checking out the usual blogs these days).

The Strokes. Last Night.

The Study (free full text): Older Women, Depression, Omega 3 Ratios, Inflammation, and Supplementation

Bam. I'm getting all Emeril about it because finally we are getting some thoughtful and complete studies. We're talking measuring the plasma membrane ratios of omega 3 to omega 6, supplementing, measuring again, and measuring inflammatory markers as well as response to supplementation. These studies are not phoned in by the statisticians after they whip up another algorithm on the supercomputer over at HSPH.*

Here we have a small randomized placebo-controlled trial of 22 elderly (66-95 y/o) depressed females given omega 3 supplementation (2.5 grams daily of an EPA/DHA 2:1 mix for 8 weeks) and 24 given a placebo (parrafin oil, lemon flavored, just like the other--known for being insoluble in water, poorly absorbed, and flammable). Not only were pre and post depression scales measured, but so were plasma membrane omega 6/3 ratios (measured as AA/EPA in HUMAN SUBJECTS, Chris Barrera), and lots of inflammatory markers (notably CD2, CD3, CD4, CD8, CD16, CD19 and the cytokines IL-5 and IL-15. What, no IL-6 and TNFa?  Little evolutionary psychiatry joke**).  (But it is important to remember that depression is associated with T cell dysfunction, particularly the regulatory T cells that but the kibosh on inflammation).

The paper proper begins with a rather awkward but correct statement: "An unbalance in polyunsaturated fatty acid (PUFA) status is observed in various pathological conditions, especially in chronic and/or degenerative diseases associated with antioxidant system deficiency."

Low DHA in the central nervous system has been associated with all sorts of badness, such as depression, anxiety, ADHD, and dementia. The elderly seem to be particularly at risk, because their ability to change other forms of omega 3 to the long chain forms needed in the CNS is decreased compared to younger folks. (Less delta6 desaturase activity.)

Results!

Rachmaninov (Vocalise for Violin).

After 8 weeks, only the intervention group with the omega 3 had a significant decrease in the Geriatric Depression Scale scores. AA/EPA ratio were significantly higher in depressed patients than in healthy ones (from another group of healthy, non-depressed elderly women who were not taking omega3 supplementation). Not surprisingly, the AA/EPA ratio decreased significantly in those taking the omega 3 supplement in the depression group, which correlated with the decreased depression scores. Ratios did not change in the placebo group or in the "healthy" group.

Inflammatory markers were significantly correlated with being depressed at the beginning of the study (not exactly a newsflash) but were not correlated at the end of the study, though there were some shifts in markers. Hey, it was only 8 weeks.

I like this study a lot, for several reasons. They used an omega 3 supplement with EPA greater than DHA, which are the only sorts of supplements shown to be effective in depression. They used an inert placebo (coconut oil is another acceptable substitute) in lieu of olive oil or (gasp) omega6 oil. They measured plasma ratios, depression scores, and inflammation.

I also learned something very interesting that I didn't know before, which is that mood stabilizers, particularly lithium, have been associated with greater AA turnover and increased DHA in the plasma membranes in the frontal cortex. One more mechanism whereby lithium is an essential micro nutrient? Maybe. One more reason to consider that we don't fully understand nutrition or the brain but we should probably take in a reasonable amount of these? Yes.

Stabby thinks we should add vitamin E as well.

*There is something to be said for supercomputers and 100,000 person data sets. But I'm not going to eat corn oil and kashi.

** from the study "numerous studies have indicated major depression as an inflammatory state with elevated levels of proinflammatory cytokines, e.g. Interleukin IL-6, IL-12, interferon (IFN)-γ [15], IL-1 and tumor necrosis factor (TNF)-α [16]. For this reason we decided to evaluate cytokines that have not yet been sufficiently studied to date, such as IL-5 and IL-15, in this study."