Food Additives and ADHD: New Evidence of Genetic Factors involving Histamine

Just in time for Halloween, a post about candy, children, and behavior problems.  For many years, parents have noted an association between certain foods and their children's behavior.  "If he eats candy he's out of control."  "If she has anything with red dye in it, she'll be up all night."

These observations have caused many parents to have intimate knowledge of ingredient lists of food items, searching for things like sunset yellow, tartrazine, sodium benzoate, carmoisine, ponceau 4R, allura red, and quinoline yellow.  Avoiding these can be challenging -- find a processed food without sodium benzoate.

Double-blind, placebo-controlled trials have shown that artificial food colors have a significant effect in children with ADHD.  However, many have not been convinced of the association, given a lack of plausible explanations for how this range of food additives could cause behavior changes, including inattention, impulsivity, and overactivity.  Granted, any child will have these characteristics at times, but the Attention Deficit Hyperactivity Disorder (ADHD) diagnosis is reserved for those with such severe symptoms that they interfere with home and school functioning.  And, even in toddlers and 4th-graders without ADHD, food additives have been shown to have and adverse behavioral effect (McCann et al, 2007).

Most of the treatments for ADHD have direct effects on the brain chemical, dopamine.  Indeed, genes influencing the dopamine system (eg, DRD4, DAT1) have been found to be involved.  Yet, there has not been clear evidence of a connection between food additives and dopamine.  There have been some observations that certain food dyes can provoke the release of histamine, causing hives and itching but also inattention, hyperactivity, and dopamine release in prefrontal brain areas.

In the October issue of "the green journal" (American Journal of Psychiatry), McCann's group analyzed six genetic polymorphisms (I explained these here) involving genes affecting dopamine and histamine (Stevenson et al, 2010) in the same group of general population kids (not just those with ADHD) from the 2007 study.  What they found provides one possible explanation for why these additives cause behavior problems.

They found that two polymorphisms in the histamine enzyme gene, HNMT, and one in the dopamine transporter (DAT1) gene, were associated with inattentive and hyperactive symptoms when kids were given juice with the additives in it, compared with juice without the additives.

Meaning that children with these specific polymorphisms (think a genetic code swap, like the difference between "their" and "thier") will have an enhanced effect of histamine on their brain's histamine (H3) receptors and an altered effect of dopamine on the brain.

So, what's it mean?  It means those parents were right, of course.  And, for foods that are targeted for children, the food industry now should pay attention (!) to finding alternatives to these artificial chemical additives.

Back Roads: Lost or Distracted?

A few days ago, I posted on The Journey Versus The Destination and I've still been thinking about the comments that came in. Warning: This is going to turn into one more post on illness versus the spectrum of normal, one of our favorite Shrink Rap themes.

First off, there's no such thing as Journey people or Destination people. I made the whole thing up, so there's not really any arguments about definition because...well, it doesn't exist.

A lot of the comments that came in reflected the idea of 'stopping to smell the roses'....the idea that if one is reaching for a goal, there is no time to appreciate or enjoy the process of getting there. This isn't what I meant at all, I just didn't do the best job of describing what I did mean. Mostly what I meant was that there are people who have the ability to set goals, and know how to go about reaching them. Those are Destination people. If, on the way, a destination person changes her mind and sets a new and different goal (I don't want to be President, I want to bake cookies), they are still a Destination person, they have simply changed the destination. Cookies, I assure you, are a good destination, but a Destination person looks at the recipe first, buys the ingredients, and if the cookies burn, they either try again to bake them, or they get a new goal (e.g. buy cookies at bakery).

So MWAK asked how I knew she was a Destination person. Pretty much by definition (remember, I wrote the definition), the number of years, courses, planning ahead, it takes to go to medical school makes physicians Destination people. You can't do this on impulse, you have to sign up for specific courses, many of them boring and hard, do well in them, initiate applications to medical school, get to the interviews at your own expense, arrange housing, take a zillion courses, dissect bodies, go to clinical rotations at the right place and time, pass tests, remember to register for those exams and show up with your number 2 pencils, apply for residency training. Interview at your own expense. Get to the interviews (arranging the transportation and place to stay), survive residency, and it's good to remember which days you're on call. If you can do this while growing and smelling flowers, raising children, playing in a rock band, then more power to you! So MWAK, I read your blog and you have tons of goals-- currently you're on vacation, someone planned it and arranged for your coverage. See, you're at a destination (looks like Seattle), you're a destination person!

I think Mrs. Cake did a good job of capturing what I meant by Journey People. She wrote:

I think I am a journey person (think Drunkard's Walk) who always tried and failed to be a destination person. The number of endeavors I have embarked on, and rapidly failed at or lost interest in, could fill quite a crowded book. Currently I'm convinced it's the not-yet-diagnosed ADHD that kicked my feet out from under me in such a predictable pattern. I am in my 50s and mourn the books I could have written not because I couldn't write them, but because I have the skill and the ideas but not the persistence. dx on the horizon, I hope, but how many of us journey people are members of the 4 to 5% of ADHD adults, 90% of whom are not diagnosed? Mrs Cake

Yes, this is what I meant! People who set goals, sometimes extremely modest goals (I will clean out a closet) and can't negotiate to follow through on them. Time goes by and nothing gets done in a forward moving way towards accomplishing them. Often, these patients are diagnosed with ADHD, and that provides them with an explanation. I haven't found this to be all that helpful. I tell them to read books on ADHD and try the behavioral suggestions: get a Palm Pilot, (or a Franklin Planner), get back-up alarms, make lists, fall into a routine. While some patients find stimulants helpful, for unknown reasons, they haven't been my patients: my patients have had trouble tolerating stimulants and they've been surprisingly unhelpful at getting people to move towards their goals. Often people are equivocal about whether they helped at all and they forget to take them.

So there are two issues here: one is that some people are Destination people and don't know it: they can't meet some goals, but they meet others fine: can't get the house cleaned, can't finish a major paper, can't finish they're degree, but they do fine at getting a job, planning a vacation, getting to social events, whatever. These are Journey people because they are locked into Destinations they feel they should have, not the ones they want. They would simply do better to redefine their goals to things they Want them to be, not what society says they should be. They need to reframe life, and this is often a hard sell.

I said this in the comment section of the last post, but I'll repeat it here:
Journey people choose goals (sometimes unrealistic ones) and they swerve, take the long road, somehow don't make or take a much longer time than they'd planned, they don't know what the next step is or how to get there, but often they get an interesting ride, see somethings that those of us in the library (or on the treadmill or changing the diapers) didn't get to see, smell, feel, or experience. It's good stuff and it's bad stuff. It's often unexpected, often painful.

The second issue is whether ADHD is an illness that captures this phenomena or whether we haven't simply redefined a spectrum of people who don't meet society's rigid expectations into being ill. I guess you can say that about lots of disorders (shy vs. social phobia pops into my brain). One set of alarmists will talk about the gross under-diagnosis of the illness, another set of alarmists will talk about the gross over-medication of school children, especially boys, and how stimulants are the most abused drugs out there among high school students.

Just to think about. Thanks for joining us Mrs. Cake. And Roy, just to clarify, you're a Destination Person (there's no doubt), you just keep changing the destination.

My Three Shrinks Podcast 44: Guest J. Raymond Depaulo MD

[43] . . . [44] . . . [45] . . . [All]

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We are pleased to have the head of Johns Hopkins Psychiatry, Dr. J. Raymond DePaulo, joining us here to talk about diagnoses, labels, and the ethics of using drugs to enhance one's cognitive skills (a fascinating discussion).

Dr. DePaulo joins us on the next podcast as well (#45) to talk about treatment-resistant depression, bipolar disorder, favorite quotes, and words we don't like. That should be up by April 6.

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March 30, 2008: #44 Guest Dr. Ray DePaulo

Topics include:

• NYT: The Ethics of Artificial Brain Enhancement, by Benedict Carey. On using cognitive enhancers, like Adderall, Vyvanse, and Provigil, to perform better. The article quotes NIDA's Nora Volkow, who wrote, "Even though stimulants and other cognitive enhancers are intended for legitimate clinical use, history predicts that greater availability will lead to an increase in diversion, misuse and abuse." Dr. DePaulo addresses the treatment of symptoms (eg, inattention in pilots) vs diagnoses, on the bases of functional impairment and subsequent consequences. Be sure to listen to the part around 24 minutes, where we discuss the ethics of a hypothetical drug that increases IQ by 30 points.
  
  
• Diagnosis in Psychiatry. Also some comments on ADHD vs Bipolar diagnosis, which led into an interesting discussion about the nature of diagnosing psychiatric "syndromes" in the absence of a definitive diagnostic aid, like a blood test or brain scan.
  Other references and topics mentioned by Dr DePaulo: Kraepelin. // Quote from Paul McHugh: "A good clinician in Psychiatry is someone who makes prudent decisions based on insufficient information." // Judy Rapoport's 1978 study of stimulants in normal kids. // The history of "ADHD" and "minimal brain dysfunction". // Labels and diagnoses. // William Styron // Kraepelin's Manic-Depressive Insanity.
  
  
• Prison Health Care. Clink compares correctional psychiatry capabilities with those in free society and wonders why care can be provided in jails and prisons yet we are the only country still without some sort of national health care.
  
  
• JAMA: Loss of Serendipity in Psychopharmacology, by Donald Klein. Article in the March 5 issue of JAMA. "This Commentary on the psychopharmacological revolution focuses on 2 mysteries: fostering medication discovery and finding out how they work."
  

Dr. DePaulo's most recent book is Understanding Depression.

There are three audiences for this authoritative book: people who think they may be depressed, those whose condition has already been diagnosed and are in treatment, and those who are concerned about someone who is either in treatment or probably needs to be.

Credit: At the end is a few seconds of "Manic Monday" by The Bangles [iTunes, Amazon].

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Find show notes with links at: http://mythreeshrinks.com/. The address to send us your Q&A's is there, as well (mythreeshrinksATgmailDOTcom). This podcast is available on iTunes (feel free to post a review) or as an RSS feed. You can also listen to or download the .mp3 or the MPEG-4 file from mythreeshrinks.com. Thank you for listening.

My Three Shrinks Podcast 43: How Doctors Think

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The Benzo Wars are over now, and podcast #43 is much more dispassionate and level-headed. Later this week, we'll also put out podcast #44, with the head of Johns Hopkins Psychiatry, Dr. J. Raymond DePaulo.

The three of us have been busy with other things, so we apologize for not getting these podcasts our more regularly, but please keep coming back for more.

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March 18, 2008: #43

Topics include:

• My Three Shrinks: The Book. We've been talking about writing a book which explains how psychiatrists go about thinking about approaching problems, such as selecting medications or diagnosing illness. We are debating about how to format the chapters in the book. One option is for each of us to write individual chapters about various topics. Another is to maintain the conversational tone so that we each would have some back-and-forth commentary within each chapter. What do you think? Let us know in the comments below, or email us.
  
  
• NYT: Time Off From Electronics. Mark Bittman had an article in last week's New York Times called "I Need a Virtual Break. No, Really." The article talks about forgoing today's electronic trappings for one day each week, similar to some business' "email-free Fridays." No cell phone. No voicemail. No Blackberry. No internet. This provoked anxiety for Dinah (and "what's the point" from Clink and me), who speculates further about "internet addiction" and the risk of death by videogame. Addiction vs compulsion.
  
  
• PT: Why Psychiatrists Should Read the Humanities. Clinkshrink discusses a Psychiatric Times article from the Feb 2008 issue by Cynthia M.A. Geppert, suggesting that more humanities should be taught to medical students and residents. Dinah remembers my first blog post about Tom Cruise.
  
  
• Female Sociopaths in Literature. Clink lists a number of female sociopaths portrayed in operas, books, and other literary works.
  
  
• Brain Maturation Delayed in ADHD. Also in the Feb 2008 issue of Psychiatric Times is this article by Arline Kaplan, describing research suggesting that the brains of kids with ADHD mature a little later than others, bringing into question the medication treatment of this disorder, rather than more behavioral and "tincture of time" methods.
  
  
• How Doctors Think, book by Jerome Groopman MD. Dinah is reading this now and notes that Dr Groopman chose not to discuss how psychiatrists think, because this is "beyond [his] abilities." (We really need to get our book written.)
  
  
• How Psychiatrists Think. Once again, we are starting a book and would like some feedback from our listeners and readers. The question is about the style of writing. Option 1 would be for each of us to take on topics and write a short (1-5 pages) chapter on a given topic. Option 2 would be for each of us to chime in within each topic/chapter, thus more resembling a discussion. Option 1 is more traditional. Option 2 would sound more like our podcast, at the risk of confusing the reader about who is "talking" at any given point.
  
  Email us with your thoughts about these options at mythreeshrinksATgmailDOTcom.
  

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Find show notes with links at: http://mythreeshrinks.com/. The address to send us your Q&A's is there, as well (mythreeshrinksATgmailDOTcom). This podcast is available on iTunes (feel free to post a review) or as an RSS feed. You can also listen to or download the .mp3 or the MPEG-4 file from mythreeshrinks.com. Thank you for listening.

FDA Drugs: February 2007

2007: Mar | Feb | Jan . . . 2006: Dec | Nov | Oct | Sep

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FDA Drugs: February 2007

• Warning Letter: Signature Genetics. Seryx is the company that markets an excellent (but expensive) pharmacogenetics program which will take your blood or cheek cells and analyze your DNA for various genotypes which affect how your body metabolizes certain drugs, many of which are psychotropic drugs. This information may be used to help a prescriber make decisions about starting dosages or drugs or combinations of drugs to use or avoid. This topic is a whole 'nother post I could do, but this type of testing can be used inappropriately (2002 Quackwatch page), as well. Anyway, this computer program is considered by the FDA to be a "device", and it has not applied for FDA approval, so the FDA is telling it to stop until approval is obtained.
• Wellbutrin (bupropion) Medication Guides updated: PDF versions of Medication Guides for Wellbutrin and Wellbutrin SR were updated.
• Generic Focalin (dexmethylphenidate) approved.
• Only 22 New Drugs Approved in 2006: Merrill Goozner comments on his blog, GoozNews, about the lowering of innovation in the pharma industry.
• FDA Starts Podcasts: The FDA Commissioner, Dr. Andy von Eschenbach, has started a series of drug safety-oriented podcasts. The first one just announces the series. Go to the XML feed to subscribe.
• ADHD Drug Warnings: The FDA is requiring all manufacturers of drugs used to treat ADHD, including Adderall, Concerta, Ritalin, and Strattera, to develop Medication Guides to warn patients about the risks of cardiovascular (sudden death, stroke, heart attack, blood pressure) and psychiatric (mania, psychosis, aggression) side effects.
• Vyvanse releases Medication Guide: Shire's Vyvanse (lisdexamfetamine dimesylate) was listed last month (before the name was changed from Vynase) as a new ADHD drug. It is a prodrug, meaning it is metabolized into an active drug by the body. Advantages are said to be that it is once-daily and that it is less likely to be abused (ie, 4 out of 5 drug abusers prefer other stimulants to this one). It now has full approval as a Schedule II drug (for full prescribing info, see link to Label Info here.)
• Changes in Nardil (phenelzine) Prescribing Info: added severe renal impairment or renal disease to list of contraindications; added cautions about use in diabetes; and added warning about drug interaction with guanethidine (Ismelin).
• Changes in Cymbalta (duloxetine) Prescribing Info: a number of changes were made, though I cannot tell how substantive these were. Lilly did receive a new indication for the treatment of GAD (Generalized Anxiety Disorder) with Cymbalta.
• Changes in Effexor XR (venlafaxine) Prescribing Info: the following was added under the Precautions section: "Interstitial lung disease and eosinophilic pneumonia associated with venlafaxine therapy have been rarely reported. The possibility of these adverse events should be considered in venlafaxine-treated patients who present with progressive dyspnea, cough, or chest discomfort. Such patients should undergo a prompt medical evaluation and discontinuation of venlafaxine therapy should be considered."
• Zimulti or Acomplia (rimonabant) review extended: This cannibinoid receptor antagonist, which is being reviewed as a weight loss drug (you guessed it... it blocks the munchies, even if you are not smoking pot), was to have a final decision on approval status on April 26. The review period has been extended to July 27. (I reported in November's update that this drug was approved in Mexico.) The latest proposed brand name is Zimulti. The hearing for this drug will be held on June 13, 2007, before the Metabolic & Endocrinologic Drugs Advisory Committee. When the background resource documents are ready, they will be found here.
• Warning Letter: Provigil (modafinil). Cephalon got slapped for promoting its wakefulness-promoting drug (indicated for use in narcolepsy, obstructive sleep apnea, and Shift Work Sleep Disorder) by distributing a document by Dr. Kerasidis which states the drug is effective in multiple sclerosis, Parkinson's, depression, ADD, and chronic fatigue syndrome. Interesting, in that this document was provided as testimony to the Maryland Dept of Health and Mental Hygiene's Committee which is responsible for making decisions about which drugs will be placed on the Medicaid formulary list.
  

FDA Drugs: January 2007

2007: Mar | Feb | Jan . . . 2006: Dec | Nov | Oct | Sep

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FDA Drugs: January 2007

• Vynase (now Vyvanse) gets approvable letter: New River Pharm and Shire are poised to release a new ADHD drug, lisdexamfetamine (was NRP-104).
• Generic Wellbutrin XL approved: by Anchen Pharma.
• Wellbutrin Package Insert was modified: to reflect the following additional info regarding its use in people with renal failure: "An inter-study comparison between normal subjects and patients with end-stage renal failure demonstrated that the parent drug Cmax and AUC values were comparable in the 2 groups, whereas the hydroxybupropion and threohydrobupropion metabolites had a 2.3- and 2.8-fold increase, respectively, in AUC for patients with end-stage renal failure." Also added was mention of double vision and increased intraocular pressure as reported adverse reactions.
  
• FDA releases Guidance on Pharmacogenetic data. The FDA released definitions for genomic biomarkers, pharmacogenomics, and pharmacogenetics.
• Alexza is working on Schizophrenia Agitation drug: The drug is an inhaled form of loxapine, a typical antipsychotic.
• New Antidepressant: Pristiq. Wyeth, who makes Effexor XR (venlafaxine), received an approvable letter for Pristiq (desvenlafaxine succinate), which is a metabolic derivative of Effexor; both drugs are serotonin-norepinephrine reuptake inhibitors (SNRIs). Approvable letters have conditions which must be met before the product can be marketed. The Wyeth facility in Puerto Rico must pass FDA's muster, and the marketing plan must be approved, prior to its release for the Major Depression indication. Wyeth is also going after an indication for Vaso-Motor Symptoms (VMS) related to menopause ("hot flashes" in English).