Wednesday, September 24, 2008

Science or Scam: Neuro-imaging for ADHD?

More than a dozen years or so ago I was attending a conference in Israel on ADHD when one of the organizers--a neurologist-- asked me to please address the problem of Dr. Daniel Amen's claims about his subtyping of ADHD through the use of the SPECT imaging technology. The problem she said, was that many of her patients were flying from Israel to the U.S. in order to be "subtyped" and then treated by Dr. Amen in California. Single photon emission computed tomography (SPECT)) is a nuclear medicine tomographic imaging technique using gamma rays. It is very similar to conventional nuclear medicine planar imaging using a gamma camera. However, it is able to provide true 3D information. This information is typically presented as cross-sectional slices through the patient. One disadvantage of this technology, in contrast to MRI or fMRI, is that it requires giving a dose of a radioactive tracer. In response to Dr. Amen's talk I asked to see any data supporting his claims. He responded by saying that he had over 12,000 cases on which to base his typology. "What statistical methods did you use?" I asked. He replied that they had not been published yet, but that researchers like me would have to undertake such a huge job. More recently, 11 years later in La Jolla, California I happened to be on a panel with Dr. Amen and the same issue was raised about publications. He responded that there was now a publication, but he didn't recall the name of the journal; but he asked one of his colleagues in the audience for the name. The colleague looked puzzled, threw up his arms quizzically, and said he didn't know. So much for supportive scientific proof. A prominent neurologist and imaging researcher, George Busch, M.D. happened to be on the same panel. He unequivocally denounced Dr. Amen's claims and asserted that no respectable scientist had yet to find a way to use neuro-imaging to make those clinical subtype distinctions, let alone a diagnosis. Work by Jay Giedde, Judy Rapaport, and Javier Castellanos at NIMH with MRI and fMRI have indeed shown that there are important brain differences between ADHD and normal controls, both cross-sectionally and developmentally. But no one claims that any diagnostic rules from those data are capable of the precision required to beat clinical assessments. Here's what Dr. Amen claims about ADHD subtypes: Type 1 — Classic ADHD. Symptoms such as short attention span, distractibility, disorganization, procrastination, poor internal supervision plus hyperactivity and impulsivity.* Type 2 — Inattentive ADHD. Classic ADHD symptoms, but instead of hyperactivity, there is low energy.* Type 3 — Overfocused ADHD. Classic ADHD symptoms as well as negative thoughts and behaviors, such as opposition and arguing.* Type 4 — Temporal Lobe ADHD. Classic ADHD symptoms plus irritability, aggressiveness, and memory and learning problems.* Type 5 — Limbic ADHD. Combines ADHD with depression and low energy and decreased motivation.* Type 6 — The Ring of Fire. Cross between ADHD and bipolar disorder. Characterized by moodiness, aggressiveness, and anger. Now any experienced clinician will undoubtedly agree that these are recognizable forms of presentation at a child clinic. In fact, these are classic descriptions from the literature: the hyperactive/impulsive type; the inattentive type; the overfocused type (e.g. Kinsbourne's type); the hypoactive type, etc. But are these "types" confirmed by an appropriate methodology as variants of ADHD? Where is the cluster analysis or factor analysis of large samples characterized through rigorous clinical documentation? Where are the structured or unstructured interviews and histories to validate the diagnosis? What are the statistical boundaries among these so-called types? What is the evidence that they respond differently to treatments or have other biological or genetic markers to distinguish them? If I had 12,000 cases in my database, I would not waste a day before exploring the typologies that might be hidden there. Amen's work is classic quasi-scientific mystification: the failure to distinguish between anecdotes and data, and between hypothesis and fact. Like all fringe quasi-scientific appeals to a needy public, there are classic signs of when the patients are being fooled: 1) There is an impressive and truly science-based technology, so sophisticated that the ordinary public must take the claims on faith; 2) The proponent of this new method, though possibly trained in traditional clinical and scientific paths, breaks with the majority of scientists and fails to pass the test of peer review; 3) The proponent himself (or herself) is too busy seeing patients and collecting large fees to do the necessary research themselves; 4) The proponent tirelessly appears at conferences and seminars worldwide, and develops an adoring but uninformed following despite repeated criticisms to produce real data; 5) Standard treatments are often the outcome from the elaborate workups and tests, though actual followup studies are seldom provided. I have to admit that personally Dr. Amen is charming, well-informed, and well-trained. He gives a convincing talk, and if I were an uninformed normal patient, I would probably agree that there is no definitive biological test for ADHD, no pathogonomic sign, and a truly complex clinical picture. I might possibly end up in desperation spending thousands of dollars after seeing the lovely colored pictures of the brain, with hot spots where ADHD resides. But fortunately, I have been around long enough to spot mumbo-jumbo when I see it. Let the buyer beware.

Tuesday, September 16, 2008

Fish Oil as a treatment for ADHD?

Some physicians are now recommending fish oil in the form of omega-3 fatty acids or PUFAs (Poly-unsaturated fatty acids) as a therapy for ADHD children, adolescents and adults. This is partly in response to the persisting fears of parents about stimulant medications and partly on the basis of the always-hopeful findings in the literature, i.e. on the basis of inconclusive studies that "suggest further research is needed." As in most alternative therapies, some elements of basic neuroscience are cited as the rationale for the therapy, followed by "preliminary studies" which give hopeful signs (one might cynically say especially signs of future funding from government or pharmaceutical companies). In this case there are a number of animal studies which compare spontaneously hyperactive rats with their cool Sprague-Dawley cousins, who show signs of better cognition after dietary supplementation with PUFAs. Also, it appears that lack of these fatty acids are known to impede neural development in young babies. However, as for the scientific rationale, one respectable scientist says that, "...our current understanding of the importance of essential fatty acids (EFAs) and their metabolites to optimal brain function is based on an enormously complex set of interlinked biochemical, neurological, and laboratory observations. The applicability of these research findings to children with attention-deficit/hyperactivity disorder (ADHD) is unknown." (Betsy Busch, Polyunsaturated fatty acid supplementation for ADHD? Fishy, fascinating, and far from clear. J. Devel. & Behav. Pediatrics, Vol 28(2) Apr 2007, 139-144). What about clinical trials? One comprehensive recent review (E.H. Clayton, et al., Acta Neuropsychiatrica, Vol 19(2) Apr 2007, 92-103) found that 4 randomized controlled trials showed uncertain benefit for ADHD and no benefit for autism and bipolar disorder. A typical research story is illustrated from a controlled trial by A. Richardson and colleagues, who studied 41 children with ADHD and LD randomly assigned to highly unsaturated fatty acids (HUFAs) or placebo for 12 weeks. They found a mean improvement on 7 of 14 parent rating scales, "reaching significance levels on 3 of 14 scales." (Progress in Neuro-Psychopharm. & Biol. Psychiat. Vol 26, 2002, 233-39) Of course, they did not adjust for multiple tests, so technically the results are nil, but they call for further research.. By 2006, when reviewing the field, the same author concludes, "Omega-3 is not supported by current evidence as a primary treatment for ADHD or related conditions...." but still calls for further research. (A.J. Richardson, Omega-3 fatty acids in ADHD and related neurodevelopmental disorders. Int. Rev. Psychiat. Vol 18, April 2006, 155-172). Well, this is merely the research game as we have come to know it. I too have been enticed by small pilot studies that lead to larger grants (as in my flirtation with the Feingold diet studies, though there I took satisfaction in stopping a national trend sweeping the country which was diverting many parents from worthwhile treatments). One final research note on the dietary studies that also applies to drug trials involving parents and children. Many of these trials use apparently blind judgments by the physician which are in turn based upon reports by parents. But virtually all drugs create subjective awarenness by the patient that something is happening, and patients follow the demand characteristics of the experiment to give some response they think is expected, and parents as well as physicians become aware of side effects which allows a peek through the double blind. Note that in the previous study above the effects were found in parents but not by teachers (who are generally much more unaware of side effects and subjective bodily changes). When a trial shows parent reported changes but not teacher reported changes, one needs to be very suspicious about the signficance of any positive findings. All of those physicians out there who use the DSM-IV rating scale or global judgments as their outcome measures are likely to be subject to a positive bias about the drug being studied. After all, they get paid by the pharmaceutical companies and there is strong incentive to produce positive results and continued study. I have made this point many times at advisory committee meetings, but I have yet to find a single pharmaceutical company that pays attention to the suggestion of using blind raters who are separate from the physicians controlling the monitoring for side effects or adverse reactions. My conclusion from reviewing the literature on Fish Oil as therapy for ADHD is that it clearly is not proven. There are two therapies supported by research over a 40 year period: the combination of behavioral management (both in the classroom and at home); and stimulant drugs. But I make the following observation from my practice: it is usually quite useless to argue with a parent when they are predisposed against the use of drugs, no matter how noxious the child's behavior has become in their own lives. For those parents I make a therapeutic alliance by saying, sure, there are dietary therapies. First, make sure your child has a well-balanced diet, especially limiting their preference for high carb foods, and making sure there is plenty of protein at breakfast (I give them a pretty good story from our studies on this subject). I take a dietary history and recommend a 3-day diet diary, recording everything the child eats, and use it to steer the child and family away from obvious imbalances (there is good evidence that ad liibidem access to carbohydrates leads to an over use of them, especially in ADHD and Conduct-Disordered kids). I recommend limited access to sugar and sweets, but always balancing them with protein. For adolescents I am especially cautious about caffienated drinks. Eventually most parents return to the clinic after a few weeks saying, "Yes he (or she) is much better! But, you know, it's still a problem. What else can I do? I still don't want Ritalin." "Ahem, Madam, I agree and I can recommend a great medicine that is not Ritalin! (Well, it might be Metadate or Focalin or Adderall or Concerta or one of the other possibilities down the line when those don't work. But see my physician colleague, he (or she) knows all about it and can give you the latest medicine that works...") You get my drift. Since I do not myself prescribe, I rely on my savvy physician colleagues to know about the MTA study and the nuances of psychopharmacology that make for an effective treatment plan over the entire lifespan. (More on the MTA study in future postings.)

Monday, September 15, 2008

Food and Behavior

A colleague of mine who works in the public school system recently remarked that one of the parents with an ADHD child wanted to know whether her physician was correct in prescribing fish oil instead of a stimulant medication for her pre-adolescent son. This immediately prompted a deja vu flashback to my years studying the role of food additives (the Feingold diet), aspartame, coffee, and other foods as cures or causes of ADHD. Everything I learned back then was summarized in several journal articles and 2 books (Food Additives and Hyperactive Children, Springer, 1980; and Feeding the Brain, Perseus Publishing, 1989). What I learned from the Feingold/food additive controversy was the following:
  • Ben Feingold was an honest scientist and allergist with a sincere belief that Food Additives caused hyperactivity; a white-haired, persuasive charismatic figure who convinced thousands of his theory.
  • Just as he alleged, it was possible to "turn the hyperactivity on and off by giving or removing food additives." An effect we replicated in an ABAB design;
  • But all of the effect could be accounted for by placebo once a proper control group was added.
  • The only exception appeared to be for pre-school children where there was a slight indication that food additives increased hyperactivity (replicated by the Wisconsin group of nutritionists).

The power of placebo was strikingly illustrated by the very first child in our double-blind trial where food additve-loaded chocolate cookies were compared with additive-free chocolate cookies. On the first day of the trial the parent of the 6 yr old boy called, angrily threatening to sue us: "I don't know what you guys put in those cookies, but Kevin grabbed a knife and tore up our couch; he then took a hammer next door and destroyed the neighbor's motorcycle." Oh, oh...a looming court suit with big dollars flashed before me, but as fate would have it, you guessed it, he was on the placebo cookies. (Incidentally, this confirms Denny Cantwell's dictum that any red-haired boy named Kevin will grow up to be hyperactive.)

As Martin Orne once showed, the first thing a subject learns in an experiment is to obey what they think the experimenter wants to find.

Now back to feeding the brain. While at G. Washington and Children's Hospital in Washington DC, I carried out a number of experiments based on the Wurtman-Fernstrom hypothesis. They had demonstrated that a carbohydrate challenge elicits an insulin reaction which causes an efflux of large neutral amino acids (LNAA) from the blood, with the exception of tryptophan, which is lightly bound to albumin. Since LNAA cross the blood-brain barrier by competitive transport, tryptophan is given preferential input to the brain. Since tryptophan is a precursor for serotonin, the result is an increase in serotonin output, which is not regulated by positive feedback, so a burst of it can produce a sedative effect or other effects on the neurotransmitter systems.

We carried out several experiments in which we pre-fed normal and ADHD children with either a high protein breakfast, a carbohydrate breakfast, or a fasting condition, and tested them following a high level of carbohydrate beverage or aspartame placebo. An indwelling catheter was used to monitor hormonal responses, and tests of attention (CPT), cardiac response to warned reaction time (RT), and event-related potentials (ERP), monitored throughout the day. There were several results compatible with the Wurtman-Fernstrom hypothesis:

  • Baseline levels of carbohydrate were significantly higher in the ADHD than normals. (Judy Rapaport at the NIMH had reported no differences in serum carbohydrate levels, but the breakfast the children ate beforehand was not monitored, thus invalidating the results).
  • Attentional performance on the CPT (continuous performance task) and evoked cardiac response was impaired in the ADHD, but only when they had a carbohydrate breakfast, not a protein or fasting breakfast. The effect aoppeared to be in the early processing phase.
  • ERPs showed marked lowering of amplitude and slowed latency in the carb condition but only for the ADHD children.
  • Two hormones important in regulating carb levels (cortisol and growth hormone), were under-reactive in response to the carb challenge compared with controls.

I don't think we can conclude that high carbohydrate levels and increased serotonin cause ADHD. Instead, we propose that the recognized deficits in dopamine production or dopamine receptor function may be responsible for the hormonal effects, which in turn lead to a dysregulation of carb levels and the tryptophan/serotonin effect. This hypothesis has not to my knowledge been tested, and remains in my mind as an important future research problem.

Now, back to the fish oil issue. There is a small number of studies on the role of essential fatty acids (EFA), particularly omega-3, and ADHD, and some related areas like bipolar disorder and depression. In my next posting I will review this evidence. As a preview I can say that unlike neurofeedback and megavitamins, it is not the dictum of "Let the buyer beware" that applies, but the Scottish one, "Not proven."

Sunday, September 14, 2008

My First Blog

I retired from Duke 5 years ago, and it is with some trepidation that I launch myself back into the world of ADHD. When I retired I took Winston Churchill's advice to use oil painting as a past- time (paintings which readers can view on my Facebook website), but I find myself often thinking about ADHD issues and receiving queries from patients, parents and other strangers. I thought it might be useful to share some of these thoughts, and in future blogs here I plan to comment upon some of the perennial issues in this field:
  • Do foods, fish oil, additives, supplements, vitamins, etc. affect or cause ADHD?
  • Are there really as many ADHD children out there as are being reported in the media?
  • What are the important issues in the use of pharmacologic treatment of ADHD?
  • Is ADHD an evolutionary advantage of some kind? Is it truly increasing in the world?
  • What are the advantages and disadvantages of using rating scales in the diagnostic process?
  • What should we think about the big pharmaceutical companies in the world of ADHD?
  • Is there any role for sedatives, hypnotics, and tranquilizers in therapy of ADHD?
  • What ar some the myths about ADHD?
  • ADHD in schools: should we be concerned about how they are labeled and treated there?

In the meanwhile, I welcome any and all queries and comments from my colleagues, physicians and psychologists alike; as well as concerns and comments from parents or patients. I cannot of course give medical advice, but only my opinions based first on good science, and second on my own educated guesses acquired over my lifetime in the trenches of ADHD World. Join me!