In 2006, a drug promising cognitive enhancement to people with schizophrenia emerged from phase I clinical trials. Press releases, message boards, scientific meetings, and blog postings rang out.This month, the schizophrenia phase II clinical trial results were released (Am J Psychiatry, Freedman et al.). As far as I can tell, no editorials or reviews accompany the paper. No press releases or message boards were updated. Even the blogger world has been silent. Albeit, I'm talking about a paper that came out ahead of print but that was a month ago. Here I will render its data into a story with a beginning, a middle; the ending –you decide.
This is a provocative tale starting twenty years ago when a young researcher combed the rocky shores of Washington for small worms (Nemerteans). Dr. William Kem, now a professor of pharmacology at the University of Florida, still investigates invertebrate compounds for research as well as practical purposes.
Dark on top with light bellies, these worms carry toxins that bind human brain receptors. I have yet to see one of these worms in the wild (despite hours of logged beach time). I was, however, fortunate enough to see a few faded versions floating in jars at Santa Barbara's Natural History Museum.
In 2007, thirty one patients with schizophrenia were deemed eligible for the trial. DMXB-A (or GTS-21), the cognitive enhancing drug, would be administered alongside the patients' standard medications, the idea being that schizophrenia has multiple symptoms (only one of which is cognitive challenges) and may need to be treated accordingly. In addition, the subjects had to be free of nicotine or tobacco for at least a month.
“You'd be hard pressed to find a schizophrenic that didn't smoke,” were the words that brought my attention to the link between smoking and schizophrenia. They came from a researcher at a Tobacco Related Disease conference who went on to explain that between 80%-95% of all patients with the disease use nicotine products. Smoking increases attention. Because people with schizophrenia have marked cognitive challenges, scientists attribute their nicotine use as a self-medicating attempt to focus.
The problem with smoking (excluding the negative health consequences), is that receptors binding nicotine desensitize and effectively stop working. Increasing the dosage (the number of cigarettes, tobacco products -or even the patch/gum) works only temporarily and also results in significant negative physical reactions.
Dr. Kem knew he had made a significant discovery when he realized the initial worm extractions had nicotine-like properties. For the clinical trials, DMXB-A was not purified from the worms themselves, but rather synthesized in a laboratory and placed into capsules.
The original proof of concept study showed that when eight healthy Scottish men were dosed with DMXB-A, they performed better on tasks requiring focus and memory. In 2004, phase I subjects with schizophrenia were dosed and tested for just one day. The phase II tests were designed to determine effectiveness and safety in patients with schizophrenia for a longer term treatment -one month.
Through the course of the month, some patients experienced trembling; some felt nauseated and restlessness. One patient became suicidal after a breakup with his girlfriend but the medication was not likely the cause. There were no significant adverse effects.
But what about the cognitive effects? Did the patients get smarter?
For me reading this clinical trial paper, it's really hard to tell. The answer seems to depend on the way cognition is evaluated. One analysis shows no improvement but the next offers promise. The patients report positively but placebo clearly betters things too. One sentence from the conclusion reads, “the clinical utility of this treatment is not yet determined.”
The company currently investigating this medication, CoMentis, has also studied the drug in relation to Alzheimer's disease as well as attention deficit and hyperactivity disorder. I can tell you even less about those trials -except they have been completed.
While the CoMentis scientific officer and Dr. William Kem were more than happy to talk with me -and very helpful regarding the drugs history and mechanism, they both referred me to Dr. Robert Freedman when my questions skirted to current study results. Unfortunately, Dr. Freedman declined an interview.
This is where you decide the ending to this tale. Are the people involved quietly trying to lay this once thought giant to rest? Or perhaps this is the time before the big reveal? Or is it like many scientific stories -the ones not often told- where results are not black and white and data is a gray smudge worming its way from one side of a line to the other?
For more information see Smoking Away Schizophrenia, a Scientific American Mind Head Lines article that I wrote.
Kitagawa, H., Takenouchi, T., Azuma, R., Wesnes, K.A., Kramer, W.G., Clody, D.E., Burnett, A.L. (2003). Safety, Pharmacokinetics, and Effects on Cognitive Function of Multiple Doses of GTS-21 in Healthy, Male Volunteers. Neuropsychopharmacology, 28(3), 542-551. DOI: 10.1038/sj.npp.1300028
Olincy, A., et, al. (2006). Proof-of-concept trial of an alpha7 nicotinic agonist in schizophrenia. Archives of General Psychiatry, 63(6), 630-638.
Freedman, R., Olincy, A., Buchanan, R.W., Harris, J.G., Gold, J.M., Johnson, L., Allensworth, D., Guzman-Bonilla, A., Clement, B., Ball, M., Kutnick, J., Pender, V., Martin, L.F., Stevens, K.E., Wagner, B.D., Zerbe, G.O., Soti, F., Kem, W.R. (2008). Initial Phase 2 Trial of a Nicotinic Agonist in Schizophrenia. American Journal of Psychiatry DOI: 10.1176/appi.ajp.2008.07071135
2 comments:
I think that you have a thought proviking article here though the refernce I want to relay is buried in the coding of my pages [at the time] the general idea is that a sexually dimorphic pattern [is a case for an argument in the blind much like yours but more effectiv and convincing...] of [NRG] cause and effect follows-GH (139250-Growth hormone) secretion is stored in secretory granules the signal is bound to the GH stabalized in the circulating system that influences the serum concentration and anti-viral infection in human uterine microvascular endothelial cells and embryo recruitment and tropoblast migration of the IGF1/[GH] axis for patients with growth hormone gene deletion who have developed neutralizing antibodies to growth hormone, and to produce IGF1 during wakefulness (heritability estimate of 0.74) on the 24-hour GH and placental lactogen CSH1 (150200-similar to pituitary growth hormone.) this situation results in many dismorphic associations I have read of relateing to the idea of the apperant casual relationship of sperm and the uretheral channel with the development of BBB defcits and syndromes resulting in phylogenic snp's of this empherical data as to the method of imunogenic compromise in individuals and on the basis of nucleotide development in this area to close the barrier as opposed to the complexity of the controversies shared among ethnic-individuals hritable and non-schyztophy relatives participation reviewed and accepted here refd. transperantly carrying this NRG workups anomolous divergence during the [M] chase period.
postscript comment
This comment above is referenced as being peer reviewed as a multi-ethnic sampling OMIM-146732.
Like what it says is its kind of difficult to communicate with someone who is metabolically more prone to the disorder when they are awake when the symptoms are less pronounced when asleep, that dosent make much of a evolutionary theory which is controversial and open to debate that can be shared between related multi-ethnic-homologous phylogeny
and the other awake people,is sort of what I mean.
Post a Comment