Worming Your Way to the End –Smart Drugs For Schizophrenia

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

Honey Dressing Wound Care Part II

In a correspondence with Professor John E. Moore of Northern Ireland's Public Health Laboratory regarding his MRSA/honey publication, he mentioned two important factors to consider when using honey for wound dressings:

Patients should use only medical-grade and not honey plucked off the shelf in their nearest food store. This is not a tactic to boost Big Pharma profits, but a very necessary step to avoid potential infection from dormant bacteria in foodgrade honey. Such honey is not sterile but may contain many spore-forming organisms, which is not a good idea to apply to a wound. The medical grade honey is sterilized to wipe out such bacterial contaminants.

Infant botulism: One spore-forming contaminant may be Clostridium botulinum. Therefore newborns and young children should avoid ingesting natural honey to avoid getting infant botulism. There may be a temptation for young children to “taste the cure”.

Cheers to Professor Moore for bringing this fascinating topic to us -see previous post for full story.

Honey Dressing: Treating Methicillin-Resistant Staphylococcus aureus

The threat of hospital and community associated Methicillin-Resistant Staphylococcus aureus (MRSA) has clinicians, parents, and the infirmed panicky. New research, not to mention ancient practices, suggest that a medication-free solution may be sitting in our cupboards.

Two weeks ago, I watched my two year old son play in a mound of worms and rolly pollies located in our back yard dirt pile. Had I known that within his blue sandal a small cut on his fourth toe was beginning to fester, I would have washed more than his hands upon entering the house for a snack--on this occasion yogurt with honey.

Staphylococcus aureus, named for the golden color of its colonies (aereus was an ancient Roman gold coin), is a spherical bacteria that forms clusters. Found on skin, in noses, and in dirt piles, it's unavoidable. The intensity of the yellow pigment is proportional to the severity of infection. While the pigment doesn't cause drug resistance, there is an association with virulence and infection intensity. MRSA is scary not just because it is resistant to treatment with antibiotics, but also because it is extremely aggressive.

When our pediatrician saw the toe four hours after prescribing an oral antibiotic, she took a step back. The speed at which the infection was progressing made her suspect that his growing purple blister was concealing a MRSA bug. He was hospitalized immediately and placed on intravenous antibiotics.

For me the idea of squirting honey on an open wound is akin to bandaging a chocolate bar to it. But well before the advent of antibiotics ancient peoples used it regularly. It is also currently utilized for similar treatments in parts of the world outside of the US. When I first heard this, I imagined places ill equipped with medical supplies--places where drinking water, let alone intravenous antibiotics, is scant. This is not the case. Experts in New Zealand, Germany, Ireland and other places are dipping gauze in the amber gooiness and pushing it against the nastiest injuries.

The scientific reports are astonishing. Researchers growing bacteria on petri dishes watch colonies disappear with honey application. Doctors have seen children once needing anesthesia for a dressing change, hardly wince with application. In addition to anecdotal data, one randomized control trial concluded “There was no evidence of a real difference between honey and IntraSite Gel as healing agents. Honey is a safe, satisfying and effective healing agent.” Studies comparing other agents with honey on the treatment of ulcers report greater healing power of honey dressings.

Historical studies determined the effectiveness results from honey's osmotic properties. The bacteria, having more water in them than the honey, literally shrivel and die. This attribute, however, is contradicted by the diluting effect of a weeping wound. Never-the-less, experiments repeatedly show the therapeutic effectiveness in the treatment of Staphylococcus infected wounds. Honey also has enzymes with antiseptic bi-products (namely, hydrogen peroxide). While scientists continue to unravel the reasons for its potency, data is showing that it works even for bacteria harboring antibiotic resistant genes, MRSA!

Despite antibiotics, the blister was growing fast and had an ominous appearance. With a team of six clinicians (including two pediatric surgeons), blue gloves gripped scalpel and forceps, hovering bright lights were centered, nurse readied with gauze dripping brown liquid, and doctor pushed anesthesia through an intravenous tube. As the scalpel poked through the skin, cloudy fluid spurted past the table and onto the floor. Swabs, rubbed on the inner surface of the skin, were placed in test tubes and sent to the laboratory. Freed from the infected skin, the remaining wound was wiped, coated with a white creamy topical antibiotic and wrapped with gauze. We were treated similarly and transferred to an isolation room. Entering staff had to suit up in blue plastic aprons and gloves, meal trays were left outside the room and visitation was discouraged. It seemed that the only thing entering the room were clear bags of antibiotics.

While there are claims that honey from particular locations carry more antiseptic properties than others (including anti-fungal and anti-viral properties), with some even marketed as medical grade honey, the fact that all varieties tested demonstrate antibacterial properties should be enough to transfer the kitchen product into our first aid kits. So why is it that today after meeting with our pediatrician, I filled the prescription for a topical antibiotic and dutifully dressed the still healing wound?

Honey is healing and cost-effective but until clinicians embrace it, it's useless. Our culture confides in the advice of white coats handing out prescriptions. In order for the golden liquid to effectively combat the golden colonies, we need to embrace ancient wisdom and current research at the level of the doctor's office.

Incidentally, the bacterial culture results revealed the toe culprit to be a simple everyday Staphylococcus aureus, not the dreaded MRSA.

***
Also see Professor Moore's comments regarding this post and medical grade honey.

Some of many relevant references:

Yapucu Güneş U, Eşer I. Effectiveness of a honey dressing for healing pressure ulcers.
J Wound Ostomy Continence Nurs. 2007 Mar-Apr;34(2):184-90

Ingle R, Levin J, Polinder K. Wound healing with honey--a randomised controlled trial. S Afr Med J. 2006 Sep;96(9):831-5.

Boukraâ L, Niar A, Benbarek H, Benhanifia M. Additive Action of Royal Jelly and Honey Against Staphylococcus aureus. J Med Food. 2008 Mar;11(1):190-2.

Maeda Y, Loughrey A, Earle JA, Millar BC, Rao JR, Kearns A, McConville O, Goldsmith CE, Rooney PJ, Dooley JS, Lowery CJ, Snelling WJ, McMahon A, McDowell D, Moore JE. Antibacterial activity of honey against community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA). Complement Ther Clin Pract. 2008 May;14(2):77-82.

Sweet Pleasure: Calories Register Reward Independent of Taste

That the brain has the ability to appreciate calories hedonistically without input from the tongue is a momentous report. A new study, using mice incapable of tasting sweetness, determined that the brain's pleasure system is activated when sugar is consumed independent of taste.

When the mice consumed sugar -whether they could taste it or not- dopamine levels increased suggesting that the mice were experiencing pleasure. When given a choice, taste deficient mice like normal mice selected the sipper containing a sugar solution over water. But when artificial sweetener was substituted, the “sweet blind” mice showed no bottle preference or change in dopamine levels indicating that the feel good effect was due to the calories.

Interestingly, mice with intact sweet taste did not have a greater pleasure effect from sugar than the artificial sweetener. So does taste trump calories? The authors imply that it might not and speculate that obesity and overeating may involve this calorie sensing sweet pleasure.

. de Araujo IE, Oliveira-Maia AJ, Sotnikova TD, Gainetdinov RR, Caron MG, Nicolelis MA, Simon SA. Food reward in the absence of taste receptor signaling.
Neuron. 2008 Mar 27;57(6):930-41

Do You Need Another Reason to Drink Coffee?

A new study suggests that you can have your cake and eat it too -or at least, have your caffeine and protect your brain from damaging dietary cholesterol.

The report shows that caffeine counters the negative influences that high cholesterol can have on the brain without changing the blood cholesterol levels. Giving rabbits a high cholesterol diet in addition to caffeine (equivalent to one cup of coffee a day), researchers at the University of North Dakota tested the hypothesis that “chronic ingestion of caffeine protects against high cholesterol diet-induced disruptions of the blood brain barrier” in their recent Journal of Neuroinflammation publication.

Previous studies indicate that caffeine protects the brain from neurological diseases such as Alzheimer's disease. What makes this study interesting is that it provides a mechanism for the protective effects. High dietary cholesterol compromises the blood brain barrier (a network of cells that line small blood vessels to impede damaging compounds circulating in the blood stream).

The authors point out that the finding has two therapeutic implications. One being that caffeine consumption may be used as a treatment for brain diseases by itself. The other is that withholding caffeine might facilitate the entry of other medications into the brain.

So what is caffeine doing to prevent cholesterol induced breakdown of the blood brain barrier? It blocks reduction of specialized proteins that join cells together. In other words, caffeine sustains the proteins that physically bind one cell to the next.

Another interesting caveat is that increasing the caffeine dosage (by ten) did not change the effect. However, to achieve protection the dosage did need to be “chronic”. So take comfort when having your daily cup of coffee.

The image above (from Fig 1 of the sited paper) shows that when caffeine is present, cholesterol-induced blood brain barrier damage is prevented. The brown splotches are areas reactive to blood factors that seep into the brain following leakage.

Xuesong Chen, Jeremy W. Gawryluk, John F. Wagener, Othman Ghribi and Jonathan D. Geiger, Caffeine blocks disruption of blood brain barrier in a rabbit model of Alzheimer's disease, Journal of Neuroinflammation 2008, 5:12 doi:10.1186/1742-2094-5-12

Fishy Brain Cells Take Sides

One of our fish has an unnaturally long fin on its left side. I call him Flag Fin. Our tank houses ten zebrafish: small, cheap and hearty. Our fish were intended for conditioning the tank -to prepare the environment for more sophisticated creatures- but we never got around to flushing and replacing them so here they are, swimming.

Most things have direction in life -with reference sidedness, not purpose. The snail collective dutifully scrapping algae off the tank's walls all have shells that spiral to the right (though I understand the shells can coil counterclockwise). To notice this lopsidedness in yourself, look at the reflection of your reflection. It really brings out facial asymmetries.

Most days, I walk by the tank without taking notice. But today, I sit next to it and look closely. One fish has a bulging belly. One looks almost orange between the dark stripes. And then there's Flag Fin. All of them have equally small heads. Tiny, pea-sized heads.

That brains have sides is no news. How our right hand corresponds to our left brain, or how our verbal skills are distinct from our musical talents, has scientists linking regions with function left and right.

Only recently did I make the connection that the zebrafish used in lab experiments are the same feeder fish swimming in my living room. A study published last week in Neural Development used the fish to show that the brain's asymmetry coincides at the level of single neurons.

Two pea sized nodes in the human brain (the habenula) have been implicated in functions including control of the circadian rhythm, behavior and mood. In the zebrafish, this structure is notably lopsided.

The researchers based at University College London embedded the fish embryos (no longer than the width of a toothpick) in a gelatinous substance and injected DNA corresponding to a green or red fluorescent protein using a series of electric pulses. This enabled them to visualize individual brain cells that display elaborate shapes. What they saw was telling. Looking at cells from the left and right habenula, the team noticed an unprecedented feature. The axons crossed over to the other side -not once, not twice, but lots of times. In fact, they made spirals.

The team also noticed that most of the cells on the left looked different than those on the right. The shape typical of left cells were “domed crowns” and the right-typical looked more flattened and shallow.

This experiment exemplifies reductionism on two levels: 1. the brains microscopic building blocks dictate or “encode” the macroscopic shape and 2. primitive critters are important to advanced concepts.

Zebrafish have primed so much more than a fish tank for the introduction of more sophisticated content. How our brain cell morphologies dictate asymmetry and how that corresponds to differences in behavior and cognition will keep scientists whirling in experiments.

Inside the glowing tank, Flag Fin waves. I imagine a spiraling green cell deep in his little brain. “Good night Flag Fin,” I say, flipping off the light.


The images displayed above show cells from the larval zebrafish habenula that extend into spirals. They correspond to Figures 1C and 2A from the article referenced.

Isaac H Bianco et al. 2008

Nutty Brain Humor

Every year on April first, I play a small prank on my husband. The jokes are not incredibly funny but we (well, I) manage to get a chuckle. Since I have a hard time keeping a straight face, I usually set up an ambush -think, bath towel laced with glitter dust.

What makes silly jokes funny?

One year when I was a grad student frantically pulling together a journal club presentation, I came across reference to a brain region called the amygdala. In consult with a professor, I asked about the brain area. He was either unaware or had a good sense of humor; his response was “I don't know, a dance?”

Data from functional magnetic resonance imaging suggests that the amygdala (particularly the structure on the left side of the brain) is involved with the emotions relating to amusement. But the amygdalae are funny things linked to critical functions including fear conditioning and maternal behaviors.

While the general role of the amygdala in associating memories with emotional events explains the smile I get when seeing glitter remnants in the caulking, I'm sure that the science of humor is more convoluted than activity in one nut sized region.

Bartolo et al. 2006