The Rest of the Story

Michael Rack, MD, (blog: sleepdoctor) scooped me on this one: ramelteon (formerly named TAK-375, now called Rozerem® - Takeda Pharmaceuticals North America) was recently approved by the USA FDA for treatment of insomnia.  Check his post for details.  Basically, it acts on melatonin MT1 receptors, so it should be nonaddictive and should be extremely safe in overdose.  That latter point is of great interest to psychiatrists.  

Melatonin is a popular "natural" substance used to treat insomnia.  Success is highly variable.  It helps some people, but it seems that most people get no benefit.  There is no FDA quality control for nutritional supplements, so some OTC versions of "melatonin" actually contain no active ingredient.  That is one reason why traditional MD's tend to be skeptical of such products.  Plus, there was a small case series of patients with bipolar disorder who did not improve when treated with melatonin; one developed a free-running (unentrained) sleep-wake cycle after melatonin withdrawal.  I hope Takeda is watchful for this kind of thing in their post-marketing surveillance; it's the kind of thing that is unlikely to show up in phase I-III studies, but may show up when a larger, more heterogeneous population is exposed.

Practical matters aside, it is time to move on the the fun part: pure, preclinical, science, with no obvious practical application.  One such thing that caught my attention recently was this:

Regulation of brain-derived neurotrophic factor (BDNF) during sleep apnoea treatment
R Staats, P Stoll, D Zingler, J C Virchow and M Lommatzsch
Department of Pneumology, University of Rostock, Germany

Background: Patients with obstructive sleep apnoea syndrome (OSAS) often display persistent cognitive dysfunction despite effective treatment with continuous positive airway pressure (CPAP). Brain-derived neurotrophic factor (BDNF) is a key mediator of memory and cognition, but its regulation in OSAS and during CPAP treatment is unknown.

Methods: Serum and plasma BDNF concentrations, BDNF secretion by peripheral blood mononuclear cells, and overnight polysomnography were evaluated in 17 men with newly diagnosed OSAS (as defined by a respiratory disturbance index of >10/hour with >70% obstructive events and corresponding daytime symptoms) and 12 healthy control men. In the patients all the parameters were monitored after 1 night and 3 months of CPAP treatment.

Results: There was no significant difference in baseline serum BDNF, plasma BDNF, or spontaneous BDNF secretion by peripheral blood mononuclear cells between untreated patients and controls. After 1 night of CPAP treatment there was a steep fall in median serum BDNF (from 18.0 ng/ml to 4.1 ng/ml) and plasma BDNF (from 58.7 pg/ml to 22.0 pg/ml) concentrations. Following 3 months of treatment BDNF concentrations did not return to baseline. In contrast, BDNF secretion was not suppressed by CPAP treatment.

Conclusions: Patients with untreated OSAS have normal serum and plasma BDNF levels. CPAP treatment is associated with a rapid decrease in serum and plasma BDNF levels which may reflect enhanced neuronal demand for BDNF in this condition.

This is one of those really cool situations in which a biomarker is normal in both the diseased people and the normal people, but becomes abnormal when the patients are treated.  This is not what one would expect, ordinarily.  The authors hypothesize that this may reflect an increased need for BDNF in the patients with OSA.  

In commentary on Medscape (Free registration), the authors state:

Dr. Marek Lammatzsch and colleagues at the University of Rostock note that BDNF has been shown to be essential for cognitive function and consolidation of memory. It has been speculated that the interplay between sleep and cognition may involve BDNF.

Despite successful CPAP treatment, they add, many sleep apnea patients continue to display persistent cognitive dysfunction. To investigate the effect of CPAP on BDNF, the researchers studied 17 men with sleep apnea and 12 healthy controls. [...]

The researchers hypothesize that "this phenomenon reflects increased neuronal demand for BDNF during treatment, since neurons can acquire peripheral BDNF to change neuronal activity and synaptic transmission."

Dr. Lammatzsch told Reuters Health that "deficits in memory and learning often persist even after sleep restoration in patients with sleep apnea. Our observations open the door to a completely new understanding of this condition and might thus lead to a specific therapy in the future."

I will state again, that often nonscientist-journalists conclude their articles with a statement like this: "...might thus lead to a specific therapy in the future..."  I assume they do that so that the reader gets the impression that the research might have some practical significance.  Personally, I deplore this practice, because the implication is that research has to have a practical application in order to be important.  This is a disservice to the public.  Sure, it would be great to find a way to restore cognitive function to normal in those patients with OSA who continue to have problems even after successful implementation of CPAP, but that is not why the study is important.  

The thing is, there are a zillion things we would need to figure out before having any hope of developing something clinically useful, and even then, it probably would take about 10-20 years to get it to market.  

First, we would have to figure out exactly why BDNF goes down when patients are treated, and find out whether it eventually goes back toward normal.  We would have to figure out exactly what regulates the level of BDNF.  We would have to find out if anything dreadful happens to people if their level of BDNF is increased artificially.  We would have to find a practical way to increase it, and see if it actually helps anyone.  

Interestingly, we already have at least a partial answer to one of these questions, uncovered by an undergraduate student at UCLA:

The Role of Serotonergic and Noradrenergic Systems in the Regulation of BDNF Expression. Autumn Ivy, (Amelia Russo-Neustodt), Department of Biology, California State University, Los Angeles
Depression, aggression, agitation, and apathy are among the most common and problematic systems in neurodegenerative diseases such as Alzheimer's disease (AD). Brain-derived neurotrophic factor (BDNF), which enhances the growth and maintenance of various neuronal mechanisms, is diminished in the brains of AD patients. Animal studies have suggested that BDNF mRNA levels are increased by physical activity in the rat hippocampus. The aim of this study is to determine whether the 5-HT and/or the NE systems are involved in the up-regulation of BDNF expression occurring with exercise. Rats were treated with either Propranolol (2 mg/kg), which blocks the NE receptors, or Ketanserin (5 mg/kg), which blocks serotonin 5HT-2 receptors. At the same time, rats underwent voluntary exercise via a running wheel. BDNF mRNA levels were quantified in the hippocampus by in situ hybridization and computer densitometry. The NE receptor-blockade agent Propranolol appeared to reduce the up-regulation of BDNF mRNA normally expressed, suggesting that the activation of the NE system may be important in BDNF up-regulation. On the other hand, the serotonergic system receptor-blockade agent Ketanserin did not attenuate BDNF expression, which suggests the possibility that the 5-HT system is not involved in the observed BDNF regulation. An understanding of the mechanism of BDNF up-regulation could lead to the development of faster acting and more effective therapeutic approaches to AD.

So it appears that BDNF, at least the BDNF mRNA, is increased by exercise, at least in rat hippocampus, and that norepinephrine (NE) may play a role.  We also know that plasma norepinephrine is increased in untreated OSA patients.  So perhaps the drop in BDNF after treatment of OSA reflects a normalization of plasma NE.  To my mind, these findings indicate that we are looking at a complex system that does not necessarily act the way one's intuition might suggest.  

There could be important clinical benefits to increasing BDNF, as indicated by this Wikipedia snippet:

Exposure to stress and the stress hormone corticosterone has been shown to decrease the expression of BDNF in rats, and leads to an eventual atrophy of the hippocampus if exposure is persistent. Similar atrophy has been shown to take place in humans suffering from long-term depression. On the other hand, voluntary exercise, caloric restriction, intellectual stimulation, and various treatments for depression (such as antidepressants and electroconvulsive therapy) strongly increase expression of BDNF in the brain, and have been shown to protect against this atrophy.

Various studies have shown possible links between low levels of BDNF and conditions such as depression, Obsessive-compulsive disorder, Alzheimer's disease, Huntington's disease, and dementia, though it is still not known whether these levels represent a cause or a symptom.

If it does improve cognition, then we have to deal with the thorny ethical issue of whether it should be given to non-diseased persons who want to improve their cognition.  

However, given the complexity of the system, if anyone is planning on artificially manipulating BDNF levels in actual humans, it sure would be nice to understand the entire system beforehand.  Obviously, if treating something life-threatening such as Alzheimer disease or Huntington disease, a little risk would be no big deal.  But for treatment of depression, or residual cognitive impairment in treated OSA patients, we would want to see a firm assurance of safety.  It is hard to get that kind of assurance until the entire system is understood.

Therefore, the reason the Staats et.al. study is important is that it brings us one step closer to understanding a complex system that may play a role in many disease states.  If any actual treatment is found, that would be icing on the cake.

Lest all this neurochemisty lead us to forget why sleep is so important:

Sleep
     
Sleep sleep sleep
deep magnificent sleep
cradles me like
a mother holding
her newborn
for the first time.
I close my eyes and feel
the warm sensation
of precious pure sleep
immortal sleep outside
of a mixed up world.
Sweet vanilla scent
from dreams of beauty
holding me forever,
brings me everything
I need to stay a
sleep sleep sleep.

-- Charles Lara