24 April 2008

Chemical youth

Fake delight
Sergey Stepanov, SmartMoney No. 14-2008

If the fire in your pet's eyes has gone out, she is constantly in a depressed mood and, when you are not at home, chews things, howls loudly and scratches furniture with her paws, this does not mean that she is a bad dog. This is how the separation syndrome manifests itself — a special clinical condition of the dog's brain, suggests the pharmaceutical company Eli Lilly. To bring back the joy of communication, she has a reliable remedy — chewable tablets reconsil with beef flavor.

Tested on humans: the active principle of reconsil is fluoxetine, the basis of the world's most popular antidepressant prozac. The same fluoxetine became the main hero of the scientific news of the week. Scientists from the Pisa Institute of Neurobiology and the Center of Neurology at the University of Helsinki have shown that fluoxetine not only lifts the mood of experimental rats, but also returns their brain cells to a younger, more trainable state*. This news can greatly spoil the mood of those who believe that a healthy person should be independent of medications. "Despite the fact that we have studied the effect of antidepressants on rats," says one of the authors of the work, Professor Ero Kastren of the University of Helsinki, "our results can be transferred to humans."

Chemical youthThe main cause of depression is an incorrect signal transmission between nerve cells in the brain.

The signal either ceases to be transmitted, or is not transmitted to the extent that is normally necessary. Back in the 1950s, scientists found out that insufficient production of three substances by nerve cells was to blame: norepinephrine, serotonin and dopamine. Biologists have been struggling over how to compensate for this shortcoming for decades.

Just injecting these substances to a person is like hitting the keys of a piano with a log, trying to play a melody. It is necessary not just to increase the level of these substances in the brain tissue (which is why nerve cells can forget how to produce them on their own), but to increase their release only where necessary. Then scientists proposed a different approach, which eventually led to the emergence of the "prozac generation".

In a normal brain, norepinephrine, dopamine and serotonin are reabsorbed by nerve cells after the transmission of information — until the next signal transmission. If you slow down this process, the signal will be amplified exactly at the time and place of its transmission. Modern antidepressants are based on this principle. Their first generations increased the concentration of all three substances in the brain at once, but then scientists came to the conclusion that it was enough to focus only on serotonin.

So in the clinic there were drugs that are called selective serotonin reuptake inhibitors. Their consumption grew rapidly: from 3 million doses prescribed worldwide in 1995, it increased to 10 million doses in 2004. In 2001, before Eli Lilly's patent for prozac expired, sales of the drug set a record of $2.4 billion. Pfizer in 2005, before its patent expired for zoloft, a drug that operates on the same principle, sold it for $3.3 billion.

Studies by Castren and his colleagues give serotonin reuptake inhibitors a second youth, due to the fact that these substances restore youth to brain cells. Experimenting with fluoxetine, Castren and his colleagues deprived rats of normal development: they closed one eye. The animals developed amblyopia — a visual impairment, which is colloquially called a lazy eye. The cerebral cortex serving the closed eye did not work. Having missed the critical period of early rat childhood, this cortex never developed, even if the eye was opened.

However, after fluoxetine was administered to the adult rats that had gone stale for a week, their "unnecessary" neurons became activated and started working — vision was restored. "The cells of the cerebral cortex seemed to have become younger and returned back to childhood," explains the scientist. He believes that the results can be directly transferred from rats to humans, that is, fluoxetine can be used in the treatment of amblyopia.

But the main conclusion, according to scientists, is much broader: if fluoxetine helps restore the lost functions of neurons in a rat, then in humans it can also restore the plasticity of the brain lost in adulthood.

A similar conclusion was reached by Professor Klaus Norman from the University of Freiburg Clinic, who last year demonstrated that antidepressants increase the activity of the visual cortex in humans **. And two years ago, a graduate of the MSU biofactory, Grigory Enikolopov from the Cold Spring Harbor laboratory, discovered that fluoxetine not only stops depression, but also stimulates the growth of new neurons in the part of the brain that is responsible for the transition of short-term memory into long-term memory.

The Economics of DepressionIt is not difficult to imagine what the development of these studies will lead to.

Already today, prozac, zoloft, paxil and other antidepressants are the most commonly prescribed prescription drugs in the world. The World Health Organization scares with depressing forecasts: by 2020, depression will become the second most important cause of disability in the world after cardiovascular diseases. No matter how widely the concept of depression is interpreted, it is clear how promising the market is for its treatment.

Analyzing hundreds of clinical trials conducted on tens of thousands of people, scientists argue whether antidepressants have long-term side effects. Most of the discussion revolves around the question of whether they increase the number of suicides — an extreme manifestation of human despair. The article analyzes the tendency to publish positive and conceal negative results (which are unprofitable for pharmaceutical companies to announce), and testing techniques, and many other subtleties. The spread of values is obtained from reducing the number of suicides by 2 times to increasing it by the same number of times.

Chicago social scientist professor Jens Ludwig, together with colleagues from the University of Maryland and psychiatrist Karen Norberg from Boston University, tracked the dynamics of suicides over 25 years in 26 countries, some of which were covered by a wave of antidepressants, and some were bypassed. An increase in the intake of antidepressants by 12%, the researchers conclude, causes a decrease in the number of suicides by 5%. One life saved, if you calculate the cost of treatment, costs society by American standards $20,000 — cheaper than with other methods of mass prevention ***.

The ambiguity of the safety assessments of antidepressants is explained, in the opinion of Andrei Anokhin, professor of the Faculty of Psychology at the University of Washington, by the fact that we still have a bad idea of how the brain works. "It is impossible to say exactly how this or that drug changes brain functions in all people," he says. Even now, the professor says, there are drugs that greatly improve the learning ability and memory of laboratory animals: "It is quite possible that after some time they can already be prescribed to a person."

If such drugs are devoid of obvious side effects, they will inevitably enter the daily diet of those who are willing to do a lot to increase their competitiveness in the labor market. They will be followed by those who do not want to remain second-class people. Not the most terrible scenario of the future development of mankind, but there is something depressing in it.

* Vetencourt  J. et al. The antidepressant fluoxetine restores plasticity in the adult visual cortex. Science. 18 Apr. 2008.
Vol. 320. P. 385-388.
** Normann  C. et al. Long-term plasticity of visually evoked potentials in humans is altered in major depression. Biol. Psychiatry. 2007. Vol. 373. P. 373-380.
*** Ludwig  J., Marcotte  D., Norberg  K. Anti-depressants and suicide. NBER WP No. 12906. Feb. 2007.

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