Of Magic Bullets and the Connectome

An 1822 illustration of Der Freischütz depicting the opening scene with Max and Kilian

I wrapped Sebastian Seung's Connectome yesterday, It's a wonderfully comprehensive, yet easy to grasp tour-de-force dissertation on neuroscience, biology, and more.

His chapter on psychopharmacology, Changing, has several interesting tidbits which I will reprise here.

 I found out the oft-used drug term "magic bullet" comes from a 1940 Warner Bros. film, Dr. Ehrlich's Magic Bullet, the title perhaps in turn inspired by a plot device in Carl Maria Von Weber's opera Der Freishutz. In this opera Max sells his soul to the devil for seven magic bullets which are guaranteed to hit their mark. Dr. Paul Erlich first imagined, and then discovered chemicals that killed bacteria, but spared other cells, like a magic bullet that flew unerringly to its target. This has been the ideal for medical treatments ever since --  the "magic bullet" that hits its target and avoids "side effects."

Historically, most psychoactive drugs have been discovered by chance, as "side effects" themselves. The first antipsychotic, chlorpromazine (Thorazine), started out as a chemical die for the textile industry. In 1891 Dr. Erlich discovered that some of the chemicals in the same phenothiazine class could be used to treat malaria. After giving the drug to psychiatric patients as a sedative, doctors came to realize that it specifically reduced symptoms of psychosis. By the end of the fifties chlorpromazine had swept through the psychiatric hospitals of the world.

1940 Theatrical Poster

Then iproniazid, originally developed for tuberculosis, was found to have an antidepressant side effect. Imipramine was developed as a "me-too" drug in the footsteps of Thorazine. It failed as an antipsychotic, but seemed to relieve depression. Thus began the use of the tri-cyclic antidepressants.

After these accidental discoveries, attempts were made to develop an actual "rational" drug discovery, based on a modern understanding of biology and neuroscience.

According to well-known theories dating from the sixties, certain disorders are caused by surplus or deficiencies of neurotransmitters levels. So came the development of fluxotine (Prozac) and the other "me-too" SSRIs, said to be the only real psychopharmacolical advances since the "Golden Age" of the fifties.

But there is a problem with the neurotransmitter theory. Fluxotine affects serotonin levels immediately, yet it lifts mood only after several weeks. What could account for this long delay?

According to one speculation, the serotonin boost causes other changes in the brain over the longer term. Perhaps it's these changes that relieve depression, but what exactly could they be? Neuroscientists have looked for effects of fluxotine of the four "Rs" (reconnection, rewiring, regeneration, and reweighting), and found that it increases the creation of new synapses, branches, and neurons in the hippocampus. Moreover as Mr. Seung mentioned in his discussion of rewiring, fluxotine restores ocular dominance plasticity in adults, possibly by stimulating cortical rewiring. This doesn't prove that the drug's antidepressant effects are caused by connectome change, but it has opened the minds of neuroscientists to the idea.

It's time to practice the four Rs -- reconnect, rewire, reweight, and regenerate.