Why Are We Still Developing Brain Drugs?

The social stigma surrounding the pharmaceutical industry has gotten pretty bad lately. The business of saving lives is now rated positively by only 32% of the public, tucked neatly between oil and banking in consumer confidence polls – down eight places since 1996. Without dwelling too much into the reasons for pharma’s tumbling social status, one can sense an undeniable skepticism surrounding the intentions of the industry, and, most frighteningly, the effectiveness of its drugs.

It would be bitterly unfair to agree with the hardline pharma critics in that drugs simply do not work. After all, antibiotics, HIV retrovirals, chemotherapy and heart disease drugs continue to attest to just the opposite. Survival prognosis for infection, atherosclerosis or even cancer is so great today, that 95% more people reach the age of 80 than they did a century ago.

But with longer-living populations come older-age diseases, and the therapeutic landscape begins to dramatically shift towards diseases like dementia, Alzheimer’s and Parkinson’s, and diseases which have remained poorly treated, such as schizophrenia, bipolar disorder and depression.

Brain Drugs: 50 years later, we still can’t tell you how they work

Note that the common denominator of all “modern” disorders is that they are all diseases of the brain. These ailments bear an economic burden of more than $2 trillion in the US and EU and rake in upwards of $80 billion a year for the pharmaceutical industry.

But nearly all brain medications have come about serendipitously — through observation that certain chemicals improved certain symptoms, rather than through research tailored to the disease. An overwhelming majority of today’s Thorazines, Valiums, Prozacs and Xanaxes are still characterized by widely unknown mechanisms of action 60 years after their market debuts. Even more frighteningly, in recent clinical trial re-runs involving Prozac and Xanax the drugs fared hardly better than placebo.

Is Big Pharma shying away from CNS drugs?

Because the brain remains so poorly understood, Big Pharma are having a bad time developing pharmaceuticals which act upon the central nervous system (CNS). After a number of very loud and painful CNS clinical trial failures in recent years, GSK, AstraZeneca and Novartis have announced total closures of neuroscience divisions globally. Meanwhile Pfizer, Sanofi, Janssen and Merck have begun to significantly downsize CNS operations.

Few remain in the race. And who can blame them, when CNS drug development can cost billions more than any other therapeutic area, yet has a 45% higher chance of failure than drugs targeting other disorders?

Electricity and chemistry rule the brain in equal measure

The complexity of the brain is unrivaled. The intricate network of neuronal connections (the “connectome”), the densely populated molecular environment, and the electric behavior of brain cells, all in addition to the vast individual genomics and metabolomics of any given brain are difficult to ponder even in a single sentence. Unlike the peripheral nervous system, where molecules govern tissues, the central nervous system is just as much ruled by the binary patterns of electrical stimulation as by the neurotransmitter molecules which carry brain messages throughout the body.

And this is the crucial point: chemicals and electricity share a 50:50 responsibility in the brain. A chemical release between two neurons will cause the downstream neuron to “electrically detonate”, sending the message forward, yet electric stimulation of the upstream neuron will succeed to do just the same, albeit without collateral damage to much of the neuronal neighborhood (chemicals spread multridirectionally, whilst electricity does not).

The future is electric

Scientists have known of the effectiveness of neuro-electric brain therapy for decades, and many such systems are already in use today. Deep Transcranial Magnetic Stimulation (Deep TMS), for instance, is a novel, non-invasive, FDA-approved therapy to-date found effective for the treatment of Parkinson’s disease, depression, chronic pain and schizophrenia.

Deep TMS involves magneto-electric activation of regions deep (up to 7cm) within the brain. The stimulation can be applied at virtually any 3D brain coordinates. Thus the more we map the brain, the more useful the treatment becomes.

Pill lovers needn’t get disheartened by the prospect of an electric future, either. Meticulous brain mapping and advances in drug delivery systems could potentially culminate in the birth of a highly lucrative pharmaceutical — the electroceutical — or, rather more bluntly, electricity in a pill.

Electroceuticals may eventually take the form of electro-charged nano-robots we ingest in a pill, which would, with military precision, deliver electric current to any desired brain coordinates. In the era of electroceuticals, chemical “cross-contamination” of tissues and brain areas, along with unwanted side effects and liver toxicity would become a figment of the past.

How close are we to the electric future?

An often surprising fact is that electric therapy is already very widely used in the hospital, even in what would be considered traditional surgical settings. According to Itzhak Fried — Israel’s leading brain surgeon famed for his 22-hour separation surgery on Siamese twins literally sharing a brain — many procedures performed at his department already require an electric element.

In a breakthrough surgery two years ago, Fried’s team implanted tiny electrodes into the brain of an epilepsy patient. The electrodes, much like a tape recorder, listened to and recorded the activity of neurons in an area suspected of generating seizures. The “playback” of the recorded cell activity then gave clues as to the exact location of where the seizures originated. This turned out to be a tiny brain area next to the speech center of the brain which then was safely and successfully excised. Just a millimeter in the wrong direction could have rendered the patient forever unable to speak. All hail electricity.

Obama thinks the future is electric, too

And here is why all the electricity talk is not just cuckoo clairvoyance. Firstly, there is an unmissable brain project frenzy scurrying across the world. Projects like the “Brain Research through Advancing Innovative Neurotechnologies” (BRAIN), initiated by President Obama in the U.S., The Human Brain Project in Europe and Israel Brain Technologies are all aimed at electrically mapping the brain. Some lab projects have gone so far as to make mouse skulls completely transparent or to implant fiber optics into rat brains.

An equally telling development is the injection (or diversion from previous CNS research and development) of funds into electroceutical research done by Big Pharma themselves. In August 2013, GSK unveiled a $50 million bioelectrics venture fund aimed at sponsoring projects “that begin detailing how nerves in the body are related to particular diseases, understand the firing patterns of those nerves, and explore new technologies that will enable us to interface with multiple individual nerve fibres”. As CNS departments are ubiquitously shutting down, other players are left with no choice but to shortly follow suit.

It certainly seems that there is one thing neurosurgeons, neuroscientists and Big Pharma all finally agree on: neuro-chemistry is just so 2004.

Image via Palau / Shutterstock.

Julia Skripka-Serry, BSc, MSc

Julia Skripka-Serry, BSc, MSc, works as a life science analyst at Israel's largest local life science consultancy - Bioassociate. Her most recent work was titled Israel's Reign in the Golden Age of Neuroscience . She holds a BSc in Biotech and MSc in Computational Drug Discovery from the University of Edinburgh.
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