Super Expectations from the Ashes of the Best Damn Medicine Ever (Part 1)
Anxiety and depression prey on the weak and strong alike, and they roam freely in nearly every place where humans dwell. These mental illnesses often hunt together – destroying the hope of a normal existence for millions of people and taking one million lives every year. As we and other neuroscientists lie awake at night, thinking about how to thwart these formidable foes, the solution could be right under our noses. At Akhu Therapeutics, we want to make anxiolytics and antidepressant drugs obsolete. To accomplish that goal, we are embracing 40-year-old data, which provide a blueprint of the best damn medicine for anxiety and depression ever.
Designing Medicine for Brain Disorders
Anxiety and depression afflict 675 million people worldwide with emotional and physical disabilities and susceptibility to other serious illnesses. These mental illnesses are also leading causes of death, particularly by suicide. They are difficult to treat because they are complex. The symptoms of anxiety are so numerous and varied that they are divided into several disorders, such as generalized anxiety disorder, panic disorder, posttraumatic stress disorder (PTSD), etc. Depression is likewise divided into major depression, dysthymic disorder, seasonal affective disorder, etc. To complicate things further, anxiety and depression often strike together.
It stands to reason that if you want to solve problems in a complex system, you should understand how that system works before devising solutions that might create additional problems. That’s where we find the main shortcoming of previous attempts to design medicine for anxiety and depression. In the past, too many scientists and physicians have plunged into making and prescribing drugs with too little information about how the brain works when it is ill (or healthy).
Our philosophy is as simple as ABC – Allow Biology to lead Chemistry. Why? Because chemistry is blind to the workings of the brain (and body). Chemical compounds can be extracted from many different plants, animals, fungi, bacteria, etc. with the intent of combating an ailment. Likewise, drugs can be synthesized in the lab, based on plant or other chemicals. The important question that should be posed before they are prescribed widespread for chronic illnesses is, what are the long-term effects likely to be? In the cases of anxiolytics and antidepressants, for decades the answer has been, we have no clue. We now know, however, that the answer is, in some cases, serious damage to brain function. On the other hand, biology (in this case, neurobiology) informs us how to align chemistry with brain function.
Our philosophy is as simple as ABC – Allow Biology to lead Chemistry.
The practice for decades, centuries, even millennia has been to try different chemicals for various ailments, and then sort out the side effects later. Only the advent of randomized controlled trials (clinical trials) has put that approach to rest. Or has it? You might be surprised to find that as late as the second half of the 20th century, amphetamine was widely prescribed for depression. That practice was unfortunate in that it allowed chemistry to lead biology.
The ideal sequence of events for making drugs for mental illnesses is to allow biology to lead chemistry. That can be done in two ways. First, understand the neurobiology (and its long-term responses to drugs). Second, design drugs to work with the neurobiology. Understanding neurobiology is crucial for designing and prescribing psychoactive drugs.
We already know the dire consequences of violating this sequence. For those who seek treatment for anxiety, physicians often prescribe anxiolytic (anxiety breaking) drugs like Valium. The problem with anxiolytics is that they cause addiction and impair normal thinking and memory, if taken long term, and many people need long-term treatment. Why then, are they still being prescribed and used long-term? Because the die was cast before we knew how bad these drugs could be for the brain. And now, society is more or less “addicted” to this practice.
For those who seek relief from depression, antidepressants like Prozac provide some relief. The problem with antidepressants is that the placebo effect (in which sugar pills reduce symptoms of depression) is pretty strong, and it causes antidepressants to fail many clinical trials. A strong placebo effect delays or prevents antidepressants from reaching the market. So, why not just up the dose? When drug makers try that, they find that the side effects come on too strong.
So, an important problem to be solved for anxiety and depression treatment, is trying to produce medicine that is much more effective than placebo, safe to take long term or works over a long period of time, and does not damage peoples’ brains or bodies while making them feel a bit better. Welcome to Utopia. This state of bliss will never be achieved with anxiolytics and antidepressants. The reason is that they target the wrong systems in the brain (and body). Anxiolytics activate a component of the GABA (gamma-aminobutyric acid) system. Why is that wrong?
Any undergraduate neuroscience major (or minor) who paid attention in class can inform you that GABA is the major inhibitory neurotransmitter in the adult mammalian brain. Translation out of nerdy science-speak – GABA tells just about every major brain system to calm down. That’s why multiple GABA activators are capable of calming you, reducing your sensation of pain, putting you gently to sleep, and at high doses rendering you unconscious and even killing you. Think alcohol, Valium, anesthetics, etc. This class of drugs is generally addictive and messes with your ability to remember and think straight. This should not be the first choice of drugs that are needed long-term.
What about antidepressants? Surely, smart, sane teams of scientists would not design these important drugs with similar pitfalls as anxiolytics. No, not exactly. Antidepressants can’t get you high like some anxiolytics, but they flood the entire brain with neurotransmitters called monoamines, primarily serotonin, followed by norepinephrine, and followed by dopamine. Who cares about that, if they work? Well, for millions of people, they don’t work. For the people who derive modest benefits from them, there are inherent problems that will never go away. The term, serotonin, let’s you know up front there will be a price to pay. “Sero” means blood-related, and “tonin” means an agent that increases tone. Is anyone surprised that selective serotonin reuptake inhibitors (SSRIs), the most widely used class of antidepressant, can promote hypertension?
Something’s Gotta Give.
If experimental drugs for anxiety or depression aren’t so good, then why do drug makers keep making new ones? That’s just it. They won’t for much longer. Major regulatory agencies, the United States Food & Drug Administration (FDA) and European Medicines Agency (EMA), have given warnings that they will no longer approve antidepressants with incremental improvements in effectiveness. What comes along now has to be significantly better than what’s already on the market. Insurance providers have issued similar warnings. Because antidepressants (and anxiolytics) target the wrong systems in the brain, drug makers find it increasingly difficult to get updated versions of old drugs approved. Accordingly, big pharmaceutical companies have been divesting in the R&D of antidepressants for the past half of a decade.
What hope is there for better drug treatments? If this task can only be entrusted to the conglomerates, and they are throwing in the towel, then we might as well … Hey! Wait a minute! Just because makers of anxiolytics and antidepressants haven’t gotten it right, doesn’t mean it can’t be gotten right. Why should we trust the folks at our local neighborhood drug-making conglomerate to tell us what can and cannot be done? Hmmm? We’ll wait for you to arrive the correct answer, which is, “We shouldn’t”! After all, they haven’t gotten anxiolytics and antidepressants right since … well … forever!!! Isn’t it time to stop barking up the wrong tree? The correct answer is, “Yeah!!!”.At this point, you might be thinking that the phrase, “barking up the wrong tree”, implies that better treatment is possible. As it turns out, not only is it possible, better treatment for depression had long been discovered before we got involved in this area of research.
Of course, such a bold statement should spark questions like, “Is this better treatment something I can only find by watching infomercials on broadcast TV late at night?” and “Why haven’t I heard about this better treatment before?” The answers to these two questions are simple. First, you shouldn’t watch infomercials because they’re bad for your brain. Watch lots of cat videos on YouTube instead. Second, you haven’t heard about the better treatment for depression because, at the time it came along (1970s – 1990s), your friendly neighborhood pharmaceutical juggernaut didn’t think it was possible to make a gigantic pile of cash on it. We’re not talking millions of dollars. We’re talking billions of dollars over 10 to 15 years.
… better treatment for depression has already been discovered.
We should unpack the last statement because different antidepressants have certainly earned over a billion dollars in annual sales for one or more years. If something better has already come along, what stopped your friendly neighborhood pharmaceutical mega-corporation from making 1, 5, or 10 billion dollars a year? Was it only a bit more effective? Did it have worse side effects? Did it work more slowly? Did it cost a lot more to make? No, no, no, and no. It worked a lot better, had fewer side effects, worked faster (the only drug that works more slowly than the antidepressant is the cigarette, which is a near-perfect means of inducing lung cancer over a 20-year period), and it likely would have cost less to make. This is really sounding like an infomercial now, right? That’s until you realize that making medicine is more about making money than about making people healthy – at least for some conglomerates.
What’s Up Next?
In Part 2 of this series, we detail the mysterious medicine that beat antidepressants (by a lot). In the meantime, we’ll give you a homework assignment. Take just one minute to Google “MIF1 depression”. You’ll uncover a treasure trove of papers on the first best damn medicine for depression. MIF1 and its sibling molecules are like the grandmother and great aunts of the medicine we are developing at Akhu. Those first-generation compounds clearly outperformed antidepressants in clinical tests. We’ll also describe a second-generation derivative of MIF1 – a daughter compound. It performed like MIF1 in several categories, and outperformed MIF1 in a crucial category.
In Part 3 of this series, we’ll describe one of our prototype medicines, which is essentially a granddaughter of MIF1. In animal studies, it has already outperformed antidepressants in effectiveness and speed. It also outperforms MIF1 in speed. Of course, we will provide an explanation for why the early generation compounds never hit the market (and never will), and what makes our products superior. In the meantime, we’ll leave you with a teaser. In the business of making medicine, if it cannot be commoditized, it’s unlikely to get produced. In other words, if it doesn’t make dollars, then it doesn’t make sense.
Caurnel Morgan, PhD