In Part 1, we asserted that most anxious and depressed people cannot be helped significantly by anxiolytics and antidepressants. In Part 2, we described the work of scientists who used early-generation melanocortin blockers decades ago to outperform antidepressants. Here we’ll talk about our next-generation melanocortin blockers, which outperform antidepressants in proven animal models of depression and anxiety.
Rise of The Super Mouse
The Morgan Lab began investigating the role of the melanocortin system in mouse models of depression and anxiety at Cornell University Medical College in 2001. We used assays for anxiety- and depression-related behaviors, which is an established way to predict how well anti-anxiety drugs (e.g., Valium) and antidepressants (e.g., Prozac) work in humans. We continued this work at Texas A&M University until 2015, and John joined our research team in 2007. Specifically, we studied the role of a particular component of the melanocortin system – the melanocortin-5 receptor (MC5R).
Importantly, we didn’t just investigate how MC5R controls emotional states in ordinary mice. We had a secret weapon – a strain of mice that completely lack the MC5R gene. MC5R-deficient mice behaved in specific tests like they were on a high dose of an ideal antidepressant combined with a high dose an ideal anti-anxiety drug. For example, stressful conditions that caused ordinary mice to “give up”, lose interest in food treats, avoid areas that provoke anxiety, etc., hardly phased MC5R-deficient mice. Moreover, the so-called MC5R knockout mice lived to a ripe old age (for mice) and continued to perform like young knockouts in tests for anxiety- and depression-related behaviors. In contrast, the performance of ordinary mice deteriorated progressively with age, kind of the way it does in people who are susceptible to depression and anxiety.
On top of that, our “super mice” performed normally in control tests. The results of control tests provide crucial information because, if the absence of the MC5R gene causes an effect like amphetamine does, the mice would only seem to not “give up”. In that case, they would show unusually high activity levels in the control tests. We know that amphetamine is not good for depression because it was prescribed a lot for depressed (and overweight) housewives from the 1930s at least until the 1950s.
Now, for something that’s even more interesting, for science geeks at least (non-science-geeks can skip this paragraph). There’s a bunch of reasons why removing a gene from the mouse genome (knocking it out) can be exciting in the lab, but have few implications for the treatment of disease. One important reason is that mice, like humans, are highly adaptable. Scientists can knock out a gene, find that it appears to play a role in a disease model, and find out after close examination that they’ve been looking at a secondary effect (genetic adaptation) that will not translate into a cure. Alas, no eureka moment. One important way to determine whether the product of a knocked out gene makes a good therapeutic target is to use an alternative method to block that product (hint: design a drug to act on the same gene product).
The Third-Generation Depression (and Anxiety) Super Drug
Now, we finally get to talk about our MC5R blockers. We used several proven animal models of anxiety and depression to test these prototype medicines. We predicted, from their pharmacologic pedigree (i.e., similarities to early-generation melanocortin blockers), that MC5R blockers would beat antidepressants. We also predicted, after one and one-half decades of studying MC5R knockout mice, that MC5R blockers would not be inherently toxic to the brain or body.
How did MC5R blockers measure up? They decreased depression-related behaviors, of course. If you’re tired of relying on current treatments for depression or you know somebody who is (that covers just about everybody on the planet), you should be wondering, “Just how good are those results?” Our work showed that MC5R blockers are 3X more effectivethan antidepressants! That feat makes them like early-generation melanocortin blockers, which is exceptional. They’re also 1000X faster than antidepressants! You read that correctly. While antidepressants take 1000 hours (that’s six weeks) to improve behaviors in specific tests, MC5R blockers work in just ONE HOUR!!! That means they’re even faster (up to 100X faster) that early-generation melanocortin blockers, which is outstanding. Interestingly, we get such a robust effect at one hour that we think MC5R blockers likely work in as little as 30 minutes, and perhaps in just 20 minutes! There’s another way they surpassed early-generation melanocortin blockers. Our MC5R blockers also suppressed anxiety-related behavior with great effectiveness and speed. Some of this work was presented in a mini-symposium at the Society for Neuroscience meeting in 2015.
If the information above isn’t enough to get you to accept how well MC5R blockers work, pay attention to the actions of two major research institutions. Texas A&M University (TAMU) and the University of Arizona (UA) have filed a total of nine patent applications for the use of MC5R blockers to treat anxiety and depression. Dr. Morgan (while at TAMU) and Drs. Victor Hruby and Minying Cai (at UA) are the co-inventors. The evidence that MC5R blockers are potentially excellent treatments for anxiety and depression came from the Morgan Lab. The drugs under development were designed in the Hruby lab. And now, Akhu Therapeutics has acquired an exclusive, worldwide license from TAMU and UA to develop this patent-pending technology.
Texas A&M University and the University of Arizona have filed nine patent applications for the use of MC5R blockers in the treatment of anxiety and depression. Dr. Morgan is a co-inventor
Of course, all of the above information is about mice. You might be thinking, just because a drug works in mice, doesn’t mean it will work in humans. That’s true for many drugs, but there are plenty of animal models and behavioral tests that distinguish anti-anxiety or antidepressant drugs from other classes of drugs. Once these drugs have been screened in animals, they actually tend to work in people. They just don’t work well. Anti-anxiety drugs reduce symptoms only by about 48%, and antidepressants reduce symptoms of depression by even less – about 30%. The main problem, in our opinion, is that these drugs operate at the threshold of toxicity. That means that increasing the dose to reduce symptoms more effectively results in greater side effects.
Anti-anxiety and antidepressant drugs operate at the threshold of toxicity. Increasing the dose to reduce symptoms results in greater side effects.
Overall, there is compelling evidence that the melanocortin system is a much better target for treating anxiety and depression than the targets of anxiolytics and antidepressants. Moreover, we have generated compelling evidence that MC5R, in particular, is potentially the best target of all. This could mean a much better future for the treatment of anxiety and depression. Such a fundamentally different approach opens up exciting possibilities. Nonetheless, we have hard work ahead of us. Some of it stems from resistance to the idea that some newfangled invention could actually succeed where anxiolytics and antidepressants failed for decades.
No matter what the outcome, we are pleased and thankful to have an opportunity to develop ground-breaking research, based on our patent-pending technology, into a genuine medical breakthrough. Wish us good luck, and please share the posts in this series.