BDNF agonists: The Holy Grail of Psychiatry

There are many kinds of antidepressant medications, and they act through a variety of mechanisms. Because of the apparent mechanism by which the first discovered antidepressants acted, it was long thought that antidepressants worked primarily by increasing the activities of the neurotransmitters serotonin, norepinephrine and dopamine in the brain. The monoamine oxidase inhibitors, whose antidepressant effects were discovered quite by accident while being used to treat tuberculosis, were found to prevent the chemical destruction of those neurotransmitters in the brain thus enhancing their effects. The second class of antidepressants to be discovered were the so-called tricyclics. Also discovered by accident, the tricyclic antidepressants were found to block the ability of neurons to take back up the neurotransmitters they released thus magnifying their effects. After the discovery in 1972 of the antidepressant drug Prozac, which seemed to selectively enhance the effects of serotonin, the explanation for Major Depression came to be that the brain lacked sufficient levels of serotonin. Over the last 50 years, many things have been discovered that cast doubt upon that simple explanation.

Perhaps the strongest argument against that notion depression was due to “not enough serotonin” was the lack of evidence that the brains of those who suffered Major Depression actually had those suspected depleted levels of serotonin. Also, it came to be known that there were many types of serotonin receptors in the brain—fourteen at last count—that likely had different roles in Major Depression. Activation of some seemed to elevate mood, whereas activation of others depressed it. There also came the discoveries of a number of so-called “atypical” antidepressants that had less effect on serotonin than did the SSRIs. Wellbutrin appeared to primarily enhance the effects of dopamine and norepinephrine. Amisulpride, used in many countries around the world, appears to produce its antidepressant effect by blocking certain serotonin and dopamine receptors. The antidepressant drug tianeptine, used in Europe but banned in the United States, was found to enhance rather than inhibit the re-uptake of serotonin as did the SSRI antidepressants. Thus, in some respects, tianeptine appeared to do the opposite of the SSRI antidepressants. The drug ketamine, which can produce a rapid antidepressant effect, has no direct effects on serotonin or serotonin receptors. Parallel to those findings noted above were the discoveries that many changes take place in the brains of those who suffer Major Depression that do not directly involve serotonin.

Dr. Bruce McEwen and co-workers at the Rockefeller University made critical discoveries in how the brain adjusts to severe stress and the price it pays in trying to maintain function when this stress persists over time. When the brain maintains its ordinary biochemical and physiological activities, the balance it establishes is called homeostasis. However, when the brain is challenged due to stress, disease, injury, infections, or other conditions, the brain shifts how it acts and produces a new balance of give and take referred to as allostasis. Ordinarily, the state of allostasis is temporary and homeostasis is soon restored. However, this is not always the case. The brain’s cumulative burden of prolonged stress and the necessary maintenance of allostasis was referred to by McEwen as allostatic load. Among the adverse changes that occur as part of allostatic load are neuroinflammation with release of damaging signaling molecules; oxidative stress with damage to mitochondria; inhibition of neurogenesis, the process by which the brain replenishes neurons;  shortening and loss of dendritic branches by which neurons signal and communicate with each other; desensitization of some neurotransmitter receptors but enhancement of others; disruption of  how glucose is transported, utilized, and regulated in the brain; and other changes that impair brain function and manifest as Major Depression. 

An important adverse effect of prolonged stress and allostasis is decreases in the activity of a protein in the brain called Brain-derived Neurotrophic Factor, or BDNF.  Among the roles BDNF plays in the brain are maintaining the dendritic branches of neurons; stimulating neurogenesis;  upregulating subtypes of neurotransmitter receptors that enhance mood and dampening activity of some that depress mood; dampening neuroinflammation; enhancing neuronal response to insulin and the metabolism of glucose; and stimulating the creation of new mitochondria in neurons, thus improving neuronal function. By improving neuronal functions such as connectivity, dendritic tree maintenance, and long-term potentiation that mediate learning, normal levels of BDNF also enhance cognitive flexibility and enables the brain to form new adaptive behavioral and emotional responses.

Although the many antidepressant medications act by a variety of mechanisms, some even seemingly in opposite fashion, a common effect of all antidepressants—including MAO Inhibitors, tricyclics, SSRIs, Wellbutrin, tianeptine, amisulpride, mianserin, trazodone, Auvelity, zuranolone, mirtazapine, ketamine and psilocybin—is enhancement of BDNF activity. Indeed, even the non-pharmacological treatments of Major Depression, Electroconvulsive Therapy and the newer Transcranial Magnetic Stimulation, robustly enhance BDNF activity in the brain.

BDNF manifests its actions in the brain by acting at its own special receptor, the tropomyosin receptor kinase B, or trkB receptor. While no currently prescribed antidepressant directly stimulates the trkB receptor, thus  mimicking the effect of BDNF, many do act on the trkB receptor to enhance the effect of BDNF on that receptor. In technical terms, they act as positive allosteric modulators of BDNF. That is likely part of their antidepressant effect. However, direct stimulation of the trkB receptor would likely have great potential as an antidepressant treatment. Indeed, animal studies have shown that administering BDNF directly into the brain has potent and rapid antidepressant-like effects.

BDNF is a protein, and administering BDNF by oral, intravenous, subcutaneous or intramuscular routes, is ineffective as the half-life of BDNF in the blood is very short, and it does not pass the so-called Blood Brain Barrier to reach brain tissue. The only route of administration of BDNF that may hold promise is by nasal spray. However, intranasal BDNF is extraordinarily expensive and currently prohibitive for practical clinical or personal use. Thus, a Holy Grail of psychiatry is discovering an orally administered small molecule that passes into the brain, stimulates the trkB receptor, and thus mimics the effects of BDNF. Promising candidates have been found.

7,8-Dihydroxyflavone (7,8-DHF) is a naturally occurring substance found in several plant species. Among these are Lepisorus ussuriensis, Godmania aesculifolia, Tridax procumbens, and Primula helleri. All of those  plants have been used in various herbal medicine traditions, albeit not specifically for treatment of mental illnesses. The discovery of 7,8-DHF as a selective, small-molecule agonist of the trkB receptor was first reported in 2010 by Dr. Sung-Wuk Jang and Dr. Keqiang Ye at Emory University School of Medicine. It was also found that 7,8-DHF had potent antidepressant-like activity in lab animals. Although 7,8-DHF has antidepressant-like effects in animals, it was not well suited for human use due to its very short half-life in the body. Derivatives of 7,8-DHF were then synthesized and evaluated for penetration into the brain and antidepressant-like effects in animals. Two such substances, 4,Dimethylamino,7,8-dihydroxy flavone and the mouthful name of  4-Oxo-2-phenyl-4H-chromene-7,8-diyl bismethylcarbamate, now thankfully referred to as R13, penetrate the brain, act as longer acting agonists at the trkB receptor, and produce antidepressant-like effects in animals. R13 displayed better bioavailability and tolerance of liver metabolism than did 4,Dimethylamino,7,8-dihydroxy flavone, and further studies were pursued.

Drs. Jang and Ye returned to China where they have continued their research. Most recently, they have successfully used R13 in Phase I trials in human beings as a treatment for Alzheimer’s Disease. Trials for Major Depression and other psychiatric and neurological diseases are not far behind. Thus, it appears that a Holy Grail of psychiatry, a small molecule agonist of the trkB receptor that can be given in a pill, is on the horizon. It will likely revolutionize treatment in psychiatry and neurology.