Suicide Biomarkers and Ketamine Rescue 

Our fate may not be written in the stars, but our risk of suicidal depression could be written in microRNA (miRNA) that affects neurotransmitters including serotonin and dopamine.

“When we compared post mortem brain tissue of suicides to that of people who were depressed but not suicidal, we found specific miRNAs in those who had killed themselves that were not present in other samples,” Yogesh Dwivedi, PhD, said. A mood disorders researcher in the UAB Department of Psychiatry, Dwivedi is Elesabeth Ridgely Shook Endowed Professor and Director of Translational Research. He is working with a five-year, $3.5 million grant from the National Institute of Mental Health to identify biomarkers that predict the likelihood of developing suicidal depression.

“We have developed blood tests to detect the presence in living patients of 12 specific miRNAs that have a high correlation with psychiatric disorders. Much as certain miRNAs have been linked to some types of cancer, we are finding miRNAs that seem to be associated with mental health conditions including bipolar disorder, schizophrenia and suicidal depression,” Dwivedi said. “These molecules are very small and quite unique. They bond to specific regions so desired proteins are not produced in sufficient quantities. They can also bond to multiple locations at the same time, giving them the capacity to disregulate gene transcription and alter genetic machinery.”

Although there are associations that suggest some inherited genetic mutations may be linked to depression, the problems with miRNA seem to arise out of epigenetic changes, particularly in patients who suffered maltreatment in childhood.

 Stress is a part of life that everyone faces, and periods of high or prolonged stress are virtually inevitable. The question of why some people have a hardiness that allows them to cope and survive in even the most extreme conditions while others take their own lives may be answered as the effects of miRNA are better understood.

“Not everyone who is depressed commits suicide, and not every suicide is depressed. One of our ultimate goals is early intervention by identifying and treating patients who are at risk before their condition becomes severe. Being able to identify and follow the levels of miRNA should also help us design and test the effectiveness of potential new drugs,” Dwivedi said.

One not-so-new drug that is showing remarkable results in rapidly reversing suicidal states is ketamine, an anesthetic developed in the 1970s. Dwivedi’s fellow researcher Richard Shelton, MD, who is the Charles B. Ireland Professor and Vice Chair for Research in the UAB School of Medicine Department of Psychiatry, is testing the use of low-dose ketamine infusions in suicidal depression and medication-resistant depression.

 “Many antidepressants can take a month to become effective. When patients are in a suicidal state, a month is too long to wait. A ketamine infusion can begin to reverse suicidal thinking in less than an hour, and often resolves a suicidal state in one to two days. Within 24 hours, neurons begin to grow synapses with other neurons that improve the ability of the brain to regulate itself,” Shelton said.

 “Ketamine targets NMDA receptors of the neurotransmitter glutamate. Even a brief blockade of NMDA receptors reduces distress and helps people recover,” Shelton said. “This receptor is linked to calcium channels. Calcium is an important regulator within cells and a cofactor for enzymes. Ketamine’s action on the receptor creates downstream effects that result in the improved response we see.”

The response seems to peak at around ten days. When only a single treatment is given, most symptoms return. With repeated treatments over four to eight weeks, symptoms don’t seem to come back as soon. The UAB research is the first large scale investigation into the effects of using ketamine on suicidal thinking and depression.

“Around 75 to 80 percent of patients respond, and there is some indication that nonresponders will respond to higher doses. The protocol for most patients is likely to have an induction phase of two treatments per week for four to eight weeks, then step down to once a week or every other week,” Shelton said. “I anticipate seeing ketamine approved for use soon in suicidal depression and in patients with medication-resistant depression. It could also be helpful in PTSD.

“Treatment would likely take place in a clinic rather than a physician’s office, since ketamine is a controlled drug and there is a potential for side effect. In the low doses we use, hallucinations aren’t typically a problem, but there can be short term illusions with visual or sound distortions. “Ketamine is likely to be only the first step. We’ve already developed an intranasal spray that can be used more conveniently than an infusion, and we’ve tested another drug that acts on the same receptors without the side effects. There are several other drugs on the shelf that act in a similar way. Some were Alzheimer’s drugs that didn’t perform up to expectations, but they could have new potential in treating psychiatric diseases.”Understanding the role of miRNA in mental health disorders could be the key to unlocking new treatments like ketamine and a whole new range of medications that not only save lives—but also make those lives more livable.