A Career Devoted to Identifying the Brain Biology Associated with Suicide

From The Quarterly, Fall 2014

J. John Mann, M.D., of Columbia University, is one of a small number of neuroscientists who have quietly transformed our understanding of suicide over the last three decades. A member of the Foundation’s Scientific Council and a 2008 recipient of a NARSAD Distinguished Investigator Grant, Dr. Mann, together with colleagues, has published hundreds of studies that are building a biological science to understand what leads to—and what might prevent—suicide.

In the United States, the suicide rate has remained virtually unchanged in 60 years. In 2011, the most recent year for which data are available, nearly 40,000 suicides were reported. It is the tenth leading cause of death for Americans. There are behavioral warning signs that have been associated with increased risk of suicide: behavior and symptoms of recurrent major depressive episodes, expressions of hopelessness and negativity, impulsive behavior and a pattern of impaired decision making and problem solving.

Early in his career, Dr. Mann, The Paul Janssen Professor of Translational Neuroscience in Psychiatry and Radiology at Columbia University, realized the behavioral warning signs weren’t doing enough to help those at risk. He began his journey to find ways to more reliably predict who might attempt suicide and to develop means to more effectively intervene. Working with postmortem human brain tissue early on, Dr. Mann set out to discover what was different in the brains of people who had suffered from major depression and taken their own life. His team and other colleagues discovered abnormally low levels of the neurotransmitter serotonin*, a message-transmitting chemical that is the target of today’s widely used SSRI (selective serotonin reuptake inhibitor) antidepressant medicines such as fluoxetine (Prozac®) and paroxetine (Paxil®). These medications are designed to increase brain serotonin signals.

Dr. Mann and a colleague noticed, critically, that in people who had died by suicide, serotonin was low—not only in those who suffered from major depression, but also in other disorders including schizophrenia, bipolar disorder and anxiety. In depressed people who had taken their life, “there were abnormalities that were confined to areas of the brain involved in decision making and the ability to restrain oneself,” Dr. Mann explains. These areas in the frontal part of the brain are called the orbitofrontal cortex and the anterior cingulate cortex.

This early evidence contributed to a theory of suicide aimed at prediction. Called the stress-diathesis theory of suicide risk, it focuses on the impact of stress upon people who are biologically predisposed to handle stress poorly. In the presence of stress—whether a sudden psychosocial trauma and/or acute episode of a psychiatric illness— people with specific brain abnormalities appear predisposed to, and are at higher risk of, suicide. “Our research highlighted the predisposition, which had been overlooked,” says Dr. Mann. “Once you took the list of things associated with suicides, and divided it into these two domains of stress and predisposition, everything we knew became more meaningful. There is the stressor part, or life events; and there is the way you cope when things go wrong.”

Some major advances have been made with the introduction of functional imaging of the living brain. “It led us to think: Well, what’s going on in the brain of a person who hasn’t died of suicide but might?” Dr. Mann says. Additional insight has also been obtained with gene-sequencing technologies, which have begun to flesh out what risk might be genetic. The overall contribution of genetic factors to the predisposition portion of suicide risk is estimated to be as high as 50 percent. Epigenetic factors—chemical modifications of DNA that change gene activity—also seem to be implicated in predisposition risk.

Several lines of suicide research point to aberrations in the human stress-response system, referred to by scientists as the HPA axis (for the hypothalamus, the pituitary and the adrenal glands that regulate the stress response). “HPA dysfunction is linked to depression and unstable mood, changes in cognition and decision making,” Dr. Mann says. “One thing that distinguishes serious, often lethal suicide attempts from non-lethal ones is an individual who retrieves disproportionately negative memories. In problem solving, these people cannot rethink the problem; there is cognitive rigidity. We often hear such people say, ‘There’s no way out; I’m stuck.’ This is due to deficits in cognitive processing.”

Serotonin deficiency likely contributes to these deficits. In addition to transmitting messages between neurons, serotonin enhances the release of growth hormones in the brain such as BDNF* (brain-derived neurotrophic factor). “BDNF causes neurons to get bigger, to form more connections,” says Dr. Mann. It also causes new nerve cells to be born in the hippocampus. Low serotonin affects all these vital processes.

“I can see blood tests becoming an important part of screening for suicidal patients,” Dr. Mann says. “There’s also a potential role for brain imaging. There may be 20 different ways to arrive at disordered neural circuitry in the cortex, which predicts suicide risk. We may not fully understand how all of these occur for a long time. But we may be able to scan people right now to predict the probability,” he says.

Volunteers Needed for “Paradigm-Shifting” Study on Rapid Antidepressant

“Becoming suicidal is not a fluke. And it’s not just because of the circumstances someone has experienced,” says Dr. J. John Mann. Using combat veterans as an example, he emphasizes the component of biological predisposition that determines “how resilient you happen to be” when trauma or stress occurs. To the extent this vulnerability is determined by genes, serotonin deficiency, problems in the brain’s dopamine* or noradrenergic pathways*, problems in cellular docking ports for stress hormones called glucocorticoid receptors, or other problems in the stress-response system, the current thinking is that it takes more than severe trauma to make someone determined to act on suicidal thoughts. Dr. Mann gives this example: many people enter combat; about 20 percent develop PTSD or major depression. “But of that 20 percent, only a fraction will have additional vulnerability that places them at higher risk for suicide: poor decision making, excessive pessimism, impaired problem solving. Those dysfunctions are not about the severity of the stressor—we can find examples of all soldiers in the same unit being exposed to the same trauma. They are about individual biological predisposition.”

At some point, Dr. Mann hopes that advanced brain imaging, measures of decision making and blood tests for biomarkers of elevated suicide risk can screen for people predisposed in this way. Such tests might, for example, be given to soldiers before being sent into combat.

More immediately, Dr. Mann is excited about a potential medication to reverse high suicide risk in select patients who are depressed. His group and others at Columbia University are currently seeking patients to take part in two NIH-funded clinical trials for ketamine*. Dr. Mann invites patients aged 18 to 65 with major depression but no history of other psychiatric illness to inquire about participating. For more information call 646-774-5788.

“Ketamine does two things to people with major depression that are different from all the other antidepressants now in use,” says Dr. Mann. “First, when it gets people better, it gets them a lot better. Second, it does this in a couple of hours. This is a paradigm shift in the way we think antidepressants can work.”

Ketamine inhibits the NMDA receptor, which is ubiquitous in the brain. Originally used as an anesthetic, ketamine in higher doses has side effects such as dissociative symptoms*, like those seen in psychosis. However, the clinical trials use a low-dose pharmaceutical derivative of ketamine whose one-time administration in the studies is carefully controlled, and side effects are milder and transient. In one of the two trials, ketamine is compared to another medication, midazolam, to determine its impact, if any, on suicidal thoughts. In a second clinical trial, the brain is imaged in real time as ketamine is administered via an IV to study how the brain chemistry changes with the medication’s astonishingly rapid antidepressant effect.

“The Foundation has been really important in our field, and this is an example,” Dr. Mann says. “Our idea of doing an imaging study in real time of patients being given ketamine would not have been funded by NIMH without some pilot data. A NARSAD Distinguished Investigator Grant enabled me to get pilot data for this, and that led to a major NIH grant. Some of my group’s most creative and original ideas would never have gotten off the ground if it had not been for the paradigm-shift approach that the Foundation encourages.”