Scientists Study Serotonin Markers for Suicide Prevention

Brain serotonin levels as a predictor of suicide has been thesubject of intense research scrutiny over the past several years,with scientists trying to find easily accessible markers so thatthe neurotransmitter's levels might someday be readily measuredin clinical settings.

One of the leading investigators of this biological indicatoris Australian-born J. John Mann, M.D., professor of psychiatryat Columbia University and chief of the department of neuroscienceat New York State Psychiatric Institute, who recently presentedcurrent knowledge on the subject to a packed room at the historicHarvard Club of New York City.

The evening event, hosted by the American Suicide Foundationand the College of Physicians and Surgeons of Columbia University,was a prelude to the foundation's annual Lifesavers Dinner heldthe following night at the Waldorf-Astoria. There, Mann-in additionto former governor Mario Cuomo and actress Heather Locklear-receivedfoundation awards.

Preceding Mann's Harvard Club lecture, two new researchers fundedby the foundation briefly discussed their ongoing studies. DorothyE. Grice, M.D., postdoctoral research fellow in child psychiatryat the Yale Child Study Center, talked about exploring geneticroots of abnormal levels of serotonin that are present in suicidalteenagers. Susan I. Wolk, M.D., research fellow in anxiety andaffective disorders at New York State Psychiatric Institute andColumbia University, outlined a study of serotonin tests as predictorsof suicide in a cohort of patients formerly treated for majordepression while they were children.

Mann's talk, titled "The Neurobiology of Suicide," revieweddifferent tests that characterize chemical abnormalities foundin the brains of people who carried out serious suicide attemptsor successfully committed suicide. He discussed his research group'sefforts to validate these tests and move them out of the laboratoryand into clinical practice.

Showing a slide depicting a graph of suicide and suicide attempts,Mann said rates of attempts to completions are about 10 to 1,depending on the study.

"With 30,000 suicides a year-the eighth leading cause ofdeath in the U.S.-and 300,000 attempts annually, this gives youan idea of the magnitude of the problem," Mann pointed out.

He cited a major study conducted in Finland which found that only6 percent of all suicides related to a depressive illness werereceiving adequate doses of antidepressant treatment prior todeath.

"And almost half were in treatment," Mann said."So only a small minority were receiving adequate treatment.We have a long way to go in addressing this lack."

Mann presented a model of suicidal behavior in which there arethree categories of triggers: acute psychiatric illness; substance,alcohol or medication abuse; and social or family crisis.

"These triggers appear to be necessary for suicide to takeplace-and determine timing-but in and of themselves they are notsignificant factors," he said. "In other words, there'ssomething else involved than just the trigger, and that's thethreshold. It's the interaction of the threshold with triggerthat determines risk."

Mann said factors governing the threshold for suicidal behaviorinclude genetics, personality, alcohol, family and social support,chronic illnesses and serotonin levels.

For instance, 95 percent of those who commit suicide have psychiatricillness. There is evidence for a lower threshold for suicidalacts in a subgroup with major depression. Severity of depressionis a poor predictor of suicide risk.

"Yet this is the one factor clinicians rely on," Mannsaid, adding that his group looked at the timing of suicide followingthe onset of major depressive disorder and found that after threeyears, the slope flattens out. "So most suicide attemptsoccurred relatively early in the course of illness."

Therefore, finding more specific ways to predict suicidal behavioris important, he stressed.

Serotonin Deficiency

"Research has shown that well over 95 percent of suicides'brains have deficiencies in serotonin which are most strikingin certain brain regions. Serotonin deficiency is characteristicof those who make the most dangerous suicide attempts, the groupthat really stands out biologically."

In addition to studying brains of those who have successfullycommitted suicide, looking at "failed suicides"-thosewho made serious attempts and survived only fortuitously-can yieldimportant data.

He showed an X-ray of a man's head with a nail lodged in it. Theman had shot himself through the forehead with a nail gun andsuffered almost no significant injury.

"By studying serious attempters who have survived, we canlearn important things for treatment," Mann said. "It'snot to say that those who swallow a couple of aspirin are notat risk-they are more so than the general population-but thereis a difference between these and those who make serious attempts."

Mann said people who succeed at suicide are the ones who planthe most carefully, rather than acting impulsively.

"Low serotonin occurs three times more frequently in highplanners than low planners," he said.

An interesting finding is that serotonin levels are remarkablystable over time, so people can present at any time for evaluation.

"It doesn't matter if the attempt happened eight months priorto testing," he said. "We still can detect the typeof behavior with serotonin deficiency."

But simply having low levels of serotonin is insufficient as apredictor.

"It has more to do with the predisposition to suicide thanto generating suicidal behavior," said Mann. "Serotoninis detectable and independent of timing. So by evaluating thefunction of the serotonin system, we can identify who is vulnerableand plan more specific pharmacological intervention."

Mann said serotonin indexes which have been employed in the labinclude the cerebrospinal fluid level of 5-hydroxyindoleaceticacid, prolactin response to serotonin agonists-such as fenfluraminehydrochloride (Pondimin)-and platelet serotonin-related proteinsor serotonin content (Mann and others, 1992).

Said Mann, "Three different measures of serotonin function-completelyunrelated approaches-all show the same thing, mainly a deficiencyin patients with a history for more lethal suicide attempts."

Now, Mann and his group are looking at imaging of serotonin responsesin the brains of patients, using positron emission tomography(PET).

Deficiency Factors

So what causes serotonin deficiency?

"Genetics are an important area, but there are some environmentalfactors that increase or decrease serotonergic activity,"he said, listing factors such as genetics, diet, drugsand alcohol, gender and age.

For instance, lowering and raising cholesterol levels in monkeyssignificantly lowers and raises serotonin activity. So althoughlowering levels in humans does reduce heart attacks, it may raisethe risk of dying from other causes, including suicide.

"For those who utilize an actuarial approach to life, reducingcholesterol may result in a net loss in terms of survival,"Mann said. "But cholesterol creates only a subtle shift inpredisposition to suicide, so this must be recognized before weorder pizzas to be delivered to patients' homes."

Returning to the subject of serotonin markers, Mann addressedthe development of standard tests for clinical use.

"Serotonin measures are certainly not yet routine tests outsideof the laboratory," Mann said. "They're certainly takenup by researchers but not by clinicians."

The issue, said Mann, is that in psychiatry, "we're reluctantto use tests that are overly invasive. But given that this isthe eighth leading cause of death, and given that people withlow levels of serotonin are six to 10 times more likely to commitsuicide, we may have to rethink about developing tests. Furtherresearch is needed to find more direct tests rather than relyingon indirect measures, such as CSF 5-HIAA, or the prolactin responseto fenfluramine. That will happen."

Concluded Mann, "Clinicians are frustrated by not knowingwho is really at risk. And delivery of good treatment to depressedpatients is very suboptimal. But if you can say 'here's a test,'you may raise the sense of urgency and improve the delivery ofhealth care."

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Reference

Mann J, McBride A, Brown R, et al. Relationship between centraland peripheral serotonin indexes in depressed and suicidal psychiatricinpatients. Arch Gen Psychiatry. 1992;49:442-446.