Why? The Neuroscience of Suicide

New research addresses the wrenching question left when someone
ends his or her own life

By Carol Ezzell

In 1994, two days after returning from a happy family vacation,
my 57-year-old mother put the muzzle of a handgun to her left breast and
fired, drilling a neat and lethal hole through her heart--and,
metaphorically, through our family's as well.
It was around midnight on a Saturday night in July, the time of
year, I was later surprised to learn, that has the highest incidence of
suicide in the Northern Hemisphere. My stepfather was at home but
didn't hear the single shot because he was taking a shower in a bathroom at
the other end of the house. When he returned to their bedroom, she was
crumpled on the carpet in her pajamas, almost gone. She tried to say
something to him before she died, but he couldn't make out what it was.
The emergency medical technicians arrived to find a patient, but not the
one they expected: my stepfather nearly died himself that night after
hyperventilating from the shock, which all but overwhelmed lungs already
compromised by emphysema.

Through it all, I was asleep in my apartment 200 miles away. I
was awakened at 2 a.m. by a call from my building's front desk, telling
me that my sister-in-law was downstairs and wanted to come up. My first
words to her when I opened my door were, "It's Mother, isn't it?"

Our family has too much company in suffering the agony of having
a loved one die by suicide: annually, 30,000 people in the U.S. take
their own lives. That is roughly half again the number who died of AIDS
last year. Why do they do it?

Like an estimated 60 to 90 percent of U.S. suicides, my mother
had a mental illness. In her case, it was manic-depression, also called
bipolar disorder. Unless they are taking--and responding well to--the
appropriate medication, manic-depressives oscillate between troughs of
despair and peaks of elation or agitation. Most who end their lives have
a history of depression or manic-depression, but people with severe
depression differ in their propensity for suicide.

Scientists have begun uncovering behavioral tip-offs and are also
exploring clues to anatomical and chemical differences between the
brains of suicides and of those who die of other causes. If such changes
could be detected in medical imaging scans or through blood tests,
doctors might one day be able to identify those at highest risk of dying by
suicide--and therefore attempt to prevent the tragedy from occurring.
Sadly, that goal is not immediately in sight: many who have suicidal
tendencies still end up taking their own lives, despite intensive
intervention.

My Mother's Legacy


The question of what drove my mother to her desperate act that
humid night nearly nine years ago is the second most difficult thing I
live with. Scarcely a day has gone by that I haven't been pierced by the
anguish of wanting to know exactly what prompted her suicide on that
particular night as well as the crushing guilt over what I could have
done--should have done, would have done--to stop her. The hardest thing I
have to live with is the realization that I will never know the answer
for sure.

In the future, some parts of her story should become less
mysterious, because researchers are studying those very issues. One age-old
question, whether a tendency to commit suicide is inborn or the result of
an accumulation of bad experiences, is at least closer to resolution.

Although the nature-versus-nurture debate still rages in some
psychiatric circles, most researchers who study suicide fall somewhere in
the middle. "You need several things to go wrong at once," explains
Victoria Arango of the New York State Psychiatric Institute, which is
affiliated with Columbia-Presbyterian Medical Center. "I'm not saying that
suicide is purely biological, but it starts with having an underlying
biological risk." Life experience, acute stress and psychological
factors each play a part, she asserts. At the root of the mystery of suicide,
however, lies a nervous system whose lines of communication have become
tangled into unbearably painful knots.

Arango and her Columbia colleague J. John Mann are leading the
effort to pick apart those knots and discern the neuropathology of
suicide. They have assembled what is generally acknowledged to be the
country's best collection of brain specimens from suicide victims. Twenty-five
deep freezers in their laboratories hold a total of 200 such brains,
which the researchers are examining for neuroanatomical, chemical or
genetic alterations that might be unique to those compelled to end their
lives. Each brain is accompanied by a "psychological autopsy," a
compendium of interviews with family members and intimates probing the
deceased's state of mind and behavior leading up to his or her final act. "We
try to get a complete picture," Mann says, "and come up with an
aggregate explanation for that person." A suicide brain is matched against a
control brain from a person of the same sex without a psychiatric
disorder who died at approximately the same age of a cause other than suicide.

Contained within the three-pound gelatinous mass of the human
brain are the cells and molecules that were inextricably linked to what
that person once thought--and, indeed, once was. Mann's and Arango's
research concentrates in part on the prefrontal cortex, the portion of the
brain encased in the bone of the forehead. The prefrontal cortex is the
seat of the so-called executive functions of the brain, including the
internal censor that keeps individuals from blurting out what they
really think in awkward social situations or acting on potentially dangerous
impulses.

The impulse-dampening role played by the prefrontal cortex
particularly interests Mann and Arango. Scientists have looked to impulsivity
as a predictor for suicide for decades. Although some people plan their
deaths carefully--leaving notes, wills and even funeral plans--for
many, including my mother, suicide appears to be spontaneous: a very bad
decision on a very bad day. So Arango and Mann search in these brains for
clues to the biological basis for that impulsivity. One focus is on
differences in the availability of the brain chemical serotonin--previous
research on the basis of impulsivity has indicated a dearth of it.

Serotonin is a neurotransmitter, one of the molecules that jumps
the tiny gaps known as synapses between neurons to relay a signal from
one such brain cell to another. Tiny membranous bubbles called vesicles
erupt from each signal-sending, or presynaptic, neuron, releasing
serotonin into the synapse. Receptors on the receiving, or postsynaptic,
neurons bind to the neurotransmitter and register biochemical changes in
the cell that can change its ability to respond to other stimuli or to
turn genes on or off. After a short while, the presynaptic cells
reabsorb the serotonin using molecular sponges termed serotonin transporters.

Serotonin somehow exerts a calming influence on the mind. Prozac
and similar antidepressant drugs work by binding to serotonin
transporters and preventing presynaptic neurons from soaking up the secreted
serotonin too quickly, allowing it to linger a bit longer in the synapse
and continue to transmit its soothing effect.

Traces of Pain
More than two decades of reports have linked low serotonin levels
in the brain to depression, aggressive behavior and a tendency toward
impulsiveness, but the evidence has been particularly confusing with
regard to suicide. A number of studies have found reductions in serotonin
in the brains of suicides, whereas others have not. Some have observed
a lack of serotonin in one part of the brain but not elsewhere. Still
others have described increases in the number of receptors for serotonin
or deficits in the chain of chemical events that convey the serotonin
signal from those receptors to the inside of a neuron.

Despite the inconsistencies, the bulk of evidence points strongly
to a problem in the brains of suicides involving the serotonin system.
That line of thinking has been bolstered by the recent findings of
Arango and Mann.


In a second-floor laboratory at the upper tip of Manhattan,
Arango's technician leans into an open freezer to use a machine called a
microtome to pare a feather-light slice from a frozen brain donated by
grieving relatives anxious to help science address the mystery of suicide.
Using a chilled brush, she delicately coaxes the rime of icy tissue
onto a glass slide the size of a snapshot. With the body heat from her own
gloved hands, she then melts the brain sliver onto the glass; observing
the process is reminiscent of watching bright sunlight on a frigid
winter day dissolve frost on a window.

The scientists working with the Columbia collection divide the
brains into left and right hemispheres and then carefully section each
hemisphere into 10 or 12 blocks from front to back. Once frozen and put
through the microtome, every block yields roughly 160 slices that are
thinner than a human hair.

The chief benefit of this approach is that Arango's and Mann's
groups can perform several different biochemical tests on the same brain
slice and know the exact anatomical locations of the variations they
find. By reassembling the slices virtually, they can compile an overall
model of how those abnormalities might work in concert to affect a
complex behavior.

At a conference of the American College of
Neuropsychopharmacology in 2001, Arango reported that the brains of people who were depressed
and died by suicide contained fewer neurons in the orbital prefrontal
cortex, a patch of brain just above each eye. What is more, in suicide
brains, that area had one third the number of presynaptic serotonin
transporters that control brains had but roughly 30 percent more
postsynaptic serotonin receptors.

Together the results suggest that the brains of suicides are
trying to make the most of every molecule of serotonin they have, by
increasing the molecular equipment for sensing the neurotransmitter while
decreasing the number of transporters that absorb it back again. "We
believe there is a deficiency in the serotonergic system in people who
commit suicide," Arango concludes. "They can be so sick Prozac can't help
them." Inhibiting the reuptake of serotonin isn't always enough to
prevent suicide: it wasn't for my mother, who died despite taking 40
milligrams of Prozac a day.

Mann and his colleagues are now trying to devise a positron
emission tomography (PET) test that might one day aid doctors in determining
which among their depressed patients have the most skewed serotonin
circuitry--and are therefore at highest risk of suicide. PET scans mirror
brain activity by monitoring which brain regions consume the most blood
glucose; administering drugs, such as fenfluramine, that cause the
release of serotonin can help scientists zero in on active brain areas
using serotonin.

In the January Archives of General Psychiatry, Mann and his
co-workers reported a relation between activity in the prefrontal cortex of
people who had attempted suicide and the potential deadliness of the
attempt. Those who had used the most dangerous means--for example, by
taking the most pills or jumping from the highest point--had the least
serotonin-based activity in the prefrontal cortex. "The more lethal the
suicide attempt, the bigger the abnormality," Mann observes.

Ghanshyam N. Pandey of the University of Illinois agrees that the
brain's serotonin system is key to understanding suicide. "There is a
lot of evidence to suggest serotonin defects in suicide, but these
defects do not exist in isolation but in concert with other deficits," he
says. "The whole system appears to be altered."

The serotonin hypothesis does not rule out important
contributions by other neurotransmitters, however. Serotonin is only one molecule
in the intricate biochemical network named the
hypothalamic-pituitary-adrenal (HPA) axis, in which the hypothalamus and pituitary glands in the
brain communicate with the adrenal glands atop the kidneys. The HPA is
responsible for the so-called fight-or-flight response exemplified by
the racing heartbeat and sweaty palms you get after a close scrape while
driving, say. In particular, corticotrophin-releasing factor, which the
hypothalamus releases in times of stress, causes the anterior pituitary
to make adrenocorticotropic hormone, which in turn causes the adrenal
cortex to produce glucocorticoids such as cortisol. Cortisol prepares
the body for stress by raising blood sugar concentrations, increasing
heart rate and inhibiting the overreaction of the immune response.


Serotonin fits into the HPA because it modulates the threshold of
stimulation. Researchers such as Charles B. Nemeroff of the Emory
University School of Medicine and his colleagues are finding that extremely
adverse early life experiences, such as child abuse, can throw the HPA
axis off kilter, literally leaving biochemical imprints on the brain
that make it vulnerable to depression as a result of overreacting to
stress later on.

In 1995 Pandey's group reported indications