Carol Ezzell - The Neuroscience of Suicide

COPYRIGHT 2003 SCIENTIFIC AMERICAN, INC.

w w w . s c i a m . c o m S C I E N T I F I C A M E R I C A N 45

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WHYThe neuroscience

of suicide

By Carol Ezzell

New research

addresses the

wrenching question

left when someone

ends his or her

own life

???COPYRIGHT 2003 SCIENTIFIC AMERICAN, INC.

It was around midnight on a Saturdaynight in July, the time of year, I was latersurprised to learn, that has the highest in-cidence of suicide in the Northern Hemi-sphere. My stepfather was at home butdidn’t hear the single shot because he wastaking a shower in a bathroom at the oth-er end of the house. When he returned totheir bedroom, she was crumpled on thecarpet in her pajamas, almost gone. Shetried to say something to him before shedied, but he couldn’t make out what itwas. The emergency medical techniciansarrived to find a patient, but not the onethey expected: my stepfather nearly diedhimself that night after hyperventilatingfrom the shock, which all but over-whelmed lungs already compromised byemphysema.

Through it all, I was asleep in myapartment 200 miles away. I was awak-ened at 2 A.M. by a call from my building’sfront desk, telling me that my sister-in-law was downstairs and wanted to comeup. My first words to her when I openedmy door were, “It’s Mother, isn’t it?”

Our family has too much company insuffering the agony of having a loved onedie by suicide: annually, 30,000 people inthe U.S. take their own lives. That is rough-ly half again the number who died of AIDSlast year. Why do they do it?

Like an estimated 60 to 90 percent ofU.S. suicides, my mother had a mental ill-ness. In her case, it was manic-depression,also called bipolar disorder. Unless theyare taking—and responding well to—theappropriate medication, manic-depres-sives oscillate between troughs of despairand peaks of elation or agitation. Mostwho end their lives have a history of de-pression or manic-depression, but peoplewith severe depression differ in theirpropensity for suicide.

Scientists have begun uncovering be-

havioral tip-offs and are also exploringclues to anatomical and chemical differ-ences between the brains of suicides andof those who die of other causes. If suchchanges could be detected in medicalimaging scans or through blood tests,doctors might one day be able to identifythose at highest risk of dying by suicide—

and therefore attempt to prevent thetragedy from occurring. Sadly, that goal isnot immediately in sight: many who havesuicidal tendencies still end up taking theirown lives, despite intensive intervention.

My Mother’s LegacyTHE QUESTION of what drove mymother to her desperate act that humidnight nearly nine years ago is the secondmost difficult thing I live with. Scarcelya day has gone by that I haven’t beenpierced by the anguish of wanting toknow exactly what prompted her suicideon that particular night as well as thecrushing guilt over what I could havedone—should have done, would havedone—to stop her. The hardest thing Ihave to live with is the realization that Iwill never know the answer for sure.

In the future, some parts of her storyshould become less mysterious, becauseresearchers are studying those very issues.One age-old question, whether a tenden-cy to commit suicide is inborn or the re-sult of an accumulation of bad experi-ences, is at least closer to resolution.

Although the nature-versus-nurturedebate still rages in some psychiatric cir-cles, most researchers who study suicidefall somewhere in the middle. “You needseveral things to go wrong at once,” ex-plains Victoria Arango of the New YorkState Psychiatric Institute, which is affili-ated with Columbia-Presbyterian MedicalCenter. “I’m not saying that suicide ispurely biological, but it starts with having

SUICIDE IS THE 11THLEADING CAUSE OFDEATH IN THE U.S.,ACCOUNTING FOR

1.2 PERCENT OF ALL FATALITIES.

A PERSON DIES BY SUICIDE

ROUGHLY EVERY 18MINUTES IN THE U.S. SOMEONE ATTEMPTS SUICIDE

EVERY MINUTE.

FOUR MALES DIE BY SUICIDE FOR

EVERY FEMALE, BUT AT LEAST

TWICE AS MANY WOMENAS MEN ATTEMPT SUICIDE.

APPROXIMATELY

80 AMERICANS TAKE

THEIR OWN LIVES EVERY DAY.

THE SUICIDE RATE FOR

WHITE MALESAGED 15 TO 24 HAS TRIPLED SINCE 1950.

F E B R U A R Y 2 0 0 3

In 1994, two days after returning from a happy familyvacation, my 57-year-old mother put the muzzle of a handgunto her left breast and fired, drilling a neat and lethal hole throughher heart—and, metaphorically, through our family’s as well.



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PHYSICAL CLUES TO SUICIDE

CHANGES IN THE DORSAL RAPHE NUCLEUSNeurons in the dorsal raphe nucleus of the brain stem of someone who died by suicidecontain more of the enzyme that synthesizes serotonin (dark staining) than thecorresponding brain region of someone who died of another cause. The differenceindicates that the brains of suicides are attempting to produce more serotonin.

Orbital prefrontal cortex

Plane ofsectioning

Dorsal raphenucleus

Throughout the cortex, serotonintransporters (gold) absorbserotonin. In the markedsubsection, the number of thesetransporters is reduced.

The analyzed area also exhibitsmore binding of serotonin(orange) per neuron. Together the analyses indicate that thebrain tried to make the most ofthe serotonin it had.

CONTROLSUICIDE VICTIM

CHANGES IN THE ORBITAL PREFRONTAL CORTEX

IN PEOPLE WHO DIE BY SUICIDE, anatomical and chemical changes occur in two brain regions:the orbital prefrontal cortex, which lies just above the eyes, and the dorsal raphe nucleus ofthe brain stem. The alterations are evidence of a reduced ability to make and use serotonin, akey neurotransmitter known to be lacking in the brains of impulsive people and in thosesuffering from depression. Neurons in the dorsal raphe nucleus produce serotonin; they havelong projections (blue arrow) that carry the neurotransmitter to the orbital prefrontal cortex.In suicide victims, the dorsal raphe nucleus sends less than normal amounts of serotonin tothe orbital prefrontal cortex. —C.E.

SINGLE HEMISPHERE OF BRAIN

Slices from the brain of a suicidevictim contain fewer neurons in asubsection (circled) of the orbitalprefrontal cortex.

Plane of sectioning


an underlying biological risk.” Life expe-rience, acute stress and psychological fac-tors each play a part, she asserts. At theroot of the mystery of suicide, however,lies a nervous system whose lines of com-munication have become tangled into un-bearably painful knots.

Arango and her Columbia colleagueJ. John Mann are leading the effort topick apart those knots and discern theneuropathology of suicide. They have as-sembled what is generally acknowledgedto be the country’s best collection of brainspecimens from suicide victims. Twenty-five deep freezers in their laboratorieshold a total of 200 such brains, which theresearchers are examining for neuroana-tomical, chemical or genetic alterationsthat might be unique to those compelledto end their lives. Each brain is accompa-nied by a “psychological autopsy,” a com-pendium of interviews with family mem-bers and intimates probing the deceased’sstate of mind and behavior leading up tohis or her final act. “We try to get a com-plete picture,” Mann says, “and come upwith an aggregate explanation for thatperson.” A suicide brain is matched againsta control brain from a person of the samesex without a psychiatric disorder whodied at approximately the same age of acause other than suicide.

Contained within the three-poundgelatinous mass of the human brain arethe cells and molecules that were inextri-cably linked to what that person oncethought—and, indeed, once was. Mann’sand Arango’s research concentrates in parton the prefrontal cortex, the portion of thebrain encased in the bone of the forehead.The prefrontal cortex is the seat of the so-called executive functions of the brain, in-cluding the internal censor that keeps in-dividuals from blurting out what they re-ally think in awkward social situations oracting on potentially dangerous impulses.

The impulse-dampening role playedby the prefrontal cortex particularly in-terests Mann and Arango. Scientists havelooked to impulsivity as a predictor forsuicide for decades. Although some peo-ple plan their deaths carefully—leavingnotes, wills and even funeral plans—formany, including my mother, suicide ap-pears to be spontaneous: a very bad deci-

sion on a very bad day. So Arango andMann search in these brains for clues tothe biological basis for that impulsivity.One focus is on differences in the avail-ability of the brain chemical serotonin—

previous research on the basis of impul-sivity has indicated a dearth of it.

Serotonin is a neurotransmitter, oneof the molecules that jumps the tiny gapsknown as synapses between neurons torelay a signal from one such brain cell toanother. Tiny membranous bubbles calledvesicles erupt from each signal-sending,or presynaptic, neuron, releasing sero-tonin into the synapse. Receptors on thereceiving, or postsynaptic, neurons bindto the neurotransmitter and register bio-chemical changes in the cell that canchange its ability to respond to other stim-uli or to turn genes on or off. After a shortwhile, the presynaptic cells reabsorb theserotonin using molecular sponges termedserotonin transporters.

Serotonin somehow exerts a calminginfluence on the mind. Prozac and similarantidepressant drugs work by binding toserotonin transporters and preventingpresynaptic neurons from soaking up thesecreted serotonin too quickly, allowingit to linger a bit longer in the synapse andcontinue to transmit its soothing effect.

Traces of PainMORE THAN two decades of reportshave linked low serotonin levels in thebrain to depression, aggressive behaviorand a tendency toward impulsiveness, butthe evidence has been particularly con-fusing with regard to suicide. A numberof studies have found reductions in sero-tonin in the brains of suicides, whereasothers have not. Some have observed alack of serotonin in one part of the brainbut not elsewhere. Still others have de-scribed increases in the number of recep-tors for serotonin or deficits in the chainof chemical events that convey the sero-tonin signal from those receptors to theinside of a neuron.

Despite the inconsistencies, the bulkof evidence points strongly to a problemin the brains of suicides involving theserotonin system. That line of thinkinghas been bolstered by the recent findingsof Arango and Mann.

F E B R U A R Y 2 0 0 3

BETWEEN 1980 AND 1996 THE SUICIDE RATE FOR

AFRICAN-AMERICANMALES AGED 15 TO 19 INCREASED 105 PERCENT.

SUICIDE IS THE

THIRD-RANKINGCAUSE OF DEATH FORTEENS AGED 10 TO 19.

WHITE MEN 85 ANDOLDER DIE BY SUICIDE

AT SIX TIMES THE OVERALL

NATIONAL RATE.

SUICIDE RATES FORWOMEN PEAK BETWEEN

THE AGES OF 45 AND 54 AND

SURGE AGAIN AFTER AGE 85.

ALCOHOLISM IS A FACTORIN ROUGHLY 30 PERCENT OF ALL

COMPLETED SUICIDES.

APPROXIMATELY 7 PERCENT OF

PEOPLE WITHALCOHOL DEPENDENCEWILL DIE BY SUICIDE.

EIGHTY-THREE PERCENT OF

GUN-RELATED DEATHSIN THE HOME ARE THE RESULT

OF SUICIDE.

DEATH BY FIREARMS IS THE

FASTEST-GROWINGMETHOD OF SUICIDE.



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Lithium appears to prevent suicide. Why do so few suicidal people take it?

“Lithium . . . is the lightest of the solid elements, and it isperhaps not surprising that it should in consequence possesscertain modest magical qualities.” —G. P. Hartigan, psychiatrist

“Only crazy people take lithium!” my mother shouted during oneof our many arguments over her not receiving the besttreatment for her manic-depression. She accused me and mystepfather of wanting to medicate her so she would “just shutup.” To be honest, she was partially right: it is very trying to bearound someone in the grip of a mania, which often brings onincessant, stream-of-consciousness talking.

Many people find lithium—which generally comes incapsules of lithium carbonate or lithium citrate—difficult totake. It can cause hand tremors, constant thirst, frequenturination, weight gain, lethargy, reduced muscle coordination,blurred thinking and short-term memory deficits. People on itmust also have its concentration in their blood assessedregularly to ensure that it is within the therapeutic range: thedrug is usually ineffective below 0.6 millimole per liter of bloodserum and can cause life-threatening toxic reactions if the levelbecomes higher than two millimoles per liter.

Lithium is used routinely to even out the extreme moodswings of patients with manic-depressive illness, or bipolardisorder. Increasingly, however, it is also offered to people withdepression. But a growing body of evidence indicates that thiscompound can literally keep people who are at risk of suicidealive. In 1998 lithium pioneer Mogens Schou of the PsychiatricHospital in Risskov, Denmark, pulled together the results ofvarious studies of lithium as a suicide preventive and observedthat people not taking the drug were three to 17 times as likelyto end their own lives as depressed people who took themedication. Likewise, Schou determined that lithium reducedsuicide attempts by a factor of between six and 15.

How does it exert its salutary effects? Despite a number oftantalizing leads, researchers are still not certain. “It’s hard tosay at this time,” says Ghanshyam N. Pandey of the Universityof Illinois. “There are so many modes of action.” Lithium isthought to affect tiny ports called ion channels on the surfacesof nerve cells, or neurons. As they open and close, ion channelsadmit or bar charged atoms that determine the electricalpotential within the cells, thereby dictating their activity andability to communicate with other neurons. Scientists posit thatthe drug stabilizes the excitability of the neurons by influencingthe ion channels or by skewing the chain reaction ofbiochemical events that occur within an excited cell.

A drug only works, though, if someone takes it properly. Inthe May 2002 issue of the Journal of Clinical Psychiatry, Jan

Scott and Marie Pope of the University of Glasgow reported thathalf of a group of 98 patients who were taking a mood-stabilizing drug such as lithium failed to stick with their drugregimen. Yet, the researchers noted, just 1 percent of scientificpublications on the subject of mood stabilizers looked at whypatients did not take their lithium as prescribed.

J. John Mann of the New York State Psychiatric Institutesays that a major factor in noncompliance is the human desirenot to want to think of oneself as ill. “There’s a natural reluctanceto take any medicine long-term,” Mann explains. “When a personis depressed, they have a problem imagining ever getting better.When they’re well, they can’t imagine getting sick again.”

The side effects of lithium also play a role. Kay RedfieldJamison, a psychiatrist at Johns Hopkins University whostudies manic-depression and suicide—and who is a manic-depressive herself—has found that the most common reasonspatients stop taking the drug are cognitive side effects, weightgain and impaired coordination. In her moving memoir, AnUnquiet Mind, she recounts her own struggle to come to termswith the fact that she will probably be coping with lithium’s sideeffects for the rest of her life. Perhaps if my mother had lived toread it, she would have been heartened by Jamison’s exampleand motivated to begin lithium therapy. —C.E.

THE “MAGIC” OF LITHIUM

LITHIUM is thelightest of the solidelements and, in itspure form, floats(left). Whencompounded in pillform as lithiumcarbonate or lithiumcitrate (above), it can be taken tostabilize moods.


In a second-floor laboratory at the up-per tip of Manhattan, Arango’s techni-cian leans into an open freezer to use amachine called a microtome to pare afeather-light slice from a frozen brain do-nated by grieving relatives anxious to helpscience address the mystery of suicide. Us-ing a chilled brush, she delicately coaxesthe rime of icy tissue onto a glass slide thesize of a snapshot. With the body heatfrom her own gloved hands, she thenmelts the brain sliver onto the glass; ob-serving the process is reminiscent ofwatching bright sunlight on a frigid win-ter day dissolve frost on a window.

The scientists working with the Co-lumbia collection divide the brains intoleft and right hemispheres and then care-fully section each hemisphere into 10 or12 blocks from front to back. Oncefrozen and put through the microtome,every block yields roughly 160 slices thatare thinner than a human hair.

The chief benefit of this approach isthat Arango’s and Mann’s groups can per-form several different biochemical tests onthe same brain slice and know the exactanatomical locations of the variations theyfind. By reassembling the slices virtually,

they can compile an overall model of howthose abnormalities might work in concertto affect a complex behavior.

At a conference of the American Col-lege of Neuropsychopharmacology in2001, Arango reported that the brains ofpeople who were depressed and died bysuicide contained fewer neurons in theorbital prefrontal cortex, a patch of brainjust above each eye. What is more, in sui-cide brains, that area had one third thenumber of presynaptic serotonin trans-porters that control brains had but rough-ly 30 percent more postsynaptic sero-tonin receptors.

Together the results suggest that thebrains of suicides are trying to make themost of every molecule of serotonin theyhave, by increasing the molecular equip-ment for sensing the neurotransmitterwhile decreasing the number of trans-porters that absorb it back again. “We be-lieve there is a deficiency in the serotoner-gic system in people who commit sui-cide,” Arango concludes. “They can be sosick Prozac can’t help them.” Inhibitingthe reuptake of serotonin isn’t alwaysenough to prevent suicide: it wasn’t formy mother, who died despite taking 40milligrams of Prozac a day.

Mann and his colleagues are now try-ing to devise a positron emission tomog-raphy (PET) test that might one day aiddoctors in determining which amongtheir depressed patients have the mostskewed serotonin circuitry—and are there-fore at highest risk of suicide. PET scansmirror brain activity by monitoring whichbrain regions consume the most bloodglucose; administering drugs, such as fen-fluramine, that cause the release of sero-tonin can help scientists zero in on activebrain areas using serotonin.

In the January Archives of GeneralPsychiatry, Mann and his co-workers re-ported a relation between activity in theprefrontal cortex of people who had at-tempted suicide and the potential deadli-ness of the attempt. Those who had usedthe most dangerous means—for example,by taking the most pills or jumping fromthe highest point—had the least serotonin-based activity in the prefrontal cortex.“The more lethal the suicide attempt, thebigger the abnormality,” Mann observes.

Ghanshyam N. Pandey of the Univer-sity of Illinois agrees that the brain’s sero-tonin system is key to understanding sui-cide. “There is a lot of evidence to suggestserotonin defects in suicide, but these de-fects do not exist in isolation but in con-cert with other deficits,” he says. “Thewhole system appears to be altered.”

The serotonin hypothesis does notrule out important contributions by oth-er neurotransmitters, however. Serotoninis only one molecule in the intricate bio-chemical network named the hypothala-mic-pituitary-adrenal (HPA) axis, inwhich the hypothalamus and pituitaryglands in the brain communicate with theadrenal glands atop the kidneys. TheHPA is responsible for the so-called fight-or-flight response exemplified by the rac-ing heartbeat and sweaty palms you getafter a close scrape while driving, say. Inparticular, corticotrophin-releasing fac-tor, which the hypothalamus releases intimes of stress, causes the anterior pitu-itary to make adrenocorticotropic hor-mone, which in turn causes the adrenalcortex to produce glucocorticoids such ascortisol. Cortisol prepares the body forstress by raising blood sugar concentra-tions, increasing heart rate and inhibitingthe overreaction of the immune response.

Serotonin fits into the HPA because itmodulates the threshold of stimulation.Researchers such as Charles B. Nemeroffof the Emory University School of Medi-cine and his colleagues are finding that ex-tremely adverse early life experiences,such as child abuse, can throw the HPAaxis off kilter, literally leaving biochemi-cal imprints on the brain that make it vul-nerable to depression as a result of over-reacting to stress later on.

In 1995 Pandey’s group reported in-dications that the abnormalities in sero-tonin circuitry present in those at risk forsuicide could be detectable using a rela-tively simple blood test. When he and hisco-workers compared the number ofserotonin receptors on platelets (clottingcells) in the blood of suicidal people withthose of nonsuicidal people, they ob-served that individuals considering sui-cide had many more serotonin receptors.(Platelets just happen to have receptorsfor serotonin, although it is unclear why.)

50 S C I E N T I F I C A M E R I C A N F E B R U A R Y 2 0 0 3

SUICIDES OUTNUMBERHOMICIDES TWO TO ONEEVERY YEAR IN THE U.S.

SUICIDE ACCOUNTS FOR NEARLY57 PERCENT OF ALLFIREARM DEATHS IN THE U.S.;60 PERCENT OF ALL SUICIDES

INVOLVE FIREARMS.


Pandey says that his group concludedthat the boost in receptors reflects a sim-ilar increase in the suicide-prone brains—

a vain attempt to garner as much sero-tonin as possible. To prove the link, Pan-dey would like to determine whether theassociation holds up in people who go onto take their own lives. “We want toknow if platelets can be used as markersfor identifying suicidal patients,” Pandeysays. “We are making progress, but it’sslow.”

A Curse of GenerationsUNTIL RESEARCHERS can developtests to forecast those at highest risk forsuicide, doctors might concentrate theirefforts on the biological relatives of sui-cide victims. In the September 2002 issueof Archives of General Psychiatry, Mann,David A. Brent of the Western PsychiatricInstitute and Clinic in Pittsburgh and theircolleagues reported that the offspring ofsuicide attempters have six times the riskof people whose parents never attemptedsuicide. The link appears in part to be ge-netic, but efforts to pin down a predis-posing gene or genes have not yet yieldedany easy answers. In studies in the early1990s Alec Roy of the Department ofVeterans Affairs Medical Center in EastOrange, N.J., observed that 13 percent ofthe identical twins of people who died bysuicide also eventually took their ownlives, whereas only 0.7 percent of frater-nal twins traveled the same path as theirsuicidal siblings.

These statistics serve as warnings tome and to others with biological ties tosuicide. In a small jar in my bedroom Ikeep a bullet from the same box that con-tained the one that killed my mother. Thepolice took the gun after her death, and Imyself threw away the remaining bulletswhile cleaning out her bedroom closet.But I like to think that I hold on to thatsingle, cold pellet of metal as a reminderof how tenuous life is and how one im-pulsive act can have immense and rip-pling consequences. Perhaps someday sci-ence will better understand the basis forsuch harrowing acts so that families likemine will be spared.

Carol Ezzell is a staff editor and writer.


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Night Falls Fast: Understanding Suicide. Kay Redfield Jamison. Vintage Books, 2000.

Reducing Suicide: A National Imperative. Institute of Medicine. Edited by Sarah K. Goldsmith, Terry C. Pellmar, Arthur M. Kleinman and William E. Bunney. National Academies Press, 2002.

Information and education materials on preventing suicide can be obtained from the NationalMental Health Association (www.nmha.org), the American Foundation for Suicide Prevention(www.afsp.org) and the American Association of Suicidology (www.suicidology.org). The groupsalso have support materials for the survivors of loved ones who died by suicide.

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Carol Ezzell - The Neuroscience of Suicide