Our Serotonin, Our Selves?

Can the Brains of the Dead Give Hope to the Living?

Magazine Issue
September/October 2008
Our Serotonin, Our Selves?

“My mother died today. Or perhaps it was yesterday,” says Victoria Arango. She’s a tall, lean, handsome woman, who happens to be one of the world’s most productive neuroscientists. She’s just quoted (accurately, I discover later) the first line of The Stranger by Albert Camus.

I hadn’t expected to be talking about Camus on this dreary Monday morning in our present setting—Arango’s orderly but welcoming office in the New York State Psychiatric Institute in northern Manhattan. PI, as everyone calls it, is a gleaming monument to science, situated in a curved, $80-million building sheathed with green-turquoise glass that resembles nothing so much as a large ocean liner. The water motif is fitting—PI is a stone’s throw from the Hudson, and I can see that stately river, and the George Washington Bridge that spans it, behind Arango as we talk.

“I don’t know why I remember that line from Camus 35 years after I read it in high school!” she says to me, laughing. She speaks in a soothing Latin accent that sounds almost British in its precision.

Then again, it’s entirely appropriate that we’re talking about Albert Camus. The question of suicide was at the heart of his writing and philosophy—and so it is in the work of Victoria Arango. For Camus, the central question of philosophy was whether one lives or dies, given the pain and absurdity of life. Only once that question has been settled (and Camus was personally emphatic that “suicide was not an option”) can one entertain other philosophical questions of being, like free will, the existence of God, and the nature of evil.

What was a philosophical issue for Camus is a physiological and biochemical one for Arango. For the last two decades, she’s been studying the brains of people who committed suicide, and has discovered, along with her research partners, John Mann, Chief of Neuroscience at PI and Columbia University, and Mark Underwood, her husband and close collaborator, that the biochemistry of their brains differs significantly from that of people who don’t commit suicide.

I’ve read a lot about Arango’s work, and I know that it has significant implications. Not least are the treatment implications: she and her team hope some day to be able to use physiological evidence to detect people who are at risk of suicide, and then get them into better, earlier treatment and supervision. But there are aspects of their work that trouble me. Can the eternal questions that for centuries have been in the capable hands of Camus, William Shakespeare, Friedrich Nietzsche, and endless other philosophers, poets, novelists, and spiritual thinkers, all come down to, or be dismissed by, a few errant and unruly neurotransmitters? There but for the grace of God, and an untenable level of serotonin, go I? Could our brains be so sick that they’ll kill us? How much do our brain chemicals control our lives, and what control is left to us?

It seems to me that Arango’s work puts the basic questions of neuroscience—who’s really running the show; ourselves, our soul, our free will, whatever you want to call it, or our brain chemicals?—into the most dramatic relief. So of all the neuroscience labs in the world, hers is the one I want to visit, and of all the neuroscientists in America, whose numbers are increasing daily, she’s the one I want to talk to.

A Collection of Brains

As I sit in Arango’s office, I know there’s a large room down the hall filled with freezers that hold the brains of 261 people who’ve committed suicide. She and her collaborators have been collecting such brains for decades.

It isn’t easy to collect the brains of suicides. Arango tells me that when she and her team were at the University of Pittsburgh, they used to get the brains from the coroner’s office in Allegheny County, Pennsylvania. When they came to New York, they got their specimens from the Manhattan coroner’s office. Then the Manhattan office abruptly cut off their supply, and they were forced to go abroad.

“Now we get our brains from Macedonia,” she says. “We have a number of psychologists and psychiatrists there with whom we collaborate. We work closely with them to assure adherence to very strict protocols. We are looking for a very specific type of sample—there can be no drugs in the body, and the brain needs to be intact and free of neurological disease. The brain must also be frozen within 24 hours, but the earlier the better. That preserves the integrity of all the information in the brain we are looking for. Then, for each specimen, our people in Macedonia do what is called a ‘psychiatric autopsy,’ a structured interview with survivors, family members, and healthcare professionals to find out the healthcare history for each person, what the precipitants of their suicide were, and generally what the person was like.”

She continues: “The findings are reviewed by a team of psychiatrists here and we come up with a provisional psychiatric diagnosis. For each ‘suicide brain,’ we must do a matched control—matched by sex, age, postmortem interval, and race—with which to compare it. So if we have a 40-year-old Caucasian man who died, say, by hanging, we need a matching sample of a white male between age 38 and 42 who died in a natural way, and who had taken no drugs for three months before dying. We don’t want the drugs to confound the brain chemistry.”

Later I see the details of one such matched pair in a study she gives me:

Suicide brain: 28 year old white female, brain stored for 4547 days, fell from a height, with diagnosis of major depression and eating disorder, post mortem interval 19 hours.

Match control brain: 27 year old white female, brain stored for 4313 days, died of a motor vehicle accident, no psychiatric diagnosis, post mortem interval 15 hours.

Given all these procedures, I think, it’s remarkable they’ve collected 261 brains, and that it’s taken them 21 years.

Remembering Clients Lost

While Arango and I talk, I find myself thinking of Juan, one of my clients when I ran a supportive housing program for formerly homeless people with mental illness about three blocks away from where we now sit. Juan died by suicide, or probable suicide, and I imagine his brain would have been interesting to Arango. I’d like to know what she’d have found in it.

When I first met Juan, he described his previous life—the life when he used every drug he could snort, ingest, or inject, though heroin was his primary addiction—as that of a “Puerto Rican punk gangbanger,” who was homeless, opportunistic, depressed (he’d had a number of suicide attempts), and mean. His former zeal for substances was such that on the last day of his brief career as a machinist, he took a bunch of pills and got very drunk, reported to his work station, took a deep breath, and jammed his finger directly into a circular saw. His finger was immediately sliced off and he was rushed to the emergency room. Ultimately, he received a $30,000 payout from the company, which wanted to avoid insurance claims and litigation. Juan used the cash to buy a host of street drugs.

By the time I met him, he’d been clean for three years, and he was anything but disreputable. Modest, well-spoken, polite, and trying to make amends, he was earnestly pursuing a difficult reconciliation with his wife and three kids (whom he visited each weekend at their rundown Bronx apartment). He was taking classes at a community college with the goal of becoming a physician’s assistant, was repeatedly elected to be the client representative in his housing residence, and was the leader of the substance abuse prevention group

Juan had thick black hair, which he wore slicked back, in a ponytail. He had a broad, handsome face, and was often smiling, a few missing teeth showing. He had any number of highly idiosyncratic beliefs and behaviors. His diagnoses, other than major depression, were bizarre and vague: “intermittent explosive disorder” and “psychotic disorder NOS.” What those meant, in English, was that he apparently had a rough time keeping his temper (although I never saw evidence of that: in all my experience with him, he was the embodiment of equanimity) and that, as he related to me after I got to know him well, he believed that a woman who’d stood a few feet from him in the line at a Bronx movie theater sometime in the mid-’80s cast spells over him. In some insidious way, she controlled everything, or everything bad, in his life.

I could never ascertain what it was about that person—a bystander, whom Juan never spoke to—that instilled such a deep-seated belief. He’d sort of trail off when bringing up the story of the woman in the movie line. It was clearly too painful a subject to speak about.

His morbid, brooding nature was occasionally misinterpreted by inexperienced clinicians. A novice psychiatrist once called me to say that she was hospitalizing Juan because he’d revealed in their session that he’d wanted to go back to sleep that morning after waking up. The doctor interpreted this as an indication of suicidality, and she hospitalized him against his will that same day. I knew him well enough that I felt, in this instance, he was really just saying he wanted to go back to sleep.

At a less clinical level, Juan was deeply absorbed with the pop star Prince, all things having to do with American Indians, and Bruce Lee movies. He named his son Brandon, after Bruce Lee’s son. His favorite sports team was the Chicago Black Hawks, simply because their jersey features the silhouette of an Indian in full battle regalia. I was deeply moved when he once spontaneously gave me a Black Hawks jersey, which hangs in my closet to this day.

He was heavily involved with the Santeria, a traditional Caribbean religion. In his room was an ornate and beautiful Santeria shrine, filled with incense, candles, little figurines, photos of his family, and unusual objects of all kinds. I suspected that, by means of his shrine and prayers, he was continually trying to execute a reverse hex on the woman in the movie line.

I was at home watching the New York Jets on television when I got a call that Juan had died. That weekend, he’d gone to visit his family and was found by his wife Sunday morning collapsed in the bathroom, a heroin syringe on the floor. While it’s possible that he’d picked up some heroin and inadvertently overdosed, that wasn’t the way I interpreted it. The levels of heroin detected in the autopsy were high, and Juan, who was expert in all matters pharmaceutical, would have known that such an amount would likely be fatal for someone who hadn’t used for years.

He’d recently been going through a lot of stress with his wife, and, in response to concerns that neither he nor his wife was capable of taking care of the kids, the department of child services had been called. The department’s investigators had started an inquiry after finding no food in the refrigerator during their first visit. Juan had been defiant and despondent about this turn of events. He loved his wife and kids, even if he had a limited ability to take care of them.

The staff and residents of the supportive housing residence were devastated by his death. All of us, except for a paranoid person who never left his room, attended Juan’s funeral in a Roman Catholic barrio church a few feet from the el. The church rattled to its foundations each time a train passed. The priest condemned Juan’s manner of death and neglected to offer the Eucharist. I remember thinking that Juan would have much preferred a Santeria ceremony and hoping that his family was going to arrange for one. I recalled—as one always does, morbidly, in these situations—that the last time I’d spoken to him he’d been wearing a black T-shirt covered with hundreds of little skulls. Was that a sign he was suicidal? Why hadn’t I questioned him about the shirt? Instead, I’d talked to him about how his budgeting was going.

Conversing with Arango brings thoughts to mind of another client who committed suicide: Michael. I worked intensively with Juan and Michael in the capacity of a counselor and program director. While there were immediate “psychosocial stressors” for both of them, I wondered what separated them from any number of equally troubled clients who didn’t take their lives. Was it their brain chemicals? Did the supports that they received from me and many other people really make no difference? Should I have just let the neurotransmitters fire away and stand back, because their lives and deaths were just a preordained journey, to which my work was utterly and completely irrelevant?

A Look at the Science

Arango interrupts my reveries. “Would you like to see the brains?” she says.

“Yes,” I answer, a little tentatively.

We walk down the hall and enter a back room. It’s about 20 by 40 feet and cold, filled with banks of six-foot freezers. Arango opens one to reveal racks upon racks of plastic bags, each with an extremely detailed label. Each bag contains a frozen, pinkish-grey substance, which I can’t make out exactly, so the general picture isn’t quite as morbid as I’d feared. For some reason, I’d expected to see the brains intact, under glass domes or something.

“We must always keep the brains frozen at minus 80 degrees centigrade,” says Arango. “We were very worried when there was a blackout in Manhattan a few years ago and Upper Manhattan lost power for three days. We have a backup generator, but I came here myself, with my husband and others, and stayed here the whole time just to make sure everything was okay. We cannot lose our brains!” she says, with sudden vehemence.

Arango was teaching neuroscience to first-year medical students when she answered an advertisement from Mann, who was seeking a research associate. Initially, she had no idea of what aspect of neuroscience he was studying, but she was intrigued and excited when she learned more about his work. She tells me that she’s personally been touched by suicide: two of her cousins, who suffered from severe mental illness, committed suicide, and while she was studying for her doctorate, a fellow student who was a good friend killed herself. “She died of an overdose, and she used my pharmacology textbook to tell her what drugs to take,” Arango says, her voice trailing off.

We leave the freezer room and go on to other parts of the lab. There’s a room for treating and preserving the brains with a huge variety of chemicals and dyes, a room for sectioning the brains, a room for computer analysis, and numerous offices for the postdoctoral candidates and faculty. The New York City traffic below on Riverside Drive is visible, but can’t be heard in the lab. On the walls are large images of neurotransmitters, posters from past presentations and conferences, and copies of recent papers. The whole place has an air of happy productivity.

Arango introduces me to the international staff. The brain sectioner, Manuela, is Cuban. She used to work as a housekeeper in the hospital, until Arango discovered and promoted her. A lab scientist is from Iraq, with a master’s degree from a university in Baghdad. A postdoctoral student is from Italy. Helene, a junior scientist, is Russian American. Victoria is originally from Colombia, and Mann is Australian.

Manuela happens to be in the middle of cutting a frozen brain block using a rather boxy-looking machine called a Cryostat. With it, she cuts a piece of brain that looks exactly like a defrosting pork chop into minute sections the width of a human hair. If Manuela weren’t so soothing a presence, it would be at this point that I’d feel nauseous.

As I watch her work, it’s evident that she’s an artist at brain slicing. After the section has been cut, she deftly places it between two glass slides, and then pats the outside of the glass with her fingers. I realize she’s defrosting it with the repeated, firm taps of her fingers. The hair-thin section within the glass quickly takes on a beautiful glow, like a hologram.

Manuela explains that the brains are collected at autopsy and “flash frozen” in Freon at minus 20 degrees centigrade. Then they’re stored at minus 80 degrees centigrade, sometimes for years, until they’re sectioned. She tells me that when they’re collected, the brains are divided into right and left hemispheres, and then a hemisphere is cut into 10 or 12 blocks. Manuela produces 160 sections from each block.

Once securely placed on the glass, the samples are frozen until the day of the experiment, when they’re brought to room temperature and dried under vacuum. Each brain section goes through 20 different treatments—exposure to radioactive chemicals, immersion in liquids—repeatedly. Each step takes from a few minutes to a few hours. At the end, the slides are placed next to X-ray film and exposed in the dark for varying times, depending on the experiment. The presence of radioactivity in the molecules creates images on the film, and the exposed film reveals the different receptors that tell the story of the serotonin, allowing the scientists to measure the amounts present in the brains of those who committed suicide and those who didn’t.

Many things about the lab surprise me. I’m amazed at how “low-tech” the equipment is. Other than the computer equipment, it reminds me of a larger, more deluxe version of my high school lab. There’s an organized trail of beakers, vials, tubes, and metal trays; lots of microscopes; and numerous technicians in white coats. It all looks like it could be from the ’50s. I was expecting to see huge computers and whirring brain-imaging machines.

For two decades, Mann and Arango have been the principal investigators at this center, the only federally funded program to research suicidal behavior across the life cycle. “We’ve learned from earlier work that alteration in the serotonin system, which is under significant genetic control, may be a predictor for suicidal behavior,” Mann says. Their inquiries have led them to zero in on the prefrontal cortex, the area of the brain that lies behind the forehead, which is the source of the brain’s “executive functions,” including controlling impulsivity. This characteristic has long been implicated with suicide. While some people anticipate their suicides—making elaborate plans, leaving detailed notes, laying out insurance papers—many others do it as a spontaneous act, the product of a temporarily imbalanced mind. “Carefully planned acts of suicide are as rare as carefully planned acts of homicide,” wrote suicide researcher Erwin Stengel in 1964.

Studies have shown that people under extreme emotional stress are prone to extreme cognitive distortions. “Most people,” Stengel noted, “in committing a suicidal act, are just as muddled as when they do anything important under emotional stress.” Even a day later, the distortions may lift, and someone who almost committed suicide may see life and its daily problems in a far different light. Many survivors of a suicide attempt have attested to how fortunate they feel that they didn’t die, and have said that what led them to hurt themselves was a temporary loss of control or balance.

Uncovering the Underlying Causes of Suicide

In seeking the biological basis for suicidal impulsivity, Mann and Arango’s work has increasingly focused on the presence of serotonin, or lack thereof, in certain parts of the brain, particularly the prefrontal cortex. Serotonin seems to exert a calming influence on the mind in ways that aren’t completely understood. Thus the presence of serotonin, in the right place and the right time, might make a person more balanced and less impulsive.

Arango and Mann reviewed studies from the 1960s that found that the brains of patients who killed themselves contained abnormally low levels of serotonin and its major breakdown product, the metabolite 5-hydroxyindoleacetic acid (5-HIAA). The studies also found that in only half of these suicides did the patients suffer from depression—the other half had diagnoses of schizophrenia, alcoholism, and personality disorders.

Because these early researchers were investigating the causes and effects of depression, their study of suicides was abandoned at this stage. But a succession of later studies in the 1970s showed that patients with low levels of 5-HIAA in their spinal fluid made a greater number of serious or lethal suicide attempts. What Mann and Arango gleaned from this earlier work was that the decrease in serotonin and 5-HIAA didn’t relate to the patient’s psychiatric diagnosis or method of death, but instead related solely to their committing suicide—the link was between decreased serotonin and suicide, not diagnosis.

The next step for the team was to develop a method of examining serotonin activity at the cellular level. Through years of trial and error, they found a method of performing several different biochemical tests on the same brain slice and ascertaining the exact anatomical locations of the variations between the samples they’re evaluating. The slices then were reassembled virtually, using special software, allowing Mann and Arango to produce an overall model of how those abnormalities might operate together to influence behavior.

With their new tools, they’ve found further differences between the brains of people who commit suicide and those who don’t. For instance, the neurotransmitter acetylcholine may be implicated in suicidal behavior, while the brain chemical norepinephrine has probably been ruled out as an influencing factor.

Recently Arango has uncovered a further, illuminating discrepancy among the brains of those who choose to kill themselves: the brains of suicide subjects have about one-third fewer presynaptic serotonin transporters and about one-third more postsynaptic serotonin receptors. Arango believes this indicates that the brains of suicide subjects are desperately trying to compensate for the low serotonin levels, attempting to “make the most of every molecule of serotonin they have” by increasing the molecular equipment that senses the neurotransmitter. Clearly, though, the brain’s compensatory mechanisms or the use of antidepressants aren’t always enough. As she says, “They can be so sick, Prozac can’t help them.”


Considering the Implications

Arango is working with people who are already dead. What can all this information do for the living?

While knowing the levels of 5-HIAA holds great promise as a predictor of future suicidal behavior, measuring those levels in a living person requires a spinal tap—an expensive, painful, and difficult procedure. The next step for Mann and Arango is to develop something along the lines of a Positron Emission Tomography test to detect those who might be at risk for the “dysregulaton” of suicidal behavior. Such a test would be vastly less invasive and could become a feature of sophisticated clinical practice. Patients shown to be at risk would then be referred to early, preventative psychiatric treatment (both pharmacological and psychotherapeutic). As Mann has written, “Protecting the patient against suicide in this way buys time for the treatment of the depression and other psychiatric disorders that underlie their suicidal wish.” Arango and Mann’s work could ultimately save many lives.

I realize I’ve been thinking, somewhat despondently, of Juan and Michael throughout my visit to the lab. I’d been intensely involved in their lives, because they were so needy, and because I liked them both a lot. I did my best, under the circumstances, to help them—to get them into treatment, to help find them a decent place to live, offering counsel and advice, but mainly just listening to their problems and stories. Based on their brain chemistries, though, was everything already stacked against them?

I ask Arango: was it all for nothing?

“No, absolutely not,” she says. “Biology, mental illness, life events, personality traits, and genetics—all are involved in suicide. While I think that nobody will kill themselves without biology, it is just one part of it,” she adds. “Environmental factors, or factors that are influenced by the environment—life events, personality traits, psychiatric disorders—are all huge players. And even genetic expression is related to the environment. My work involves the interactions of all these factors. In other words, we are not biologically predestined.”

Indeed, recent research shows that mind and brain are inseparable. The work of Eric Kandel, and others, has shown that the common metaphor that compares the mind to a computer, with unmodifiable hardware (a brain) and malleable software (thoughts, memories), is entirely misguided. Rather, thoughts and feelings can actually change the structure of the brain—that is, the software modifies the hardware. It’s all a two-way street—one’s life experiences are capable of changing the biochemistry of the brain.

But the current trends in psychiatry are mostly toward altering the brain’s chemistry, rather than working with the mind. I worry that that subtleties of Victoria Arango’s message are lost on some practitioners, who don’t realize that the mind, personality, free will, and—dare I say—soul all remain central to the question of whether, and how, we live or die.

As I leave Arango’s office, my thoughts flash to something I once read about the pattern of suicides from the Golden Gate Bridge. Since the bridge opened, in 1937, more than 1,200 people have committed suicide from it, making it the most “popular” place to kill oneself in the world. Ninety percent of those suicides plunge to their deaths from the San Francisco side of the bridge, with its views of the city. Only a small portion chooses to spend their last moments on the Pacific side of the bridge, with its endless void of water and what Jack Kerouac called an “end of continent sadness.” While there may be a practical explanation—the city side of the bridge is easier to access—the overwhelming discrepancy in numbers is striking.

It seems to me that these figures indicate the persistence of an essential human characteristic. Even in their final, desperate act, soon-to-be suicides yearn to be connected to people, to society, to all those myriad human influences—positive and negative—that have led them to the precipice.

Charles Barber

Charles Barber is the author of Comfortably Numb: How Psychiatry Is Medicating a Nation and Songs from the Black Chair: A Memoir of Mental Interiors. He’s a senior administrator at The Connection, a social services agency, and a lecturer in psychiatry at the Yale University School of Medicine.