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  There are many lines of evidence to suggest that serotonin functioning in the brain is determined by both genetic and environmental factors. Genes certainly are important. Rhesus monkeys separated from their biological parents and raised by an unrelated “wet nurse” monkey have CSF 5-HIAA levels similar to those of their biological parents. Impulsivity and aggressiveness are strongly heritable in both humans and other animals. And specific genes (such as the tryptophan hydroxylase, or TPH, gene) have been isolated that appear to be involved in CSF 5-HIAA concentrations, as well as being associated with impulsivity and suicide attempts.

  But rearing patterns and the social environment exert a strong influence as well. Adult male vervet monkeys, for example, appear to show a day-to-day consistency in their blood serotonin concentrations as long as they are living in stable group environments. When there is a shift in a group’s dominance pattern, however, the transition from a lower to a higher position is accompanied by an increase in serotonin. When dominant male vervet monkeys are isolated in cages and have no visual or tactile contact with other members of their group, their serotonin concentrations drop by 50 percent. If they are returned to their original social group, their serotonin concentrations rise to their original levels.

  Studies of rhesus monkeys have shown the importance of maternal influences on serotonergic functioning and social behavior. If infant monkeys are separated at birth from their mothers and reared with other infants of their own age—thus allowed to grow up without any adult influence on their behavior—several things happen. First, they are unable to control their impulses as well as monkeys that are raised by their mothers: their aggression escalates out of control much more quickly; they are more likely to consume alcohol in excess; and they are more likely to be aggressive toward infant monkeys. They also have more difficult relationships with their peers and are more likely to be wounded and to have to be removed from their social group.

  The mother clearly plays an important modulating role in the infant’s developing serotonergic system. Critically, when the CSF 5-HIAA levels of peer-raised monkeys are examined, they are significantly lower than in monkeys raised by their mothers. If the peer-raised monkeys are given serotonin reuptake inhibitors (antidepressant drugs that increase the availability of serotonin in the brain), their levels of aggressiveness and alcohol intake are reduced. While it is unlikely that any single explanation, such as elevated or decreased serotonergic functioning, can begin to explain the highly complex chemical events and interacting neurotransmitter systems in the brain, primate experiments provide an exceptionally interesting and valuable way of looking at aggressive and self-destructive behaviors.

  The evidence is strong that serotonin inhibits violent, aggressive, and impulsive behavior, but what do we know about the connection between these behaviors and suicide? Several lines of observation converge to support a compelling association. First, we know that suicidal acts are often impulsive; that is, they are undertaken without much forethought or regard for consequence. More than half of suicide attempts occur within the context of a premeditation period of less than five minutes, and many researchers and clinicians, as well as patients who survive medically serious suicide attempts, lay stress on the role of impulse in the decision to commit suicide. (Although many suicidal patients have well-formulated plans for suicide, the ultimate timing and final decision to act are often determined by impulse.) Professional handwriting analysts, when asked to distinguish between suicide notes written by those who have actually committed suicide and notes using the same wording but written by nonsuicidal individuals, are easily and consistently able to differentiate the two groups; the writing of those who kill themselves is judged by the graphologists to be highly “impulsive,” “aggressive,” and “agitated.”

  Suicidal patients, in addition to being more impulsive, are also more likely to commit violent or aggressive acts than nonsuicidal patients. In one English study, those who actually killed themselves were three times more likely to have had a history of violent behavior than individuals matched with them for age, gender, and social class. The argument for a relationship between violence and suicide is further bolstered by many international investigations that demonstrate that homicide is frequently followed by suicide. In England and Wales, for example, murder is followed by suicide 33 percent of the time. Most other countries show high murder-suicide rates as well: Denmark (42 percent), Australia (22 percent), and Iceland (9 percent). (However, in countries with very high homicide rates and easy access to firearms, such as the United States, the murder-suicide rate is much lower—for example, 1 to 2 percent in North Carolina and Los Angeles and 4 percent in Philadelphia.)

  In addition to the evidence for a relationship between violence and suicide, there is evidence of heightened irritability and violence in several of the major psychiatric conditions most associated with suicide. Although the majority of people who suffer from depression, manic-depressive illness, schizophrenia, or personality disorders are not more violent than the rest of the population, there are some phases of illness that are not infrequently accompanied by physical violence. This is particularly true for the acutely paranoid and agitated phase of schizophrenia and for the mixed states associated with manic-depressive illness and for mania itself. Nearly 50 percent of all manic episodes are characterized by at least one act of physical violence; this proclivity to violence is further compounded by the drinking that frequently accompanies mania. Extreme irritability is also a hallmark of mood disorders, present in 80 percent of episodes of mania and depression and virtually always during mixed states.

  Given the connection between neurotransmitter functioning and depression and the impressive series of studies demonstrating a link between serotonin functioning and impulsive, aggressive behaviors, it is not surprising that clinical researchers next turned to comparing serotonin functioning in suicidal and nonsuicidal psychiatric patients. The result of their studies were unexpectedly consistent. In fact, one of the most replicated findings in psychiatric research is the association between suicide risk and low levels of CSF 5-HIAA, the serotonin metabolite. Although some scientists have questioned the methods and findings, more than twenty studies document that across diagnostic groups (mood disorders, alcoholism, personality disorders, and schizophrenia), low concentrations of CSF 5-HIAA are associated with a significant increase in suicide risk. The lifetime severity of aggressive behaviors and the severity of suicide attempts both are correlated with CSF 5-HIAA levels.

  Marie Åsberg and her colleagues at the Karolinska Institute in Sweden, as well as scientists from other countries, have shown, for instance, that if CSF 5-HIAA is measured in patients with mood disorders after they have attempted suicide, those with very low concentrations of the serotonin metabolite are far more likely to be dead from suicide within a year than are those with higher levels. It is possible that a low CSF 5-HIAA level is correlated with a tendency to act impulsively and violently while in acute emotional turmoil or during a severe episode of psychiatric illness.

  Low CSF 5-HIAA levels are found in many psychiatric and behavioral syndromes other than heightened suicidality, but most of them, like suicide, are associated with problems of impulse control: for example, children who are impetuously aggressive or who are cruel to animals; alcoholics who are particularly aggressive, even when sober; depressed patients with histories of marked argumentativeness, frequent clashes with colleagues or employers, or sporadic contacts with the police; individuals with bulimia or Gilles de la Tourette’s disease; and impulsive arsonists or others who engage in a pattern of impulsive criminal behaviors. People who are highly obsessive and inhibited, on the other hand, such as those suffering from anorexia nervosa or obsessive-compulsive disorder, tend to have relatively elevated levels of CSF 5-HIAA. (Interestingly, obsessive-compulsive disorder, unless it is accompanied by severe depression, is one of the few major psychiatric illnesses that do not seem to place their sufferers at an increased risk for suicide.) Smoking ciga
rettes, which is far more common in those who commit suicide than those who do not—and also more common in patients with schizophrenia, alcoholism, depression, and antisocial personality disorder—appears to be associated with low CSF 5-HIAA levels. It is unclear whether smoking causes the reduction or a low level of serotonin functioning increases the likelihood that an individual will take up or persist in smoking.

  The association between serotonin and suicide is further supported by postmortem studies of the brains of individuals who have killed themselves. The evidence is strong that there are serotonin abnormalities in the prefrontal cortex of the brain, an area strongly implicated in the inhibition of behavior. Reduced serotonergic functioning in this part of the brain may cause disinhibition, which may in turn result in acting precipitously on suicidal thoughts and feelings.

  The number of noradenergic neurons in the brains of completed suicides also appears to be markedly depleted, suggesting a pathology in the circuitry of norepinephrine, a transmitter implicated in sleep regulation, depression, attention, and the sleep-wake cycle. These changes in the noradenergic system may be due to abnormalities in the development of the brain or to the effects of acute or chronic stress. An acute or chronic stress, such as depression, alcoholism, or a shattering emotional setback, may trigger the serotonergic vulnerability, precipitating a lethal cascading of biological events within the brain.

  The hypothalamus, pituitary, and adrenal glands are primary actors in generating the chemicals regulating the body’s response to stress. Under normal circumstances, the release of stress hormones such as cortisol and adrenaline (epinephrine) will increase heart rate, suppress hunger, and pulse more blood to the muscles; in short, it will mobilize an animal’s adaptive response to stress. But if for some reason—early trauma, genetic factors, mental illness—this stress response cannot be shut off, the result may be prolonged and dangerous. Rats, if subjected to stressful experiences at the time of birth or prematurely separated from their mothers, may show irreversible social and cognitive damage. If, on the other hand, rat pups are exposed to more intensive grooming and licking from their mothers, their later ability to learn, explore, and interact with other rats is enhanced.

  In humans, a hyperactive stress response, which is set into play by both biological factors and experience, may adversely affect mood, immune activity, and serotonin functioning. Pathological levels of anxiety and agitation, both implicated in suicide, are not uncommon. Autopsy studies of suicide victims reveal evidence of hyperactivity in the hypothalamo-pituitary-adrenocortical axis, lending further support to the role of stress in suicide.

  Scientists have repeatedly found significant brain pathology when conducting imaging studies (pictures taken of the brain, such as positron-emission tomography, or PET, scans) of the anatomy and functioning of the brains of patients with depression, schizophrenia, or manic-depression—showing, for example, in bipolar patients that there is an enlargement of the amygdala, which is involved in generating emotions and regulating mood; an increase in white-matter lesions, known as hyperintensities, which are associated with the water content of brain tissue; and severe depletions in the number of glial cells, which are involved in the development of the brain and also provide growth factors and nutrients to the nerve cells—and it is possible that repeated psychosis or depression may exacerbate the already fragile chemistry of a vulnerable brain. There is some evidence that structural changes in the brains of patients with chronic schizophrenia may correspond with suicide attempts and that white-matter lesions in patients with Alzheimer’s disease may be associated with the presence of suicidal thinking. Eileen Ahearn and her colleagues at Duke University are currently studying the relationship between suicide attempts and hyperintensities in the periventricular region of the brain, an area concerned with, among other things, stress response and biological rhythms. These studies are preliminary only and complicated by possible changes to the brain brought about by psychiatric medications, but they are indicative of the direction of an important field of suicide research.

  Scientists have also been looking at the possible effects of serum lipids, such as cholesterol and polyunsaturated essential fatty acids, on depression and suicide. Concerned by reports that individuals who had low cholesterol levels (either naturally or because they had made dietary changes, exercised more, or taken cholesterol-lowering medications) were more likely to die prematurely from suicide, investigators sought to understand the link. Not every study showed an association between suicide and low cholesterol levels, but enough did to warrant taking it seriously.

  Several explanations were set forth. Some researchers suggested that low cholesterol levels were simply an artifact of the real cause of suicide, namely, depression; many people, when depressed, lose weight, and their cholesterol levels drop accordingly. What looks causative may therefore, in fact, be incidental. However, a few studies, which controlled for weight loss and diet, still found a link.

  Other scientists, including Jay Kaplan at the Bowman Gray School of Medicine in North Carolina, believe that cholesterol intake affects serotonin functioning and behavior in critical ways. In a series of intriguing studies on macaque monkeys, he and his colleagues studied social behavior and plasma lipids. For two years, monkeys were fed diets either high or low in saturated fat and cholesterol. Their behavior was rated for fleeing, attacking, grooming, and social isolation. The monkeys fed a low-fat diet exhibited more extreme physical violence than those that were not. Other studies conducted by the same scientists confirmed that cholesterol-lowering diets potentiate aggressive or antisocial behavior. Low cholesterol was also linked to low serotonergic functioning in other investigations.

  Kaplan and his colleagues propose that the links among cholesterol, aggression, and serotonin functioning may have served an important evolutionary role: When foods high in animal fat were abundant, the resultant relatively high serotonergic activity in the brain may have created “behavioral complacency.” In times of food scarcity, on the other hand, especially when the scarcity involved foods rich in animal fat, a low plasma cholesterol level may have precipitated impulsive, risk-taking behavior such as aggressive hunting and foraging.

  The links among cholesterol, serotonergic functioning, and suicide are an important theoretical concept, as well as one that has potentially critical clinical implications. But the evidence so far is mixed, and much more research is necessary before any conclusions can be reached.

  Among the scientists disputing the centrality of cholesterol in depression and suicide is Joseph Hibbeln, a researcher in the Laboratory of Membrane Biophysics and Biochemistry at the National Institutes of Health. He strongly believes that the important lipid players are actually the omega-3 essential fatty acids, not cholesterol, and speculates that one reason for the increasing rates of depression and suicide during recent decades may be due to an increase in society’s consumption of saturated fatty acids, coupled with a decrease in the intake of omega-3 essential fatty acids, found in fish. Low plasma concentrations of these fatty acids, which are selectively concentrated in neural tissue, are associated with low concentrations of CSF 5-HIAA. Societies that consume a large amount of fish (for example, Japan and Taiwan) appear to have lower rates of depression, though not necessarily suicide, than those that do not (for example, Germany and New Zealand).

  Paleolithic and modern hunter-gatherer populations, Hibbeln and others argue, consumed a diet much lower in saturated fats (and higher in polyunsaturated ones) than the modern diet. As agriculture became more specialized and focused on raising fewer plant species, the animals that were used as the basis of our food supply had a commensurately lower proportion of the necessary fatty acids. Hibbeln and others estimate that during the earlier periods of human evolution the ratio of saturated to polyunsaturated fats was perhaps one to one; in current diets that ratio is as high as twenty-five to one. Over the past fifty years, the widespread use of infant formula, which, unlike breast milk, contains virtually no polyunsatur
ated fats, may have resulted in subtle neurological deficits that have had an effect not only on mood and behavior but possibly on rates of suicide as well. The results from the studies of omega-3 essential fatty acids are preliminary, and await replication before their significance can be established.

  Studies of cholesterol and essential fatty acids raise core questions about the development of the nervous system, the possible effects of diet on depression, aggression, and suicide, and potentially critical issues of clinical assessment and treatment. (There may be a link between impaired fatty acid metabolism and schizophrenia as well, as suggested by researcher David Horrobin in Scotland.) The findings so far are by no means definitive, but by all means fascinating.

  CERTAINLY, MUCH is decided by our biology. Genes, in the main, determine our temperaments, and our temperaments in turn influence our choices about which environments we seek out or avoid. Our temperaments also mold how we respond to our environments and how we are shaped by them. For those who are low-key and stable, a disappointment or rejection, the loss of a job or the end of a marriage, or an extended bout of depression will be painful and distressing but not life-threatening. For those with a short wick, a savage temper, and impulse-laden wiring, life’s setbacks and illnesses are more dangerous. For them, it is as though the nervous system had been soaked in kerosene: a fight with a lover, a gambling loss or a run-in with the law, or an irritable flash from a mental illness can ignite a suicidal response.

  Most who encounter the ordinary, if awful, stresses and losses handed out by life handle them well or reasonably well. In fact, very few people commit suicide under even the most terrible and prolonged situations of physical or mental suffering. Yet there are others who are impelled by the seemingly slightest of reasons to reach for a gun or throw a rope across a beam. For these more biologically vulnerable, the threshold for suicide is very low; their flash point may be triggered by the inconsiderable. For yet others, the threshold may be low but not dangerously so; in the presence of depression, schizophrenia, alcoholism, or crippling anxiety, however, the threshold may drop precipitously.