Issues related to Human Nature
Aggression, Suicide, and Serotonin:
Is There a Biochemical Basis for Violent and Self-Destructive Behavior?
Donald F. Calbreath*
Whitworth College
dcalbreath@whitworth.edu
300 W. Hawthorne
Spokane, WA 99251
From Perspectives on Science and Christian Faith 53.2 (June 2001): 84-95.
Contemporary biomedical science has attempted to explain behavior in terms of genetic determinism, with specific mental states being produced by alterations in the brain concentrations of one or more specific biochemical components. The literature relating to the presumed association between low brain levels of the neurotransmitter serotonin and aggression and suicide is reviewed and critiqued. Due to the variety of methodological shortcomings in this research, conclusions based on the data cannot be considered valid. Implications for the legal profession and for Christian moral principles are discussed.
What Determines Behavior?
The debate about what molds human behavior--nature versus nurture--has been with us for a long time. However, in the last two decades or so, questions have intensified as an outpouring of new discoveries in the neurosciences has become available. Whether the phenomenon is called "sociobiology"1 (a term popularized by E. O. Wilson) or the idea of "biological determinism" and the "selfish gene"2 (a concept promoted by Richard Dawkins), a growing body of scientific literature suggests that many behaviors may be produced by changes in biochemical processes in the body. For conditions ranging from depression through overeating to risk-taking and sexual immorality, arguments are being made that we do these things as a result of our individual genetic make-up and as a result of biochemical imbalances in the brain.
In addition to issues of personal responsibility and behavior, there is a growing interest in the legal profession about questions dealing with neurochemical imbalances and legal liability for an individual's actions. Over the years, several court cases have dealt with the question of alcoholism and an individual's responsibility for his actions. A review article in the Bulletin of the American Academy of Psychiatry and Law focused specifically on information related to serotonin and behavior.3 The writer called on forensic psychiatrists to be more aware of the current neuroscience literature on how actions are influenced by biochemical changes so that these findings could be incorporated into a better understanding of the legal issues before the courts today.
For the Judaeo-Christian tradition, the question is cast further in terms of individual responsibility, sin, and accountability to God. If we are driven solely by biochemical processes over which we have no control, then are we to be held accountable for our behavior? Do the findings of modern science create a situation in which sin no longer exists because we no longer are in control of our lives?
Given the variety of concerns that exist about the relationship between biochemistry and behavior and the implications, both legally and theologically, of current research in the field, a careful examination of the professional literature is justified. Christians need to evaluate the available information and to explore the consequences of accepting conclusions based on this research. The focus of this paper is on the relationship between serotonin and aggressive and suicidal behavior.
Serotonin Biochemistry
Structure and Function of Serotonin
Serotonin (5-hydroxytryptamine, 5-HT) is a neurotransmitter that is formed from the amino acid tryptophan. This molecule has a chemical structure similar to that of epinephrine (adrenaline) and dopamine, both of which are known neurotransmitters. Interestingly, serotonin is also structurally quite similar to the psychedelic drugs LSD, psilocybin, and DMT (dimethyltryptamine), all three of which possess hallucinogenic properties.
The first studies on biochemical properties of serotonin dealt with the effect of this compound in blood pressure.4 When serotonin was first isolated from blood in 1948, it was shown to promote constriction of blood vessels, increasing blood pressure. Although platelets do not synthesize serotonin themselves, they do pick up the molecules from the circulation. The molecule is also found in high concentrations in the intestinal wall (where it is synthesized) and is responsible for increased gastrointestinal mobility.
Biosynthesis and Metabolism
The amino acid tryptophan is the source of serotonin in the body; approximately 1% of the total tryptophan pool is converted to serotonin.5 Tryptophan initially undergoes conversion to 5-hydroxytryptophan, which then becomes serotonin. Inactivation of serotonin is accomplished by the enzyme monoamine oxidase, which also is involved in the inactivation of other neurotransmitters. The inactivation product is 5-hydroxyindoleacetic acid (5-HIAA). In the pineal gland, serotonin is changed to melatonin, a molecule involved in the regulation of processes associated with the light-dark cycle (and implicated in such phenomena as jet lag and seasonal affective disorder).
The major tissue site for serotonin synthesis from tryptophan is the gastrointestinal tract. Other sites include the thyroid gland, pancreas, and the thymus. These tissues are primarily responsible for the serotonin detected in the blood. The brain synthesizes its own serotonin from tryptophan which is able to cross the blood-brain barrier. Serotonin cannot cross this barrier, so the body essentially has two separate pools of serotonin: a blood-borne pool and a separate and distinct brain pool. The serotonin in the brain cannot penetrate the blood-brain barrier to reach the general circulation, and serotonin synthesized elsewhere in the body cannot enter the brain. Measurements of serotonin and 5-HIAA in cerebrospinal fluid (CSF) are thought to reflect the brain content of serotonin, since the CSF is formed in a portion of the brain and then drains into the spinal column.
Serotonin as Neurotransmitter
The propagation of a nerve impulse by serotonin is illustrated in Figure 1.6 Serotonin is synthesized and stored in vesicles in the pre-synaptic region of the neuron. When the nerve impulse moves down the fiber, it causes the release of serotonin molecules, which then pass from the pre-synaptic membrane, cross the synapse, and attach to specific receptors on the post-synaptic side. Interaction between serotonin and the receptor then continues the nerve impulse further down the fiber. Next, the serotonin dissociates from the receptor, is taken back up at the pre-synaptic site, and is either inactivated by conversion to 5-HIAA or is stored for reuse.
Where is serotonin located in the brain? How much is there? These are difficult questions to answer. Although serotonin neurons comprise only about 0.01% of the total number of neurons in the brain, these relatively few cells are connected to an extensive network of nerve fibers that extend throughout the entire brain. Serotonin nerve cells are clustered in the base of the brain and interact intimately with other types of neurons (mainly those stimulated by dopamine, epinephrine and norepinephrine). This complex interplay among several neurotransmitters makes the task of elucidating the specific behavior of serotonin and the influences this molecule exerts on the nervous system a daunting task.7
Age and Gender Differences in Serotonin Content
The literature on reference values for serotonin and 5-HIAA (normal values for age and gender) is sparse and confusing. In general, the CSF concentrations of the serotonin metabolite 5-HIAA are lower during middle age (35-55 years of age) than those seen in younger and older populations.8 This lower concentration correlates with the lowered amount of the enzyme monoamine oxidase (which converts serotonin to 5-HIAA) in the 35-55 year-old group. In addition, the number of serotonin receptors (which transmit the effects of serotonin to the nervous system) decreases with age in both men and women.
Significant gender differences exist in serotonin production and conversion between men and women. The rate of brain synthesis of serotonin in women is roughly half that in men.9 Some researchers have suggested that this lower rate of serotonin formation is responsible for the much higher incidence of depression (3:1) and eating disorders (10:1) in women than men. However, women have the same amounts of the 5-HIAA metabolite, possibly due to higher concentrations of the enzyme monoamine oxidase in the female brains. Women also have been shown to have a lower number of serotonin receptors than men.10
Searching for Markers of Aggression and Suicide
A large body of research focuses on the question of whether altered levels of serotonin in the body will precipitate aggression or suicide. Benefits in identifying such a predictive biochemical marker include both an improved understanding of these behaviors and possible pharmaceutical intervention to prevent many incidents of violent behavior toward others or oneself.
One positive outcome of this area of research is the identification of specific areas of the brain where abnormalities in serotonin synthesis, metabolism, or utilization occur. If there are sites where the "cause" can be localized, this information may suggest effective therapeutic interventions. An improved understanding of the possible malfunction can lead to the development of safe and appropriate pharmacological treatment. While these medications may not cure the problem (if it is indeed a genetically determined disorder), greater control over behavior can be achieved.
Christians involved in pastoral counseling and hospital ministry need to be aware of this research. Some disorders (such as schizophrenia and manic-depressive illness) apparently have a strong biological basis for their causes. If these situations and current medical developments in the field are understood, the ability to minister to patients and their families and to communicate these issues and concerns to others in the congregation will be enhanced. Pastoral counseling can be more effective in working with individuals and in educating the body at large.
A large body of research focuses on the question of whether altered levels of serotonin in the body will precipitate aggression or suicide.
Some behavioral disorders apparently have a biological cause and can be treated with good success. In many instances, schizophrenia, which appears to have some common ground with aggression and suicide, is very manageable with appropriate medication. Even though this disorder (which appears to have a strong genetic component to it) cannot be "cured" in the conventional sense of the word, individuals with schizophrenia can lead productive lives when a proper drug regimen is followed faithfully. Over 75% of persons with Cushings syndrome (due to a tumor on the adrenal gland) experience profound depression because of excessive cortisol production. In the vast majority of these patients, removal of the tumor leads to an alleviation of the depressive state as the cortisol levels return to normal. Although we do not yet understand all of the neurochemical issues associated with bipolar depression (manic-depressive illness), the manic phase has been successfully treated for decades with the use of lithium. A similar beneficial outcome might be seen in individuals prone to violence or suicide if a biochemical cause could be identified.
Much more problematic are the current trends related to the explanation of behavior based on neurotransmitter concentrations. On the one hand, we have extensive literature suggesting that our genes are our destiny, that our behavior is determined by our biochemistry. In other words, "it's not our fault." Current research can be interpreted in such a way as to remove the idea of personal responsibility for our actions. On the other hand is the reluctance on the part of some constituencies to explore all aspects of the issue of violence. Research on violence has been branded as racist because of concerns related to the use of the data.11 Certain ethnic groups and socioeconomic classes fear further stereotyping (often with good reason) as a result of investigations of violence in human society. Consequently, they strongly object to all studies on the topic, fearing the outcome of the study before it is even carried out.
What Parameters Are Studied?
Various approaches have been taken to investigate the relationship(s) between serotonin concentrations in the body and altered behavior. Many studies have been carried out using nonhuman organisms, including crabs, mice, and monkeys. For many reasons, it is difficult to extrapolate data and interpretations from animals to humans. Often metabolism, enzyme properties, and behavioral influences are not the same when studies from animal systems are extrapolated to humans. All of the information discussed in this article will deal with data from human subjects.
Direct information has been obtained from brain samples after death. Measurement of serotonin in these tissues gives some indication of the status of the neurotransmitter at a specific point in time. Information is not readily available concerning stability of tissue or neurotransmitter concentrations after death. Nor is there any reliable data as to the specific emotional state of the individual at the time of death. Many studies do not have a good way to assess prior drug or alcohol use, parameters that are known to influence serotonin concentrations.
In living subjects, serotonin metabolic rates can be indirectly assessed using magnetic resonance imaging and positron emission tomography (PET). The latter technique is an especially powerful tool for monitoring changes in serotonin concentration during the course of an experiment, providing real-time data on how rapidly this neurochemical is utilized in specific situations.
A somewhat less direct assessment of serotonin production by the brain has been employed in measuring cerebrospinal fluid (CSF) levels of serotonin or (more commonly) the concentrations of the metabolite 5-HIAA. The assumption is that CSF values correspond in some fashion to the concentrations in the brain, since most CSF is produced in the choroid plexus of the brain. The CSF circulates through various parts of the brain and also drains into the spinal column. Although methods for detection of either serotonin or 5-HIAA are fairly reliable, it is not clear how well the CSF concentrations accurately reflect the biochemical processes taking place in the brain itself. The average adult only has approximately 140 mL of cerebrospinal fluid, which effectively eliminates the taking of a number of samples in succession. In addition, the hazards associated with obtaining CSF samples preclude serial testing, using multiple samples to obtain a dynamic picture of changes that may be occurring over time.
Blood platelets have long been considered to serve as a model for neurons affected by monoamines such as serotonin. Platelets actively take up serotonin and store it in vesicles similar to those in pre-synaptic neurons. This uptake can be blocked by drugs such as tricyclic antidepressants. Several studies on the relationship between serotonin and behavior have examined the number of serotonin uptake sites and the binding properties of these sites in an attempt to gain a better understanding of serotonin biochemistry in various disorders.
A few investigations have examined the serotonin content of blood as a parameter that may affect the emotional state. While concentrations can be reliably assayed using sophisticated immunoassay techniques, the relationship between blood serotonin levels and brain concentrations is questionable.
Serotonin and Violent Behavior
Any research into the root causes of violent or aggressive behavior is fraught with pitfalls. Political agendas can override the presumably dispassionate scientific objectivity of research. Groups sometimes fear that the findings will be used inappropriately, to justify discrimination or to focus undue attention on particular segments of the population. In studies of the relationship between serotonin and aggressive behavior, ethnic background has been ignored whenever possible, perhaps due to the fear of creating unneeded controversy. Although some studies allow identification of ethnicity (research on arsonists in Finland,12 genetic studies on an isolated Dutch family13), race does not appear to be considered in research on violence.
Studies that relate serotonin and violence draw from three sources: (1) CSF or other body fluid measurements from those convicted of aggressive or violent behavior or those with a psychiatric problem associated with this form of behavior; (2) tryptophan restriction studies to explore how lowering of the precursor amino acid affects mood; and (3) studies of persons with seasonal affective disorder (in which serotonin levels and exposure to sunlight are linked).14
The most direct evidence for a link between lowered serotonin and aggression comes from CSF studies of violent individuals. These persons tend to have 5-HIAA values in the CSF that are lowered when compared to a "normal" population. Not well documented, however, is the relationship between low CSF levels of 5-HIAA (the metabolite) and brain serotonin. Do low levels of 5-HIAA in the spinal fluid necessarily correlate with low brain serotonin? In a previously mentioned Dutch family,15 the biochemical finding was a lowered level of monoamine oxidase, the enzyme responsible for converting serotonin to 5-HIAA. In this situation, there conceivably could be a normal (or elevated) brain serotonin content that is simply not being metabolized to form 5-HIAA in the CSF. Other concerns about these studies deal with the lack of reliable assessments of the tendency toward violence. A number of different measures are used, many of which do not correlate well with other means of assessing the same parameter.
The most direct evidence for a link between lowered serotonin and aggression comes from CSF studies of violent individuals.
Several studies have been carried out to examine attempts to alter brain serotonin in presumably normal individuals. Since no good pharmacological intervention exists to decrease brain serotonin content, the strategy has been to reduce tryptophan intake in the diet. The amino acid tryptophan is the precursor for brain serotonin; the assumption is that lowering tryptophan consumption will lower production of brain serotonin. While tryptophan restriction studies are more indirect, an increase in hostile and aggressive attitudes is seen in those whose dietary intake of tryptophan is decreased. However, these experiments have not directly demonstrated that serotonin is the only brain component altered. Other presumably unknown factors could play a significant role in the understanding of these data.
Even less conclusive are the arguments that attribute increases in aggressive behavior to seasonal affective disorder (SAD) and to presumed changes in serotonin concentration in the brain.16 SAD is considered to be a form of depression triggered by decreases in sunlight and the resultant changes in melatonin production by the pineal gland in the brain. While an increase in serotonin (produced by consumption of pasta or other similar complex carbohydrates) can often alleviate many of the symptoms of SAD, the major contributor to this form of depression is the melatonin cycle being disrupted by the change in the amounts and timing of light and dark in the environment. Apparently, multiple factors are involved in the depression and in the resulting violence seen in individuals affected by SAD.
Serotonin and Suicide
In contrast to the limited data available from subjects who exhibit aggressive or violent behavior, information from individuals who commit suicide is more comprehensive.17 Analyses of both brain tissue and spinal fluid yield interesting, but conflicting, information about the concentrations of serotonin and 5-HIAA in these samples. A number of studies have shown a decline in either serotonin or 5-HIAA concentrations in brainstem samples from suicide victims. However, measurements of these compounds in another area of the brain (the frontal cortex) suggest that no significant difference exists between serotonin or 5-HIAA concentrations in those individuals who committed suicide and in victims of accidents or other non-neurological fatalities. In addition, studies of 5-HIAA levels in CSF of persons who had attempted suicide show a mixed and inconsistent collection of results--some papers report decreases in values, others report essentially no differences in values.
Complications in the analysis of data in serotonin and suicide are many. Usually, no history of drug use, especially long-term involvement, is readily available. Some of the common modes of suicide (drug overdose and carbon monoxide poisoning) have not been evaluated in terms of the changes in brain chemistry that could be produced by the drug or by carbon monoxide. Brain tissue stability after death, time between death and autopsy, accuracy in removing and identifying the locale of brain samples, diet, and time of year are all parameters that will affect serotonin and 5-HIAA levels in the brain. These parameters have not been carefully controlled in the vast majority of the reported studies.
As is noted in the next section, decreases in CSF serotonin and/or 5-HIAA have often been reported in patients diagnosed with clinical depression. Many papers, looking at a possible link between low serotonin and suicide, examine depressed patients with suicidal behavior. Therefore, conclusions reached for suicidal patients must be considered even more questionable, since two variables (depression and suicide) are being mingled together in the data analysis.
Serotonin and Depression
Investigations of possible relationships between altered serotonin biochemistry and depression are of particular importance because of the possibility of manipulating these levels with drugs in an attempt to treat the depression.18 The original hypothesis of lowered serotonin levels resulting in clinical depression has not been well substantiated. Studies show mixed results, with some researchers reporting decreased 5-HIAA values in the CSF of depressed individuals, while others observe no difference in values between patients with depression and the control population. Tryptophan depletion in the diet can induce depression in some normal individuals (presumably due to the diminished availability of tryptophan for brain synthesis of serotonin), but gives variable results in patients who are already depressed.19 As previously noted, these studies do not demonstrate directly a decrease in brain serotonin; the presumed lowering is inferred from the dietary restriction on tryptophan. However, as we see in the next section, pharmacological manipulation of serotonin levels is widely used in modern-day psychiatric treatment for depression.
Furthermore, most studies do not provide clear boundaries that distinguish the types of individuals seen in the research. Patients are often suicidal and depressed, depressed and schizophrenic, schizophrenic and violent, violent and alcoholic, or any combination of the above. A well-defined patient population with only a single psychological issue does not appear to be available for study.
Prozac, Other SSRIs, and Serotonin
As the need for more effective antidepressants became obvious in the late 1960s, research began on a class of drugs known today as selective serotonin re-uptake inhibitors (SSRI).20 Prozac (fluoxetine) is probably the best-known product of this class of drugs. These inhibitors work primarily by blocking the ability of the pre-synaptic neuron to "reabsorb" serotonin after the molecule has interacted with the post-synaptic serotonin receptor to continue propagation of the nerve impulse (see Fig. 1, step 5). The net result is a prolonged exposure of the post-synaptic receptor to serotonin, effectively increasing the concentration of serotonin at that site. The rationale behind the use of SSRIs is that the elevated amount of serotonin at the synapse presumably alleviates some of the behavioral symptoms believed to be associated with low serotonin levels.
Prozac (first prescribed in the U.S. in 1988) and its companions appear to be better tolerated than the tricyclic antidepressants they are replacing, whose side-effects include dryness of mouth, sedation, and low blood pressure. The SSRIs appear to be more effective in treating depression than other classes of antidepressants, presumably due to the increase in serotonin at the post-synapse produced by this class of drugs.
The results of research on the use of SSRIs to modify suicidal or aggressive behavior are mixed.21 Few studies have been carried out to date. No large patient populations have been investigated. Treatment results are not consistent, since some patients show positive change while others demonstrate no improvement in behavior. Several investigations raise the possibility that SSRIs induce an increase in suicidal ideation among some patients,22 a behavior directly contrary to that predicted by the prevailing paradigm. If a true causal relationship between lowered synaptic serotonin and these behaviors existed, a more consistent relationship between SSRI use and alleviation of aggressive or suicidal tendencies would be expected. However, this relationship appears to be either weak or non-existent.
Problems with Studies on Serotonin and Behavior
At first glance, it might appear that the available data support the idea that low brain serotonin will produce changes in behavior that have a high probability of leading to aggression, violence, or suicide. However, a closer examination of the studies raises some significant methodological questions.
Inconsistencies among Studies
One concern is the inconsistent data obtained from the various research studies. Attempts to affect the brain supply of serotonin by either depleting or increasing body tryptophan loads provide mixed results in terms of the observed behavior. Some studies show the predicted effect, while others do not. Measurements of receptor numbers and binding affinity for serotonin are plagued by the fact that there are at least thirteen known serotonin receptors in humans, with little known about exactly which receptor mediates which neurochemical process.23 The rate of serotonin synthesis in the brains of women is much lower than for men, an observation used to explain the higher incidence of depression (and suicide?) in women. However, fewer aggressive acts are committed by women, a fact that is inconsistent with their presumed lower brain serotonin content. While SSRIs are used to increase brain serotonin content to alleviate aggressive and suicidal tendencies, a review of the literature shows mixed and contradictory results obtained from the use of Prozac and related drugs. Recent newspaper articles indicate that the pharmaceutical company which manufactures Prozac suppressed evidence that the drug produced suicidal behavior in a number of patients taking it, raising further questions about proposed links between low serotonin concentrations and suicide.24
Methodological Shortcomings
A variety of methodological problems plague the research findings that attempt to link decreased amounts of serotonin with behavioral change. I will simply list them briefly:
1. The amount of 5-HIAA in the CSF does not necessarily correlate with the concentration of serotonin in the brain.
2. Platelet studies are not a good indicator of serotonin activity or concentration in the brain. Similarity of biochemical properties does not imply similarity of neurotransmitter concentration or receptor number.
3. Many studies did not take into account the recent findings dealing with gender differences in the amount of serotonin in the brain.
4. Serotonin receptor populations in the brain are poorly characterized, in terms of both the number of receptors and the specific sub-types of serotonin receptors.
5. "Cross-talk" among different neurotransmitters and receptors is poorly characterized at present. We know that serotonin can produce some activation of dopamine and epinephrine receptors, and these other neurotransmitters can stimulate serotonin receptors, although the extent of these cross-interactions is not clear. Therefore, we must look at concentrations of at least three different neurotransmitters simultaneously. Little data exist dealing with this question.
6. Information about prior drug use (either prescription medications or illicit drugs) is often not available or is unreliable. We learned the hard way from earlier research on schizophrenia that certain drugs can drastically alter the number and behavior of specific receptors. Further research into the effects of drugs on serotonin neurochemistry is definitely needed.
7. The effect of sampling technique on the values obtained for the neurotransmitter and metabolites has not been thoroughly explored. One recent paper indicates that CSF samples collected soon after the lumbar puncture procedure yield 5-HIAA values about 54% of those were obtained several hours later, after the sampling apparatus was in place.25 The stress of the sampling procedure was thought to have produced the initial decrease in metabolite concentration. Most (if not all) of the studies conducted on living patients utilized CSF samples collected immediately upon puncture. The lower values thus obtained could well have been due to the stress of the situation and not the underlying psychological condition. This factor needs further exploration and validation.
Recent findings about serotonin and stress open some interesting doors to the impact of emotions on brain biochemical processes and later behavioral states.
8. No longitudinal studies exist to explore whether the serotonin levels decrease over time as the psychiatric problem worsens (to show that the increasingly aberrant behavior is produced by the decline in neurotransmitter concentration). In addition, no studies show that individuals who have low serotonin levels early in life are more likely to be overtly violent or suicidal later. While some significant ethical problems are involved in carrying out this type of research, the information is definitely needed to substantiate the present paradigm.
9. Information is becoming available which could suggest that psychological stress can contribute to a decrease in serotonin concentration,26 and be the precipitating agent in aggressive or suicidal behavior. Therefore, the change in the amount of brain or CSF serotonin would be the result of altered psychology, and not the other way around.
The idea that psychological stress can alter biochemical production in humans is well documented. We are all familiar with the surge of energy, the increase in heart rate and respiration, and the heightened awareness that comes when we are suddenly frightened. A major contributor to these responses is the increase in catecholamines (such as adrenaline) in response to a sudden stress. The same increase can come over a longer period of time, when the stress is not so apparent (as has been documented with students taking an exam). Prolonged increase in catecholamine concentrations can have profound effects upon other biochemical functions in the body.
Another hormone response to stress is cortisol, a steroid hormone. Disturbances in both the total daily output of cortisol and in its diurnal rhythm can be produced by emotional stress (either short-term or long-term). Emotional stress causes an increase in the amount of cortisol and a tendency for the diurnal cycle to disappear. The loss of the diurnal cycle results in the elevation of cortisol levels throughout an entire twenty-four hour period, instead of decreasing at night. Alterations in both cortisol and catecholamine metabolism are both affected significantly by stress.27
The role of stress in mediating serotonin output is confusing, but intriguing. Not only does stress affect the release of serotonin, but also an intricate interplay between serotonin levels and the regulation of systems leads to the production of catecholamines and cortisol, among other hormones.28 Coupled with the widespread speculation that long- term stress can produce altered brain function (especially in small children), these recent findings about serotonin and stress open some interesting doors to the impact of emotions on brain biochemical processes and later behavioral states.
Sensitivity, Specificity, and Serotonin
One key test for the utility of a diagnostic marker is its sensitivity and specificity.29 Any test used to assist in the diagnosis of a disease must successfully identify those individuals who have the disease while reliably excluding those who do not have the disease. Ideally, there is no overlap between these two populations, but in real life this is not possible. There will usually be some overlap between the two groups. Two ideas are used to assess the diagnostic utility of laboratory data: sensitivity and specificity. "Sensitivity" describes the "incidence of true- positive results obtained when a test is applied to patients known to have the disease." This number indicates how well the lab test allows detection of patients with the disorder under consideration. "Specificity" is used to "characterize the incidence of true-negative results obtained when a test is applied to subjects known to be free of the disease." Therefore, if a lab test has 100% sensitivity, it will provide abnormal results for all of those individuals who have a certain disease. A lab test that shows 100% specificity gives normal results for 100% of the population who do not have the disease. False- positive results (an abnormal value in a person who does not have the disorder) and false-negative results (a normal value in a person who does have the disorder) lower the predictive value of the test.
Using these concepts, we see that low serotonin values are not predictive for a certain type of behavior (i.e., suicide or violence). Two flaws appear in the literature. First, there are no good reference values to be used for comparison purposes. As pointed out earlier, population studies are few and comparison groups are sparse. Methodological problems mar most of the studies. Perhaps more telling is the range of conditions for which low serotonin or HIAA values have been reported. These psychological problems include alcoholism, obsessive- compulsive disorder, schizophrenia, Alzheimer's disease, anorexia/bulimia, panic disorder, anxiety, pre-menstrual syndrome, migraine, and autism.30 Clearly, these disorders represent a wide variety of psychological and/or neurological problems. The association of low serotonin levels with each of these disorders may be more a reflection of some underlying psychological state that produces the altered neurotransmitter concentration than some unified effect of lowered serotonin values on this myriad of behaviors.
One interesting wrinkle in this area of "behavioral biochemistry" is the repeated finding that low serum cholesterol values are associated with an increased incidence of aggressive behavior.31 Are there biochemical links between the amount of cholesterol synthesized and brain production of serotonin? Increasingly, we are seeing reports of a relationship between the amounts of certain steroid hormones (all of which have cholesterol as the precursor molecule) and changes in serotonin metabolism. These data provide just one small hint that our understanding of the connections between our biochemical selves and our behavioral selves is extremely limited.
Implications of Research on Serotonin and Behavior
Scientists who study factors that determine behavior will readily concede that a specific behavior is influenced by both environmental and genetic determinants. However, the studies considered in this paper attribute (directly or often by implication) the abnormal behavior to changes in the concentration of a specific neurotransmitter. In most primary research publications, the investigators simply indicate "an association with" or "a correlation between" low serotonin activity and behavior, but offer no mechanism of action or cause-effect relationship. Yet, a strong thread runs through both research publications and more popular science articles to involve diminished serotonin content in the brain as a precipitating agent for violent behavior. Here is a selection of quotes from the research literature on serotonin and suicide:
The concept that suicide has a biochemical basis is relatively new.32
To our knowledge, this is the first report to implicate a specific gene in the predisposition of a behavior (suicidality) postulated to be regulated by serotonin.33
The link between serotonin functions and suicidal behavior might be a deficient control of aggressive impulses.34
The more "popular" science literature and reports in newspapers and news magazines also clearly state the belief that low serotonin is the cause of suicidal behavior:
Some studies ... already have hinted that distinctive biological mechanisms might be responsible for suicidal behavior.35
This predisposes a person to act on suicide thoughts ... Serotonin is important for restraint. If serotonin is reduced, a person is more apt to act on powerful feelings.36
A mutant gene that affects brain chemistry in unknown ways may drive some depressed people to kill themselves, say Canadian psychiatric researchers.37
Although these quotes deal specifically with serotonin and suicide, equivalent thinking can be documented for other issues associated with low serotonin.
The overall mechanism usually suggested (when one is proposed) is that serotonin is an inhibitory neurotransmitter in the central nervous system, modulating impulse control. Decreased brain concentrations of serotonin are believed to release the brain from this control, which then allows the person to act out a variety of behaviors, especially aggressive or violent actions. If this is true, then behavior (to some extent) is determined by factors outside our control. If we cannot control our behavior, then (by implication) we are not responsible for that behavior. There is a growing assumption in some of the medical literature, and certainly in the popular press, that we cannot be held accountable for many of our actions. Alcoholics are treated as if their condition were caused (at least in part) by some defective gene that gives rise to the excessive consumption of alcohol, even though every study that claims to demonstrate the presence of a gene for alcoholism has quickly been refuted. The destructive behavior that often accompanies depression is attributed to a "chemical imbalance."
There is a growing assumption in some of the medical literature, and certainly in the popular press, that we cannot be held accountable for many of our actions.
This line of thinking is being translated into legal considerations. In both British38 and American39 law journals, the legal implications of current research on biochemistry and behavior have been discussed. While the Bradford (American) article is primarily a survey of the scientific literature, the Fenwick (British) article considers some of the legal implications of violent acts committed while under the influence of a disease or temporary abnormal brain function. The conclusion of both authors is that demonstration of altered neurochemistry can successfully be used in court as a mitigating circumstance, which could lead to either a reduced sentence or acquittal.
One such case involved Tony Mobley, who had a history of violent behavior. During his 1995 trial for murder, his attorneys argued that he was not responsible for his behavior and that it was possibly due to serotonin deficiency.40 Although the judge agreed that this possibility might exist, he denied the request of the defense to have Mobley tested and to have the results admitted in court. Mobley was found guilty and the attorney filed an appeal based in part on the judge's refusal to admit test data into evidence.
If aggressive or suicidal behavior is due to a serotonin imbalance, the logical next step is to attempt to correct that imbalance by way of pharmacology. Administration of Prozac or other serotonin-selective re-uptake inhibitors has been extensively used as treatment for these states (not always successfully). The presumed success of these pharmacological approaches provides the "easy" solution, but does not deal with the root cause of the behavior. Our society continues to become even more a society that solves its problems by taking a pill.
Some ethnic minorities have expressed grave concern about the implications of research on violence and often have actively opposed studies exploring the causes of this behavior. If violence is clearly linked to a serotonin imbalance, and if that serotonin imbalance is genetically determined (which has not been demonstrated to date), then it follows that the incidence of violence could be reduced by limiting reproduction of the defective gene. Earlier efforts to control the further development of sickle-cell disease (an abnormality of hemoglobin structure that primarily affects individuals of African descent) led to accusations of "genetic cleansing" by some segments of the population. The eugenics movement of the early twentieth century in the Unites States and elsewhere and the efforts of Hitler to eliminate "defective populations" are reminders of the persecution that can be visited upon minority populations under the guise of a greater social good.
What Does This Mean for Christians?
Dean Hamer in Living with Our Genes (Doubleday, 1998) argues that genes are a major influence on our personalities and behaviors. In her book, The Biology of Violence (Free Press, 1999), Debra Niehoff explores the relationship between brain chemistry and behavior, concluding that our behavior is based to a great extent on neurobiological processes. In the April 1998 issue of Atlantic Monthly, E. O. Wilson argues that religion and ethics "can all eventually be explained as functions of brain circuitry and deep genetic history." An April 21, 1997 article in U.S. News and World Report states: "For both political and scientific reasons--and it's often impossible to disentangle the two--everything from criminality to addictive disorders to sexual orientation is seen today less as a matter of choice than of genetic destiny." Eric Kandel, M.D., of the Center for Neurobiology and Behavior at Columbia University, recently issued a challenge to his colleagues in the psychiatric field when he proposed that biology was central to the future of psychoanalysis.41 Kandel indicated several areas where biology would provide the definitive answers to issues in behavior (psychopathology) and sexual orientation.
Admittedly, there is more to the above picture, although the extent of the "more" is being strongly debated. Environment certainly plays a role, but the question is that of extent. Nurture and nature are intimately intertwined, with nurture often having a lasting impact upon nature--early childhood stress and abuse, for example, appear to produce lasting changes in brain structure and chemistry. But the questions remain: Is behavior determined by our biochemistry or by our moral sense? Are we responsible for what we do or can we blame it on our biology, our genes, and then not be held accountable for the consequences?
The issues raised in this paper are but one component of a discipline known as evolutionary psychology. This field of study explores the way we behave as being expressed through our genetic make-up. Just as Darwin and his successors have given us a world in which the physical realm appears to be all there is, evolutionary psychology tries to provide explanations for our behavior in terms of biology. However, this field presents not just a scientific endeavor, but also a philosophical commitment. This component of the field was best explained by Charles Colson and Nancy Pearcey in a Christianity Today column (August 10, 1998):
Some Christians have hoped to make peace with Darwinism as long as it is restricted to biology. But evolutionary psychology demonstrates that there is an inexpungable imperialism in Darwinism--a compulsion to reduce all society to material mechanisms. Just as Darwinist theory in biology aims to replace divine design with natural processes, so in ethics it aims to replace revealed morality with a naturalistic morality. Sociologist Howard Kaye observes evolutionary psychology is nothing less than a secularized natural theology--an attempt to justify a secular world view.
As Christians, we represent a counterculture to the norms of secular society. We are led, on the basis of Scripture, to conclude that each person is accountable for his or her behavior. When the broader society offers the message of biological determinism, we have a responsibility to challenge that paradigm. Moreover, we are called to proclaim truth, whether that is truth of the Bible or a truth that goes against the secular world.
Investigation of the research linking low serotonin levels to violent or suicidal behavior suggests that the basic conclusions can be successfully challenged. The research obviously is incomplete (as most workers in the field readily acknowledge). The role of stress as the initiating factor in altering brain serotonin concentrations and later behavior appears to have strong support from the empirical data. Relationships between serotonin content and aberrant behavior are being proposed without a thorough consideration of all of the parameters involved. Much of the research has not been evaluated according to criteria used to assess whether or not a particular biochemical marker is a true indicator of a specific disease. Those criteria seem to indicate that low brain serotonin is a nonspecific phenomenon associated with a variety of situations that have no apparent common denominator other than stress.
As our knowledge of neurotransmitter biochemistry increases, we need to include that new knowledge in the interpretation of data. There is a growing awareness of the interconnections between mind and body--our emotional state can profoundly influence the concentrations of specific biochemicals just as the changes in the amount of certain materials can have an influence on our mood and behavior. We cannot assume a one-way link between biochemistry and behavior.
As Christians, we represent a counterculture to the norms of secular society. We are led, on the basis of Scripture, to conclude that each person is accountable for his or her behavior.
We intuitively believe that we are more than a simple collection of chemicals and therefore are responsible for our behavior. Increasingly, we are able to challenge the naturalistic paradigm not only with reason, but with hard data. A careful review of the literature, challenging the assumptions and methodologies of the studies cited above, allows us both to do good science and to establish more firmly the idea of personal moral responsibility. In a broader context, the philosophy that underlies much of evolutionary psychology must be seen for what it is--an attempt to dethrone revealed moral law and replace it with an ethical and political philosophy that frequently serves only as a rationalization for giving in to our basest desires.
As Christians and as scientists, we have a unique role to play in the societal debates that take place around us. Too often believers are asked to alter or abandon fundamental Christian beliefs and practices because science has supposedly shown them to be incorrect in some way. If we believe that God is a God of truth, then the claims of the secular society need to be evaluated and challenged when they contradict the revelation we have received. Those claims just may turn out to be wrong.
a
Notes
1E. O. Wilson, Sociobiology: The New Synthesis (Cambridge, MA: Belknap Press of Harvard University Press, 1975).
2Richard Dawkins, The Selfish Gene (New York: Oxford University Press, 1978).
3J. M. W. Bradford, "The Role of Serotonin in the Future of Forensic Psychiatry," Bulletin of the American Academy of Psychiatry and Law 24 (1996): 57.
4I. H. Page, "The Discovery of Serotonin," Perspectives in Biology and Medicine 20 (1976): 1.
5A. Yuwiler, G. L. Brammer, and K. C. Yuwiler, "The Basics of Serotonin Neurochemistry" in The Neurotransmitter Revolution: Serotonin, Social Behavior, and the Law, ed. R. D. Masters and M. T. McGuire (Carbondale, IL: Southern Illinois University Press, 1994).
6R. F. Borne, "Serotonin: The Neurotransmitter for the '90s," Drug Topics (October 10, 1994): 108.
7T. G. Dinan, "Serotonin and the Regulation of Hypothalamic-Pituitary-Adrenal Axis Activity," Life Sciences 58 (1996): 1683.
8A. Yuwiler, G. L. Brammer, and K. C. Yuwiler, "The Basics of Serotonin Neurochemistry."
9S. Nishzawa, et al., "Differences Between Males and Females in Rates of Serotonin Synthesis in Human Brain," Proceedings of the National Academy of Sciences, U.S. 94 (1997): 5308.
10F. Biver, et al., "Sex Difference in 5HT2 Receptor in the Living Human Brain," Neuroscience Letters 204 (1996): 25.
11W. Roush, "Conflict Marks Crime Conference," Science 269 (1995): 1808.
12M. Virkkunen, et al., "Cerebrospinal Fluid Monoamine Metabolite Levels in Male Arsonists," Archives of General Psychiatry 44 (1987): 241.
13H. G. Brunner, et al., "Abnormal Behavior Associated with a Point Mutation in the Structural Gene for Monoamine Oxidase," Science 262 (1993): 578.
14For a review of representative students, see V. Markku, et al., "Aggression, Suicidality, and Serotonin," Journal of Clinical Psychiatry 53, supplement (1992): 46.
15H. G. Brunner, et al., "Abnormal Behavior Associated with a Point Mutation in the Structural Gene for Monoamine Oxidase."
16J. Tiihonen, et al., "Seasonal Variation in the Occurrence of Homicide in Finland," American Journal of Psychiatry 154 (1997): 1711.
17For a typical review of the literature, see M. Stanley and B. Stanley, "Postmortem Evidence for Serotonin's Role in Suicide," Journal of Clinical Psychiatry 51, supplement (1990): 22.
18D. S. Charney, "Monoamine Dysfunction and the Pathophysiology and Treatment of Depression," Journal of Clinical Psychiatry 59, supplement 14 (1998): 11.
19K. A. Smith, C. G. Fairburn and P. J. Cowen, "Relapse of Depression after Rapid Depletion of Tryptophan," Lancet 349 (1997): 915.
20M. D. Lemonick, "The Mood Molecule," Time (September 29, 1997): 75.
21A. F. Schatzberg, "Noradrenergic versus Serotoninergic Antidepressants: Predictors of Treatment Response," Journal of Clinical Psychiatry 59, supplement 14 (1998): 15.
22For example, M. S. Hamilton and L. A. Opler, "Akathisia, Suicidality and Fluoxetine," Journal of Clinical Psychiatry 53 (1992): 401-6.
23J. J. Lucas and R. Hen, "New Players in the 5-HT Receptor Field: Genes and Knockouts," Trends in Pharmacological Sciences 16 (1995): 246.
24L. R. Garnett, "Prozac's Dark Side Kept Quiet," Boston Globe (June 11, 2000).
25K. K. Hill, et al., "The Effect of Lumbar Puncture on Dopamine and Serotonin Metabolites in Human Cerebrospinal Fluid," Neuroscience Letters 276 (1999): 25-8.
26B. Azar, "Environment is Key to Serotonin Levels," APA Monitor (April 1997).
27G. P. Chrousos and P. W. Gold, "The Concepts of Stress and Stress Disorders. Overview of Physical and Behavioral Homeostasis," Journal of the American Medical Association 267 (1992): 1244-52.
28J. F. Lopez, et al., "Neural Circuits Mediating Stress," Biological Psychiatry 46 (1999): 1461-71.
29R. S. Galen and S. R. Gambino, Beyond Normality: The Predictive Value and Efficiency of Medical Diagnoses (New York: John Wiley and Sons, 1975).
30E. M. Coccaro and D. L. Murphy, eds., Serotonin in Major Psychiatric Disorders (Washington, DC: American Psychiatric Press, 1990).
31P. H. A. Steegmans, et al., "Low Serum Cholesterol Concentration and Serotonin Metabolism in Men," British Medical Journal 312 (1996): 221.
32M. Stanley and B. Stanley, "Postmortem Evidence for Serotonin's Role in Suicide."
33D. A. Nielsen, et al., "Suicidality and 5-Hydroxyindoloeacetic Acid Concentration Associated with a Tryptophan Hydroxylase Polymorphism," Archives of General Psychiatry 51 (1994): 34-8.
34L. Tr”skman, et al., "Monoamine Metabolites in CSF and Suicidal Behavior," Archives of General Psychiatry 38 (1981): 631-6.
35D. L. Wheeler, "Scholars Seek a Biological Basis for Suicide," Chronicle of Higher Education (December 13, 1996).
36"Low Serotonin Levels Linked to Suicide," interview with Dr. J. John Mann of Columbia Presbyterian Medical Center, Tacoma (WA) News Tribune (November 19, 1996).
37"Gene May Drive Some to Suicide, Report Says," Seattle Times (February 8, 2000).
38Peter Fenwick, "Brain, Mind and Behaviour. Some Medico-Legal Aspects," British Journal of Psychiatry 163 (1993): 565-73.
39J. M. W. Bradford, "The Role of Serotonin in the Future of Forensic Psychiatry."
40M. Curriden, "Guilt by Heredity? His Lawyer Says It's in the Killer's Genes," The National Law Journal (November 7, 1994): A12.
41E. R. Kandel, "Biology and the Future of Psychoanalysis: A New Intellectual Framework for Psychiatry Revisited," American Journal of Psychiatry 156 (1999): 505-24.
Donald F. Calbreath is currently an associate professor of chemistry at Whitworth College (Spokane, WA) where he has taught for seventeen years. He received a B.S. in Chemistry from North Texas State University in 1963 and a Ph.D. in biochemistry from Ohio State University in 1968. From 1968-1970, he did post-doctoral research in the Biochemistry Department at Duke University. Then he directed a clinical chemistry laboratory for Durham County General Hospital in Durham, NC, and taught laboratory medicine as an adjunct faculty member in the Duke University Medical School program for physicians assistants. He has had a longstanding interest in biochemical aspects of mental illness and the relationship between biochemistry and behavior. The current research was funded by a Pew summer research grant and an award from the faculty research grant program at Whitworth. In his spare time, Calbreath is a devotee of traditional Southern music and (along with his wife Sandy) enjoys spoiling his three grandchildren.