The Serotonine Aproch to violence

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SEROTONIN HYPOTHESIS AGGRESSION REVISITED

Mitchell E. Berman

The University of Southern Mississippi

Joseph 1. Tracy and Emil F: Coccaro

Medical College of Pennsylvania + Hahnemann University School of Medicine

ABSTRACT. Many contemporary theorists believe serotonin (5.HTT) neurotransmitterfunction- ing plays a role in the regulation of human aggressive behavior We argue that the evidence

supporting this 5-HT hypothesis of human aggression is less compelling than commonly assumed,

due to (a) conflicting study results, and {b) signiJicant methodological limitations of existing

studies. Recent models that integrate the role of psychological and contextual variables in

5-HT-associated aggression are reviewed. The need to incorporate psychometrically sound mea-

sures of aggression in 5-HT studies, to use experimental and longitudinal designs, and to test

hypotheses drawn from multifactorial models in future research is advocated. 0 I997 Elsevier

Scien,ce Ltd

NEUROTRANSMITTERS ARE chemical messengers that allow communication among neuronal cells in the central and peripheral nervous systems. Neurotransmit-

ters serve either to activate or to prevent the firing of downstream neurons. In the

human brain, this feature of neurotransmitter functioning helps to regulate information flow across complex neural networks associated with emotional, cognitive, and behavioral experiences.

Careful clinical observation of individuals with structural lesions in specific brain areas gave rise in the late 1800s to seminal findings on brain-behavior relationships,

such as Brocas observation of speech localization at the base of the third convolution in the left cerebral hemisphere (Boring, 1950). In contrast to gross structural defects, neurotransmitter abnormalities are not so readily identifiable. Thus the role of nemotransmitter systems in brain-behavior relationships in humans had to await the

Correspondence should be addressed to Mitchell E. Berman, University of Southern Missis-

sippi, Department of Psychology, P.O. Box 5025, Hattiesburg, MS 39406-5025.

651

652 M. B. Berman, J. I. Tracy, and E. I? Coccaro

development of reliable strategies to study neurotransmitter functioning, such as histologic stains, markers of biosynthetic pathways, and advances in psychopharmacology.

To date, more than 50 molecules are known or suspected to play a role in neurotransmission. Of these neurotransmitter substances, the potential influence of serotonin (5-HT) activity on human aggression has been the source of much specu- lation and research. It is believed that 5-HT serves to modulate or constrain ongoing behavior (Coccaro, 1992; Spoont, 1992). Defects in the serotonin system are, therefore, believed to be associated with a variety of extreme behaviors, including aggression, suicide, arson, and alcoholism (e.g., Coccaro, 1992; Linnoila SC Virkkunen, 1992; van Praag et al., 1990).

The earliest published human study directly addressing the relation between serotonin activity and human aggression is less than 20 years old (i.e., Brown, Goodwin, Ballenger, Coyer, & Major, 1979), but the number of studies in this area has grown rapidly. Surveys of this literature led earlier reviewers to conclude that there is compelling evidence to support the notion that serotonin neurotransmitter activity plays an important role in human aggressive behavior (e.g., Coccaro, 1992; Linnoila & Virkkunen, 1992; van Praag et al., 1990). For several reasons, however, concluding that 5HT functioning plays an integral role in human aggression may be premature. First, surprisingly few studies have examined the relation between .5-HT status and actual aggressive behaviors. Many studies in this area have relied on measures of emotions, attitudes, or personality traits to support the idea that 5-HT regulates aggressive behavior (e.g., Coccaro, 1992; Linnoila & Virkkunen, 1992). Second, previous reviewers have paid little attention to the methodological flaws and limitations of existing studies. Finally, equivocal or contradictory evidence either is not acknowledged or does not seem to attenuate the conclusions drawn by reviewers.

The primary purpose of this paper is to attempt a more critical examination of the 5-HT and aggression literature than has been done in the past. We will focus on human studies that include measures of aggressive behavior (e.g., self- or clinician- ratings of actual aggressive behaviors, laboratory observations of aggressive behavior, or a documented history of aggressive or violent behavior). Studies relying on measures of anger or hostility will not be used to support the serotonin hypothesis of aggression for two reasons. First, anger and hostility are considered conceptually distinct from the construct of aggression (Biaggio & Maiuro, 1985). Second, anger and hostility measures may underestimate the relation between aggressive behavior and biologic variables (see Archer, 1991, for a discussion of this issue).

The second purpose of this paper is to examine contemporary biopsychosocial conceptualizations of 5-HT-related aggression and evaluate the empirical support for these perspectives. If the serotonin hypothesis is supported by the literature, developing testable models may help guide future research efforts and explain divergent findings. More important, biopsychosocial conceptualizations may help increase our understanding of how and why 5-HT activity contributes to the expression of aggressive behavior.

EVIDENCE FOR SEROTONERGIC REGULATION OF AGGRESSION IN HUMANS

Measurement of 5-HT Activity

Neurotransmitter activity is typically assessed using one of the following strategies: (a) central neurochemical measures, (b) hormonal measures following pharmacochallenge of neuroregulatory systems, or (c) peripheral measures obtained from urine or

Serotonin and Aggression 653

blood (e.g., concentration of neurotransmitter metabolites; platelet binding parame- ters). Each strategy provides an index of neurotransmitter activity that can be correlated with dimensional measures of aggression (e.g., self- or other-rating scales) or used to discriminate groups of individuals characterized by aggressive behavior (e.g., violent criminal offenders).

Peripheral measures, though easy to obtain, are considered the least informative source about central nervous system functioning (see Coccaro & Ravoussi, 1994). The evidence for the 5-HT hypothesis of aggression provided by peripheral measures is complex and equivocal, and has been recently reviewed elsewhere (Berman, Ravoussi, & Coccaro, in press). Therefore, peripheral studies will not be included in this review.

Neurochemical Measures and Aggression

Concentration of 5-HIAA (5-hydroxyindoleacetic acid, a major metabolite of 5-HT) in cerebrospinal fluid (CSF) taken from a puncture in the lumbar sack has been used as an index of central 5-HT activity. CSF 5-HIAA is produced by neurons in the spinal column, and levels of this metabolite correlate with 5HIAA in the frontal cortex of the brain. For this reason, CSF 5-HIAA is considered one of the more useful indexes of neurotransmitter activity. However, CSF 5-HIAA levels provide no information about neuronal activity in specific brain regions.

Brown and colleagues were among the earliest researchers to report an inverse association between CSF 5-HIAA and aggressive behavior in humans in a study involving 26 men confined to a military forensic unit (Brown et al., 1979). All participants had at least one ZXM-ZZpersonality disorder diagnosis, but no other major psychopathology. Lifetime ratings of various aggressive and antisocial behaviors were calculated using information from hospital records and psychiatric interviews. Rating scores were summed to produce a total life-history of aggression score (Brown- Goodwin Aggression scale: BGA). CSF 5-HIAA was negatively associated with BGA scores (r = - .%), accounting for almost 61% of the variance. An index of behavioral impulsivity (p. 135) was also inversely associated with CSF 5-HIAA levels. Specifically, men with antisocial, explosive, immature, and hysterical personality disorder diagnoses had lower CSF 5-HIAA compared with those with passive-aggressive, schizoid, and obsessive compulsive personality disorder diagnoses. Weaker support for the serotonin hypothesis of aggressive behavior was reported in a follow-up study of 12 military men diagnosed with DSM-ZZZ borderline personality disorder (Brown et al., 1982). In the latter study, a nonsignificant trend was found for the association between BGA scores and CSF 5-HIAA levels (T = -.53, p < .08).

One shortcoming of the Brown studies is a failure to include any comparison groups. Thus, the results of these studies tell us nothing about the association of CSF 5-H&4 and aggression in individuals with no diagnosable personality disorder. A second shortcoming concerns the item content of the BGA. This scale reflects both aggressive behaviors (e.g., assault, fighting) and antisocial behaviors that may or may not be related to aggression (e.g., school disciplinary problems, problems with the legal system). It is therefore unclear from the results of these studies whether low CSF 5-HIAA is related specifically to aggressive behavior. Brown et al. (1979) reported high interrater agreement for the BGA (T = .98), but the procedures used to derive this statistic were not described. Test-retest stability and internal consistency statistics for the scale were not reported, and almost no validity evidence was provided. Lack of standardized administration and scoring procedures prohibits comparison of BGA

scores across studies. Despite these limitations, various versions of the BGA have been used routinely by different research groups.

The findings of the Brown group have been replicated, but with statistical associations of less impressive magnitude. Specifically, Limson et al. (1991) found a modest bttc significant negative correlation (r = - ..?l) between CSF 5HIAA and aggression in a satnple of alcoholics (n = .57) and healthy volunteers (n = 15) using a tnodification of the BGA. Itetn content, scoring procedures, and psychometric characteristics of the aggression measure were not described in this study.

In conttzt to these positive findings, one study found that men convicted of murder were tto different than healthy controls on CSF 5HIAA (Lidberg, Tuck, sberg, Scalia-Totnba, & Bertilsson, 1985). However, exploratory analyses revealed lower CSF 5HIAA in certain subtypes of violent men. Specifically, nonalcoholic violent tnen had lower (SF 9HIAA levels than alcoholic violent men, and men who murdered a sexual partner had lower CSF 9HIAA tI~nn men who murdered a nonintimate acquaintance. The Lidberg et al. findings arc difficult to interpret givett that (a) Each subtype group of violent tnen consisted of only 5 to 10 suejects; (1,) multiple t-tests were conducted without adjustment for T>pe I error; and (c) no relationship was found for aggression per se.

Due to the invasive nature of the procedttrc used to obtain CSF, studies of children are almost ttonexistent. However, Kruesi, Rapoport, Hamburger, Hibbs, and Potter (1990) cxanlitlrd the relation between (ZSF 5-HIAA and aggression both in children with disruptive behavior disorders (i.e., conduct disorder, attention deficit hyperactivity disorder [ADHD], oppositional defiant disorder; n = 33) and children with obsessive compulsive disorder ( n = 43). Consistettt with expectations, age-corrected (SF 5HIAA levels were inversely correlated with ratings of aggressive behavior, but only in the disruptive behavior disorder group. However, only 3 of 32 correlations between (:SF .5-HIAA and measures of impulsive behavior, negative affect, and aggression wet-e statistically significant. No adjustment was made for the number of statistical tests conducted, complicating the interpretation of the results.

In contrast to the suggesti\,e findings reviewed above, two studies failed to find a relation between CSF 5HIAA and a historv of aggressive behavior (Gardner, Lucas, SC Cowdry, 1990; Simeon et al., 1992). Sitneo;) et al. ( 1992) compared individuals with a history of self-tllntilation (rr = 26) to individuals with no history of self-mutilation (n = 26). The groups wet-e similar on rele&ult demographic variables and percentages of specific major mental disorders and personality disorders found within each group, with major depression and borderline personality disorder being the most common diagnos~~s tot- both groups. Life history of aggressive behavior was quantified using data obtained from a sem-structured interview. Results indicated that self-mutilators had higher aggression scores than non-selfltnutilators, but the groups did not differ on either CSF-.5-HIAA levels or peripheral ittdexes of 5HT functioning. Moreover, no significant correlatiotts between indexes of 5HT functioning and aggressive behavior were found in either

Serotonin and Aggression 65.5

Linnoila, 1987; Virkkunen, Rawlings et al., 1994). In a frequently cited study of 36 Finnish men who committed or attempted to commit homicide, impulsively violent men were reported to have lower CSF 5HIAA concentrations than nonimpulsively violent men (Linnoila et al., 1983). Men were categorized as impulsively violent if, based on clinical

judgment, no rationale could be determined for their act (i.e., it was not premeditated) and the offender was not close to his victim. The authors concluded, that ...low 5-HIAA concentration in the CSF of violent offenders is more a marker of impulsivity than violence per se (p. 2610). For several reasons, however, the idea that compromised .5-HT functioning is principally associated with an impulsive subtype of aggressive behavior was not conclusively supported. Evidence for the reliability and validity of the method used to categorize offenders as impulsive versus nonimpulsive was not reported. It could also be argued that impulsive, unplanned violence is more likely to occur in intimate relationships (e.g., intrafamilial violence) than in casual relationships or when the victim is unknown to the aggressor. Indeed, the results of Linnoila et al. seem at odds with those reported by Lidberg et al. (1985)) in which homicide among intimates was associated with lower CSF 5HL4A levels. More important, the study by Limroila et al. (1983) did not address the issue of whether a life history of violent behavior, in general, is associated with compromised CSF 5-HIAA.

In a follow up study, CSF 5-HIAA levels in a subgroup of 20 impulsively violent men from Linnoila et al. (1983) were compared to 20 Finnish arsonists and 10 healthy controls recruited in the United States (Virkkunen et al., 1987). The arsonists also had a history of violent behavior, but apparently did not set fires for economic gain. Based on this lack of economic motive, the authors classified the fire-setting behavior as impulsive. The results indicated that arsonists had lower CSF 5-HIAA compared to both violent men and controls, and that violent men had lower CSF 5-HIAA than controls. These results also provide support for the idea that impulsive forms of destructive behaviors are associated with compromised 5-HT functioning. There are at least two reasons, however, why these results should be interpreted cautiously. First, participants in the control group were of a different nationality and, in contrast to the forensic groups, both men and women were included in the control group. Second, the validity of labeling the fire-setting behavior of the arsonists as impulsive is unclear. That is, the motivation for these individuals acts may have been premeditated but not economic in nature (e.g., revenge arson).

In an attempt to provide further support for an impulsive aggression-serotonin link, impulsive offenders were compared to both nonimpulsive offenders and healthy controls (Virkkunen, Rawlings et al., 1994). Offenders included both arsonists and men who committed homicide. Impulsive behavior was defined as in Linnoila et al. (1983) and Virkkunen et al. (1987). The results indicated that impulsive offenders had lower CSF 5-HTAA than nonimpulsive offenders. However, CSF 5-HIAA levels of healthy controls fell between the impulsive and nonimpulsive offenders, with CSF 5-HIAA levels of impulsive offenders being close to healthy controls and nonimpulsive offenders having generally higher CSF 5-HIAA levels. Nonsignificant differences between impulsive offenders and healthy controls on CSF 5-HIAA make these results somewhat difficult to interpret. The fact that nonimpulsive offenders had high CSF 5HIAA levels could be interpreted to mean that 5-HT plays a substantial role in well-planned violent behaviors rather than impulsive aggression.

In summary, the idea that 5-HT regulates aggressive behavior is modestly supported by CSF 5-HIAA studies. Although CSF 5-HIAA levels were inversely related to aggressive behavior in some studies (Brown et al., 1979, 1982; Limson et al., 1981), other

656 M. B. Berman, J. I. Tracy, and E. I! Coccaro

studies provide modest (Kruesi et al., 1990; Lidberg et al., 1985) or no (Gardner et al., 1990; Simeon et al., 1992) support for the 5-HT hypothesis of aggression. The conflicting findings regarding human aggression and CSF 5-HIAA may be explained in several ways. The most obvious explanation is that there is no relation between CSF 5-HIAA and a life history of aggressive behavior. This explanation is least satisfactory given that several studies have reported significant findings. Methodological shortcomings may also account for the contradictory findings. These include small sample sizes, a tendency to compare groups that differ on potentially important uncontrolled extraneous variables, a failure to include appropriate comparison groups, and the use of aggression measures with questionable psychometric properties.

Pharmacochallenge Measures and Aggression

Pharmacochallenge assessment of nemotransmitter functioning involves administer- ing a drug (probe) that targets one or more neurotransmitter systems and then measuring hormonal (e.g., cortisol, prolactin) responses. Because hormonal output is controlled, in part, through neurotransmitter activity in the brain, reduced hormonal response to a probe is thought to reflect compromised neurotransmitter functioning. No probe, however, is specific to a single neurotransmitter or receptor subtype system. It is also difficult to determine if hormonal response to drug infusion results from the stimulation of brain neurons (which would reflect neurotransmitter functioning), or if the effects are produced by the direct activation of the glands that manufacture specific hormones (Coccaro & Kavoussi, 1994).

Pharmacochallenge studies of aggressive behavior in adults have provided somewhat more consistent results than those provided by neurochemical studies. For example, aggressive behavior and 5-HT functioning was examined in 20 men with personality disorders, 25 with depressive disorders, and 18 with no evidence of psychopathology using a fenffuramine pharmacochallenge procedure (Coccaro et al., 1989). Fenfluramine is a drug that stimulates postsynaptic receptors by both releasing 5-HT and blocking its reuptake. Results indicated that prolactin response to fenfluramine challenge was inversely correlated with scores on a modified version of the BGA in the personality-disordered group (r = -.57, p < .05), but not in the healthy controls or individuals with depression. Thus, it is possible that a relation between aggression and 5-HT functioning may be found only in certain populations (e.g., individuals with personality psychopathology).

The results of other pharmacochallenge studies also provide support for the 5-HT hypothesis of aggression (Coccaro, Berman, Kavoussi, & Hauger, 1996; Moeller et al., 1994; OKeane et al., 1992). OKeane et al. found that prolactin response to challenge with 30 mg d-fenfluramine (an isomer of fenfluramine) was lower in nine nonde- pressed, nonpsychotic men convicted of murder compared with nine healthy controls. This result supports the notion that 5-HT functioning is inversely related to aggressive behavior. However, the forensic and control groups differed on several important uncontrolled variables (e.g., height, weight, and the stress of incarceration in a forensic hospital). Correlations between prolactin response and measures of aggressive behavior within groups were not reported.

A recent study showed that prolactin response to d-fenfluramine was inversely related both to scores on a modified version of the BGA and to a laboratory task of aggressive behavior in 14 males with personality disorder diagnoses (Coccaro et al., 1996). In contrast to most studies in this area, interrater agreement and internal


consistency data for the aggression ratings were reported. Another recent study found that growth hormone response to buspirone, an agonist that stimulates postsynaptic 5-HT,, receptors, was inversely correlated with BGA scores in 10 adults with a history of cocaine dependence (r = - .73), but not in 10 age- and gender-matched controls (Moeller et al., 1994).

As with central neurochemical studies, few pharmacochallenge investigations of children have been conducted. In contrast to studies in adults, pharmacochallenge data do not support an inverse relation between 5-HT and aggressive behavior in children. Stoff et al. (1992), in a study of prepubertal and adolescent males with disruptive behavior disorders, found no relation between hormonal response to fenfluramine challenge and aggressive behavior. Halperin et al. (1994) also failed to

find a relation between prolactin response to fenfluramine and a scale assessing the frequency and intensity of aggressive acts in boys with ADHD. However, higher prolactin responses were found in a subgroup of boys classified as aggressive compared with those classified as nonaggressive. This finding, which is in the opposite direction from most other reports, has been replicated in a study of 34 younger brothers of convicted delinquents (Pine et al., 1997).

Overall, pharmacochallenge studies provide some support for an inverse relation between 5-HT functioning and aggressive behavior. This relationship has been shown in individuals diagnosed with personality disorders, adults with a history of cocaine dependence, and men with a history of violence (but not in children, depressed adults, or healthy volunteers). One explanation for these conflicting findings is that healthy controls, depressed individuals, and children may exhibit a restricted range of scores on aggression measures, thus attenuating statistical associations. Unfortunately, descriptive statistics that would help to determine if these conflicting findings are merely an artifact of different data distributions are not always presented (but see Moeller et al., 1994).

Experimental Studies of 5-HT and Human Aggression

The studies discussed so far employed nonexperimental research designs. Experimen- tal or longitudinal methodology is necessary to establish a causal relation between 5-HT neurotransmission and aggressive behavior. Unfortunately, few experimental studies in this area have been conducted. To date, no longitudinal study involving repeated measurement of both neurobiological status and aggressive behavior has been conducted. In addition, results of nonexperimental studies are uninformative about the direction of potential relationships. It could be argued that engaging in aggressive behavior alters serotonin brain chemistry, rather than compromised serotonin being the cause of aggressive behaviors. Indeed, neurotransmitter activity is not static, and is influenced by early social influences in both nonhuman primates (Higley, Suomi, & Linnoila, 1991; Kraemer, Ebert, Schmidt, & McKinney, 1989) and humans (Galvin et al., 1991; Gerra et al., 1993).

For these reasons, investigators have begun to use experimental methodology (that is, manipulation of neurotransmitter activity and random assignment to treatment conditions) to examine 5-HT functioning and human aggressive behavior. In these studies, aggressive behavior is observed using one of several laboratory paradigms. For example, aggressive behavior can be operationally defined as the intensity or duration of shock or loud noise delivered to a fictitious participant, or the number of points

with monetary value taken away. There is substantial evidence supporting the construct validity of these paradigms (see Giancola & Chermack, in press).

At this time, all published experimental studies have used healthy research volunteers with no documented psychopathology. Manipulation of dietary tryptophan has been used to alter .5-HT functioning in several of these studies. This amino acid is necessary for the synthesis of central 5-HT. Enhancement or depletion of dietary tryptophan is correlated with changes in CSF 5-HIAA levels in humans and lower primates (Young, Ervin, Pihl, & Finn, 1989; Young 8c Gauthier, 1981). The earliest experimental study in this area reported that neither increasing nor decreasing tryptophan in participants diets affected aggressive behavior, with aggression defined as the intensity and duration of shock delivered to a fictitious participant (Smith, Pihl, Young, 8c Ervin, 1986). Smith et al. suggested that their nonsignificant results may have been due to the failure of a provocation manipulation to elicit retaliatory aggressive behavior in participants. In a follow-up study, this group used a laboratory task that incorporated different levels of provocation by a fictitious adversary (Pihl et al., 1995). In this second study, participants in the tryptophan-depleted group tended to set higher shocks tbr a moderately provocative adversary than participants who received a tryptophan-augmented diet. Another study using a similar paradigm found modest posthoc evidence that tryptophan depletion increased aggressive behavior when an opponent was moderately provocative (Cleare PC Bond, 1995). None of these tryptophan manipulation studies, however, included pharmacologically inactive placebo control conditions, making interpretation of the results problematic. A recent placebo-controlled study found that eltoprazine, a putative 5-HT,,, and 5-I-IT, 1s agonist, produced lower aggressive responding compared with placebo (Cherek, Spiga, & Creson, 1995). Although eltoprazine consumption was associated with lower aggressive responding in this study, it was also associated with decreased responding on a topographically similar nonaggressive response option. It is, therefore, unclear whether increased 5-HT specifically decreased aggressive behavior, or merely suppressed ongoing behavior in general.

In summary, experimental studies have provided modest evidence that manipulat- ing central 5-HT can alter aggressive behavior in humans. The limited effects found in experimental studies may be due to the exclusive use of healthy volunteers. This population may, in general, exhibit low levels of aggressive behavior urlder controlled laboratory conditions.

THEORIES OF 5-HT AND AGGRESSION

Though not definitive, some neurochemical, pharmacochallenge, and experimental studies have reported inverse associations between 5-HT activity and aggressive behavior in humans. How 5-HT activity influences aggressive behavior in humans, however, is not yet known. Multifactorial models have been developed to explain the role of 5-HT in aggression. All models assume that reduced 5-HT functioning is not specific to aggressive behavior, but that aggression is merely one behavioral correlate of compromised neurotransmitter functioning. The models differ, however, in the psychological processes posited to be responsible for the expression of aggression.

The Low Serotonin Syndrome (LSS) Model

Linnoila and Virkkunen (1992) propose a disinhibition model of aggression called low serotonin syndrome (p. 46). Th is model holds that decreased 5-HT functioning

Serolonin and Aggression 659

is associated with a biologically determined impulsive personality style that is not specific to aggressive behavior. One implication of this model is that aggressive and other problematic behaviors are largely the result of internal processes. That is, individuals with low 5-HT lack the appropriate internal controls to resist destructive impulses.

As discussed earlier, there is some support for the notion that 5-HT regulates impulsive behaviors. Arsonists who are not motivated by economic gain and murderers who do not premeditate their crime seem to have lower CSF 5-HIAA than nonimpulsive criminals (e.g., Virkkunen et al., 1987). Further support for the idea that low 5-HT is associated with impulsive behaviors comes from studies showing low 5-HT activity in violent suicide attempters and individuals with early onset alcohol dependence (see Linnoila & Virkkunen, 1992, for a review). It is intuitively appealing to classifj the behavior of arsonists, murderers, suicide attempters, and alcoholics as impulsive. However, whether or not these behaviors are valid representations of impulse control problems has only modest support (e.g., Virkkunen, Kallio et al., 1994). Further complicating this issue, scores on self-report measures of impulsivit) have been associated with reduced 5-HT activity in some (e.g., Coccaro et al., 1989). but not all studies (e.g., Coccaro et al., 1996; Coccaro, Kavoussi, Sheline, Lish, 8~ Csernansky, 1996; Limson et al., 1991; Simeon et al., 1992; Virkkunen, Kallio et al., 1994). For these reasons, it has not been conclusively demonstrated that low 5-HT is associated with trait impulsivity.

According to the LSS model, 5-HT is only indirectly related to aggressive behavior. The psychological processes posited for the development of aggressive behavior ill impulsive individuals involves mood regulation by alcohol consumption. Specifically, reduced 5-HT activity is associated with both sleep disruption and a proneness to hypoglycemia and depressed mood. In an attempt to alleviate depression, excessive amounts of alcohol are consumed, temporarily raising 5-HT levels. However, long- term, heavy alcohol consumption depresses 5-HT activity and further exacerbates problems with sleep, glucose metabolism, and mood. Because alcohol consumption can elicit aggressive behavior (see Chermack 8c Giancola, this issue), the continued use of alcohol to relieve negative affect increases the likelihood of impulsive aggressive outbursts in these individuals. This model, therefore, accounts for the observation that low 5-HT activity is associated with both early onset alcoholism and impulsive violence (e.g., Buydens-Branchey, Branchey, Noumair, & Lieber, 1989).

The LSS model could be criticized for its limited emphasis on contextual and psychological factors (other than alcohol consumption) associated with human aggressive behavior. Even if 5-HT is associated with a general predisposition to engage in impulsive acts, this model does little to inform LET about the factors that may elicit aggressive acts in individuals with impulsive personality traits. That is, although a biologically-determined predisposition to impulsive aggression is postulated, this model does not address the environmental or psychological factors necessary for ~hc expression of aggressive behavior.

The lnforma tion-Processing Model

Spoont (1992) proposes an information (i.e., signal) processing model of 5-HT- related aggression that puts greater emphasis on external factors than the LSS model. She argues that 5-HT neurotransmission fine-tunes an organisms behavioral responses to internal signals (i.e., changes in various hormonal and neurotransmitter

systems) and to external signals (i.e., environmental cues). According to this perspec-

tive, the primary function of the 5-HT neurotransmitter system is to constrain or

stabilize information flow. This results in controlled behavioral, cognitive, and affec-

tive output when the organism is confronted with changing environmental demands.

Preclinical studies support the idea that 5-HT plays a role in stabilizing various

neuroregulatory information circuits. For example, reduced 5-HT activity is associated

with increases both in behaviors normally suppressed by punishment and exploratory

behavior (rather than neophobic responses) to novel environments (Spoont, 1992, for

a review). These behaviors are proposed to result from serotonins modulatory effects

on signals generated by other neurotransmitter systems (e.g., dopamine, GABA).

The information processing model has in common with the LSS model the idea

that compromised 5-HT neurotransmitter functioning is not specific to aggressive

behavior. However, the psychological mechanisms responsible for the exhibition of

aggressive behavior implied by Spoonts information processing theory are some-

what different from those associated with the LSS model. The information pro-

cessing perspective holds that 5-HT neurotransmitter functioning modulates in-

formation flow in neurotransmitter systems and anatomical structures controlling

fight/flight responses to environmental cues. When 5-HT activity is reduced, the

organism experiences heightened sensitivity to provocative or threatening cues,

decreased sensitivity to cues associated with behavioral suppression, and reduced

sensitivity to pain when aroused. Substantial evidence exists to suggest that these

conditions are important antecedents of aggression (Berkowitz, 1993; Geen,

1990). However, why an organism will engage in aggressive responding, versus

other response options (e.g., flight), is not addressed by this model. The infor-

mation processing model provides a promising theoretical framework to under-

standing BHT-associated aggression, but hypotheses drawn from this model have

not yet been directly tested in humans.

An important implication of the information processing model is that intact, or

elevated, 5-HT functioning should be associated with effective decision-making and

prosocial behaviors in group settings. Indeed, some primate evidence indicates that

this may be so. In a series of crossover, vehicle-controlled experiments, free-ranging

vervet male monkeys were administered drugs that either lowered or raised indexes of

5-HT functioning (Raleigh, McGuire, Brammer, Pollack, & Yuwiler, 1991). Before

drug administration, the highest-ranking male animal in the colony was removed to

destabilize the existing dominance hierarchy. Males treated with 5-HT-enhancing

drugs quickly achieved social dominance. This effect was not found when treated with

drugs that lowered 5-HT. Dominance behavior was associated with effective social

decision-making, increased sensitivity to positive social overtures, increased affiliative

behavior, and decreased unplanned solitary aggressive behavior (impulsive aggressive behavior). Intact or elevated 5-HT functioning may therefore facilitate effective

social information processing and decision-making, which leads to the attainment of

high rank and access to reproductive partners. In addition, existence of stable dominance hierarchies may facilitate group cohesion, reduce the occurrence of counter-

productive aggressive behavior among group members, and foster cooperative de-

fenses against common threats (see Scott, 1992). Thus, the presence of intact serotonergic functioning may have implications for group stability and survival.

Scrotonin and Aggression 661

The Irritable Aggression Model

According to this perspective, reduced serotonergic activity produces a generalized state of hyperirritability. However, aggressive behavior only occurs if the organism is confronted with a noxious environmental event and the neuronal systems responsible for arousal and goal directed behavior (e.g., dopamine, norepinephrine) are suffi- ciently activated (e.g., Coccaro, 1989). Specifically, low 5-HT is associated with irritable mood, reducing the threshold at which an organism responds to provocative stimuli.

Although not yet directly tested in humans, some evidence exists for the idea that threatening, provocative, or noxious stimuli are necessary for aggressive behavior to occur in a hyposerotonergic state. For example, chemical lesioning of 5-HT neurons increases muricidal behavior in rats. However, this effect can be reduced when the animal is preexposed to mice before the destruction of 5-HT neurons (Marks, OBrien, & Paxinos, 1977). It is reasonable to propose that rats habituate to a provocative stimulus (i.e., a mouse) with pre-exposure, thereby decreasing aggressive behaviors associated with compromised 5-HT activity. Further support for the role of provocation in 5-HT associated aggression comes from a study of vervet monkeys placed on a tryptophan-depletion diet (Chamberlain, Ervin, Pihl, & Young, 1987). Male primates with central 5-HT reduced using this method exhibited aggressive behaviors primarily when competing for food, which can be considered a highly provocative social encounter.

In humans, moderate levels of attack or provocation seem necessary for eliciting aggressive behavior when 5-HT activity is experimentally decreased in humans (Pihl et al., 1995). In the absence of provocative stimuli, decreased 5-HT functioning may not affect the level of aggressive behavior exhibited by humans (Smith et al., 1986). The results of these animal and human studies suggest that the effect of 5-HT on aggressive behavior may be moderated by provocation. That is, decreased 5-HT activity may heighten perception of, or responsivity to, provocation or attack.

A shortcoming of all models is their limited emphasis on the development of compromised 5-HT functioning. Genetic influences on the development of 5-HT nemotransmitter functioning are acknowledged by theorists (e.g., Spoont, 1992, p. 336). However, the effects of environmental events on the developing 5-HT system, and whether or not these biological changes serve some adaptive function over time, are not systematically incorporated in any model.

SUMMARY AND FUTURE DIRECTIONS

Evidence exists to suggest that 5-HT functioning is associated with aggressive behavior in humans, at least in some populations. However, this evidence seems less compelling than commonly assumed. It is still unclear, given the lack of experimental evidence, whether 5-HT functioning is causally related to aggression, or is merely correlated with aggressive behavior in humans. 5-HT status is likely to play but a small role in such complex social behaviors as aggression. It is therefore important that future studies avoid the various methodological shortcomings common in this research area.

First, more attention should be paid to using sample sizes large enough to detect actual effects in the population, especially for investigations studying various subtypes of aggressive individuals. Second, studies of group differences should include appropriate comparison groups. That is, 5-HT status must also be examined in individuals without marked aggression while controlling for as many relevant confounding variables as possible. Between-group research should also examine and report correla-

tions between 5-HT status and aggressive behavior within each group, and report descriptive statistics for both biologic and behavioral measures. This would help elucidate whether a relation between 5-HT and aggression is limited to certain populations. Third, testing hypotheses drawn from multifactorial rnodels should receive consideration in future research efforts. Laboratory paradigms exist that allow for the experimental manipulation of environmental variables proposed to be important in 5-HT-associated aggressive behavior, such as perceived provocation or attack (Cherek, Spiga, Steinberg, & Kelly, 1990; Taylor, 1967). As discussed earlier, serotonergic functioning may also be experimentally manipulated by dietary precursors and drugs with serotonergic properties. By continued implementation of experimental methodologies, the interaction of environmental events and 5-HT status on aggressive behavior predicted by some models may be examined under controlled, laboratory conditions. Finally, the development and use of psychometrically sound, standardized measures of aggressive behavior are the most press- ing methodological needs in this area.

Research should continue to address the specific forms of aggressive behavior controlled by 5-HT. Th e impulsive versus nonimpulsive distinction, despite the limitations discussed earlier, provides a promising starting point. Potentially important, but unexamined, mediator variables between 5-HT and aggressive behavior also deserve consideration. Indeed, it is reasonable to expect that the influence of 5-HT on human behavior is partially controlled by individual differences in information processing and emotional regulation. It is also likely that the link between serotonin neurotransmission and aggression is dependent on the functioning of other neurotransmitter and hormonal systems. Thus, at the micro level, both the role of specific receptor subtypes and the interaction of multiple biologic systems deserve attention.

If reduced 5-HT functioning is associated with aggressive behavior, it follows that drugs that increase 5-HT activity, such as fluoxetine (Prozac), may be useful in reducing some forms of aggressive behavior. ,4 recent double-blind, placebo- controlled study found that Prozac was rlseful in reducing verbal outbursts and indirect aggression (e.g., breaking objects) in personality-disordered outpatients (Coccaro & Kavoussi, in press). Such results, however, do not necessarily support the idea that pharmacotherapy approaches are the only useful treatment for aggressive behavior, Psychotherapeutic interventions have also been effective for the manage- ment of aggressive behaviors (see Bornstein, Weisser, & Balleweg, 1985). An interest- ing, though yet untested, hypothesis is that reductions in aggressive behavior after psychotherapeutic interventions may also lead to enduring increases in 5-HT activity. It is also possible that a stable rearing environment and the opportunity to learn social competency skills during childhood will produce intact 5-HT functioning in adults. In this way, psychosocial interventions in childhood may reduce the probability of adult impulsive aggressive behavior. Though costly and time-consuming, longitudinal studies of at-risk individuals may provide important information about how biological, psychological, and contextual factors combine to affect the development of aggressive behavior. For example, children of parents who have a history of violent behavior may be followed across time to determine which factors inoculate, and which facilitate, the development of neurotransmitter and behavioral abnormalities, and also the direction of these relationships.

In summary, there is suggestive, but far from definitive, evidence that 5-HT abnormalities are associated with human aggressive behavior. Future systematic research on this potentially important biologic variable may provide crucial information about how individual differences in human aggressive behavior develop, and how biological

Serotonin and Aggression 66.?

and psychological factors combine to elicit or inhibit destructive, aggressive acts. More precise identification of the nervous system distribution of serotonin receptors (Tecott, Maricq, & Julius, 1993) will allow more specific tests of the serotonin- aggression hypothesis through imaging techniques such as PET or fMRI. For instance, viewing aggressive scenes or other inductions of aggressive mental states should produce reliable activation in forebrain amygdaloid areas. Serotonin-aggression findings also need to be evaluated for their consistency with other findings about serotonins role in behavior. Serotonin abnormalities have been noted in obsessive- compulsive disorder, eating disorders, mood disorders, among others. Articulations of the serotonin hypothesis of aggression need to be integrated with such findings to provide a full understanding of the role of serotonin in human behavior.

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The Serotonine Aproch to violence