Neurochemistry and Pharmacotherapeutic Management of Aggression and Violence

Klaus A. Miczek, Margaret Haney, Jennifer Tidey, Jeffrey Vivian, and Elise Weerts

NEUROSCIENCE PERSPECTIVE

Violence and aggression like all other behaviors are ultimately a function of brain activity. The evolution of brain mechanisms that mediate aggressive and violent behaviors may be traced from humans to other animal species, and most of the neurochemical and neuropharmacologic evidence stems from studies with non-human species. The relevant neurochemical systems start with genetic instructions, undergo critical maturation periods, and—as evidence during the past two decades demonstrates—environmental, social, nutritional, and experiential factors modulate these systems continuously.

Insight into the neurochemical mechanisms of violence in humans has been obtained only indirectly by correlating biochemical markers in peripheral fluids or in the spinal cord with past behavioral events. In the meantime, an explosion of neuroscience research continuously informs on highly discrete neuroanatomical processes, pools of synthetic and metabolic enzymes, exquisitely regulated neural receptor populations, and transducer systems. None of these newly developed research methods have been applied to the issues of violence as of yet.

Klaus Miczek, Margaret Haney, Jennifer Tidey, Jeffrey Vivian, and Elise Weerts are at the Department of Psychology, Tufts University.



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Understanding and Preventing Violence: Volume 2, Biobehavioral Influences Neurochemistry and Pharmacotherapeutic Management of Aggression and Violence Klaus A. Miczek, Margaret Haney, Jennifer Tidey, Jeffrey Vivian, and Elise Weerts NEUROSCIENCE PERSPECTIVE Violence and aggression like all other behaviors are ultimately a function of brain activity. The evolution of brain mechanisms that mediate aggressive and violent behaviors may be traced from humans to other animal species, and most of the neurochemical and neuropharmacologic evidence stems from studies with non-human species. The relevant neurochemical systems start with genetic instructions, undergo critical maturation periods, and—as evidence during the past two decades demonstrates—environmental, social, nutritional, and experiential factors modulate these systems continuously. Insight into the neurochemical mechanisms of violence in humans has been obtained only indirectly by correlating biochemical markers in peripheral fluids or in the spinal cord with past behavioral events. In the meantime, an explosion of neuroscience research continuously informs on highly discrete neuroanatomical processes, pools of synthetic and metabolic enzymes, exquisitely regulated neural receptor populations, and transducer systems. None of these newly developed research methods have been applied to the issues of violence as of yet. Klaus Miczek, Margaret Haney, Jennifer Tidey, Jeffrey Vivian, and Elise Weerts are at the Department of Psychology, Tufts University.

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Understanding and Preventing Violence: Volume 2, Biobehavioral Influences Up to the 1960s, the canonical transmitter substances such as norepinephrine (NE), dopamine (DA), serotonin (5-hydroxytryptamine, 5-HT), and acetylcholine (ACh) were the major focus of neuroscience research. Accelerating since the 1970s has been the research on receptor subtypes for endogenous neurotransmitters and neuromodulators and for psychoactive drugs. The discovery of peptides and steroids in the brain, as well as their neural receptors, prompts the consideration of possible new mechanisms that may be relevant to aggressive and violent behavior. In the early zeal, neuroscience research attempted to discover the ''chemical code" of specific behavioral functions; noradrenergic feeding and cholinergic drinking were initial examples of normal homeostatic functions, the dopamine hypothesis of schizophrenia was advanced, and serotonin was sometimes referred to as a "civilizing neurohumor" keeping sex and aggression under control. However, by now, nearly every neurotransmitter has been implicated in the neural mechanisms for these complex physiologic and behavioral phenomena, and this applies also to aggressive and violent behavior. It is highly unlikely that the problem of violence can be reduced to a dysfunction in a single enzyme, receptor, or molecular component of a nerve cell. The present framework for studies on neurochemical mechanisms of violence distinguishes a neurochemical profile of individuals with an aggressive "trait" from those events that mediate the initiation, execution, and termination of aggressive and violent acts on a moment-to-moment "state" basis. The latter are significant in the development of rational therapeutic interventions. In general, clinical studies focus on biochemical markers of aggression, or violence as a trait, whereas experimental studies in animals provide mostly data on the proximal antecedents and consequences of aggressive behavior (state). Genetic studies of aggressive traits in animals have only rarely included concurrent assessments of their biochemical basis (see Carey, in this volume). It has become a truism to point out that each type of violent and aggressive behavior is associated with distinctive neurochemical changes, and more selective logical interventions modulate these different behavior patterns in an increasingly specific manner. In order to appreciate the range of aggressive and violent behaviors at the animal and human level that have been studied for their neurochemical basis, it will be useful to briefly summarize the major animal models as well as clinical types of aggression and violence.

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Understanding and Preventing Violence: Volume 2, Biobehavioral Influences TYPES OF AGGRESSIVE AND VIOLENT BEHAVIOR In the psychiatric clinic, violent and aggressive behaviors are not very well defined, although these behavior patterns may be symptoms of many disorders (e.g., Eichelman, 1986). According to the terminology and criteria of the revised Diagnostic and Statistical Manual of Mental Disorders (DSM-IIIR) (American Psychiatric Association, 1987), these may include conduct disorder in adolescents, isolated or intermittent explosive disorder in adults, parent-child problem in certain cases of child abuse, dementia, schizophrenia, alcohol and substance abuse, depression, mania, antisocial personality disorder, mental retardation, and attention-deficit disorder. Several neurological diseases feature in their symptomatology violent or pathological aggressive behavior; most noteworthy are aggressive and violent outbursts in some patients with Gilles de la Tourette's syndrome, Down's syndrome, Lesch-Nyhan syndrome, epilepsy, and limbic as well as hypothalamic tumors (see Mirsky and Siegel, in this volume). Ethological, experimental-psychological, and neurophysiologic concepts and methods have contributed to the development of preclinical models of aggressive behavior that have been investigated for their neurochemical and neuropharmacologic bases (e.g., Miczek, 1987). Several schemes have been proposed to categorize the different types of animal aggression in terms of the experimental manipulations, either pervasive (e.g., isolated housing) or discrete (e.g., exposure to pain stimuli, omission of scheduled reinforcement, brain stimulation, brain lesion); the type of behavioral phenomena (e.g., affective defense, killing); or the potential function (e.g., territorial defense, maternal aggression, dominance-related aggression). Table 1* summarizes the major experimental models of animal aggression in laboratory research by differentiating those that are based on (A) aversive environmental manipulations, (B) brain manipulations, and (C) ethological situations. Killing (D) highlights *   The tables appear at the end of this paper, beginning on page 349.

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Understanding and Preventing Violence: Volume 2, Biobehavioral Influences the difficulties of these categorical schemes; since variants of this behavior have been referred to as a form of "predatory aggression" (ethological) or "irritable aggression" (aversive environmental manipulations), it may be produced by brain stimulation or brain lesions (brain manipulations) and it may be self-reinforcing as in the case of "excess'' killing. The attempt to assign biologic functions to animal models of aggression demonstrates the ambiguities associated with most of these models (last column in Table 1), and the difficulties in relating many types of animal aggression to the phenomena of human violence, as defined legally or clinically, are important for the present discussion. CONCLUDING STATEMENT Clinical and preclinical definitions of violent and aggressive behavior range across a variety of behavioral phenomena that differ in terms of distal and proximal antecedents, intensity and frequency of behavioral acts, and functions. During the past 15 years, animal aggression research, influenced by an ethological framework, has begun to focus on adaptive patterns of behavior in biologically meaningful contexts, while clinical research is concerned with aggressive and violent acts as "behavioral pathologies," viewing aggression alternatively as a trait or a state. In order to trace the evolutionary origins of aggressive behavior at the behavioral, physiologic, and neurobiologic levels, detailed functional and structural analyses at each level are needed; this need is particularly acute at the behavioral and diagnostic levels. NEUROCHEMISTRY AND NEUROPHARMACOLOGY OF AGGRESSION AND VIOLENCE Until the development during the last decade of microdissection and imaging techniques for neural tissue, as well as techniques for in vivo microdialysis and improved sensitivity of biochemical assay, the evidence for the involvement of ACh, gamma-aminobutyric acid (GABA), NE, DA, and 5-HT in neural mechanisms of animal aggression was based entirely on single measures that summarized an experimental subject's entire brain activity at one time point. In humans, access to the central nervous system (CNS) is even more limited, so clinical researchers have relied on more readily collected indirect measures such as blood and urine; a somewhat more invasive technique is spinal

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Understanding and Preventing Violence: Volume 2, Biobehavioral Influences punctures to obtain cerebrospinal fluid (CSF). Again, these indirect indices are single values, totally reflecting the activity of many anatomically differentiated, functionally opposing, and interacting systems that follow a daily rhythm and are greatly influenced by environmental and nutritional factors. For present purposes, the most frequently and thoroughly investigated of the more than 50 identified neurotransmitter and neuromodulator substances are surveyed. The evidence that is examined links (1) direct neurochemical measures, as well as (2) neuropharmacologic manipulations of norepinephrine, dopamine, serotonin, acetylcholine, and GABA to aggressive and violent behavior both in animals and in humans. (3) Major pharmacotherapeutic interventions are reviewed and evaluated for their effectiveness and selectivity in modulating aggressive and violent behavior. Key features of the cited empirical studies are summarized in tabular form. CATECHOLAMINES Noradrenergic Correlates of Animal Aggression Massive adrenergic activity in the sympathetic nervous system and in the adrenal gland accompanies intense emotional behavior, including aggressive and violent behavior (e.g., Lamprecht et al., 1972; Stoddard et al., 1986; Barrett et al., 1990). However, the focus here is less on the autonomic correlates and consequences, then on levels of brain norepinephrine, the noradrenergic neuronal pathways, the alpha- and beta-adrenergic receptor subtypes, and their respective role in violent and aggressive behavior (Table 2, section A). Divergent changes are reported for whole brain levels of NE, as well as indices of NE turnover and synthesis in animals, just before or after they have engaged in a range of aggressive behaviors. In lobsters, rainbow trout, and pheasants, octopamine (the invertebrate counterpart to NE) and NE are decreased in the more aggressive dominant member in comparison to the subordinate member (Kravitz et al., 1981; McIntyre et al., 1979; McIntyre and Chew, 1983). In mice, whole brain NE is elevated after isolated housing that renders many animals aggressive (Welch and Welch, 1965) or after they have just fought (Modigh, 1973). NE turnover is either increased or decreased in isolated, presumably aggressive mice (Valzelli, 1973; Rolinski, 1975) or immediately after a fight (Modigh, 1973). Either aggressive strains of mice do not differ

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Understanding and Preventing Violence: Volume 2, Biobehavioral Influences from less aggressive ones in terms of their NE turnover (Karczmar et al., 1973; Goldberg et al., 1973) or turnover is increased in the more aggressive strains (Bernard, 1975). When rats are reacting defensively to electric shock, their diencephalic and mesencephalic NE turnover is increased (Stolk et al., 1974). Cats as well as rats that rage after acute brain stem transection or after septal lesions show elevated hindbrain NE turnover (Reis and Fuxe, 1964, 1968; Salama and Goldberg, 1973b), but "rage" due to amygdaloid stimulation lowers NE levels in their brain stem (Reis and Gunne, 1965). Hypothalamic and amygdaloid levels of the NE metabolite MHPG (3-methoxy-4-hydroxyphenylglycol) were also reduced in rats that engaged in stress-induced biting (Tsuda et al., 1988). When rats have just killed a mouse, their forebrain NE turnover is increased (Goldberg and Salama, 1969; Salama and Goldberg, 1973b; Tani et al., 1987). Anatomically more discrete measurements of noradrenergic activity in aggressive animals often reveal opposite changes in different brain regions. Increased synaptosomal uptake of cortical NE was measured in mice after intense fighting (Hendley et al., 1973; Hadfield and Weber, 1975). Isolated mice of particularly aggressive strains show increased turnover of NE in three brain areas (frontal cortex, caudate, hypothalamus; Tizabi et al., 1979). After exhibiting fighting behavior they have less NE in olfactory tubercle and substantia nigra, but increased NE in the septal forebrain (Tizabi et al., 1980). Increased levels of NE were also found in the hypothalamus of rats that kill mice (Tani et al., 1987). However, many investigations fail to detect any changes in NE levels, turnover, or synthesis in brain regions of animals exhibiting aggressive behavior (e.g., Payne et al., 1984, 1985). Brain norepinephrine undergoes large changes before, during, and after different kinds of aggressive and defensive behavior in animals; these changes are, however, localized in specific brain regions that even within the limbic system appear to exert opposing behavioral effects. At present, it is not yet possible on the basis of experimental evidence from animal models to map a "noradrenergic neurochemical profile" of different brain regions that are critically important just preceding or consequent to an aggressive act. Dopaminergic Correlates of Animal Aggression As detailed in Table 2, section B, levels of DA and measures of DA synthesis and turnover in the whole brain have been found

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Understanding and Preventing Violence: Volume 2, Biobehavioral Influences to increase in aggressive strains of mice and in mice that have just engaged in aggressive behavior (e.g., Bernard et al., 1975; Modigh, 1973). With regard to specific brain regions, isolation-induced aggressive behavior in mice has been reported to increase DA levels in the striatum (Tizabi et al., 1979); DA uptake in the prefrontal cortex, but not striatum (Hadfield, 1981, 1983); and DA turnover in striatum (Hutchins et al., 1975), frontal cortex, and hypothalamus (Tizabi et al., 1979); hypothalamic DA levels were also elevated in attacking rats (Barr et al., 1979). In mice attacking for the first time, DA turnover in the nucleus accumbens is increased, but not after multiple aggressive experiences (Haney et al., 1990). When mice or rats defend against attacks, several limbic forebrain structures show elevated metabolite levels of DA (Mos and van Valkenburg, 1979; Louilot et al., 1986; Puglisi-Allegra and Cabib, 1990). Defensive reactions to electric shock are also correlated with increased DA uptake in striatum (Hadfield and Rigby, 1976), and increased DA turnover in cortical and limbic areas (Dantzer et al., 1984). Rats that kill mice do not significantly differ from so-called nonkillers in limbic DA but may differ slightly in hippocampal DA (Broderick et al., 1985; Barr et al., 1979); muricidal rats may also show increased DA metabolite levels (Tani et al., 1987). The activity of brain dopamine undergoes large changes subsequent to either aggressive or defensive behavior. At present, different experimental preparations have implicated all three major forebrain dopamine systems (i.e., nigrostriatal, mesolimbic, and mesocortical). Brain dopamine systems appear to be particularly significant in (1) the reinforcing or rewarding aspects of violence and aggression, possibly via the mesolimbic and mesocortical DA systems, and/or (2) the neural mechanisms for initiation, execution, and termination of violent or aggressive behavior patterns, possibly via the nigrostriatal and mesolimbic DA systems. In order to assess these possibilities, it will be important to apply methodology with greater temporal, anatomically, and behaviorally differentiating resolution. Catecholaminergic Correlates Of Human Aggression And Violence The evidence from studies with humans on the role of NE in neural mechanisms responsible for violent and aggressive behavior is limited to measurements of noradrenergic activity in the

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Understanding and Preventing Violence: Volume 2, Biobehavioral Influences CSF, blood, or urine (see Table 2, section C). In military personnel rated as highly aggressive in terms of nine categories of lifestyle, the MHPG level in CSF was positively correlated with average "aggression score" (Brown et al., 1979). However, NE turnover rates in the CSF of men convicted of violent crimes did not differ among those that were judged to be premeditated versus those considered to be impulsive (Linnoila et al., 1983). Similarly, DA levels and turnover in CSF of five XYY patients arrested for assaults did not differ from controls (Bioulac et al., 1980). Several studies attempted to identify indices of catecholamine activity in blood or urine that may characterize aggressive or violent individuals. For example in one series of studies, higher urinary NE values, particularly in response to an upcoming experimental stressful event, appear to be more prevalent in violent incarcerated male patients in a maximum security hospital setting (Woodman et al., 1977; Woodman and Hinton, 1978a, b; Woodman, 1979) than in nonviolent controls. Violent male offenders also differ in their levels of free and conjugated plasma phenylacetic acid, although one study finds increases and another, decreases (Sandler et al., 1978; Boulton et al., 1983). These correlative studies of indices of catecholamine activity in CSF, blood, or urine provide little support for brain NE as a specific "marker" for aggressive or violent behavior. A promising diagnostic strategy is to examine an individual's catecholamine response to an environmental or pharmacologic challenge rather than to rely on basal levels undergoing circadian rhythmic oscillations. NE, DA, and their metabolites are highly compartmentalized in the brain, and their concentrations are relatively low compared to those in other organs of the body. Conclusions about brain catecholamines and the propensity to aggressive and violent behavior on the basis of peripheral measures are to be considered very tenuous. Neuropharmacologic Manipulations of Catecholamines The pharmacologic evidence from animal and human studies suggests a permissive role for catecholamines in aggressive and violent behavior. One type of experimental strategy is to compromise catecholamine synthesis, storage, or release; these manipulations reliably reduce aggressive and defensive behavior in animals ranging from mice to monkeys (e.g., Eichelman, 1981; Torda, 1976). Of course, brain catecholamine (CA) systems are of critical significance in a large variety of basic physiologic and behavioral

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Understanding and Preventing Violence: Volume 2, Biobehavioral Influences processes such as sleep/wakefulness rhythmicity, homeostatic and motor functions, and a range of active and reactive behavior patterns. The critical issue in these data is the relative lack of specificity with which these pharmacologic interventions reduce aggressive behavior. Pharmacologic inhibition of catecholamine synthesis, presynaptic storage, or release profoundly alters all active behavior, including aggressive acts. Consistent evidence during the past three decades repeatedly demonstrates that inhibition of the synthetic enzymes tyrosine hydroxylase or dopamine ß-oxidase, as well as depletion of storage sites, decrease many behavioral initiatives, including attacks and threats in mice, rats, cats, and monkeys (see Table 2, section D; e.g., Redmond et al., 1971a,b; Torda, 1976; Katz and Thomas, 1976; Diringer et al., 1982). This evidence emphasizes the necessity of intact catecholamine synthesis, storage, and release for aggressive behavior to occur, but does not establish a specific role for catecholamines in these types of behavior patterns. A further approach in assessing the role of brain catecholamines in animal aggression is to produce degenerations of catecholamine-containing neurons or, more specifically, those neurons that contain either dopamine or norepinephrine with selective cytotoxic agents and subsequently to measure alterations in aggressive behavior patterns. Rage-like reactions and heightened irritability may be produced by CA-depleting doses of the cytotoxic agent 6-hydroxydopamine (6-OHDA) in laboratory rats, and the indiscriminate biting and defensive reactions can further be amplified by exposure to pain stimuli (e.g., Eichelman et al., 1972; Eichelman and Thoa, 1973; Nakamura and Thoenen, 1972; Geyer and Segal, 1974; Pucilowski and Valzelli, 1986; Beleslin et al., 1986; see Table 2, section D). In contrast to these observations are the suppressive effects of 6-OHDA on aggressive behavior in monkeys when confronting conspecifics (Redmond et al., 1973) or in cats preying on rats (Dubinsky et al., 1973). Of course, destruction of brain catecholamine-containing neurons renders an organism severely impaired in a wide range of important bodily functions, which in turn may be indirectly leading to a hyperreactive defensive mode of behavior. Another strategy consists of modulating aggressive behavior by the administration of catecholamine precursors. During the 1960s and 1970s the "l-dopa-rage" phenomenon attracted attention, and it continues to serve as evidence for an important role of brain dopamine in aggressive behavior (e.g., Eichelman, 1981, 1987). In laboratory rats and mice, administration of very large doses of

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Understanding and Preventing Violence: Volume 2, Biobehavioral Influences the CA precursor, l-dopa (l-dehydroxyphenylalanine) facilitates or induces indiscriminate biting and other defensive reactions. These reactions are further intensified if the animals are exposed to chronic cannabis, are withdrawn from opiates, have sustained CA neurotoxicity or depletion, or have inhibition of CA synthesis or of monoamine oxidase (see Table 2, section D; Everett, 1961; Vander Wende and Spoerlein, 1962; Randrup and Munkvad, 1966, 1969a,b; Ernst, 1967; Lammers and van Rossum, 1968; Zetler and Otten, 1969; Yen et al., 1970; Lal and Puri, 1971; Benkert et al., 1973; Rolinski, 1973). The relevance of the experimental l-dopa-rage phenomenon to aggressive behavior in animals or human violence is, however, tenuous because it occurs only after massive pharmacologic interventions and consists of behavioral fragments of uncertain significance (e.g., Krsiak, 1974b). L-Dopa actually suppresses fighting behavior in mice but increases defensive responses to painful stimuli (e.g., Karczmar and Scudder, 1969; Thoa et al., 1972a). The amino acid precursors l-tyrosine and l-phenylalanine, if added to the diet, may transiently increase aggressive behavior in mice (Thurmond et al., 1979, 1980). DA, when given directly into the cerebral ventricles, may also increase pain-induced defensive responses in rats (Geyer and Segal, 1974). Most of the evidence on brain NE and DA derives from studies with increasingly selectively acting receptor agonists and antagonists. Initial evidence indicated that the nonselective DA receptor agonist, apomorphine, results in hyperdefensive responses similar to those seen after l-dopa in mice and rats, particularly under conditions in which brain dopamine receptors are unusually sensitive (see Table 2, section D; e.g., Senault, 1968; McKenzie, 1971; Thoa et al., 1972a,b; Lal and Puri, 1971; Torda, 1976; Baggio and Ferrari, 1980; Pucilowski et al., 1986, 1987). By contrast, in situations requiring coordinated pursuit, threat, and attack, apomorphine exerts suppressive effects on aggressive behavior in mice (e.g., Hodge and Butcher, 1975; Lassen, 1978; Baggio and Ferrari, 1980). These studies suggested a clear pharmacologic differentiation between offensive aggression and exaggerated defense. Recently developed selective agonists for the D1 and D2 receptor subtypes mimic the effects of apomorphine in terms of hyperdefensive and indiscriminate biting reactions in laboratory rodents (e.g., Puglisi-Allegra and Cabib, 1988, 1990; Cabib and Puglisi-Allegra, 1989). A large number of studies have consistently documented the inhibitory effects of catecholaminergic and particularly dopaminergic receptor agonists on killing behavior by omnivorous rats and carnivores (see Table 2, section D; e.g., Schmidt, 1979, 1983; Bandler,

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Understanding and Preventing Violence: Volume 2, Biobehavioral Influences 1970, 1971a; Rolinski, 1975; Berzsenyi et al., 1983; Molina et al., 1987; Isel and Mandel, 1989). Although the literature on human violence uses the term "predatory" in analogy to stalking and killing in carnivorous animal species, the relationship between the predatory behavior of certain animal species and human aggressive or violent behavior remains to be explored. Dopamine receptor antagonists have been studied extensively for their antiaggressive effects; however, their selectivity as antiaggressive drugs remains unsatisfactory (e.g., Eichelman, 1986; Miczek, 1987; Miczek et al., 1994). Most of these substances have been developed as potential antipsychotic or neuroleptic drugs, and this literature is reviewed below (Table 7). Recently, selective antagonists for D1 and D2 receptors have been developed (e.g., McMillen et al., 1989; Redolat et al., 1991). Initial evidence indicates that blockade of either dopamine receptor subtype potently decreases aggressive behavior in mice and monkeys, albeit with limited behavioral specificity (Ellenbroek and Cools, 1990; Tidey and Miczek, 1992; Miczek et al., 1994). Future studies will have to identify the dopamine receptor populations that are most relevant in the initiation and execution of aggressive and defensive behavior patterns in animals in order to develop a rational basis for clinical trials in humans. The successful use of beta-adrenergic receptor blockers in the management of violent patients identifies these substances as potential therapeutic options (e.g., Ratey et al., 1986, 1987). The clinical evidence on beta-blockers is reviewed below. When the prototypical beta-blocker, propranolol, was found to be beneficial in calming violent individuals who are unresponsive to other medications (e.g., Elliott, 1977), its therapeutic value was thought to derive from its blockade of noradrenergic beta-receptors. In the meantime, propranolol, pindolol, nadolol, and similar substances, which have been found to show high affinity for 5-HT1A, act as antagonists (Olivier et al., 1990), and it is this serotonergic mechanism of action that may be the basis for the antiaggressive effects of beta-blockers. SEROTONIN No other neurotransmitter has been more intimately implicated in the neurobiologic mechanisms of aggressive and violent behavior than 5-HT (e.g., Brown et al., 1979; Valzelli, 1981; van Praag et al., 1987; Roy and Linnoila, 1988; Coccaro, 1989; Miczek and Donat, 1989). A major theme in the biological psychiatry

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Understanding and Preventing Violence: Volume 2, Biobehavioral Influences Salzman et al. 1969 40 male volunteers that had low anxiety and hostility ratings were administered placebo or chlordiazepoxide (10 mg 3x/day for 1–2 weeks). 1/2 of the subjects received instructions that the drug would produce a pleasant, friendly, more relaxed feeling. Subjects were evaluated with Buss-Durkee Hostility inventory Both the placebo group that received instructions about the drug and the unaware chlordiazepoxide group showed increased hostility ratings. Podobnikar 1971 36 patients with anxiety related symptoms and neurotic hyperaggressiveness were administered placebo or chlordiazepoxide (10 mg 2x/day) 11 of 22 patients showed no signs of aggressiveness compared to placebo after 2–4 weeks treatment. Salzman et al. 1974 48 male volunteers assigned to 3 person groups were evaluated with Buss-Durkee hostility inventory and self-rated and group member-rated questionnaires. Subjects were administered placebo or chlordiazepoxide (30 mg/day) for 7 days Chlordiazepoxide produced an increase in self-rated hostile affect, but not in behavior hostility. When a frustration stimulus was presented to the group, chlordiazepoxide increased interpersonal behavioral hostility; rage reaction was observed in 1 subject. Rickels and Downing 1974 225 neurotic outpatients (majority were women) from 3 clinical settings administered placebo or chlordiazepoxide (40 mg/day for 4 weeks); patients were evaluated by physicians and by patient symptom checklist and grouped according to low, medium or high anxiety All symptoms of hostility, irritability and anxiety were reduced by chlordiazepoxide treatment in all groups. No evidence for increased aggressiveness or "paradoxical rage" reactions. Kochansky et al. 1975 33 paid volunteers, mean of 24.5 years old, responded to newspaper add that scored greater than 12 but less than 26 on TMAS (Taylor Manifest Anxiety Scale) in discussion groups of 3 were and administered the BDHI (Buss-Durkee Hostility Inventory) before and after group interaction; self administered 15 mg/kg oxazepam, 10 mg/kg chlordiazepoxide, or placebo 3x/day for 1 week tested again 8th day Following "frustration" stimulus (telling subjects they had performed inadequately and would have to repeat task) chlordiazepoxide increased verbal hostility whereas oxazepam reduced verbal hostility compared to placebo.

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Understanding and Preventing Violence: Volume 2, Biobehavioral Influences References Methods and Procedures Results and Conclusions Kochansky et al. 1977 32 paid volunteers, 21–29 years old, responding to newspaper ads were classified as medium or highly anxious with TMS (Taylor Manifest Anxiety Scale); discussed TAT (Thematic Apperception Test) cards in groups of 3 in predrug condition; subjects self administered 15 mg/kg oxazepam, 10 mg/kg chlordiazepoxide, or placebo 3x/day for 1 week ''Frustration" was induced by telling subjects they had performed inadequately and would have to repeat task; chlordiazepoxide reduced total verbal units initially, but following frustration stimulus, increased verbal hostility as measured by viewer-rated aggression scale. Oxazepam reduced verbal hostility even after frustration stimulus. Zisook et al. 1978 51 outpatients with neurotic anxiety were administered placebo or halazepam (40 mg 2–4x/day) in a double blind study; patients were evaluated with Hamilton Anxiety Scale, MMPI and patient symptom check list Of the 20 patients that completed the study, halazepam did not alter hostility or anger scores over a 6 week period. Lion 1979 45 outpatients with histories of temper tantrums, assaultive behavior, and impulsiveness associated with irritability and hostility were administered placebo (4x/day), chlordiazepoxide (25–50 mg 4x/day) or oxazepam (30–60 mg 4x/day); patients were evaluated by physicians and with scored questionnaires using Buss-Durkee Hostility scale and Scheir-Cattell anxiety scale Oxazepam significantly reduced irritability and hostility measures when compared to placebo or chlordiazepoxide. Griffiths et al. 1983 12 men with histories of abusing barbiturates and benzodiazepines; 3 subjects also on methadone treatment. Subjects received placebo and two high doses of diazepam (50 and 100 mg/day for 5 days) in a double blind random block design. Subjects filled out questionnaires for drug effect, drug liking, ARCI (Addition Research Center Inventory) and POMS (Profile of Mood States) Diazepam decreased social interactions and increased ratings of hostility by staff (but not by subject); carry over effects observed in 2 week washout period. Gardner and Cowdry 1985 16 female outpatients with borderline personality disorder and histories of dyscontrol (suicide attempts, self-abuse, assaults) were administered alprazolam (1–6 mg) or placebo for 6 weeks in a double blind random crossover design Alprazolam produced episodes of dyscontrol in 7 out of 12 patients (58%) compared to 1 out of 13 patients taking placebo; episodes were more severe, frequent and unpredictable than previous episodes prior to drug treatment.

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Understanding and Preventing Violence: Volume 2, Biobehavioral Influences Lipman et al. 1986 387 outpatients with depressive and anxiety disorders between 18 and 70 years old that answered newspaper add completed a double blind study of 5 medications including chlordiazepoxide (20–60 mg/day for 8 weeks). Subjects completed self-rating check lists, POMS (Profile of Mood State). Physicians evaluated patients progress with HAM-A, HAM-D (Hamilton Anxiety Scale and Depression Scale), anxiety depression check list, Covi Anxiety, and Raskin Depression Screen, and Global Improvement Scale Patients that received chlordiazepoxide scored consistently higher on measures of anger and hostility than the placebo controls throughout treatment period. Literature Reviews     Maletzky 1973 Review of case histories of 22 patients with episodic dyscontrol syndrome evaluated from interviews of patient, family and friends Relatives and patients noted an increase in violent episodes by chlordiazepoxide and diazepam in 5 patients. Salzman et al. 1975 Review of 28 references of clinical reports and research on oxazepam and aggression No clinical observation of increased hostility from oxazepam administration. In laboratory, oxazepam reduced aggression or hostile mood even in presence of frustration. Oxazepam differs from chlordiazepoxide or diazepam in reference to increased aggression. Greenblatt et al. 1975 Review of 88 references on clinical pharmacology of flurazepam In animals, flurazepam produces taming effects in some cases and in other cases produces an increase in aggressive hostile behavior, possibly by releasing anxiety-bound aggression. Azcarate 1975 Review of 43 references on treatment of aggression Clinical trials of the efficacy of minor tranquilizers have revealed results similar to preclinical animal studies; some studies report increases in hostility and a paradoxical rage reactions; Variations in results may be attributed to dose, specific compound administered, acute vs. chronic administration, individual baseline levels of anxiety and/or hostility, and personality type.

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Understanding and Preventing Violence: Volume 2, Biobehavioral Influences References Methods and Procedures Results and Conclusions Zisook and Devaul 1977 Review of case studies Chlordiazepoxide and diazepam can produce rage attacks, whereas oxazepam does not; chlordiazepoxide can increase interpersonal hostility and frustration. Bond and Lader 1979 Review of 49 references on benzodiazepines and hostility in normal and violent individuals Evidence for rage attacks in patients administered benzodiazepines is based on uncontrolled clinical studies and few case histories. Generally, outbursts occur in patients who received doses in excess of 50 mg/day, perhaps due to drug toxicity. Increased hostility by benzodiazepines has been observed in normal subjects in controlled laboratory experiments; chlordiazepoxide increases hostility after 1 week administration, but oxazepam does not produce these results. Valzelli 1979 Review of 129 references on the effects of sedatives and anxiolytics on aggression Benzodiazepines reported to increase and decrease aggression in man and animals. Suggests drugs that are capable of lowering aggression are equally capable of enhancing it. Gunn 1979 Review of 20 references on the use of drugs in the violence clinic Increases in hostile aggressive tendencies, and in some cases, aggression and violence, have been observed in some individuals after acute chlordiazepoxide; oxazepam not implicated in paradoxical "rage" response. Lion 1981 Review of 22 references on medical treatment of violent patients Benzodiazepines have little antiaggressive activity except in paranoid patients where benzodiazepines reduce hypervigilance. BZD often produce a paradoxical "rage" response in alcoholic patients, possibly by disinhibitory action. Atkinson 1982 Review of 18 references on managing violent hospital patients Concern with increased aggression in some patients administered diazepam and chlordiazepoxide, suggests shorter acting benzodiazepines like oxazepam because of lack of active metabolites.

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Understanding and Preventing Violence: Volume 2, Biobehavioral Influences Sheard 1983 Review of 60 references on psychopharmacology of aggression Violent states associated with personality disorders are controlled with diazepam (0.15 mg/kg/hour, i.v.); chlordiazepoxide or oxazepam (10 mg 3x/day) is especially useful in epileptic patients. Evidence for benzodiazepine-induced paradoxical "rage" reactions may be explained by toxic reactions, or benzodiazepine withdrawal. No reports of paradoxical "rage" with oxazepam. Sharon 1984 Review of 42 references on the use of benzodiazepines in correctional facilities The concern of paradoxical rage and increased aggression induced by benzodiazepines in the prison populations is unsubstantiated. Very few studies exist to warrant removal of a potentially helpful agent from an anxiogenic setting. Studies that report increases in aggression fail to consider individuals that are already very aggressive prior to benzodiazepine treatment, as well as predisposing conditions (borderline personality disorder). Suggests care in prescribing benzodiazepines in these individuals, but encourages use in individuals with disabling anxiety. Sheard 1984 Review of 59 references on the clinical pharmacology of aggression Increases in rage and aggressive outbursts are not strongly supported by clinical data. Reductions in hostility and anxiety in double blind studies in delinquent boys, veteran outpatients and anxious out patients. Increases in hostility and paradoxical rage reactions have been associated with chlordiazepoxide but not oxazepam. In addition to antipsychotic medications, benzodiazepines are useful in treating aggressive and combative behavior related to psychosis.

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Understanding and Preventing Violence: Volume 2, Biobehavioral Influences References Methods and Procedures Results and Conclusions Tupin 1985 Review of 36 references on psychopharmacology and aggression in clinical settings Anxiolytic substances are used to treat anxious, agitated patients, but have been shown to aggravate violence reactions in some patients, and in a few cases produce paradoxical rage reactions. Suggests importance of treating the basis for aggression, namely the underlying psychiatric and/or medical problem, instead of a symptom. Benzodiazepines are useful in treating outbursts associated with borderline personality disorders, but are not as effective in treating serious panic and combativeness associated with psychosis. Yudofsky et al. 1987 Review of 30 references on pharmacologic treatment of aggression Benzodiazepines' effect on aggressive behavior is inconsistent. Benzodiazepines can produce paradoxical "rage" in some patients; reductions in aggression occur at higher doses that can produce sedation. Benzodiazepines are helpful for acute management of violence, but chronic use not recommended. Eichelman 1987 Review of 136 references on neurochemical and pharmacological aspects of aggressive behavior Benzodiazepines (chlordiazepoxide, diazepam, oxazepam) are claimed to reduce aggressive behavior in psychotic patients, prisoners with schizophrenic and personality disorders, as well as patients with episodic dyscontrol and hostile outbursts. However, rage reaction and enhanced aggressive behavior have been reported in some patient populations in open clinical trials. Oxazepam less associated with increases in aggression than chlordiazepoxide, but notes need for blind clinical trials.

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Understanding and Preventing Violence: Volume 2, Biobehavioral Influences Brizer 1988 Review of 145 references on psychopharmacology and the management of violent patients Evidence for the efficacy of benzodiazepines for controlling aggression is inconclusive. Although in open clinical trials, chlordiazepoxide, diazepam and oxazepam have been shown to reduce measures of hostility and/or aggression in schizophrenics, epileptics, and patients with organic brain dysfunction and episodic behavioral outbursts, some anecdotal reports indicate an increase of paradoxical rage reaction may be associated with benzodiazepines. Notes the lack of adequate controls for concurrent medications, medication blood levels, and psychiatric and neurologic diagnosis. Dietch and Jennings 1988 Review of case reports and experimental studies Clinically used BZDs increase irritability, verbal aggression, assaultiveness and self mutilation; incidence of aggression is estimated at 1% of patients treated with BZDs, with differential effects with different BZD compounds. Clonazepam most likely to induce aggression, and oxazepam least likely. B. 5-HT1A Receptor Agonists   Treatment of Inpatients     Ratey et al. 1989 Case reports in mentally retarded patients Buspirone (5–15 mg 3x/day) reduced aggression, self-injurious behaviors and maladaptive behavior in 9 out of 14 patients. Ratey and O'Driscoll 1989 Case reports in mentally retarded patients Buspirone (5–15 mg/kg 3x/day) reduced agitation in 10 patients; however some showed an increase in hyperactivity and agitation at higher doses. C. ß-Blockers   Treatment of Inpatients     Polakoff et al. 1986 Case study of an extremely violent 36 year old retarded man on mesoridazine (120 mg/d) + propranolol (120–200 mg/d) or nadolol (80 mg/d). ß-blocker in combination with neuroleptic treatment stopped assaultive behavior and allowed outpatient status after 26 years of institutionalization.

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Understanding and Preventing Violence: Volume 2, Biobehavioral Influences References Methods and Procedures Results and Conclusions Luchins and Dojka 1989 Evaluation of mentally retarded with aggressive and self-injurious behaviors; patients received propranolol (90–410 mg/day) or lithium (600–1800 mg/day) Aggression and self-abuse were controlled by either propranolol (83% reduction in both behaviors) or lithium (64% reduction for aggression, 82% reduction for self-abuse). Elliott 1977 Case reports of 7 belligerent patients (2 exhibited explosive rage responses) with acute brain damage who received propranolol (60—320 mg/day). Propranolol reduced irritation and anger, prevented aggressive outbursts and violent rage reaction. When propranolol was discontinued, symptoms reappeared in most cases. Schreier 1979 Case report of 12 year old boy with postencephalitic psychosis administered 20 mg propranolol b.i.d. increased to 100 mg over 2 days with other medications; maintained on propranolol for 2 weeks Propranolol reduced agitation and verbal aggression over the 2 week treatment period. The day after the last dose, he became increasingly aggressive and destructive (breaking pictures, wrecking room, tearing clothes); propranolol was reintroduced and symptoms disappeared. Yudofsky et al. 1981 Case reports of 4 inpatients with Chronic Brain Syndrome and episodes of aggressive and violent outbursts; propranolol (320–520 mg/day) administered with other medications Propranolol eliminated rage and violent outbursts and improved social ability with no adverse effects when carefully monitoring vital signs. Williams et al. 1982 Case reports of 26 male and 4 female patients (9 were inpatients) ranging in age from 7 to 35 years with organic brain dysfunction; all had ongoing psychiatric and/or neurological disturbance since childhood or adolescence and prior pharmacological intervention. Patients received 10–20 mg propranolol 3–4x/day initially, and were titrated upwards to achieve a maximal dosage of 50–1600 mg/day 12 patients showed marked improvement and 12 patients showed moderate improvement in control of rage outbursts following propranolol treatment; side effects included hypertension, somnolence and lethargy. One patient showed bradycardia when taking dose twice (=320 mg). Ratey et al. 1983 Case reports of 3 brain damaged or mentally retarded patients with episodes of provoked and unprovoked rage. Propranolol (90–300 mg/day) was administered with other medications. All three patients that had been unresponsive to other medications, showed improvement in control of temper tantrums and rage outbursts following propranolol treatment. When propranolol dosage was reduced rage episodes returned. Symptoms subsided with reinstitution of propranolol. One patient showed bradycardia at 300 mg/day.

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Understanding and Preventing Violence: Volume 2, Biobehavioral Influences Greendyke et al. 1984 Case reports of 6 assaultive patient with organic brain disease administered propranolol (200–520 mg/day for 40–80 days); assault behavior recorded by shift nurses and observations were conducted 15 minutes every 2 hours 7 times a day Results indicate a minimum of 1 month administration for effective treatment; propranolol decreased assaultive behaviors, pacing, agitation, and resistiveness. Yudofsky et al. 1984 Case report of 40 year old male alcoholic with Korsakoff's psychosis; extremely violent, physical assaults included injury to nursing staff and self; required physical restraints (ankle and hand or camisole). 20 mg x 4/day increased to 150 mg x 4/day in addition to other medications (haloperidol, phenytonin, pentobarbitol) Rage attacks were markedly reduced allowing removal of physical restraints; when propranolol dosage was reduced rage attacks returned, but disappeared with reinstitution of propranolol. No adverse effects were observed. Ratey et al. 1986 19 institutionalized mentally retarded patients given propranolol (40–200 mg/d) along with current medications 16 of 19 showed less assaultive and self-injurious behaviors when on ß-blocker. Attribute effects to a lowered level of arousal. Sorgi et al. 1986 Retrospective chart review of 7 assaultive chronic schizophrenics given ß-blocker, nadolol (40–160 mg/d) or propranolol (80 mg bid), in addition to their normal antipsychotic medication. Six of the seven patients improved. Four had > 70% reduction in assaultive behavior. Average peak effect was seen after 12 weeks of ß-blocker. Whitman et al. 1987 Three chronically aggressive psychotic patients treated with doses of propranolol up to 600 mg/d Treatment with ß-blocker plus neuroleptics resulted in remission and prevented assaultive behavior in one of three patients. Site of action is uncertain. Ratey et al. 1987 8 autistic adults given propranolol (120–420 mg/d) and/or nadolol (120 mg/d) and behavior evaluated over 2–19 months. ß-blocker treatment resulted in reduction or cessation of self-abuse and assaultive behavior in all 8 patients. Emphasizes possible soothing effect of ß-blockers. Experimental Studies on Aggression     Lindem et al. 1990 22 mentally retarded patients received pindolol or placebo in a double blind study for 16 wks. Destructive behaviors assessed with the Modified-Overt Aggression Scale. Frequency of destructive acts decreased by 30% with ß-blocker, the patients' communication (47%) and socialization (149%) also improved markedly.

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Understanding and Preventing Violence: Volume 2, Biobehavioral Influences References Methods and Procedures Results and Conclusions Ratey et al. 1990 Chronic psychiatric patients with histories of aggression received nadolol (n=20) or placebo (n=26) in a double-blind study. Nadolol (beta-blocker) significantly reduced aggressive outbursts and decreased severity of illness. Effects required 1–2 weeks. Literature Reviews     Sheard 1984 Review of 59 references on clinical pharmacology of aggressive behavior Propranolol (60–320 mg/day) has been used successfully in treating irritability, temper outbursts, and explosive rage responses, particularly in patients with organic brain dysfunction. Notes return of symptoms when propranolol is withdrawn. Improvement does not include primary symptoms of disease (disorientation, memory impairment, or psychotic thinking). Side effects include low blood pressure, headaches, dizziness, fatigue, insomnia, and depression. Mattes 1986 Review of 100 references on the pharmacological treatment of temper outbursts Propranolol treatment has been successful in controlling temper outbursts in patients with severe organic brain disease, brain-damage, belligerence, Korsakoff's psychosis, schizophrenia, and in violent elderly individuals, yet no predictors of benefit are found. Mechanism of action in controlling outbursts in uncertain; may be related to membrane stabilizing effect, alteration of brain cetacholamines and/or indoles, elevation of seizure thresholds, or action on serotonergic systems. Eichelman 1987 Review of 136 references on neurochemical and pharmacological aspects of aggressive behavior Propranolol has been reported to effectively reduce aggressive behavior in patients with organic brain injury, Korsakoff's psychosis, schizophrenics, and children with organic impairment in open clinical trials.

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Understanding and Preventing Violence: Volume 2, Biobehavioral Influences Horn 1987 Review of 58 references on control of disruptive, aggressive behavior in brain-injured patients Although FDA (Food and Drug Administration) has only approved the use of ß-blockers for cardiovascular disorders, they have been used with success in patients with anxiety disorders and for control of violent and disruptive behaviors; highlights lack of a specific symptom complex, EEG finding, injury location or temporal relationship to guide clinicians in treating patients as well as difficulty in determining length of treatment and control of side effects. Suggests treatment range starting at 60–129 mg/day divided in 2–3 dosages and gradual increases to a maximum of 800 mg/day. Brizer 1988 Review of 145 references on psychopharmacology and the management of violent patients Propranolol and other ß-blockers have been successful in controlling aggressive patients with organic brain syndromes, Korsakoff's psychosis, viral encephalitis, schizophrenia, autism, episodic dyscontrol and explosive disorders. Most patients were previously refractory in multiple medication trials, but treatment is particularly effective in patients with organic brain disease. Exact mechanism of action unclear as patients often receive ß-blockers with other medications (e.g. neurleptics). Side effects include hypertension, bradycardia, and depression, but are not frequent with careful monitoring at suggested doses (up to 800 mg/day).