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NeuroRehabilitation 5 (1995) 233-244
New frontiers of neuropharmacologic treatment of brain injury agitation Kathleen R. Bell*, Diana C. Cardenas University of Washington, Seattle, Washington, DC, USA Accepted 17 April 1995
Abstract
The treatment of agitation and aggression in the TBI patient continues to be a challenge in both the immediate period following injury and later, in the community setting. While there are few studies of non-traditional pharmacologic compounds in TBI subjects, studies of other patient populations with related disorders have been referenced for information on new and experimental compounds. In this article, medications such as the serotonergic system enhancers, atypical neuroleptics, central nervous system stimulants, hormonal agents, and opioid antagonists are reviewed at a basic science and clinical level. Possible directions for their use in the brain-injured patient are discussed. Keywords: Brain injury; Agitation; Pharmacology
1. Introduction
Agitation after traumatic brain injury may result in the inability to benefit from rehabilitative therapies, physical harm to the affected patient and surrounding staff members and distress to family members. Adequate control of agitation is an incomplete art rather than a science. At this time, the use of medications to control agitation remains an empirical exercise with trial and error efforts the center of the treatment plan.
* Corresponding author.
The ideal medication to treat agitation and aggression should result in a calm yet attentive patient with normal sleep-wake cycles. No adverse effects on cognition, arousal, attention, or coordination would result. The diagnostic classifications for agitation and aggression would be clear, resulting in a choice of the proper chemical replacement based on knowledge of the neurophysiological basis for the presence of the behavioral disorder. Although it is possible that frontal-limbic dysfunction is a common basis for the observed agitation, it is likely that agitated or aggressive behavior manifesting in diverse ways at different times on the recovery curve indicate
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different pathophysiological bases for the behaviors. However, we are far from understanding either the pathophysiology of aggression or the spectrum of responses to medications given, particularly in the population with acquired brain injuries. This article will review some of the directions that future treatment of the agitated patient might take. Little or no research has been done on the use of these medications in the population with acquired brain injuries (Table 1). It is not clear if the research performed on animals or on other populations, such as children with aggressive behaviors and attention deficit disorders or the elderly with agitated dementias, can be easily applied to the patient with traumatic brain injury. However, the information gained from these studies may be examined with a critical eye to evaluate the possibilities of applying these findings to persons with brain injury. 2. Medications which primarily affect the serotonergic system 2.1. Role of serotonin in affective and aggressive disorders
The role of serotonin (5-hydroxytryptamine; 5HT) in neurological systems which underlay mood, anxiety, sexual behavior, sleep, temperature control, and sensory perception is becoming increasingly important. In addition, there is an apparent association between aggression, motoric activity level, self-stimulation activities and activation of the serotonin system. Lesions of the raphe nuclei in the brainstem which contain high proportions of serotonergic neurons result in aggressive behavior in animals [1]. Central dysfunction of 5-HT seems more associated with impulsive aggressive behavior than other subtypes of aggression, such as defense behaviors or maternal aggression [2]. There is some evidence to support that increased aggressiveness associated with reduced central 5-HT activity may be due to a lack of gating of environmental and internal stimuli, that is, of increased sensitivity to provocative stimuli [3] (see Fig.1). It is now known that there are mUltiple subtypes of serotonin receptors (5-HT1A, 5-HTlB,
Table 1 Drugs being explored for the treatment of agitated/aggressive behavioral disorders Source: Author Serotonergic drugs Tryptophan Selective serotonin reuptake inhibitors Fluoxetine Citalopram Fluvoxamine Sertraline Paroxetine Buspirone Serenics Eltoprazine Amperozide CNS stimulants Methylphenidate Amantadine Atypical neuroleptics Clozapine Risperidone Hormonal agents Thyrotropin-releasing hormone Opioicl antagonists Naltrexone Naloxone
5-HT1C, 5-HT1D, 5-HT2, 5-HT3, 5-HT4) and compounds with selective affinity for these different receptor subtypes. In animals, selective activation of receptor subtypes results in alleviation of depression and anxiety and amelioration of aggression [4]. It appears that drugs which bind with high affinity to 5-HTlA, 5-HTlB, and 5HT1C receptors are active anti-aggressive agents (it is interesting to note that propranolol also binds with high affinity to 5-HT1A receptors) [5]. In addition, studies done in animals and humans indicate that depletion of CNS serotonin results in up-regulation of the 5-HTl receptors, indicating a role for these receptors in the modulation of aggression [6,7]. The serotonergic system does not function in isolation, however, to produce agitated or aggressive behavior. Evidently, an intact noradrenergic system is essential as a linkage between serotonin dysfunction and subsequent aggressive behavior. Studies in mice have demonstrated that animals who have lesions in both the serotonergic and
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Fig. 1. Schematic representation of the corticostriatothalamic feedback loop controlling thalamic sensorimotor gating. Although the neurochemical anatomy and many of the transmitter interactions of this circuit have been defined, the role of serotonin in the regulation of sensorimotor gating is almost completely unknown. (From Schmidt C.l. et ai, Int Clin Psychopharmacol 1993;8:28).
noradrenergic systems do not display the same aggressive behavior as animals with lesions only in the serotonergic system [8,9]. The noradrenergic system is felt to have a crucial role in arousal and attention and, as such, allows the animal to respond to environmental stimuli [8]. There is early evidence in humans which also suggests a critical role for the serotonergic system in aggressive disorders. Fenfiuramine, which acts both as a 5-HT releaser and reuptake blocker, can be used as a challenge to elicit the prolactin response, which gives a net measure of 5-HT neurotransmission [3]. A study by Halperin et al. examined the prolactin response to fenfturamine in young boys with attention deficit hyperactivity disorder; those boys with a history of aggression had a greater response to fenfturamine than those boys without such a history. This study suggested that central serotonin functioning differs with degree of aggressive tendencies in this population [10]. The same differential response to the fenfturamine challenge exists in persons with personality disorder with and without irritable and assaultive behavior [3].
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2.2. Tryptophan L-tryptophan is an essential amino acid which has been marketed in the past as a nutritional supplement but which has been used widely in the therapeutic management of insomnia and depression (see Table 2). A number of studies in the 1970s and 1980s reported positive effects when used for the treatment of various forms of aggressive and self-injurious behavior in different patient populations. One study examined the effect of treatment with tryptophan on aggressive psychiatric patients. Using a double-blind, placebo-controlled ABA design, it was demonstrated that the use of tryptophan reduced the need for sedative and antipsychotic injections in these patients, although the number of violent episodes did not change [12]. There have also been a number of case reports of the successful use of tryptophan in conjunction with trazodone for control of aggressive behavior in patients with dementia of various types [13-15]. 5-hydoxytryptophan has been used by a few investigators to treat self-injurious behavior in Lesch-Nyhan and Gilles de la Tourette's syndrome; both reported successful reduction compared with placebo trials [16,17]. Tryptophan presently is not available for clinical usage in the United States because of its association with the eosinophilia-myalgia syndrome which occurred in an epidemic form in 1989, resulting in myalgia, eosinophilia, cutaneous lesions, progressive neuropathy and myopathy. While it is felt that this may have been due to a contaminant in the biologic preparation, this has not been established as the etiology of this syndrome [18-20]. 2.3. Fluoxetine and other selective serotonin reuptake inhibitors (SSRIs) These medications (including citalopram, ftuoxetine, ftuvoxamine, sertraline, and paroxetine) act to specifically inhibit presynaptic neuronal reuptake of serotonin. This results in increased extraneuronal concentrations of serotonin in the raphe nucleus and frontal cortex and reduced intraneuronal concentrations of serotonin in the raphe nucleus [21]. These drugs are being used
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Table 2 Non-traditional drugs used to treat agitation: recommendations for use, usual dosage, onset and duration, adverse effects and contraindications Class/name
Atypical neuroleptics Clozapine (not recommended for first-line use)
Risperidone (not recommended for first-line use)
Catecholaminergic Agonists Amantadine (can be used in average clinical setting)
Serotonergic agonists Buspirone (can be used in in average clinical setting) Tryptophan (not presently recommended for use) Fluoxetine (can be used in average clinical setting)
Sertraline (can be used in average clinical setting)
Dosage range
Onset /Duration
Adverse Effects/Contraindications Very high sedation, moderate anticholinergic, moderate-high hypotensive, akathisia, dystonia, perioral tremor, delirium, seizures, heat stroke, confusion, increased aggression, sedation, leukopenia and agranulocytosis, transient mild hyperthermia, impaired psychomotor performance, photosensitivity, hypersalivation, NMS, orthostatic hypotension, seizures (0.3%), somnolence, impaired psychomotor performance, hyperkinesia, nausea, anxiety, extrapyramidal, constipation, dyspepsia, rhinitis, rash, tachycardia, insomnia, elevation prolactin levels, weight gain, sexual dysfunction, sl. extrapyramidal risk
300-450 mg/ day
1-6 mg/day
100-400 mg/ day
Onset of action against agitation 2-4 days
Depression, rare hallucinations, nightmares in elderly, peripheral edema, lightheadedness, orthostatic hypotension, rash, livedo reticularis, may lower seizure threshold in low doses, irritability, agitation, psychosis, tics
15-60 mg/day
Slow
Dizziness, headache, nervousness, lightheadedness
Eosinophilia-myalgia syndrome
Not available in U.S. 5-40mg/day
half-life 4-16 days
50-200 mg/ day
Half-life 26 h
Sexual dysfunction (anorgasmia and ejac. dist. more than with TCA's) tremors, extrapyramidal, akathisia, insomnia, mania, anxiety, hypervigilance, suicidal or angry obsessions, nausea, weight loss, seizures 0.2% Drug interactions. Erythema multiforme, serum sickness. weight loss, mania, hyponatremia, GI complaints, tremor, dizziness, insomnia, somnolence, increased sweating, dry mouth, male sexual dysfunction
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Table 2 (Continued) Class/name
Dosage range
Onset/Duration
Adverse Effects/Contraindications
Paroxetine (can be used in average clinical setting)
10-50 mg/day
10 days till steady state
mania (1 %), seizures 0.1 %, hyponatremia, somnolence, insomnia, agitation, tremor, anxiety, GI complaints, asthenia, sexual dysfunction, sweating. Appears in breast milk. Drug interactions: less than fluoxetine, more than sertraline. Coumadin, phenytoin, digoxin, cimetidine, MAOI**.
12.5-150 mg/day must be Opioid free
peak 1 h; half-life 4-13 h
GI complaints, hepatocellular injury (dose related above rec.), difficulty sleeping, anxiety, nervousness, abdominal pain/cramps, nausea or vomiting, low energy, joint and muscle pain, headache, loss of appetite, diarrhea, constipation, thirst, increased energy, irritability, dizziness, skin rash, delayed ejaculation, decr. potency, chills
Pemoline (can be used in average clinical setting)
37.5-112.5 mg/day
peak 2-4 h; half-life 12 h
Methylphenidate (can be used in average clinical setting)
10·-60 mg/day
short half-life; sustained release form not markedly different in duration of action and may not be as effective
insomnia, elevated liver enzymes, rare aplastic anemia, seizures, precipitation of Tourette's syndrome, hallucinations, dyskinesia, mild depression, dizziness, irritability, headache, drowsiness, anorexia, caution with h/o substance abuse. Anxiety, dysphoria, incr. irritability, cardiovascular, headache, palilalia, stereotypical thoughts, cognitive impairment, hallucinations, insomnia, motor disorders, anorexia, nausea, dizziness, palpitations, dyskinesia, drowsiness, tachycardia, seizure?, caution with h/o substance abuse
Opioid antagonists Naltrexone (can be used in average clinical setting - no clear efficacy in TBI agitation)
Neurostimulants
Hormonal agents Corticotropinreleasing factor (not available for clinical usage) Thyroid-releasing hormone (not currently recommended for clinical usage for agitation)
Not available
Only available IV form
blood pressure, syncope, breast enlargement, headaches, seizures rare with predisposing conditions, nausea, urinary urgency, flushed feeling lightheadedness, bad taste, abd. discomfort, dry mouth
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for the treatment of depression and a long list of disorders including obsessive-compulsive disorder, eating disorders, and Tourette's syndrome [11] (see Table 2). Although these drugs are commonly thought to be 'activating' when used to treat depression, it is not uncommon for patients to experience sedation as an adverse effect [22]. One of the primary differences between fluoxetine and the other SSRIs is the duration of action; the half-life of fluoxetine is approximately 2 days while the other SSRIs have shorter elimination half-lives of about 1 day [23]. The question of whether these agents cause agitation and anxiety when used to treat other emotional disorders has not been entirely answered. Conflicting studies have indicated both success in treating anxiety disorders and the induction of anxiety when given for depression in patients taking SSRIs [24-26]. A recent study which retrospectively examined a data base of 2963 patients treated with paroxetine for depression found no evidence for the new production of anxiety or agitation but rather a positive effect in patients whose depression was associated with agitation [27]. A non-blinded, AB design trial of fluoxetine to treat obsessive-compulsive behaviors in mentally retarded adults demonstrated favorable responses in seven of ten affected persons and had no discernible effects in a comparison group of mentally retarded adults without these behaviors [28]. An uncontrolled open study of 21 severely mentally retarded individuals with self injurious behavior treated with fluoxetine resulted in decreased levels of self-abuse, agitation and aggression in 13 of those treated [29]. One placebo-controlled, parallel group study of patients with Alzheimer's disease or vascular dementia with behavioral problems found that citalopram was effective in improving confusion, irritability, and motor restlessness in patients with Alzheimer's only [30]. An interesting peculiarity which may be considered in certain brain injured patients is that, when these medications are used to treat panic disorder in addition to other mood disorders, the dosage at which they are effective for panic disorder is far below that used to treat depression. In fact, dosages at the anti-depression level can
induce extreme agitation in patients with panic disorder [31]. As with most of the medications contained in this review, almost no studies on subjects with TBI exist. One study, which used fluoxetine in an open uncontrolled trial to treat emotional lability in six patients with TBI, reported marked improvement within 1 week; there were no reported side effects, including agitation [32].
2.4. Buspirone Buspirone, which is a partial serotonin agonist acting either as an agonist on presynaptic 5-HTIA receptors or as an antagonist on postsynaptic 5-HTIA receptors, is used primarily as an anxiolytic drug [5] (see Table 2). Buspirone has been shown in both animal and human studies to be effective in minimizing anxiety [33-35]. It appears to have no anticonvulsant or sedative activity unlike the benzodiazepines. Buspirone is not a muscle relaxant and appears to have minimal effects on motor coordination [36]. Possible adverse effects may include reversible involuntary movements such as akathisia, dystonia, and oral dyskinesias [37]. It does not appear to have a high abuse potential [36]. Buspirone dose not interact with anticonvulsants or other CNS agents [38]. The use of buspirone in a variety of behavior disorders has been described. A number of series and case reports describe decreased undesirable behaviors (such as aggression, self-injurious activities and disinhibition) when patients with mental retardation or autism were treated with buspirone [33,39-41]. Improved behaviors in elderly demented persons have been observed with the use of buspirone [42-44]. A retrospective study of 20 patients at a psychiatric facility demonstrated some improved behavior in 15 of these patients; this study did not control for the use of other medications or treatments [45]. A few reports of buspirone's use in acquired brain injury exist. A case study of a single brain injured patient who responded positively to buspirone as measured by participation in rehabilitation programs was reported in 1988 by Levine; two other patients may also have responded but in a less clear fashion [46]. Ratey and his col-
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leagues reported on two cases, one with TBI and one with anoxic/metabolic encephalopathy, who responded to the addition of buspirone to a number of other CNS active drugs with a decrease in hypersexual activity and decreased assaultive behavior [38].
2.5. Potential serotonergic drugs A number of drugs are presently under evaluation for clinical use in aggression disorders. EItoprazine and amperozide, both potent antagonists at 5-HT2 receptors, probably also have effects on limbic dopamine activity [31]. Eltoprazine, sometimes called a 'serenic' drug, reduces aggression while having little effect on beneficial activities in animals, such as social interest and exploration [47,6]. Serotonergic drugs hold great promise for use in the treatment of agitation and aggressive behavior in patients with acquired brain injury. They are generally well tolerated and have minimal effects (as tested in other populations) on cognitive functioning. The adverse effect profiles are also attractive in comparison with other available drugs used for this purpose: minimal sedation, no cardiovascular effects and little effect on seizure threshold. As more basic research further delineates the role of the various 5-HT receptor subtypes and new compounds are developed with more specific actions, specific outcomes with the use of serotonergic drugs may be possible. The challenge will be to better identify the subtypes and pathophysiology of agitation and injurious behaviors in the brain injured person to allow application of these drugs. 3. Central nervous system stimulants Although a number of compounds could potentially be discussed in this section (such as amantadine, levodopa, bromocriptine, dextroamphetamine)' most of the pertinent literature available concentrates on methylphenidate. Methylphenidate is a piperidine CNS stimulant which causes the release of stored norepinephrine (see Table 2). At higher doses, some of its actions may be mediated by dopamine. A vast amount of experience with methylphenidate derives from its
use in children with attention deficit hyperactivity disorder (ADHD); a few studies examine its use in acquired brain injury. It is well-appreciated that the clinical use of methylphenidate in children with ADHD improves attention and overall cognitive abilities. A number of recent studies have examined the differential effects of methylphenidate on ADHD children with or without behavioral characteristics of aggression and oppositionality [48]. Most of these have noted reduced levels of physical and verbal aggression, disruptiveness, motor movement and non-compliance [49-51], others, however, found no improvement in activity level or impulsivity despite improvements in attention [52]. The state of information on whether methylphenidate is helpful in managing behavioral abnormalities in the TBI population is considerably more muddled. Two studies of patients with chronic TBI found no clear improvements on behavioral or cognitive scales (both used the Katz Adjustment Scale for social personality functioning) [53,54]. Another study which specifically examined anger outcome measures (using the State-Trait Anger Scale, the Belligerence scale from the Katz Adjustment Scale and the AngerHostility factor score of the Profile of Mood States) found significant improvement in anger scores in methylphenidate-treated patients as compared to controls. In this study, as in some of the studies of adolescents with aggressive ADHD. responders were more likely to have a high anger score prior to treatment [55]. Amantadine is a drug used for anti-viral and anti-Parkinson's disease treatment, and for the treatment of fatigue in certain neurologic diseases such as multiple sclerosis (see Table 2). It is thought to increase dopamine release in the eNS. Amantadine has been studied for general behavioral effects in geriatric patients with dementia. These patients frequently displayed overactivity. anxiety and visual hallucinations which decreased after treatment with amantadine [56]. Amantadine has also been shown to ameliorate the locomotor stimulation which is produced in rats by amphetamines and other neurostimulants [57]. Amantadine has been used in a few reports of
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brain injured patients with destructive behaviors with positive effect [58]. It is not possible to discuss guidelines for the use of neurostimulants in the agitated or aggressive TBI patient because of the lack of supportive research. The most likely candidate to respond to this class of medication is one who displays agitation along with impaired attention as a primary deficit. Another group might be the higher-functioning outpatient with a mild brain injury who experiences a high degree of anger and problems with anger management along with some evidence of attention disorder. As it is doubtful that methylphenidate and amantadine are harmful to cognitive functioning (and may, indeed, be helpful), trials of the stimulant medications would certainly not be unreasonable in these patients. 4. Atypical neuroleptics
Clozapine is an atypical antipsychotic agent which has been shown to be effective in schizophrenics resistant to traditional neuroleptics and lacks acute extrapyramidal effects (see Table 2). It has pharmacological effects on both the dopamine and serotonin systems. It is not known by which mechanism clozapine decreases agitation and aggressive behavior. In addition to the effects on aggression by the serotonin system discussed above, it has been shown that increased central levels of dopamine can induce fighting behavior in animals [1]. For instance, studies of rats lesioned by 6-0HDA as neonates, then treated with levodopa (resulting in self mutilitatory behavior), show that clozapine reduced this behavior in a dose-related fashion [59]. Unlike other antipsychotic agents, clozapine is a dopamine D4 and D1 receptor antagonist. While other neuroleptic agents preferentially block the D2 receptor, clozapine is a relatively weak D2 blocker [60]. In addition, clozapine blocks both the 5-HT2 and 5-HTlB autoreceptors [61]. Unlike other neuroleptic agents, the atypical agents have few extrapyramidal adverse effects and little possibility of producing tardive dyskinesia [60]. Common side effects of clozapine include drowsiness, dizziness, increased salivation, constipation, tachycardia, nausea and vomiting. Clozap-
ine does lower the seizure threshold in a dosedependent fashion. A more serious adverse side effect is the possibility of agranulocytosis (with an incidence of 0.8% after 1 year of treatment) which requires weekly complete blood count monitoring [62]. A retrospective study of severely agitated and aggressive behavior in chronically institutionalized schizophrenics demonstrated significant amelioration of self-injurious behavior, agitation and verbal aggressiveness and assaultive behavior with the use of clozapine, allowing increased socialization and decreased use of restraints [61]. Although this may have been a consequence of decreases in pyschoses, the lessening of aggressive episodes was dramatically more noticeable in comparison to other psychiatric symptoms. One series of case reports on the use of clozapinc in patients with brain injury has been published. All patients treated were in the chronic stages, one at 10 months post-injury and the rest at least 4 years after injury. Most had evidence of psychotic symptoms in addition to agitation, aggression and self-abuse. Of these, three had significant improvement in aggression or bizarre behaviors; the remainder had only mild or indeterminate response to treatment. Two of the patients had seizure onset thought. to be related to the use of clozapine [62]. Because of the potentially serious adverse events associated with the use of clozapine, it would not be a desirable first-line agent. In addition, traditional neuroleptics are associated with impaired cognition and may slow or permanently alter recovery after brain injuries; as these factors have not been explored in these agents, caution is prudent. Those patients with severe behavioral disorders associated with psychotic manifestations may be the likeliest to respond to these agents. Risperidone is a compound with high affinity for 5-HT2 receptors, dopamine D2 receptors, and a 1 and a 2-receptors (see Table 2). In animal models, it inhibits apomorphine-induced agitation and amphetamine-induced agitation. The most common adverse effects are asthenia and sedation. Prolactin levels are significantly increased and galactorrhea or amenorrhea may result [60].
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5. Hormonal agents Anabolic steroids, such as testosterone, have long been linked with certain types of aggressive behavior in humans and primates. Diseases which result in the overproduction of androgens, such as prenatal androgenization of females or adrenogenital syndrome, may be related to aggressive activity [1]. However, the association between serum testosterone level and aggressive behavior is tenuous and poorly supported by experimental evidence [63]. There is, however, reason to further explore the hypothalamic pituitary adrenal (HPA) axis and the hypothalamic pituitary thyroid (HPT) axis and their relation to aggression. The presence of thyroid abnormalities in patients with various affective disorders (depression, agitation, anxiety, suicidality, and panic attacks) has been documented [64]. In patients with depression, the thyrotropin-stimulating hormone (TSH) response to thyrotropin-releasing hormone (TRH) appears to be especially blunted (see Table 2). In particular, depression with agitated features has been associated with a blunted TSH response. There is evidence to link the noradrenergic system with the HPT axis; the adrenergic system innervates the TRH-secreting neurons in the hypothalamus and the thyroiQ gland itself. There is conflicting evidence on the interaction of the serotonergic system and the HPT axis [64]. In rats with induced TBI, TRH analogs have improved behavioral abnormalities although aggression was not specifically studied. In these studies, TRH analogs modified to minimize endocrine actions were still successful in altering behavioral outcome in rats, indicating that the CNS protective effects of TRH may not be due to their endocrine activities [65,66]. Indirect indication for the involvement of the HPA axis exists. These is some early evidence that patients with Alzheimer's disease who are unable to suppress the production of cortisol after the administration of dexamethasone have higher levels of agitation (defined in this study as uncooperativeness, pacing, increased motor activity and tremors) [67]. Certain peptides with hormonal effects may also have direct central action
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on behavioral activity. For instance, corticotropin-releasing factor, which stimulates the release of adrenocorticotropin hormone and t3-endorphin from the anterior pituitary gland, also seems to have a direct effect on the neurons of the locus coerulus, mediating increased motor activity and arousal [68] (see Table 2). Hypersecretion of corticotropin releasing factor (CRF) appears to be involved in the etiology of anxiety disorders in humans [69]; no study of CRF secretion in humans has been reported for agitated states. 6. Opioid antagonists Opioid antagonists such as naltrexone and naloxone are discussed for possible inclusion in a future armamentarium of medications for treatment of agitation largely on the basis of the research done in the area of self-injurious behavior (SIB). These substances block the opioid receptors and have no agonist effects. An animal model for SIB exists which uses chronic administration of high-dose opiate agonists [70]; other studies in rats demonstrate an increased threshold for self-stimulation in animals treated with naloxone, an effect that persisted after the drug was discontinued [71]. Veterinary literature also documents a decrease in self-licking and -chewing behavior in dogs after treatment with narcotic antagonists [72]. In addition, a relationship -between opioids and lack of nociception exists [73]. A possible model of a relationship between the hypothalamic-pituitary-adrenal axis and proopiomelanocortin which results in hyperproduction of opioid peptides, nonopioid peptides and 5-HT has been proposed [74]. Narcotic antagonists have also been shown to attenuate the motor activity response of rats to administration of amphetamine, implying an interaction of the opioid receptors with the central stimulant effects of amphetamine [75,76]. Naltrexone can be given by mouth unlike naloxone, which has a very short duration of action in the central nervous system (see Table 2). Naltrexone has few adverse effects but may cause nausea and reduce food intake in recovering ad-
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dicts. In addition, reversible elevations in liver enzymes may occur. The existing studies of the use of naltrexone for agitation in clinical settings have all involved mentally retarded and/or autistic adolescents or adults. All studies have been quite small, with one to eight subjects included. Many studies reported significant decreases in SIB; the criterion for efficacy generally was a decreased number of selfinjury episodes per day [77-82]. A study done by Zingarelli on autistic adults with SIB and 'socially inappropriate behavior', using a double-blind crossover C-ABAB design demonstrated no clear behavioral changes related to the administration of naltrexone [83]. A similar study by Szymanski described similar negative results [84]. Studies utilizing narcotic antagonists have not been done in animal or human TBI populations. Opioid receptor antagonists have been studied in rat models of fluid percussion-induced TBI and have been shown to limit behavioral abnormalities in a general sense, although aggression has not been specifically addressed [65]. Opioid antagonists may have some utility in treating those brain injured patients with selfabusive behaviors although careful documentation of drug-response effects should be carried out to justify the use of these drugs. The studies indicating that narcotic antagonists are effective in modulating the motor hyperactivity associated with amphetamine usage may offer some indication of possible benefits in TBI. 7. Summary Although a number of avenues have shown some promise in the treatment of agitation-related disorders in other populations, a paucity of literature exists supporting their use in TBI populations. One of the problems commonly encountered by the clinician treating the patient with TBI and agitation is the variable definition of agitation by both clinicians and experimentalists. Extrapolating experimental information from other populations to the TBI population will demand improved delineation of the behaviors being measured in order to define efficacy of interventions. The variety of behaviors for which the above
compounds are used indicate a possible future in which medications will be very specifically targeted at specific behaviors, rather than continued attempts at treating global 'agitation'. None of the compounds discussed in this article are clearly going to be panaceas for behavioral disturbances but many offer some direction for further exploration of the nature of and appropriate treatment for agitation and aggression in TBI patients.
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Watson AJS, Phillips K. Serotoninergic treatment of screaming and banging in dementia. Lancet 1986;2:1464-1465. Wilcock GK, Steven J, Perkins A. Trazadone/tryptophan for aggressive behavior. Lancet 1987;1:929-930. Mizuno T, Yugari Y. Prophylactic effect of L-5-hydroxytryptophan on self-mutilation in the Lesch-Nyhan syndrome. Neuropadiatrie 1975;6:13-23. Van Woert MA, Yip LC, Balis ME. Purine phosphoribosyl transferase in Gille de la Tourette syndrome. N Engl J Med 1977;296:210-212. Kaufman LD, Philen RM. Tryptophan. Current status and future trends for oral administration. Drug Saf 1993;8:89-98. Varga J, Jimenez SA, Vitto J. L-tryptophan and the eosinophilia-myalgia syndrome: current understanding of the etiology and pathogenesis. J Invest Dermatol 1993;100:975-1055. Kaufinan LD. The eosinophilia-myalgia syndrome: current concepts and future directions. Clin Exp Rheumatol 1992;10:87-91. Wilde MI, Plosker GL, Benfield P. Fluvoxamine: An updated review of its pharmacology, and therapeutic use in depressive illness. Drugs 1993;46:895-924. Beasley CM, Potvin JH. Fluoxetine: activating and sedating effects. Int Clin Psychopharmacol 1993;8:271-275. van Harten J. Clinical pharmacokinetics of selective serotonin reuptake inhibitors. Clin Pharmacokinet 1993;24:203-220. Evans L. Effect of a selective serotonin uptake inhibitor in agoraphobia with panic attacks. A double blind comparison of zime1idine, imipramine and placebo. Acta Psychiatr 1986;80:49-53. Goodman WI
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NeuroRehabilitation 5 (1995) 233-244
New frontiers of neuropharmacologic treatment of brain injury agitation Kathleen R. Bell*, Diana C. Cardenas University of Washington, Seattle, Washington, DC, USA Accepted 17 April 1995
Abstract
The treatment of agitation and aggression in the TBI patient continues to be a challenge in both the immediate period following injury and later, in the community setting. While there are few studies of non-traditional pharmacologic compounds in TBI subjects, studies of other patient populations with related disorders have been referenced for information on new and experimental compounds. In this article, medications such as the serotonergic system enhancers, atypical neuroleptics, central nervous system stimulants, hormonal agents, and opioid antagonists are reviewed at a basic science and clinical level. Possible directions for their use in the brain-injured patient are discussed. Keywords: Brain injury; Agitation; Pharmacology
1. Introduction
Agitation after traumatic brain injury may result in the inability to benefit from rehabilitative therapies, physical harm to the affected patient and surrounding staff members and distress to family members. Adequate control of agitation is an incomplete art rather than a science. At this time, the use of medications to control agitation remains an empirical exercise with trial and error efforts the center of the treatment plan.
* Corresponding author.
The ideal medication to treat agitation and aggression should result in a calm yet attentive patient with normal sleep-wake cycles. No adverse effects on cognition, arousal, attention, or coordination would result. The diagnostic classifications for agitation and aggression would be clear, resulting in a choice of the proper chemical replacement based on knowledge of the neurophysiological basis for the presence of the behavioral disorder. Although it is possible that frontal-limbic dysfunction is a common basis for the observed agitation, it is likely that agitated or aggressive behavior manifesting in diverse ways at different times on the recovery curve indicate
1053-8135/95/$09.50 © 1995 Elsevier Science Ireland Ltd. All rights reserved.
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different pathophysiological bases for the behaviors. However, we are far from understanding either the pathophysiology of aggression or the spectrum of responses to medications given, particularly in the population with acquired brain injuries. This article will review some of the directions that future treatment of the agitated patient might take. Little or no research has been done on the use of these medications in the population with acquired brain injuries (Table 1). It is not clear if the research performed on animals or on other populations, such as children with aggressive behaviors and attention deficit disorders or the elderly with agitated dementias, can be easily applied to the patient with traumatic brain injury. However, the information gained from these studies may be examined with a critical eye to evaluate the possibilities of applying these findings to persons with brain injury. 2. Medications which primarily affect the serotonergic system 2.1. Role of serotonin in affective and aggressive disorders
The role of serotonin (5-hydroxytryptamine; 5HT) in neurological systems which underlay mood, anxiety, sexual behavior, sleep, temperature control, and sensory perception is becoming increasingly important. In addition, there is an apparent association between aggression, motoric activity level, self-stimulation activities and activation of the serotonin system. Lesions of the raphe nuclei in the brainstem which contain high proportions of serotonergic neurons result in aggressive behavior in animals [1]. Central dysfunction of 5-HT seems more associated with impulsive aggressive behavior than other subtypes of aggression, such as defense behaviors or maternal aggression [2]. There is some evidence to support that increased aggressiveness associated with reduced central 5-HT activity may be due to a lack of gating of environmental and internal stimuli, that is, of increased sensitivity to provocative stimuli [3] (see Fig.1). It is now known that there are mUltiple subtypes of serotonin receptors (5-HT1A, 5-HTlB,
Table 1 Drugs being explored for the treatment of agitated/aggressive behavioral disorders Source: Author Serotonergic drugs Tryptophan Selective serotonin reuptake inhibitors Fluoxetine Citalopram Fluvoxamine Sertraline Paroxetine Buspirone Serenics Eltoprazine Amperozide CNS stimulants Methylphenidate Amantadine Atypical neuroleptics Clozapine Risperidone Hormonal agents Thyrotropin-releasing hormone Opioicl antagonists Naltrexone Naloxone
5-HT1C, 5-HT1D, 5-HT2, 5-HT3, 5-HT4) and compounds with selective affinity for these different receptor subtypes. In animals, selective activation of receptor subtypes results in alleviation of depression and anxiety and amelioration of aggression [4]. It appears that drugs which bind with high affinity to 5-HTlA, 5-HTlB, and 5HT1C receptors are active anti-aggressive agents (it is interesting to note that propranolol also binds with high affinity to 5-HT1A receptors) [5]. In addition, studies done in animals and humans indicate that depletion of CNS serotonin results in up-regulation of the 5-HTl receptors, indicating a role for these receptors in the modulation of aggression [6,7]. The serotonergic system does not function in isolation, however, to produce agitated or aggressive behavior. Evidently, an intact noradrenergic system is essential as a linkage between serotonin dysfunction and subsequent aggressive behavior. Studies in mice have demonstrated that animals who have lesions in both the serotonergic and
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Fig. 1. Schematic representation of the corticostriatothalamic feedback loop controlling thalamic sensorimotor gating. Although the neurochemical anatomy and many of the transmitter interactions of this circuit have been defined, the role of serotonin in the regulation of sensorimotor gating is almost completely unknown. (From Schmidt C.l. et ai, Int Clin Psychopharmacol 1993;8:28).
noradrenergic systems do not display the same aggressive behavior as animals with lesions only in the serotonergic system [8,9]. The noradrenergic system is felt to have a crucial role in arousal and attention and, as such, allows the animal to respond to environmental stimuli [8]. There is early evidence in humans which also suggests a critical role for the serotonergic system in aggressive disorders. Fenfiuramine, which acts both as a 5-HT releaser and reuptake blocker, can be used as a challenge to elicit the prolactin response, which gives a net measure of 5-HT neurotransmission [3]. A study by Halperin et al. examined the prolactin response to fenfturamine in young boys with attention deficit hyperactivity disorder; those boys with a history of aggression had a greater response to fenfturamine than those boys without such a history. This study suggested that central serotonin functioning differs with degree of aggressive tendencies in this population [10]. The same differential response to the fenfturamine challenge exists in persons with personality disorder with and without irritable and assaultive behavior [3].
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2.2. Tryptophan L-tryptophan is an essential amino acid which has been marketed in the past as a nutritional supplement but which has been used widely in the therapeutic management of insomnia and depression (see Table 2). A number of studies in the 1970s and 1980s reported positive effects when used for the treatment of various forms of aggressive and self-injurious behavior in different patient populations. One study examined the effect of treatment with tryptophan on aggressive psychiatric patients. Using a double-blind, placebo-controlled ABA design, it was demonstrated that the use of tryptophan reduced the need for sedative and antipsychotic injections in these patients, although the number of violent episodes did not change [12]. There have also been a number of case reports of the successful use of tryptophan in conjunction with trazodone for control of aggressive behavior in patients with dementia of various types [13-15]. 5-hydoxytryptophan has been used by a few investigators to treat self-injurious behavior in Lesch-Nyhan and Gilles de la Tourette's syndrome; both reported successful reduction compared with placebo trials [16,17]. Tryptophan presently is not available for clinical usage in the United States because of its association with the eosinophilia-myalgia syndrome which occurred in an epidemic form in 1989, resulting in myalgia, eosinophilia, cutaneous lesions, progressive neuropathy and myopathy. While it is felt that this may have been due to a contaminant in the biologic preparation, this has not been established as the etiology of this syndrome [18-20]. 2.3. Fluoxetine and other selective serotonin reuptake inhibitors (SSRIs) These medications (including citalopram, ftuoxetine, ftuvoxamine, sertraline, and paroxetine) act to specifically inhibit presynaptic neuronal reuptake of serotonin. This results in increased extraneuronal concentrations of serotonin in the raphe nucleus and frontal cortex and reduced intraneuronal concentrations of serotonin in the raphe nucleus [21]. These drugs are being used
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Table 2 Non-traditional drugs used to treat agitation: recommendations for use, usual dosage, onset and duration, adverse effects and contraindications Class/name
Atypical neuroleptics Clozapine (not recommended for first-line use)
Risperidone (not recommended for first-line use)
Catecholaminergic Agonists Amantadine (can be used in average clinical setting)
Serotonergic agonists Buspirone (can be used in in average clinical setting) Tryptophan (not presently recommended for use) Fluoxetine (can be used in average clinical setting)
Sertraline (can be used in average clinical setting)
Dosage range
Onset /Duration
Adverse Effects/Contraindications Very high sedation, moderate anticholinergic, moderate-high hypotensive, akathisia, dystonia, perioral tremor, delirium, seizures, heat stroke, confusion, increased aggression, sedation, leukopenia and agranulocytosis, transient mild hyperthermia, impaired psychomotor performance, photosensitivity, hypersalivation, NMS, orthostatic hypotension, seizures (0.3%), somnolence, impaired psychomotor performance, hyperkinesia, nausea, anxiety, extrapyramidal, constipation, dyspepsia, rhinitis, rash, tachycardia, insomnia, elevation prolactin levels, weight gain, sexual dysfunction, sl. extrapyramidal risk
300-450 mg/ day
1-6 mg/day
100-400 mg/ day
Onset of action against agitation 2-4 days
Depression, rare hallucinations, nightmares in elderly, peripheral edema, lightheadedness, orthostatic hypotension, rash, livedo reticularis, may lower seizure threshold in low doses, irritability, agitation, psychosis, tics
15-60 mg/day
Slow
Dizziness, headache, nervousness, lightheadedness
Eosinophilia-myalgia syndrome
Not available in U.S. 5-40mg/day
half-life 4-16 days
50-200 mg/ day
Half-life 26 h
Sexual dysfunction (anorgasmia and ejac. dist. more than with TCA's) tremors, extrapyramidal, akathisia, insomnia, mania, anxiety, hypervigilance, suicidal or angry obsessions, nausea, weight loss, seizures 0.2% Drug interactions. Erythema multiforme, serum sickness. weight loss, mania, hyponatremia, GI complaints, tremor, dizziness, insomnia, somnolence, increased sweating, dry mouth, male sexual dysfunction
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Table 2 (Continued) Class/name
Dosage range
Onset/Duration
Adverse Effects/Contraindications
Paroxetine (can be used in average clinical setting)
10-50 mg/day
10 days till steady state
mania (1 %), seizures 0.1 %, hyponatremia, somnolence, insomnia, agitation, tremor, anxiety, GI complaints, asthenia, sexual dysfunction, sweating. Appears in breast milk. Drug interactions: less than fluoxetine, more than sertraline. Coumadin, phenytoin, digoxin, cimetidine, MAOI**.
12.5-150 mg/day must be Opioid free
peak 1 h; half-life 4-13 h
GI complaints, hepatocellular injury (dose related above rec.), difficulty sleeping, anxiety, nervousness, abdominal pain/cramps, nausea or vomiting, low energy, joint and muscle pain, headache, loss of appetite, diarrhea, constipation, thirst, increased energy, irritability, dizziness, skin rash, delayed ejaculation, decr. potency, chills
Pemoline (can be used in average clinical setting)
37.5-112.5 mg/day
peak 2-4 h; half-life 12 h
Methylphenidate (can be used in average clinical setting)
10·-60 mg/day
short half-life; sustained release form not markedly different in duration of action and may not be as effective
insomnia, elevated liver enzymes, rare aplastic anemia, seizures, precipitation of Tourette's syndrome, hallucinations, dyskinesia, mild depression, dizziness, irritability, headache, drowsiness, anorexia, caution with h/o substance abuse. Anxiety, dysphoria, incr. irritability, cardiovascular, headache, palilalia, stereotypical thoughts, cognitive impairment, hallucinations, insomnia, motor disorders, anorexia, nausea, dizziness, palpitations, dyskinesia, drowsiness, tachycardia, seizure?, caution with h/o substance abuse
Opioid antagonists Naltrexone (can be used in average clinical setting - no clear efficacy in TBI agitation)
Neurostimulants
Hormonal agents Corticotropinreleasing factor (not available for clinical usage) Thyroid-releasing hormone (not currently recommended for clinical usage for agitation)
Not available
Only available IV form
blood pressure, syncope, breast enlargement, headaches, seizures rare with predisposing conditions, nausea, urinary urgency, flushed feeling lightheadedness, bad taste, abd. discomfort, dry mouth
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for the treatment of depression and a long list of disorders including obsessive-compulsive disorder, eating disorders, and Tourette's syndrome [11] (see Table 2). Although these drugs are commonly thought to be 'activating' when used to treat depression, it is not uncommon for patients to experience sedation as an adverse effect [22]. One of the primary differences between fluoxetine and the other SSRIs is the duration of action; the half-life of fluoxetine is approximately 2 days while the other SSRIs have shorter elimination half-lives of about 1 day [23]. The question of whether these agents cause agitation and anxiety when used to treat other emotional disorders has not been entirely answered. Conflicting studies have indicated both success in treating anxiety disorders and the induction of anxiety when given for depression in patients taking SSRIs [24-26]. A recent study which retrospectively examined a data base of 2963 patients treated with paroxetine for depression found no evidence for the new production of anxiety or agitation but rather a positive effect in patients whose depression was associated with agitation [27]. A non-blinded, AB design trial of fluoxetine to treat obsessive-compulsive behaviors in mentally retarded adults demonstrated favorable responses in seven of ten affected persons and had no discernible effects in a comparison group of mentally retarded adults without these behaviors [28]. An uncontrolled open study of 21 severely mentally retarded individuals with self injurious behavior treated with fluoxetine resulted in decreased levels of self-abuse, agitation and aggression in 13 of those treated [29]. One placebo-controlled, parallel group study of patients with Alzheimer's disease or vascular dementia with behavioral problems found that citalopram was effective in improving confusion, irritability, and motor restlessness in patients with Alzheimer's only [30]. An interesting peculiarity which may be considered in certain brain injured patients is that, when these medications are used to treat panic disorder in addition to other mood disorders, the dosage at which they are effective for panic disorder is far below that used to treat depression. In fact, dosages at the anti-depression level can
induce extreme agitation in patients with panic disorder [31]. As with most of the medications contained in this review, almost no studies on subjects with TBI exist. One study, which used fluoxetine in an open uncontrolled trial to treat emotional lability in six patients with TBI, reported marked improvement within 1 week; there were no reported side effects, including agitation [32].
2.4. Buspirone Buspirone, which is a partial serotonin agonist acting either as an agonist on presynaptic 5-HTIA receptors or as an antagonist on postsynaptic 5-HTIA receptors, is used primarily as an anxiolytic drug [5] (see Table 2). Buspirone has been shown in both animal and human studies to be effective in minimizing anxiety [33-35]. It appears to have no anticonvulsant or sedative activity unlike the benzodiazepines. Buspirone is not a muscle relaxant and appears to have minimal effects on motor coordination [36]. Possible adverse effects may include reversible involuntary movements such as akathisia, dystonia, and oral dyskinesias [37]. It does not appear to have a high abuse potential [36]. Buspirone dose not interact with anticonvulsants or other CNS agents [38]. The use of buspirone in a variety of behavior disorders has been described. A number of series and case reports describe decreased undesirable behaviors (such as aggression, self-injurious activities and disinhibition) when patients with mental retardation or autism were treated with buspirone [33,39-41]. Improved behaviors in elderly demented persons have been observed with the use of buspirone [42-44]. A retrospective study of 20 patients at a psychiatric facility demonstrated some improved behavior in 15 of these patients; this study did not control for the use of other medications or treatments [45]. A few reports of buspirone's use in acquired brain injury exist. A case study of a single brain injured patient who responded positively to buspirone as measured by participation in rehabilitation programs was reported in 1988 by Levine; two other patients may also have responded but in a less clear fashion [46]. Ratey and his col-
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leagues reported on two cases, one with TBI and one with anoxic/metabolic encephalopathy, who responded to the addition of buspirone to a number of other CNS active drugs with a decrease in hypersexual activity and decreased assaultive behavior [38].
2.5. Potential serotonergic drugs A number of drugs are presently under evaluation for clinical use in aggression disorders. EItoprazine and amperozide, both potent antagonists at 5-HT2 receptors, probably also have effects on limbic dopamine activity [31]. Eltoprazine, sometimes called a 'serenic' drug, reduces aggression while having little effect on beneficial activities in animals, such as social interest and exploration [47,6]. Serotonergic drugs hold great promise for use in the treatment of agitation and aggressive behavior in patients with acquired brain injury. They are generally well tolerated and have minimal effects (as tested in other populations) on cognitive functioning. The adverse effect profiles are also attractive in comparison with other available drugs used for this purpose: minimal sedation, no cardiovascular effects and little effect on seizure threshold. As more basic research further delineates the role of the various 5-HT receptor subtypes and new compounds are developed with more specific actions, specific outcomes with the use of serotonergic drugs may be possible. The challenge will be to better identify the subtypes and pathophysiology of agitation and injurious behaviors in the brain injured person to allow application of these drugs. 3. Central nervous system stimulants Although a number of compounds could potentially be discussed in this section (such as amantadine, levodopa, bromocriptine, dextroamphetamine)' most of the pertinent literature available concentrates on methylphenidate. Methylphenidate is a piperidine CNS stimulant which causes the release of stored norepinephrine (see Table 2). At higher doses, some of its actions may be mediated by dopamine. A vast amount of experience with methylphenidate derives from its
use in children with attention deficit hyperactivity disorder (ADHD); a few studies examine its use in acquired brain injury. It is well-appreciated that the clinical use of methylphenidate in children with ADHD improves attention and overall cognitive abilities. A number of recent studies have examined the differential effects of methylphenidate on ADHD children with or without behavioral characteristics of aggression and oppositionality [48]. Most of these have noted reduced levels of physical and verbal aggression, disruptiveness, motor movement and non-compliance [49-51], others, however, found no improvement in activity level or impulsivity despite improvements in attention [52]. The state of information on whether methylphenidate is helpful in managing behavioral abnormalities in the TBI population is considerably more muddled. Two studies of patients with chronic TBI found no clear improvements on behavioral or cognitive scales (both used the Katz Adjustment Scale for social personality functioning) [53,54]. Another study which specifically examined anger outcome measures (using the State-Trait Anger Scale, the Belligerence scale from the Katz Adjustment Scale and the AngerHostility factor score of the Profile of Mood States) found significant improvement in anger scores in methylphenidate-treated patients as compared to controls. In this study, as in some of the studies of adolescents with aggressive ADHD. responders were more likely to have a high anger score prior to treatment [55]. Amantadine is a drug used for anti-viral and anti-Parkinson's disease treatment, and for the treatment of fatigue in certain neurologic diseases such as multiple sclerosis (see Table 2). It is thought to increase dopamine release in the eNS. Amantadine has been studied for general behavioral effects in geriatric patients with dementia. These patients frequently displayed overactivity. anxiety and visual hallucinations which decreased after treatment with amantadine [56]. Amantadine has also been shown to ameliorate the locomotor stimulation which is produced in rats by amphetamines and other neurostimulants [57]. Amantadine has been used in a few reports of
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brain injured patients with destructive behaviors with positive effect [58]. It is not possible to discuss guidelines for the use of neurostimulants in the agitated or aggressive TBI patient because of the lack of supportive research. The most likely candidate to respond to this class of medication is one who displays agitation along with impaired attention as a primary deficit. Another group might be the higher-functioning outpatient with a mild brain injury who experiences a high degree of anger and problems with anger management along with some evidence of attention disorder. As it is doubtful that methylphenidate and amantadine are harmful to cognitive functioning (and may, indeed, be helpful), trials of the stimulant medications would certainly not be unreasonable in these patients. 4. Atypical neuroleptics
Clozapine is an atypical antipsychotic agent which has been shown to be effective in schizophrenics resistant to traditional neuroleptics and lacks acute extrapyramidal effects (see Table 2). It has pharmacological effects on both the dopamine and serotonin systems. It is not known by which mechanism clozapine decreases agitation and aggressive behavior. In addition to the effects on aggression by the serotonin system discussed above, it has been shown that increased central levels of dopamine can induce fighting behavior in animals [1]. For instance, studies of rats lesioned by 6-0HDA as neonates, then treated with levodopa (resulting in self mutilitatory behavior), show that clozapine reduced this behavior in a dose-related fashion [59]. Unlike other antipsychotic agents, clozapine is a dopamine D4 and D1 receptor antagonist. While other neuroleptic agents preferentially block the D2 receptor, clozapine is a relatively weak D2 blocker [60]. In addition, clozapine blocks both the 5-HT2 and 5-HTlB autoreceptors [61]. Unlike other neuroleptic agents, the atypical agents have few extrapyramidal adverse effects and little possibility of producing tardive dyskinesia [60]. Common side effects of clozapine include drowsiness, dizziness, increased salivation, constipation, tachycardia, nausea and vomiting. Clozap-
ine does lower the seizure threshold in a dosedependent fashion. A more serious adverse side effect is the possibility of agranulocytosis (with an incidence of 0.8% after 1 year of treatment) which requires weekly complete blood count monitoring [62]. A retrospective study of severely agitated and aggressive behavior in chronically institutionalized schizophrenics demonstrated significant amelioration of self-injurious behavior, agitation and verbal aggressiveness and assaultive behavior with the use of clozapine, allowing increased socialization and decreased use of restraints [61]. Although this may have been a consequence of decreases in pyschoses, the lessening of aggressive episodes was dramatically more noticeable in comparison to other psychiatric symptoms. One series of case reports on the use of clozapinc in patients with brain injury has been published. All patients treated were in the chronic stages, one at 10 months post-injury and the rest at least 4 years after injury. Most had evidence of psychotic symptoms in addition to agitation, aggression and self-abuse. Of these, three had significant improvement in aggression or bizarre behaviors; the remainder had only mild or indeterminate response to treatment. Two of the patients had seizure onset thought. to be related to the use of clozapine [62]. Because of the potentially serious adverse events associated with the use of clozapine, it would not be a desirable first-line agent. In addition, traditional neuroleptics are associated with impaired cognition and may slow or permanently alter recovery after brain injuries; as these factors have not been explored in these agents, caution is prudent. Those patients with severe behavioral disorders associated with psychotic manifestations may be the likeliest to respond to these agents. Risperidone is a compound with high affinity for 5-HT2 receptors, dopamine D2 receptors, and a 1 and a 2-receptors (see Table 2). In animal models, it inhibits apomorphine-induced agitation and amphetamine-induced agitation. The most common adverse effects are asthenia and sedation. Prolactin levels are significantly increased and galactorrhea or amenorrhea may result [60].
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5. Hormonal agents Anabolic steroids, such as testosterone, have long been linked with certain types of aggressive behavior in humans and primates. Diseases which result in the overproduction of androgens, such as prenatal androgenization of females or adrenogenital syndrome, may be related to aggressive activity [1]. However, the association between serum testosterone level and aggressive behavior is tenuous and poorly supported by experimental evidence [63]. There is, however, reason to further explore the hypothalamic pituitary adrenal (HPA) axis and the hypothalamic pituitary thyroid (HPT) axis and their relation to aggression. The presence of thyroid abnormalities in patients with various affective disorders (depression, agitation, anxiety, suicidality, and panic attacks) has been documented [64]. In patients with depression, the thyrotropin-stimulating hormone (TSH) response to thyrotropin-releasing hormone (TRH) appears to be especially blunted (see Table 2). In particular, depression with agitated features has been associated with a blunted TSH response. There is evidence to link the noradrenergic system with the HPT axis; the adrenergic system innervates the TRH-secreting neurons in the hypothalamus and the thyroiQ gland itself. There is conflicting evidence on the interaction of the serotonergic system and the HPT axis [64]. In rats with induced TBI, TRH analogs have improved behavioral abnormalities although aggression was not specifically studied. In these studies, TRH analogs modified to minimize endocrine actions were still successful in altering behavioral outcome in rats, indicating that the CNS protective effects of TRH may not be due to their endocrine activities [65,66]. Indirect indication for the involvement of the HPA axis exists. These is some early evidence that patients with Alzheimer's disease who are unable to suppress the production of cortisol after the administration of dexamethasone have higher levels of agitation (defined in this study as uncooperativeness, pacing, increased motor activity and tremors) [67]. Certain peptides with hormonal effects may also have direct central action
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on behavioral activity. For instance, corticotropin-releasing factor, which stimulates the release of adrenocorticotropin hormone and t3-endorphin from the anterior pituitary gland, also seems to have a direct effect on the neurons of the locus coerulus, mediating increased motor activity and arousal [68] (see Table 2). Hypersecretion of corticotropin releasing factor (CRF) appears to be involved in the etiology of anxiety disorders in humans [69]; no study of CRF secretion in humans has been reported for agitated states. 6. Opioid antagonists Opioid antagonists such as naltrexone and naloxone are discussed for possible inclusion in a future armamentarium of medications for treatment of agitation largely on the basis of the research done in the area of self-injurious behavior (SIB). These substances block the opioid receptors and have no agonist effects. An animal model for SIB exists which uses chronic administration of high-dose opiate agonists [70]; other studies in rats demonstrate an increased threshold for self-stimulation in animals treated with naloxone, an effect that persisted after the drug was discontinued [71]. Veterinary literature also documents a decrease in self-licking and -chewing behavior in dogs after treatment with narcotic antagonists [72]. In addition, a relationship -between opioids and lack of nociception exists [73]. A possible model of a relationship between the hypothalamic-pituitary-adrenal axis and proopiomelanocortin which results in hyperproduction of opioid peptides, nonopioid peptides and 5-HT has been proposed [74]. Narcotic antagonists have also been shown to attenuate the motor activity response of rats to administration of amphetamine, implying an interaction of the opioid receptors with the central stimulant effects of amphetamine [75,76]. Naltrexone can be given by mouth unlike naloxone, which has a very short duration of action in the central nervous system (see Table 2). Naltrexone has few adverse effects but may cause nausea and reduce food intake in recovering ad-
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dicts. In addition, reversible elevations in liver enzymes may occur. The existing studies of the use of naltrexone for agitation in clinical settings have all involved mentally retarded and/or autistic adolescents or adults. All studies have been quite small, with one to eight subjects included. Many studies reported significant decreases in SIB; the criterion for efficacy generally was a decreased number of selfinjury episodes per day [77-82]. A study done by Zingarelli on autistic adults with SIB and 'socially inappropriate behavior', using a double-blind crossover C-ABAB design demonstrated no clear behavioral changes related to the administration of naltrexone [83]. A similar study by Szymanski described similar negative results [84]. Studies utilizing narcotic antagonists have not been done in animal or human TBI populations. Opioid receptor antagonists have been studied in rat models of fluid percussion-induced TBI and have been shown to limit behavioral abnormalities in a general sense, although aggression has not been specifically addressed [65]. Opioid antagonists may have some utility in treating those brain injured patients with selfabusive behaviors although careful documentation of drug-response effects should be carried out to justify the use of these drugs. The studies indicating that narcotic antagonists are effective in modulating the motor hyperactivity associated with amphetamine usage may offer some indication of possible benefits in TBI. 7. Summary Although a number of avenues have shown some promise in the treatment of agitation-related disorders in other populations, a paucity of literature exists supporting their use in TBI populations. One of the problems commonly encountered by the clinician treating the patient with TBI and agitation is the variable definition of agitation by both clinicians and experimentalists. Extrapolating experimental information from other populations to the TBI population will demand improved delineation of the behaviors being measured in order to define efficacy of interventions. The variety of behaviors for which the above
compounds are used indicate a possible future in which medications will be very specifically targeted at specific behaviors, rather than continued attempts at treating global 'agitation'. None of the compounds discussed in this article are clearly going to be panaceas for behavioral disturbances but many offer some direction for further exploration of the nature of and appropriate treatment for agitation and aggression in TBI patients.
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