Aggression, either acute or chronic, is the single most common reason for referral to child and adolescent mental health clinicians, reaching as high as 50% to 60%.1 This may be explained, at least in part, by the concept of equifinality, or the presence of divergent etiologic roots that lead to phenotypically similar behavior patterns.2 Many disorders in childhood may present with externalizing behavior such as aggression. Furthermore, aggression may be the single most distressing psychiatric sign to parents, teachers, siblings, and others, often prompting urgent referral. Aggression may be nearly impossible to overlook.
Aggressive children and adolescents often have significant functional impairment in many arenas, including familial, educational, social, and legal. Aggression is not only functionally impairing in the present but also portends ominously for the future. Many children who are disruptive, disobethent, and defiant by first grade progress to delinquency in their teenage years.1 Aggression also has a significant deleterious effect on parents, siblings, teachers, and society as a whole.
DEFINITIONS AND SUBTYPES OF AGGRESSION
Aggression has been defined in many ways, but it may be defined as simply as hostile or offensive action or words. Aggression may have positive or negative associations, but negative associations are more common. Aggression often implies intent to harm another person or damage an inanimate object.
Aggression may be subtyped along several non-mutually exclusive dimensions, including acute versus chronic, verbal versus physical, overt versus covert, adaptive versus maladaptive, and reactive-affective-defensive-impulsive (RADI) versus proactive-instmmentalplanned-predatory (PIPP).3 Each subtype has treatment implications.
Acute and Covert Aggression
Acute aggression is often encountered in hospital emergency rooms and acute psychiatric wards. When acute aggression presents, there may not be adequate time to conduct a thorough diagnostic evaluation and, thus, acute aggression is often treated via a target-symptom approach. Acute aggression may be treated on an asneeded basis with a variety of medications that have a rapid-onset calming effect (eg, sedating antihistamines, antipsychotics), either in oral or intramuscular formulation. Benzodiazepines also may be helpful but may be problematic if they lead to paradoxical reactions (ie, disinhibited behavior). Medication management strategies for acute aggression3 and principles of crisis management,4 including de-escalation strategies, indications for the use of seclusion and restraint, and the ordering and monitoring of seclusion and restraint, are reviewed elsewhere.
Covert aggression, such as lying, cheating, stealing, vandalizing, or spreading nefarious rumors, is often difficult to detect and even more difficult to treat, yet may signal significant psychopathology.
Aggression may be normative and adaptive and does not require treatment. For example, a toddler who cries "mine" as he reaches for a toy may be signaling a consolidated sense of self. Adolescents living in a gang-infested neighborhood may have to act aggressively to defend themselves. However, aggression that is brought to the attention of a physician or other mental health clinician usually is maladaptive. Maladaptive aggression has been defined by Connor5 as "aggression that does not serve the individual or group, violates societal rules, and is the expression of a disordered internal mechanism, which occurs in the context of a psychiatric disorder."
Maladaptive aggression has been subtyped as either impulsive with a significant affective component (ie, RADI aggression) or proactive, instrumental, planned, and predatory (ie, PIPP aggression).6·7 Negative effects frequently associated with RADI aggression include fear, anxiety, frustration, and anger. Approximately 7% of 13-year-old children have a problem with RADI aggression, 3% have a problem with PIPP aggression, and 1 0% have a problem with both RADI and PIPP aggression. However, 80% are free of problematic aggression.8
Thus, 17% of 13-year-old children deal with problematic RADI aggression, either alone or in combination with PIPP aggression. Children with PIPP aggression hold strong beliefs that aggression will help them obtain desired goals. It may be presumed that PIPP aggression will continue m any given child until perceived risks or consequences outweigh the anticipated goals of an instrumental act of aggression. This subtype of aggression is a very poor target for psychopharmacologic treatment However, a target-symptom approach combined with behavioral interventions may be judicious, especially if aggression is overt, severe, and violent.
It has been postulated that children with a propensity for RADI aggression - often children with conduct disorder or oppositional defiant disorder - misread social cues and have a hair-trigger response to stimuli. They often attribute hostile intent to others in benign social situations. They frequently have significant trauma histories, and their malignant misattribution possibly is an effort to make the present conform to past experiences and to transform passive experiences active. This allows children with aggression a sense of mastery with, it hoped, a non-traumatic outcome. less of possible unconscious motivation, children with a propensity for aggression overreact to a minor, times misperceived, provocation often feel remorse soon after the commission of the aggressive act, with avowal not repeat it. Unfortunately, they usually do repeat the aggressive acts.
Psychotherapy in children with RADI aggression is multifocal. Cognitive therapy is used to help the child re-evaluate social cues as ne utral or friendly than hostile. Insight-oriented therapy can help the child understand how expectations of ufe are influenced by traumatic or disappointing experiences. Anger management is useful to help the child identify feelings, especially somatic sensations, and to interpret those feelings as cues to stop the behavior and consequences of impulsive aggression. Despite the efficacy of psychotherapy behavior modification, many children with RADI aggression may benefit from trial of psychotropic medication. Medications may help to reduce irritability, explosiveness, and impulsivity. Medications also may work synergisticaUy with psychosocial interventions because nonpharmacologic interventions receive adequate trial without such reduction of irritability, explosiveness, impulsivity.
DIAGNOSIS OF AGGRESSIONRELATED DISORDERS
Before consideration of psychopharmacotherapeutic options, a thorough diagnostic evaluation of subacute or chrome aggression, including assessment of predisposing, precipitating, and perpetuating factors, is of utmost importance. Diagnosis of treatable mental disorders is imperative, as treatment of a primary disorder frequently leads to a significant reduction in RADI aggression. Common primary mental disorders that may present with RADI aggression include attention-deficit/hyperactivity disorder (ADHD), major depressive disorder, bipolar disorder (BP), anxiety disorders, posttraumatic stress disorder (PTSD), conduct disorder (CD), oppositional defiant disorder, traumatic brain injury, mental retardation, and pervasive developmental disorders (PDD). Core symptoms of ADHD, major depressive disorder, bipolar affective disorder, and PTSD are considered treatable psychopharmacologically.
Subacute or chronic maladaptive RADI aggression occurring in patients in whom a primary mental disorder cannot be established may be treated via a targetsymptom approach. Patients with a primary mental disorder who have responded to treatment but in whom residual RADI aggression persists may benefit from a target-symptom approach as well. Thus, treatment of RADI aggression is largely nonspecific much of the time.
One of the most difficult complexities of child and adolescent psychiatry is symptom overlap and comorbidity. From a nosologie perspective, diagnostic terminology can be confusing, especially with ADHD, mania, and depression. What is called "inattention" iir patients with ADHD is called "distractibility" in patients with mania and "impaired concentration" in patients with depression. What is called "hyperactivity" in patients with ADHD is called "psychomotor agitation" in patients with mania or depression. Furthermore, clinicians often are asked to distinguish between primary inattention, oppositionality, noncomformity to societal norms, and mood disturbance as the source of aggression. Frequently, disturbance in any of these domains leads to disturbance in others.
For example, the core symptoms of ADHD include inattention, hyperactivity, and impulsivity. Many children with ADHD suffer academically because they are unable to focus. Their hyperactivity and potentially disruptive behaviors further impair their learning experiences and often stigmatize and alienate them from teachers and peers alike. What may result is a very demoralized and possibly depressed child. These children frequently have difficulty with RADI aggression. Furthermore, ADHD and CD frequently coexist. Approximately two-thirds of children with CD have ADHD as well. Conversely, approximately one-third of children with ADHD have CD as a comorbid condition. It is thus important to attempt to determine chronology of symptoms.
Although the onset of comorbid disorders may differ, the onset of inattention and academic difficulties before the onset of depressed mood and RADI aggression suggest a primary diagnosis of ADHD. It is suggested that the first psychopharmacologic approach should be to treat the ADHD to response - preferably to remission - and then reassess the aggression.
Mediine and PubMed computerized searches (see Sidebar, page 320) were conducted for meta-analyses and reviews of psychopharmacologic treatment of aggression in children and adolescents from 1995 to 2003. Keywords included aggression, children and adolescents, pharmacology, antipsychotics, lithium, mood stabilizers, anti-epileptic drugs, stimulants, selective serotonin reuptake inhibitors (SSRIs), antidepressants, betablockers, clonidine, alpha agonists, buspirone, benzodiazapines, amantadine, conduct disorder, oppositional defiant disorder, disruptive behavior, BD, depression, mental retardation, PDD, ADHD, and externalizing behavior. Further expansion of the literature reviewed was conducted using a "snowballing" effect on search results. The textbooks shown in the sidebar (page 320) were reviewed
Following is a summary of various psychopharmacologic agents used in the treatment of aggressive children and adolescents. For each agent or class of agents, the literature is reviewed, and prescribing considerations, such as dosage, side effects, and potential drug-drug interactions, are detailed.
Because they have become commonly prescribed by non-psychiatrists, relatively more pharmacokinetic detail is provided about SSRIs. A general principle guiding all medication trials is that trials should be optimized with regard to dosage and duration before concluding that a trial has failed. The prescriber should attempt to remain patient in the face of pressure from outside forces, including parents, teachers, and third-party payers, to make a quick decision.
Mood stabilizers have been defined in various ways. Lithium would be the only mood stabilizer if the most stringent definition were used - an agent that is effective in the treatment of all phases of BD, including acute mania, bipolar depressive episodes, and prophylaxis against cycling into either mania or depression.9 More conventionally, an agent is considered to be a mood stabilizer if it has been shown to be effective in any phase of BD. Acute mania usually is the first indication sought by drug manufacturers. Many antiepileptic drugs are generally considered to be mood stabilizers; however, only divalproex and carbamazepine have been studied in aggressive children without mental retardation in either double-blind, placebo-controlled trials - also known as randomized controlled trials (RCTs) - or open-label trials.
Lithium. Lithium is the oldest and most studied mood stabilizer. Seven RCTs have been conducted with lithium.6 Three studies demonstrated the effectiveness of lithium over placebo and one study was questionable. In the first RCT published in 1984, 61 children ages 5 to 12 who were hospitalized for treatmentresistant aggressive behavior were randomized to receive lithium, haloperidol, or placebo.10 Dosages ranged from 500 to 2,000 mg per day for lithium and from 1 to 6 mg per day for haloperidol. Although both haloperidol and lithium were found to be significantly superior to placebo in decreasing aggression, haloperidol was associated more often with negative side effects than lithium.
In a more recent study, lithium was also found to be a safe and effective treatment for aggression in inpatients with CD, although its use is associated with adverse effects.11 Investigators conducted a 2-week, placebo-baseline period, with elimination of placebo responders from the study. These authors also pointed out that previous studies in which lithium was not found to be superior to placebo were conducted on outpatients, possibly because of a different function of study design or participant sample. Previous studies also were too short in duration or were conducted on subjects with less severe, less explosive aggression.
Use of lithium is somewhat limited by its narrow therapeutic window and the need for blood monitoring of patients receiving lithium treatment. Common side effects include gastrointestinal distress, tremor, lethargy, and a benign polyuria-polydypsia syndrome. Weight gain and acne may also be a concern, especially in a pediatrie population. The presence of so many complicating side effects may be problematic in children who are easily dissuaded from taking medications, such as is often the case with adolescents with disruptive behavior disorders. In addition, more serious side effects exist and include diabetes insipidus, cardiac arrhythmia, thyroid abnormalities, leukocytosis, seizure, and coma. Also a consideration in a population known for high physical activity, concurrent street-drug use, and noncompliance is that lithium levels may be affected significantly by many commonly prescribed or over-the-counter medications, or by dehydration.
Divalproex. Divalproex has been studied in two RCTs of children and adolescents with aggression. Both showed superior efficacy to placebo. In one study, 20 outpatient children and adolescents ages 10 to 18 with either CD or oppositional defiant disorder were studied.12 The patients also had explosive tempers, defined by four or more outbursts of rage, property destruction, or fighting per month, and mood lability defined by multiple daily distinct shifts from normal to irritable mood. They were randomized to either divalproex or placebo. At the end of 6 weeks, participants in the divalproex group were crossed over to placebo and vice versa. At the end of the first phase, 8 of 10 participants had responded to divalproex, while none responded to placebo. Of the 15 participants who completed both phases of the study, 12 had superior response to divalproex.
In a more recent RCT, high-dose divalproex (usually about 1,000 mg per day) was compared to low-dose divalproex (up to 250 mg per day) in 58 boys with CD.13 The mean age of the study group was 16. Researchers found 53% were responders in the high-dose group, while 8% were responders in the lowdose group. Divalproex also improved self-reported impulse control and selfrestraint, variables shown to be predictive of criminal recidivism.
Divalproex is generally well tolerated but requires blood monitoring for valproic acid levels and liver enzymes. Common divalproex-related side effects include gastrointestinal distress (which may be minimized by ingesting with food), diarrhea, sedation, and rash. Serious side effects include hepatotoxicity, pancreatitis, polycystic ovarian syndrome, syndrome of inappropriate antidiuretic hormone secretion, hyponatremia, blood dyscrasias (including bleeding due to thrombocytopenia), and lifethreatening rashes (including erythema multiforme and Stevens Johnson syndrome). Divalproex, if taken by a pregnant woman, may cause neural tube defects in the unborn child.
Both lithium and divalproex usually become effective within 2 to 4 weeks. Lithium dosage is between 20 and 40 mg/kg daily, and divalproex dosage is between 15 and 20 mg/kg daily. Therapeutic blood levels range between 0.6 and 1 .2 mEq/L for lithium and between 60 and 120 µ-g/mL for divalproex. Although both divalproex and lithium are effective in the treatment of subacute or chronic RADI aggression, divalproex has the advantage of having a wider therapeutic window. Divalproex also may be loaded as long as adequate monitoring for treatment-emergent side effects is conducted. Either lithium or divalproex may be first-line treatments for treatment of aggression in the context of BD; however, divalproex may be more effective for rapid-cycling BD, dysphoric mania, and BD with comorbid substance use.14
Carbamazepine. Carbamazepine was found not superior to placebo in reducing aggressive behavior in children with CD in one RCT.15 Common side effects associated with Carbamazepine include gastrointestinal distress, sedation, dizziness, lethargy, and elevated liver enzymes. Serious reactions include blood dyscrasias (including aplastic anemia), life-threatening rashes, syndrome of inappropriate antidiuretic hormone secretion, hepatitis, pancreatitis, and pulmonary hypersensitivity.
Carbamazepine has many potential drug interactions due to extensive induction of cytochrome P-450 (CYP) enzymes, including auto-induction of CYP 3A4. It is believed that carbamazepine's 10,11-epoxide metabolite is responsible for its CYP induction and probably its bone marrow suppression. Because of its toxic effect on bone marrow and auto-induction of metabolism, blood monitoring of Carbamazepine levels and complete blood counts are necessary.
Dosages of Carbamazepine usually are between 20 and 30 mg/kg per day, with therapeutic blood levels between 6 and 12 \Lg/mL. Because of its relatively toxic side-effect profile and the lack of evidence for its efficacy, a trial of carbamazepine should be prescribed only after the other mood stabilizers have been tried and failed, or if there are special reasons to think that the medication might be effective (ie, when a first-degree relative has responded well to it).
Typical antipsychotics (ie, D2 antagonists or neuroleptics) are some of the earliest-studied psychotropics for the treatment of aggression regardless of diagnosis. In an RCT in 1984, haloperidol (mean dose - 2.95 mg per day) was compared to lithium and placebo for the treatment of aggressive children with CD.10 Both medications were clinically superior to placebo; haloperidol, however, was associated more often with negative side effects than was lithium.
Despite their efficacy for the treatment of aggression, safety concerns limit neuroleptics' utility. Neuroleptics, especially those that are high potency, may cause extrapyramidal side effects (EPS) such as acute dystonia, tardive and withdrawal dyskinesias, and parkinsonism. Low-potency neuroleptics have a greater propensity to cause orthostatic hypotension, sedation, and weight gain than EPS. All neuroleptics may also cause dysmetabolic syndromes, including glucose resistance and diabetes mellitus, neuroleptic malignant syndrome, and hyperprolactinemia.
Atypical or second-generation antipsychotics, such as clozapine, risperidone, olanzapine, quetiapine, ziprasidone, and aripiprazole, are characterized by a high 5-HT2A to D2 ratio of antagonism and a low propensity to cause EPS and hyperprolactinemia.
Rapendone. Rísperidone is the only SGA that has been studied in a doubleblind, placebo-controlled design in aggressive children and adolescents. Several RCTs have shown risperidone to be safe and effective for the treatment of aggression in children autism16 and mental retardation.17 In the only RCT of an SGA for the treatment of aggression in children with CD but without mental retardation, risperidone was found to be superior to placebo in ameliorating aggression.18 In that study, risperidone was reasonably well tolerated, with no patients treated with risperidone experiencing EPS. Of the SGAs, risperidone is the most potent D2 antagonist It follows that risperidone has a somewhat higher propensity to cause EPS and hyperprolactinemia than other SGAs.
A retrospective study pooled data from five clinical trials (n = 700) of children and adolescents ages 5 to 15 with subaverage IQ and CD or another disruptive behavior disorder that were treated with risperidone.19 That study found prolactin levels tended to rise and peak within the first 1 to 2 months of treatment and then steadily decline to values within or very close to the normal range by 3 to 5 months. These prolactin levels varied from a mean of 7.8 ng/mL at baseline to 29.4 ng/mL at 4 to 7 weeks, 16.1 ng/mL at 40 to 48 weeks, and 13 ng/mL at 52 to 55 weeks. No direct correlation was found between prolactin levels and side effects hypothetically attributable to prolactin (eg, galactorrhea). Among the SGAs, risperidone has an intermediate risk for causing weight gain and diabetes mellitus.
Other SGAs. Second-generation antipsychotics other than risperidone have proven to be effective for the reduction of aggression in adults with schizophrenia and children with mental retardation, both with and without PDD. Clozapine, in particular, is effective in reducing aggression in adults with schizophrenia.20 However, clozapine's unique and unfavorable sideeffect profile, which includes risk of agranulocytosis, seizure, and sialorrhea, severely limits its usage hi any population other than patients with schizophrenia who have been refractory to multiple other antipsychotic trials.
Among the SGAs, clozapine carries a high risk of causing sedation, weight gain, and dysmetabolic syndromes, including hyperlipidemia, glucose resistance, and diabetes mellitus. Olanzapine and quetiapine may also be effective in the treatment of aggressive children and adolescents but RCTs have not been conducted to confirm this. Among the SGAs, quetiapine possibly has the lowest incidence of EPS and hyperprolactinemia. However, quetiapine carries an intermediate risk of causing weight gain and dysmetabolic syndromes. Among the SGAs, olanzapine carries a high risk of causing weight gain and dysmetabolic syndromes.
Ziprasidone and aripiprazole are the newest SGAs, feature unique pharmacodynamic properties, and carry a low risk of causing sedation, weight gain, or diabetes mellitus. No RCTs exist for either, however, similar efficacy to other SGAs might be expected. Ziprasidone, in addition to D2 and 5-HT2A antagonism, possesses 5-HT1 A agonism and fairly potent blockade of 5-HT and norepinephrine transporter proteins. These provide a theoretical basis for antidepressant, anxiolytic, and perhaps anti-aggressive effects distinct from other SGAs. However, due to its 5-HT and norepinephrine reuptake inhibition, caution should be exercised when considering ziprasidone for the treatment of aggression in children and adolescents with a bipolar diathesis (eg, individual history of mood lability, family history of BD). Ziprasidone may also cause QTc prolongation, which has been associated with ventricular arrhythmias and Torsades de Pointe in other medications. No cases of Torsades de Pointe associated with ziprasidone have been reported, however. Aripiprazole is a D2 partial antagonist and 5-HT IA partial agonist. Aripiprazole may act to stabilize dopamine transmission, and it may have an additional anti-aggressive effect due to its 5-HT IA agonism.
One advantage that antipsychotics have over mood stabilizers is rapidity of onset of action. Although full anti-aggressive effect may take weeks, an immediate calming effect - anxiolysis independent of sedation - is often experienced For children with both problematic acute and chronic aggression, antipsychotics may be a first-line agent. Antipsychotics may also be first-line agents for children with problematic RADI aggression and thought disorder. A formal thought disorder may portend schizophrenia prodome. Thought disorders may be disorders of the content of thought, such as paranoia, or the process of thought, such as disorganization. A recent two-part review of antipsychotic use in aggressive children and adolescents was published elsewhere and discusses treatment of aggression using antipsychotics in detail.21·22
Psychostimulants increase dopamine and norepinephrine transmission. Psychostimulants have proven effective in treating the core symptoms of ADHD and carry a favorable side-effect liability. They may also be effective in reducing antisocial behavior by improving the functioning of the reticular activating system.
A meta-analysis of 28 studies showed treatment with stimulants results in significant reduction of aggression-related behaviors occurring in patients with ADHD.8 These results were found to be independent from effects on core symptoms of ADHD. Not surprisingly, this study found a larger effect size for overt (0.84) than for covert aggression (0.69). The authors suggested symptoms of overt aggression in patients with ADHD in the context of CD may be especially difficult to treat They also noted a diminished effectiveness of stimulants in the treatment of aggression in children with ADHD and comorbid mental retardation.
The largest single study of psychostimulants to date focused on behavior problems associated with CD.23 All of the 84 participants, ages 6 to Í5, met criteria for CD, and two-thirds met criteria for comorbid ADHD. Participants were randomly assigned to receive up to 60 mg per day of methylphenidate or placebo for 5 weeks. The average dose was 41.3 mg per day. Contrary to the investigators' expectations, ratings of aggression as well as antisocial behavior spe- " cific to CD, such as cheating and stealing, were significantly reduced by methylphenidate treatment. However, distinction was not made between impulsive and predatory aggression.
One of the most frequent, reliable, and replicable findings in biologic psychiatry is that of central serotonin (5-HT) functioning being inversely related to impulsive aggression and violence.24 Low levels of CSF 5-hydroxymdoIacetic acid (5HLAA), a serotonin metabolite, have been consistently found in studies of adults with affective or personality disorders and impulsive destructive behavior. Low CSF 5-HIAA levels have also been 4 reported in children with disruptive behavior disorders who reported aggression toward people.25
One open-label, 6-week study found citalopram significantly reduced impulsive aggression and irritability in chil- *" dren and adolescents with normal intelligence and an established pattern of aggressive behavior.26 No significant difference was found in predatory aggression or internalizing problems, , such as anxiety or depression.
When choosing an SSRI, a few guiding principles should be kept in mind The clinician should choose an agent with minimal potential drug interactions. Of the SSRIs, citalopram and sertraline have the fewest CYP P-450 interactions. Paroxetine is a fairly potent inhibitor of CYP 2D6. Fluoxetine also is a fairly potent inhibitor of CYP 2D6, and its active metabolite (norfluoxetine) is a moderate inhibitor of CYP 3A4. Fluvoxamine is an inhibitor of CYP 1A2, 2C9, 2Cl 9, and 3 A4. Sertraline is a weak inhibitor of CYP 2D6. The agent chosen should also have a favorable side-effect profile. Most SSRI-related side effects are class effects; however, paroxetine also exerts an antimuscarinic effect that may result in typical anticholinergic side effects, such as sedation, cognitive dulling, blurred vision, constipation, and urinary retention.
Incidence of discontinuation syndromes (including withdrawal) may vary widely among SSRIs. Generally, the SSRIs with shorter half-lives, fluvoxamine and paroxetine, have a greater propensity to cause withdrawal upon abrupt discontinuation. Citalopram and sentraline, SSRJs with half-lives between 24 and 48 hours, have an intermediate propensity to cause withdrawal syndromes. Fluoxetine, along with its active metabolite norfluoxetine, has the longest half-life and the least propensity to cause a withdrawal syndrome. If daily compliance is problematic, then consideration may be given to fluoxetine because it may be administered on a once or twice weekly schedule regardless of formulation.
When considering an SSRI for the treatment of aggression, one must be thorough in the evaluation of possible bipolarity. History of manic symptoms, especially thought disorder, or family history of mania may indicate a possible underlying bipolar diathesis. Implementation of SSRI therapy may unmask the bipolar diathesis and increase the frequency or intensity of mood cycling, resulting in a more severe bipolar illness. Clinicians might consider antidepressants to be mood destabilizers in patients with BD. Diagnosis of BD in younger children may be even more challenging than in adolescents because children frequently present in mixed states or with ultradian cycling, cycling through distinct mood states within the same day.
A recent study compared clonidine in doses of 0. 10 to 0.20 mg per day to placebo for aggression and hyperactivity reduction when added to the psychostimulant treatment of children ages 6 to 14 with ADHD and either CD or oppositional defiant disorder.27 Significantly more clonidine-treated children than controls were responders on the Conners Behavioral Checklist Conduct subscale, with 21 of 37 patients responding in the clonidine group versus 6 of 29 patients in the placebo group (P < .01). However, only 13 of 37 patients were responders in the clonidine group versus 5 of 29 in the placebo group according to the Hyperactive Index subscale. Clonidine was relatively well tolerated but was associated with a greater reduction in systolic blood pressure and more frequent transient sedation and dizziness than placebo.
An open-label pilot study also found clonidine was effective in reduction of aggression in children ages 5 to 15 who were characterized by cruel behavior and destruction of property.28 This study also found that clonidine induced increases in plasma gamma aminobutyric acid (GABA), and postulated that increased GABA may account for clonidine's antiaggressive effect and serve a useful marker for drug compliance.
Although none of the following agents have been studied in RCTs of aggressive children or adolescents without mental retardation, some may be considered appropriate treatment options in select patients.
Amantadme. Used in children for influenza prophylaxis, amantadine acts both as an indirect dopamine agonist and as an N-methyl-D-aspartate receptor antagonist Because a growing body of literature implicates interactions between glutamatergic and neostriatal dopaminergic neurotransmitter systems in impulsivity, hyperactivity, and stereotypy, an openlabel study of amantadine for the treatment of impulsive aggression in children was conducted.29 The investigators found amantadine was associated with marked clinical improvement in four of eight patients, and that clinical improvement was also observed in the other four.
Baclofen. Baclofen, a GABA-B receptor agonist, was studied in aggressive adult parolees with and without a history of CD.30 Baclofen was found to suppress aggressive responses in patients with a history of childhood CD, while producing the opposite effect in controls (aggressive adult parolees without a history of CD). These results suggested a possible unique role for GABA in the regulation of aggression in patients with CD; but treatment implications remain unclear.
Benzodiazapines. Benzodiazapines (BZs) act on specific GABA receptor sites, known as BZ-GABA receptors. The mechanism of action of BZs is the enhanced opening of chloride ion channels, thereby decreasing neuronal excitability and enhancing the inhibitory effect of GABA. BZs are a mainstay in the treatment of acute aggression. However, BZs should not be considered as first- or even second-line agents in the treatment of sub-acute or chronic aggression because they carry the propensity for causing sedation, cognitive dulling, and behavioral disinhibition. There are also risks of abuse and dependence with BZs.
Beta-blockers. Beta-blockers have been shown to be safe and effective in the treatment of aggression in patients with many psychiatric conditions. However, no RCTs have been conducted in aggressive children or adolescents without mental retardation or PDD. One open-label study found nadolol to be well tolerated and an effective treatment of aggression but not of inattention or hyperactivity in developmentally delayed children.31 Beta-blockers vary widely in lipophilicity and somewhat in plasma-protein binding. Drugs that are lipophilic (eg, metoprolol, propranolol, nadolol) are more likely to cross the blood-brain barrier and achieve adequate central nervous system concentrations than drugs that are hydrophilic (eg, atenolol).
Buspirone. Buspirone is a 5-HT1A receptor agonist approved for the treatment of generalized anxiety disorder. It has been postulated that 5-HT1A receptor agonism in the limbo-hypothalamic tract is responsible for the decreased aggression reported in adults with personality disorders.32 Further evidence for buspirone's anti-aggressive effect is provided by a study that showed a blunted prolactin response to buspirone in parolees with a history of violence compared with nonviolent parolees.33 Buspirone is usually administered in divided doses totalling between 15 and 45 mg per day. Buspirone remains an attractive treatment alternative because of its favorable side-effect profile, including lack of tolerance and dependence. Common side effects include mild gastrointestinal distress, headache, lethargy, insomnia, and mild anticholinergic effects. No serious adverse reactions have been reported.
Novel anti-epileptic drugs, such as gabapentin, lamotrigine, oxcarbazepine, tiagabine, and topiramate, are frequently used as putative mood stabilizers in patients with BD. These drugs have a variety of pharmacodynamic properties including GABAergic activity, anti-glutamatergic activity, and multiiple other transcellular and intracellular mechanisms, which account for their membrane stabilizing and anti-seizure activity. Antimanic and mood stabilizing mechanisms of action for these agents are currently theoretical. Gabapentin is a GABAergic agent that has been shown to have no increased efficacy over placebo either as an adjunct in acute mania34 or as monotherapy in treatment-resistant BD, mainly rapid-cycling.35 Gabapentin has also been reported in the literature as possibly causing or exacerbating intolerable aggression.36 Lamotrigine is the only novel anti-epileptic drug with an indication for the treatment of BD. Lamotrigine has been reported to improve aggression in patients after a traumatic brain injury37 but may provoke aggression in patients with epilepsy and low IQs.38 Oxcarbazepine is a cousin of carbamazepine in that is not metabolized through the 10,11-epoxide. It has the advantages over carbamazepine of not causing significant bone marrow suppression, not inducing CYP isoenzymes (save mild induction of 3A4),39 and not requiring blood level monitoring. However, no evidence exists supporting its use either as a mood stabilizer or for the treatment of aggression. Tiagabine is a selective GABA reuptake inhibitor; a case series reported improvement of impulse control with aggressive features in two patients with postencephalitic epilepsy.40 However, in one patient, titration from 20 to 24 mg per day resulted in increased irritability that resolved with tiagabine reduction to 20 mg per day. The authors concluded that optimal dosing to maximize anticonvulsant and psychotropic effects needed to be established.
Trazodone is an antidepressant that is a weak inhibitor of the serotonin transporter protein and a potent antagonist at the 5-HT2A and 5-HT2C receptors. Trazadone possesses antidepressant, anxioytic, hypnotic, and anti-aggressive effects. Trazodone was shown to be a safe and effective treatment of aggression in children with disruptive behavior disorders in one open-label study.41 Multiple studies found trazodone to be an effective treatment of aggression and agitation in children and adults with various types of organic brain disorders, including mental retardation, PDD, trau- ¿ malie brain injury, and dementia. One survey found trazadone and amantadine were significantly more likely to be chosen by experts (members of the Brain Injury Special Interest Group of the American Academy of Physical Medi- ^ cine and Rehabilitation) than nonexperts for the treatment of agitation after a traumatic brain injury.42 Trazadone usually is administered in doses between 50 and 250 mg per day. ^1 Common side effects include sedation, gastrointestinal distress, anticholinergic side effects, anti-alpha-adrenergic side effects (eg, orthostatic hypotension, priapism), and tremor. Serious side effects include priapism, orthostatic hypotension, and syncope.
Knowledge regarding psychopharmacology is increasingly based on clinical trials and rational algorithms. Medications are increasingly regarded as useful adjuncts in the treatment of maladaptive aggression, whether it appears as a target symptom or as a complication of a whole range of psychopathology. Properly integrated into a treat- 4 ment package that uses psychotherapies and environmental manipulation, medications can provide relief from one of the most destructive forms of psychopathology. Still, more controlled clinical trials are needed, especially those comparing active interventions and those testing the synergistic and antagonistic effects of different treatment modalities.
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2. Barkley RA, Mash EJ, eds. Child Psychopaihalogy. 2nd ed. New YoA, NY: Guilford Press; 2002.
3. Steiner H, Saxena K, Chang K. Psychopharmacologic strategies for the treatment of aggression in juveniles. CNS Spectr. 2003:8(4):298-308.
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