Adjunctive Amantadine Treatment for Aggressive Behavior in Children: A Series of Eight Cases

Introduction

Aggression is overt behavior that has the intention of inflicting physical damage on another individual (Moyer 1971). Both instrumental and impulsive aggression subtypes have been identified in humans (Vitiello and Stoff 1997), with physical aggression and verbal abuse being common reasons for referral to mental health services in youth (Dean et al. 2007). Staff training, individualized patient management plans, and a standardized framework for behavioral management have reduced aggressive behavior, physical restraints, and seclusion time in inpatient settings (Dean et al. 2007). Pharmacotherapy may be utilized when nonpharmacologic methods are inadequate. Current pharmacotherapy options for aggressive behavior in youth include alpha-agonists, antiepileptics, antipsychotics, and stimulants among others. New treatment options are needed when lack of efficacy or intolerable adverse drug events occur.

Amantadine is a noncompetitive N-methyl-D-aspartate receptor antagonist that increases synaptic dopamine (Farnebo et al. 1971; Kornhuber et al. 1994). Mattes (1980) first described improvement of hyperactivity with amantadine in two of nine patients with attention-deficit/hyperactivity disorder (ADHD). Masters (1997) later commented on his experience using amantadine for hyperactivity and irritability in patients with ADHD. Amantadine has been assessed in a prospective, open-label study of eight inpatient children with impulsive and aggressive behavior who primarily had neurodevelopmental disorders (King et al. 2001a). These patients had failed an average of eight drug therapies, were initiated on amantadine, and then titrated to a maximum daily dose (range 3.7–8.2 mg/(kg·day over a 1- to 2-week period. Four children were noted to have a marked response and four had a moderate response after receiving amantadine for a range of 5 to 14 hospital days (King et al. 2001a). A randomized double-blind, placebo-controlled trial evaluated amantadine's effects on aberrant behavior in 39 youth with autism spectrum disorder (ASD) (King et al. 2001b). Subjects were assigned to placebo or amantadine 2.5 mg/(kg·day) for the first week and then to 5 mg/(kg·day) for an additional 3 weeks. Clinician-rated Aberrant Behavior Checklist-Community version (ABC-C) showed a statistically significant decrease on hyperactivity and inappropriate speech items with amantadine versus placebo, although statistical significance was not reached through parent-rated assessment. Clinical Global Impression of Improvement (CGI-I) scores noted moderate or marked improvement in 53% of subjects on amantadine compared with 25% taking placebo (p = 0.076) (King et al. 2001b). A second randomized, placebo-controlled trial evaluated adjunctive amantadine to risperidone in 40 severely disruptive children with ASD (Mohammadi et al. 2013). All subjects initiated risperidone and were titrated to a maximum tolerated dose of 2 mg/day. Subjects assigned to amantadine therapy received either 100 or 150 mg/day depending on weight. Clinician-rated ABC-C showed a statistically significant decrease on irritability and hyperactivity/noncompliance items with amantadine versus placebo after 10 weeks. CGI-I scores showed amantadine to yield either very much or much improvement in 50% of subjects compared with 20% of subjects taking placebo (p = 0.047) at 10 weeks (Mohammadi et al. 2013). More recent research efforts have shown amantadine dosed at 200 mg/day to reduce aggression and irritability in patients with traumatic brain injury, although improvements did not always statistically separate from placebo (Hammond et al. 2014, 2015). Based on these studies, amantadine is perceived to show clinical benefit in a variety of psychiatric and neurologic disorders.

The neurobiology of impulsive aggression is complex and may involve impaired decision-making (Blair 2016). It is believed the amygdala, hypothalamus, and periaqueductal gray mediate the acute threat response that is regulated by the ventromedial prefrontal cortex (vmPFC) (Blair 2016). If the vmPFC has compromised function, a threat may be inappropriately detected and lead to impulsive aggressive behavior (Blair 2016). Multiple neurotransmitters are believed to have a role in aggressive behavior (Nelson and Trainor 2007), and although amantadine's mechanism of action is unknown in pediatric aggression, it has been theorized to enhance cognitive function and subsequently decrease behavioral disinhibition in TBI-related aggression (Hammond et al. 2014). Children with aggressive behavior and co-occurring psychiatric disorders are frequently admitted to our hospital. We have utilized amantadine successfully in a small number of patients in recent years who have appeared to be resistant to more common therapies. We aim to describe eight cases that resulted in clinical global improvement following adjunctive amantadine therapy.

Methods

We conducted a retrospective chart review of psychiatric inpatients who were initiated on amantadine for the management of aggressive behavior between November 2013 and October 2015. All included patients took amantadine for a minimum of 20 days. Patients were not included in this report if they initiated amantadine for an indication other than aggressive behavior, were taking amantadine at time of hospital admission, or had been hospitalized for less than 7 days before initiation of amantadine. Clinical improvement on amantadine was assessed through use of the CGI-I scale performed by a child and adolescent psychiatrist. In addition, the number of weekly physical restraints, seclusions, and as needed (PRN) medications for aggression were obtained at baseline (1 to 2 weeks before amantadine initiation), and weekly following achievement of concentration steady state at the maximum amantadine dose utilized. Physical restraint was defined as the involuntary immobilization of a person through the means of one or more staff members in bodily contact with the patient. Seclusion was defined as the involuntary confinement of a person in a room alone so that the person was physically prevented from leaving. Confidence intervals and paired two-tailed t-tests were utilized to identify differences between objective measures. This project was designated as IRB exempt by the Shodair Children's Hospital Research Review Committee due to its retrospective design, patient de-identification, and the Basic Health and Human Services (HHS) policy for protection of human research subjects 56 FR 28012,28022 46.101(b)4.

Results

A total of eight Caucasian children were included (Table 1). Most patients were male (n = 7) and ranging in age from 6 to 10 years (mean 8.5). The most common diagnoses were ADHD (n = 5), intermittent explosive disorder (IED) (n = 4), oppositional defiant disorder (ODD) (n = 3), and bipolar disorder (n = 3). Five patients had either borderline intellectual functioning or an unspecified cognitive disorder and four patients had either confirmed or suspected in utero substance exposure (i.e., methamphetamine or alcohol). The duration of hospitalization ranged from 58 to 156 days (mean 113). The duration of treatment days on amantadine ranged from 20 to 92 days (median 43.5). Mean amantadine starting dose was 2.6 mg/(kg·day) and the mean discharge dose was 6.7 mg/(kg·day). The number of days to achieve maximum amantadine dose ranged from 5 to 12 days (mean 7.8).

Five patients were noted to be very much improved and three patients were much improved according to the CGI-I following amantadine therapy. Changes in mean weekly physical restraints, seclusions, and PRN medications are summarized in Figure 1. Average seclusions and PRN medications per week were reduced from baseline to week 1 of amantadine (1.81, 95% CI [1.02, 2.61] versus 0.25, 95% CI [0.00, 0.55] [p = 0.01] and 4, 95% CI [2.22, 5.78] versus 1.63, 95% CI [0.71, 2.54] [p = 0.02]), respectively. Both physical restraints and seclusions were reduced from baseline in the second week of amantadine (1.56, 95% CI [0.45, 2.68] versus 0.00, 95% CI [0.00, 0.00] [p = 0.04] and 1.81, 95% CI [1.02, 2.61] versus 0.13, 95% CI [0.00, 0.35] [p = 0.01]), respectively. Mean reductions from baseline in physical restraints, seclusions, and PRN medications were observed in weeks 3 and 4 of amantadine treatment, but failed to reach statistical significance. No patients were readmitted to our facility within 60 days following discharge, and one patient was readmitted within 180 days following discharge. Amantadine was well tolerated and no adverse effects were identified under our care.

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FIG. 1.

Mean weekly as-needed (PRN) medications used for aggression, physical restraints, and seclusions before and after adjunctive amantadine initiation. Error bars denote 95% confidence intervals. Patient number five was not included in week 4 results, and patient number eight was not included in week 3 and 4 results due to hospital discharge. *Statistically significant change from baseline (p < 0.05).

Discussion

We report clinical improvement of aggressive behavior in children using adjunctive amantadine, a response similar to other reports (Masters 1997; King et al. 2001a, 2001b; Mohammadi et al. 2013). Our patient population appears similar to that described by King et al. (2001a) due to the high frequencies of ADHD and borderline intellectual functioning, although our patients may have had a higher frequency of in utero substance exposure and mood disorders. Our results suggest that adjunctive amantadine reduces physical restraints and seclusions in the early weeks of therapy, but these effects were not sustained over time. This observation may be explained by a small patient sample size, which was then further reduced in weeks 3 and 4 of therapy due to hospital discharge. Amantadine was well tolerated in our population using a mean starting dose of 2.6 mg/(kg·day) and a mean discharge dose of 6.7 mg/(kg·day). In children with ASD, amantadine has been shown to have no difference in adverse events compared to placebo when used adjunctively with risperidone (Mohammadi et al. 2013) and was described as “too well tolerated” using a dose of 5 mg/(kg·day) as monotherapy (King et al. 2001b). Alternatively, doses of 3.7–8.2 mg/(kg·day) caused transient sedation (25%), sleep disturbance (25%), and early morning awakenings (12.5%) in patients with developmental disorders, with one child experiencing hallucinations at a dose of 17 mg/(kg·day) (King et al. 2001a). Given these data, the ideal amantadine dose for the treatment of aggressive behavior is unknown. The use of therapeutic drug monitoring in future studies may better explain therapeutic and toxic amantadine concentrations and identify possible drug–drug interactions.

Conclusion

Fifteen years ago, King et al. (2001a) suggested that amantadine deserved further study in a wide variety of behavioral disorders in children with developmental disability. Our naturalistic report supports this finding. We found adjunctive amantadine to very much improve aggressive behavior in five children and much improve aggressive behavior in three children. These observations are supported by a decrease in restraints and seclusions in early therapy. Open-label use of medications, small sample size, frequent use of other mood stabilizing medications and stimulants, and nonutilization of objective clinical rating scales limit our ability to produce firm conclusions. Amantadine needs well-designed efficacy and effectiveness studies on aggressive children to confirm or reject our observations.

Clinical Significance

The clinical significance of our report is modest due to the number of limitations associated with a retrospective case series. Our report illuminates the need for well-designed clinical trials to be conducted in patients with aggressive behaviors and cognitive disorders. These trials may contribute to finding alternative therapies for aggressive behavior in youth.