Abstract
This retrospective study examined clinical parameters associated with amantadine treatment of psychiatric symptoms in children. A total of 297 pediatric patients were prescribed amantadine and met study criteria to assess clinical responses and medication outcomes. More than 62% of patients experienced clinically significant symptom control and 83% achieved at least maintenance symptom control, while 11% discontinued amantadine for nonresponse and 6% stopped amantadine because of side effects. Among patients previously receiving other psychotropic medication, 42% and 28% of patients fully discontinued second- or third-generation antipsychotics or antidepressants, respectively. Patients responsive to amantadine who discontinued or reduced antipsychotic dose experienced a significant reduction in body mass index. Amantadine appears be an efficacious and safe alternative for treatment of a broad set of psychiatric symptoms in children and adolescents. Specifically, it may serve as an effective adjunct to stimulants for attention deficit/hyperactivity disorder–related symptoms and appears to be a safer alternative to second- or third-generation antipsychotics.
Keywords: Amantadine, attention-deficit hyperactivity disorder, child and adolescent psychiatry, major depressive disorder, psychotropic medications
Amantadine hydrochloride, an indirect dopamine agonist and N-methyl-D-aspartate receptor antagonist, can modulate symptoms of childhood psychiatric disorders.1–4 Multiple studies have reported effective off-label use of amantadine in attention deficit/hyperactivity disorder (ADHD) and as an augmenting agent in treatment-resistant unipolar depression, autism spectrum disorder, and obsessive-compulsive disorder.5–13 Common side effects of amantadine include nausea, dizziness, and insomnia.14 Rare side effects include psychosis, hypertension, livedo reticularis, and rash.15 Stimulants and nonstimulants used to treat ADHD are associated with more severe side effects, while antipsychotics have been associated with weight gain, extrapyramidal symptoms, QTc prolongation, and sedation.16,17 Some studies report that amantadine can reverse weight gain induced by antipsychotics.18–23 This study was a retrospective chart review of children and adolescents prescribed amantadine to assess its tolerability and treatment outcomes for psychiatric symptoms.
METHODS
We conducted a retrospective cohort study at the Baylor Scott & White Pediatric Mental Health Clinic in Temple, Texas, to establish the proportion of successful treatments compared to failures as well as the proportion of patients who were able to reduce or transition off their existing psychotropic medications. Eligible patients were defined as any patients aged 5 to 18 years who were prescribed amantadine by a psychiatrist.
We accessed child psychiatry outpatient charts in the Epic electronic medical record from February 1, 2014, to February 1, 2018, and extracted data on age, sex, ethnicity, body mass index (BMI), weight percentile, duration of psychotropic treatment, dosage of amantadine response, clinical psychiatric diagnoses, target symptoms, clinic notes, other medication history, medications decreased in dose and/or discontinued after initiation of amantadine, and side effects attributed to amantadine. Comorbidities were recorded for each patient, including diagnoses of ADHD, depressive and anxiety disorders, oppositional defiant disorder, conduct disorder, posttraumatic stress disorder, obsessive compulsive disorder, and autism.
We classified clinical responses to amantadine as “success” or “partial success” based on clinician-reported assessment of patient psychiatry status over a minimum of 3 months, while all “treatment failure” or “side effect” discontinuations were classified independent of the interval. Chart notation of symptom improvement or abatement or dose decrease without discontinuation was classified as a treatment success. Partial behavioral control, defined as a decreased level of symptom compared to baseline, which warranted the continuation of amantadine, was classified as a partial success. Discontinuation of amantadine due to poor behavioral control was classified as treatment failure. Discontinuation due to side effects was classified as a side effect discontinuation. Patients were further classified as having their original doses of antipsychotics, stimulants, and antidepressants reduced by >50% or discontinued completely after starting amantadine. For patients originally taking second- or third-generation antipsychotics, BMI was calculated at the initial appointment when amantadine was prescribed and then after 1 year of amantadine treatment.
A total of 297 patients newly prescribed amantadine with available data during the 48-month look-back window were included in the database. Data analysis was performed using descriptive statistics and one-way analysis of variance with post hoc testing.
RESULTS
Of the 297 patients who ranged from 6 to 18 years and were diagnosed with a variety of psychiatric illnesses (ADHD being the most common), 62.3% achieved treatment success and 20.5% achieved partial success after >3 months of new prescriptions of amantadine (Table 1). Among patients who achieved partial or full therapeutic responses, 91.1% (224/246) continued amantadine therapy for at least 6 months and 79.7% (196/246) continued for 1 year. Many patients who achieved treatment success continued amantadine therapy beyond the review interval. Regarding nonresponse and discontinuation, 11.4% (34/297) of patients failed to achieve any symptom relief and 5.7% (17/297) experienced side effects that led to discontinuation of amantadine. The most common side effects noted for discontinuation were irritability, anxiety, gastrointestinal/weight loss, and sedation.
Table 1.
Treatment outcomes of amantadine in children and adolescents, overall and by diagnosis
| Diagnosis | Total | Success | Minimal | Failure | SE D/C |
|---|---|---|---|---|---|
| Full study group | 297 | 185 (62.3%) | 61 (20.5%) | 34 (11.4%) | 17 (5.7%) |
| ADHD | 251 | 162 (64.5%) | 52 (20.7%) | 27 (10.8%) | 10 (4.0%) |
| ODD/CD | 190 | 114 (60%) | 43 (22.6%) | 19 (10%) | 14 (7.4%) |
| Depressive disorder | 36 | 24 (66.7%) | 10 (27.8%) | 2 (5.6%) | 0 |
| Anxiety disorder/OCD | 92 | 62 (67.4%) | 17 (18.5%) | 9 (9.8%) | 4 (4.4%) |
| Autistic spectrum disorder | 59 | 40 (67.8%) | 12 (20.3%) | 2 (3.4%) | 5 (8.5%) |
| PTSD | 18 | 10 (55.6%) | 2 (11.1%) | 6 (33.3%) | 0 |
| Intellectual disability | 43 | 28 (65.1%) | 10 (23.3%) | 4 (9.3%) | 1 (2.3%) |
ADHD indicates attention deficit/hyperactivity disorder (combined and inattentive); OCD, obsessive-compulsive disorder; ODD/CD, oppositional defiant disorder/conduct disorder; PTSD, posttraumatic stress disorder; SE D/C, side effect discontinuation.
For treatment success, the median dose of amantadine was 200 mg daily; 13 patients needed 100 mg daily or less, whereas 12 patients needed as much as 400 mg daily. Most patients had multiple psychiatric comorbidities, with ADHD and oppositional defiant disorder/conduct disorder being the most common (Table 2). Amantadine success and partial success rates were similar across all diagnoses. Except for posttraumatic stress disorder (6 out of 18 failures, 33%), failure rates were also similar across all diagnoses (Table 1).
Table 2.
Comorbidities by psychiatric diagnosis for patients taking amantadine
| ADHD | ODD/CD | Depressive disorder | Anxiety/OCD | Autistic disorder | PTSD | ID | |
|---|---|---|---|---|---|---|---|
| ADHD (n = 251) | – | 160 (64%) | 33 (13%) | 82 (33%) | 44 (18%) | 15 (6%) | 34 (14%) |
| ODD/CD (n = 190) | 160 (84%) | – | 25 (13%) | 61 (24%) | 22 (12%) | 8 (4%) | 24 (13%) |
| Depressive disorder (n = 36) | 33 (92%) | 25 (69%) | – | 10 (28%) | 2 (6%) | 1 (3%) | 4 (11%) |
| Anxiety/OCD (n = 92) | 82 (89%) | 61 (66%) | 10 (11%) | – | 11 (12%) | 3 (3%) | 12 (13%) |
| Autistic disorder (n = 59) | 44 (75%) | 22 (37%) | 2 (3%) | 11 (19%) | – | 1 (2%) | 11 (19%) |
| PTSD (n = 18) | 15 (83%) | 8 (44%) | 1 (6%) | 3 (17%) | 1 (6%) | – | 4 (22%) |
| ID (n = 43) | 34 (79%) | 24 (56%) | 4 (9%) | 12 (28%) | 11 (26%) | 4 (9%) | – |
ADHD indicates attention deficit/hyperactivity disorder; ID, intellectual disability; OCD, obsessive-compulsive disorder; ODD/CD, oppositional defiant disorder/conduct disorder; PTSD, posttraumatic stress disorder.
Eight out of 184 patients who were considered a treatment success were able to eventually discontinue amantadine because symptoms improved to the point that amantadine and any other psychotropic medications were no longer necessary. Clinician follow-up during the study interval found no indication that their symptoms relapsed, and neither amantadine nor any other psychotropic medication was restarted. No study patients were diagnosed with bipolar disorder because clinicians were aware of prior reports describing a switch to mania after amantadine initiation.24,25
We studied several specific symptom clusters across all diagnosis groups (Table 3). Amantadine treatment was most efficacious with impulsivity symptoms, with over 70% of patients reporting symptom improvement. Irritability/anger saw the next greatest improvement, at over 50%.
Table 3.
Reported symptom improvement by psychiatric diagnosis after amantadine
| Diagnosis | Impulsivity | Irritability/anger | Focus/concentration | Aggression/outbursts | Thought processing |
|---|---|---|---|---|---|
| ADHD (n = 214) | 176 (82%) | 112 (52%) | 109 (51%) | 63 (29%) | 44 (21%) |
| ODD/CD (n = 157) | 130 (83%) | 85 (54%) | 69 (44%) | 47 (30%) | 31 (20%) |
| Depressive disorder (n = 34) | 25 (74%) | 18 (53%) | 12 (35%) | 17 (50%) | 4 (12%) |
| Anxiety disorder/OCD (n = 79) | 65 (82%) | 44 (56%) | 29 (37%) | 13 (16%) | 24 (30%) |
| ASD (n = 52) | 41 (79%) | 29 (56%) | 28 (54%) | 7 (13%) | 10 (19%) |
| PTSD (n = 12) | 10 (83%) | 6 (50%) | 7 (58%) | 1 (8%) | 4 (33%) |
| Intellectual disability (n = 38) | 32 (84%) | 20 (53%) | 10 (26%) | 10 (26%) | 10 (26%) |
ADHD indicates attention deficit/hyperactivity disorder; ASD, autism spectrum disorder; OCD, obsessive-compulsive disorder; ODD/CD, oppositional defiant disorder/conduct disorder; PTSD, posttraumatic stress disorder.
We found that 114 of 297 patients (38.4%) completely discontinued or decreased the dosage by >50% of their existing psychotropic prescriptions after a successful or partially successful response to amantadine. Of the patients previously prescribed second- or third-generation antipsychotics who had successful or partial response to amantadine, 38 out of 83 (45.8%) were able to completely discontinue or reduce (aripiprazole being the most common). Patients taking nonstimulant medication (e.g., atomoxetine, guanfacine) approved for ADHD discontinued or reduced doses at a much higher rate (44.9%) compared to the discontinuation rate (19.2%) of stimulant medication (e.g., methylphenidate, amphetamine). Of note, 103 of 214 patients (48.1%) diagnosed with ADHD who responded to amantadine received combination therapy with a stimulant. Patients who had previously failed a Food and Drug Administration (FDA)–approved medication had good outcomes with amantadine; 63 of 72 patients (87.5%) who had failed stimulants and 56 of 62 (90.3%) who had failed guanfacine or atomoxetine achieved treatment success or partial success. Twenty-one of 75 patients (28.0%) were able to discontinue their selective serotonin reuptake inhibitor antidepressant medication.
Amantadine treatment responders experienced statistically significant improvements in BMI 1 year after antipsychotic reduction or discontinuation (4.5% reduction, P < 0.027) (Figure 1). Treatment responders remaining on antipsychotics experienced a mean 4% increase in BMI over this interval. The difference between remaining on or discontinuing antipsychotics for 1 year was on average thus close to 8% of total BMI, a substantial reduction. The BMI reduction for many patients started early after antipsychotic discontinuation or reduction, with 22 of 29 (75.9%) experiencing a net decrease in BMI and 13 of 29 (44.8%) experiencing a >5% decrease after 6 months.
Figure 1.
Effect of atypical antipsychotic dose reduction on body mass index (BMI). Doses of second- or third-generation antipsychotics were either not reduced (No) or reduced by 50% to 100% (R/DC) after initiating amantadine. BMI was calculated at the initial date of amantadine prescription and then at 12 months. *t test indicates antipsychotic reduction or discontinuation improved BMI over a 12-month interval (t = 2.30, P < 0.027).
DISCUSSION
The primary goals of this study were to report on amantadine’s utility and tolerability in child and adolescent psychiatric patients. A large majority reported at least partial symptom improvement on amantadine. Amantadine was most effective in decreasing symptoms of impulsivity, irritability, and anger and improving focus/concentration. Amantadine was well tolerated, with less than 6% discontinuing due to side effects. Most patients continued amantadine therapy for more than a year and <12% of patients discontinued amantadine due to lack of response. The median daily dose was 200 mg per day.15
Only 19% of patients were able to fully discontinue stimulant use, providing support for previous reports that amantadine is not as efficacious as stimulants in children with ADHD.7,8 Rather, the utility of amantadine in ADHD patients may be as an adjunct to stimulants or as a third-line therapeutic, with over 88% of patients who had previously failed FDA-approved ADHD medication achieving at least maintenance symptom control. Almost half of the patients who successfully responded to amantadine were able to continue a stimulant at lower doses.
Clinicians often utilize antipsychotics off-label for many child psychiatric conditions.26 These treatments have concerning side effects, including dyslipidemia, metabolic disorders, weight gain, and diabetes mellitus.27–31 We found that amantadine use in children who were previously prescribed antipsychotics allowed many of them (46%) to either completely discontinue or decrease dosages of antipsychotic by >50%. After 1 year of antipsychotic reduction or discontinuation, there was a statistically significant decrease in BMI, whereas those who did not decrease or discontinue antipsychotics had an increase in BMI. Previously, our group found oxcarbazepine to be effective in treating child psychiatric symptoms, with similar utility for reducing BMI in patients who were able to reduce dose or discontinue antipsychotics.32
The limitations of the present study are its nonrandomized, nonblinded design and data collection method based on clinician-reported assessments of symptoms. However, the findings are based on a large set of cases involving a wide range of psychiatric conditions treated in an academic medical center–based child health care system.
Overall, our study provides additional evidence demonstrating amantadine’s effectiveness in child psychiatry. Clinicians should consider amantadine as a useful off-label alternative for many psychiatric illnesses. Controlled clinical trials with large study populations comparing amantadine head-to-head to stimulants and antipsychotics are needed.
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