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Autism
Doyle CA, McDougle CJ. Pharmacotherapy to control behavioral symptoms in children with autism. Expert Opinion. Pharmacother. 2012;13(11):1615‐1629. doi:10.1517/14656566.2012.674110
Abstract
INTRODUCTION: Autistic disorder, Asperger's disorder, and pervasive developmental disorder not otherwise specified (PDD-NOS) are pervasive developmental disorders (PDDs) frequently associated with behavioral symptoms that may require pharmacotherapy to manage.
AREAS COVERED: Behavioral symptoms in children with autism include interfering repetitive behaviors, irritability, and hyperactivity and inattention, among others. The psychotropic medications examined in this review include: serotonin reuptake inhibitors, typical and atypical antipsychotics, medications used to treat attention-deficit/hyperactivity disorder, naltrexone, buspirone, divalproex sodium, lamotrigine, levetiracetam, memantine, mirtazapine, riluzole, pioglitazone, and topiramate.
EXPERT OPINION: For the treatment of interfering repetitive behaviors, serotonin reuptake inhibitors demonstrate less efficacy and are more poorly tolerated in children with autism compared to adults. Antipsychotics are the most efficacious drugs for the treatment of irritability in children with autism and other PDDs. For the treatment of hyperactivity and inattention, psychostimulants demonstrate some benefit. However, they are overall less efficacious and cause more side effects inchildren with PDDs compared to typically developing children with attention-deficit/hyperactivity disorder. Results from double-blind, placebo-controlled trials of these agents and others for the treatment of the behavioral symptom domains described above will be discussed in this review.
Campbell M, Adams P, Small AM, Tesch LM, Curren EL. Naltrexone in infantile autism. Psychopharmacol Bull. 1988;24(1):135‐139.
Campbell M, Overall JE, Small AM, et al. Naltrexone in autistic children: an acute open dose range tolerance trial. J Am Acad Child Adolesc Psychiatry. 1989;28(2):200‐206. doi:10.1097/00004583-198903000-00009
Abstract
The safety and efficacy of naltrexone was explored in an open acute dose range tolerance trial in 10 hospitalized autistic children, ages 3.42 to 6.50 years (mean, 5.04). Naltrexone was given in ascending doses: 0.5, 1.0, and 2.0 mg/kg/day. Behavioral side effects were observed as early as 1/2 hour after dosing. Ratings on the Children's Psychiatric Rating Scale showed that withdrawal was reduced across all three dose levels; administration of 0.5 mg/kg/day dose resulted in increased verbal production; and the 2.0 mg/kg/day dose resulted in reduction of sterotypies. Mild sedation of brief duration was the only side effect. Electrocardiogram, liver function tests, and all other laboratory studies remained unchanged throughout the study. These preliminary findings require replication in a larger sample of patients under double-blind and placebo controlled condition.
Campbell M, Anderson LT, Small AM, Locascio JJ, Lynch NS, Choroco MC. Naltrexone in autistic children: a double-blind and placebo-controlled study. Psychopharmacol Bull. 1990;26(1):130‐135.
Abstract
A double-blind, placebo-controlled study was designed to assess critically the effects of naltrexone on behavioral symptoms and learning in autistic children, and its safety. This is a preliminary report on 18 children, ages 3.08 to 7.99 years, who completed this ongoing study. Subjects were randomly assigned to naltrexone or placebo and received daily doses over a period of 21 days. Naltrexone was superior to placebo according to blind Clinical Global Consensus Ratings (unpublished scale). However, other behavioral rating measures did not confirm this result. There was only a suggestion that naltrexone reduced fidgety and hyperactive behavior and tended to alleviate overall symptomatology in older children. Naltrexone did not appear to affect discrimination learning. Results are preliminary and, owing to the small sample size, can be considered only suggestive until this study is completed or replication is obtained from independent research.
Taylor DV, Hetrick WP, Neri CL, Touchette P, Barron JL, Sandman CA. Effect of naltrexone upon self-injurious behavior, learning and activity: a case study. Pharmacol Biochem Behav. 1991;40(1):79‐82. doi:10.1016/0091-3057(91)90324-u
Abstract
Naltrexone significantly attenuated self-injurious behavior in a 20-year-old mildly retarded autistic male patient. The patient was videotaped daily and behavior was evaluated with a time-sampling procedure. Behavioral ratings of SIB frequency, SIB severity, and activity were collected automatically with a computerized system. Learning and memory were tested on a weekly basis with a modification of a paired associate learning test (PALT). Treatment with naltrexone resulted in (a) attenuation of SIB in the unstructured setting and (b) improvements in learning and memory without influencing activity levels
Panksepp J, Lensing P. Brief report: a synopsis of an open-trial of naltrexone treatment of autism with four children. J Autism Dev Disord. 1991;21(2):243‐249. doi:10.1007/BF02284764
Lensing P, Klingler D, Lampl C, et al. Naltrexone open trial with a 5-year-old-boy. A social rebound reaction. Acta Paedopsychiatr. 1992;55(3):169‐173.
Abstract
The neurobiological rationale for an opiate antagonist pharmacotherapy of autism is presented. Naltrexone efficacy in decreasing autistic behaviour and in increasing social-affiliative behaviour was explored in a 5-year-old autistic boy. Naltrexone (0.5 mg/kg 3 times peer week) was effective in immediately decreasing gross motor activity and stereotyped behaviour and caused a delayed increase of crying, smiling and rough-and-tumble play. This single case presents preliminary evidence that a therapeutically valuable rebound reaction is possible and that the human opioid system modulates social-affective processes. The possibility of psychological factors being instrumental in achieving this effect is discussed as being suitable for future clinical trials.
Leboyer M, Bouvard MP, Launay JM, et al. Brief report: a double-blind study of naltrexone in infantile autism. J Autism Dev Disord. 1992;22(2):309‐319. doi:10.1007/BF01058158
Abstract
This double-blind study compared 3 daily doses of naltrexone (0.5, 1.0, and 2.0 mg/kg) and placebo, each administered for 1 wk in random sequence to 4 autistic children (aged 4–19 yrs). The purpose was to determine whether the efficacy of naltrexone (NTX) could be predicted from blood levels of β-endorphin (β-EP), arginine vasopressin (AVP), or catecholamines (dopamine, norepinephrine [NE], and epinephrine). Results confirm the beneficial action of NTX, with the lowest dose providing optimal results. Elevated plasma β-EP concentration supported the existence of abnormalities of endogenous opioid dynamics in autistic children. Elevated levels of plasma β-EP, AVP, and NE were normalized during the NTX trial, raising the possibility that these abnormal biochemical parameters predict the efficacy of NTX in autism.
Lensing P, Klingler D, Panksepp J, et al. Opiathypothese zur Genese des frühkindlichen Autismus und Folgerungen zur Psychopharmakotherapie [Opiate hypothesis of the origin of early childhood autism and sequelae for psychopharmacotherapy]. Z Kinder Jugendpsychiatr. 1992;20(3):185‐196.
Hetrick WP, Krutzik MN, Taylor DV, Sandman CA, Rusu L, Martinazzi VP. Naltrexone has no hepatotoxic effects in a self-injurious patient with chronic hepatitis. J Clin Psychopharmacol. 1993;13(6):453‐454.
Ernst M, Devi L, Silva RR, et al. Plasma beta-endorphin levels, naltrexone, and haloperidol in autistic children. Psychopharmacol Bull. 1993;29(2):221‐227.
Abstract
Measured plasma beta-endorphin levels (BELs) in 13 autistic children (aged 3.67–11.67 yrs) at the end of treatment (naltrexone, haloperidol, pimozide, or placebo) and in 5 of the 13 Ss also at baseline. Baseline plasma BELs were lower than those reported in the literature. There was a strong correlation between plasma BELs and severity of stereotypies in all Ss. Naltrexone did not seem to have a specific effect on plasma BELs; short-term haloperidol treatment was associated with an increase, whereas long-term haloperidol treatment seemed to have a depressive effect on plasma BELs, which rose after withdrawal of haloperidol.
Leboyer M, Bouvard MP, Launay JM, et al. Une hypothèse opiacée dans l'autisme infantile? Essais thérapeutiques avec la naltrexone [Opiate hypothesis in infantile autism? Therapeutic trials with naltrexone]. Encephale. 1993;19(2):95‐102.
Abstract
The opioid hypothesis suggests that childhood autism may result from excessive brain opioid activity during neonatal period which may constitutionally inhibit social motivation, yielding autistic isolation and aloofness (Panksepp, 1979). Thishypothesis has now received strong support and is currently based on three types of arguments: (1) similarity betweenautistic symptomatology and abnormal behaviors induced in young animals by injections of exogenous opioids, such as increasing social aloofness and decreasing social vocalization; (2) direct biochemical evidence of abnormalities of peripheral endogenous opioids being reported in autism and (3) therapeutic effects of the long lasting opioid receptor blocking agentnaltrexone in autism. In this article, we give description of open and double-blind studies of naltrexone in autism. Naltrexonehas been tested in several open studies. We performed an open trial with naltrexone in 2 autistic girls, displaying serious self-injurious behavior, reduced crying and a marked preference for salty and spicy foods, symptoms that could be related to a dysfunction of the opioid system. With dosages of 1 mg/kg/day, we observed an immediate reduction of hyperactivity, self-injurious behavior and aggressiveness, while attention improved. In addition, social behaviors, smiling, social seeking behaviors and play interactions increased (Leboyer, Bouvard et Dugas, 1988). Campbell et al. (1988) has also reported a tranquilizing and a stimulating effect in 6 out of 8 children with autism. We did confirm these preliminary results in a double-blind study performed on 4 children with autism. In a cross-over double-blind study, three dosages of naltrexone (0.5, 1 and 2 mg/kg/day) and placebo were compared.(ABSTRACT TRUNCATED AT 250 WORDS)
Campbell M, Anderson LT, Small AM, Adams P, Gonzalez NM, Ernst M. Naltrexone in autistic children: behavioral symptoms and attentional learning. J Am Acad Child Adolesc Psychiatry. 1993;32(6):1283‐1291. doi:10.1097/00004583-199311000-00024
Abstract
Assessed the short-term efficacy and safety of naltrexone in 41 autistic child inpatients (aged 2.9–7.8 yrs) and its effects on discrimination learning in the laboratory. After a 2-wk placebo baseline period, Ss were randomly assigned either to naltrexone or to placebo for a period of 3 wks followed by a 1-wk posttreatment placebo period. Multiple raters and rating scales were employed in a variety of conditions. Naltrexone reduced hyperactivity on 3 different measures under 3 conditions. Naltrexone had no effect on discrimination learning in the laboratory; however, there was a suggestion that it had a beneficial effect on decreasing self-injurious behavior. Untoward effects were mild and transient.
Gonzalez NM, Campbell M, Small AM, et al. Naltrexone plasma levels, clinical response and effect on weight in autistic children. Psychopharmacol Bull. 1994;30(2):203‐208.
Abstract
Measured naltrexone (NLX) levels in plasma in 41 hospitalized autistic children (34 males, 7 females; aged 2.9–7.8 yrs), to assess the relationship between behavioral response to NLX levels, and the effects of NLX on weight. A double-blind, placebo-controlled, parallel groups design was used, with random assignment to NLX or placebo. NLX levels measured in 17 children ranged from 0.12 to 5.60 ng/mL. There was no relationship between plasma levels and age, level of intellectual functioning, scores on the 14 selected Children's Psychiatric Rating Scale (CPRS) items, Clinical Global Impressions, Global Clinical Consensus, and the CPRS hyperactivity factor. There was a trend for children receiving NLX in the highest weight percentile to lose weight but this was not the case for those in the lower weight percentiles.
Willemsen-Swinkels SH, Buitelaar JK, Weijnen FG, van Engeland H. Placebo-controlled acute dosage naltrexone study in young autistic children. Psychiatry Res. 1995;58(3):203‐215. doi:10.1016/0165-1781(95)02749-m
Abstract
In a double-blind, placebo-controlled crossover trial 23 autistic children were treated with a single 40-mg dose of the opiate antagonist naltrexone. Drug effects were monitored by detailed playroom observations, actometers, and parents' checklist ratings (Aberrant Behavior Checklist, social items and target behaviors). Naltrexone treatment failed to produce significant changes in social behavior, but it did reduce irritability and target scores on behavior checklists. The playroom data indicated that naltrexone significantly affected indices of activity and attention.
Bouvard MP, Leboyer M, Launay JM, et al. Low-dose naltrexone effects on plasma chemistries and clinical symptoms in autism: a double-blind, placebo-controlled study. Psychiatry Res. 1995;58(3):191‐201. doi:10.1016/0165-1781(95)02601-r
Abstract
The effect of month-long naltrexone (NTX) treatment at a daily oral dose of 0.5 mg/kg/day was contrasted with placebo (PLC) in a double-blind study with conjoint clinical and biochemical evaluations of therapeutic effects. Modest clinical benefits were achieved with both PLC and NTX, with marginally better overall results following NTX, and degree of improvement appeared to be related to plasma chemical profiles. Massively elevated levels of beta-endorphin were observed in all children with assays using C-terminal antibody but not with an N-terminal antibody assay. In addition, 70% of the children exhibited abnormally low levels of adrenocorticotropic hormone, and smaller subsets exhibited elevated norepinephrine (60%), arginine-vasopressin (50%), and serotonin (20%). The best clinical responders exhibited the clearest normalization of the elevated plasma chemistries, especially in C-terminal-beta-endorphin and serotonin. There was some evidence of therapeutic carry-over effects in both clinical and biochemical measures in those children who received NTX before PLC. The results suggest that NTX only benefits a subgroup of autistic children, who may be identified by the presence of certain plasma abnormalities. These results suggest a possible linkage between abnormal plasma chemistries, especially those related to the pro-opiomelanocortin system, and autistic symptoms.
Akkök F. The effects of naltrexone in autistic children: report of two cases. Turk J Pediatr. 1995;37(1):19‐23.
Abstract
This paper reports the observations associated with a brief course of administration of naltrexone (NTX) to two autistic children. One male and one female child, aged 5.3 and 4.4, respectively, completed the trial. The children were placed on NTX for two weeks for six administrations. The dose was 0.5 mg/kg. The Behavior Summarized Evaluation and Childhood Autism Scale were completed by the teacher and the social worker for baseline and post-experimentation observations. The patients' parents were asked to fill out the Parental Satisfaction Survey. Although the literature indicates that NTX is effective in some children, our observations confirm that NTX is effective in the two cases with different degrees of severity of disease.
Kolmen BK, Feldman HM, Handen BL, Janosky JE. Naltrexone in young autistic children: a double-blind, placebo-controlled crossover study. J Am Acad Child Adolesc Psychiatry. 1995;34(2):223‐231. doi:10.1097/00004583-199502000-00018
Abstract
OBJECTIVE: This study evaluated the efficacy and safety of naltrexone, an opiate blocker, in the treatment of autism.
METHOD: Thirteen children with autistic disorder, aged 3.4 to 8.3 years (mean 5.4), were studied in home, school, and outpatient laboratory. Naltrexone, 1.0 mg/kg, was given daily in a randomized, double-blind, placebo-controlled crossoverdesign. Dependent measures included parent and teacher Clinical Global Impressions (CGI), Conners Rating Scales, andNaltrexone Side-Effects (SE) Rating Scale; laboratory CGI, movement actometer readings, and a 10-second interval recording system analysis of on-task, communication initiations, disruptive behavior, and self-stimulation.
RESULTS: Eight of 13 subjects improved in two or more settings. Changes in parent measures (CGI, Conners Impulsivity-Hyperactivity Factor, and SE-Restlessness) and Teacher CGI achieved statistical significance. Teacher SE-Restlessness and initiation of communication in the clinic showed a trend toward improvement. Actometer readings improved in two childrenwho were very active at baseline. Adverse side effects were behavioral, mild, and transient. Administering the bitter tablet was a challenge.
CONCLUSIONS: Naltrexone offers promise as an agent for modest improvement of behavior and social communication inyoung children with autism. Parent and teacher measures can be useful in outpatient trials to evaluate change.
Willemsen-Swinkels SH, Buitelaar JK, van Engeland H. The effects of chronic naltrexone treatment in young autistic children: a double-blind placebo-controlled crossover study. Biol Psychiatry. 1996;39(12):1023‐1031. doi:10.1016/0006-3223(95)00297-9
Abstract
In a double-blind placebo-controlled crossover trial 23 autistic children, aged 3-7 years, were treated with a mean daily dosage of 1 mg/kg naltrexone for 4 weeks. Drug effects were monitored with behavior checklists rated by parents and teachers, and ethological playroom observations. On average, parents' checklists and playroom data could not differentiate between naltrexone treatment and placebo treatment; however, teachers significantly favored naltrexone treatment. They reported a decrease in hyperactivity and irritability. No effects of naltrexone on social and stereotypic behavior could be demonstrated.
Campbell M, Harris JC. Resolved: autistic children should have a trial of naltrexone. J Am Acad Child Adolesc Psychiatry. 1996;35(2):246‐251.
Scifo R, Cioni M, Nicolosi A, et al. Opioid-immune interactions in autism: behavioural and immunological assessment during a double-blind treatment with naltrexone. Ann Ist Super Sanita. 1996;32(3):351‐359.
Abstract
The emerging concept of opioid peptides as a new class of chemical messengers of the neuroimmune axis and the presence of a number of immunological abnormalities in infantile autism prompted us to correlate biological (hormonal and immunological) determinations and behavioural performances during treatment with the potent opiate antagonist, naltrexone (NAL). Twelve autistic patients ranging from 7 to 15 years, diagnosed according to DSM-III-R, entered a double-blind crossover study with NAL at the doses of 0.5, 1.0 and 1.5 mg/kg every 48 hours. The behavioural evaluation was conducted using the specific BSE and CARS rating scales NAL treatment produced a significant reduction of the autistic symptomatology in seven ("responders") out of 12 children. The behavioural improvement was accompanied by alterations in the distribution of the major lymphocyte subsets, with a significant increase of the T-helper-inducers (CD4+CD8-) and a significant reduction of the T-cytotoxic-suppressor (CD4-CD8+) resulting in a normalization of the CD4/CD8 ratio. Changes in natural killer cells and activity were inversely related to plasma beta-endorphin levels. It is suggested that the mechanisms underlying opioid-immune interactions are altered in this population of autistic children and that an immunological screening may have prognostic value for the pharmacological therapy with opiate antagonists.
Kolmen BK, Feldman HM, Handen BL, Janosky JE. Naltrexone in young autistic children: replication study and learning measures. J Am Acad Child Adolesc Psychiatry. 1997;36(11):1570‐1578. doi:10.1016/S0890-8567(09)66567-9
Abstract
OBJECTIVE: This study expanded upon previous work on naltrexone efficacy and safety in young autistic children and assessed performance on learning measures.
METHOD: Eleven children with autistic disorder, aged 3.0 to 8.3 years, were studied in home, school, and outpatient laboratory, bringing to 24 the combined study sample. Naltrexone, 1.0 mg/kg, was given daily in a randomized, double-blind, crossover design. Dependent measures were parent and teacher Clinical Global Impressions (CGI) and Naltrexone Side Effects Rating Scale (SE), Conners Parent Impulsivity/Hyperactivity Factor, Teacher Hyperactivity Factor, laboratory CGI, and analysis of videotaped behavior. Learning measures were the Early Intervention Developmental Profile-Language and paired-associate learning.
RESULTS: Comparisons between naltrexone and baseline, but not naltrexone and placebo, on parent and teacher ratings showed statistical significance. Three of 11 subjects improved in two or more settings. Side effects were mild. Administering naltrexone was a challenge. The combined study sample showed improvement on all parent measures and on Teacher CGI and SE-Restlessness compared with baseline and placebo. Eleven of the 24 children improved in two or more settings. Scores on learning measures did not change across conditions.
CONCLUSIONS: Naltrexone was associated with modest improvement of behavior in 11 of 24 children, but learning did not improve.
Sandman CA, Hetrick W, Taylor DV, Chicz-DeMet A. Dissociation of POMC peptides after self-injury predicts responses to centrally acting opiate blockers. Am J Ment Retard. 1997;102(2):182‐199. doi:10.1352/0895-8017(1997)102<0182:DOPPAS>2.0.CO;2
Abstract
Apparent insensitivity to pain, ritualistic patterns of behavior, and improvement in symptoms after administration of opiate receptor blockers implicated the endogenous opioid system in the initiation and maintenance of SIB. This study was designed to determine whether plasma levels of proopiomelanocortin (POMC)-derived peptides, beta-endorphin-like activity (beta E), ACTH, and adrenal cortisol immediately after an episode of SIB predicted subsequent response to an opiate blocker. Blood samples were collected from 10 patients with mental retardation within minutes of a self-injuring act and during an SIB-free control period. On another day, morning and afternoon samples were collected at least one week apart from the other samples. Effects on SIB of naltrexone hydrochloride (NTX) were examined in a double-blind, placebo-controlled crossover study. After an SIB episode, beta E, but not ACTH, was elevated compared with morning levels, p < .003. Patients with increased plasma levels of beta E after SIB had the most positive response to 2 mg/kg NTX, p < .03. Results suggest that changes in the hypothalamic-pituitary-adrenal axis after SIB may predict differences in individual patient response to opiate blockers.
Buitelaar JK, Willemsen-Swinkels S, Van Engeland H. Naltrexone in children with autism. J Am Acad Child Adolesc Psychiatry. 1998;37(8):800‐802. doi:10.1097/00004583-199808000-00006
Feldman HM, Kolmen BK, Gonzaga AM. Naltrexone and communication skills in young children with autism. J Am Acad Child Adolesc Psychiatry. 1999;38(5):587‐593. doi:10.1097/00004583-199905000-00021
Abstract
OBJECTIVE: To evaluate the effect of naltrexone on communication skills of young children with autism.
METHOD: Twenty-four children with autism, 3.0 to 8.3 years old (mean 5.1) who were living at home and attending appropriate school programs, participated in a randomized, double-blind, placebo-controlled, crossover trial. Naltrexone, 1.0 mg/kg, or placebo was administered daily for 2 weeks. Communication was evaluated from videotaped samples of seminaturalistic parent-child interaction. Child and parent language were assessed using similar measures.
RESULTS: In this heterogeneous sample, the median number of words the child produced on placebo was 9.5 (range 0-124). The median proportion of utterances with echolalia was 0.16. No differences were found between the naltrexone and placebo conditions in any of the measures of children or parents' communication. Significant correlations were found between the child's number of words and developmental quotient (Spearman rho = 0.58, p = .003) and between the child's and parent's number of words (rho = 0.55, p = .005).
CONCLUSIONS: Previous studies showed that naltrexone was associated with modest reduction in hyperactivity and restlessness in this group of children with autism. In this short-term study, the medication did not lead to improvement in communication, a core deficit of autism.
Cazzullo AG, Musetti MC, Musetti L, Bajo S, Sacerdote P, Panerai A. Beta-endorphin levels in peripheral blood mononuclear cells and long-term naltrexone treatment in autistic children. Eur Neuropsychopharmacol. 1999;9(4):361‐366. doi:10.1016/s0924-977x(99)00010-3
Riddle MA, Bernstein GA, Cook EH, Leonard HL, March JS, Swanson JM. Anxiolytics, adrenergic agents, and naltrexone. J Am Acad Child Adolesc Psychiatry. 1999;38(5):546‐556. doi:10.1097/00004583-199905000-00016
Abstract
OBJECTIVE: To review extant data on the efficacy and safety of anxiolytic medications (benzodiazepines, buspirone, and other serotonin 1A agonists), adrenergic agents (beta-blockers and alpha 2-adrenergic agonists clonidine and guanfacine), and the opiate antagonist naltrexone that have been used to treat various psychopathologies in children and adolescents. To identify critical gaps in our current knowledge about these agents and needs for further research.
METHOD: All available controlled trials of these medications in children and adolescents published in English through 1997 were reviewed. In addition, selected uncontrolled studies are included.
RESULTS: The major finding, that there are virtually no controlled data that support the efficacy of most of these drugs for the treatment of psychiatric disorders in children and adolescents, is both surprising and unfortunate. For some drugs, e.g., buspirone and guanfacine, this is because no controlled studies have been carried out in children and/or adolescents. For other drugs, e.g., clonidine and naltrexone, most of the placebo-controlled studies have failed to demonstrate efficacy.
CONCLUSIONS: The strongest recommendations for controlled studies of safety and efficacy in children and adolescents can be given for the following drugs: benzodiazepines for acute anxiety; buspirone (and newer serotonin 1A agonists as they become available) for anxiety and depression; beta-blockers for aggressive dyscontrol; guanfacine for attention-deficit/hyperactivity disorder; and naltrexone for hyperactivity, inattention, and aggression in autistic disorder.
Pao M. Lactose in buspirone. Letter to the Editor. J Am Acad Child Adolesc Psychiatry. 1999;38(11):1327. doi:10.1097/00004583-199911000-00001
Willemsen-Swinkels SH, Buitelaar JK, van Berckelaer-Onnes IA, van Engeland H. Brief report: six months continuation treatment in naltrexone-responsive children with autism: an open-label case-control design. J Autism Dev Disord. 1999;29(2):167‐169. doi:10.1023/a:1023000929040
Abstract
There is controversy about the status of naltrexone, an orally active opioid antagonist, in the treatment of autism. It has been posited that excessive activity of opioid systems in the brain is basic to autism and that opioid antagonists would be of therapeutic value (Panksepp, 1979). Double-blind placebo-controlled studies with naltrexone in children (Campbell et al., 1993; Kolmen, Feldman, Handen & Janosky, 1995, 1997; WillemsenSwinkels, Buitelaar, & Van Engeland, 1996; WillemsenSwinkels, Buitelaar, Weijnen, & Van Engeland, 1995) and adults (Willemsen-Swinkels, Buitelaar, Nijhof, & Van Engeland, 1995) with developmental disorders failed to find significant effects on social and communicative behavior. A remarkably consistent finding across all studies on children with autism was that treatment with naltrexone resulted in a modest reduction of hyperactivity. Since many subjects with autism present with concomitant symptoms of motor restlessness, it was recommended to offer these subjects a trial with naltrexone, and particularly those who failed to respond to treatment with neuroleptic agents (Campbell & Harris, 1996). We report here on a 6-month continuation treatment with naltrexone of six children who had shown to be responsive to naltrexone in a 4-week trial. The aim is to examine effectiveness and safety of naltrexone over a long period.
Aman MG, Langworthy KS. Pharmacotherapy for hyperactivity in children with autism and other pervasive developmental disorders. J Autism Dev Disord. 2000;30(5):451‐459. doi:10.1023/a:1005559725475
Abstract
We reviewed pharmacological treatments used in children with autism and PDD-NOS who present with hyperactive symptoms. Some 41 studies were identified from the following drug categories: antipsychotics (n = 13), serotonin reuptake inhibitors (n = 3), antianxiety drugs (n = 4), psychostimulants (n = 10), alpha adrenergic agonists (n = 2), opiate blockers (n = 7), and other drugs (n = 2). Empirical evidence for significant reductions in hyperactive symptoms was strongest for the antipsychotics, psychostimulants, and naltrexone. Most studies have focused on the reduction of overactivity, and more emphasis needs to be placed on distractibility and attentional variables. A theoretical model was proposed in which participants' attentional performance may be used to predict clinical response to psychostimulants. More carefully controlled and comprehensive studies of hyperactivity are badly needed in these children.
Sandman CA, Hetrick W, Taylor DV, et al. Long-term effects of naltrexone on self-injurious behavior. Am J Ment Retard. 2000;105(2):103‐117. doi:10.1352/0895-8017(2000)105<0103:LEONOS>2.0.CO;2
Abstract
A subgroup of self-injuring patients responds positively to the opiate-blocking agent naltrexone in acute, double-blind studies. In this study we examined the effects of naltrexone after acute treatment and the long-term effects of naltrexone on SIB. Rates of SIB were collected from pretreatment baseline; a second baseline a year after the acute trial; and a subsequent 12-month double-blind, placebo-controlled treatment. A subgroup of patients decreased SIB for a year without treatment after acute exposure to naltrexone. Five participants who decreased SIB by 70% after acute treatment increased SIB to the long-term treatment with naltrexone. In contrast, those for whom SIB increased over the one-year treatment hiatus decreased their SIB after the first long-term treatment. Discussion of these complex effects considered the role of background opioid levels, dosing, and treatment regimen of naltrexone and other factors limiting receptor adaptation among patients who exhibit SIB.
Symons FJ, Sutton KA, Bodfish JW. Preliminary study of altered skin temperature at body sites associated with self-injurious behavior in adults who have developmental disabilities. Am J Ment Retard. 2001 Jul;106(4):336-43.
Erratum in: Am J Ment Retard 2001 Sep;106(5):469
Abstract
In this study, the sensory status of 4 nonverbal adults with mental retardation and severe self-injury was examined using skin temperature measures prior to opiate antagonist treatment. Double-blind, placebo-controlled, experimental ABAB designs were used to evaluate the effects of naltrexone hydrochloride (1.5 mg/kg/day). For each participant, the body site targeted most frequently for self-injury was associated with altered skin temperature and reduced by naltrexone. In all cases, neither infrequent self-injury body sites nor non-self-injury body sites were associated with altered skin temperature. Further controlled studies are warranted to examine the value of assessing pain status and skin temperature in nonverbal patients with mental retardation and related developmental disabilities who present with tissue-damaging SIB.
Symons FJ, Tapp J, Wulfsberg A, Sutton KA, Heeth WL, Bodfish JW. Sequential analysis of the effects of naltrexone on the environmental mediation of self-injurious behavior. Exp Clin Psychopharmacol. 2001;9(3):269‐276. doi:10.1037//1064-1297.9.3.269
Abstract
Accumulated evidence shows that biology and the environment can mediate self-injurious behavior (SIB) in persons with mental retardation. Whether pharmacological treatment alters the environmental mediation of self-injury is unclear. Opioid antagonist effects on sequential dependencies for self-injury were studied in the context of experimental single-subject double-blind placebo-controlled designs. Direct observational data were collected for 4 adult subjects in real time on daily rate of SIB and staff interactions. Clinically significant reductions (i.e., > or = 33%) in SIB rate were observed for 3 of the 4 subjects. For all subjects, the magnitude of the sequential dependency between staff behavior and self-injury was significantly greater during treatment with naltrexone than during treatment with a placebo. Results are discussed in relation to behavioral mechanisms of action regulating medication effects for self-injury.
Symons FJ, Thompson A, Rodriguez MC. Self-injurious behavior and the efficacy of naltrexone treatment: a quantitative synthesis. Ment Retard Dev Disabil Res Rev. 2004;10(3):193‐200. doi:10.1002/mrdd.20031
Abstract
People with mental retardation, autism, and related developmental disabilities who self-injure are treated with a wide array of behavioral techniques and psychotropic medications. Despite numerous reports documenting short-term and some long-term changes in self-injury associated with the opiate antagonist naltrexone hydrochloride, no quantitative review of its efficacy has been reported. We conducted a quantitative synthesis of the peer-reviewed published literature from 1983 to 2003 documenting the use of naltrexone for the treatment of self-injurious behavior (SIB). Individual-level results were analyzed given subject and study characteristics. A sample of 27 research articles involving 86 subjects with self-injury was reviewed. Eighty percent of subjects were reported to improve relative to baseline (i.e., SIB reduced) during naltrexone administration and 47% of subjects SIB was reduced by 50% or greater. In studies reporting dose levels in milligrams, males were more likely than females to respond. No significant relations were found between treatment outcomes and autism status or form of self-injury. Results are discussed with respect to future efficacy work related to study outcomes and the pharmacological treatment of self-injury.
Elchaar GM, Maisch NM, Augusto LM, Wehring HJ. Efficacy and safety of naltrexone use in pediatric patients with autistic disorder. Ann Pharmacother. 2006;40(6):1086‐1095. doi:10.1345/aph.1G499
Abstract
OBJECTIVE: To review the efficacy and safety of naltrexone in pediatric patients with autistic disorder (AD).
DATA SOURCES: Using the terms pediatric, child, naltrexone, autism, and autistic disorder, a literature search was performed using MEDLINE (1966-May 18, 2006) and the International Pharmaceutical Abstracts (1971-May 18, 2006) database. The references of these articles were scanned for additional relevant literature.
STUDY SELECTION AND DATA EXTRACTION:All articles describing or evaluating the efficacy and/or safety of naltrexone in pediatric patients with AD were included in this review. Three case reports, 8 case series, and 14 clinical studies were identified as pertinent.
DATA SYNTHESIS: Naltrexone has been used most commonly at doses ranging from 0.5 to 2 mg/kg/day and found to be predominantly effective in decreasing self-injurious behavior. Naltrexone may also attenuate hyperactivity, agitation, irritability, temper tantrums, social withdrawal, and stereotyped behaviors. Patients may also exhibit improved attention and eye contact. Transient sedation was the most commonly reported adverse event. Small sample size, short duration, and inconsistent evaluative methods characterize the available research.
CONCLUSIONS: A child affected by AD may benefit from a trial of naltrexone therapy, particularly if the child exhibits self-injurious behavior and other attempted therapies have failed. Serious adverse effects have not been reported in short-term studies.
Parikh MS, Kolevzon A, Hollander E. Psychopharmacology of aggression in children and adolescents with autism: a critical review of efficacy and tolerability. J Child Adolesc Psychopharmacol. 2008;18(2):157‐178. doi:10.1089/cap.2007.0041
Abstract
BACKGROUND: Autism is characterized by a clinical triad of symptoms that affect social, language, and behavioral domains. Aggression and self-injury may be associated symptoms of autism and can result in significant harm to those affected as well as marked distress for their families. The precise nature of the relationship between aggressive or self-injurious behavior (SIB) and autism remains unclear and as a result, these symptoms are treated with a broad range of pharmacological approaches. This review seeks to systematically and critically examine the evidence for the pharmacological management of aggression and SIB in children with autism spectrum disorders.
METHOD: The entire PubMed database was searched for English language biomedical articles on clinical trials with medication in autism spectrum disorders. Studies were selected based on the following inclusion criteria: (1) randomized placebo-controlled trials; (2) a sample population that included children and adolescents; (3) at least one standardized assessment of aggression as a primary outcome measure of the study.
RESULTS: Twenty one trials with 12 medications were identified. Five medications produced significant improvement as compared to placebo, including tianeptine, methylphenidate, risperidone, clonidine, and naltrexone. Only risperidone and methylphenidate demonstrate results that have been replicated across at least two studies.
CONCLUSIONS: Although many medications have been studied under placebo-controlled conditions, few produce significant improvement. Additional placebo-controlled trials are needed to increase the number of therapeutic options available in the treatment of aggression in autism.
Rossignol DA. Novel and emerging treatments for autism spectrum disorders: a systematic review. Ann Clin Psychiatry. 2009;21(4):213‐236.
Abstract
BACKGROUND: Currently, only one medication (risperidone) is FDA-approved for the treatment of autism spectrum disorders (ASD). Perhaps for this reason, the use of novel, unconventional, and off-label treatments for ASD is common, with up to 74% of children with ASD using these treatments; however, treating physicians are often unaware of this usage.
METHODS: A systematic literature search of electronic scientific databases was performed to identify studies of novel and emerging treatments for ASD, including nutritional supplements, diets, medications, and nonbiological treatments. A grade of recommendation ("Grade") was then assigned to each treatment using a validated evidence-based guideline as outlined in this review: A: Supported by at least 2 prospective randomized controlled trials (RCTs) or 1 systematic review. B: Supported by at least 1 prospective RCT or 2 nonrandomized controlled trials. C: Supported by at least 1 nonrandomized controlled trial or 2 case series. D: Troublingly inconsistent or inconclusive studies or studies reporting no improvements. Potential adverse effects for each treatment were also reviewed.
RESULTS: Grade A treatments for ASD include melatonin, acetylcholinesterase inhibitors, naltrexone, and music therapy. Grade B treatments include carnitine, tetrahydrobiopterin, vitamin C, alpha-2 adrenergic agonists, hyperbaric oxygen treatment, immunomodulation and anti-inflammatory treatments, oxytocin, and vision therapy. Grade C treatments for ASD include carnosine, multivitamin/mineral complex, piracetam, polyunsaturated fatty acids, vitamin B6/magnesium, elimination diets, chelation, cyproheptadine, famotidine, glutamate antagonists, acupuncture, auditory integration training, massage, and neurofeedback.
CONCLUSIONS: The reviewed treatments for ASD are commonly used, and some are supported by prospective RCTs. Promising treatments include melatonin, antioxidants, acetylcholinesterase inhibitors, naltrexone, and music therapy. All of the reviewed treatments are currently considered off-label for ASD (ie, not FDA-approved) and some have adverse effects. Further studies exploring these treatments are needed. Physicians treating children with an ASD should make it standard practice to inquire about each child's possible use of these types of treatments
Desjardins S, Doyen C, Contejean Y, Kaye K, Paubel P. Traitement d'un enfant autiste par la naltrexone [Treatment of a serious autistic disorder in a child with Naltrexone in an oral suspension form]. Encephale. 2009;35(2):168‐172. doi:10.1016/j.encep.2008.01.004
Abstract
CLINICAL BACKGROUND: Autism is a developmental disorder that is usually diagnosed in early childhood. According to ICD-10 criteria, autism can be characterized by delays in language skills, by impaired social interaction, verbal or non-verbal communication and by repetitive, stereotyped or severely restricted activities and interests. The causes of autism are not yet elucidated, but both genetics and environment seem to play a role in 10 to 25% of autism cases. Several biochemical abnormalities, such as impairment of serotoninergic, catecholinergic, dopaminergic, and opioid systems have been reported. Autism therapies are designed to treat symptoms, and medication can be associated with psychoeducational and environmental interventions. Generally, the medications that are currently used are not intended for autism, and must be used with caution and selected according to the type and intensity of symptoms. The most common medication consists of psychotropic therapies by administration of dopaminergic and/or serotoninergic receptor antagonists (haloperidol, risperidone, clomipramine). Several drugs, such as anxiolytics (buspirone), mood stabilisers (lithium, sodium valproate), vitamins (vitamins B6, B12) or opioid antagonists (naltrexone) can be prescribed, in second intention, in cases of severe behavioural disorders. The prescription of opioid antagonists is based on the possible implication of an opioid system disorder observed in some cases. Nevertheless, several clinical studies reveal its variable effectiveness. Naltrexone is a competitive antagonist of opioid receptors OPRM1, OPRD1 and OPRK1. In France, this drug is prescribed for treating opioid and alcohol dependence. Moreover, several studies describe naltrexone as a possible treatment of autistic children in cases of developmental disorder and hyperactivity.
CLINICAL CASE: In the Child and Adolescent Psychopathology Department of Sainte-Anne's Hospital, autistic children benefit from a multidisciplinary treatment program that sometimes includes the administration of psychotropic medication. One of these children presented with a severe autistic disorder according to the Childhood Autism Rating Scale (CARS). Considering ICD-10 criteria, he benefited from a multidisciplinary program, associating cognitive psychotherapy, psychomotor rehabilitation, speech therapy and educational intervention. However, persistent sleep disorder and motor instability led to successive prescriptions of several different psychotropic drugs. Initial treatment by thioridazine (10mg per day) followed by propericiazine (2.5mg per day) improved sleep, but was not efficient in reducing self-mutilating behaviour. A new treatment by risperidone (from 0.5mg to 1.5mg per day) was therefore chosen; however it lost its efficacy after five months. Finally, an anxiolytic (cyamemazine) and a thymoregulator (sodium valproate) were successively tried without yielding any clinical improvement. Owing to the persistence of communication difficulties, major instability, self-mutilating behaviour and heteroaggressiveness, treatment with naltrexone was subsequently chosen with parental consent. In France, naltrexone hydrochloride is only available in tablet form (Nalorex 50mg and Revia 50mg), which is not adapted to children at the efficient dose. Consequently, an oral suspension form marketed in Spain (Antaxone 50mg) was imported, having obtained the Afssaps' (the French drug administration) authorisation for its temporary use. The Connors and Nisonger scales were used as outcome measures of behavioural symptom change. The Conners scale is used to assess attention deficit and hyperactivity, whereas the Nisonger scale analyses social skills and behaviour disorders in children and adolescents with mental retardation. The onset of treatment, at a dose of 1mg/kg/day, led to a transitory increase in negative behaviour. However, a dose of 0.75mg/kg per day subsequently led to significant improvements, as shown by outcome measurements. Self-mutilating behaviour disappeared completely. Certain side effects were observed, namely transitory sedation at the beginning of treatment and moderate constipation.
CONCLUSION: This clinical case confirms that treatment of a serious autistic disorder in children using Naltrexone in oral suspension form is a potentially interesting therapeutic alternative for treating behavioural symptoms resistant to classical drug therapy.
Doyle CA, McDougle CJ. Pharmacotherapy to control behavioral symptoms in children with autism. Expert Opin Pharmacother. 2012;13(11):1615‐1629. doi:10.1517/14656566.2012.674110
Abstract
INTRODUCTION: Autistic disorder, Asperger's disorder, and pervasive developmental disorder not otherwise specified (PDD-NOS) are pervasive developmental disorders (PDDs) frequently associated with behavioral symptoms that may requirepharmacotherapy to manage.
AREAS COVERED: Behavioral symptoms in children with autism include interfering repetitive behaviors, irritability, and hyperactivity and inattention, among others. The psychotropic medications examined in this review include: serotonin reuptake inhibitors, typical and atypical antipsychotics, medications used to treat attention-deficit/hyperactivity disorder, naltrexone, buspirone, divalproex sodium, lamotrigine, levetiracetam, memantine, mirtazapine, riluzole, pioglitazone, and topiramate.
EXPERT OPINION: For the treatment of interfering repetitive behaviors, serotonin reuptake inhibitors demonstrate less efficacy and are more poorly tolerated in children with autism compared to adults. Antipsychotics are the most efficacious drugs for the treatment of irritability in children with autism and other PDDs. For the treatment of hyperactivity and inattention, psychostimulants demonstrate some benefit. However, they are overall less efficacious and cause more side effects inchildren with PDDs compared to typically developing children with attention-deficit/hyperactivity disorder. Results from double-blind, placebo-controlled trials of these agents and others for the treatment of the behavioral symptom domains described above will be discussed in this review.
Brown N, Panksepp J. Low-dose naltrexone for disease prevention and quality of life. Med Hypotheses. 2009;72(3):333‐337. doi:10.1016/j.mehy.2008.06.048
Abstract
The use of low-dose naltrexone (LDN) for the treatment and prophylaxis of various bodily disorders is discussed. Accumulating evidence suggests that LDN can promote health supporting immune-modulation which may reduce various oncogenic and inflammatory autoimmune processes. Since LDN can upregulate endogenous opioid activity, it may also have a role in promoting stress resilience, exercise, social bonding, and emotional well-being, as well as amelioration of psychiatric problems such a autism and depression. It is proposed that LDN can be used effectively as a buffer for a large variety of bodily and mental ailments through its ability to beneficially modulate both the immune system and the brain neurochemistries that regulate positive affect.