Background
Autism spectrum disorder (autism) is a condition that begins in childhood. Core symptoms include persistent difficulties with social communication (e.g. difficulties with back-and-forth conversations, communication without words, and in developing and maintaining relationships), and repetitive and restricted interests and behaviours (e.g. repetitive mannerisms, restricted interests and behaviours, resistance to change and sensory sensitivities). Around 1% to 2% of children have autism. Autistic people often have other conditions such as attention deficit hyperactivity disorder (ADHD), anxiety, language impairments (e.g. difficulties understanding and using grammar) and intellectual disability. Autism can have negative impacts on quality of life, school achievement and social relationships. Memantine is a medication traditionally used to treat dementia, but some studies suggest that it may decrease core autistic symptoms. If memantine is being used to change the core symptoms of autism, it is important to assess whether it works and is safe. This review combines the research evidence on the use of memantine in autism.
Review question
Does memantine change the core symptoms of autism and related behaviours?
Search date
The evidence is current to 14 February 2022.
Study characteristics
We found three studies with 204 people that had evaluated the effectiveness of memantine in autism. All studies were randomised controlled trials, meaning participants were randomly allocated to receive either the treatment or a dummy pill (placebo). This is the best design for assessing the effectiveness of treatments. All three studies included children diagnosed with autism spectrum disorder, with an average age of 9.40 years. We found no studies in adults. The children received memantine (for 12 weeks in two studies and for 24 weeks in one study), and their behaviour was assessed before treatment and immediately after treatment.
Study funding sources
One study was sponsored and funded by a laboratory that makes memantine (Forest). The study sponsor helped to design the study, collect information, analyse and interpret the information, and take the decision to publish the results. The authors of the other two smaller studies said they did not receive any funding; though in one of these studies, Forest Pharmaceuticals provided the medicine for free.
Key results
It is unclear if memantine makes any difference to the core symptoms of autism. Additionally, there may be no difference between memantine and placebo in the occurrence of side effects, language ability, memory, adaptive behaviour or the autism-related behaviours of hyperactivity and irritability.
Limitations of the evidence
We are not confident about the evidence for core symptoms of autism because it comes from only three small studies; because the studies included different types of people and delivered the medicine in different ways; and because the studies did not always provide information about everything we were interested in. Additionally, we have little confidence in the evidence on side effects and language because it comes from only two small studies; and we have little confidence in the evidence on intelligence, memory, adaptive behaviour, hyperactivity and irritability, because it comes from only one small study.
It is unclear whether memantine is an effective treatment for autistic children. None of the three included trials reported on the effectiveness of memantine in adults. Further studies using rigorous designs, larger samples, longer follow-up and clinically meaningful outcome measures that are important to autistic people and their families will strengthen our knowledge of the effects of memantine in autism.
Autism spectrum disorder (ASD; also known as autism) is a developmental disability that begins in childhood and is typically seen in around 1% to 2% of children. It is characterised by social communication difficulties and repetitive and restricted behaviours and routines that can have a negative impact on a child's quality of life, achievement at school, and social interactions with others. It has been hypothesised that memantine, which is traditionally used to treat dementia, may be effective in reducing the core symptoms of autism as well as some co-occurring symptoms such as hyperactivity and language difficulties. If memantine is being used to treat the core symptoms of autism, it is important to review the evidence of its effectiveness.
To assess the effects of memantine on the core symptoms of autism, including, but not limited to, social communication and stereotypical behaviours.
We searched CENTRAL, MEDLINE, Embase, nine other databases and three trials registers up to February 2022. We also checked reference lists of key studies and checked with experts in the field for any additional papers. We searched for retractions of the included studies in MEDLINE, Embase, and the Retraction Watch Database. No retractions or corrections were found.
We included randomised controlled trials (RCTs) of any dose of memantine compared with placebo in autistic people. We also included RCTs in which only one group received memantine, but both groups received the same additional therapy (e.g. a behaviour intervention).
We used standard Cochrane methods. Our primary outcomes were core autism symptoms and adverse effects. Secondary outcomes were language, intelligence, memory, adaptive behaviour, hyperactivity, and irritability. We used GRADE to assess certainty of evidence.
We included three RCTs (two double-blind and one single-blind) with 204 participants that examined the short-term effect (immediately postintervention) of memantine in autistic people. Two studies took place in the USA and the other in Iran. All three studies focused on children and adolescents, with a mean age of 9.40 (standard deviation (SD) 2.26) years. Most participants were male (range across studies 73% to 87%). The diagnosis of ASD was based on the Diagnostic and Statistical Manual of Mental Disorders (4th edition; 4th edition, text revision; or 5th edition). To confirm the diagnosis, one study used the Autism Diagnostic Observation Schedule (ADOS) and the Autism Diagnostic Interview-Revised (ADI-R); one used ADOS, ADI-R or the Autism Diagnostic Interview Screener; and one used the Gilliam Autism Rating Scale. Dosage of memantine was based on the child's weight and ranged from 3 mg to 15 mg per day.
Comparisons
Two studies examined memantine compared with placebo; in the other study, both groups had a behavioural intervention while only one group was given memantine.
Risk of bias
All studies were rated at high risk of bias overall, as they were at high or unclear risk of bias across all but four domains in one study, and all but two domains in the other two studies. One study was funded by Forest Laboratories, LLC, (Jersey City, New Jersey), Allergan. The study sponsor was involved in the study design, data collection (via contracted clinical investigator sites), analysis and interpretation of data, and the decision to present these results. The other two studies reported no financial support or sponsorship; though in one of the two, the study medication was an in-kind contribution from Forest Pharmaceuticals.
Primary outcomes
There was no clear evidence of a difference between memantine and placebo with respect to severity of core symptoms of autism, although we are very uncertain about the evidence. The standardised mean difference in autism symptoms score in the intervention group versus the control group was –0.74 standard deviations (95% confidence interval (CI) −2.07 to 0.58; 2 studies, 181 participants; very low-certainty evidence; medium effect size); lower scores indicate less severe autistic symptoms. Two studies (144 participants) recorded adverse effects that the authors deemed related to the study and found there may be no difference between memantine and placebo (odds ratio (OR) 0.64, 95% CI 0.17 to 2.39; low-certainty evidence).
Secondary outcomes
There may be no difference between memantine and placebo on language (2 studies, 144 participants; low-certainty evidence); memory or adaptive behaviour (1 study, 23 participants; both low-certainty evidence); or hyperactivity or irritability (1 study, 121 participants; both low‐certainty evidence).