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Research and Evidence Backing Memantine (Namenda)

Frontier Health and Wellness (FHW) developed its memantine (Namenda) autism protocol to sit alongside guideline-consistent ASD care—not in place of it. AACAP practice parameters and SIGN guidelines emphasize comprehensive diagnostic assessment, multidisciplinary formulation, and behavioral/educational interventions as first-line care, with pharmacotherapy reserved for clearly defined target symptoms when benefits plausibly outweigh risks. Because glutamatergic agents (including memantine) are not guideline-recommended ASD treatments, FHW frames memantine as an explicitly off-label, adjunctive, time-limited, measurement-based trial offered only after diagnostic reconfirmation, comorbidity clarification, and baseline characterization consistent with standard-of-care expectations (Volkmar et al., 2014; SIGN 145, 2016).

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The research base for memantine in ASD is best understood as “mixed overall, but not uniform.” Systematic reviews and meta-analyses converge on low-to-very-low certainty evidence for broad, unselected ASD samples, with several larger RCT programs failing to meet primary efficacy endpoints at the group level (Brignell et al., 2022; Dessus-Gilbert et al., 2024; Aman et al., 2017; Hardan et al., 2019). FHW’s protocol was built on the observation—supported across mechanistic, open-label, adjunctive, and biomarker-enriched work—that efficacy signals appear more coherent when the intervention is aligned to a subset definition (e.g., augmentation contexts or glutamate-sensitive profiles) rather than treating the whole Autism spectrum as a single pharmacologic target. The Joshi et al. (2025) RCT, enriched for a glutamatergic biomarker-positive subgroup and showing a notably stronger social-impairment signal in those with elevated pgACC glutamate, was the key inflection point that justified moving from “theory” to a structured clinical protocol development process.

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Although this is not a comprehensive list of the research that was used to inform the development of this protocol and the GPS-A, it provides an appropriate foundation to present here.

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Clinical Guidelines

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Volkmar, F., Siegel, M., Woodbury-Smith, M., King, B., McCracken, J., State, M., & American Academy of Child and Adolescent Psychiatry (AACAP) Committee on Quality Issues (CQI) (2014). Practice parameter for the assessment and treatment of children and adolescents with autism spectrum disorder. Journal of the American Academy of Child and Adolescent Psychiatry, 53(2), 237–257. https://doi.org/10.1016/j.jaac.2013.10.013

  • No treatment protocol for ASD would be complete without the AACAP practice parameters—the benchmark for assessment and treatment emphasizing comprehensive, multidisciplinary evaluation and evidence-based behavioral/educational interventions as first-line care. This functions as standard-of-care comparator: glutamatergic agents like memantine are not guideline-recommended, so our protocol is framed as adjunctive, experimental use layered onto guideline-consistent care with transparent evidence gaps.

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Healthcare Improvement Scotland & Scottish Intercollegiate Guidelines Network (SIGN) (2016). Assessment, Diagnosis and Interventions for Autism Spectrum Disorders: A National Clinical Guideline. Edinburgh, Scotland: SIGN. https://www.sign.ac.uk/assets/sign145.pdf

  • Non-US analogue to AACAP: prioritizes structured interventions; recommends medications only for clearly defined target symptoms where benefits outweigh risks. Reinforces that glutamatergic drugs are not standard ASD care, positioning memantine use as carefully monitored, adjunctive, and explicitly off-label.

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Systematic Reviews & Meta-Analyses

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Brignell, A., Marraffa, C., Williams, K., & May, T. (2022). Memantine for autism spectrum disorder. The Cochrane database of systematic reviews, 8(8), CD013845. https://doi.org/10.1002/14651858.CD013845.pub2

  • Concludes that evidence from RCTs is low to very-low certainty but suggests memantine does provide possible benefit on core symptoms, with generally good tolerability; this informed FHW's decision frame a memantine protocol as a careful, time limited clinical trial aligned with current evidence strength.

Iffland, M., Livingstone, N., Jorgensen, M., Hazell, P., & Gillies, D. (2023). Pharmacological intervention for irritability, aggression, and self-injury in autism spectrum disorder (ASD). The Cochrane database of systematic reviews, 10(10), CD011769. https://doi.org/10.1002/14651858.CD011769.pub2

  • While not memantine exclusive, this review situates glutamatergic agents within the broader evidence base for behavioral dysregulation in ASD and supports the selection of memantine as an alternative or adjunct where traditional agents are only partially effective.

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Elshahawi, H. H., Taha, G. R. A., Azzam, H. M. E., El Ghamry, R. H., Abdelgawad, A. A. M., & Elshiekh, M. A. A. A. (2021). N-Methyl-d-aspartate (NMDA) receptor antibody in relation to autism spectrum disorder (ASD): presence and association with symptom profile. Middle East Current Psychiatry, 28(1), 62. https://doi.org/10.1186/s43045-021-00141-5

  • Elshahawi et al. (2021) measured serum anti-NMDA receptor antibodies in 80 children with ASD versus controls and found significantly higher prevalence (35% vs 5%) associated with more severe irritability, hyperactivity, stereotypy, and social withdrawal on ABC subscales. NMDA antibody-positive ASD patients showed a distinct symptom profile with prominent behavioral dysregulation and core social deficits, suggesting an autoimmune-mediated glutamatergic hypersensitivity phenotype potentially amenable to NMDA antagonism. For FHW's memantine protocol and GPS-A development, this study provided evidence that elevated NMDA receptor antibodies mark a severe, biologically-distinct ASD subgroup with glutamate-related pathophysiology—directly informing screening tool prioritization of patients with combined high irritability (>ABC-I 25) + social withdrawal + stereotypy as high-probability responders exhibiting glutamatergic signatures alongside the sensory-social-rigid cluster.

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Lee, S., Moon, H., & Kim, E. (2025). NMDAR dysfunction in autism spectrum disorders: Lessons learned from 10 years of study. Current Opinion in Neurobiology, 92, 103023. https://doi.org/10.1016/j.conb.2025.103023

  • Lee et al. (2025) synthesized a decade of mouse model research revealing predominant NMDAR hypofunction across multiple ASD genetic models (not hyperfunction), with abnormalities varying by mutation dosage, genetic background, sex, age, brain region, and cell type—emphasizing phenotypic heterogeneity as the key challenge. The review highlights social deficits, repetitive behaviors, and cognitive rigidity most consistently across models. For FHW's memantine protocol and GPS-A development, this authoritative 2025 synthesis supported NMDAR antagonism as mechanistically rational for ASD core symptoms while stressing that no single biomarker captures all responders, directly informing GPS-A's multi-domain approach (social + sensory + rigid) as the practical clinical solution to model heterogeneity.

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Dessus-Gilbert, M. L., Nourredine, M., Zimmer, L., Rolland, B., Geoffray, M. M., Auffret, M., & Jurek, L. (2024). NMDA antagonist agents for the treatment of symptoms in autism spectrum disorder: a systematic review and meta-analysis. Frontiers in pharmacology, 15, 1395867. https://doi.org/10.3389/fphar.2024.1395867

  • DessusGilbert et al. (2024) conducted a systematic review and meta-analysis of 10 randomized and quasi-experimental trials (588 participants) testing NMDA antagonist drugs (including memantine, amantadine, dcycloserine) for autism spectrum disorder. Across the three studies (248 participants) that reported core ASD symptom scales, NMDA antagonists were not superior to placebo for overall autism severity, social/communication, or repetitive behaviors. Meta-analysis of irritability and behavioral outcomes likewise found no clear efficacy signal, while pooled safety data from five studies (310 participants) showed a higher risk of experiencing at least one adverse event with NMDA antagonists versus placebo (OR about 2.0), though serious events were uncommon and rarely judged drug related. The authors conclude that current evidence is limited and low quality, insufficient to recommend NMDA antagonists for ASD symptoms or irritability in general, but they highlight persistent glutamatergic and NMDA receptor abnormalities in ASD and call for better designed, phenotype targeted trials, leaving room for more precise "glutamatergic subtype" approaches like FHW's protocol.

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Choi, W. S., Wang, S. M., Woo, Y. S., & Bahk, W. M. (2024). Therapeutic Efficacy and Safety of Memantine for Children and Adults With ADHD With a Focus on Glutamate-Dopamine Regulation: A Systematic Review. The Journal of clinical psychiatry, 86(1), 24r15507. https://doi.org/10.4088/JCP.24r15507

  • Synthesizes multiple memantine ADHD studies and reports that serious AEs were rare and overall tolerability in children was good, which you can cite as higherlevel safety evidence across heterogeneous pediatric samples.

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Aboul-Fotouh, S., Zohny, S. M., Elnahas, E. M., Habib, M. Z., & Hassan, G. A. (2025). Can memantine treat autism? Answers from preclinical and clinical studies. Neuroscience and Biobehavioral Reviews, 169, 106019. https://doi.org/10.1016/j.neubiorev.2025.10601

  • Aboul-Fotouh et al. (2025) conducted a narrative review synthesizing preclinical (animal models showing memantine reverses synaptic deficits, neuroinflammation, BDNF reduction, BBB leakage) and clinical evidence (mixed RCT results with social/repetitive behavior signals), concluding memantine shows promise for core ASD symptoms despite conflicting trial outcomes due to glutamate/GABA imbalance and excitotoxicity mechanisms. The review identifies optimal responders as those with prominent social interaction deficits, repetitive behaviors, and sensory abnormalities—precisely the GPS-A targeted phenotype—and notes consistent safety across pediatric studies. For FHW's memantine protocol and GPS-A development, this 2025 synthesis (pre-Joshi 2025 RCT) provided high-level confirmation that phenotype-specific memantine targeting is mechanistically and clinically justified, while honestly acknowledging the need for refined patient selection that GPS-A operationalizes through social/sensory/rigid composite scoring.

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SuchoÅ‚biak, K., et al. (2025). Could memantine be a treatment option for ADHD and ASD? Psychiatria Polska, 59(2), 175–181. 10.15557/PiPK.2025.0022

  • Narrative review summarizing memantine clinical data across ADHD and ASD; explicitly noting dose ranges, tolerability, and domains with the most consistent signal (social functioning, irritability, attention), useful as an UpToDate secondary source supporting the protocol's target symptom cluster.

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Memantine RCTs in ASD

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Joshi, G., Gönenc, A., DiSalvo, M., Faraone, S. V., Ceranoglu, T. A., Yule, A. M., Uchida, M., McDougle, C. J., & Wozniak, J. (2025). Memantine to Treat Social Impairment in Youths With Autism Spectrum Disorder: A Randomized Clinical Trial. JAMA network open, 8(10), e2534927. https://doi.org/10.1001/jamanetworkopen.2025.34927

  • Joshi et al. (2025) reported a double blind, randomized, placebo controlled trial of memantine in 121 youths with autism spectrum disorder (roughly school age through adolescence), enriched for a glutamatergic "biomarker positive" subgroup based on pregenual anterior cingulate cortex glutamate levels. Memantine produced significantly greater improvement than placebo on clinician rated social impairment (primary outcome), with the strongest effect in participants with elevated baseline glutamate, directly supporting a targeted, glutamatergic subtype approach to ASD treatment. The medication was generally well tolerated; adverse events were mostly mild to moderate (e.g., headache, irritability, gastrointestinal symptoms), and discontinuations for side effects were infrequent, reinforcing the pediatric safety profile at doses similar to FHW's memantine protocol.

  • This study peaked our attention and is primarily responsible for starting us on the process of developing our protocol. FHW's screening tool directly incorporates Joshi's pgACC glutamate enrichment strategy by prioritizing patients with severe social withdrawal + sensory/rigid features as glutamate-sensitive proxies, since direct MRS is not feasible clinically.

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Aman, M. G., Findling, R. L., Hardan, A. Y., Hendren, R. L., Melmed, R. D., Kehinde-Nelson, O., Hsu, H. A., Trugman, J. M., Palmer, R. H., Graham, S. M., Gage, A. T., Perhach, J. L., & Katz, E. (2017). Safety and Efficacy of Memantine in Children with Autism: Randomized, Placebo-Controlled Study and Open-Label Extension. Journal of child and adolescent psychopharmacology, 27(5), 403–412. https://doi.org/10.1089/cap.2015.0146

  • Aman et al. (2017) report a large, multicenter, double blind, randomized, placebo controlled trial of memantine in 6–12yearold children with autism, followed by an open label extension to further assess tolerability and durability of response. In the acute randomized phase, memantine did not demonstrate a statistically significant advantage over placebo on the primary outcome (change in core autism symptoms), which provides important evidence that broad, unselected pediatric ASD samples may not show robust group level benefit. Nonetheless, the study found that memantine was generally well tolerated, with adverse events mostly mild to moderate and similar in overall frequency to placebo, and the open label extension did not reveal new safety signals. This trial underlined that memantine is not an established, broadly effective ASD treatment while simultaneously supplying relatively strong pediatric safety data that was used to justify a carefully targeted, subtype focused, time limited trial rather than routine use.

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Hardan, A. Y., Hendren, R. L., Aman, M. G., Robb, A., Melmed, R. D., Andersen, K. A., Luchini, R., Rahman, R., Ali, S., Jia, X. D., Mallick, M., Lateiner, J. E., Palmer, R. H., & Graham, S. M. (2019). Efficacy and safety of memantine in children with autism spectrum disorder: Results from three phase 2 multicenter studies. Autism: the international journal of research and practice, 23(8), 2096–2111. https://doi.org/10.1177/1362361318824103

  • Hardan et al. (2019) pooled data from three phase 2, multicenter, randomized, double-blind, placebo-controlled trials of memantine (flexible dosing up to 20 mg/day) in children and adolescents with autism spectrum disorder (ages 6–17 years), assessing core symptoms, social responsiveness, and language function. The studies did not meet their primary endpoints for significant group-level superiority over placebo on ABC-Irritability or VABS-II social domain scores, providing rigorous evidence that memantine lacks broad-spectrum efficacy across unselected ASD populations. However, pooled safety analysis across 387 participants confirmed excellent tolerability, with adverse events (somnolence, cough, pyrexia) comparable to placebo rates and no new safety signals emerging even at higher doses or longer exposures. This makes the paper a cornerstone for protocol safety justification while honestly acknowledging efficacy limitations that necessitate phenotype selection and time-limited trials.

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Ghaleiha, A., Asadabadi, M., Mohammadi, M. R., Shahei, M., Tabrizi, M., Hajiaghaee, R., Hassanzadeh, E., & Akhondzadeh, S. (2013). Memantine as adjunctive treatment to risperidone in children with autistic disorder: a randomized, double-blind, placebo-controlled trial. The international journal of neuropsychopharmacology, 16(4), 783–789. https://doi.org/10.1017/S1461145712000880

  • Ghaleiha et al. (2013) conducted a randomized, double-blind, placebo-controlled trial of memantine (up to 20 mg/day) as an adjunct to risperidone in 40 children with autistic disorder (ages 4–12 years), focusing on core symptoms, irritability, and repetitive behaviors. Memantine augmentation produced significantly greater improvements than risperidone alone on clinician-rated autism severity (CGI-I), ABC-irritability subscale, and several core symptom domains, suggesting potential synergy for behavioral symptoms in antipsychotic-refractory or partially responsive ASD cases. Adverse events were comparable between groups (mild sedation, constipation), with no serious safety signals, providing pediatric tolerability data in a comorbid population. This study offered a positive efficacy signal in a specific context (adjunctive use) but was limited by small sample size, and foreign population, making it supportive rather than definitive evidence for broad memantine protocols.

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Karahmadi, M., Tarrahi, M. J., Vatankhah Ardestani, S. S., Omranifard, V., & Farzaneh, B. (2018). Efficacy of Memantine as Adjunct Therapy for Autism Spectrum Disorder in Children Aged <14 Years. Advanced biomedical research, 7, 131. https://doi.org/10.4103/abr.abr_100_18

  • Karahmadi et al. (2018) conducted a randomized, double-blind, placebo-controlled trial of memantine (up to 10 mg/day) added to risperidone versus risperidone alone in 42 Iranian children under age 14 with autism spectrum disorder, targeting irritability, hyperactivity, and stereotypies. The memantine group showed significantly greater reductions on ABC-Irritability, ABC-Hyperactivity/Noncompliance, and ABC-Stereotypy subscales compared to placebo, indicating potential benefit as an adjunct for behavioral symptoms in this age group. Side effects were mild and comparable across groups (e.g., sedation, constipation), with no discontinuations for adverse events, adding to the pediatric tolerability evidence base. Like the Ghaleiha (2013) study, this small single-site study provides another positive adjunctive signal but shares limitations with similar Iranian trials (e.g., modest sample, cultural/generalizability questions), positioning it as preliminary support rather than robust standalone evidence for memantine monotherapy protocols.

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Open-Label & Mechanistic ASD Studies

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He, J.L., Oeltzschner, G., Mikkelsen, M. et al. (2021). Region-specific elevations of glutamate + glutamine correlate with the sensory symptoms of autism spectrum disorders. Translational Psychiatry, 11, 411. https://doi.org/10.1038/s41398-021-01525-1

  • He et al. (2021) conducted proton magnetic resonance spectroscopy (MRS) in 49 children with ASD vs 43 controls, identifying significantly elevated glutamate+glutamine (Glx) specifically in sensorimotor cortex and superior temporal gyrus—regions implicated in sensory processing. Higher Glx levels directly correlated with parent-reported sensory processing difficulties (sensory profile scores), particularly sensory hyper-reactivity (sounds, lights, textures) and under-responsivity, establishing a neurochemical link between glutamatergic excess and the sensory phenotype in ASD. For FHW's protocol development, this study provided critical phenotypic guidance: sensory processing dysfunction can serve as a clinical proxy for glutamate dysregulation when advance neuroimaging is unavailable, informing screening tool criteria that prioritize patients with prominent sensory hyper/hypo-reactivity alongside social/rigid features as a strong signal for a glutamate-sensitive subtype. This bridges biomarker data (elevated Glx) to observable clinical traits (sensory symptoms), supporting a phenotype-driven memantine protocol.

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Brown, M. S., Singel, D., Hepburn, S., & Rojas, D. C. (2013). Increased glutamate concentration in the auditory cortex of persons with autism and first-degree relatives: a (1)H-MRS study. Autism Research, 6(1), 1–10. https://doi.org/10.1002/aur.1260

  • Brown et al. (2013) used proton MRS to measure glutamate in the auditory cortex of individuals with ASD, their first-degree relatives, and neurotypical controls, and found significantly elevated glutamate concentrations in both autistic participants and relatives compared with controls, suggesting a heritable glutamatergic abnormality associated with the broader autism phenotype. This region-specific glutamate increase was linked to auditory processing differences and social-communication traits, reinforcing the idea that sensory and communication abnormalities in ASD are partly driven by excitatory–inhibitory imbalance in sensory cortices. For FHW’s memantine protocol and GPS-A development, this study supports weighting auditory/sensory hyper- or hypo-responsivity and communication difficulties as clinical proxies for glutamatergic dysregulation, and it strengthens the argument that glutamate-related traits extend into first-degree relatives, consistent with a biologically grounded, trait-based screening approach rather than a pure diagnosis-based one.

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Johnson, A. J., Shankland, E., Richards, T., Corrigan, N., Shusterman, D., Edden, R., Estes, A., St John, T., Dager, S., & Kleinhans, N. M. (2023). Relationships between GABA, glutamate, and GABA/glutamate and social and olfactory processing in children with autism spectrum disorder. Psychiatry Research: Neuroimaging, 336, 111745. https://doi.org/10.1016/j.pscychresns.2023.111745

  • Johnson et al. (2023) conducted MRS in children with ASD (ages 7–13) and age-matched controls, measuring GABA, glutamate, and GABA/glutamate ratios in regions implicated in social and olfactory processing, and found altered GABA/glutamate ratios specifically correlated with impaired social cognition and olfactory identification ability. Higher glutamate levels and lower GABA/glutamate ratios were associated with poorer performance on social tasks (e.g., Reading the Mind in the Eyes) and olfactory processing, establishing social cognition + sensory integration deficits as downstream markers of E/I imbalance in ASD. For FHW's memantine protocol and GPS-A screening tool development, this study provides direct evidence linking combined social cognition and multi-sensory processing impairments to glutamatergic dysregulation, supporting composite screening criteria that require both social deficits AND sensory dysfunction as high-yield glutamate-sensitive phenotype screening markers.

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Rojas, D. C. (2014). The role of glutamate and its receptors in autism and the use of glutamate receptor antagonists in treatment. Journal of Neural Transmission, 121(8), 891–905. https://doi.org/10.1007/s00702-014-1216-0

  • Rojas (2014) provides a comprehensive review synthesizing MRS evidence of elevated glutamate concentrations across multiple cortical regions (auditory cortex, temporal lobe, frontal regions) in ASD, alongside genetic findings of glutamate receptor abnormalities (GRIN2B, metabotropic receptors) and animal model data showing glutamatergic disruption of synaptic pruning and E/I balance. The paper specifically synthesizes emerging clinical trial data on glutamate receptor antagonists (memantine, riluzole, others) and proposes glutamate-modulating pharmacotherapy as rational for ASD phenotypes with sensory processing abnormalities, repetitive behaviors, and social withdrawal, while acknowledging inconsistent trial results due to patient heterogeneity. For FHW's memantine protocol and GPS-A development, Rojas provided the conceptual framework integrating biomarker (elevated cortical glutamate), genetic, and phenotypic (sensory-social-rigid) evidence to justify phenotype-specific screening rather than unselected treatment, establishing the scientific foundation for prioritizing patients with consistent, biologically-grounded glutamatergic dysfunction phenotypic patterns. Within the larger context of our research review, Rojas represented a pre-2014 synthesis that anticipated subsequent biomarker-social correlation findings (Joshi 2025 & He 2021), prophetically demonstrating that glutamate-targeting rationale was mechanistically sound years before positive clinical signals emerged.

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Naaijen, J., Zwiers, M., Amiri, H. et al. Fronto-Striatal Glutamate in Autism Spectrum Disorder and Obsessive Compulsive Disorder. Neuropsychopharmacol 42, 2456–2465 (2017). https://doi.org/10.1038/npp.2016.260

  • Naaijen, J., Zwiers, M., Amiri, H. et al. (2017) used proton MRS to compare fronto-striatal glutamate concentrations in youths with ASD, OCD, and typically developing controls. The study found elevated glutamate in the dorsal striatum and anterior cingulate/fronto-striatal circuitry in clinical groups, with glutamatergic abnormalities partially overlapping across ASD and OCD rather than being disorder specific. Importantly for phenotype work, higher striatal glutamate was associated with greater repetitive behaviors/compulsivity, supporting the idea that rigid, compulsive, and “stuck” behavioral presentations in ASD may reflect underlying fronto-striatal glutamatergic dysregulation. For FHW’s memantine protocol, this paper directly informed FHW’s GPS-A development logic by reinforcing a dimension-first phenotype strategy (weighting rigidity/compulsivity-style features and their functional signature) rather than relying on generic ASD severity or assuming a single neurochemical pattern across all ASD presentations.

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Cochran, D. M., Sikoglu, E. M., Hodge, S. M., Edden, R. A., Foley, A., Kennedy, D. N., Moore, C. M., & Frazier, J. A. (2015). Relationship among Glutamine, γ-Aminobutyric Acid, and Social Cognition in Autism Spectrum Disorders. Journal of child and adolescent psychopharmacology, 25(4), 314–322. https://doi.org/10.1089/cap.2014.0112

  • Cochran et al. (2015) conducted MRS in psychotropic-naïve children/adolescents with ASD (ages 7-14) and found elevated glutamine (Gln) and reduced GABA in frontal regions correlated with impaired social cognition (SRS Social Cognition subscale). Higher Gln/GABA ratios predicted poorer social awareness, theory of mind, and peer relationships, establishing an excitatory/inhibitory imbalance signature specifically for social dysfunction in ASD. The paper’s practical contribution to FHW’s conceptual model is that “glutamatergic involvement” may present less as a generic ASD marker and more as a pattern tied to social-cognition/social-communication impairment, potentially mediated by ACC physiology—and that MRS signal may be better reflected by glutamine (glutamate–glutamine cycling) rather than glutamate alone. This supports why a phenotype-informed screener (GPS-A) should weight how impairments manifest (e.g., overload-linked social withdrawal/poor social-cognitive efficiency) rather than simply counting DSM-level ASD symptoms, because the neurochemical signal appears linked to functional signature, not diagnosis label alone.

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Ford, T. C., Nibbs, R., & Crewther, D. P. (2017). Increased glutamate/GABA+ ratio in a shared autistic and schizotypal trait phenotype termed Social Disorganisation. NeuroImage: Clinical, 16, 125–131. https://doi.org/10.1016/j.nicl.2017.07.009

  • Ford et al. (2017) used MRS in neurotypical adults and identified a transdiagnostic "Social Disorganisation" phenotype (high autistic + schizotypal traits) characterized by elevated glutamate/GABA+ ratio in occipital cortex, specifically correlating with poor social cognition, communication difficulties, and disorganized interpersonal style. Unlike diagnosis-specific findings, this establishes social disorganization as a glutamate-driven behavioral dimension cutting across the neurodevelopmental spectrum. For FHW's GPS-A development, this paper provided validation that social dysfunction severity + disorganization (not just ASD diagnosis) marks glutamatergic dysregulation, directly informing screening tool construction to prioritize patients with specific patterns of social impairment alongside sensory/rigidity. It demonstrates conserved glutamate-social dysfunction biology across populations, supporting phenotype-based screening.

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Owley, T., Salt, J., Guter, S., Grieve, A., Walton, L., Ayuyao, N., Leventhal, B. L., & Cook, E. H., Jr (2006). A prospective, open-label trial of memantine in the treatment of cognitive, behavioral, and memory dysfunction in pervasive developmental disorders. Journal of child and adolescent psychopharmacology, 16(5), 517–524. https://doi.org/10.1089/cap.2006.16.517

  • Owley et al. (2006) conducted a 10week prospective open label trial of memantine in 18 individuals with pervasive developmental disorders (mostly children and adolescents) targeting cognitive, behavioral, and memory symptoms. Participants showed modest improvements on clinician and caregiver rated measures of irritability, hyperactivity, and social withdrawal, along with some gains in memory and language, although the uncontrolled design limits efficacy conclusions. Memantine was generally well tolerated; adverse effects were mostly mild (e.g., irritability, agitation, sedation) and rarely led to discontinuation, supporting preliminary pediatric safety at doses overlapping FHW's ASD protocols.

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Joshi, G., Wozniak, J., Faraone, S. V., Fried, R., Chan, J., Furtak, S., Grimsley, E., Conroy, K., Kilcullen, J. R., Woodworth, K. Y., & Biederman, J. (2016). A Prospective Open-Label Trial of Memantine Hydrochloride for the Treatment of Social Deficits in Intellectually Capable Adults With Autism Spectrum Disorder. Journal of clinical psychopharmacology, 36(3), 262–271. https://doi.org/10.1097/JCP.0000000000000499

  • 12week open label study in intellectually capable adults with ASD; memantine was associated with significant reductions on informant rated and clinician rated autism severity, and improvements in executive function and nonverbal communication, with good tolerability. Provides evidence that a glutamatergic approach is mechanistic as evidence can be found in support of it across the lifespan.

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Nair, N., Hegarty, J. P., 2nd, Cirstea, C. M., Gu, M., Appling, C. B., & Beversdorf, D. Q. (2022). Relationship Between MR Spectroscopy-Detected Glutamatergic Neurometabolites and Changes in Social Behaviors in a Pilot Open-Label Trial of Memantine for Adults With Autism

Spectrum Disorder. Frontiers in psychiatry, 13, 898006. https://doi.org/10.3389/fpsyt.2022.898006

  • Pilot open label memantine trial in adults correlated baseline glutamatergic MRS measures with social behavior change, supporting a biomarker informed, glutamatergic subtype approach similar to FHW's protocol concept. The MRS-social response correlation findings from this study informed FHW screening tool development by establishing social behavior as the key clinical readout for glutamate modulation efficacy.

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Uzunova, G., Hollander, E., & Shepherd, J. (2014). The role of ionotropic glutamate receptors in childhood neurodevelopmental disorders: autism spectrum disorders and fragile x syndrome. Current neuropharmacology, 12(1), 71–98. https://doi.org/10.2174/1570159X113116660046

  • Uzunova et al. (2014) reviewed converging evidence that ionotropic glutamate receptors (NMDA, AMPA, kainate) are dysregulated in autism spectrum disorder and fragile X syndrome, contributing to excitatory–inhibitory imbalance, synaptic plasticity abnormalities, and downstream behavioral symptoms. For the development of FHW's protocol, the key point was that the approach is mechanistic: it supports glutamatergic dysfunction as biologically plausible yet stops short of establishing that NMDA modulating drugs like memantine will be clinically effective in ASD populations as a whole. The authors highlight altered receptor expression, disrupted long term potentiation/depression, and animal models showing that correcting glutamatergic signaling can normalize aspects of social and cognitive behavior, all of which highlighted the need to define who might fall into this "glutamatergic subtype" for ASD. At the same time, they stress heterogeneity and the complexity of glutamate systems, which further argues that any memantine protocol should be framed as phenotype specific rather than a generalized ASD treatment.

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Wei, H., Dobkin, C., Sheikh, A. M., Malik, M., Brown, W. T., & Li, X. (2012). The therapeutic effect of memantine through the stimulation of synapse formation and dendritic spine maturation in autism and fragile X syndrome. PloS one, 7(5), e36981. https://doi.org/10.1371/journal.pone.0036981

  • Demonstrates in vitro and in vivo that memantine normalizes spine morphology and synaptogenesis in autism/fragile X models, mechanistically aligning with the rationale for targeting ASD patients with presumed glutamatergic excitotoxicity and synaptic immaturity. Provides conceptual support for a memantine treatment protocol at a mechanistic level.

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Pediatric Safety – Non-ASD Populations

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Findling, R. L., McNamara, N. K., Stansbrey, R. J., Maxhimer, R., Periclou, A., Mann, A., & Graham, S. M. (2007). A pilot evaluation of the safety, tolerability, pharmacokinetics, and effectiveness of memantine in pediatric patients with attention-deficit/hyperactivity disorder combined type. Journal of child and adolescent psychopharmacology, 17(1), 19–33. https://doi.org/10.1089/cap.2006.0044

  • 8week open label dose finding trial titrated to 10 vs 20 mg/day; no serious AEs, no discontinuations for AEs, most AEs mild and early; 20 mg/day better tolerated and more effective on ADHDIV and CGIS, providing pediatric PK and safety ranges useful for FHW's memantine protocol.

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Mohammadi, M. R., Mohammadzadeh, S., & Akhondzadeh, S. (2015). Memantine versus Methylphenidate in Children and Adolescents with Attention Deficit Hyperactivity Disorder: A Double-Blind, Randomized Clinical Trial. Iranian journal of psychiatry, 10(2), 106–114. PMID: 26884787. PMCID: PMC4752523

  • Double blind RCT found memantine improved ADHD symptoms with no significant difference from methylphenidate on parent scales; mild AEs were common but there were no serious safety signals, supporting comparative tolerability vs a standard pediatric psychotropic.

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Niemeyer, L., Mechler, K., Dittmann, R. W., Banaschewski, T., Buitelaar, J., Durston, S., & Häge, A. (2022). Memantine as treatment for compulsivity in child and adolescent psychiatry: Descriptive findings from an incompleted randomized, double-blind, placebo-controlled trial. Contemporary clinical trials communications, 29, 100982. https://doi.org/10.1016/j.conctc.2022.100982

  • Children were randomized to memantine (5–15 mg/day) vs placebo for 10 weeks; PAERS captured 163 AEs, only 20.2% drug related, mostly mild (sedation, stomach ache in single patients), no SAEs or discontinuations, explicitly concluding memantine was well tolerated and safe in this pediatric OCD/ASD group. Provides helpful information supporting safety in pediatric populations.

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Schiller, K., Berrahmoune, S., Dassi, C., Corriveau, I., Ayash, T. A., Osterman, B., Poulin, C., Shevell, M. I., Simard-Tremblay, E., Sébire, G., & Myers, K. A. (2023). Randomized placebo-controlled crossover trial of memantine in children with epileptic encephalopathy. Brain: a journal of neurology, 146(3), 873–879. https://doi.org/10.1093/brain/awac380

  • Memantine improved EEG abnormalities and seizures; neuropsychiatric data suggested improvements in ADHD/ASD like symptoms, and authors describe memantine as a safe and effective treatment with acceptable side effect profile in this medically complex pediatric population. Provides FHW with evidence to support the inclusion of medical complex cases with ASD in the memantine treatment protocol.

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Marimuthu, P., Varadarajan, S., Krishnan, M., Shanmugam, S., Kunjuraman, G., Ravinder, J. R., Arumugam, B., Alex, D., & Swaminathan, P. (2016). Evaluating the efficacy of memantine on improving cognitive functions in epileptic patients receiving anti-epileptic drugs: A double-blind placebo-controlled clinical trial (Phase IIIb pilot study). Annals of Indian Academy of Neurology, 19(3), 344–350. https://doi.org/10.4103/0972-2327.179971

  • Marimuthu et al. (2016) conducted a double-blind RCT showing memantine 10 mg daily over 16 weeks improved cognition in epileptic patients on anti-epileptic drugs with a favorable AE profile; although not pediatric, this aided FHW’s protocol development with additional long-term safety exposure data in neurologically vulnerable patients to better inform monitoring parameters.

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Bakhla, A. K., Verma, V., Soren, S., Sarkhel, S., & Chaudhury, S. (2013). An open-label trial of memantine in treatment-resistant obsessive-compulsive disorder. Industrial psychiatry journal, 22(2), 149–152. https://doi.org/10.4103/0972-6748.132930

  • Bakhla et al. (2013) conducted an open-label trial noting beneficial effects of memantine in refractory OCD, including pediatric cases, supporting that NMDA modulation can alleviate compulsive symptoms with generally manageable side effects; informed FHW protocol target symptom selection for patients with co-occurring rigidity/compulsivity.

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Choi, W. S., Wang, S. M., Woo, Y. S., & Bahk, W. M. (2024). Therapeutic Efficacy and Safety of Memantine for Children and Adults With ADHD With a Focus on Glutamate-Dopamine Regulation: A Systematic Review. The Journal of clinical psychiatry, 86(1), 24r15507. https://doi.org/10.4088/JCP.24r15507

  • Choi et al. (2024) conducted a systematic review synthesizing multiple memantine ADHD studies. This research review of pediatric trials argues that across multiple diagnoses, memantine at 10–20 mg/day (weight-adjusted where appropriate) has a consistent pattern of mild, early, and generally transient adverse effects, with very low serious AE rates and few discontinuations. The patient samples are often medically or psychiatrically complex (ADHD, OCD, DEE), suggesting tolerability even in higher-risk children, which informed FHW protocol safety parameters and dosing ranges.

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Supporting Protocols & Regulatory

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Häge, A., Banaschewski, T., Buitelaar, J. K., Dijkhuizen, R. M., Franke, B., Lythgoe, D. J., Mechler, K., Williams, S. C., Dittmann, R. W., & TACTICS Consortium (2016). Glutamatergic medication in the treatment of obsessive compulsive disorder (OCD) and autism spectrum disorder (ASD) - study protocol for a randomized controlled trial. Trials, 17(1), 141. https://doi.org/10.1186/s13063-016-1266-8

  • Häge et al. (2016) present a detailed multicenter randomized controlled trial protocol testing glutamatergic medications (including memantine) for youths with OCD and/or ASD, explicitly built around the hypothesis that a subset of these patients has clinically relevant glutamatergic dysregulation. The paper lays out strict inclusion criteria, stratification by diagnosis, standardized outcome measures, and a comprehensive safetymonitoring plan, demonstrating how a glutamatetargeted approach can be operationalized within rigorous trial methods. It also underscores the uncertainty of efficacy, and emphasizes the need to identify which phenotypes or biomarker profiles actually benefit, which aligns with the implementation of a "glutamatergic subtype" memantine protocol. Of additional value, FHW adapted Häge's strict inclusion criteria and phenotype stratification approach for our screening tool, requiring clear target symptoms and a degree of clinical stability before memantine initiation.

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A Study of Memantine Hydrochloride (Namenda®) for Cognitive and Behavioral Impairment in Adults With Pervasive Developmental Disorders. ClinicalTrials.gov Identifier: NCT01333865. https://clinicaltrials.gov/study/NCT01333865

  • Unpublished clinical trial: Provides detailed inclusion criteria, dosing schedule, and primary outcome (CGIPDD improvement) for adults aged 18–50 with PDD/ASD. This provided supporting evidence for feasibility and safety of adult dosing similar to FHW’s protocol, even though full peer reviewed results are limited.

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Forest Pharmaceuticals, Inc. Namenda (memantine hydrochloride) tablets; Namenda XR (memantine hydrochloride) extended-release capsules. Prescribing information. US Food and Drug Administration; 2023.

  • The manufacturer’s prescribing information served as a safety and dosing “ceiling” for the protocol, anchoring pediatric titration schedules to well characterized adult Alzheimer’s regimens so that target doses did not exceed established exposure ranges. It informed key exclusion and caution criteria—renal impairment, seizure history, and potential drug–drug interactions—so that higher risk youth can be screened out or titrated more slowly in line with label warnings. Large adult trial safety tables helped shaped how expected adverse effects were framed (e.g., dizziness, headache, constipation, confusion) and set up monitoring/check-in points to catch these early, even though the indication and population differ. Finally, because the label makes clear that memantine is not approved for ASD or pediatric use, it heightened the need to establish to patients and families that the protocol represents an off label, time limited, exploratory trial with informed consent that explicitly addresses the gap between regulatory evidence and the ASD use case.

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FHW’s safety justification is intentionally conservative and rests on a relatively consistent theme across the pediatric literature: while efficacy is heterogeneous, tolerability is generally predictable and serious adverse events are uncommon at studied dose ranges. The larger ASD trials that were non-supportive for efficacy nonetheless provide the strongest pediatric tolerability base, with adverse events typically mild-to-moderate and broadly comparable to placebo and no novel safety signals emerging in pooled analyses and extensions (Aman et al., 2017; Hardan et al., 2019). This aligns with additional pediatric experience outside ASD (e.g., ADHD, compulsivity/OCD-spectrum, epileptic encephalopathy), where memantine is repeatedly described as well tolerated with low serious AE rates (Findling et al., 2007; Mohammadi et al., 2015; Niemeyer et al., 2022; Schiller et al., 2023; Choi et al., 2024). FDA labeling and known cautions (e.g., renal considerations, interaction risks with certain NMDA-active agents, and other label-specified warnings) were used as a “ceiling” and monitoring anchor, reinforcing a safety-first posture even while our clinical target differs (Forest/FDA prescribing information, 2023).

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The clinical logic of the FHW protocol is therefore not “memantine works for autism in general,” but rather: (1) ASD neurobiology plausibly implicates glutamatergic dysregulation in an ASD subset (Uzunova et al., 2014; Wei et al., 2012), (2) broad-sample trials dilute subgroup effects and yield mixed/negative aggregate efficacy signals, and (3) when trials are phenotype- or biomarker-aligned—or when used as augmentation in more narrowly defined contexts—the signal can be more robust (Ghaleiha et al., 2013; Karahmadi et al., 2018; Joshi et al., 2025). Because the biomarker stratification used in research is not clinically accessible for most families, FHW filled that translational gap by creating a structured, phenotype-informed screening-and-tracking workflow and pairing it with a time-limited, stop/continue decision framework grounded in standardized outcomes and consistent safety monitoring. This approach is designed to be transparent about uncertainty, minimize iatrogenic risk, and avoid “open-ended off-label prescribing” while allowing carefully selected patients to access a potentially meaningful option in the present rather than waiting years for commercialization and validation of clinical stratification tools.

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