Main Research Findings

1) Patients receiving whole brain radiotherapy experienced a delayed time to cognitive decline, and reduced degeneration rate of memory, executive functioning, and processing speed following treatment with memantine.

2) Memantine has the potential to enhance auditory function, indicating that the compound may act as an additional treatment in schizophrenia, as well as facilitate learning and promote gains from auditory-based targeted cognitive training.

 

Selected Data

1) This clinical trial performed by researchers Brown et al, evaluated the potential neuroprotective effect of memantine in patients with brain metastases receiving whole-brain radiotherapy. Eligible participants were adults with a confirmed diagnosis of a solid malignancy within five years of enrollment and radiographically evident brain metastases on contrast-enhanced MRI, or CT if MRI was not feasible. Additional inclusion criteria required patients to have a Karnofsky Performance Status score of at least 70, indicating they were able to care for themselves, and stable systemic disease for the preceding three months. Laboratory values were used to screen for renal and hepatic function, with eligibility restricted to patients with serum creatinine ≤3 mg/dL, creatinine clearance ≥30 mL/min, total bilirubin ≤2.5 mg/dL, and blood urea nitrogen <20 mg/dL. A Mini-Mental State Examination score above 18 was also necessary, to ensure patients had sufficient cognitive function for assessment [1].

Patients were excluded if they had allergies to memantine, active substance abuse, chronic benzodiazepine use, or any severe comorbid conditions. Previous treatment for brain metastases with surgery or radiosurgery was allowed, but prior cranial external beam radiotherapy was not. Patients undergoing systemic therapy could participate if they had completed such treatment at least 14 days prior to the study, and they were required to delay any new chemotherapy until at least 14 days after the completion of radiotherapy. All patients gave informed consent, and the study protocol received approval from the institutional review boards of all participating centers.

The study design employed a randomized, placebo-controlled format using the Zelen allocation method. Patients were stratified by Recursive Partitioning Analysis class I or II, and whether they had undergone surgery/radiosurgery within eight weeks or had no prior surgical treatment. Within each stratum, patients were randomly assigned in a 1:1 ratio to receive either memantine or placebo [1].

The treatment protocol consisted of whole brain radiotherapy administered in 15 fractions of 2.5 Gy for a total dose of 37.5 Gy. Patients began taking the study drug no later than the third day of whole brain radiotherapy. Memantine or placebo was administered over 24 weeks, with a dose escalation schedule during the first four weeks. The initial dosage was 5 mg once daily in week 1, increasing to 5 mg twice daily in week 2, 10 mg in the morning and 5 mg in the evening in week 3, and reaching the target dose of 10 mg twice daily from week 4 onwards. Dosage adjustments were made based on renal function: it was reduced if creatinine clearance fell below 30 mL/min and withheld entirely if clearance dropped below 5 mL/min [1].

Participants underwent evaluations at baseline and at weeks 8, 16, 24, and 52 after starting the study drug. These assessments included neurological and physical exams, performance status measurements, brain imaging, laboratory testing including creatinine, BUN, and bilirubin, and neuropsychological testing. The neuropsychological battery assessed memory through the Hopkins Verbal Learning Test-Revised (HVLT-R), processing speed assessed by the Trail Making Test Part A, executive function evaluated by the Trail Making Test Part B, verbal fluency assessed by Controlled Oral Word Association, and general cognition evaluated by the MMSE. Previous research has demonstrated that changes in these metrics are associated with quality of life, independence, and clinical outcomes such as survival and disease progression [1].

The primary endpoint of the trial was the preservation of memory function, specifically delayed recall, as measured by the HVLT-R Delayed Recall at 24 weeks. Secondary endpoints included time to cognitive failure defined as the first instance of decline on any neurocognitive test, overall survival, progression-free survival, and adverse event assessment. Adverse events were reported using the Common Terminology Criteria for Adverse Events version 3.0.

The trial’s statistical foundation was based on previous studies showing a decline of 0.87 points in HVLT-R DR scores over 24 weeks following whole brain radiotherapy. It was hypothesized that memantine would mitigate this decline. Using a one-sided Wilcoxon rank-sum test with a significance level of 0.025, the study aimed for 80% power to detect this difference, requiring 221 patients per arm. To account for potential attrition, the target sample size was increased to 536 participants [1].

An intent-to-treat analysis was employed, including all randomized patients who met eligibility criteria. For patients unable to complete cognitive assessments due to neurological deterioration, the lowest possible scores were assigned. Additionally, missing values for surviving patients were imputed using the Markov chain Monte Carlo method. Cognitive performance was analyzed using both raw scores and standardized z scores. A composite score was derived from the average z scores of all cognitive tests, and decline was defined as either a 2-standard-deviation drop from baseline or a score change exceeding the Reliable Change Index.

Time to cognitive failure was analyzed using the cumulative incidence method, accounting for competing risks like disease progression and death. Gray’s test was applied to evaluate group differences at the 0.025 significance level. Cox proportional hazards models were used to estimate hazard ratios and 95% confidence intervals for treatment effects. For disease progression, criteria included a ≥50% increase in lesions ≤1 cm, ≥25% increase in lesions >1 cm, or new brain metastases. Death was also classified as progression. Progression-free and overall survival times were calculated using Kaplan–Meier methods, with group comparisons tested via a stratified log-rank test [1].

In summary, this randomized trial evaluated whether memantine could preserve cognitive function in patients undergoing whole brain radiotherapy for brain metastases. By including neurocognitive assessments, careful stratification, and detailed statistical analyses, the study aimed to determine if memantine could mitigate cognitive decline associated with cranial irradiation. The results of this trial contribute to understanding how best to protect brain function in patients with metastatic cancer undergoing radiation therapy [1].

2) This study, conducted by researchers Swerdlow et al, investigated the effects of the NMDA receptor antagonist, memantine, on auditory processing and learning in individuals with schizophrenia or schizoaffective disorder, as well as healthy subjects. Participants with schizophrenia were required to be on a stable regimen of antipsychotic medication for at least 30 days and diagnosed with either schizophrenia or depressed-type schizoaffective disorder. Both patients and healthy subjects were screened through phone or field interviews, including assessments for medical, psychiatric, and substance use history [2].

Participants who passed the initial screening completed an in-person evaluation, which included a confirmatory diagnostic interview, physical examination, electrocardiogram, vision and hearing tests; with exclusion for hearing detection thresholds over 40 dB at 1000 Hz, urine toxicology screening for drug use, and pregnancy testing. Those who qualified completed symptom assessments and baseline evaluations of reading ability through the Wide Range Achievement Test–Reading and neurocognitive function using the MATRICS Consensus Cognitive Battery (MCCB).

Participants were randomly assigned to one of two dosing sequences: receiving placebo first followed by memantine, or vice versa. Testing was conducted on two separate days, 7–10 days apart. On each test day, participants ingested a single 20 mg dose of memantine or a placebo. Approximately 4.5 to 7 hours after ingestion, participants were tested on a range of auditory processing measures designed to assess auditory discrimination, temporal resolution, and auditory learning [2].

Three primary tests were used to evaluate auditory fidelity: the Words-in-Noise (WIN) test, the Quick Speech-in-Noise (QuickSIN) test, and the Gaps-in-Noise (GIN) test. WIN and QuickSIN assess how well participants can understand speech over background noise, simulating real-world auditory challenges. WIN uses single-word stimuli, while QuickSIN uses full sentences, both embedded in four-talker babble noise at varying decibel levels. Participants repeated what they heard, and performance was measured as the number of correct repetitions. The maximum score was five correct per noise level, with expected ceiling effects in normal-hearing individuals at low noise levels and floor effects at high noise levels [2].

The GIN test evaluates auditory temporal resolution, or the ability to detect brief silent intervals within a continuous noise stream. This test, which is sensitive to central auditory deficits in schizophrenia, requires participants to identify gaps ranging from 2 to 20 milliseconds, presented within 6-second white noise bursts. Each gap duration was repeated six times, for a total of 60 gaps. Performance was based on the number of correctly identified gaps and a calculated gap detection threshold [2].

Auditory learning was assessed using the “Sound Sweeps” task from the PositScience BrainHQ platform. This task requires participants to identify the direction of pitch change as ascending or descending in frequency-modulated sound pairs. The task is adaptive, becoming more challenging following correct responses and easier after incorrect ones. Performance was measured in terms of auditory processing speed, with lower times indicating better performance. Each test day included one hour of Sound Sweeps training, and the key outcome was the change in auditory processing speed from baseline to the best performance during that session.

Two subjects with schizophrenia had maximum latency scores of 1000 ms both before and after training, regardless of treatment condition, and analyses were performed with and without these cases to assess their impact. In addition to performance metrics, subjective symptoms such as happiness, drowsiness, queasiness, dizziness, attentional focus, and anxiety, were recorded using visual analog Symptom Rating Scales at eight points during each test day. Auditory training was administered 265 minutes post-dose, followed by auditory discrimination and temporal processing tests 430 minutes post-dose [2].

The study’s primary hypothesis was that memantine would improve auditory processing in schizophrenia patients. Since these auditory tasks are not commonly used to evaluate pharmacological effects and previous evidence from other auditory paradigms such as mismatch negativity, auditory steady-state response, and prepulse inhibition did not point to a specific auditory domain, the researchers had no prior expectation about which measure would be most sensitive. However, they anticipated that the largest effects would be observed when baseline performance left room for improvement, avoiding ceiling or floor effects [2].

Primary dependent variables including correct responses on WIN, QuickSIN, and GIN, as well as learning-induced APS changes, were analyzed using ANOVA. Diagnosis served as a between-subject factor, and treatment condition was a within-subject factor. Additional within-subject factors included dB salience for WIN and QuickSIN and gap duration for GIN. For WIN and QuickSIN, scores from 0 dB conditions were both included and excluded from the analyses to ensure robustness.

Given the restricted scoring range of these tasks, nonparametric analyses were also conducted to confirm significant findings from the ANOVAs and to examine correlations between measures. The researchers also investigated whether baseline levels of attention and vigilance, as measured by the MCCB, influenced performance outcomes. This was assessed through a median split analysis comparing participants with high vs. low baseline attention scores [2].

Finally, exploratory analyses examined the potential impact of additional factors such as age, baseline hearing thresholds, smoking status, medication, and drug administration order. These exploratory variables were considered based on prior research suggesting they may influence auditory processing performance or modulate responses to pharmacological intervention [2].

In conclusion, this controlled, crossover study used a battery of validated auditory tasks and neurocognitive measures to evaluate whether memantine could enhance auditory discrimination, temporal resolution, and learning in individuals with schizophrenia. The design allowed for the examination of within-subject treatment effects, and the inclusion of healthy controls enabled comparisons to normative performance levels [2].

Discussion
1) The randomized, double-blind clinical trial was conducted by the research team of Brown et al evaluated the effects of memantine in patients receiving whole-brain radiotherapy for brain metastases. The trial aimed to assess whether memantine could preserve cognitive function and improve clinical outcomes when administered alongside whole brain radiotherapy. After screening, 508 patients were deemed eligible for analysis, while 46 were excluded primarily due to elevated creatinine or BUN levels. The two treatment groups defined as those receiving whole brain radiotherapy plus memantine and those receiving whole brain radiotherapy plus placebo, were generally balanced in terms of baseline demographics, neurological function, and tumor characteristics, except for a slightly higher proportion of patients in the memantine group who were taking steroids at baseline [1].
The median age of participants was 59 years, with 56% being female. The most common primary cancer type at 70% was lung cancer. Steroid and chemotherapy use remained relatively stable throughout the study. Chemotherapy usage hovered around 29–33% at various time points, while steroid use declined over time, from 42% at 3 months to 24% at 12 months. Whole brain radiotherapy adherence was high, with 93% of patients completing treatment per protocol. Similarly, memantine and placebo compliance were comparable; 31% of patients in the memantine group and 33% in the placebo group completed all six months of drug therapy without modifications or delays [1].

Analysis of baseline characteristics revealed that patients who completed cognitive evaluations tended to have better prognoses, longer survival, and better neurological function. These patients were more likely to be classified as RPA Class I and to have undergone prior surgical resection or radiosurgery. Importantly, survival data supported this trend, with patients who completed cognitive assessments demonstrating significantly longer median survival times compared to those who did not. For instance, at the 8-week evaluation, median survival was 12.4 months for those completing assessments compared to just 2.7 months for those who did not.

Regarding cognitive outcomes, the primary endpoint focused on changes in delayed recall measured by HVLT-R DR scores at 24 weeks. The memantine group experienced a median decline of 0 in HVLT-R DR, whereas the placebo group had a median decline of –0.90, suggesting the benefits of memantine. Similar trends favoring memantine were observed at 8 weeks, however, statistically significant differences were found in several secondary cognitive outcomes. These included improved performance in HVLT-R Delayed Recognition, MMSE scores, and Controlled Oral Word Association (COWA) scores, with less deterioration observed in the memantine group [1].

Furthermore, the time to cognitive failure was defined as the first failure on any neurocognitive test, and significantly favored the memantine group. At 24 weeks, the probability of cognitive failure was 53.8% in the memantine group compared to 64.9% in the placebo group, reflecting a 21% relative reduction in risk.

Linear regression models were employed to adjust for baseline assessment scores and intracranial progression. These models reinforced the consistency of the findings. While no significant differences were observed in HVLT-R DR scores in complete-case analysis, a significant benefit in COWA scores at 8 weeks was observed in the memantine group. The influence of steroid use on cognitive outcomes was also assessed. The only significant difference emerged in the HVLT-R DR scores at 8 weeks, where patients on steroids had greater declines compared to those not on steroids of –2 vs. –0.5, respectively. This suggests that steroid usage might negatively impact cognitive function [1].

In terms of survival outcomes, there were no significant differences between treatment arms. The median progression-free survival was 4.7 months in the memantine group and 5.5 months in the placebo group (HR = 1.06; P = 0.27). Similarly, overall survival was 6.7 months for memantine and 7.8 months for placebo (HR = 1.06; P = 0.28). Thus, memantine did not adversely affect survival outcomes [1].

In summary, while memantine did not significantly improve the primary cognitive outcome measure, HVLT-R DR, due to limited statistical power, it showed consistent trends favoring cognitive protection across several secondary measures. It also significantly delayed time to cognitive failure and was well tolerated, without compromising overall or progression-free survival. These findings support the use of memantine to mitigate cognitive decline in patients undergoing WBRT for brain metastases, particularly given its favorable safety profile and the observed preservation of cognitive function over time [1].

2) This study performed by the team of Swedlow et al investigated the effects of memantine, an NMDA receptor antagonist, on auditory processing in individuals with schizophrenia compared to healthy controls. The results provide a comprehensive look at how memantine influences different facets of auditory perception and learning, with particular attention to group differences, cognitive function, and potential confounding factors such as age, medication, and smoking status [2].

The study involved a chronically ill schizophrenia patient group that was moderately to severely impaired and on multiple medications. Compared to healthy subjects, these patients were older, heavier, less educated, more likely to be smokers, and had lower scores on the Wide Range Achievement Test (WRAT). Patients also had modestly elevated hearing thresholds for 1000 Hz and 6000 Hz tones, though not for 500 Hz. As expected, patients performed significantly worse on most domains of the MCCB, except for reasoning and problem solving [2].

Memantine, at a 20 mg dose, did not produce strong subjective effects, as evidenced by measures such as the Subjective Rating Scale and autonomic parameters such as heart rate and blood pressure. Notably, “Focus Attention” scores on the Subjective Rating Scale declined more in healthy subjects across the session, an effect counteracted by memantine. However, this interaction was not moderated by age, smoking status, or auditory/visual MCCB scores. Most participants could not reliably distinguish between memantine and placebo, indicating minimal perceptual or physiological impact.
The WIN task showed that both schizophrenia patients and healthy subjects experienced expected performance declines with increasing background noise. Although there were no significant main effects of diagnosis or drug overall, a significant interaction between drug and decibel level emerged. Specifically, memantine significantly improved performance at the 4 dB level among patients, but not in healthy subjects, including an age-matched subgroup. This improvement was confirmed with nonparametric tests. Notably, the benefit of memantine was most pronounced in patients with lower baseline MCCB auditory/visual scores, suggesting that cognitive ability moderated drug response. The performance enhancement in patients corresponded to a 1.74 dB gain in effective signal intensity, suggesting a “normalizing” effect [2].

QuickSIN results paralleled those of WIN in that performance declined with decreasing signal-to-noise ratios. However, unlike WIN, QuickSIN did not reveal a clear threshold of maximal performance loss. Both groups showed modest but statistically significant improvements with memantine, and this was consistent across all speech intensities. There was no interaction between drug and decibel level. Again, nonparametric tests supported these results. However, the cognitive modulation effect seen in WIN was absent and the benefit of memantine did not vary by MCCB auditory/visual scores [2].
GIN performance revealed a significant impairment in patients compared to healthy subjects, although this difference disappeared in age-matched subgroups, suggesting age as a confounding factor. Memantine did not significantly affect performance in either group. A performance drop was most evident at the 5 ms gap duration, especially in patients, but this was unrelated to memantine administration or cognitive ability.

Baseline performance on the Sound Sweeps task indicated that schizophrenia patients had slower auditory processing speeds than healthy subjects, with a large effect size. These differences persisted when groups were age-matched. While higher MCCB auditory/visual scores were associated with more learning, the differences were not statistically significant. On test days, patients again demonstrated slower auditory processing speed, with no main effect of memantine or significant learning across blocks [2].

However, a notable finding was a significant diagnosis and drug interaction for auditory processing speed. Memantine significantly enhanced learning in patients but not in healthy subjects, a pattern confirmed even when ceiling-level performers were excluded. This suggests that memantine’s effect on auditory learning may be specific to the schizophrenia group. Additionally, memantine-induced auditory processing speed improvements “carried forward” to subsequent testing sessions, implying that these effects were not merely state-dependent [2].

Performance on different auditory tasks did not correlate significantly within individuals, suggesting that sensitivity to memantine varies across auditory domains. However, patients classified as “high responders” to memantine on one task also tended to show improvements on other tasks, pointing to some consistency among sensitive individuals. Demographic and clinical variables such as age, hearing threshold, medication dose, and smoking status did not significantly correlate with memantine’s effect, although there were trends suggesting possible negative and positive influences from age and antipsychotic dosage, respectively.

This study demonstrates that memantine selectively enhances certain aspects of auditory processing in schizophrenia, particularly in speech-in-noise recognition and auditory learning. These effects are most evident among cognitively lower-functioning patients and appear independent of subjective drug effects, age, medication dose, or smoking. The specificity of memantine’s benefits across auditory tasks, as well as the absence of strong inter-measure correlations, suggests complex and domain-specific mechanisms of auditory dysfunction and pharmacological response in schizophrenia [2].

 

Disclaimer

**LAB USE ONLY**
*This information is for educational purposes only and does not constitute medical advice. THE PRODUCTS DESCRIBED HEREIN ARE FOR RESEARCH USE ONLY. All clinical research must be conducted with oversight from the appropriate Institutional Review Board (IRB). All preclinical research must be conducted with oversight from the appropriate Institutional Animal Care and Use Committee (IACUC) following the guidelines of the Animal Welfare Act (AWA).

 

Citations

[1] Brown PD, Pugh S, Laack NN, et al. Memantine for the prevention of cognitive dysfunction in patients receiving whole-brain radiotherapy: a randomized, double-blind, placebo-controlled trial. Neuro Oncol. 2013;15(10):1429-1437. doi:10.1093/neuonc/not114.

[2] Swerdlow NR, Bhakta SG, Talledo J, et al. Memantine effects on auditory discrimination and training in schizophrenia patients. Neuropsychopharmacology. 2020;45(13):2180-2188. doi:10.1038/s41386-020-00865-8

 

 

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