Memantine for Refractory Obsessive-Compulsive Disorder: Protocol for a Pragmatic, Double-blind, Randomized, Parallel-Group, Placebo-Controlled, Monocenter Trial

Background Obsessive-compulsive disorder (OCD) is a psychiatric syndrome characterized by unwanted and repetitive thoughts and repeated ritualistic compulsions for decreasing distress. Symptoms can cause severe distress and functional impairment. OCD affects 2% to 3% of the population and is ranked within the 10 leading neuropsychiatric causes of disability. Cortico-striatal-thalamo-cortical circuitry dysfunction has been implicated in OCD, including altered brain activation and connectivity. Complex glutamatergic signaling dysregulation within cortico-striatal circuitry has been proposed in OCD. Data obtained by several studies indicate reduced glutamatergic concentrations in the anterior cingulate cortex, combined with overactive glutamatergic signaling in the striatum and orbitofrontal cortex. A growing number of randomized controlled trials have assessed the utility of different glutamate-modulating drugs as augmentation medications or monotherapies for OCD, including refractory OCD. However, there are relevant variations among studies in terms of patients’ treatment resistance, comorbidity, age, and gender. At present, 4 randomized controlled trials are available on the efficacy of memantine as an augmentation medication for refractory OCD. Objective Our study’s main purpose is to conduct a double-blind, randomized, parallel-group, placebo-controlled, monocenter trial to assess the efficacy and safety of memantine as an augmentative agent to a selective serotonin reuptake inhibitor in the treatment of moderate to severe OCD. The study’s second aim is to evaluate the effect of memantine on cognitive functions in patients with OCD. The third aim is to investigate if responses to memantine are modulated by variables such as gender, symptom subtypes, and the duration of untreated illness. Methods Investigators intend to conduct a double-blind, randomized, parallel-group, placebo-controlled, monocenter trial to assess the efficacy and safety of memantine as an augmentative agent to a selective serotonin reuptake inhibitor in the treatment of patients affected by severe refractory OCD. Participants will be rated via the Yale-Brown Obsessive Compulsive Scale at baseline and at 2, 4, 6, 8, 10, and 12 months. During the screening period and T4 and T6 follow-up visits, all participants will undergo an extensive neuropsychological evaluation. The 52-week study duration will consist of 4 distinct periods, including memantine titration and follow-up periods. Results Recruitment has not yet started. The study will be conducted from June 2023 to December 2024. Results are expected to be available in January 2025. Throughout the slow-titration period, we will observe the minimum effective dose of memantine, and the follow-up procedure will detail its residual efficacy after drug withdrawal. Conclusions The innovation of this research proposal is not limited to the evaluation of the efficacy and safety of memantine as an augmentation medication for OCD. We will also test if memantine acts as a pure antiobsessive medication or if memantine’s ability to improve concentration and attention mimics an antiobsessive effect. Trial Registration ClinicalTrials.gov NCT05015595; https://clinicaltrials.gov/ct2/show/NCT05015595 International Registered Report Identifier (IRRID) PRR1-10.2196/39223


Background and rationale 6a
A growing number of RCTs have assessed the utility of different glutamate-modulating drugs as an augmentation or monotherapy in OCD, including refractory patients.
6b Placebo Objectives 7 The main purpose of this study is to conduce a trial to assess the efficacy and safety of memantine as an augmentative agent to a SSRI in treatment of moderate to severe OCD. The second aim of the study is to evaluate the effect of memantine on cognitive funtions in OCD patients. The third aim is to investigated if response to memantine could be modulate by variables such as gender, symptoms subtypes and duration of untrated illness. Interventions 11a This is a double blind, randomized, parallel group, placebo controlled, monocenter trial in subjects with OCD. The trial includes one active dose arm of Memantine and placebo. The trial consists of four distinct periods: • Screening: The screening period may last up to 4 weeks for each eligible patient. • Thirty-two-week double-blind up-titration treatment period (from T0 to T4): After screening, patients who meet all eligibility criteria will be randomly assigned to one of two arms (Memantine or placebo) in a 1:1 ratio. Following baseline assessments, each patient will receive a daily administration of Memantine/placebo up to 20mg/day. • Eight-week double-blind down-titration treatment period (from T4 to T5): At T4, the dose of Memanntine/placebo will be reduced at 10mg/day due to safety reasons before the end of treatment (T5). • Follow-up period (from T5 to T6): After the 40-week doubleblind treatment period, patients will be asked to come back for the follow-up visit (T6) 8 weeks after the end of the treatment (T5).
11b As soon as a severe adverse event occurs, an ad hoc form for severe adverse events will be completed, in accordance with the EU regulation about pharmacovigilance in clinical research [52]. If for any reason the disadvantages of participation appear to be significantly greater than foreseen, the investigator will inform the principal investigar and the bodies providing ethical oversight to evaluate to evaluate trial discontinuation for the patient.
11c The Investigator will also clearly inform the patient that she can leave the study at any time and for any reason without giving an explanation, and that this discontinuation would not in any case deteriorate the patient's relationship with the physician and/or the possibility of receiving alternative therapies. Study design consists of four distinct periods (52 weeks) including memantine titration and follow-up. (see Figure 1 and 2) Sample size 14 The sample size has been calculated using the GPower 3.1.9.2 software [53]. Using the ANOVA repeated measures test a with a within-between groups interaction approach (considering changes in YBOCS scale as primary outcome), with alpha=0.5, power (1beta)=0.85, with 2 groups (SSRI + memantine vs SSRI + placebo) and 7 measurements (T0 -T6), and assuming a correlation among repeated measures=0.5 and a nonsphericity correction epsilon=1, a total sample size of 20 participants (10 in each group) will be necessary to achieve a moderate effect size (f=0.25).

Recruitment 15
Strategies for achieving adequate participant enrolment to reach target sample size

Methods: Assignment of interventions (for controlled trials)
Allocation: Sequence generation 16a In advance we will prepared a random-number sequence that a computer-generated for random group assignment Allocation concealment mechanism 16b Mechanism of implementing the allocation sequence (eg, central telephone; sequentially numbered, opaque, sealed envelopes), describing any steps to conceal the sequence until interventions are assigned Implementation 16c Treatment allocation will be concealed from patients and physician will rated patients and from statistician.

Blinding (masking)
17a Separate individuals will be responsible for randomization and rating patients.
17b In case a severe adverse events, related to trial, will be occurrent the unblinding is permissible

Methods: Data collection, management, and analysis
Data collection methods 18a Participants were rated by Y-BOCS at baseline and at 2, 4, 6, 8, 10 and 12 months. During the screening period, T4 and T6 follow-up visits all participants will undergo an extensive neuropsychological evaluation Data management 19 Patients will be enrolled after the doctor-in-charge and a supervisor check the patient information regarding the inclusion and exclusion criteria. The data of all participants including those who will be discontinued or dropped from intervention protocols will be collected according to study protocol. Whereas the quality control will be performed by a external data manager (recruited exclusively for this project).
Statistical methods 20a Descriptive statistics for baseline characteristics and the final measurement at each time point will be calculated. A repeated measures will be used to detect the statistical significance of overall differences across the psychological variables when comparing the two groups. Test ANOVA will be used for multivariate correlation. All p-values =0.05 were considered statistically significant. Data were analyzed using SPSS version 13.0.

Methods: Monitoring
Data monitoring 21a A.D.V. and F.D. will assign the patients to the two groups and monitoring the study.

Harms 22
Adverse events occurred during the clinical trial will be assessed by the Investigator in terms of seriousness and relationship with the investigational product and will be notified to principal investigator and local ethics committee.

Ethics and dissemination
Research ethics approval 24 local ethics committee (Prot. 0784/2022) Protocol amendments 25 / Consent or assent 26a Only patients legally capable of giving their consent can participate in the study. The Investigator is responsible for the correctness of the recruitment procedure and is asked to use a comprehensible verbal communication in providing information to the patients. Before entering the study, patients will be fully informed about the purposes of the research, possible benefits, any potential personal reasonable risk or discomfort, the expected duration of their participation in the trial.
26b / Confidentiality 27 At baseline, during the trial, follow up and after socio-demographic and clinical information will be collected along with the administration af the aforementioned validated rating scales.

Declaration of interests 28
All authors declare the absence of conflict of interests related to the present study.
Access to data 29 The data generated and analyzed during this study will be available from the corresponding author on reasonable request following the completion of the trial and publication of the main outcomes paper and will be included in any published articles.
Ancillary and post-trial care 30 / Dissemination policy 31 /

Appendices
Informed consent materials 32 Before recruitment, a copy of the informed consent form and personal data processing consent form will be given to the patient, together with any needed clarification.
Biological specimens 33 / *It is strongly recommended that this checklist be read in conjunction with the SPIRIT 2013 Explanation & Elaboration for important clarification on the items. Amendments to the