MemaROCD: Memantine for Refractory OCD Patients

Sponsor

University of Roma La Sapienza (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT05015595

Collaborator

(none)

Enrollment

Arms

Anticipated Duration (Months)

Study Details

Study Description

Brief Summary

Obsessive-compulsive disorder (OCD) is a psychiatric syndrome characterized by unwanted and repetitive thoughts and repeated ritualistic compulsions aimed to decrease the distress. Symptoms can cause severe distress and functional impairment. OCD affects 2-3% of the population and is ranked within the ten leading neuropsychiatric causes of disability. Dysfunction of the cortico-striatal-thalamo-cortical circuitry (CSTC) has been implicated in OCD, including altered brain activation and connectivity. A complex dysregulation of glutamatergic signaling within the cortico-striatal circuitry has been proposed in OCD. Data obtained by several studies are suggesting of a reduced glutamatergic concentrations in the anterior cingulate cortex, combined with overactivity of glutamatergic signaling in the striatum and orbitofrontal cortex. A growing number of RCTs have assessed the utility of different glutamate-modulating drugs as an augmentation or monotherapy in OCD, including refractory patients. However, there are relevant variations in between studies in terms of treatment-resistance, comorbidity, age and gender of the patients. At the present time four RCTs are available on the efficacy of memantine as an augmentation medication for refractory OCD patients. Investigators intend to conduce a double-blind, randomized, parallel group, placebo-controlled, monocentric trial to assess the efficacy and safety of memantine, a low-to-moderate affinity noncompetitive NMDAR antagonist that is currently approved for the treatment of Alzheimer disease, as an augmentative agent to a SSRI in treatment of patients affected by severe refractory OCD. Study design consists of four distinct periods (52 weeks) including memantine titration, neuropsychological assessment and follow-up.

Condition or Disease	Intervention/Treatment	Phase
Obsessive-Compulsive Disorder	Drug: Memantine Oral Tablet Drug: Placebo	Phase 3

Detailed Description

Obsessive-compulsive disorder (OCD) is a severe and debilitating neuropsychiatric condition that has an estimated lifetime prevalence of 2.5-3.0% of the general population. Traditionally it is characterized by repetitive and intrusive thoughts (obsessions) and repeated ritualistic behaviours (compulsions) performed from affected individual to decrease the distress.

Conventionally OCD is driven by irrational beliefs (obsessions) considered as the product of a cognitive bias (including overestimation of threat, increased personal responsibility and thought-action fusion) and compulsions are rational avoidance response triggered by these irrational beliefs, a coping mechanism which neutralize anxiety and reduce the likelihood that fears will be realized. Recent data suggest that OCD is driven by a disruption in the balance between habit learning system and goal directed system. The habit learning system operates purely on the basis of historical information, whether or not actions were rewarded in the past, it can lead to behavioural inflexibility and in isolation is not an optimal way to make choices when faced with rapid changes in the environment; while goal directed system exerts control over habits in light of new information, including changes in the desirability of outcomes and changes to the contingency between actions and outcomes. Habits depend on recurrent circuits that connect cerebral cortex to the basal ganglia, termed cortico-striatal-thalamo-cortical circuitry (CSTC) loops. In the CSTC model of OCD, these loops become hyperactive or hyperconnected, self-exciting in a runaway positive feedback loop. This leads to the urge to perform compulsions, which in turn consolidates/strengthens the habit of performing compulsions, increasing the urge. Glutamate is the primary neurotransmitter within the implicated in OCD CSTC. Glutamatergic neurotransmission has a fundamental role for neuronal plasticity, learning, and memory. Excessive glutamate levels could lead to glutamate receptor hyperactivity or even excitotoxicity in neurons. However, in pathological conditions glutamate can act as a neuronal excitotoxin, leading to rapid or delayed neurotoxicity. Dysregulation of glutamatergic signaling within the CSTC has been proposed in OCD, with reduced glutamatergic concentrations in the anterior cingulate cortex, combined with overactivity of glutamatergic signaling in the striatum and orbitofrontal cortex. Increased glutamate levels have been measured in cerebrospinal fluid of OCD patients compared to healthy controls. Traditionally medications for OCD have targeted on serotonergic pathways. Serotonin reuptake inhibitors (SRIs); unfortunately, around 40% of patients with OCD do not achieve remission of their symptoms with SRIs. Even when switching to another selective serotonin re-uptake inhibitor or clomipramine, or when an atypical antipsychotic is added, the portion of refractory patients still remains around 30%. Refractoriness is defined by the fail of almost three trials with different Selective Serotonin Reuptake Inhibitors (SSRIs) at high dosages. In light of a possible role of glutamatergic signalling dysregulation in the OCD it is possible found candidates for augmentation strategy of OCD's therapy in glutamatergic drugs. This background has motivated interest in studying glutamate modulators in patients who are unresponsive to standard pharmacotherapeutic approaches. In particular, some studies using memantine and riluzole have been reported promising suggestions of benefit. Other studies have explored the role of stimulants and nutritional supplements such as inositol and N-acetylcysteine. Several clinical studies were conducted to evaluate the effect of glutamate-modulating drugs in OCD, however they significant differ in terms of treatment-resistance, comorbidity, age and gender of the patients. A recent review on the argument conduced by Marinova et al concluded that memantine is the compound most consistently showing a positive effect as an augmentation therapy in OCD. Moreover randomized placebo-controlled trials in clinical samples are necessary in order to draw definitive conclusions on the utility of glutamate-modulating drugs in OCD. Identifying and confirming the efficacy and safety of new therapeutic approaches for the OCD could be very useful also for improving disability and quality of life in these patients.

At the present time four RCTs are available on the efficacy of memantine as an augmentation medication for refractory OCD patients.

The main aim of this study is to conduce a double-blind, randomized, parallel group, placebo-controlled, monocentric trial to assess the efficacy and safety of memantine, a low-to-moderate affinity noncompetitive NMDAR antagonist that is currently approved for the treatment of Alzheimer disease, as an augmentative agent to a SSRI in treatment of patients affected by severe refractory OCD.

The second aim of the study is to evaluate the minimum effective dose of memantine in this patients and effects after drug withdrawal through follow up. The third aim is to investigated the effect of memantine on patients without cognitive impairment an improvement of cognitive functions.

Methods: A double-blind, randomized, parallel group, placebo-controlled, monocentric trial will be conduce over 52 weeks at the outpatient clinic of the Department of Human Neurosciences (Policlinico Umberto I, Rome). The study will be conducted in agreement with the Declaration of Helsinki and its subsequent revisions. At the same time the study will be subject to the ethics committee of Policlinic Umberto I of Rome. Written informed consent will be obtain from all eligible participants following complete description of study details. Participants will be informed regarding their freedom to withdraw from the trial anytime without any negative effect on their therapy. The trial will be registered at the Italian Registry of Clinical Trials.

Consecutively the investigators will enroll patients who met the diagnostic criteria of Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM 5) with criteria of moderate to severe OCD and a Yale Brown Obsessive Compulsive Scale (Y-BOCS) score of >21 were selected to be in this study. Y-BOCS will be used to evaluate treatment efficacy. This is a well-validated 10-item rating scale, which is widely used to measure the severity of OCD symptoms. 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. Speed processing by using the WAIS-IV Digit Symbol, attention by means of the Trial Making Test and a computerized alertness and Go/no go task memory by using the Digit and Corsi Span, a modified version of Corsi Block Tapping test, the Story recall of Rivermead Behavioral Memory Test and a modified version of Babcock Story recall test executive functions by means of Stroop Task, a modified version of Tower of London and the Modified Five Point Test.

Interventions:

This is a double blind, randomized, parallel group, placebo controlled, monocentric 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 Memantine/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 double-blind treatment period, patients will be asked to come back for the follow-up visit (T6) 8 weeks after the end of the treatment (T5).

Trial Design:

Placebo and memantine tablets will be identical in shapes, colors, weight and scent. In advance the investigators will prepared a random-number sequence that a computer-generated for random group assignment. Treatment allocation will be concealed from patients and physician will rated patients and from statistician. Separate individuals will be responsible for randomization and rating patients.

Sample size:

The investigators based the power calculation on previous study. Taking into account two groups and seven measurement time points, the minimum sample size will be 20 (calculated with G*Power 3.1).

Study Design

Study Type:

Interventional

Anticipated Enrollment :

20 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Treatment

Official Title:

Memantine for Refractory OCD Patients: a Pragmatic Double Blind, Randomized, Parallel Group, Placebo Controlled, Monocentric Trial

Anticipated Study Start Date :

Sep 1, 2021

Anticipated Primary Completion Date :

Oct 31, 2022

Anticipated Study Completion Date :

Dec 31, 2022

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Memantine For thirty-two-week double-blind up-titration treatment period (from T0 to T4) each patient will receive a daily administration of Memantine up to 20mg/day. Subsequently, each patient will undergone to a double-blind down-titration treatment period for eight-weeks (from T4 to T5). At T4, the dose of Memantine will be reduced at 10mg/day due to safety reasons before the end of treatment (T5).	Drug: Memantine Oral Tablet Thirty-two-week double-blind up-titration treatment period (from T0 to T4): patients will be randomly assigned to one of two arms (Memantine or placebo) in a 1:1 ratio and 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 Memantine/placebo will be reduced at 10mg/day due to safety reasons before the end of treatment (T5).
Placebo Comparator: Placebo For thirty-two-week double-blind up-titration treatment period (from T0 to T4) each patient will receive a daily administration of placebo 20 mg/day. Subsequently, each patient will undergone to a double-blind down-titration treatment period for eight-weeks (from T4 to T5). At T4, the dose of Placebo will be reduced at 10mg/day, following the study protocol, before the end of treatment (T5).	Drug: Placebo Thirty-two-week double-blind up-titration treatment period (from T0 to T4): patients will be randomly assigned to one of two arms (Memantine or placebo) in a 1:1 ratio and 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 Memantine/placebo will be reduced at 10mg/day due to safety reasons before the end of treatment (T5).

Arm

Intervention/Treatment

Active Comparator: Memantine

For thirty-two-week double-blind up-titration treatment period (from T0 to T4) each patient will receive a daily administration of Memantine up to 20mg/day. Subsequently, each patient will undergone to a double-blind down-titration treatment period for eight-weeks (from T4 to T5). At T4, the dose of Memantine will be reduced at 10mg/day due to safety reasons before the end of treatment (T5).

Drug: Memantine Oral Tablet

Thirty-two-week double-blind up-titration treatment period (from T0 to T4): patients will be randomly assigned to one of two arms (Memantine or placebo) in a 1:1 ratio and 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 Memantine/placebo will be reduced at 10mg/day due to safety reasons before the end of treatment (T5).

Placebo Comparator: Placebo

For thirty-two-week double-blind up-titration treatment period (from T0 to T4) each patient will receive a daily administration of placebo 20 mg/day. Subsequently, each patient will undergone to a double-blind down-titration treatment period for eight-weeks (from T4 to T5). At T4, the dose of Placebo will be reduced at 10mg/day, following the study protocol, before the end of treatment (T5).

Drug: Placebo

Outcome Measures

Primary Outcome Measures

Improvement of OCD symptoms will be intended as a rate of more then 1/3 on the Y-BOCS total score. [From the week number 5 to the week number 52]
The investigators will evaluate the improvement of symptoms through a decrease of OCD, intended as a rate of more then 1/3 on the Y-BOCS total score.

Secondary Outcome Measures

Evaluate the minimum effective dose of memantine [From the week number 5 to the week number 46]
The second aim of the study is to evaluate the minimum effective dose of memantine in these patients. The investigators will evaluate the improvement of symptoms through reduction of both subscales (obsessive thoughts and compulsive behaviors) and of the total Y-BOCS score.
Evaluate the effects after drug withdrawal through follow up [From the week number 5 to the week number 46]
Moreover the investigators will evaluate the effects after drug withdrawal during follow up through reduction of both subscales (obsessive thoughts and compulsive behaviors) and of the total Y-BOCS score.

Other Outcome Measures

Improvement at the WAIS-IV. [from the week number 5 to the week number 52]
The third aim is to investigate the effect of memantine on patients without cognitive impairment, on improvement of cognitive functions through the reduction of total score of the WAIS-IV Digit Symbol.
Improvement at the Trial Making Test. [from the week number 5 to the week number 52]
The fourth aim is to evaluate the effect of memantine on patients without cognitive impairment, on improvement of cognitive functions through the reduction of total score of the Trial Making Test.
Improvement at the Digit and Corsi Span. [from the week number 5 to the week number 52]
The fifth aim is to evaluate the effect of memantine on patients without cognitive impairment, on improvement of cognitive functions through the reduction of total score of the Digit and Corsi Span.
Improvement at the Corsi Block Tapping test. [from the week number 5 to the week number 52]
The sixth aim is to evaluate the effect of memantine on patients without cognitive impairment, on improvement of cognitive functions through the reduction of total score of the Corsi Block Tapping test.
Improvement at the Story recall of Rivermead Behavioral Memory Test. [from the week number 5 to the week number 52]
The sixth aim is to evaluate the effect of memantine on patients without cognitive impairment, on improvement of cognitive functions through the reduction of total score of the Story recall of Rivermead Behavioral Memory Test.
Improvement at the Babcock Story recall test. [from the week number 5 to the week number 52]
The eighth aim is to evaluate the effect of memantine on patients without cognitive impairment, on improvement of cognitive functions through the reduction of total score of the Story recall of Babcock Story recall test.
Improvement at the Stroop Task. [from the week number 5 to the week number 52]
The ninth aim is to evaluate the effect of memantine on patients without cognitive impairment, on improvement of cognitive functions through the reduction of total score of the Stroop Task.
Improvement at the Tower of London. [from the week number 5 to the week number 52]
The tenth aim is to evaluate the effect of memantine on patients without cognitive impairment, on improvement of cognitive functions through the reduction of total score of the Tower of London.
Improvement at the the Modified Five Point Test. [from the week number 5 to the week number 52]
The eleventh aim is to evaluate the effect of memantine on patients without cognitive impairment, on improvement of cognitive functions through the reduction of total score of the the Modified Five Point Test.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 55 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

diagnosis by a psychiatrist of current OCD according to the DSM 5
patients in therapy with a stable SSRI for at least three weeks prior
written informed consent.

Exclusion Criteria:

Substance dependence
IQ <70
comorbid psychiatric disorders
female pregnant or breast-feeding or intend to become pregnant during the period of the study
concomitant treatments (rTMS, CBT, other glutamate-modulating drugs)