Cognitive functioning, severity of psychopathology and treatment response (positive symptoms and negative symptoms of schizophrenia), depressive symptoms, social cognition, obsessive-compulsive symptoms, psychosocial functioning, quality of life and adverse effects in outpatients with refractory schizophrenia and a nonsatisfactory response to clozapine (duration of adequate clozapine treatment at least six months). MedDRA version: 17.1 Level: PT Classification code 10039626 Term: Schizophrenia
Conditions
Interventions
Trade Name: Ebixa
Product Name: Memantine hydrochloride
Product Code: EU/1/02/219/023
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: Memantine hydrochloride
CAS Number: S 10102-43-9
Curr
Sponsors
Mental Health Services North Holland North
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: Eligible for the study are outpatients, both sexes, age 18 to 60, meeting DSM-IV criteria for schizophrenia, based on the definitions in the Mini International Neuropsychiatric Interview Plus (MINI-Plus) with persistent residual psychopathology, failing to achieve the remission criteria, after adequate treatment with clozapine for at least 6 months. Before the start of the study clozapine plasma concentration has been at least 350 ng/ml for 12 weeks or has not reached 350 ng/ml due to intolerability. Remission defined as simultaneous ratings of mild or less (= 3 points) on 8 of the PANSS items evaluating the core symptoms of schizophrenia (P1 delusions, G9 unusual thought content, P3 hallucinatory behaviour, P2 conceptual disorganisation, G5 mannerisms and posturing, N1 blunted affect, N4 passive or apathetic social withdrawal, N6 lack of spontaneity and flow of conversation) (Os van and Kahn, 2007). Patients should be able to understand the study information and procedures and give informed consent. All participants fulfilling the inclusion and not fulfilling the exclusion criteria may, after a detailed description by a doctor and the written declaration of informed consent on an according form, participate in the study. Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 52 F.1.3 Elderly (>=65 years) no F.1.3.1 Number of subjects for this age range
Exclusion criteria
Exclusion criteria: - Pregnancy. - Lactating women. - Female subjects without adequate contraception. - Known hypersensitivity to memantine or ingredients used in this tablet. - Uncontrolled epilepsy. - Recent myocardial infarction. - Uncontrolled hypertension. - Renal insufficiency (GFR < 30 ml/min). - Severe liver failure (ASAT 175 U/l and/or ALAT 225 U/l in men and 175 U/l in women). - Lactose intolerance. - Co-medication with NMDA-antagonists such as amantadine, ketamine, dextromethorphan. - Co-medication with glutamate antagonists such as lamotrigine and topiramate. - Extremely ill patients (Global Assessment of Functioning [GAF] = 20), who are not reliably able to give their informed consent. - Moderate or severe Alzheimer’s disease.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: 1. Is memantine efficacious as an adjunctive treatment to clozapine in patients with refractory schizophrenia to improve cognitive impairment? 2. Does memantine in combination with clozapine diminish the severity of psychopathology, positive and negative symptoms? ;Secondary Objective: 1. Does memantine have a beneficial effect on depressive symptoms? 2. Does memantine add-on therapy to clozapine have a beneficial effect on social cognition? 3. Does memantine improve obsessive-compulsive symptoms? 4. Are there differences in efficacy and tolerability of clozapine treatment combined with memantine compared to clozapine treatment in combination with placebo in other areas of clinical outcome: psychosocial functioning, quality of life and dropout rate? ;Primary end point(s): a. Cognitive functioning will be assessed by the Cambridge Neuropsychological Test Automated Battery (CANTAB), an outstandingly sensitive and extensively validated cognitive testing battery. The tests are computerized, non-linguistic and culturally blind, consisting of 9 tests: 1. Motor screening (MOT) (3 minutes); 2. Verbal Recognition Memory (VRM)-immediate (20 minutes); 3. Rapid Visual Information Processing (RVP) (7 minutes); 4. Intra/ Extradimensional Set Shifting (IED) (7 minutes); 5. Reaction Time: Simple and 5 Choice (RTI) (5 minutes); 6. Verbal Recognition Memory (VRM)-delayed; 7. One Touch Stockings of Cambridge (OTS) (10 minutes); 8. Paired Associates Learning (PAL) (7 minutes); 9. Spatial Working Memory (SWM) (8 minutes). b. Severity of psychopathology and treatment response: 1. Clinical Global Impression Severity Scale (CGI-S), a 7-point scale that requires the clinician to rate the severity of the patient's psychiatric illness at the time of assessment, relative to the clinician's past experience with patients who have the same diagnosis (Guy, 1976). 2. Subscale for positive symptoms of the Positive And Negative Syndrome Scale, based on a semi-structured inter | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): a. Severity of depressive symptoms: 1. Calgary Depression Scale for Schizophrenia (CDSS); a semi-structured goal directed interview with an administration time of approximately 10 to 15 minutes, especially designed to distinguish depressive symptoms from negative symptoms and extrapiramidal symptoms in patients with schizophrenia (Addington et al, 1990). b. Social cognition will be assessed by 2 computerized tests: 1. Reading the Mind in the Eyes test (theory of mind) (10 minutes); 2. Emotion Recognition Task of the CANTAB (facial emotion recognition) (15 minutes). c. Obsessive-compulsive symptoms: 1. Yale-Brown Obsessive-Compulsive Scale (Y-BOCS), based on information collected in a semi-structured interview of 10 items with an administration time of approximately 10 to 15 minutes (Goodman et al, 1989). d. Psychosocial functioning: 1. Health of the National Outcome Scales (HoNOS), the most widely used routine clinical outcome measure used by English mental health services. The test is simple, reliable and valid to measure the health and social functioning of people with severe mental illness (Wing et al, 1999). The HoNOS consists of 12 items with 4 subscales: behavioral problems, impairments, symptoms and sociale problems. All items are assessed on a 5-point Likert scale. The administration time amounts to approximately 5 to 15 minutes. e. Quality of life: 1. Manchester Short Assessment of Quality of Life (MANSA) a reliable, valid questionnaire for registration of subjective quality of life (Priebe et al, 1999). The MANSA consists of 16 items. The administration time amounts to approximately 5 minutes. f. Safety measures: 1. Liverpool University Neuroleptic Side-Effect Rating Scale (LUNSERS) is a 51-item self-rating scale for measuring neuroleptic induced side-effects (Day et al., 1995). The administration time amounts to approximately 15 minutes. 2. Possible side effects of memantine, which are not mentioned in the | — |
Countries
Netherlands
Contacts
Public ContactSelene Veerman, MD
Mental Health Services North Holland North
Outcome results
None listed