Memantine as an adjunctive therapy to ongoing clozapine treatment: a proof-of-concept study and follow-up study

INTERVENTION: Proof‐of‐concept study The proof‐of‐concept trial consists of two cross‐over, 12‐week treatment phases and a placebo wash‐out period of two weeks in the 13th and 14th week to avoid carry‐over effects. Subjects are randomly assigned to receive either an identical number of identical looking memantine or placebo tablets. During the first treatment phase subjects receive either placebo or memantine once daily, starting with 10 mg during the first week, built up in the second week to 20 mg during eleven weeks as add‐on therapy to ongoing clozapine treatment. After cross‐over in the second treatment phase (1 week titration and 11 weeks treatment) the group treated with placebo switches to memantine and vice versa. Anticipated start date: 01/08/2013 and actual start date: 05/08/2013 Recruitment start date: 05/08/2013 Recruitment end date: 17/12/2013 Anticipated date of last follow‐up: 01/08/2014 and actual date of last follow‐up: 05/08/2014 Actual date of closure to data entry: 05/08/2014 and date trial data considered complete: 10/09/2014 Follow‐up study In the follow‐up study, patients who have experienced beneficial effect of memantine will receive memantine add‐on therapy to clozapine. Patients who have not experienced clinical improvement after 12 weeks of memantine addition in the proof‐of‐concept study will not receive any other clozapine add‐on therapy. Anticipated and actual start date: 07/08/2014 Recruitment start date: 07/08/2014 Recruitment end date: 22/08/2014 Anticipated date of last follow‐up: 11/09/2015 Planned date of closure to data entry: 16/09/2015 and date trial data considered complete: 02/10/2015 CONDITION: Refractory schizophrenia with a non‐satisfactory response to clozapine after a treatment duration of at least six months ; Mental and Behavioural Disorders PRIMARY OUTCOME: 1. Cognitive functioning, assessed with the Cambridge Neuropsychological Test Automated Battery (CANTAB), a computerized, non‐linguistic cognitive testing battery (Levaux et al., 2007), consisting of eight tests:; 1.1. Motor screening (MOT) for induction; 1.2. Rapid Visual Information Processing (RVP) and Reaction Time; 1.3. Simple and 5 Choice (RTI) for attention; 1.4. Verbal Recognition Memory (VRM)‐immediate (free recall) and Verbal Recognition Memory (VRM)‐delayed (recognition) for verbal memory; 1.5. Paired Associates Learning (PAL) for visual memory; 1.6. One Touch Stockings of Cambridge (OTS) and Spatial Working Memory (SWM) for executive function. ; ; Other primary outcomes are:; 2. Severity of psychopathology (Clinical Global Impression Severity Scale [CGI‐S]); 3. Positive, negative and overall symptoms of schizophrenia (Positive and Negative Syndrome Scale [PANSS]); ; In the proof‐of‐concept study assessments take place at baseline, 12 weeks (phase 1), 14 weeks (after wash‐out), 26 weeks (phase 2) or at withdrawal of study. In the follow‐up study assessments take place at baseline, 26 weeks, 52 weeks or at withdrawal of study. SECONDARY OUTCOME: 1. Depressive symptoms (Calgary Depression Scale for Schizophrenia [CDSS]); 2. Social cognition (Reading the Mind in the Eyes test [RME] for theory of mind and Emotion Recognition Task [ERT] of the CANTAB for facial emotion recognition); 3. Obsessive‐compulsive symptoms (Yale‐Brown Obsessive‐Compulsive Scale [Y‐BOCS]); 4. Psychosocial symptoms (Health of the National Outcome Scales [HoNOS]; 5. Quality of life (Manchester Short Assessment of Quality of Life [MANSA]); 6. Side effects (Liverpool University Neuroleptic Side‐Effect Rating Scale [LUNSERS] and a list of possible side effects of memantine which are not mentioned in the LUNSERS (thrombosis, dyspnea and mycosis) specifically noted in Likert ratings); 7. Safety measures (blood pressure, waist circumference and laboratory tests of blood glucose, lipids, liverenzymes, renal function, white blood cell count and differentiation, plasma clozapine level); 8. Drop‐out rate; ; In the proof‐of‐concept study assessments take place at baseline, 12 weeks (phase 1), 14 weeks (after wash‐out), 26 weeks (phase 2) or at withdrawal of study. In the follow‐up study assessments take place at baseline, 26 weeks, 52 weeks or at withdrawal of study. ; INCLUSION CRITERIA: The inclusion criteria for the proof‐of‐concept study include: 1. Outpatients (including sheltered housing) and patients living in long‐stay wards 2. Both sexes 3. Age 18 to 60 4. Meeting DSM‐IV criteria for schizophrenia, based on the definitions in the Mini International Neuropsychiatric Interview Plus (MINI‐Plus) with persistent residual psychopathology 5. Failing to achieve the remission criteria (remission is defined as simultaneous ratings of mild or less (= 3 points) on eight 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) 6. 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 7. Able