Computational protocol: Memantine augmentation in clozapine-refractory schizophrenia: a randomized,double-blind, placebo-controlled crossover study

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Protocol publication

[…] We used the Cambridge Neuropsychological Test Automated Battery (CANTAB), a computerized, non-linguistic cognitive testing battery (Levaux et al. ). Test selection was based on six cognitive domains, recommended by the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS): reaction time and psychomotor speed, sustained visual attention, verbal memory, visuospatial memory, learning and association ability, working visuospatial memory and strategy use, spatial planning and motor control and emotion recognition (Nuechterlein et al. ; Barnett et al. ). One cognitive domain of the MATRICS Consenus Cognitive Battery (MCCB) was not assessed, because Intra/Extra-Dimensional Set-Shifting (IED) for reasoning and problem solving was too difficult for our patient population with severe cognitive disturbances.Two cognitive domains were selected as primary outcomes: memory and executive function (see Table 2). Memory was assessed by computing a composite score of the sum of the CANTAB scores of four tasks: verbal recognition memory (VRM) free recall and VRM recognition, and paired associates learning (PAL) total errors and PAL first trial memory score. To reduce practice effects a parallel form of the VRM task, equivalent in difficulty, was used for the second and fourth measurement. Executive function was assessed by computing a composite of three CANTAB task scores: One Touch Stockings of Cambridge (OTS) problems solved on first choice, and spatial working memory (SWM) strategy and SWM between errors.The PANSS was used to assess severity of positive, negative and total symptoms of schizophrenia (Kay et al. ). We assessed the effect of memantine on two subdomains of negative symptoms: (1) expressive deficits [flat affect (N1), poor rapport (N3), lack of spontaneity and flow of conversation (N6), mannerisms and posturing (G5), motor retardation (G7) and avolition (G13)]; and (2) social amotivation [emotional withdrawal (N2), passive/apathetic social withdrawal (N4) and active social avoidance (G16)] (Liemburg et al. ; Millan et al. ). Global severity of psychopathology was determined by using the Clinical Global Impression Severity Scale (CGI-S) (Guy, ).Careful clinical procedures were performed to assess safety and tolerability of memantine add-on therapy to clozapine. Physical examination included measurements of waist circumference and blood pressure. Regular controls of white blood cell count and differentiation were combined with measurements of liver and renal function, blood glucose, lipids and plasma clozapine level (12 ± 0.5 h after ingestion). The occurrence and intensity of side effects were assessed by self-rating on the Liverpool University Neuroleptic Side-Effect Rating Scale (LUNSERS) (Day et al. ) augmented with rating of Likert scales for possible side effects of memantine (thrombosis, dyspnoea, and mycosis).All outcomes were rated before treatment initiation, after 12 weeks, after 14 weeks, and after 26 weeks. Two raters were trained in diagnostic interviewing and all clinical assessments. Inter-rater exact and adjacent agreement (within one scale point) was 96% for the PANSS, based on seven assessments (two live patient interviews and five videotaped patient interviews).Adverse events (AEs) were defined as any undesirable experience occurring to a subject during the study, whether or not they were considered to be related to memantine ingestion. All AEs, reported by either the subject or treatment staff, were recorded. Admission to a psychiatric hospital was no reason to break the code or for withdrawal from the study. A medical emergency was the only reason to break the code and withdraw the subject from the study. [...] To determine the effects of memantine on the hypothesized cognitive functions, schizophrenia symptoms, safety measures, and side effects, the two phases (memantine or placebo) of the crossover trial were compared using a linear mixed-effects model conducted in SPSS Statistics version 22.0.0 (SPSS Inc., ). This analytic approach can estimate random and fixed effects simultaneously (Putt & Chinchilli, ). A natural log transformation was applied to cognitive function scores assessed via the CANTAB, which are non-normally distributed, so that estimates from the linear mixed-effects models would be trustworthy.We conducted the analyses using an intention-to-treat (ITT) analytic approach and a per-protocol analytic approach, which included only protocol completers. Protocol completion was defined as having completed both treatment phases without a serious protocol violation in the memantine phase. There was no significant difference in study completion rate by random group assignment (group 1 = 23/26, group 2 = 21/26; χ21 = 1.209, p = 0.47). We also tested a number of covariates in the model, which are potentially related to the dependent variables. Covariates included patient age and gender, years of education, age of onset, duration of psychosis and duration of untreated psychosis. We followed the backwards trimming method described by Singer & Willett () to construct our models: as covariates were entered into the model, one at a time, those that were significantly related to one of the model's parameters were retained. Only the patient's years of education variable was related to the slope paramater; thus, this variable was retained in the final model and the others were discarded.We first tested a model with random intercepts. However, the models failed to converge or produced errors in the Hessian matrix, so the intercept parameter was fixed to ensure trustworthy parameter estimates. The slope parameter was treated as a fixed effect after it was found that models with random slopes resulted in worse model fit. This indicates that models with fixed intercepts and slopes (i.e. constraining these parameters to be equal across participants) do not significantly differ from models in which these parameters are individually estimated. All tests of significance were two-tailed, and α was set to 0.05. Standardized ESs (Cohen's d) were calculated (Cohen, ). We performed a post-hoc analysis to assess whether memantine had a more pronounced effect on expressive deficits or social amotivation. To evaluate possible differences between in-patients admitted to long-stay wards and other included patients we performed a post-hoc analysis of demographic variables and baseline characteristics and also conducted a post-hoc analysis of out-patients, excluding patients admitted to long-stay wards. […]

Pipeline specifications

Software tools CANTAB, SPSS
Applications Miscellaneous, Neuropsychology analysis
Organisms Homo sapiens
Chemicals Clozapine, Memantine, N-Methylaspartate