Augmentation Of Antipsychotic Treatment With Memantine In Patients With Schizophrenia: A Systematic Review And Meta-Analysis

Objective: Many patients with schizophrenia respond partially to treatment with antipsychotic medications. A wide range of pharmaceutical agents are utilized as augmentation therapy in order to increase the efficacy of antipsychotic medication treatment. Memantine, a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist is one of these add-on agents. In this study we aimed to assess the efficacy of memantine augmentation by conducting a systematic review and meta-analysis on the psychopathology of patients with schizophrenia receving antipsychotic medication. Method: We analyzed the double-blind, randomized, placebo-controlled trials of memantine add-on treatment given to schizophrenia patients receiving antipsychotic medications. The primary outcome measure was amelioration of negative symptoms and the secondary outcome measures were amelioration of positive, total and general psycopathology symptoms. Publication bias was evaluated by the Funnel plot and Egger test. Results: Eleven studies on a total of 570 cases were included. Although memantine add-on treatment was superior to placebo for ameliorating negative symptoms (SMD=0.596, 95% CI=0.075-1.118, p=0.025), there were not any statistically significant differences in the amelioration of general psycopathology (SMD=0.034, 95% CI=0.419-0.488, p=0.883), the positive (SMD=-0.041, 95% CI=0.217-0.135, p=0.650) and the overall symptoms. (SMD=0.315, 95% CI=0.256-0.887, p=0.280). Publication bias was not observed between studies according to the results of the Funnel plots and Egger tests. Conclusion: Memantine augmentation treatment is beneficial for treating particularly the negative symptoms of schizophrenia patients. Further studies on the subject with larger sample size and longer follow-up durations are needed.WoSScopu

S103. Examination Of Formal Thought Disorder And Its Clinical Correlates With The Turkish Version Of The Thought And Language Disorder Scale (Tald-Tr) In Schizophrenia

Background Formal thought disorder (FTD) is considered to be a fundamental feature of schizophrenia (SZ). It is crucial to assess FTD comprehensively in a practical, operationalized way for etiopathogenesis, neurobiology and imaging studies. Kircher and his colleagues (2014) have developed the Thought and Language Disorder (TALD) scale which captures both positive/negative and objective/subjective FTD symptoms. This study aims to analyze psychometric properties of the Turkish version of TALD (TALD-TR) and investigate the relationship between FTD and various clinical characteristics in patients with SZ. Methods The original TALD manual was adapted into Turkish and applied to a total of 149 participants of which 114 had DSM-5 psychiatric diagnoses (schizophrenia N=70, mania N=20, depression N=24) and 35 were healthy controls. To analyze interrater reliability of the TALD-TR, interviews of 20 patients diagnosed with SZ were recorded on video. The records were viewed and scored by two independent raters. Positive and Negative Syndrome Scale (PANSS), Hamilton Depression Rating Scale, Young Mania Rating Scale, and Clinical Global Impression-Severity Scale were administered to detect illness severity. Results The principle component analyses revealed that the TALD-TR consisted of four factors including the Objective Positive (OP), Subjective Negative, Objective Negative (ON) and Subjective Positive symptom dimensions which were in line with the original TALD factorial structure. The crohnbach alpha values of the factors were found to be 0.91, 0.78, 0.76, 0.53 respectively. Intraclass correlation coefficient was 0.95. It was concluded that TALD-TR shows strong construct validity and high interrater reliability. The correlation analyses with TALD-TR and PANSS showed that there are significant positive correlations between the TALD-TR total score and the PANSS total and subscale scores. In the SZ group, a strong correlation was found between TALD-TR total score and PANSS Conceptual disorganization item. Following PANSS items, which were highly correlated with TALD-TR total score, were Stereotyped thinking, Suspiciousness, Delusions and Unusual thought content. The mania group exhibited the highest mean total score in the OP, whereas the SZ group exhibited the highest mean total score in the ON factor. In the SZ group, age controlled partial correlation analysis revealed that there was a positive correlation between the TALD-TR total score and the duration of illness. A negative correlation was found between the TALD-TR total score and age at illness onset. Additionally, clozapine users had higher TALD-TR ON score than non-clozapine users. Discussion This study showed that TALD-TR is a valid and reliable tool with good psychometric properties to assess FTD by its unique four-factorial structure as in the original study. The correlation between FTD and PANSS items associated with thought content suggest that thought content and thought process are not completely discrete entities. The comparison of FTD among different diagnostic groups showed a distinct pattern regarding the TALD-TR factors. In line with literature, the results of this study suggest that FTD is related with higher illness severity, longer duration of illness and early age at illness onset in patients with SZ. These findings emphasize the need to develop new treatment strategies aiming to improve FTD from the early stages of SZ. In patients with treatment refractory schizophrenia, especially the Objective Negative symptoms remain to be one of the main treatment targets. Finally, successful adaptation of TALD into different languages seems to be possible, bringing in an international tool for research on FTD.PubMe

J Clin Psychopharmacol

PURPOSE/BACKGROUND: A recent article in this journal presented a US perspective regarding the modernization of clozapine prescription and proposed an escape from the long shadow cast by agranulocytosis. METHODS: Here, an international group of collaborators discusses a point of view complementary to the US view by focusing on worldwide outcomes of clozapine usage that may be uneven in terms of frequency of clozapine adverse drug reactions. FINDINGS/RESULTS: Studies from the Scandinavian national registries (Finland and Denmark) did not find increased mortality in clozapine patients or any clear evidence of the alleged toxicity of clozapine. Data on clozapine-associated fatal outcomes were obtained from 2 recently published pharmacovigilance studies and from the UK pharmacovigilance database. A pharmacovigilance study focused on physician reports to assess worldwide lethality of drugs from 2010 to 2019 found 968 clozapine-associated fatal outcomes in the United Kingdom. Moreover, the United Kingdom accounted for 55% (968 of 1761) of worldwide and 90% (968 of 1073) of European fatal clozapine-associated outcomes. In a pharmacovigilance study from the UK database (from 2008 to 2017), clozapine was associated with 383 fatal outcomes/year including all reports from physicians and nonphysicians. From 2018 to 2021, UK clozapine-associated fatal outcomes increased to 440/year. IMPLICATIONS/CONCLUSIONS: The interpretation of fatal outcomes in each country using pharmacovigilance databases is limited and only allows gross comparisons; even with those limitations, the UK data seem concerning. Pneumonia and myocarditis may be more important than agranulocytosis in explaining the uneven distribution of fatal outcomes in clozapine patients across countries

An International Adult Guideline for Making Clozapine Titration Safer by Using Six Ancestry-Based Personalized Dosing Titrations, CRP, and Clozapine Levels

This international guideline proposes improving clozapine package inserts worldwide by using ancestry-based dosing and titration. Adverse drug reaction (ADR) databases suggest that clozapine is the third most toxic drug in the United States (US), and it produces four times higher worldwide pneumonia mortality than that by agranulocytosis or myocarditis. For trough steady-state clozapine serum concentrations, the therapeutic reference range is narrow, from 350 to 600 ng/mL with the potential for toxicity and ADRs as concentrations increase. Clozapine is mainly metabolized by CYP1A2 (female non-smokers, the lowest dose; male smokers, the highest dose). Poor metabolizer status through phenotypic conversion is associated with co-prescription of inhibitors (including oral contraceptives and valproate), obesity, or inflammation with C-reactive protein (CRP) elevations. The Asian population (Pakistan to Japan) or the Americas' original inhabitants have lower CYP1A2 activity and require lower clozapine doses to reach concentrations of 350 ng/mL. In the US, daily doses of 300-600 mg/day are recommended. Slow personalized titration may prevent early ADRs (including syncope, myocarditis, and pneumonia). This guideline defines six personalized titration schedules for inpatients: 1) ancestry from Asia or the original people from the Americas with lower metabolism (obesity or valproate) needing minimum therapeutic dosages of 75-150 mg/day, 2) ancestry from Asia or the original people from the Americas with average metabolism needing 175-300 mg/day, 3) European/Western Asian ancestry with lower metabolism (obesity or valproate) needing 100-200 mg/day, 4) European/Western Asian ancestry with average metabolism needing 250-400 mg/day, 5) in the US with ancestries other than from Asia or the original people from the Americas with lower clozapine metabolism (obesity or valproate) needing 150-300 mg/day, and 6) in the US with ancestries other than from Asia or the original people from the Americas with average clozapine metabolism needing 300-600 mg/day. Baseline and weekly CRP monitoring for at least four weeks is required to identify any inflammation, including inflammation secondary to clozapine rapid titration