Methodological issues in negative symptom trials

Individuals from academia, the pharmaceutical industry, and the US Food and Drug Administration used a workshop format to discuss important methodological issues in the design of trials of pharmacological agents for improving negative symptoms in schizophrenia. The issues addressed included the need for a coprimary functional measure for registration trials; the characteristics of individuals who should enter negative symptom trials; the optimal duration for a proof-of-concept or registration trial; the optimal design of a study of a broad-spectrum agent that treats both positive and negative symptoms or a co-medication that is added to an antipsychotic; the relative strengths and weaknesses of available instruments for measuring negative symptoms; the definition of clinically meaningful improvement for these trials; and whether drugs can be approved for a subdomain of negative symptoms.     

Discontinuation of alprazolam treatment in panic patients

Alprazolam treatment was tapered in 17 panic patients at a rate of 10% of the starting dose every 3 days. Only four subjects completed withdrawal on schedule (4-5 weeks); four additional subjects discontinued treatment in 7-13 weeks. During withdrawal 15 patients had recurrent or increased panic attacks and nine had significant new withdrawal symptoms. Most common among the latter were malaise, weakness, insomnia, tachycardia, lightheadedness, and dizziness. None had seizures, psychosis, or significant neurological or EEG abnormalities. Results indicate that relapse and withdrawal are important considerations in the choice of alprazolam treatment for panic attacks.     

The therapeutic role of naltrexone in negative symptom schizophrenia

1. 1. Naltrexone (50 mg bid, p.o.) was administered in a double-blind fashion (with placebo control) to chronic schizophrenic patients who maintained their routine neuroleptic and anxiolytic therapy.

2. 2. Both positive and negative symptom patients who received naltrexone improved with regard to symptoms involving deterioration and social withdrawal. No significant amelioration was recorded in subjects assuming placebo relative to the same psychopathological areas.

3. 3. Favourable results were obtained mainly from patients affected by negative symptom schizophrenia.

4. 4. Naltrexone may have acted by direct or indirect neurochemical mechanisms related to negative symptom schizophrenia.

     

奎硫平治疗精神分裂症阴性症状Meta分析

目的：了解奎硫平与其他抗精神病药对精神分裂症阴性症状的疗效差异。方法：应用Meta分析对34项研究奎硫平与其他抗精神病药治疗精神分裂症阴性症状文献进行再分析，评价其合并效应量的大小和综合显著性差异。结果：奎硫平治疗前后的自身对照，表明对阴性症状疗效明显，效应极强；与其他抗精神病药比较差异无显著性。结论：奎硫平对精神分裂症阴性症状的疗效显著，与其他抗精神病药差异无显著性，但差异效应因药物不同而异。     

阴性与阳性症状为主的精神分裂症患者执行功能的比较

目的:探讨以阴性或阳性症状为主的精神分裂症患者执行功能的特点。方法:采用威斯康星卡片分类测验(WCST)、Stroop色词测验(SCW)、空间广度测验、数字序列测验和伦敦塔测验分别对46例以阴性症状为主(阴性症状组)和46例以阳性症状为主(阳性症状组)的精神分裂症患者、以及46名健康者(对照组)进行执行功能测评。结果:阴性症状组和阳性症状组各项执行功能指标治疗前后差异无统计学意义,但两组的各项指标均明显差于对照组(P均0.01)。阴性症状组治疗前后WCST中的完成分类数、持续性错误数、随机错误数、数字序列测验的正序和倒序得分、SCW中的反应时(RTA、RTB、RTC)、干扰效应、以及空间广度测验和伦敦塔测验成绩均差于阳性症状组(P0.05或P0.01)。结论:精神分裂症患者执行功能缺损明显,尤以阴性症状为主的患者缺损更为明显。     

Validation of Turkish version of brief negative symptom scale

Objective: Negative symptoms in schizophrenia have been assessed by many instruments. However, a current consensus on these symptoms has been built and new tools, such as the Brief Negative Symptom Scale (BNSS), are generated. This study aimed to evaluate reliability and validity of the Turkish version of BNSS.

Methods: The scale was translated to Turkish and backtranslated to English. After the approval of the translation, 75 schizophrenia patients were interviewed with BNSS, Positive and Negative Syndrome Scale (PANSS), Calgary Depression Scale for Schizophrenia (CDSS) and Extrapyramidal Symptom Rating Scale (ESRS). Reliability and validity analyses were then calculated.

Results: In the reliability analysis, the Cronbach’s alpha coefficient was 0.96 and item-total score correlation coefficients were between 0.655–0.884. The intraclass correlation coefficient was 0.665. The inter-rater reliability was 0.982 (p?Conclusions: Our study confirms that the Turkish version of BNSS is an applicable tool for the evaluation of negative symptoms in schizophrenia.     

The timing of negative symptom exacerbations in relationship to positive symptom exacerbations in the early course of schizophrenia

Although positive and negative symptoms appear to represent independent symptom dimensions of psychopathology when evaluated cross-sectionally among individuals with schizophrenia, it is not known if exacerbations of symptoms on these two dimensions are independent. This prospective longitudinal study examined the temporal relationship between the positive and negative symptom exacerbations among 48 recent-onset schizophrenia or schizoaffective patients who received symptom ratings every 2 weeks on the Brief Psychiatric Rating Scale. Patients were followed for a period of at least 1 year and a mean of 3 years. To examine the temporal relationship between positive and negative symptoms, six time periods were defined in relation to psychotic exacerbation or relapse (e.g., prodromal, concurrent, post-psychotic) and used to compare the timing of positive and negative symptom exacerbations. A substantial proportion of patients had exacerbations of positive symptoms (77%) and negative (42%) symptoms. Negative symptom exacerbations occurred simultaneously with positive symptom exacerbations to a significantly greater extent than expected by chance, and occurred less frequently than expected by chance during the time period most temporally removed from positive symptom exacerbations. Results suggest that the timing of some negative symptom exacerbations is linked to that of positive symptom exacerbations during the early course of schizophrenia.     

阿立哌唑治疗精神分裂症阴性症状Meta分析

目的探讨阿立哌唑与其他抗精神病药治疗精神分裂症阴性症状的疗效差异。方法用Meta分析对24项阿立哌唑与其他抗精神病药治疗精神分裂症阴性症状文章进行再分析,评价其合并效应量大小和综合显著性检验。结果阿立哌唑治疗前后的自身对照,提示阿立哌唑治疗精神分裂症阴性症状疗效明显,效应极强（χ2=15.32,P〈0.01）;与其他抗精神病药比较差异无显著性。结论阿立哌唑治疗精神分裂症阴性症状疗效显著,与其他抗精神病药差异无显著性,但差异效应因药物不同而异。     

Assessment of enduring deficit and negative symptom subtypes in schizophrenia.

The clinical importance of subtypes based on enduring deficit or negative symptoms was examined in a group of schizophrenic patients who were assessed twice over a 1-year period. Subgroups of patients with high levels of enduring negative or deficit symptoms, based on the Scale for the Assessment of Negative Symptoms and the Quality of Life Scale, had a poorer prognosis and were consistently worse in social adjustment, quality of life, and thought disorder over the year than were patients with less severe negative symptoms. Subtypes based on Andreasen's negative schizophrenia classification and on enduring thought disorder were only weakly related to other symptoms and social adjustment. Social-skill deficits were weakly related to the enduring negative symptom subtype and Andreasen's negative schizophrenia. The results suggest that enduring negative and deficit symptoms may be associated with a poor outcome in schizophrenia, including more severe positive symptoms, lower levels of social adjustment, and a poorer quality of life.     

Relationship of cognitive functioning, adaptive life skills, and negative symptom severity in poor-outcome geriatric schizophrenia patients

The authors assessed whether cognitive functioning and negative symptoms are related to functional outcome across severity of negative symptoms and examined relationships between symptom domains in patients with high versus low negative symptom severity. The interrelationships between cognitive functioning and functional skills in poor-outcome geriatric schizophrenic patients were compared between those who were in the first (n = 81) and the fourth quartiles (n = 127) of negative symptom severity based on the normative data in the Positive and Negative Syndrome Scale. It was found that negative symptoms and cognitive functioning were the strongest correlates of functional status in geriatric poor-outcome schizophrenic patients--regardless of negative symptom severity. Interestingly, the greater the severity of negative symptoms, the less strongly negative symptoms were related to functional outcome. The present findings demonstrate that the relationship of cognitive functioning to social and adaptive functioning remains significant despite differing levels of negative symptom severity.     

Scales of the "O" symptom questionnaire

The article presents the scales of the "O" Symptom Check-list which were derived on the basis of an analysis of a patient population of over three thousand. The patients filled out the "O" Symptom Check-list before treatment. 14 variables of various syndromes were constructed, which corresponded with most of the neurotic disorders classified in ICD-10. The results obtained were compared with the scales constructed 20 years ago, in an attempt to explain the dynamics of the psychopathology in the course of those years. It was noted that the analysis of the results of the single scales can be helpful in defining and observing the most common neurotic disorders and noting their comorbidity.     

Emergence of depressive symptoms in patients receiving alprazolam for panic disorder

The authors relate their clinical experience with 46 panic disorder patients who were receiving 3-10 mg/day of alprazolam. Fifteen (33%) developed symptoms consistent with DSM-III criteria for major depression despite remission of their panic symptoms. Clinicians should be alert to this potentially reversible complication.     

Effortful cognitive resource allocation and negative symptom severity in chronic schizophrenia

BACKGROUND: The relationship between negative symptoms, early visual information-processing deficits, and effortful processing resource allocation was investigated. METHODS: Older patients with chronic schizophrenia (n = 58) and healthy controls (n = 71) participated. Pupillary responses were recorded during performance of the span of apprehension task (blocks of 3- and 10-letter arrays) as an index of resource allocation or mental effort during the task. RESULTS: Patients and controls showed larger pupillary responses in higher relative to lower processing loads both during array processing and just prior to array onset (preparation). Both groups, therefore, invested more cognitive effort preparing for and then processing larger arrays. A subgroup of patients with abnormally small pupillary responses and impaired performance showed greater negative symptom severity relative to a subgroup of patients with normal pupillary responses. Smaller pupillary responses in the patients were also significantly correlated with greater negative symptom severity, independent of positive symptom severity. Patients with reduced effortful resource allocation, therefore, exhibited greater negative symptomatology. A subgroup of patients with normal pupillary responses still showed impaired detection accuracy relative to controls, suggesting that reduced cognitive effort or resource allocation problems cannot account for impairments in early visual information processing in this subgroup. CONCLUSIONS: The study illustrates important relationships between cognitive effort and performance that can impact conclusions about the nature of cognitive impairments and associations between negative symptoms and neurocognition in schizophrenia.     

Double-blind comparison of alprazolam, diazepam, and placebo for the treatment of negative schizophrenic symptoms

Fifty-five schizophrenic outpatients with negative symptoms were treated for up to six weeks by the addition of alprazolam (mean dose, 4.2 mg/d), diazepam (mean dose, 40.4 mg/d), or placebo to their ongoing neuroleptic treatment. A repeated-measures analysis of variance with baseline measurements entered as covariates indicated the presence of a significant time X drug interaction effect for the weekly Brief Psychiatric Rating Scale (BPRS) withdrawal/retardation subfactor scores. During the initial weeks of the study, the alprazolam-treated group had lower scores, while the diazepam-treated group had higher scores than the placebo-treated group. However, an end point analysis performed on the final BPRS withdrawal/retardation subfactor scores showed no significant differences among the three groups, nor were beneficial effects observed on any of the BPRS subfactor scores that assess positive symptoms. Plasma alprazolam levels were maintained throughout the study and ranged from 20 to 100 ng/mL. These results suggest that alprazolam had no sustained significant effect on negative schizophrenic symptoms.     

合并心境稳定剂治疗精神分裂症的短期效果评估

目的通过总结精神分裂症患者合并使用心境稳定剂的现状及其对短期预后的影响,了解患者的获益与风险。方法对纳入的334例精神分裂症患者进行自然观察,按是否合并使用心境稳定剂分组。采用阳性和阴性症状量表(PANSS)、自知力和治疗态度问卷(ITAQ)、副反应量表(TESS)及健康状况量表(SF-36)分别测评精神症状、自知力、药物不良反应及生活质量。结果入院时合并组PANSS总评分、兴奋因子、认知因子评分高于未合并组(P0.05);出院时合并组PANSS阳性因子、认知因子评分仍高于未合并组(P0.05);ITAQ、SF-36精神心理维度评分低于未合并组(P0.05)。结论合并心境稳定剂治疗对精神分裂症患者的兴奋冲动攻击行为有效,但不影响总体症状改善,且对生活质量和自知力可能有负面影响,故使用前应谨慎评估。     

Case studies of adjunctive agents in clozapine-resistant schizophrenic patients

Approximately 40%-70% of neuroleptic-resistant schizophrenic patients are nonresponders even to clozapine. Several clozapine augmentation strategies have come into clinical practice, although often without evidence-based support. This study aims to critically review all the reported case studies regarding the efficacy and safety of adjunctive agents in clozapine-resistant schizophrenic or schizoaffective patients. All published case studies examining the efficacy and safety of adjunctive agents in clozapine-resistant schizophrenic patients were searched for in the MEDLINE database from January 1980 to February 2004. Case studies regarding ECT as a clozapine augmentation strategy were not included in our study. All the included papers were critically reviewed and examined against a set of clinical and pharmacological parameters, outcome measures, and reported side effects. Fifteen case studies regarding the efficacy and safety of sulpiride, risperidone, olanzapine, lithium, lamotrigine, fluvoxamine, and bromocriptine as clozapine adjuncts were found. A total of 33 schizophrenic or schizoaffective patients were included. Of the 15 studies, 8 were associated with risperidone. The duration and dosage of previous clozapine monotherapy was adequate for 16 patients. Plasma clozapine level was assessed for only 7 patients. Outcome measures were used for only 11 patients. The outcome was positive in 13 studies. Combined treatments were generally well tolerated, and side effects never resulted in discontinuation of treatment. Most case studies favor the use of risperidone as an adjunctive agent in clozapine-resistant schizophrenic or schizoaffective patients. However, small numbers of patients and other methodological shortcomings limit the impact of evidence provided.     

Validation of the Danish version of the brief negative symptom scale

Abstract

Objective: The Brief Negative Symptom Scale (BNSS) is an instrument for evaluating negative symptoms (NS) in schizophrenia based on the 2005 consensus statement by the National Institute of Mental Health. This study examines the validity and reliability of the Danish version of BNSS.

Materials and methods: Acutely and chronically affected patients with schizophrenia or schizoaffective disorder were assessed with BNSS along with other psychopathological scales and clinical measures. Convergent and discriminant validity of BNSS was evaluated by its relationships with these assessments. Inter-rater agreement was estimated by the intraclass correlation coefficient (ICC).

Results: Forty-nine subjects were included; the mean age was 33.1 (±10.8) years and 32 (65%) were males. BNSS correlated strongly with traditional assessment tools for NS and poorly with measures of depressive and extrapyramidal symptoms, except for Parkinsonism. Moreover, BNSS correlated well with the assessment of positive symptoms. The ICC of BNSS was 0.95 (n?=?19, 95% CI: 0.88–0.98).

Conclusions: Overall, BNSS holds appropriate psychometric properties in terms of reliability and validity. However, discriminant validity was compromised by correlations with positive symptoms and Parkinsonism. The former originates presumably from NS secondary to positive symptoms since the sample included acutely psychotic patients, and the latter from overlapping rating criteria regarding facial expressivity impairment.