Stip E
Université de Montréal, Chaire de Schizophrénie, Centre de Recherche Fernand-Seguin, Hôpital Louis-H. Lafontaine, Hôpital Sacré-Coeur de Montréal, 7331, rue Hochelaga, Montréal, (Québec) H1N 3V2.
Encephale. 2006 May-Jun;32(3 Pt 1):341-50. doi: 10.1016/s0013-7006(06)76162-0.
In this review, we conclude that cognitive impairments are as important as positive and negative symptoms in the clinical assessment and management of patients with schizophrenia. This is not a comprehensive review, considering that the new Measurement And Treatment Research to Improve Cognition in Schizophrenia (MATRICS) model will soon provide valuable data. It is however a product of the collective efforts of a French Canadian clinical research team that proposes a synthesis of data of pragmatic interest to clinicians. Medication with improved safety and cognition profile, gene-rally lead to better outcomes by facilitating compliance with drug regimens and rehabilitation programs. In addition, measures of attention and executive function (EF) appear to improve with novel antipsychotics when compared to traditional neuroleptics. Nevertheless, evaluating cognitive performance is not a routine procedure outside the domain of research. For example, procedural learning (PL) -- an important measure of cognitive function -- refers to cognitive and motor learning processes in which execution strategies cannot be explicitly described (ie learning by doing). These actions or procedures are then progressively learned through trial and error until automation of optimal performance is established. Procedural learning is rarely assessed in clinical practice. Inconsistent findings regarding the effects of neuroleptic drugs on PL have been reported.
Trials using acute administration of chlorpromazine in normal subjects induced PL deficits, suggesting the direct effect of neuroleptics, presumably via a D(2) dopamine blockade in the striatum. In a recent study by our group, schizophrenia patients, divided into three groups according to their pharmacological treatment (haloperidol, clozapine and risperidone) were compared to normal controls on two PL tasks; a visuomotor learning task (mirror drawing) and a problem solving learning task (Tower of Toronto). No deficits were detected in patients receiving clozapine, while haloperidol was associated with deleterious effects in both tasks. Risperidone, however, produced different effects depending on the task performed. Another 6-month double-blind Canadian study confirmed the beneficial effect of olanzapine on PL compared to haloperidol and risperidone. The differential effects of drugs on the striatal D(2) receptors, -irrespective of their classification as conventional or atypical neuroleptics and the specific process implicated in each of these PL tasks may explain these results. Tracer studies using radioactive benzamides (IBZM) specific to striatal D receptors determined a relationship between striatal D(2) receptor occupancy and PL performance such as the mirror drawing task. Using this method, data obtained in Montreal on schizophrenia patients receiving olanzapine and haloperidol have shown that the coefficient of determination in a visuomotor PL task varied inversely with D2 receptor saturation.
This review probes the effect of impaired cognitive functions on schizophrenia patients' quality of life. Cognitive deficits found in schizophrenia affect planning, along with the aptitude to initiate and -regulate a goal-directed behaviour. These impairments have been repeatedly, yet inconclusively, attributed to frontal lobe dysfunction. Morphological findings obtained from neuroimaging studies remain inconsistent, some noting no differences between patients and controls while others observing reduced prefrontal volumes in schizophrenia patients. Conversely, functional neuroimaging (fMRI) demonstrated reduced frontal blood flow relative to global cerebral perfusion in schizophrenia patients. Overall, neuroimaging literature provides reliable evidence of frontal impairments in schizophrenia, although the average magnitude of difference between patients and controls is insufficient to defend a frontal lobe dysfunction hypo-thesis, as far as brain volume, resting cerebral metabolism or blood flow are concerned. The only measurement clearly distinguishing between patients and controls is fMRI of the frontal lobe while performing an experimentally controlled task. Here, schizophrenia patients fail to activate their frontal cortex when required. Sensitive to frontal lobe dysfunction are Neuropsychological tests of executive function.
A study conducted in Montreal assessed the relation between EF impairments and difficulties in planning daily activities in schizophrenia patients scoring more than 3 on at least 4 items of the PANSS negative subscale. Performances on EF, memory and script generation were measured and compared to controls. Script production task required that subjects recite 10-20 actions that would normally be carried out for during daily life activity (going to a restaurant, buying groceries, etc.). Patients' performances were significantly lower with higher perserveration and sequencing impairments. Routine activities such as the ability to cook a meal were similarly investigated. Patients were videotaped in a kitchen while preparing a specific meal.
Optimal sequence of micro- and macro-steps necessary to prepare the meal in a minimal time were measured. Sequencing errors, repetitions and omissions were significantly higher compared to controls. In addition, temporal organization was positively correlated with negative symptoms and low EF performance on neuro-psychological tasks. Thus concluding that EF impairment interferes with basic routine activities in schizophrenia patients, notably those with negative symptoms. Last but not least, we assessed the progress of patients' subjective complaints with regards to their cognitive functions using tests such as the SSTICS, specifically developed to address subjective cognitive complaints and insight.
This review concludes that from now on cognitive deficit should be recognized as a major element in social and professional integration of schizophrenia patients, and should become a standardized assessment approach in clinical practice.
在本综述中，我们得出结论，认知障碍在精神分裂症患者的临床评估和管理中与阳性和阴性症状同样重要。鉴于新的改善精神分裂症认知的测量与治疗研究（MATRICS）模型即将提供有价值的数据，本综述并非全面综述。然而，它是一个法裔加拿大临床研究团队集体努力的成果，该团队对临床医生具有实际意义的数据进行了综合分析。具有更好安全性和认知特征的药物，通常通过促进对药物治疗方案和康复计划的依从性，带来更好的治疗效果。此外，与传统抗精神病药物相比，新型抗精神病药物似乎能改善注意力和执行功能（EF）。然而，在研究领域之外，评估认知表现并非常规程序。例如，程序学习（PL）——认知功能的一项重要指标——指的是认知和运动学习过程，其中执行策略无法明确描述（即通过实践学习）。这些动作或程序随后通过反复试验逐步学习，直到建立最佳表现的自动化。程序学习在临床实践中很少被评估。关于抗精神病药物对PL影响的研究结果并不一致。
在正常受试者中急性给予氯丙嗪的试验导致PL缺陷，提示抗精神病药物的直接作用，可能是通过纹状体中的D（2）多巴胺阻断。在我们团队最近的一项研究中，根据药物治疗将精神分裂症患者分为三组（氟哌啶醇、氯氮平和利培酮），并在两项PL任务上与正常对照组进行比较；一项视觉运动学习任务（镜像绘画）和一项解决问题学习任务（多伦多塔）。接受氯氮平治疗的患者未检测到缺陷，而氟哌啶醇在两项任务中均产生有害影响。然而，利培酮根据所执行的任务产生不同的效果。另一项为期6个月的加拿大双盲研究证实，与氟哌啶醇和利培酮相比，奥氮平对PL有有益影响。药物对纹状体D（2）受体的不同作用，无论其被归类为传统或非典型抗精神病药物，以及这些PL任务中涉及的具体过程，可能解释了这些结果。使用对纹状体D受体特异的放射性苯甲酰胺（IBZM）进行的示踪研究确定了纹状体D（2）受体占有率与PL表现（如镜像绘画任务）之间的关系。使用这种方法，在蒙特利尔对接受奥氮平和氟哌啶醇治疗的精神分裂症患者获得的数据表明，视觉运动PL任务中的决定系数与D2受体饱和度呈反比。
本综述探讨了认知功能受损对精神分裂症患者生活质量的影响。精神分裂症患者中发现的认知缺陷会影响计划，以及发起和调节目标导向行为的能力。这些损害反复但不确定地归因于额叶功能障碍。神经影像学研究获得的形态学结果并不一致，一些研究指出患者与对照组之间没有差异，而另一些研究则观察到精神分裂症患者前额叶体积减小。相反，功能神经影像学（fMRI）显示精神分裂症患者相对于全脑灌注额叶血流减少。总体而言，神经影像学文献提供了精神分裂症患者额叶损害的可靠证据，尽管就脑体积、静息脑代谢或血流而言，患者与对照组之间差异的平均幅度不足以支持额叶功能障碍假说。唯一能清楚区分患者与对照组的测量方法是在执行实验控制任务时对额叶进行fMRI检查。在此，精神分裂症患者在需要时无法激活其额叶皮质。对额叶功能障碍敏感的是执行功能的神经心理学测试。
在蒙特利尔进行的一项研究评估了在阳性和阴性症状评定量表（PANSS）阴性分量表至少4项得分超过3分的精神分裂症患者中，EF损害与日常活动计划困难之间的关系。测量了EF、记忆和脚本生成方面的表现，并与对照组进行比较。脚本生成任务要求受试者列举10 - 20项日常生活活动（去餐馆、买菜等）中通常会进行的动作。患者的表现明显较低，存在更高的持续和排序障碍。类似地对烹饪等日常活动能力进行了研究。在患者准备特定餐食时在厨房对其进行录像。
测量了在最短时间内准备餐食所需的微观和宏观步骤的最佳顺序。与对照组相比，排序错误、重复和遗漏明显更高。此外，时间组织与阴性症状以及神经心理学任务中的低EF表现呈正相关。因此得出结论，EF损害会干扰精神分裂症患者的基本日常活动，尤其是那些有阴性症状的患者。最后但同样重要的是，我们使用专门为解决主观认知抱怨和洞察力而开发的测试（如SSTICS）评估了患者对其认知功能的主观抱怨进展情况。
本综述得出结论，从现在起，认知缺陷应被视为精神分裂症患者社会和职业融入的一个主要因素，并应成为临床实践中的标准化评估方法。
