[Cognition, schizophrenia and the effect of antipsychotics].
BACKGROUND
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.


RESULTS
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.


CONCLUSIONS
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Stip
E
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.
D014150:Antipsychotic Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D001569:Benzodiazepines / Q000494:pharmacology / Q000627:therapeutic use; D003024:Clozapine / Q000494:pharmacology / Q000627:therapeutic use; D003071:Cognition / Q000187:drug effects*; D003072:Cognition Disorders / Q000175:diagnosis* / Q000453:epidemiology*; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D005625:Frontal Lobe / Q000378:metabolism; D006801:Humans; D008279:Magnetic Resonance Imaging; D009483:Neuropsychological Tests; D000077152:Olanzapine; D017397:Prefrontal Cortex / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000187:drug effects / Q000378:metabolism; D018967:Risperidone / Q000494:pharmacology / Q000627:therapeutic use; D012559:Schizophrenia / Q000188:drug therapy* / Q000453:epidemiology*; D012720:Severity of Illness Index
D014150:Antipsychotic Agents; D017448:Receptors, Dopamine D2; D001569:Benzodiazepines; D003024:Clozapine; D018967:Risperidone; D000077152:Olanzapine