The Effects of Clozapine, Risperidone, and Olanzapine on Cognitive Function in Schizophrenia

Abstract

Cognitive function is markedly impaired in most patients with schizophrenia. Antecedents of this impairment are evident in childhood. The cognitive disability is nearly fully developed at the first episode of psychosis in most patients. The contribution of cognitive impairment to outcome in schizophrenia, especially work function, has been established. Preliminary results indicate that cognitive function, along with disorganization symptoms, discriminate schizophrenia patients who are able to work full-time from those who are not. Typical neuroleptic drugs lack the ability to improve the various domains of cognitive function impaired in schizophrenia. Atypical antipsychotic drugs pharmacologically related to clozapine-quetiapine, olanzapine, risperidone, sertindole, and ziprasidone--share the ability to produce fewer extrapyramidal symptoms than typical neuroleptic drugs and more potent antagonism of serotonin2a relative to dopamine2 receptors. However, they have a number of different clinical effects. We have identified all the studies of clozapine, olanzapine, and risperidone that provide data on their effects on cognition in schizophrenia. Data for each drug are reviewed separately in order to identify differences among them in their effects on cognition. Twelve studies that report cognitive effects of clozapine are reviewed. These studies provide (1) strong evidence that clozapine improves attention and verbal fluency and (2) moderate evidence that clozapine improves some types of executive function. However, results of the effects of clozapine on working memory and secondary verbal and spatial memory were inconclusive. Risperidone has relatively consistent positive effects on working memory, executive functioning, and attention, whereas improvement in verbal learning and memory was inconsistent. Preliminary evidence presented here suggests that olanzapine improves verbal learning and memory, verbal fluency, and executive function, but not attention, working memory, or visual learning and memory. Thus, atypical antipsychotic drugs as a group appear to be superior to typical neuroleptics with regard to cognitive function. However, available data suggest that these drugs produce significant differences in specific cognitive functions. These differences may be valuable adjunctive guides for their use in clinical practice if cognitive improvements reach clinical significance. The effects of the atypical antipsychotic drugs on cholinergic and 5-HT2a-mediated neurotransmission as the possible basis for their ability to improve cognition are discussed. It is suggested that the development of drugs for schizophrenia should focus on improving the key cognitive deficits in schizophrenia: executive function, verbal fluency, working memory, verbal and visual learning and memory, and attention.

A preliminary investigation into the effects of antipsychotics on sub-chronic phencyclidine-induced deficits in attentional set-shifting in female rats

“…It has been widely reported that atypical antipsychotics have some beneficial effect on cognitive deficits [9,23,24,40,50]. However, it is important to appreciate the limitations of models such as this one as, although clozapine and risperidone effectively reversed the cognitive deficits observed in this experiment, the CATIE study highlights the fact that these antipsychotics do not provide consistent improvement of cognitive symptoms in patients [38].…”

Reversal of Subchronic PCP-Induced Deficits in Attentional Set Shifting in Rats by Sertindole and a 5-HT6 Receptor Antagonist: Comparison Among Antipsychotics

“…Specifically, clozapine has demonstrated limited or no effects on executive function (Meltzer and McGurk, 1999;Hoff et al, 1996;Bellack et al, 2004). Risperidone has been shown either to be not effective (Bellack et al, 2004;Remillard et al, 2005;Lee et al, 2007) or slightly effective, as measured by Wisconsin Card Sorting Test (Meltzer and McGurk, 1999;Harvey et al, 2005), and olanzapine produces effects in the same range as risperidone (Meltzer and McGurk, 1999;Bilder et al, 2002;Keefe et al, 2007). In a small clinical trial, sertindole has shown superiority to haloperidol on executive function performance (Gallhofer et al, 2007).…”

“…Novel antipsychotic compounds (second-generation or 'atypical' antipsychotics) such as clozapine (Fitton and Heel, 1990), olanzapine (Fulton and Goa, 1997), and sertindole (Kane and Tamminga, 1997;Azorin et al, 2006) have some beneficial effect on negative symptoms and reduced potential to produce extrapyramidal side effects, but these agents have demonstrated inconsistent effects on cognitive function in patients with schizophrenia. Depending on the type of cognitive domain measured, second-generation antipsychotics have been reported to produce improvement (Mortimer 1997;Meltzer and McGurk, 1999;Keefe et al, 2007), no effect (Hoff et al, 1996;Meltzer and McGurk, 1999), and impairment (Goldberg et al, 1993). The effect of sertindole on cognitive function has not been investigated extensively; however, a small clinical trial indicates a beneficial effect on some cognitive substrates, including executive function, in individuals diagnosed with schizophrenia (Gallhofer et al, 2007).…”

Nonstereotyped Responding in Positive Schizotypy after a Single Dose of Levodopa

“…If similarities between schizotypy and schizophrenia existed on the neurochemical level, one would expect task performance to improve in schizotypal individuals with (second-generation) DA antagonists. Specifically, atypical neuroleptic agents were found to improve neuropsychological functioning including immediate recall, visuo-spatial construction, executive functions, verbal fluency, attention, and working memory (see eg Cuesta et al, 2001;Meltzer and McGurk, 1999;Purdon et al, 2001;Sumiyoshi et al, 2003 for overviews). However, our schizotypal participants performed in a most adaptive way after a DA agonist.…”