Antipsychotic drugs reverse MK-801-induced cognitive and social interaction deficits in zebrafish (Danio rerio)

Schizophrenia is a severe mental illness characterized by positive and negative symptoms and cognitive deficits. Reduction of glutamatergic neurotransmission by NMDA receptor antagonists mimics symptoms of schizophrenia. Modeling social interaction and cognitive impairment in animals can be of great benefit in the effort to develop novel treatments for negative and cognitive symptoms of schizophrenia. Studies have demonstrated that these behavioral changes are, in some cases, sensitive to remediation by antipsychotic drugs. The zebrafish has been proposed as a candidate to study the in vivo effects of several drugs and to discover new pharmacological targets. In the current study we investigated the ability of antipsychotic drugs to reverse schizophrenia-like symptoms produced by the NMDA receptor antagonist MK-801. Results showed that MK-801 (5 μM) given pre-training hindered memory formation while both atypical antipsychotics sulpiride (250 μM) and olanzapine (50 μM) improved MK-801-induced amnesia. The same change was observed in the social interaction task, where atypical antipsychotics reversed the MK-801-induced social interaction deficit whereas the typical antipsychotic haloperidol (9 μM) was ineffective to reverse those behavioral deficits. Therefore, MK-801-treated zebrafish showed some behavioral features observed in schizophrenia, such as cognitive and social interaction deficits, which were reverted by current available atypical drugs.     

Cognitive function in schizophrenia. Deficits, functional consequences, and future treatment.

This article has discussed the relationship between cognitive deficits and functional outcome in schizophrenia. This relationship was noted first by Kraepelin and Bleuler at the beginning of the twentieth century. With the introduction of conventional neuroleptics, the focus shifted toward the treatment of positive symptoms. In the past few decades, cognitive dysfunction has been recognized as a fundamental feature of schizophrenia and has been shown repeatedly to have a negative association with functional outcome [6]. Improvement in cognitive functioning became one of the most important clinical targets in the treatment of schizophrenia in the 1990s [82]. Main domains of cognition that are disrupted significantly in schizophrenia include attention, executive function, verbal and visuospatial working memory, and learning and memory. Although conventional antipsychotics are effective in treating positive symptoms, they lack the ability to improve cognitive impairment and produce poor functional outcome. Previous research has shown superior efficacy of atypical antipsychotics on cognitive impairments in schizophrenia compared with conventional antipsychotics. Because the heterogeneity of atypical antipsychotics in their pharmacologic properties, they have differential profiles of cognitive efficacy in patients with schizophrenia. Establishing the cognitive profile of each atypical antipsychotic is an important task. This knowledge can be used to address individual cognitive problems and needs. Because cognitive deficits have been shown to have associations with different aspects of clinical symptoms, limited learning in rehabilitation programs, and functional outcome in schizophrenia, targeting individual cognitive deficits would lead to greater treatment success in terms of clinical and functional outcome. Although atypical antipsychotics have some benefit on cognitive function, further efforts to improve cognitive function are required. Attempts at improving cognition in schizophrenia with specific cognitive enhancers pharmacologically and psychological therapies such as cognitive remediation might lead to better functional outcome in patients with schizophrenia.     

Schizophrenia, psychotropic drugs and cognition

The robust and specific associations between cognitive abilities and the functional prognosis of patients suffering from schizophrenia lead to a major concern for cognitive impairment in this disorder. Among the strategies considered to correct or enhance cognition in schizophrenia, drugs hold a pivotal place. Evidently, antipsychotic drugs, which are inextricable from patients' management, have generated considerable scrutiny in this topic. This paper first aims to outline the current views on the impact of antipsychotic drugs in schizophrenia. The distinction between conventional and atypical drugs is reminded in order to more precisely review existing data comparing the impact of these two types of molecules on cognitive impairment. More specifically, an elementary framework is proposed to facilitate the recognition of methodological flaws and offer a critical examination of previous findings. It emerges subsequently that differences between atypical and conventional drugs appear far less contrasted than initially suggested. Also, atypical antipsychotics compose a disparate pharmacological class and much clarification could be obtained by differentiating the individual effects of these molecules rather than considering them as a group. Finally, the relevance of these cognitive measures is also considered. In particular, we address alternative measures closer to real life situations as well as the growing interest in the broad field of social cognition. A last part of this article deals with strategies relying on adjunctive therapies. The fairly modest results obtained with these approaches is evoked and briefly reviewed.     

Molecular targets for treating cognitive dysfunction in schizophrenia

Cognitive impairment is a core feature of schizophrenia as deficits are present in the majority of patients, frequently precede the onset of other positive symptoms, persist even with successful treatment of positive symptoms, and account for a significant portion of functional impairment in schizophrenia. While the atypical antipsychotics have produced incremental improvements in the cognitive function of patients with schizophrenia, overall treatment remains inadequate. In recent years, there has been an increased interest in developing novel strategies for treating the cognitive deficits in schizophrenia, focusing on ameliorating impairments in working memory, attention, and social cognition. Here we review various molecular targets that are actively being explored for potential drug discovery efforts in schizophrenia and cognition. These molecular targets include dopamine receptors in the prefrontal cortex, nicotinic and muscarinic acetylcholine receptors, the glutamatergic excitatory synapse, various serotonin receptors, and the gamma-aminobutyric acid (GABA) system.     

The effects of atypical antipsychotic drugs on neurocognitive impairment in schizophrenia: a review and meta-analysis.

Cognitive deficits are a fundamental feature of the psychopathology of schizophrenia. Yet the effect of treatment on this dimension of the illness has been unclear. Atypical antipsychotic medications have been reported to reduce the neurocognitive impairment associated with schizophrenia. However, studies of the pattern and degree of cognitive improvement with these compounds have been methodologically limited and have produced variable results, and few findings have been replicated. To clarify our understanding of the effects of atypical antipsychotic drugs on neurocognitive deficits in patients with schizophrenia, we have (1) reported on newly established standards for research design in studies of treatment effects on cognitive function in schizophrenia, (2) reviewed the literature on this topic and determined the extent to which 15 studies on the effect of atypical antipsychotics met these standards, (3) performed a meta-analysis of the 15 studies, which suggested general cognitive enhancement with atypical antipsychotics, and (4) described the pharmacological profile of these agents and considered the pharmacological basis for their effects on neurocognition. Finally, we suggest directions for the development of new therapeutic strategies.     

Benefits and limits of anticholinergic use in schizophrenia: Focusing on its effect on cognitive function

All currently available antipsychotic drugs are the dopamine D₂ receptor antagonists and are capable of producing extrapyramidal side‐effects (EPS). Anticholinergic drugs are primarily used to treat EPS or prevent EPS induced by antipsychotics in the treatment of psychosis and schizophrenia. However, they can cause a variety of distressing peripheral side‐effects (e.g. dry mouth, urinary disturbances, and constipation) and central adverse effects (e.g. cognitive impairment, worsening of tardive dyskinesia, and delirium). Disturbances in cognitive abilities are cardinal features of schizophrenia from its earliest phases and account for much of the functional disability associated with the illness. It is likely that long‐term concomitant administration of anticholinergics exacerbates the underlying cognitive impairment in patients with schizophrenia and subsequently affects patients' quality of life. Thus, current treatment guidelines for schizophrenia generally do not recommend the prophylactic and long‐term use of anticholinergics. However, the high use of long‐term anticholinergic drugs with antipsychotics has been identified as an important issue in the treatment of schizophrenia in several countries. To assess the benefits and limits of anticholinergic use in psychosis and schizophrenia, this article will provide a brief review of the pharmacology and clinical profiles of anticholinergic drugs and will focus on their effects on cognitive function in schizophrenia, particularly during the course of the early phase of the illness. In addition, we will address the effects of discontinuation of anticholinergics on cognitive function in patients with schizophrenia and provide a strategy for adjunctive anticholinergic use in patients treated with long‐acting injectable antipsychotics.     

Dopamine and incentive learning: A framework for considering antipsychotic medication effects

Hyperfunction of brain dopamine (DA) systems is associated with psychosis in schizophrenia and the medications used to treat schizophrenia are DA receptor blockers. DA also plays a critical role in incentive learning produced by rewarding stimuli. Using DA as the link, these results suggest that psychosis in schizophrenia can be understood from the point of view of excessive incentive learning. Incentive learning is mediated through the non-declarative memory system and may rely on the striatum or medial prefrontal cortex depending on the task. Typical and atypical antipsychotics differentially affect expression of the immediate early gene c-fos, producing greater activity in the striatum and medial prefrontal cortex, respectively. This led to the hypothesis that performance of schizophrenic patients on tasks that depend on the striatum or medial prefrontal cortex will be differentially affected by their antipsychotic medication. Results from a number of published papers supported this dissociation. Furthermore, the effects of two atypical drugs, clozapine and olanzapine, on c-fos expression were different from another atypical, risperidone that resembles the typical antipsychotics. Similarly, in tests of incentive learning, risperidone acted like the typical antipsychotics. Thus, typical and atypical antipsychotic drugs differed in the types of cognitive performance they affected and, furthermore, members of the atypical class differed in their effects on cognition. It remains the task of researchers and clinicians to sort out the symptoms associated with the endogenous illness from possible iatrogenic symptoms resulting from the antipsychotic medications used to treat schizophrenia.     

Effects of clozapine on psychiatric symptoms, cognition, and functional outcome in schizophrenia

This study focused on the symptomatic and cognitive effects of the atypical antipsychotic clozapine in chronic hospitalized schizophrenia patients. Further, it explored how these effects might be related to discharge, an important functional outcome. Patients were assessed at baseline and at regular intervals with clinical instruments and a cognitive battery. Clozapine treatment produced symptomatic and cognitive improvements, positive changes that appeared to occur independently of one another. Baseline cognitive performance, as well as cognitive change with treatment, predicted discharge. Further investigation of the effects of clozapine and other atypical antipsychotics on cognition and functional outcome is warranted.     

Effect of switching to atypical antipsychotics on memory in patients with chronic schizophrenia

While the usefulness of atypical antipsychotics for improving cognitive function has been proven, the specific effects of these drugs are still unknown. The objective of this study was to investigate changes of the immediate memory and verbal working memory in patients with chronic schizophrenia after switching to one of four atypical antipsychotic agents and cessation of anticholinergic therapy. The subjects included 77 schizophrenic patients who were treated primarily with typical antipsychotics. Treatment was randomly switched to one of four atypical antipsychotics (olanzapine, perospirone, quetiapine, or risperidone) over a 4-week period, and then the drug was continued for another 4 weeks while the patient was taken off anticholinergics. The immediate memory, verbal working memory, and symptoms were evaluated. Significant improvement of immediate memory was only seen with olanzapine and risperidone. Improvement was also seen after switching to perospirone, but immediate memory worsened after treatment with this anticholinergic drug was discontinued. Deterioration was seen after switching to quetiapine, but immediate memory improved and reached the previous level after treatment with anticholinergic drugs was discontinued. Significant improvement of the verbal working memory was only seen during risperidone administration. The findings suggested that switching chronic schizophrenic patients to atypical antipsychotics can improve both the immediate memory and the verbal working memory when risperidone is used, while improvement of immediate memory can be expected with olanzapine. From the viewpoint of improving the memory, quetiapine should not be administered concomitantly with anticholinergic drugs, and caution should be exercised when discontinuing anticholinergic drugs during treatment with perospirone.     

Effects of antipsychotics on prepulse inhibition of the startle response in drug-na?ve schizophrenic patients.

BACKGROUND: Disturbances in sensorimotor gating measured by prepulse inhibition of the startle response (PPI) have frequently been reported in medicated and unmedicated schizophrenia spectrum patients and in their relatives, suggesting that the deficit represents a stable vulnerability marker for schizophrenia. Clinical data on the effects of antipsychotics on PPI disturbances are scarce, but from preclinical studies, antipsychotics have been shown to influence PPI. To differentiate pathogenetic mechanisms from drug related effects, longitudinal clinical studies on the effect of antipsychotic treatment on PPI in drug-naive first-episode schizophrenic patients are needed. METHODS: First-episode schizophrenic patients never previously medicated with antipsychotics were examined at inclusion and after 3 months of treatment with the atypical antipsychotic compound, risperidone, or the typical drug, zuclopenthixol. Healthy controls were used as a comparison group. RESULTS: The results confirm deficits in PPI in drug-naive first-episode patients. No effect of antipsychotic treatment on PPI dysfunction was observed in any of the treatment groups. CONCLUSIONS: The data are the first to show the possible effect of treatment with antipsychotic drugs on PPI disturbances in a longitudinal study of drug-naive schizophrenic patients. The data do not support any influence of treatment with antipsychotic drugs on sensorimotor gating deficits. Instead, the results point to the impairment in PPI as a stable vulnerability indicator.     

The effects of clozapine, risperidone, and olanzapine on cognitive function in schizophrenia.

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.     

Prefrontal dysfunction and a monkey model of schizophrenia

The prefrontal cortex is implicated in cognitive functioning and schizophrenia. Prefrontal dysfunction is closely associated with the symptoms of schizophrenia. In addition to the features typical of schizophrenia, patients also present with aspects of cognitive disorders. Based on these relationships, a monkey model mimicking the cognitive symptoms of schizophrenia has been made using treatment with the non-specific competitive N-methyl-D-aspartate receptor antagonist, phencyclidine. The symptoms are ameliorated by atypical antipsychotic drugs such as clozapine. The beneficial effects of clozapine on behavioral impairment might be a specific indicator of schizophrenia-related cognitive impairment.     

On the trail of a cognitive enhancer for the treatment of schizophrenia

The aim of this critical review is to address that the study of cognition and antipsychotics is not always driven by logic and that research into real pro-cognitive drug treatments must be guided by a better understanding of the biochemical mechanisms underlying cognitive processes and deficits. Many studies have established that typical neuroleptic drugs do not improve cognitive impairment. Atypical antipsychotics improve cognition, but the pattern of improvement differs from drug to drug. Diminished cholinergic activity has been associated with memory impairments. Why atypical drugs improve aspects of cognition might lie in their ability to increase dopamine and acetylcholine in the prefrontal cortex. An optimum amount of dopamine activity in the prefrontal cortex is critical for cognitive functioning. Another mechanism is related to procedural learning, and would explain the quality of the practice during repeated evaluations with atypical antipsychotics due to a more balanced blockage of D2 receptors. Laboratory studies have shown that clozapine, ziprasidone, olanzapine, and risperidone all selectively increase acetylcholine release in the prefrontal cortex, whereas this is not true for haloperidol and thioridazine. A few studies have suggested that cholinomimetics or AChE inhibitors can improve memory functions not only in Alzheimer's disease but also in other pathologies. Some studies support the role of decreased cholinergic activity in the cognitive deficits while others demonstrate that decreased choline acetyltransferase activity is related to deterioration in cognitive performance in schizophrenia. Overall, results suggest the hypothesis that the cholinergic system is involved in the cognitive dysfunctions observed in schizophrenia and that increased cholinergic activity may improve these impairments. Furthermore, a dysfunction of glutamatergic neurotransmission could play a key role in cognitive deficits associated with schizophrenia. Further meta-analysis of various clinical trials in this field is required to account for matters on the grounds of evidence-based medicine.     

Beyond the dopamine receptor: novel therapeutic targets for treating schizophrenia

All current drugs approved to treat schizophrenia appear to exert their antipsychotic effects through blocking the dopamine D2 receptor. Recent meta-analyses and comparative efficacy studies indicate marginal differences in efficacy of newer atypical antipsychotics and the older drugs, and little effects on negative and cognitive symptoms. This review integrates findings from postmortem, imaging, and drug-challenge studies to elucidate a corticolimbic "pathologic circuit" in schizophrenia that may be particularly relevant to the negative symptoms and cognitive impairments of schizophrenia. Potential sites for pharmacologic intervention targeting glutatatergic, GABAergic, and cholinergic neurotransmission to treat these symptoms of schizophrenia are discussed.     

Long-term outcomes in chronically hospitalized geriatric patients with schizophrenia: retrospective comparison of first generation and second generation antipsychotics

INTRODUCTION: Some groups have reported the longitudinal course of elderly poor outcome schizophrenic patients to be characterized by progressive decline in cognitive functions and functional capacity. Although many of these patients experience minimal reduction of psychotic symptoms, there may be beneficial effects of antipsychotic treatments on cognitive functions and functional capacity. METHODS: This naturalistic study compared the longitudinal course of psychotic symptoms, cognitive functions and functional impairment in geriatric schizophrenic patients treated with first generation (N=97) or second generation (N=78) antipsychotic medications. Mixed effects linear regression analyses were used to examine the effects of treatment (first generation vs. second generation antipsychotic), time and treatment x time. RESULTS: Cognitive functions (Mini Mental State Examination time effect estimate=-.41, p<.001; ADAS-L Cog time effect estimate=.64, p<.001) and self-care skills (ADAS-L Self-Care time effect estimate=.65, p<.001) declined over time for the subject group as a whole and this decline was not modified by treatment with second generation antipsychotics relative to first generation antipsychotics. Similarly, second generation antipsychotic treatment produced no effect on the progressive worsening of negative symptom over time. CONCLUSION: This long-term naturalistic study of poor outcome geriatric patients with schizophrenia did not find atypical antipsychotics to produce any differential protective effect relative to typical antipsychotics on the long-term manifestations of symptoms, cognition and self-care in poor outcome geriatric schizophrenic patients.     

Antipsychotic treatment for late-life schizophrenia

The clinical characteristics of schizophrenia in older persons vary to some extent, depending on whether the onset of illness was earlier or later in life. Regardless of age of onset, antipsychotic medications are the mainstay of treatment. Age-related physiologic changes make older persons more sensitive to the therapeutic and toxic effects of antipsychotics. There is a paucity of controlled studies on the efficacy of antipsychotic medications in older persons with schizophrenia. Existing data suggest that atypical antipsychotics are at least as efficacious as and better tolerated than the conventional agents. In late-life schizophrenia, important adverse effects of antipsychotics include sedating, anticholinergic and cardiovascular effects, extrapyramidal symptoms, and tardive dyskinesia. Certain atypical antipsychotics are associated with a risk of metabolic changes as well as agranulocytosis. Clinical recommendations include a thorough diagnostic evaluation followed by treatment with low doses of atypical antipsychotics. Medication alone is likely to be less effective than when it is combined with an appropriate psychosocial intervention.     

Does stimulation of 5-HT(1A) receptors improve cognition in schizophrenia?

Cognitive impairment is a key feature of schizophrenia and may be the most important determinant of outcome in schizophrenia. This impairment is diffuse and may reflect abnormalities in frontal cortex, hippocampus and other brain regions. While deficits in glutamatergic, GABAergic, dopaminergic and cholinergic impairment have received the most attention as the basis of this impairment, there are many reasons for considering the role of serotonin (5-HT) in contributing to these deficits. This may be via its influence on dopaminergic, cholinergic, glutamatergic and GABAergic function, as well as various growth factors that have been implicated in schizophrenia. Of the 14 known serotonin receptors, the 5-HT(1A) receptor is a key candidate for mediating at least some of the influence 5-HT has on cognition. 5-HT(1A) receptors are upregulated in postmortem specimens from patients with schizophrenia, suggesting a deficit in 5-HT(1A) function in this disorder. Atypical but not typical antipsychotic drugs stimulate the efflux of dopamine from cortex by a 5-HT(1A)-dependent mechanism. A series of studies from this laboratory involving the 5-HT(1A) partial agonists tandospirone and buspirone have reported a modest ability of these agents to improve some domains of cognition in patients receiving typical or atypical antipsychotic drugs. Preclinical studies have been mixed in regard to the ability of 5-HT(1A) partial agonists to improve cognition in various paradigms; some studies report that 5-HT(1A) antagonists are effective to improve cognition. Aripiprazole, clozapine, olanzapine, perospirone, quetiapine risperidone, and ziprasidone are examples of atypical antipsychotic drugs which are either direct or indirect 5-HT(1A) agonists which have been shown to improve cognitive function in patients with schizophrenia. Further study is needed to determine the role of the 5-HT(1A) receptor to improve cognitive function in schizophrenia.     

Subjective well-being under antipsychotic treatment and its meaning for compliance and course of disease

Since the introduction of atypical antipsychotics success criteria of an effective antipsychotic treatment are more comprehensive. For instance these criteria include negative symptoms as well as cognitive deficits which are both important for the long-term prognosis of schizophrenia. However, the most fundamental change was the inclusion of the patients' perspective with respect to the treatment. Quality of life assessments as well as evaluation of subjective well-being are of increasing scientific interest and have been assessed in numerous studies. Accordingly there has been ascertained that schizophrenic patients are indeed able to fill out self reports consistently and reliably and it has been shown that patients' perspective differs enormously from the evaluation of psychiatrists with regard to antipsychotic treatment. In consideration of the variety of atypical antipsychotics and different resulting effects for compliance and prognosis of schizophrenia it seems needful to strengthen patients' perspective as an important success criterion of antipsychotic treatment.     

Cognitive function and social abilities in patients with schizophrenia: relationship with atypical antipsychotics

Although atypical antipsychotics have been associated with improvements in cognitive function in schizophrenia, the neurochemical basis for such effects is not well understood. Candidate neurotransmitter systems primarily involve dopamine and serotonin. The current study explored this issue by examining the cognitive abilities, social function and quality of life in patients with schizophrenia who were medicated with atypical antipsychotics. Comparisons were done for matched schizophrenia patients who were on antipsychotics with (i) an affinity for multiple receptors (olanzapine, clozapine, quetiapine) versus those that have preferential affinity for dopamine receptors (risperidone, amisulpride); and patients on medication with (ii) a high affinity for serotonin (5HT-2A) receptors (risperidone, olanzapine, clozapine) versus those with a low (or no) affinity for 5HT-2A receptors (quetiapine, amisulpride). No differences emerged between groups on any cognitive or social variable when the groups were compared for the dopaminergic properties of antipsychotic medication. By contrast, differences did emerge when patients were compared on the 5HT-2A affinity of their antipsychotic medications. Patients on low 5HT-2A-affinity antipsychotics exhibited a better performance on a measure of selective attention and adjustment to living. These findings accord with the notion that serotonergic mechanisms are important determinants of both the cognitive and the social effects of the atypical antipsychotics.     

Cognitive effects of atypical antipsychotic drugs in first-episode drug-nave schizophrenic patients

Cognitive impairment is a core feature of schizophrenia. The present randomized open study enrolled antipsychotic-nave patients who were experiencing their first episode of schizophrenia. After baseline neurocognitive tests and clinical assessment, subjects were randomly assigned to olanzapine, risperidone and aripiprazole treatment groups. A battery of neurocognitive tests showed that risperidone produced cognitive benefits in all five cognitive domains, including verbal learning and memory, visual learning and memory, working memory, processing speed, and selective attention; olanzapine improved processing speed and selective attention; and aripiprazole improved visual learning and memory, and working memory. However, the three atypical antipsychotic drugs failed to reveal any significant differences in the composite cognitive scores at the study endpoint. In addition, the three drugs all significantly improved clinical measures without significant differences between the drugs after 6 months. These results suggest that the atypical antipsychotics, olanzapine, risperidone and aripiprazole may improve specific cognitive domains with similar global clinical efficacy. In clinical practice, it may be feasible to choose corresponding atypical antipsychotics according to impaired cognitive domains.