clozapine and Cognition-Disorders

Clozapine is the drug of choice for patients with unsatisfactory response to routine antipsychotic treatment. Polypharmacy is widely used among patients having clozapine-resistant schizophrenia, although no solid evidence exists for any effective augmentation therapy for this patient population. We aimed to study the efficacy of lamotrigine in the treatment of clozapine-resistant schizophrenia.. We conducted electronic searches of the Cochrane PsiTri database, the Website of metaRegister of Controlled Trials, including NIH ClinicalTrials.gov, and a clinical trial register by the manufacturer of lamotrigine (GlaxoSmithKline). All randomized placebo-controlled studies on patients receiving clozapine were included in the analysis. The primary outcome measure was a total score for symptoms of psychosis, and the secondary outcome measures were scores for positive and negative symptoms of psychosis. For continuous and binary data, standardized mean differences (SMD), and odds ratios (OR) and the number needed to treat (NNT) were calculated, respectively.. Five trials with 10 to 24 weeks duration and total of 161 randomized clozapine patients were included in the meta-analysis. Lamotrigine was superior to placebo augmentation in both the primary outcome measure (SMD 0.57, 95%CI 0.25-0.89, p<0.001; OR 0.19, 95%CI 0.09-0.43, p<0.001; NNT 4, 95%CI 3-6) and secondary outcome measures (SMD 0.34, 95%CI 0.02-0.65 for positive symptoms, SMD 0.43, 95%CI 0.11-0.75 for negative symptoms).. This meta-analysis suggests that lamotrigine augmentation may be an effective treatment for patients with clozapine-resistant schizophrenia. A substantial proportion of these most severely ill patients appeared to obtain clinically meaningful benefit from this combination treatment.

Topics: Age Factors; Anticonvulsants; Antipsychotic Agents; Clozapine; Cognition Disorders; Drug Resistance; Drug Therapy, Combination; Humans; Lamotrigine; Outcome Assessment, Health Care; Psychiatric Status Rating Scales; Randomized Controlled Trials as Topic; Schizophrenia; Schizophrenic Psychology; Treatment Outcome; Triazines

Schizophrenia (SZ) that is resistant to treatment with dopamine (DA) D2 antagonists may involve changes other than those in the dopaminergic system. Recently, histamine (HA), which regulates arousal and cognitive functions, has been suggested to act as a neurotransmitter in the central nervous system. Four HA receptors-H1, H2, H3, and H4-have been identified. Our recent basic and clinical studies revealed that brain HA improved the symptoms of SZ. The H3 receptor is primarily localized in the central nervous system, and it acts not only as a presynaptic autoreceptor that modulates the HA release but also as a presynaptic heteroreceptor that regulates the release of other neurotransmitters such as monoamines and amino acids. H3-receptor inverse agonists have been considered to improve cognitive functions. Many atypical antipsychotics are H3-receptor antagonists. Imidazole-containing H3-receptor inverse agonists inhibit not only cytochrome P450 but also hERG potassium channels (encoded by the human ether-a-go-go-related gene). Several imidazole H3-receptor inverse agonists also have high affinity for H4 receptors, which are expressed at high levels in mast cells and leukocytes. Clozapine is an H4-receptor agonist; this agonist activity may be related to the serious side effect of agranulocytosis caused by clozapine. Therefore, selective non-imidazole H3-receptor inverse agonists can be considered as novel antipsychotics that may improve refractory SZ.

Topics: Animals; Antipsychotic Agents; Arousal; Autoreceptors; Avoidance Learning; Binding, Competitive; Brain; Clozapine; Cognition; Cognition Disorders; Drug Approval; Histamine; Histamine Agonists; Histamine H3 Antagonists; Humans; Imidazoles; Male; Metabolic Clearance Rate; Motor Activity; Protein Binding; Rats; Rats, Sprague-Dawley; Receptors, Histamine H1; Receptors, Histamine H3; Schizophrenia; Sulfur Radioisotopes

Second generation antipsychotic medications have become synonymous with "atypicality." To support the clinical lore of equivalent efficacy with reduced risk of extrapyramidal symptoms, clinical trials have overwhelmingly chosen a high-potency first-generation antipsychotic (e.g., haloperidol) as a comparator. Very few clinical trials have compared a second-generation antipsychotic with a low- or mid-potency first-generation antipsychotic medication.. We identified eight completed, published, double-blind, randomized clinical trials that compared a second-generation antipsychotic with a low- or mid-potency first-generation antipsychotic and reviewed outcome measures for efficacy and extrapyramidal symptoms; 1,241 patients were represented in these eight trials.. Although data are very limited, mid- and low-potency first-generation antipsychotics show efficacy and extrapyramidal side effects that are comparable to those of second-generation antipsychotics.. Aside from clozapine, first-generation and second-generation antipsychotics represent a diverse group of medications that have heterogenous receptor profiles and side effects but comparable clinical efficacy and potential to cause extrapyramidal symptoms. Clinicians may provide better treatment for patients by considering the unique pharmacological and side-effect profile of each particular antipsychotic independent of its classification as a first- or second-generation agent.

Topics: Antipsychotic Agents; Basal Ganglia Diseases; Clozapine; Cognition Disorders; Haloperidol; Humans; Quality of Life; Schizophrenia

Topics: Amisulpride; Antipsychotic Agents; Aripiprazole; Basal Ganglia Diseases; Benzodiazepines; Clozapine; Cognition Disorders; Drug Tolerance; Dyskinesia, Drug-Induced; Haloperidol; Humans; Olanzapine; Piperazines; Quinolones; Risperidone; Schizophrenia; Sulpiride; Time Factors

Numerous clinical studies demonstrate that subanaesthetic doses of dissociative anaesthetics, which are non-competitive antagonists at the NMDA receptor, replicate in normal subjects the cognitive impairments, negative symptoms and brain functional abnormalities of schizophrenia. Post-mortem and genetic studies have identified several abnormalities associated with schizophrenia that would interfere with the activation of the glycine modulatory site on the NMDA receptor. Placebo controlled clinical trials with agents that directly or indirectly activate the glycine modulatory site consistently reduce negative symptoms and frequently improve cognition in patients with chronic schizophrenia, who are receiving concurrent typical antipsychotics. Thus, there is convincing evidence that the glycine modulatory site on the NMDA receptor is a valid therapeutic target for improving cognition and associated negative symptoms in schizophrenia.

Topics: Animals; Clozapine; Cognition Disorders; Double-Blind Method; GABA Antagonists; Glycine; Humans; Randomized Controlled Trials as Topic; Receptors, Glutamate; Receptors, N-Methyl-D-Aspartate; Schizophrenia; Schizophrenic Psychology

Topics: Antipsychotic Agents; Benzodiazepines; Clozapine; Cognition Disorders; Cytoskeletal Proteins; Dibenzothiazepines; Dopamine; Dopamine Antagonists; Humans; Nerve Tissue Proteins; Olanzapine; Pirenzepine; Proto-Oncogene Proteins c-fos; Quetiapine Fumarate; Receptors, Dopamine D2; Receptors, Serotonin; Risperidone; Schizophrenia; Serotonin Antagonists

Topics: Antipsychotic Agents; Basal Ganglia Diseases; Clozapine; Cognition Disorders; Humans; Reaction Time; Risperidone; Schizophrenia; Schizophrenic Psychology; Severity of Illness Index

The syndrome of schizophrenia often includes negative symptoms and severe cognitive deficits that are resistant to change with conventional pharmacotherapy. The efficacy of clozapine in the reduction of the negative syndrome has prompted a series of studies implicating circumscribed cognitive improvements. Restrictions on the use of clozapine have encouraged the development and introduction of novel compounds with a clinical efficacy profile similar to clozapine that are hoped also to have beneficial cognitive effects. The present review summarizes studies of the cognitive efficacy of novel antipsychotic medications, particularly in regard to issues in experiment design and study implementation that might facilitate additional research. Although preliminary support exists for relatively circumscribed improvement of cognitive status with the use of clozapine and risperidone--and more general improvement with the use of olanzapine--specific inferences relating cognitive change to particular treatments will remain speculative until more sophisticated investigations are completed. The present review emphasises the most relevant design limitations in past studies to provide practical suggestions for the implementation of subsequent investigations Previous results have established the possibility of a medication-based change in cognitive status in schizophrenia Future research will determine the validity of these changes, the cerebral mechanism involved, and their significance to improved prognosis.

Topics: Antipsychotic Agents; Benzodiazepines; Clozapine; Cognition Disorders; Dibenzothiazepines; Humans; Olanzapine; Pirenzepine; Quetiapine Fumarate; Risperidone; Schizophrenia; Severity of Illness Index

Cognitive impairment is a central feature of schizophrenia and has been correlated with negative symptoms and impaired social functioning. There is a growing body of data suggesting that the so-called atypical antipsychotic drugs (e.g. clozapine, risperidone, and olanzapine) are better at enhancing cognitive function than traditional neuroleptics. Preclinical studies of information processing using a pre-pulse inhibition model show that the mechanism of action of both olanzapine and clozapine for cognitive enhancement may involve glutamatergic/N-methyl-D-aspartate (NMDA) antagonism. Using positron emission tomography, we have described the metabolic and neurochemical correlates of cognitive impairment induced by glutamatergic/NMDA antagonism. A better understanding of the underlying causes of cognitive impairment may contribute to elucidating the pathophysiology of schizophrenia and the development of more efficacious treatments for this disorder.

Topics: Antipsychotic Agents; Benzodiazepines; Clozapine; Cognition Disorders; Glutamic Acid; Haloperidol; Humans; N-Methylaspartate; Olanzapine; Pirenzepine; Risperidone; Schizophrenia; Schizophrenic Psychology

Cognitive function may be markedly impaired in patients with schizophrenia; however, it has only recently been recognized as an important factor in determining patient outcome. Research has shown that improvements in cognitive functioning occur independently of improvements in positive or negative clinical symptoms, and whereas typical antipsychotics may improve clinical symptoms, they have little or no efficacy in improving cognitive dysfunction. However, there is evidence that the atypical antipsychotic clozapine may improve this core deficit of schizophrenia. This review summarizes 12 published studies that assessed the effect of clozapine on cognitive functioning. As a group, these studies suggest that psychomotor speed, verbal fluency, and verbal learning and memory may be improved by treatment with clozapine. Such cognitive improvements with clozapine treatment may offer an advantage to patients with schizophrenia by enhancing the possibility of better vocational functioning and quality of life.

Topics: Antipsychotic Agents; Clinical Trials as Topic; Clozapine; Cognition; Cognition Disorders; Humans; Memory; Neuropsychological Tests; Schizophrenia; Schizophrenic Psychology; Verbal Learning; Visual Perception

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-mediat

Topics: Antipsychotic Agents; Attention; Benzodiazepines; Clinical Trials as Topic; Clozapine; Cognition Disorders; Humans; Mental Recall; Neuropsychological Tests; Olanzapine; Pirenzepine; Risperidone; Verbal Learning

The advent of the atypical antipsychotics marked a new era in the history of the treatment of psychotic disorders. To evaluate the published literature about the available atypical antipsychotics--clozapine, risperidone, olanzapine, and quetiapine--and select the most appropriate treatment for specific patients, physicians need to understand the outcome measures used in clinical studies, the pharmacologic differences that explain varying side effect profiles, and pharmacoeconomic assessments that are used in the decision-making process. While the atypical antipsychotics have established efficacy in the overall treatment of schizophrenia, they may differ in their effects on factors such as cognitive function, overall quality of life, adverse events, and hospitalization status. Each of these factors should be considered when weighing treatment options for an individual patient.

Topics: Antipsychotic Agents; Benzodiazepines; Clozapine; Cognition Disorders; Cost-Benefit Analysis; Dibenzothiazepines; Drug Approval; Health Care Costs; Health Status; Hospitalization; Humans; Meta-Analysis as Topic; Olanzapine; Outcome Assessment, Health Care; Pirenzepine; Quality of Life; Quetiapine Fumarate; Risperidone; Schizophrenia; Schizophrenic Psychology; Treatment Outcome; United States; United States Food and Drug Administration

Cognitive deficits are an integral feature of schizophrenia and have a deleterious effect on the ability of schizophrenic patients to work and function in a social environment. Drugs that bring about substantial cognitive improvement represent a major contribution in improving the quality of life in schizophrenia. Recent studies have suggested that the atypical antipsychotics may be more useful than conventional agents for improving cognition. There is evidence that scores on neuropsychological assessments have improved after treatment with clozapine, risperidone, and quetiapine. Future research is needed to characterize and quantify the cognitive effects of the atypical antipsychotics.

Topics: Antipsychotic Agents; Clinical Trials as Topic; Clozapine; Cognition Disorders; Dibenzothiazepines; Humans; Neuropsychological Tests; Quality of Life; Quetiapine Fumarate; Risperidone; Schizophrenia; Schizophrenic Psychology; Treatment Outcome

Topics: Antipsychotic Agents; Benzodiazepines; Clinical Trials as Topic; Clozapine; Cognition Disorders; Humans; Olanzapine; Pirenzepine; Schizophrenia; Schizophrenic Psychology

Cognitive impairment is a relatively frequent aspect of schizophrenia. Deficits are most prominent in tasks involving attention, memory, and executive function. Although some research suggests that deterioration is progressive, these deficits appear to be relatively stable over time. Imaging and biochemical studies show that schizophrenia is characterized by a number of morphological, hemodynamic, and neurochemical abnormalities within systems integrating the cortex, temporal lobes, and various limbic structures. Neurochemical assays suggest that the neurotransmitters serotonin, dopamine, and glutamate play a significant role in the disease-associated decrement. Cognitive impairment in schizophrenia impedes psychosocial performance and eventual reintegration into society and is therefore an especially relevant target in the development of new therapeutic modalities. Atypical agents, such as clozapine and olanzapine, hold special promise in this area.

Topics: Antipsychotic Agents; Benzodiazepines; Cerebral Cortex; Clozapine; Cognition Disorders; Dopamine; Glutamic Acid; Humans; Limbic System; Olanzapine; Pirenzepine; Schizophrenia; Schizophrenic Psychology; Serotonin

Clozapine has proved effective in alleviating a wide range of psychiatric symptoms in schizophrenia. Its effects on cognitive function in schizophrenia are more variable. Clozapine appears to have a salutary effect on some aspects of attention, response speed, and fluency, whereas it appears to have a mild but adverse effect on visual memory and some executive functions. This profile may be related to the affinity of clozapine for dopaminergic type I and muscarinic receptors and relative lack of affinity for dopaminergic type II receptors.

Topics: Clozapine; Cognition; Cognition Disorders; Dopamine; Humans; Isoxazoles; Neuropsychological Tests; Piperidines; Receptors, Dopamine; Receptors, Muscarinic; Risperidone; Schizophrenia; Schizophrenic Psychology; Treatment Outcome

Cognitive dysfunction may underlie some of the psychopathology of schizophrenia as well as contribute to impaired social and vocational function in this disorder. Chronic treatment with typical neuroleptics has been reported to produce only minimal improvement in and may impair cognitive function in schizophrenia. We have studied the effect of clozapine, an atypical antipsychotic drug, on cognitive function in 36 patients with treatment-resistant schizophrenia. In addition, patients with non-treatment-resistant schizophrenia were randomly assigned to clozapine (N = 24) or typical neuroleptics (N = 23). Cognitive function in the treatment-resistant schizophrenia group was studied after 6 weeks and 6 months of treatment, while the non-treatment-resistant patients were also studied at 12 months of treatment. Clozapine treatment improved several domains of cognitive function, especially attention and verbal fluency in both treatment-resistant schizophrenia and non-treatment-resistant schizophrenia. On the other hand, typical neuroleptic treatment produced minimal improvement in cognitive function. The effect of clozapine on some tests of attention and verbal fluency was significantly greater than that of typical neuroleptic treatment in non-treatment-resistant schizophrenia. These data suggest that clozapine treatment was superior to typical neuroleptics in improving cognitive function in schizophrenia. The possibility that this is related to normalization of dopaminergic function by clozapine is discussed.

Topics: Antipsychotic Agents; Clozapine; Cognition Disorders; Dopamine; Humans; Neuropsychological Tests; Psychiatric Status Rating Scales; Receptors, Dopamine; Schizophrenia; Schizophrenic Psychology; Treatment Outcome; Word Association Tests

The present 12-week open-label uncontrolled trial was aimed to explore the efficacy of reboxetine add-on pharmacotherapy on clinical symptoms and cognitive functioning in 15 patients with schizophrenia with suboptimal response (mean [SD] Brief Psychiatric Rating Scale baseline total score, 32.2 [5.4]) despite receiving clozapine monotherapy at the highest tolerated dosage. The results obtained evidenced that reboxetine at a dosage of 4 mg/d mildly reduced only depressive symptoms (Calgary Depression Scale for Schizophrenia: P = 0.035, Cohen d = 0.7), whereas worsening of performances on phonemic fluency (P = 0.012, Cohen d = 0.5) was observed. After Bonferroni correction, changes at the Calgary Depression Scale for Schizophrenia and at the Verbal Fluency Task were not further confirmed.The results obtained indicate that reboxetine seemed to be scarcely effective for reducing clinical symptoms in patients with schizophrenia who have had an incomplete clinical response to clozapine. Regarding cognitive functioning, in our sample, a trend to experience cognitive impairment in the examined domains was observed, as confirmed by a mild worsening of performances on cognitive tasks.Schizophrenia is a heterogeneous disorder with regard to pathophysiology; therefore, data reflecting the mean response of a sample of patients may fail to reveal therapeutic effects. More research is needed to better identify subgroups of patients with peculiar features, which may account for responsivity to experimental medications and augmentation strategies.

Topics: Adult; Antipsychotic Agents; Clozapine; Cognition Disorders; Drug Therapy, Combination; Female; Humans; Male; Morpholines; Pilot Projects; Reboxetine; Schizophrenia

The risks of antipsychotic drugs on metabolic syndrome (MS) present many challenges for psychiatrists.. To evaluate the effectiveness and influences on glucolipid metabolism in patients with schizophrenia and metabolic disorders switched from clozapine to ziprasidone.. Schizophrenic patients with metabolic syndrome who had been treated with clozapine for ≥ 2 years were enrolled in the open-label study. All the patients were switched to ziprasidone from clozapine and followed up for 24-week. The primary endpoints included body mass index (BMI), fasting glucose (FG), triglycerides (TG), HDL cholesterol (HDL-c) and systolic pressure (SP)/diastolic pressure (DP). Secondary endpoints included scores on the Positive and Negative Syndrome Scale (PANSS) and treatment emergent symptom scale (TESS).. A total of 213 cases satisfied the inclusion and exclusion criteria, but only 194 cases eventually completed the 24-week follow-up and were divided into ziprasidone group (n=68, complete substitution) and combined treatment group (n=126, partial substitution). In the ziprasidone group, TG at 4th and 24th week, BMI and HDL-c at 24th week were significantly improved (p < 0.05), while cognitive scores and total score of the PANSS at 4th and 24th week, negative factor, the factor of anxiety and depression at 24th week were significantly lower than those at the baseline (p < 0.05); In the combined group, cognitive factor scores (4 weekend, 24 weekends) and total score of PANSS (24 weeks) was significantly lower than baseline (p < 0.05). There was no significant difference in the TESS score (p > 0.05).. Ziprasidone completely or partially substituting clozapine can improve both glucolipid metabolism disorders, and cognitive disorders and affective disorders of schizophrenia.

Topics: Adult; Antipsychotic Agents; Blood Glucose; Blood Pressure; Body Mass Index; Cholesterol, HDL; Clozapine; Cognition Disorders; Female; Follow-Up Studies; Humans; Male; Metabolic Syndrome; Middle Aged; Piperazines; Psychiatric Status Rating Scales; Schizophrenia; Thiazoles; Triglycerides

Several placebo controlled studies investigating lamotrigine augmentation of clozapine in schizophrenia patients with partial response have shown varying results. The aim of this study was to further investigate the efficacy and safety of this augmentation strategy, and its effect on the glutamatergic system through utilizing mismatch negativity (MMN) component of auditory event related potentials.. The study was designed to evaluate the efficacy and safety of lamotrigine augmentation of clozapine in a 12-week, double-blind, placebo-controlled, prospective, randomized design. Thirty-four patients diagnosed according to DSM-IV schizophrenia criteria and with partial response to clozapine were included. Patients were randomized to 25mg/day of lamotrigine or placebo, gradually increasing up to 200mg/day on the 6th week. The change in psychopathology was assessed with Positive and Negative Syndrome (PANSS), Calgary Depression (CDS) and Clinical Global Impression-Severity (CGI-S) scales. A neuropsychological test battery was administered and MMN measurements were also obtained at baseline and endpoint. Safety evaluation included physical examination, UKU Side Effect Rating Scale (UKU) assessment and serum drug level measurements.. No significant differences were found between the two treatment groups in PANSS Positive and General Psychopathology, CDS, neurocognitive test and UKU scores, as well as MMN measurements. PANSS Total, Negative and CGI-S scores showed significant improvement compared to lamotrigine in the placebo group.. This study did not show any benefit of augmentation of clozapine with lamotrigine in schizophrenia patients with partial response. The need for further investigation of other augmentation strategies of clozapine in partially responsive schizophrenia patients is evident.

Topics: Adolescent; Adult; Aged; Analysis of Variance; Antipsychotic Agents; Calcium Channel Blockers; Chi-Square Distribution; Clozapine; Cognition Disorders; Double-Blind Method; Drug Synergism; Electroencephalography; Evoked Potentials, Auditory; Female; Humans; Lamotrigine; Male; Middle Aged; Neuropsychological Tests; Prospective Studies; Psychiatric Status Rating Scales; Schizophrenia; Severity of Illness Index; Triazines; Young Adult

Clozapine, the most widely used option in treatment-resistant schizophrenia, has been shown to be superior to other antipsychotic medications in improving cognitive function in patients. However, the results have not been consistent and the mechanisms underlying this effect have not been elucidated. Thus, the purpose of the present study was to evaluate verbal and nonverbal cognition (using visuospatial processing tests) in patients treated with clozapine (initially treatment resistant) and those treated with other second-generation antipsychotics, relative healthy control subjects. Furthermore, we examined neural correlates of visuospatial processing in the three groups.. Twenty schizophrenia patients treated with clozapine (TR-C group), 23 patients stabilised with atypical antipsychotics other than clozapine (NTR group), and 21 healthy control participants completed a battery of verbal and visuospatial cognitive tests. In addition, participants underwent functional magnetic resonance imaging (fMRI) while performing one of the visuospatial tests (the mental rotation task). The fMRI data were analysed separately in each group using Statistical Parametric Mapping software (SPM5).. Overall, schizophrenia patients exhibited deficit on verbal and nonverbal processing relative to the healthy controls, but we observed some interesting differences between the two groups of patients. Specifically, the NTR group performed better than the TR-C group on the Block Design and the Raven's Progressive Matrices. With respect to brain function during mental rotation, the NTR group showed significant activations in regions of the temporal and occipital cortex, whereas the TR-C patients did not. The relative deactivations associated with the task were also more robust in NTR compared to the other group of patients, despite a similar performance.. Present results suggest better visuospatial processing in the NTR relative to the TR-C group. This difference could be attributed to the treatment resistance itself or a lack of beneficial effect of clozapine relative to other atypical antipsychotics in ameliorating nonverbal abilities. Future studies of the relationship between clozapine and cognition, as well as between treatment resistance and cognition, are warranted.

Topics: Adolescent; Adult; Antipsychotic Agents; Benzodiazepines; Clozapine; Cognition; Cognition Disorders; Dibenzothiazepines; Drug Resistance; Female; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Olanzapine; Quetiapine Fumarate; Risperidone; Schizophrenia; Space Perception; Young Adult

To assess the cognitive effects of sertindole augmentation in clozapine-treated patients diagnosed with schizophrenia. Cognition is secondary outcome of the trial.. A 12-week, double-blinded, randomized, placebo-controlled, augmentation study of patients treated with clozapine. Participants were randomized 1:1 to receive 16 mg of sertindole or placebo as adjunctive treatment to clozapine.. Participants displayed substantial cognitive deficits, ranging from 1.6 standard deviation below norms at baseline to more than three standard deviations on tests of response readiness and focused attention. There were no significant differences between sertindole augmentation and placebo groups at study end. Correlation analysis of Positive and Negative Syndrome (PANSS) subscales, Global Assessment of Functioning subscale (GAF-F) and Clinical Global Impression (CGI) with 20 neurocognitive indices was conducted, but no significant correlations were found. Second, we tested change from baseline to endpoint for the PANSS, GAF-F, and CGI, vs. the concomitant changes in cognitive test performance, and found no significant correlations.. The clozapine-treated patients displayed marked cognitive deficits at baseline. Adding sertindole did not improve or worsen cognitive functioning, which is in line with previous negative studies of the effect on cognition of augmenting clozapine treatment with another antipsychotic drug.

Topics: Adult; Antipsychotic Agents; Clozapine; Cognition Disorders; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Imidazoles; Indoles; Male; Neuropsychological Tests; Psychiatric Status Rating Scales; Schizophrenia

Studies have shown that insulin resistance is associated with cognitive impairment. Peroxisome proliferator-activated receptor-γ (PPAR-γ) agonists improve insulin sensitivity. The purpose of this study was to evaluate the effect of rosiglitazone, a PPAR-γ agonist, on cognition in clozapine-treated patients with schizophrenia. In an eight-week double-blind, placebo-controlled pilot trial, clozapine-treated patients with schizophrenia were randomized to receive rosiglitazone (4mg/day) or placebo. A neuropsychological battery including the Digit Span subtest from the Wechsler Adult Intelligence Scale-III (WAIS-III), the verbal fluency test, the Hopkins Verbal Learning Test (HVLT), the Trail-Making Test (TMT) and the Wisconsin Card Sorting Test (WCST) was administered at baseline and week eight. Nineteen patients completed the study. There were no significant differences on any demographic or general clinical variables between the rosiglitazone group (n=9) and the placebo group (n=10). When baseline scores were controlled, there were no significant differences in change scores of cognitive performance over eight weeks between the two groups. In this pilot study, rosiglitazone had no cognitive benefit in clozapine-treated patients with schizophrenia. Future studies with longer treatment duration and larger sample size are needed to further explore the potential role of rosiglitazone in improving cognitive function in patients with schizophrenia.

Topics: Adult; Antipsychotic Agents; Clozapine; Cognition; Cognition Disorders; Double-Blind Method; Female; Humans; Hypoglycemic Agents; Male; Middle Aged; Neuropsychological Tests; Pilot Projects; PPAR gamma; Rosiglitazone; Schizophrenia; Thiazolidinediones; Treatment Outcome

A positive relationship between cholesterol levels and cognition has been reported in various human and animal studies, but has never been investigated in schizophrenia. The goal of this study was to examine this relationship in schizophrenic patients randomized to clozapine, olanzapine or haloperidol.. This was a double-blind randomized prospective 12-week study. Participants received a baseline evaluation including a cognitive battery consisting of an evaluation of psychomotor function, general executive function, visual and verbal memory, and visuospatial ability. Their fasting serum cholesterol level was also assessed. The participants were then randomized to clozapine, olanzapine, or haloperidol. They were evaluated at the end of 12 weeks. A general cognitive index (GCI) derived from the cognitive battery was the primary variable.. 82 patients had both baseline and endpoint neurocognitive assessments and cholesterol levels. There was a statistically and clinically significant positive association between change in cholesterol levels and change in GCI. This association was especially pronounced for verbal memory. There was no interaction between medication grouping and cholesterol level; the positive association was observable separately in each medication group. It was very robust and remained significant after we controlled for glucose and triglyceride levels, anticholinergic side effects, medication serum levels, cholesterol lowering medications, and pre-study antipsychotic medications.. Cholesterol levels show a strong association with cognition in schizophrenia in all medication groups. Further research on the role of lipid metabolism in cognition may suggest new treatments for this core deficit of schizophrenia.

Topics: Adolescent; Adult; Analysis of Variance; Antipsychotic Agents; Benzodiazepines; Blood Glucose; Body Weight; Cholesterol; Clozapine; Cognition Disorders; Double-Blind Method; Female; Follow-Up Studies; Haloperidol; Humans; Male; Middle Aged; Neuropsychological Tests; Olanzapine; Prospective Studies; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenic Psychology; Triglycerides; Young Adult

Clozapine has been shown to be superior to typical neuroleptic drugs for treating positive symptoms in treatment-resistant (TR) schizophrenia. Long-term data from randomized clinical trials comparing clozapine with typical neuroleptics in non-TR schizophrenia are rare. We previously reported that clozapine was superior to typical neuroleptic drugs in some domains of cognition in recent onset non-TR schizophrenia. We now present data on psychopathology and quality of life from this randomized, flexibly dosed, 24-month study of clozapine vs. typical neuroleptics in non-TR schizophrenia patients. Both treatments produced significant improvement in measures of psychopathology, quality of life, and global function, with minor exceptions. There was no difference in extrapyramidal side effects between the patients treated with clozapine or typical neuroleptics. However, significantly more relapse/rehospitalization drop-outs occurred in the typical neuroleptic group. Two patients treated with typical neuroleptics, but none treated with clozapine, became non-responsive to treatment. Clozapine was associated with significantly greater weight gain. Clozapine and typical neuroleptic drugs appear to produce equivalent improvement in psychopathology in patients with non-TR schizophrenia. Clozapine may be more effective than typical neuroleptics for treatment retention and prevention of relapse, but it produces more severe metabolic side effects. These considerations should be taken into account in decisions of how best to utilize clozapine in the treatment of schizophrenia.

Topics: Adult; Antipsychotic Agents; Clozapine; Cognition Disorders; Dose-Response Relationship, Drug; Drug Administration Schedule; Humans; Psychiatric Status Rating Scales; Quality of Life; Schizophrenia; Schizophrenic Psychology; Suicide, Attempted; Time Factors; Treatment Outcome; Young Adult

To investigate the neurocognitive effectiveness of haloperidol, risperidone, and olanzapine in first-episode schizophrenia-spectrum disorders.. This prospective, randomized, open-label study was conducted from February 2001 to February 2005. Data for the present investigation were obtained from a large epidemiologic and 3-year longitudinal intervention program of first-episode psychosis (DSM-IV criteria) conducted at the outpatient clinic and the inpatient unit at the University Hospital Marques de Valdecilla, Santander, Spain. One hundred four patients randomly assigned to haloperidol (N = 35), olanzapine (N = 30), or risperidone (N = 39) who completed clinical and cognitive evaluations at baseline, 6 months, and 1 year were included in the final analysis. Thirty-seven healthy individuals were also longitudinally assessed. A neuropsychological battery that comprised 9 cognitive domains was used. The contribution of clinical changes, concomitant medications, and the severity of motor side effects to cognitive changes was controlled. The main outcome measure was cognitive changes at 1-year follow-up.. The 3 treatment groups showed a significant improvement in cognitive scores after 1 year. The differential cognitive effectiveness between antipsychotics was insignificant. The magnitude of cognitive changes was similar in the 3 treatment groups and controls, although a greater improvement on the Finger Tapping Test, Trail Making Test B, and Rey Complex Figure Test was found in the treatment groups. Clinical changes, use of concomitant medications, and the emergence of motor side effects did not significantly account for cognitive changes over time.. Haloperidol, olanzapine, and risperidone were equally effective in treating cognitive deficits of psychosis. The effect of practice clearly contributes to cognitive score improvements after treatment with antipsychotics. Our results provide important information regarding the practical utility of antipsychotic treatments to improve cognition and could have implications for developing novel approaches for cognitive pharmacotherapy in schizophrenia.

Topics: Adult; Amisulpride; Antipsychotic Agents; Benzodiazepines; Brain; Clozapine; Cognition Disorders; Female; Follow-Up Studies; Haloperidol; Humans; Male; Neuropsychological Tests; Olanzapine; Perphenazine; Piperazines; Prospective Studies; Psychotic Disorders; Risperidone; Severity of Illness Index; Sulpiride; Thiazoles

Patients with schizophrenia often suffer from cognitive deficits and negative symptoms that are poorly responsive to antipsychotics including clozapine. Clozapine-induced sedation can worsen cognition and impair social and occupational functioning.. To evaluate the efficacy, tolerability, and safety of modafinil for negative symptoms, cognition, and wakefulness/fatigue in DSM-IV-diagnosed schizophrenia patients treated with clozapine.. A double-blind, placebo-controlled, flexible-dosed 8-week pilot trial was conducted between September 2003 and September 2007, adding modafinil up to 300 mg/d to stabilized schizophrenia outpatients receiving clozapine. Psychopathology, cognition, and wakefulness/fatigue were assessed with standard rating scales.. Thirty-five patients were randomly assigned to treatment with study drug and included in the analysis. Modafinil did not reduce negative symptoms or wakefulness/fatigue or improve cognition compared to placebo. Modafinil was well tolerated and did not worsen psychosis.. Results of this pilot trial do not support routine use of modafinil to treat negative symptoms, cognitive deficits, or wakefulness/fatigue in patients on clozapine. However, given our limited power to detect a treatment effect and the clear possibility of a type II error, larger trials are needed to resolve or refute a potential therapeutic effect of uncertain magnitude.. clinicaltrials.gov Identifier: NCT00573417.

Topics: Adolescent; Adult; Antipsychotic Agents; Benzhydryl Compounds; Central Nervous System Stimulants; Clozapine; Cognition Disorders; Double-Blind Method; Drug Therapy, Combination; Fatigue; Female; Humans; Male; Middle Aged; Modafinil; Neuropsychological Tests; Pilot Projects; Placebos; Psychotic Disorders; Schizophrenia; Schizophrenic Psychology; Treatment Outcome; Wakefulness

The purpose of this study was to compare the effects of olanzapine, clozapine, and haloperidol on neurocognitive function in schizophrenic patients who present with documented episodes of physical aggression and to determine whether change in cognitive function is related to aggression. One hundred physically aggressive schizophrenic inpatients were assigned to a randomized, double-blind, parallel-group, 12-week treatment, and received cognitive evaluations at baseline. There were 33, 34, and 33 subjects in the clozapine, olanzapine, and haloperidol groups, respectively. They were administered a battery of tests assessing psychomotor function, general executive function, visual and verbal memory, and visuospatial ability. A general cognitive index was derived from the above battery. The overall score on the Modified Overt Aggression Scale was used to measure the number and severity of the aggressive events. Psychiatric symptoms and side effects were also assessed. The improvement in the general cognitive index differed significantly among the 3 treatment groups, with olanzapine being superior to both haloperidol and clozapine. Further analyses revealed significantly greater improvement with olanzapine in several cognitive domains. Furthermore, improvement in the general cognitive index was significantly associated with a decrease in aggression in the olanzapine group but not in the other 2 medication groups. In violent schizophrenic patients, olanzapine treatment is associated with better cognitive functioning relative to haloperidol and clozapine. This improvement in neurocognitive function is associated with a decrease in aggressive behavior. As clozapine markedly reduced aggression, there may be different pathways for the antiaggressive effect of olanzapine and that of clozapine.

Topics: Adult; Aggression; Antipsychotic Agents; Benzodiazepines; Clozapine; Cognition Disorders; Double-Blind Method; Female; Haloperidol; Humans; Male; Middle Aged; Olanzapine; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenic Psychology; Severity of Illness Index; Violence

AMPA-receptor-positive modulators (Ampakines) facilitate learning and memory in animal models and in preliminary trials in human subjects. CX516 is the first Ampakine to be studied for cognitive enhancement in schizophrenia. Stable schizophrenia patients treated with clozapine (n=52), olanzapine (n=40), or risperidone (n=13) were randomly assigned to add-on treatment with CX516 900 mg three times daily or placebo for 4 weeks. Subjects were assessed with a cognitive battery at baseline, week 4, and at 4-week follow-up. Clinical scales and safety monitoring were also performed. The primary endpoint was the change from baseline in a composite cognitive score at week 4 for the intent-to-treat sample. Additional analyses examined change in symptom rating scores and examined drug effects on patients treated with clozapine separately from patients treated with either olanzapine or risperidone. A total of 105 patients were randomized and 95 (90%) completed the 4-week trial. Patients treated with CX516 did not differ from placebo in change from baseline on the composite cognitive score, or on any cognitive test at weeks 4 or 8. The between groups effect size at week 4 for the cognitive composite score was -0.19 for clozapine-treated patients and 0.24 for patients treated with olanzapine or risperidone. The placebo group improved more on the PANSS total score than the CX516 group; no other clinical rating differed between treatment groups. CX516 was associated with fatigue, insomnia and epigastric discomfort compared to placebo, but was generally well tolerated. CX516 was not effective for cognition or for symptoms of schizophrenia when added to clozapine, olanzapine, or risperidone.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Clozapine; Cognition Disorders; Dioxoles; Double-Blind Method; Female; Humans; Male; Middle Aged; Neuropsychological Tests; Olanzapine; Pilot Projects; Piperidines; Psychiatric Status Rating Scales; Psychomotor Performance; Risperidone; Sample Size; Schizophrenia; Schizophrenic Psychology

Recent data have suggested few differences in the cognitive effects of antipsychotic medications. However, assessment of such effects can be complex, due to a number of factors. Clozapine has previously shown greater clinical and lesser cognitive benefits than other atypicals. This study compared the cognitive benefits of clozapine and ziprasidone in schizophrenia patients (n=130) with a history of either failure to respond to or intolerance of previous adequate antipsychotic treatments.. Patients were randomized (double-blind) to either clozapine or ziprasidone in a single country (Italy), multi-site trial. The cognitive assessments examined episodic memory (RAVLT), executive functioning (Stroop test), and processing speed (Trail-making test (TMT) Parts A and B).. Analyses found statistically significant within-group improvements for ziprasidone in learning and delayed recall on the RAVLT and on TMT Parts A and B. Clozapine-treated patients improved on the RAVLT, but not on the TMT. A composite cognitive score improved from baseline in both groups, but the improvements were significantly larger in the ziprasidone group (p=.029).. These results indicated that cognitive functioning improved following treatment with ziprasidone in patients with a history of either treatment resistance or intolerance, and that the effects are comparable or greater than those observed with clozapine. One interpretation of these findings is that clozapine treatment interferes with the performance benefits associated with practice.

Topics: Adult; Antipsychotic Agents; Clozapine; Cognition Disorders; Double-Blind Method; Drug Resistance; Drug Tolerance; Female; Humans; Italy; Male; Memory Disorders; Neuropsychological Tests; Piperazines; Placebos; Schizophrenia; Schizophrenic Psychology; Thiazoles; Trail Making Test; Treatment Outcome

This study evaluated the association of neurocognition and symptoms with measures of social and occupational functioning in the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE).. CATIE was an 18-month study of individuals with schizophrenia. Symptoms of 1,386 patients were measured with the positive syndrome scale of the Positive and Negative Syndrome Scale (PANSS) and a PANSS negative symptom scale that eliminated items that most overlap with measures of community functioning or neurocognition. The Heinrichs-Carpenter Quality of Life Scale, which a rater completes on the basis of the patient's self-report, and recent employment were used to assess community functioning. Hierarchical regression analyses and mixed models tested the association of neurocognition and symptoms with social/occupational functioning as well as changes in these measures during treatment.. Both symptoms and neurocognition were associated with quality of life in bivariate correlation analyses. Symptoms contributed more to the incremental explained variance in quality of life than did neurocognitive functioning, but both kinds of measures were significantly related to quality of life. In an analysis including only the positive syndrome scale, the increased explained variance in quality of life was about equal to that associated with neurocognition. Neurocognition and both symptom measures were independently associated with quality of life in the cross-sectional mixed-model analysis. Changes in neurocognition and both symptom measures during treatment were also significantly associated with change in the quality of life.. Both psychotic symptoms and neurocognitive deficits appear to contribute independently to decreased quality of life in schizophrenia.

Topics: Adolescent; Adult; Aged; Antipsychotic Agents; Brain; Clozapine; Cognition Disorders; Cost-Benefit Analysis; Cross-Sectional Studies; Female; Humans; Male; Middle Aged; Neuropsychological Tests; Quality of Life; Schizophrenia; Schizophrenic Psychology; Severity of Illness Index

The purpose of this study was to investigate the influence of clozapine on plasma serotonin, platelet serotonin and monoamine oxidase (MAO) levels in schizophrenic patients and to compare their results with those of unmedicated healthy controls. Groups of 20 outpatients with schizophrenia and 20 healthy controls matched for age, sex and smoking status were recruited for the study. Psychopathology, neurocognitive functioning, plasma serotonin, platelet serotonin and MAO levels were assessed after 1-week drug free interval, and 8 weeks after initiation of clozapine treatment in an open design. The mean clozapine dose at week 8 was 382.5+/-96.4 (range: 250-600) mg/day. In the patient group, at baseline, plasma serotonin and platelet MAO levels were significantly lower, and platelet serotonin levels were significantly higher than in controls. After 8 weeks of clozapine treatment, plasma serotonin and platelet MAO levels increased significantly, while a significant decrease in platelet serotonin levels was detected compared with baseline values. Baseline platelet MAO levels explained 22% of the variance in Clinical Global Impression - Improvement (CGI-I) and improvement in attention, while baseline platelet serotonin predicted 23% of the variance in the improvement in positive symptoms during clozapine treatment. Our data indicate that clozapine may be reversing or compensating for a pre-existing alteration in serotonergic neurotransmission in schizophrenic patients. The prediction of response to clozapine through peripheral biochemical markers may have important clinical implications if repeated in larger samples.

Topics: Adult; Antipsychotic Agents; Blood Platelets; Clozapine; Cognition Disorders; Drug Administration Schedule; Female; Humans; Male; Monoamine Oxidase; Neuropsychological Tests; Schizophrenia, Paranoid; Schizophrenic Psychology; Serotonin; Severity of Illness Index; Smoking; Surveys and Questionnaires; Verbal Learning; Vocabulary

The development of therapeutic strategies for cognitive dysfunction remains one of the primary goals in the treatment of schizophrenia. The pharmacodynamic profile of mirtazapine, an antidepressant that enhances noradrenergic and serotonergic transmission, is based on a presynaptic alpha2 antagonism and postsynaptic 5-HT2 and 5-HT3 antagonism. Mirtazapine shares some pharmacological similarities with that of clozapine. This 8-week open label trial aimed to discover whether the addition of 30 mg mirtazapine could potentiate the effects on cognition of an ongoing stabilized clozapine therapy in 15 persons who met the criteria for chronic schizophrenia in the Diagnostic and Statistical Manual of Mental Disorders (4th ed., text rev.; American Psychiatric Association, 2000). Mirtazapine adjunction was well tolerated and induced a significant improvement in cognitive performance, as measured by the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS; Randolph, 1998) total score and by the subscales for immediate and delayed memory (p<.01). Since Hamilton Depression Rating Scale (HAM-D; Hamilton, 1967), Brief Psychiatric Rating Scale (BPRS; Overall & Gorham, 1962), and Scale for the Assessment of Negative Symptoms (SANS; Andreasen, 1989) scores at Week 8 did not show significant differences from baseline, the improvements in the effects of clozapine on cognition observed after the addition of mirtazapine seemed to be a direct rather than an indirect action of this drug (e.g., via mood or other psychopathological symptoms). These findings suggest a potential role for mirtazapine as a useful strategy to augment the efficacy of clozapine in the treatment of cognitive dysfunctions in chronic schizophrenia.

Topics: Administration, Oral; Adrenergic alpha-Antagonists; Adult; Antipsychotic Agents; Brief Psychiatric Rating Scale; Chronic Disease; Clozapine; Cognition; Cognition Disorders; Diagnostic and Statistical Manual of Mental Disorders; Drug Synergism; Female; Humans; Male; Mianserin; Mirtazapine; Schizophrenia; Time Factors

Atypical antipsychotic drugs produce improvement in some domains of cognition as well as psychopathology in patients with schizophrenia. However, the effect of combinations of atypical antipsychotic drugs on cognitive function is unknown. The aim of this study was to compare the effect of risperidone or placebo on cognitive function in patients with schizophrenia who were previously treated with clozapine monotherapy.. This prospective, randomized, double-blind, placebo-controlled, 6-week study included 30 patients with DSM-IV schizophrenia. Patients whose psychopathology was no more than partially responsive to clozapine treatment were randomly assigned to receive adjunctive treatment with risperidone (N = 16) up to 6 mg/day or placebo (N = 14). Cognitive test scores for verbal learning and memory, verbal fluency, attention, executive function, verbal working memory, and motor function were the primary outcome measures. Secondary outcome measures included assessment of psychopathology, extrapyramidal side effects, and global functioning. Data were collected between November 2001 and July 2003.. Significant improvement was found in both treatment groups in a variety of cognitive measures, but there was significantly greater improvement in the placebo-augmented group on measures of initial learning acquisition and attention. The improvement in cognition was not correlated with improvement in psychopathology. There were significant correlations between improvement in verbal working memory, verbal learning and memory, and attention and quality of life and global functioning in the placebo-augmented but not the risperidone-augmented group.. Adjunctive treatment with risperidone for 6 weeks in patients with schizophrenia who had received chronic treatment with clozapine does not significantly improve cognitive function.

Topics: Adult; Antipsychotic Agents; Attention; Clozapine; Cognition; Cognition Disorders; Double-Blind Method; Female; Humans; Male; Memory; Middle Aged; Prospective Studies; Quality of Life; Risperidone; Schizophrenia; Treatment Outcome

The purpose of this investigation was to evaluate the effects of clozapine and risperidone on social skill and problem solving in patients with schizophrenia.. The Wisconsin Card Sorting Test and the Maryland Assessment of Social Competence were administered at baseline, week 17, and week 29 of a multisite clinical trial.. Despite evidence of clinical improvement with both medications, there was virtually no medication effect on either social competence or problem solving.. These findings underscore the circumscribed nature of symptomatic improvement in the broader spectrum of clinical outcomes and suggest that new-generation medications may not be expected to produce substantial changes in social role functioning or social problem-solving capacity in the community. The generalizability of the findings should be viewed cautiously because of the low power of this trial, and replication is warranted.

Topics: Adult; Clozapine; Cognition Disorders; Double-Blind Method; Female; Humans; Male; Neuropsychological Tests; Problem Solving; Risperidone; Schizophrenia; Severity of Illness Index; Social Behavior

Previous research has suggested that high doses of conventional neuroleptics may induce neurocognitive deficits when assessed with standard tasks. However, little is known about the effects of high doses of neuroleptics (conventional or atypical) on subjective cognitive dysfunction. Recent research stresses the putative importance of self-reported cognitive deficits for both symptomatic outcome and medication compliance. The aim of the present study was to investigate the impact of neuroleptic medication on subjective cognition in patients treated with either conventional or atypical agents (clozapine, risperidone, olanzapine). Patients were asked to endorse the items of a questionnaire entitled 'Subjective Well-Being under Neuroleptic Treatment' prior to discharge. Subjective impairment, as assessed with the subscale 'mental functioning', was significantly correlated with greater conventional neuroleptic dosage after controlling for psychopathology (P<0.05). The difference between patients medicated with higher doses of conventional neuroleptics and those with lower doses was highly significant (P<0.001). In contrast, higher atypical neuroleptic doses were not associated with impairment.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Clozapine; Cognition Disorders; Dose-Response Relationship, Drug; Female; Humans; Male; Olanzapine; Pirenzepine; Psychiatric Status Rating Scales; Risperidone; Schizophrenia; Schizophrenic Psychology; Surveys and Questionnaires

Neurocognition and clinical symptomatology were evaluated in 27 patients with schizophrenia during a double-blind, placebo-controlled, cross-over study involving clozapine, an atypical antipsychotic agent, and haloperidol, a conventional neuroleptic. Patients were assessed 5 to 6 weeks after initiation of each phase. Clinical symptomatology, based on Brief Psychiatric Rating Scale and Scale for the Assessment of Negative Symptoms ratings, markedly improved after treatment with both haloperidol and clozapine. The beneficial effects of clozapine were statistically significantly greater than the effects from the haloperidol treatment. Regarding neurocognition, both agents proved efficacious in improving performance on nearly all measures compared with placebo. In addition, as compared with haloperidol, clozapine significantly improved performance on Trails B, Verbal Fluency, and measures of delayed verbal memory, and it tended to increase performance on most measures. Additional analyses indicated that the improvement on neurocognitive measures was not because of symptom amelioration; rather, neurocognitive deficits seem to be an intrinsic enduring feature of schizophrenia. The superiority of clozapine over haloperidol may be related to clozapine's unique psychopharmacologic profile.

Topics: Adult; Analysis of Variance; Antipsychotic Agents; Clozapine; Cognition; Cognition Disorders; Cross-Over Studies; Double-Blind Method; Female; Haloperidol; Humans; Male; Middle Aged; Neuropsychological Tests; Psychiatric Status Rating Scales; Schizophrenia; Wechsler Scales

The purpose of this study was to evaluate the effects of high-dose oral glycine on positive and negative symptoms and cognitive function when added to clozapine in adults with schizophrenia.. The authors conducted a double-blind, placebo-controlled, parallel-group trial of 60 g/day of glycine added to clozapine for 8 weeks in 30 adults with schizophrenia. Clinical ratings were performed every 2 weeks.. Twenty-seven patients completed the trial. Glycine augmentation of clozapine produced no statistically significant change in positive or negative symptoms or cognitive functioning. No subjects showed clinically significant worsening of clinical ratings.. These data, combined with data from previous trials with D-cycloserine and glycine, suggest that agonists at the glycine site may be less effective when combined with clozapine than they are when combined with conventional antipsychotics.

Topics: Adult; Ambulatory Care; Antipsychotic Agents; Clozapine; Cognition Disorders; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Female; Follow-Up Studies; Glycine; Humans; Male; Placebos; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenic Psychology; Treatment Outcome

Few controlled studies have compared the efficacy of clozapine and risperidone in treatment-refractory schizophrenic patients. The present study investigates the efficacy of both clozapine and risperidone on psychopathologic and neurocognitive measures in a prospective 12-week open-label trial in treatment-refractory schizophrenic patients from state psychiatric hospitals.. Thirty-five DSM-IV schizophrenic patients with a documented history of nonresponse to typical neuroleptics were treated with either clozapine or risperidone. Response was assessed every 2 weeks by independent raters with the Positive and Negative Syndrome Scale (PANSS), the Clinical Global Impressions (CGI) scale, neurologic rating scales, and plasma drug levels. Neurocognitive tests were administered at baseline and week 12.. Both clozapine and risperidone brought about significant (p < .003) overall improvement in psychopathology. However, clozapine was numerically superior to risperidone on PANSS total scores and PANSS positive, negative, excitement, and cognitive factors. Extrapyramidal side effects were minimal for clozapine, whereas some were present for risperidone. Patients taking risperidone improved significantly in the beginning stages of the study and remained stable thereafter. Patients taking clozapine showed a gradual improvement that occurred over the entire length of the trial. Neurocognitive measures showed minimal improvement and did not differentiate between the 2 medication groups.. Both clozapine and risperidone were comparably effective across a wide spectrum of psychopathologic measures. While the efficacy of clozapine was only numerically superior to that of risperidone, it was associated with fewer extrapyramidal side effects and with progressive improvement over the 12-week treatment period, suggesting that in longer trials clozapine may prove to be superior to risperidone in neuroleptic-refractory patients.

Topics: Adult; Basal Ganglia Diseases; Clozapine; Cognition Disorders; Female; Humans; Male; Middle Aged; Neuropsychological Tests; Prospective Studies; Psychiatric Status Rating Scales; Risperidone; Schizophrenia; Schizophrenic Psychology; Treatment Outcome

The purpose of this study was to compare the side effect +profiles of clozapine and risperidone.. The subjects were 20 outpatients with schizophrenia or schizoaffective disorder who were clinically stable on a regimen of clozapine at the time of screening. They underwent a randomized-order crossover comparison of 6 weeks of risperidone treatment and 6 weeks of clozapine treatment. Clinical and neurocognitive variables were assessed by raters blind to medication status, and severity of side effects was determined from patients' self-reports.. Side effect measures, but not clinical ratings, were significantly different after 6 weeks of treatment with the two drugs. Patients required more benztropine for motor effects and complained of more insomnia with risperidone and more sedation with clozapine. Body weight was higher at the end of clozapine treatment than at the end of risperidone treatment.. In this exploratory study, the side effect profiles of clozapine and risperidone were consistent with the different pharmacodynamic profiles of the two drugs.

Topics: Akathisia, Drug-Induced; Ambulatory Care; Clozapine; Cognition Disorders; Cross-Over Studies; Humans; Neuropsychological Tests; Pilot Projects; Psychiatric Status Rating Scales; Psychotic Disorders; Risperidone; Schizophrenia; Schizophrenic Psychology; Sleep; Sleep Initiation and Maintenance Disorders; Treatment Outcome

Cognitive dysfunction may underlie some of the psychopathology of schizophrenia as well as contribute to impaired social and vocational function in this disorder. Chronic treatment with typical neuroleptics has been reported to produce only minimal improvement in and may impair cognitive function in schizophrenia. We have studied the effect of clozapine, an atypical antipsychotic drug, on cognitive function in 36 patients with treatment-resistant schizophrenia. In addition, patients with non-treatment-resistant schizophrenia were randomly assigned to clozapine (N = 24) or typical neuroleptics (N = 23). Cognitive function in the treatment-resistant schizophrenia group was studied after 6 weeks and 6 months of treatment, while the non-treatment-resistant patients were also studied at 12 months of treatment. Clozapine treatment improved several domains of cognitive function, especially attention and verbal fluency in both treatment-resistant schizophrenia and non-treatment-resistant schizophrenia. On the other hand, typical neuroleptic treatment produced minimal improvement in cognitive function. The effect of clozapine on some tests of attention and verbal fluency was significantly greater than that of typical neuroleptic treatment in non-treatment-resistant schizophrenia. These data suggest that clozapine treatment was superior to typical neuroleptics in improving cognitive function in schizophrenia. The possibility that this is related to normalization of dopaminergic function by clozapine is discussed.

Topics: Antipsychotic Agents; Clozapine; Cognition Disorders; Dopamine; Humans; Neuropsychological Tests; Psychiatric Status Rating Scales; Receptors, Dopamine; Schizophrenia; Schizophrenic Psychology; Treatment Outcome; Word Association Tests

Emergency psychiatry has the main role of resolving suicidal behavior and aggression. These severe psychiatric symptoms can be found in many psychiatric disorders such as schizophrenia, bipolar disorder, major depression, personality disorders, cognitive disorders, intellectual disability and substance abuse. Although indications for the use of antipsychotics are limited to a specific group of diseases, they are frequently used as rescue medication in high-risk or nonresponsive cases. Clozapine, the gold standard for TRS (treatment resistant schizophrenia) is effective in controlling aggression. The aim of the research was to identify the use of clozapine for treatment-refractory aggressive behavior in psychiatric emergency. A retrospective study based on the paper files of patients admitted between 2010 and 2019 in the Clinical Hospital of Psychiatry and Neurology of Brasov, Romania. Were included all the patients admitted as a psychiatric emergency and treated with clozapine for aggressive behavior. The hospital is an academic institution with 150 beds for acute patients, serving an area of over 600,000 inhabitants. It is the main public institution where patients with psychiatric emergencies are hospitalized. Off 19,000 patients admitted during the study period, 504 patients (2,4%) with a diagnosis other than schizophrenia or schizoaffective disorder received clozapine for aggressiveness (89.5%). The first four diagnoses identified were bipolar disorder (n = 172), intellectual disability (n = 128), cognitive impairment (n = 112), and personality disorder (n = 92). Other disorders identified but with a smaller number of cases were major depressive disorder (n = 3), adjustment disorders (n = 2), delusional disorder (n = 2), obsessive compulsive disorder (n = 2) and postpartum psychosis (n = 1). Clozapine was used as 3rd or 4th choice. The dose was greater for manic patients (350.29 ± 98.01 mg/day) compared with all the other diagnoses. Clozapine was effective and safe in cases of patients with treatment-refractory aggressive behavior.

Topics: Adult; Aged; Aggression; Bipolar Disorder; Clozapine; Cognition; Cognition Disorders; Female; Humans; Intellectual Disability; Male; Personality Disorders; Psychotic Disorders; Retrospective Studies

The mechanisms underlying the beneficial effects of clozapine (CLZ) in the treatment of schizophrenia still remains far from clear. In the present work we studied the effect of CLZ on the dopamine D

Topics: Animals; Antipsychotic Agents; Brain; Clozapine; Cognition Disorders; Dopamine; Dopamine D2 Receptor Antagonists; Ketamine; Male; Mice, Inbred C57BL; Receptors, Dopamine D2; RNA, Messenger; Schizophrenic Psychology; Signal Transduction

Clozapine (CLZ) is an effective treatment for schizophrenia, producing improvements in both negative symptoms and cognitive impairments. Cognitive impairments can be modelled in animals by ketamine (KET) and assessed using the attentional set-shift task (ASST).. Our first aim was to determine whether CLZ improves cognitive function and reverses KET-induced cognitive impairments using the ASST. Our second aim was to assess dose dependency of these effects.. Our findings demonstrate that acute as well as sub-chronic administration of KET cause cognitive deficits observed as increase in number of trails and errors to reach the criterion in the EDS phase. CLZ 0.3 mg/kg reversed the effects of both acute and sub-chronic KET, with no effects on locomotor activity. However, clozapine's effect after sub-chronic administration of dose 0.3 mg/kg was not as explicit as in the case of acute treatment. Moreover, administration of 1 mg/kg CLZ to KET-treated mice induced or enhanced deficits in the extra-dimensional shift phase compared to 1 mg/kg CLZ administration to mice not receiving KET. Locomotor activity test showed sedation effects of CLZ 1 mg/kg after acute treatment; therefore, effect of CLZ 1 mg/kg on KET-induced cognitive deficits was not evaluated in the attentional set-shift task (ASST) test.. The present findings support dose-dependent effects of CLZ to reverse KET-induced cognitive deficits. The observed dose dependency may be mediated by activation of different receptors, including monomers and/or heterodimers.

Topics: Animals; Attention; Clozapine; Cognition; Cognition Disorders; Ketamine; Male; Mice; Schizophrenia

Cortical gray matter loss in schizophrenia remains a great therapeutic difficulty. Each psychotic episode causes irreversible cortical gray matter loss, that causes the patients to never regain their previous state of functioning. Microglial cells are part of the innate immune system and their functions, among others, include phagocytosis and release of neurotrophic factors. They have a key impact on developmental and plasticity-induced removal of neuronal precursors, live-but-stressed neurons and synapses, while also stimulating synaptic growth and development. We hypothesize that microglia are the culprit for the cortical gray matter loss in schizophrenia through abnormal synaptic pruning, phagocytosis of stressed neurons and lacking neurotrophic factor release. Furthermore, we propose a research that could validate the hypotheses using serum samples of first-episode early-onset patients. By measuring the serum levels of milk fat globule-EGF factor 8 (MFG-E8), subcomponent in the classical pathway of complement activation (C1q), brain-derived neurotrophic factor (BDNF), interleukin-6 (IL-6) and interleukin-10 (IL-10), we could gain an insight into the state of microglial activation during various stages of the disease. If this hypothesis is valid, new targeted drugs could be developed in order to reduce the deterioration of cortical gray matter, thereby possibly improving negative symptoms and cognitive deficits.

Topics: Anti-Inflammatory Agents; Antigens, Surface; Brain-Derived Neurotrophic Factor; Clozapine; Cognition Disorders; Complement C1q; Dizocilpine Maleate; Gray Matter; Humans; Immunity, Innate; Interleukin-10; Interleukin-6; Microglia; Milk Proteins; Models, Theoretical; Neurons; Phagocytosis; Schizophrenia; Synapses

Cognitive deficits are a core feature of schizophrenia. There is ongoing debate on whether cognition is affected by antipsychotic drugs (APDs). This study examined the effect of long-term treatment with APDs on cognition in schizophrenia. Cognitive function was assessed in 418 patients with schizophrenia on long-term treatment with APDs (215 on clozapine, 91 on risperidone and 112 on typical APDs) and 159 healthy controls using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Schizophrenia symptomatology was assessed using the Positive and Negative Syndrome Scale (PANSS). We found that cognitive test scores were significantly lower in all patients compared with the healthy controls on almost all of the total and subscores of RBANS (all P<0.001), except for the visuospatial/constructional index. Individuals taking clozapine showed worse immediate and delayed memory performance than those taking typical APDs (all P<0.01). Moreover, individuals taking clozapine showed better language performance than those taking risperidone (P<0.01). Immediate memory and delayed memory were modestly correlated with the types of APDs and the PANSS negative scores. Our results show that individuals taking clozapine performed worse in immediate and delayed memory than those taking typical APDs, but exemplified better language performance than those taking risperidone.

Topics: Adult; Aged; Antipsychotic Agents; Case-Control Studies; Clozapine; Cognition Disorders; Cross-Sectional Studies; Female; Humans; Language; Male; Memory; Middle Aged; Neuropsychological Tests; Risperidone; Schizophrenia; Schizophrenic Psychology

The aim of the present study was to investigate the effect of second-generation antipsychotics (clozapine or another second-generation antipsychotic) on perceptual abnormalities related to sensory gating deficit. Although clozapine is known to improve sensory gating assessed neurophysiologically, we hypothesized that patients with schizophrenia treated with clozapine would report less perceptual abnormalities related to sensory gating deficit than patients treated with other second-generation antipsychotics do. Forty patients with a diagnosis of schizophrenia were investigated (10 patients treated with clozapine and 30 patients treated with another second-generation antipsychotic drug). Perceptual abnormalities were assessed with the Sensory Gating Inventory. Sensory gating was assessed through electroencephalogram with the auditory event-related potential method by measuring P50 amplitude changes in a dual click conditioning-testing procedure. Patients treated with clozapine present normal sensory gating and report less perceptual abnormalities related to sensory gating than patients treated with other second-generation antipsychotics do. Although the cross-sectional design of this study is limited because causal inferences cannot be clearly concluded, the present study suggests clinical and neurophysiological advantages of clozapine compared with other second-generation antipsychotics and provides a basis for future investigations on the effect of this treatment on perceptual abnormalities related to sensory gating deficit in patients with schizophrenia.

Topics: Adult; Antipsychotic Agents; Clozapine; Cognition Disorders; Cross-Sectional Studies; Female; Humans; Male; Neuropsychological Tests; Perception; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenic Psychology; Sensory Gating

This study aimed to investigate whether cognitive impairment is more pronounced in people with treatment-resistant schizophrenia compared with those who respond well to first-line antipsychotic medication. Fifty-one patients with schizophrenia were assigned to one of three groups dependent on their clinical history: (i) 16 people who had responded well to first-line antipsychotic medication, (ii) 20 people who were treatment-resistant but responding to clozapine monotherapy, (iii) 15 people who were ultra-treatment-resistant/clozapine-resistant but responding to antipsychotic polypharmacy. Twenty-two controls were also recruited. Groups were matched for age, sex, disease duration and psychopathology. All participants undertook a computerised battery of neuropsychological tests that assessed multiple cognitive domains. Raw data were converted to z-scores, and test performance was compared between groups. People with schizophrenia performed significantly worse than controls in the majority of neuropsychological tests, with verbal memory, sustained attention, and sensorimotor the most commonly impaired domains. No significant differences in performance between people deemed to be treatment-resistant or ultra-treatment-resistant, and those who responded well to first-line antipsychotic medication were observed. There was no significant relationship between antipsychotic dose and scores on any of the neuropsychological tests. Cognitive impairment is a central feature of schizophrenia, but our results suggest that treatment-resistance may not be associated with more severe deficits.

Topics: Adolescent; Adult; Antipsychotic Agents; Attention; Case-Control Studies; Clozapine; Cognition Disorders; Drug Resistance; Female; Humans; Male; Memory; Middle Aged; Neuropsychological Tests; Psychopathology; Schizophrenia; Schizophrenic Psychology; Young Adult

Attentional set shifting, a measure of executive function, is impaired in schizophrenia patients. Current standard of care has little therapeutic benefit for treating cognitive dysfunction in schizophrenia; therefore, novel drugs and animal models for testing novel therapies are needed. The NMDA receptor antagonist, MK-801, produces deficits in a rat maze-based set-shifting paradigm, an effect which parallels deficits observed on tests of executive function in schizophrenia patients. Alpha7 nicotinic acetylcholine receptor (nAChR) agonists, currently under clinical development by several companies, show promise in treating cognitive symptoms in schizophrenia patients and can improve cognition in various animal models.. The objectives of the present study were to determine whether the MK-801 deficit in set shifting could be reproduced in a drug discovery setting and to determine whether cognitive improvement could be detected for the first time in this task with alpha7 nAChR agonists.. The data presented here replicate findings that a systemic injection of the NMDA receptor antagonist MK-801 can induce a deficit in set shifting in rats. Furthermore, the deficit could be reversed by the atypical antipsychotic clozapine as well as by several alpha7 nAch receptor agonists (SSR-180711, PNU-282987, GTS-21) with varying in vitro properties.. Results indicate that the MK-801 set-shift assay is a useful preclinical tool for measuring prefrontal cortical function in rodents and can be used to identify novel mechanisms for the potential treatment of cognitive deficits in schizophrenia.

Topics: alpha7 Nicotinic Acetylcholine Receptor; Animals; Antipsychotic Agents; Attention; Benzamides; Benzylidene Compounds; Bridged Bicyclo Compounds; Bridged Bicyclo Compounds, Heterocyclic; Clozapine; Cognition Disorders; Dizocilpine Maleate; Dose-Response Relationship, Drug; Drug Discovery; Male; Maze Learning; Neuropsychological Tests; Pyridines; Rats; Rats, Sprague-Dawley; Schizophrenia; Set, Psychology

Topics: Antipsychotic Agents; Brain Injuries; Clozapine; Cognition Disorders; Drug Therapy, Combination; Employment, Supported; Humans; Piperazines; Schizophrenia; Thiazoles

Cortical thickness may be useful as a treatment response predictor in first-episode (FE) patients with schizophrenia, although this possibility has been scarcely assessed. In this study we assessed the possible relation between cortical thickness in regions of interest selected because of previously reported structural alterations in schizophrenia and clinical and cognitive changes after two years of treatment with risperidone or clozapine in 31 neuroleptic-naïve FE patients with schizophrenia (16 of them treated with clozapine and 15 with risperidone). Using the last-observation-carried-forward (LOCF), a larger improvement in positive, negative and total symptoms was predicted by the amount of baseline cortical thinning in the right prefrontal cortex (pars orbitalis). After two years of treatment, cognitive status was reassessed in the 17 patients (11 on clozapine) who had not dropped out. Working memory improvement after reassessment was associated with a greater baseline cortical thinning in the left prefrontal cortex (pars orbitalis), and verbal memory improvement with a greater baseline cortical thinning in the left pars triangularis. Significant but weak cortical thickness decrease from baseline to follow-up was observed in patients in comparison to controls (left pars triangularis and opercularis, and left caudal middle frontal areas). These results may support a positive predictive role for cortical thinning in the frontal region with regard to clinical and cognitive improvement with clozapine and risperidone in FE patients with schizophrenia.

Topics: Adult; Antipsychotic Agents; Clozapine; Cognition Disorders; Disease Progression; Female; Follow-Up Studies; Humans; Magnetic Resonance Imaging; Male; Memory; Organ Size; Prefrontal Cortex; Psychiatric Status Rating Scales; Risperidone; Schizophrenia; Speech Perception; Treatment Outcome; Young Adult

Preclinical data suggest that the 5-hydroxytryptamine (serotonin) 6 (5-HT6) receptor may be a potential target for the development of new therapies for treating cognitive dysfunctions in schizophrenia and other central nervous system disorders. Recent evidence indicates that not only blockade but also activation of 5-HT6 receptors exerts procognitive effects. Nevertheless, little is known about the potential efficacy of 5-HT6 receptor agonists in models of schizophrenia-like cognitive deficits. The aim of the present study was to evaluate the effects of the 5-HT6 receptor agonist, EMD 386088, on the ketamine-induced deficits in the attentional set-shifting task (ASST), novel object recognition (NOR) task and prepulse inhibition (PPI) task in rats. Acute administration of EMD 386088 (2.5 and 5 mg/kg, intraperitoneally) to Sprague-Dawley rats reversed the deficit in the ASST induced by repeated ketamine administration. Moreover, the ketamine-induced deficit in the NOR task was ameliorated by EMD 386088 at a dose of 5 mg/kg. However, in contrast to the antipsychotic drug clozapine, the 5-HT6 agonist did not affect PPI disrupted by ketamine. The present study demonstrated the beneficial effects of the 5-HT6 agonist in ameliorating some of the ketamine-induced deficits relevant to schizophrenia. It thus seems likely that the 5-HT6 receptor activation may represent a useful pharmacological approach to the treatment of cognitive disturbances observed in this disorder.

Topics: Animals; Antipsychotic Agents; Attention; Clozapine; Cognition Disorders; Indoles; Ketamine; Male; Pattern Recognition, Physiological; Pyridines; Rats; Rats, Sprague-Dawley; Receptors, Serotonin; Schizophrenia; Serotonin; Serotonin Receptor Agonists

Evidence from epidemiological studies suggest that low levels of vitamin D during early life alter brain development and may increase the risk of various adverse health outcomes, including schizophrenia. The aim of this experiment was to examine the effect of developmental vitamin D (DVD) deficiency on attentional processing using the 5-choice serial reaction time task (5C-SRT) and the 5-choice continuous performance test (5C-CPT), which specifically assesses sustained attention and vigilance in rodents. DVD-deficient and control rats were exposed to a series of target and non-target trials within each operant testing session. A number of measures were recorded including hit, miss, false alarm and correct rejection, as well as premature and perseverative responses. Performance on 5C-CPT was also assessed after administration of the atypical antipsychotic, clozapine. The adult offspring of DVD-deficient rats had higher levels of impulsivity, as demonstrated by a significant increase in premature responses. On the 5C-SRT and target trials of the 5C-CPT, accuracy was not significantly affected by prenatal diet; however DVD-deficient rats made 50% fewer correct rejections compared to controls on non-target trials of the 5C-CPT. Thus, control rats were able to discriminate between target and non-target trials, whereas DVD-deficient rats were unable to make this discrimination. Clozapine reduced the occurrence of false alarms in DVD-deficient rats to a level comparable to control values. Taken together these data suggest DVD-deficient rats have increased impulsivity as well as a lack of inhibitory control, and these features may be informative in terms of modeling the cognitive deficits observed in schizophrenia.

Topics: Analysis of Variance; Animals; Antipsychotic Agents; Choice Behavior; Clozapine; Cognition Disorders; Disease Models, Animal; Female; Inhibition, Psychological; Male; Probability; Rats; Rats, Sprague-Dawley; Reaction Time; Sensitivity and Specificity; Time Factors; Vitamin D Deficiency

N-Methyl-D-aspartate (NMDA) receptor (NMDAR) hypofunction has been postulated to contribute to the cognitive deficit of schizophrenia. In this study, we examined the effect of lurasidone (Latuda; Dainippon Sumitomo Pharma Co. Ltd., Tokyo, Japan), a newly approved atypical antipsychotic drug (APD), on NMDAR synaptic function in rat frontal cortical pyramidal neurons. In vivo administration of lurasidone produced a significant and selective enhancement of NMDAR-mediated synaptic responses and surface expression of NR2A and NR2B subunits. Lurasidone has high affinity for serotonin 5-HT(1A), 5-HT(2A), and 5-HT(7) receptors and dopamine D(2) receptors. In vivo administration of the 5-HT(7) receptor antagonist (2R)-1-[(3-hydroxyphenyl)sulfonyl]-2 -(2-(4-methyl-1-piperidinyl)ethyl)pyrrolidine (SB-269970) mimicked the enhancing effect of lurasidone on NMDAR responses, whereas the D(2) receptor antagonist haloperidol failed to do so. Previous studies have found that short-term administration of lurasidone reverses the cognitive impairment induced by subchronic administration of phencyclidine (PCP), an NMDAR noncompetitive antagonist. In this study, we found that lurasidone, as well as the prototypical atypical APD clozapine, restored NMDAR-mediated synaptic responses to normal levels in the PCP model of schizophrenia. These results suggest that NMDAR is the potential key molecular target of lurasidone, possibility via antagonizing 5-HT(7) receptors, which is consistent with evidence that 5-HT(7) receptor antagonism contributes to cognitive enhancement by atypical APDs in patients with schizophrenia.

Topics: Animals; Antipsychotic Agents; Clozapine; Cognition Disorders; Disease Models, Animal; Isoindoles; Lurasidone Hydrochloride; Rats; Receptor, Serotonin, 5-HT2A; Receptors, N-Methyl-D-Aspartate; Schizophrenia; Synaptic Transmission; Thiazoles

Cognitive deficits are a core feature of schizophrenia that respond minimally to existing drugs. PCP is commonly used to model schizophrenia-like deficits preclinically although different dosing protocols may affect different domains. Here we characterise the acute, and chronic intermittent effects of PCP in the 5-choice serial reaction time task (5-CSRTT) in rats, and assess the effects of clozapine. In a novel approach, we also assess the effects of increased inhibitory load and conduct clinically relevant signal detection analysis (SDA).. The effects of acute and repeated PCP (2.58 mg/kg) treatment on attentional processes and inhibitory control were assessed during and following the chronic treatment regime in the presence or absence of chronic clozapine (20 mg/kg/day).. Thirty minutes post-PCP injection, there was an increase in anticipatory responding which disappeared after 24 h. Although, acute PCP did not change accuracy of responding or processing speed, repeated PCP revealed delayed deficits in cognitive processing speed which were partly ameliorated by clozapine. Extended inter-trial intervals increased premature responding, while SDA revealed that clozapine modified persistent PCP-induced deficits in lnBeta (a composite measure of risk taking versus caution).. Acute NMDA receptor antagonism impairs inhibitory control, whereas repeated treatment produces delayed deficits in cognitive processing speed. The ability of clozapine partially to restore persistent PCP-induced deficits in processing speed and in lnBeta is consistent with clinical findings. This suggests that the enduring effects of repeated PCP treatment, combined with SDA, offers a useful, translational, approach to evaluate novel cognitive enhancers in the 5-CSRTT.

Topics: Animals; Antipsychotic Agents; Attention; Choice Behavior; Clozapine; Cognition Disorders; Disease Models, Animal; Drug Administration Schedule; GABA Antagonists; Male; Phencyclidine; Rats; Rats, Long-Evans; Reaction Time; Receptors, N-Methyl-D-Aspartate; Signal Detection, Psychological; Time Factors

There is considerable evidence that cognitive impairment is a better predictor of work and social function in schizophrenia than are positive and negative symptoms. Atypical antipsychotic drugs have been shown to improve cognitive function in schizophrenia patients, but it is unclear whether this improves patients' ability to gain employment. Data from a prospective longitudinal study was used to test the hypotheses that (1) clozapine treatment would improve employment outcome in treatment-resistant schizophrenia or schizoaffective disorder patients, and (2) specific cognitive functioning at baseline and after treatment would predict work status at baseline and change in work status. Employment status and cognitive assessment data were collected in 59 treatment-resistant schizophrenia or schizoaffective disorder patients. Forty-seven of 59 (79.7%) patients were unemployed at baseline. Over a 12-month period, 23 (48.9%) additional patients were able to gain paid or volunteer jobs, or attend school. As predicted, neurocognitive performance was a better predictor of employment status and ability to gain of employment than clinical symptoms. Improvement in verbal working memory was found to be a better predictor of employment outcome than other cognitive functions. Treatment that enhances cognitive function, especially verbal working memory, may lead to better employment outcomes in treatment-resistant schizophrenia or schizoaffective disorder patients.

Topics: Adult; Analysis of Variance; Antipsychotic Agents; Clozapine; Cognition Disorders; Employment; Female; Follow-Up Studies; Humans; Male; Middle Aged; Neuropsychological Tests; Psychiatric Status Rating Scales; Psychotic Disorders; Schizophrenia; Schizophrenic Psychology; Treatment Outcome

Clozapine (CLZ) has been shown to have a beneficial effect on cognition in schizophrenia in some studies and a detrimental effect in others. The relative effect and exposure to CLZ and its major metabolite-N-desmethylclozapine (NDMC)-could explain these discrepancies.. Using a validated measure of global cognition, we performed 2 binary logistic regression models to assess the relationship among cognition, age, sex, CLZ dose, CLZ and NDMC plasma levels, and their ratio (CLZ/NDMC) in individuals with schizophrenia spectrum disorders. Model 1 included age, sex, CLZ dose, and CLZ and NDMC levels. Model 2 included age, sex, CLZ dose, and CLZ/NDMC.. Among 73 subjects (mean [SD] age, 41.6 [12.0] years), 16 (21.9%) had high cognitive impairment, whereas the rest had low cognitive. In model 1, age and CLZ level were associated with high cognitive impairment (odds ratio [95% confidence interval] for age, 1.079 [1.011-1.152]; CLZ level, 1.010 [1.003-1.017]), whereas NDMC level was associated with its absence (NDMC level, 0.987 [0.977-0.997]). In model 2, age, male sex, and CLZ/NDMC were associated with cognitive impairment (age, 1.083 [1.015-1.154]; sex, 0.178 [0.032-0.994]; CLZ/NDMC, 7.302 [1.823-29.253]). Clozapine dose was not associated with cognition in either model.. After controlling for age, sex, and dose, CLZ/NDMC was more strongly associated with cognition than CLZ or NDMC levels. N-desmethylclozapine agonist activity versus CLZ antagonist activity at the muscarinic receptors could explain the strength of the association of CLZ/NDMC with cognition.

Topics: Adult; Antipsychotic Agents; Clozapine; Cognition Disorders; Cross-Sectional Studies; Databases, Factual; Dose-Response Relationship, Drug; Female; Humans; Logistic Models; Male; Middle Aged; Receptors, Muscarinic; Retrospective Studies; Schizophrenia; Severity of Illness Index

Schizophrenia symptoms segregate into positive, negative and cognitive, which exhibit differential sensitivity to drugs. Recent efforts to identify treatments targeting cognitive impairments in schizophrenia have directed attention to the cholinergic system for its well documented role in cognition. Relatedly, muscarinic antagonists (e.g. scopolamine) produce an 'antimuscarinic syndrome', characterized by psychosis and cognitive impairments. Latent inhibition (LI) is the poorer conditioning to a stimulus resulting from its non-reinforced pre-exposure. LI indexes the ability to ignore irrelevant stimuli and aberrations of this capacity produced by pro-psychotic agents (e.g. amphetamine, MK-801) are used extensively to model attentional impairments in schizophrenia. We recently showed that LI was disrupted by scopolamine at low doses, and this was reversed by typical and atypical antipsychotic drugs (APDs) and the acetylcholinesterase inhibitor physostigmine. Here, at a higher dose (1.5 mg/kg), scopolamine produced an opposite pole of attentional impairment, namely, attentional perseveration, whereby scopolamine-treated rats persisted in expressing LI under strong conditioning that prevented LI expression in controls. Scopolamine-induced persistent LI was reversed by cholinergic and glycinergic cognitive enhancers (physostigmine and glycine) but was resistant to both typical and atypical APDs (haloperidol and clozapine). The latter sets scopolamine-induced persistent LI apart from scopolamine- and amphetamine-induced disrupted LI, which are reversed by both typical and atypical APDs, as well as from other cases of abnormally persistent LI including MK-801-induced persistent LI, which is reversed by atypical APDs. Thus, scopolamine-induced persistent LI may provide a pharmacological LI model for screening cognitive enhancers that are efficient for the treatment of APD-resistant cognitive impairments in schizophrenia.

Topics: Animals; Antipsychotic Agents; Attention; Cholinergic Antagonists; Clozapine; Cognition Disorders; Conditioning, Psychological; Disease Models, Animal; Dose-Response Relationship, Drug; Drinking Behavior; Glycine; Haloperidol; Inhibition, Psychological; Male; Physostigmine; Rats; Rats, Wistar; Schizophrenia; Scopolamine

Cognitive deficits in schizophrenia are a major source of dysfunction for which more effective treatments are needed. The vasopressin-deficient Brattleboro (BRAT) rat has been shown to have several natural schizophrenia-like deficits, including impairments in prepulse inhibition and memory. We investigated BRAT rats and their parental strain, Long-Evans (LE) rats, in a social discrimination paradigm, which is an ethologically relevant animal test of cognitive deficits of schizophrenia based upon the natural preference of animals to investigate conspecifics. We also investigated the effects of the atypical antipsychotic, clozapine, and the putative antipsychotic, PD149163, a brain-penetrating neurotensin-1 agonist, on social discrimination in these rats. Adult rats were administered saline or one of the three doses of clozapine (0.1, 1.0, or 10 mg/kg) or PD149163 (0.1, 0.3, or 1.0 mg/kg), subcutaneously. Following drug administration, adult rats were exposed to a juvenile rat for a 4-min learning period. Animals were then housed individually for 30 min and then simultaneously exposed to the juvenile presented previously and a new juvenile for 4 min. Saline-treated LE rats, but not BRAT rats, exhibited intact social discrimination as evidenced by greater time spent exploring the new juvenile. The highest dose of clozapine and the two highest doses of PD149163 restored social discrimination in BRAT rats. These results provide further support for the utility of the BRAT rat as a genetic animal model relevant to schizophrenia and drug discovery. The potential of neurotensin agonists as putative treatments for cognitive deficits of schizophrenia was also supported.

Topics: Animals; Antipsychotic Agents; Brain; Clozapine; Cognition Disorders; Disease Models, Animal; Dose-Response Relationship, Drug; Exploratory Behavior; Male; Mental Disorders; Neurotensin; Rats; Rats, Brattleboro; Rats, Long-Evans; Receptors, Neurotensin; Schizophrenia; Schizophrenic Psychology; Social Behavior

A growing body of evidence suggests that the alpha7 neuronal nicotinic receptor (NNR) subtype is an important target for the development of novel therapies to treat schizophrenia, offering the possibility to address not only the positive but also the cognitive and negative symptoms associated with the disease. In order to probe the relationship of alpha7 function to relevant behavioral correlates we employed TC-5619, a novel selective agonist for the alpha7 NNR subtype. TC-5619 binds with very high affinity to the alpha7 subtype and is a potent full agonist. TC-5619 has little or no activity at other nicotinic receptors, including the alpha4beta2, ganglionic (alpha3beta4) and muscle subtypes. The transgenic th(tk-)/th(tk-) mouse model that reflects many of the developmental, anatomical, and multi-transmitter biochemical aspects of schizophrenia was used to assess the antipsychotic effects of TC-5619. In these mice TC-5619 acted both alone and synergistically with the antipsychotic clozapine to correct impaired pre-pulse inhibition (PPI) and social behavior which model positive and negative symptoms, respectively. Antipsychotic and cognitive effects of TC-5619 were also assessed in rats. Similar to the results in the transgenic mice, TC-5619 significantly reversed apomorphine-induced PPI deficits. In a novel object recognition paradigm in rats TC-5619 demonstrated long-lasting enhancement of memory over a wide dose range. These results suggest that alpha7-selective agonists such as TC-5619, either alone or in combination with antipsychotics, could offer a new approach to treating the constellation of symptoms associated with schizophrenia, including cognitive dysfunction.

Topics: alpha7 Nicotinic Acetylcholine Receptor; Animals; Antipsychotic Agents; Behavior, Animal; Benzofurans; Clozapine; Cognition Disorders; Exploratory Behavior; Female; Male; Maze Learning; Mice; Mice, Transgenic; Neurons; Nicotinic Agonists; Promoter Regions, Genetic; Quinuclidines; Rats; Rats, Sprague-Dawley; Receptor, Fibroblast Growth Factor, Type 1; Receptors, Nicotinic; Reflex, Startle; Schizophrenia; Schizophrenic Psychology; Social Behavior; Tyrosine 3-Monooxygenase

Topics: Antipsychotic Agents; Benzodiazepines; Chronic Disease; Clozapine; Cognition Disorders; Dementia; Drug Resistance; Humans; Korsakoff Syndrome; Male; Middle Aged; Neuropsychological Tests; Psychomotor Agitation; Schizophrenia

Reasoning and problem solving in the spatial domain are important aspects of executive function that are reliably impaired in schizophrenia, and the Groton Maze Learning Test(c) (GMLT) provides a valid measure of spatial working memory. In the current study, 34 patients with first-episode schizophrenia and 20 matched controls were assessed for baseline spatial working memory abilities using this hidden maze learning test. Approximately one month after baseline assessment, allowing for symptoms to stabilize in response to treatment with therapeutic doses of atypical antipsychotic medications for individuals with schizophrenia, all participants were again assessed with the GMLT. Prior to pharmacologic intervention, patients with schizophrenia showed significant impairments in performance of all aspects of the GMLT, including measures of learning efficiency and error monitoring. One month of treatment was associated with a reliable improvement in these domains, although impairments in accuracy and error monitoring on this spatial working memory test persisted despite symptomatic improvement. These results indicate that impairments in spatial working memory are present at the earliest stages of the illness, and that such deficits in performance remain present, albeit ameliorated, after treatment with atypical antipsychotic medication.

Topics: Adult; Antipsychotic Agents; Clozapine; Cognition Disorders; Control Groups; Female; Follow-Up Studies; Hospitalization; Humans; Male; Maze Learning; Memory; Memory Disorders; Memory, Short-Term; Neuropsychological Tests; Problem Solving; Psychometrics; Risperidone; Schizophrenia; Schizophrenic Psychology; Space Perception; Treatment Outcome

Prospective memory (PM) refers to the ability to execute a delayed intention and is different from retrospective memory (RM) in its nature and underlying mechanism (e.g., intention formation, maintenance, detection of PM cue and intention execution). Although preliminary studies have found PM impairment in patients with schizophrenia, the nature and magnitude of this problem in this clinical group is not yet fully known. The current study aimed to further clarify the nature of this impairment in schizophrenia. Fifty-four patients with schizophrenia and fifty-four healthy volunteers matched on demographic variables, IQ and executive functions took part in the study. Time-, event-, and activity-based PM tasks and a set of neurocognitive tests were administered to the participants. Results showed that patients with schizophrenia performed significantly worse on all sub-types of PM tasks, even after controlling for neurocognitive functions such as working memory, verbal memory, visual memory, and executive function. These findings suggest PM deficit is a primary deficit rather than a secondary consequence of neurocognitive impairments in schizophrenia. Analysis found that PM deficits may be mainly due to the impairment of the cue detection and intention retrieval stage.

Topics: Adult; Clozapine; Cognition Disorders; Control Groups; Cues; Female; Form Perception; Humans; Intention; Judgment; Male; Memory Disorders; Memory, Short-Term; Mental Recall; Models, Psychological; Neuropsychological Tests; Psychomotor Performance; Schizophrenia; Schizophrenic Psychology; Semantics

Topics: Adult; Affect; Clozapine; Cognition Disorders; Drug Resistance; Facial Expression; Female; Humans; Male; Neuropsychological Tests; Recognition, Psychology; Schizophrenia; Schizophrenic Psychology; Social Perception

Compounds enhancing N-methyl-d-aspartate (NMDA) glutamate receptor function have been reported to improve cognitive deficits. Since cognitive deficits are considered to be the core symptom of schizophrenia, enhancing NMDA receptor function represents a promising approach to treating schizophrenia. In the present study, we investigated whether d-serine or a glycine transporter inhibitor N-[3-(4'-fluorophenyl)-3-(4'-phenylphenoxy)propyl]sarcosine (NFPS), both of which enhance NMDA receptor function, could improve MK-801-induced cognitive deficits in rats, and compared their effects with those of the atypical antipsychotic clozapine and of the typical antipsychotic haloperidol. To assess cognitive function, we used a novel object recognition test in rats that measured spontaneous exploratory activity of a novel object when paired with a familiar object. We then evaluated the effects of the compounds on cognitive deficits induced by treatment with MK-801, the NMDA receptor antagonist. Pretreatment with clozapine (1, 5 mg/kg, i.p.) but not haloperidol (0.03, 0.1 mg/kg, i.p.) significantly improved MK-801-induced cognitive deficits. Pretreatment with D-serine at 800 mg/kg (i.p.) or NFPS (0.3, 1 mg/kg, i.p.) significantly improved MK-801-induced cognitive deficits under this test paradigm. These findings suggest that impaired preference for novel objects induced by MK-801 in the novel object recognition test could be a useful animal model for evaluating the efficacy of compounds targeting the cognitive deficits observed in schizophrenic patients. The results also suggest that enhancing NMDA receptor function is an effective way for treating the cognitive deficits associated with schizophrenia.

Topics: Analysis of Variance; Animals; Antipsychotic Agents; Clozapine; Cognition; Cognition Disorders; Dizocilpine Maleate; Exploratory Behavior; Glycine Plasma Membrane Transport Proteins; Haloperidol; Male; Nootropic Agents; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Recognition, Psychology; Sarcosine; Serine; Statistics, Nonparametric

The absence of effective cognition enhancers for the treatment of patients with schizophrenia limits the validation of animal models and behavioral tests used for drug finding and characterization. However, low doses of haloperidol and clozapine were documented to produce moderately beneficial effects in patients. Therefore, this experiment was designed to determine the attentional effects of such treatments in a repeated-amphetamine (AMPH) animal model. Animals were trained in an operant-sustained attention task and underwent a 40-day pretreatment period with saline or increasing doses (1-10 mg per kg) of AMPH. After regaining baseline performance following 10 days of saline treatment, animals were treated with haloperidol (0.025 mg per kg), clozapine (2.5 mg per kg), or vehicle for 10 days. Furthermore, the effects of AMPH challenges (1.0 mg per kg) were assessed. In AMPH-pretreated animals, the administration of AMPH challenges resulted in the disruption of attentional performance. Treatment with haloperidol and clozapine attenuated the detrimental performance effects of these challenges, with clozapine exhibiting more robust attenuation. Furthermore, clozapine, but not haloperidol, impaired the performance of control animals. In contrast, the performance of AMPH-pretreated animals remained unaffected by clozapine. As this animal model detects the moderately beneficial cognitive effects of haloperidol and clozapine, it may be useful for preclinical research designed to detect and characterize treatments for the cognitive symptoms of schizophrenia.

Topics: Animals; Attention; Clozapine; Cognition; Cognition Disorders; Disease Models, Animal; Haloperidol; Male; Psychomotor Performance; Rats; Rats, Sprague-Dawley; Schizophrenia; Treatment Outcome

Preliminary evidence suggests that a single nucleotide polymorphism (SNP), the val108/158met SNP, within the gene that codes for catechol-O-methyltransferase (COMT), a key enzyme involved in regulating dopamine (DA) transmission within the prefrontal cortex (PFC), is related to cognitive function in schizophrenia and cognitive improvement with atypical antipsychotic drugs (APDs). Specifically, several studies have identified an association between working memory and executive functions, and COMT val108/158met genotype in schizophrenia; although there have been several negative findings that are likely related to small sample sizes and, possibly, medication status of patients at the time of testing. The association between COMT val108/158met genotype, cognitive function, and cognitive improvement with clozapine was investigated in a relatively large prospective sample of patients with schizophrenia, most of whom were unmedicated at baseline. Patients were genotyped for the COMT val108/158met SNP after completing a cognitive battery consisting of tests of attention, working memory, verbal learning and memory, executive function, and verbal fluency at baseline and after 6 weeks and 6 months of treatment with clozapine. Consistent with several previous studies, an association between COMT genotype and tests of executive function and working memory was identified at baseline. In addition, a novel interaction between genotype and improvement on tests of attention and verbal fluency was identified. Specifically, met homozygous and val/met heterozygous patients demonstrated significantly greater improvement than val homozygous patients following 6 months of treatment with clozapine. The results are discussed in relation to previous cross-sectional studies and prospective investigations of the associations between COMT genotype, cognition, and cognitive improvement with atypical APDs in schizophrenia.

Topics: Adult; Antipsychotic Agents; Catechol O-Methyltransferase; Clozapine; Cognition Disorders; Cohort Studies; Female; Follow-Up Studies; Genotype; Heterozygote; Homozygote; Humans; Male; Memory, Short-Term; Methionine; Neuropsychological Tests; Polymorphism, Single Nucleotide; Problem Solving; Prospective Studies; Schizophrenia; Treatment Outcome; Valine

Forebrain dopamine (DA) manipulation has recently been shown to selectively disrupt a conditional discrimination task whose design parameters approximate tasks repeatedly shown to be impaired in schizophrenia.. To investigate the reversal potential of the D(1)/D(2) receptor antagonist alpha-flupenthixol, the selective D(1) antagonist SCH 23390, the typical antipsychotic haloperidol and the atypical antipsychotic clozapine on acute phencyclidine (PCP)-induced disruption of a conditional discrimination task dependent on the ability to use task-setting cues that inform goal-directed performance.. Rats learned a conditional discrimination task where reinforcement was contingent on an appropriate lever press during a specific auditory stimulus.. PCP disrupted task performance at 1.5 mg/kg, attenuated correct lever pressing at 2.5 mg/kg and abolished overall responding at 5 mg/kg (experiment 1). Pavlovian-instrumental transfer task results (experiment 2) showed that 1.5 and 2.5 mg/kg PCP had no disruptive effects on basic sensory, motor or motivational processes; however, such deficits were evident in 5-mg/kg-treated animals. PCP (1.5 mg/kg) disruption of conditional discrimination was attenuated by acute pretreatment with clozapine, SCH 23390 and alpha-flupenthixol; however, pretreatment with haloperidol did not attenuate task disruption.. The predictive validity of the conditional discrimination model is enhanced as the selective task disruption by the preeminent psychotomimetic PCP is reversed by clozapine (known to ameliorate cognitive deficits in schizophrenia) and the role of DA D(1) receptors as mediators of tasks that require conditional relationships is discussed.

Topics: Analysis of Variance; Animals; Antipsychotic Agents; Behavior, Animal; Benzazepines; Clozapine; Cognition; Cognition Disorders; Conditioning, Classical; Conditioning, Operant; Discrimination Learning; Dopamine Antagonists; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Extinction, Psychological; Flupenthixol; Haloperidol; Male; Phencyclidine; Predictive Value of Tests; Rats; Reproducibility of Results; Serotonin Antagonists

In humans, the N-methyl-D-aspartate antagonist phencyclidine (PCP) induces behavioral changes that mimic schizophrenia symptoms, including positive and negative symptoms as well as cognitive deficits. In clinic, the cognitive deficits are closely associated with functional outcome. Thus, improvement of cognition may have high impact on patients' daily life.. In the present study, three second-generation antipsychotics (sertindole, risperidone, and clozapine) as well as the classical antipsychotic haloperidol were tested for the ability to reverse PCP-induced cognitive deficits in the Morris' water maze.. The second-generation antipsychotics reversed the PCP-induced cognitive impairment: sertindole (0.63-2.5 mg/kg, s.c.), risperidone (0.04 mg/kg, s.c.; whereas 0.08 and 0.16 mg/kg were without significant effect), and clozapine (0.63 mg/kg, s.c.; while 1.3 mg/kg was without significant effect). The significant effect of sertindole was observed from day 2 onwards, while clozapine and risperidone only had significant effect at day 3. The classical antipsychotic haloperidol (0.010-0.020 mg/kg, s.c.) was ineffective. No compounds influenced swimming speed at the doses used, indicating that motor function was preserved.. These results confirm that repeated PCP administration induces marked cognitive deficits. Further, second-generation antipsychotics like sertindole, clozapine, and risperidone within a certain, often narrow, dose range are able to reverse the impairment and thus might improve cognitive deficits in schizophrenic patients, whereas classical compounds like haloperidol lack this effect. The receptor mechanisms involved in the reversal of PCP's disruptive effect are discussed and likely include a delicate balance between effects on dopamine D(2), 5-HT(2A/6), alpha-adrenergic, muscarinic, and histaminergic H(1) receptors.

Topics: Analysis of Variance; Animals; Antipsychotic Agents; Behavior, Animal; Clozapine; Cognition Disorders; Disease Models, Animal; Dose-Response Relationship, Drug; Haloperidol; Imidazoles; Indoles; Male; Maze Learning; Phencyclidine; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Risperidone; Schizophrenic Psychology

Cognitive deficits in schizophrenia are severe and do not respond well to available treatments. The development and validation of animal models of cognitive deficits characterizing schizophrenia are crucial for clarifying the underlying neuropathology and discovery of improved treatments for such deficits.. We investigated whether single and repeated administrations of the psychotomimetic phencyclidine (PCP) disrupt performance in the five-choice serial reaction time task (5-CSRTT), a test of attention and impulsivity. We also examined whether PCP-induced disruptions in this task are attenuated by atypical antipsychotic medications.. A single injection of PCP (1.5-3 mg/kg, s.c., 30-min pre-injection time) had nonspecific response-depressing effects. Repeated PCP administration (2 mg/kg for two consecutive days followed by five consecutive days, s.c., 30-min pre-injection time) resulted in decreased accuracy, increased premature and timeout responding, and increased response latencies. The atypical antipsychotic medications clozapine, risperidone, quetiapine, and olanzapine and the typical antipsychotic medication haloperidol did not disrupt 5-CSRTT performance under baseline conditions except at high doses. The response depression induced by a single PCP administration was exacerbated by acute clozapine or risperidone and was unaffected by chronic clozapine. Importantly, chronic clozapine partially attenuated the performance disruptions induced by repeated PCP administration, significantly reducing both the accuracy impairment and the increase in premature responding.. Disruptions in 5-CSRTT performance induced by repeated PCP administration are prevented by chronic clozapine treatment and may constitute a useful animal model of some cognitive symptoms of schizophrenia.

Topics: Animals; Antipsychotic Agents; Attention; Benzodiazepines; Clozapine; Cognition Disorders; Dibenzothiazepines; Disease Models, Animal; Dose-Response Relationship, Drug; Hallucinogens; Haloperidol; Impulsive Behavior; Male; Olanzapine; Phencyclidine; Quetiapine Fumarate; Rats; Rats, Wistar; Reaction Time; Risperidone; Schizophrenia

Approximately one third of schizophrenia patients show partial or no response to pharmacotherapy. Despite intensive investigations, the phenomenological and biological characteristics of such patients are far from elucidated. This study examined the premorbid behavioral and intellectual functioning of schizophrenia patients who showed poor response to antipsychotic treatment.. One hundred twenty-nine schizophrenia patients who showed poor response to treatment were ascertained from a national register and matched by gender, age and education to 129 patients who showed adequate response. The groups were compared on premorbid measures of behavioral and intellectual functions.. As a group, treatment-resistant male patients had significantly lower (worse) social functioning [p=0.002], and individual autonomy [p<0.0001] scores before the onset of the illness compared to treatment non-resistant patients. Male and female treatment-resistant patients did not differ from non-resistant patients in premorbid intellectual functioning [p>0.1].. Low premorbid social functioning and individual autonomy, but not intellectual functioning, could serve as predictors of poor treatment response in schizophrenia.

Topics: Adult; Antipsychotic Agents; Clozapine; Cognition Disorders; Drug Resistance; Female; Humans; Male; Mental Disorders; Neuropsychological Tests; Registries; Schizophrenia; Social Behavior

The structurally related neuropeptides, substance P, neurokinin A, and neurokinin B, belong to a family of molecules termed tachykinins and are widely distributed in the central and peripheral nervous systems. These peptides mediate their effects through three G protein coupled receptor subtypes, the neurokinin-1, neurokinin-2 and neurokinin-3 receptors, respectively.. To study the physiological functions of NK3, a line of NK3 knockout mice were generated and characterized in a broad spectrum of well-established behavioral tests.. In several tests, including spontaneous locomotor activity, elevated plus maze, forced swim, and hot plate, wild-type and knockout mice performed similarly. However, in several cognition tests, including passive avoidance, acquisition of conditioned avoidance responding (CAR), and the Morris water maze, NK3 knockout mice displayed deficits compared to wild-type mice. Although NK3 wild-type and knockout mice performed similarly in the training phase of the passive avoidance test, knockout mice had shorter latencies to enter the dark compartment on days 3 and 4, suggesting impaired retention. In the acquisition phase of the conditioned avoidance responding assay, NK3 knockout mice acquired the CAR task at a slower rate than wild-type mice. Once the CAR test was acquired, both NK3 wild-type and knockout mice responded similarly to clozapine and risperidone, drugs which suppress responding in this test. In the Morris water maze, NK3 knockout mice showed increased latencies to find the escape platform on day 3 of training, suggesting a modest, but significant delay in acquisition compared to wild-type mice.. These studies suggest a role for NK3 in learning and memory in mice.

Topics: Age Factors; Animals; Antipsychotic Agents; Avoidance Learning; Behavior, Animal; Clozapine; Cognition Disorders; Conditioning, Operant; Dose-Response Relationship, Drug; Electric Stimulation; Gene Expression; Male; Maze Learning; Mice; Mice, Inbred C57BL; Mice, Knockout; Motor Activity; Receptors, Neurokinin-3; Reverse Transcriptase Polymerase Chain Reaction; Risperidone; Swimming; Time Factors; Weight Gain

Theory of mind (ToM), the ability to attribute mental states to others, is associated with medial prefrontal cortical (mPFC) activity and is impaired in schizophrenia. Olanzapine or clozapine but not typical antipsychotics or risperidone preferentially affect c-fos expression in mPFC in animals. We tested the hypothesis that schizophrenic patients treated with different antipsychotics would perform differently on ToM tasks. Groups receiving Typicals (n=23), Clozapine (n=18), Olanzapine (n=20) or Risperidone (n=23) and a Control group of healthy volunteers (n=24) were matched for age, gender, handedness and education. ToM functioning was assessed with picture sequence, second-order belief and faux-pas tests. Schizophrenic groups performed similarly to controls on non-ToM conditions. The Olanzapine and Clozapine groups performed similarly to Controls on ToM tasks. The Typicals and Risperidone groups performed worse than the other groups on ToM tasks. We concluded that ToM performance of schizophrenic patients is influenced by the antipsychotic they are taking. Our results suggest that olanzapine or clozapine but not typicals or risperidone may improve or protect ToM ability.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Brief Psychiatric Rating Scale; Clozapine; Cognition; Cognition Disorders; Diagnostic and Statistical Manual of Mental Disorders; Drug Prescriptions; Female; Humans; Male; Neuropsychological Tests; Olanzapine; Risperidone; Schizophrenia; Severity of Illness Index

Impaired ability to detect and correct errors may contribute to poor cognitive and social function in schizophrenia.. To test the hypothesis that impairment in error monitoring contributes to impaired executive function in schizophrenia.. 56 schizophrenia patients and 77 healthy individuals were tested with the Penn Conditional Exclusion test (PCET), a computerised test of executive function which allowed collection of accuracy and latency performance parameters. Error monitoring was assessed by analyzing reaction times for correct (RTC) and incorrect (RTI) responses. Tests of face recognition, working memory (WM) and processing speed were also administered.. Executive error-monitoring effort (EXER), calculated by dividing the difference between RTI and RTC by the sum of RTC and RTI, was significantly smaller in patients than controls. A regression model with the executive function (PCET total errors) as dependent variable showed independent contributions of EXER, verbal WM and spatial WM to test performance and explained 35% of the variance. EXER showed significant association with error-monitoring effort for face recognition in patients but not controls.. Impaired error-monitoring contributes to poor executive function in schizophrenia. Independent contributions of error-monitoring effort and verbal WM to executive functions may reflect distinct contributions of prefrontal and medial frontal cortical dysfunctions. Error-monitoring mechanisms in different cognitive domains may share more neural resources in schizophrenia than in healthy individuals, reflecting inefficient processing.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Chronic Disease; Clozapine; Cognition Disorders; Diagnostic and Statistical Manual of Mental Disorders; Female; Humans; Male; Memory, Short-Term; Neuropsychological Tests; Olanzapine; Piperazines; Reaction Time; Risperidone; Schizophrenia; Self Efficacy; Severity of Illness Index; Thiazoles

Atypical antipsychotics clozapine, olanzapine, and quetiapine have significant affinity for the muscarinic receptors in vitro, while aripiprazole, risperidone, and ziprasidone do not. Dissimilarity in binding profiles may contribute to the reported differences in the anticholinergic effects of these antipsychotics. However, it is difficult with the available data to predict the likelihood of anticholinergic effects occurring with various doses of an atypical antipsychotic.. We developed a model to assess the potential anticholinergic activity (AA) of atypical antipsychotics at therapeutic doses. A radioreceptor assay was used to measure in vitro AA at 6 clinically relevant concentrations of aripiprazole, clozapine, olanzapine, quetiapine, risperidone, and ziprasidone. Using published pharmacokinetic data, in combination with the measured in vitro AA, dose-AA curves were generated.. Clozapine, and to a lesser extent olanzapine and quetiapine showed dose-dependent increases in AA. At therapeutic doses, the AA (in pmol/mL of atropine equivalents) was estimated to range from 27-250, 1-15, and 0-5.4 pmol/mL for clozapine, olanzapine, and quetiapine, respectively. Aripiprazole, risperidone, and ziprasidone did not demonstrate AA at any of the concentrations studied.. Therapeutic doses of clozapine, olanzapine, and, to a lesser extent, quetiapine are associated with clinically relevant AA.

Topics: Adult; Antipsychotic Agents; Aripiprazole; Benzodiazepines; Binding Sites; Clozapine; Cognition Disorders; Dibenzothiazepines; Dose-Response Relationship, Drug; Female; Humans; Male; Neuropsychological Tests; Olanzapine; Piperazines; Quetiapine Fumarate; Quinolones; Receptors, Cholinergic; Risperidone; Schizophrenia; Thiazoles

Abusers of phencyclidine (PCP) often present with a symptom profile similar to that exhibited by schizophrenic patients. Animal models utilising such psychotomimetics are currently informing research into the condition. Accumulating evidence suggests that a central cognitive deficit in schizophrenia is the inability to use task-setting cues to guide goal directed behaviour and that this ability is mediated by prefrontal dopamine (DA). The current study used the non-competitive NMDA antagonist phencyclidine (PCP) and Haloperidol (typical antipsychotic) and Clozapine (atypical antipsychotic) in order to further investigate the influence of DAergic manipulation on a task that requires the use of conditional information to inform goal-directed performance. An instrumental conditional discrimination task was employed in which rats learn to respond appropriately according to the presence of specific auditory conditional stimuli. Probe test 1 showed impaired conditional discrimination performance following sub-chronic PCP administration (seven twice-daily injection protocol) compared to control which was reversed by acute treatment with clozapine (5 mg/kg) but not haloperidol (0.1 mg/kg) both administered 60 min pre-test. Probe test 2 (8 days post-treatment) showed enduring deficits to conditional discrimination performance that were again reversed by clozapine but not haloperidol (injection procedures as above). These results show that tasks dependent upon conditional relationships are particularly sensitive to manipulation of DAergic systems as prolonged treatment with PCP has been shown to selectively reduce prefrontal cortex (PFC) DA activity and treatment with clozapine (known to ameliorate cognitive deficits) but not haloperidol has been shown to selectively restore PFC DA levels.

Topics: Analysis of Variance; Animals; Antipsychotic Agents; Clozapine; Cognition Disorders; Conditioning, Operant; Discrimination Learning; Dopamine; Excitatory Amino Acid Antagonists; Goals; Haloperidol; Male; Phencyclidine; Prefrontal Cortex; Rats

Cognitive function and regional cerebral blood flow (rCBF) were studied in negative symptom profile schizophrenic patients by using WCST and SPECT.. Twenty-one schizophrenic patients who matched the criteria of Andreason's negative symptom profile received SPECT and WCST, and then were treated with clozapine for 8 consecutive weeks. There were 28 and 12 normal subjects as the control groups of WCST and SPECT, respectively.. Compared with controls, significantly poorer performance on total trials of category (TT), persevering errors (PE), and non-persevering errors (NPE) of WCST were found in schizophrenia (p < 0.05). The total score of the scale for assessment negative symptoms (SANS) was significantly related with poor TT (r = 0.45, p < 0.01) and PE performance (r = 0.45, p < 0.01). The poor TT, PE, and NPE tasks of WCST and SANS scores in the negative schizophrenic patients were significantly improved through clozapine treatment (p < 0.05). The schizophrenic patients had a significantly lower rCBF in bilateral frontal and temporal lobes and lower change rate of rCBF in bilateral frontal lobes during WCST compared to normal controls (p < 0.05).. Negative symptom profile schizophrenia has cognitive deficits and lower rCBF in bilateral frontal and temporal lobes, which suggests that negative symptom profile schizophrenic patients have hypofrontality. Clozapine can improve negative symptoms and improve cognitive dysfunction, although it cannot improve reduced rCBF in the frontal lobes.

Topics: Adult; Antipsychotic Agents; Cerebellum; Clozapine; Cognition Disorders; Depression; Dominance, Cerebral; Female; Frontal Lobe; Humans; Male; Neuropsychological Tests; Occipital Lobe; Parietal Lobe; Reference Values; Regional Blood Flow; Schizophrenia; Temporal Lobe; Tomography, Emission-Computed, Single-Photon; Treatment Outcome

The alpha(2) adrenoceptor antagonist idazoxan enhances antipsychotic efficacy of classical dopamine D(2) antagonists in treatment-resistant schizophrenia. The mechanisms are not fully understood, but we have previously shown that the combination of idazoxan with the D(2/3) receptor antagonist raclopride, similarly to clozapine but not classical antipsychotic drugs, augments dopamine efflux in the prefrontal cortex, and also generates an enhanced suppression of the conditioned avoidance response. We have now investigated the effects of clozapine, raclopride, idazoxan and the combination of raclopride and idazoxan on (i) electrically evoked excitatory post-synaptic potentials and currents in pyramidal cells of the rat medial prefrontal cortex, using intracellular electrophysiological recording in vitro, (ii) the impaired cognitive function induced by the selective N-methyl-D-aspartate (NMDA) receptor antagonist MK-801, using the 8-arm radial maze test, (iii) the in-vivo D2, alpha(2A) and alpha(2C) receptor occupancies of these pharmacological treatments, using ex-vivo autoradiography. Whereas neither idazoxan nor raclopride alone had any effect, the combination exerted the same facilitation of glutamatergic transmission in rat prefrontal pyramidal neurons as clozapine, and this effect was found to be mediated by dopamine acting at D(1) receptors. Similarly to clozapine, the combination of idazoxan and raclopride also completely reversed the working-memory impairment in rats induced by MK-801. Moreover, these effects of the two treatment regimes were obtained at similar occupancies at D(2), alpha(2A) and alpha(2C) receptors respectively. Our results provide novel neurobiological and behavioural support for a pro-cognitive effect of adjunctive use of idazoxan with antipsychotic drugs that lack appreciable alpha(2) adrenoceptor-blocking properties, and define presynaptic alpha(2) adrenoceptors as major targets in antipsychotic drug development.

Topics: Adrenergic alpha-Antagonists; Animals; Behavior, Animal; Cerebral Cortex; Clozapine; Cognition Disorders; Disease Models, Animal; Dizocilpine Maleate; Dopamine D2 Receptor Antagonists; Dose-Response Relationship, Drug; Drug Interactions; Electric Stimulation; Excitatory Amino Acid Antagonists; Excitatory Postsynaptic Potentials; Glutamic Acid; Idazoxan; In Vitro Techniques; Male; Maze Learning; Raclopride; Radioligand Assay; Rats; Rats, Sprague-Dawley; Rats, Wistar; Synaptic Transmission

In schizophrenia, elevations of serum and CSF S100B levels have been reported and related to state of the disease and negative symptoms. In elderly chronic schizophrenic inpatients with stable medication, S100B may be increased and correlated to psychopathology and neuropsychological deficits. We have measured serum levels of S100B in 41 elderly, chronic schizophrenic patients and 23 age- and gender-matched controls using an immunoluminometric assay. In patients, we assessed detailed psychopathology and neuropsychological performance and determined serum levels of haloperidol, clozapine and its two main metabolites desmethylclozapine and clozapine metabolite N-oxid by HPLC. S100B levels were increased in elderly chronic schizophrenic patients compared to healthy controls. In patients, levels were negatively correlated with deficit symptoms and positively with age. There were no significant differences of S100B between medication groups and no correlation with serum levels of antipsychotics or neuropsychological scores. Elevations of S100B in elderly chronic schizophrenic patients may be related to an active disease process lasting until old-age. Correlations point to the impact of S100B in neuroplasticity and ageing. Post-mortem studies should clarify the presence of altered S100B function in the brain and its relationship to neuroplastic or neurodegenerative processes.

Topics: Aged; Antipsychotic Agents; Chronic Disease; Clozapine; Cognition Disorders; Depressive Disorder, Major; Female; Haloperidol; Humans; Male; Middle Aged; Nerve Growth Factors; Neuropsychological Tests; Psychological Tests; S100 Calcium Binding Protein beta Subunit; S100 Proteins; Schizophrenia; Schizophrenic Psychology; Severity of Illness Index

This study was undertaken to examine the effects of subsequent administration of antipsychotic drugs (clozapine and haloperidol) on cognitive deficits in mice after repeated administration of phencyclidine (PCP). In the novel object recognition test, repeated administration of PCP (10 mg/kg) significantly decreased exploratory preference in the retention test session but not in the training test session. PCP-induced deficits were significantly improved by subsequent subchronic (2 weeks) administration of clozapine (5 mg/kg), but not haloperidol (0.1 mg/kg). These findings suggest that PCP-induced cognitive deficits using the novel object recognition test may be a potential animal model of atypical antipsychotic activity.

Topics: Analysis of Variance; Animals; Antipsychotic Agents; Behavior, Animal; Clozapine; Cognition Disorders; Exploratory Behavior; Hallucinogens; Haloperidol; Male; Mice; Mice, Inbred ICR; Phencyclidine; Time Factors

Cognitive dysfunction is increasingly considered to be the strongest clinical predictor of poor long-term outcome in schizophrenia. Associations have been found between the severity of cognitive deficits and social dysfunction, impairments in independent living, occupational limitations, and disturbances in quality of life (QOL).. In this cross-sectional study, the relationships of cognitive deficits and treatment outcomes in terms of QOL, needs, and psychosocial functioning were examined in 60 outpatients with schizophrenia who had a duration of illness over 2 years and had been treated with either clozapine or olanzapine for at least 6 months.. The present study suggests that cognitive functioning might be a predictor of work functioning/independent living outcome in stabilized patients with schizophrenia: deficits of visual memory and working memory were negatively associated with occupational functioning, and older patients lived independently and/or in a stable partnership more often. The patients' assessments of QOL and needs for care did not show any significant associations with cognitive functioning.. These findings suggest that cognitive functioning is a key determinant of work functioning/independent living for stable outpatients with schizophrenia.

Topics: Adult; Age Factors; Antipsychotic Agents; Benzodiazepines; Clozapine; Cognition; Cognition Disorders; Comorbidity; Cross-Sectional Studies; Female; Humans; Male; Memory Disorders; Neuropsychological Tests; Olanzapine; Outpatients; Predictive Value of Tests; Quality of Life; Schizophrenia; Schizophrenic Psychology; Treatment Outcome

Recently we reported the pharmacological characterization of the 9,10-dihydropyrrolo[1,3]benzothiazepine derivative (S)-(+)-8 as a novel atypical antipsychotic agent. This compound had an optimum pK(i) 5-HT(2A)/D(2) ratio of 1.21 (pK(i) 5-HT(2A) = 8.83; pK(i) D(2) = 7.79). The lower D(2) receptor affinity of (S)-(+)-8 compared to its enantiomer was explained by the difficulty in reaching the conformation required to optimally fulfill the D(2) pharmacophore. With the aim of finding novel atypical antipsychotics we further investigated the core structure of (S)-(+)-8, synthesizing analogues with specific substituents; the structure-activity relationship (SAR) study was also expanded with the design and synthesis of other analogues characterized by a pyrrolo[2,1-b][1,3]benzothiazepine skeleton, substituted on the benzo-fused ring or on the pyrrole system. On the 9,10-dihydro analogues the substituents introduced on the pyrrole ring were detrimental to affinity for dopamine and for 5-HT(2A) receptors, but the introduction of a double bond at C-9/10 on the structure of (S)-(+)-8 led to a potent D(2)/5-HT(2A) receptor ligand with a typical binding profile (9f, pK(i) 5-HT(2A)/D(2) ratio of 1.01, log Y = 8.43). Then, to reduce D(2) receptor affinity and restore atypicality on unsaturated analogues, we exploited the effect of specific substitutions on the tricyclic system of 9f. Through a molecular modeling approach we generated a novel series of potential atypical antipsychotic agents, with optimized 5HT(2A)/D(2) receptor affinity ratios and that were easier to synthesize and purify than the reference compound (S)-(+)-8. A number of SAR trends were identified, and among the analogues synthesized and tested in binding assays, 9d and 9m were identified as the most interesting, giving atypical log Y scores respectively 4.98 and 3.18 (pK(i) 5-HT(2A)/D(2) ratios of 1.20 and 1.30, respectively). They had a multireceptor affinity profile and could be promising atypical agents. Compound 9d, whose synthesis is easier and whose binding profile is atypical (log Y score similar to that of olanzapine, 3.89), was selected for further biological investigation. Pharmacological and biochemical studies confirmed an atypical antipsychotic profile in vivo. The compound was active on conditioned avoidance response at 1.1 mg/kg, a dose 100-times lower than that required to cause catalepsy (ED(50) >90 mg/kg), it induced a negligible increase of prolactin serum levels after single and m

Topics: Animals; Antipsychotic Agents; Avoidance Learning; Benzothiepins; Catalepsy; Cognition Disorders; Dopamine Antagonists; Humans; Male; Mice; Models, Molecular; Motor Activity; Pituitary Gland, Anterior; Prolactin; Pyrroles; Rats; Rats, Inbred F344; Rats, Wistar; Receptors, Dopamine D1; Receptors, Dopamine D2; Receptors, Dopamine D3; Receptors, Serotonin, 5-HT2; Serotonin Antagonists; Structure-Activity Relationship; Thiazepines

Molecular components of the dopaminergic system may play an important role in the pathophysiology of schizophrenia. In this study, we investigated the relationship of the Ser9Gly (S/G) polymorphism of the dopamine D3 receptor (DRD3) and the variable number of tandem repeats (VNTR) polymorphism of the dopamine transporter (DAT) with therapeutic response to atypical antipsychotics (clozapine, olanzapine, quetiapine, risperidone) and cognitive functions. No associations were found between the DRD3 and DAT polymorphisms and schizophrenia. The S/S genotype and the S allele were more frequent in the non-responder patients (n = 28) than in the group of responders (n = 47) (cut-off: >20-point improvement in Global Assessment of Functioning (GAF) scale). The patients with S/S genotype completed fewer categories and had more perseverative errors in the Wisconsin Card Sorting Test (WCST) compared with the S/G patients. The S/S and S/G patients did not differ in positive and negative symptoms, GAF scores, WCST failure to maintain set, and verbal learning. No differences in symptoms or WCST measures were observed in the patients with different DAT genotypes. These results suggest that the S/S genotype of the DRD3 is associated with worse therapeutic response and more severe executive dysfunctions in patients with schizophrenia.

Topics: Adult; Alleles; Analysis of Variance; Antipsychotic Agents; Benzodiazepines; Clozapine; Cognition Disorders; Dibenzothiazepines; Dopamine Plasma Membrane Transport Proteins; Female; Gene Frequency; Genotype; Humans; Male; Membrane Glycoproteins; Membrane Transport Proteins; Middle Aged; Minisatellite Repeats; Nerve Tissue Proteins; Olanzapine; Polymorphism, Genetic; Quetiapine Fumarate; Receptors, Dopamine D2; Receptors, Dopamine D3; Risperidone; Schizophrenia

There are not many studies on the use of clozapine in patients with intellectual disability (ID). The authors describe a case series of patients treated with clozapine, drawn from a medium secure unit, a low secure assessment and treatment service and a community team in the London region.. A retrospective file-review of patients treated in these three settings during the time period March-June 2002 was performed (n = 24). Information was collected using a semistructured proforma.. Of the 24 patients, 67% had schizophrenia, 17% had schizoaffective disorder and 8% had bipolar disorder. Patients had been unwell for a mean of 6 years and had been tried on a mean of four antipsychotics. The mean maximum dose of clozapine was 488 mg. The outcomes on the clinical global impression (CGI) scale showed 29% very much improved, 42% much improved, 21% minimally improved and 8% no change. 54% of the whole sample and 53% of those from the medium secure unit were discharged to homes in the community. The drug had to be stopped in four patients, of which three were because of neutropaenia.. Clozapine appears to be safe and efficacious in many people with ID. Careful monitoring of side-effects is needed during therapy.

Topics: Adult; Antipsychotic Agents; Bipolar Disorder; Child; Child Development Disorders, Pervasive; Clozapine; Cognition Disorders; Drug Resistance; Drug Utilization; Epilepsy; Female; Humans; Male; Middle Aged; Personality Disorders; Psychotic Disorders; Retrospective Studies; Schizophrenia; Substance-Related Disorders

The effectiveness of cognitive rehabilitation in ameliorating the symptomatic, cognitive, and functional deficits associated with schizophrenia and schizoaffective disorders was assessed in this prospective study. Thirty-eight participants who met DSM-IV criteria were assigned to cognitive rehabilitation treatment or treatment as usual (TAU) groups, using the method of minimization to equalize groups on prognostic variables believed to affect outcome (i.e., duration and severity of illness, Clozapine). Participants were assessed at baseline, treatment end, and 3-month follow-up. Improvement across time was found for both groups in delayed visuospatial memory and visual information processing speed, and the participant's status on the prognostic variables was found to be related to level of performance on measures of delayed visuospatial memory, negative symptoms, and speech disturbance. However, the findings did not provide evidence that cognitive rehabilitation is associated with greater improvement than TAU. Nor did the findings indicate that prognosis interacted with treatment to produce differential treatment outcomes.

Topics: Antipsychotic Agents; Clozapine; Cognition Disorders; Cognitive Behavioral Therapy; Diagnostic and Statistical Manual of Mental Disorders; Humans; Neuropsychological Tests; Prospective Studies; Psychotic Disorders; Schizophrenia; Severity of Illness Index

The aim of this study was to evaluate the effects of atypical antipsychotics on cognitive function in schizophrenic patients under clinical routine conditions.. Schizophrenic patients (n = 78) were evaluated on neuropsychological tests of attention, short-term- and working memory, learning, long-term memory (retention) and executive function. Data were analyzed according to medication, severity of illness and age.. We observed that treatment with atypical antipsychotics compared to conventional neuroleptics was significantly associated with a more favorable effect on cognitive function. Especially in short-term memory and retention a clear advantage of atypical antipsychotics could be seen.. Results from this study suggest that even under clinical routine conditions atypical antipsychotics have an advantage on cognitive function when compared with conventional neuroleptics.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Clozapine; Cognition Disorders; Drug Therapy, Combination; Female; Haloperidol; Humans; Male; Middle Aged; Neuropsychological Tests; Olanzapine; Pirenzepine; Product Surveillance, Postmarketing; Risperidone; Schizophrenia; Schizophrenic Psychology

The primary aim of our study is to evaluate the level of insight during the switch from a classical antipsychotic drug to a atypical neuroleptic. Twenty-two schizophrenic patients were admitted to the study, 9 were male and 13 were female. Standardized questionnaire were: Scale for Assessment of Negative Symptoms (SANS), Scale for Assessment of Positive Symptoms (SAPS), Brief Psychiatric Rating Scale (BPRS) and Schedule for Assessing the three components of Insight (SAI). All patients were receiving haloperidol at time of recruitment. Eight patients were switched to clozapine, 3 to risperidone and 11 to olanzapine. The global function, measured with BPRS, increased after administration of atypical antipsychotics. The positive and negative symptoms were reduced. The level of insight was increased after the administration of the atypical antipsychotics. The cognitive effect of the atypical antipsychotics changed the level of insight and augmented the compliance.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Clozapine; Cognition; Cognition Disorders; Female; Haloperidol; Humans; Male; Olanzapine; Patient Compliance; Pirenzepine; Risperidone; Schizophrenia; Severity of Illness Index; Treatment Outcome

Topics: Antipsychotic Agents; Brief Psychiatric Rating Scale; Clozapine; Cognition Disorders; Humans; Neuropsychological Tests; Receptors, Dopamine D2; Schizophrenia

To relate the pattern of neuropsychological impairments among schizophrenic patients to case history data and disease characteristics in a cross-sectional study of unselected patients, and to integrate these data with two previous longitudinal studies of neuropsychological impairments among schizophrenic patients.. One hundred consecutive schizophrenic patients were studied with respect to clinical case history and current symptoms, medication and neuropsychological impairment using a comprehensive computerized test battery.. The most salient finding was a marked slowing of response readiness, linearly related to the number of previous acute episodes. The resulting deficit was far beyond what has been obtained in any other group of subjects (average -6 SD for >five episode patients). The impairments in many of the other neuropsychological parameters could to some extent be explained with reference to response slowing, with one exception--verbal short-term memory. Adjustment for important confounding factors (age, duration of illness, medication) did not change the strong negative association between response readiness and number of previous episodes.. These findings, together with findings of our two previous longitudinal studies and a recent replication, prompted us to suggest that each acute schizophrenic episode inflicts damage to a set of hypothetical structures, cognitive pattern generators. We assume that these structures translate intentions to logistic programs. When damaged, delays are introduced into executive functions and corollary discharge processes will run out of phase with intentions. This model implicates new ways of looking at the generative mechanisms of the illness, and on treatment strategies.

Topics: Adult; Antipsychotic Agents; Brief Psychiatric Rating Scale; Clozapine; Cognition Disorders; Disease Progression; Female; Humans; Male; Neuropsychological Tests; Psychometrics; Reaction Time; Schizophrenia; Severity of Illness Index

Patients with schizophrenia have deficits in attention, cognition, and information processing. Measures such as P50 suppression are used to study cognitive and attentional dysfunction among these patients. P50 suppression is an operational measure of sensory gating that can be assessed by averaging electroencephalographic responses to multiple pairs of auditory clicks separated by 500 msec. Normally, the P50 response to the second click is smaller than the response to the first click. Many studies have demonstrated that schizophrenia patients have deficient P50 suppression, meaning that the difference between the first and second clicks is not as large as normal. Atypical antipsychotic medications may have superior clinical efficacy for negative symptoms and cognitive deficits. It is important, therefore, to evaluate the effects of atypical antipsychotic medications on measures such as P50 suppression.. P50 suppression of 13 patients with schizophrenia receiving clinically effective doses of clozapine, olanzapine, or risperidone (classified as atypical antipsychotic medications) was compared to that of 13 patients receiving conventional antipsychotic medications.. The patient groups did not differ on clinical or demographic measures. The patients receiving atypical antipsychotic medications had normal-range P50 suppression (mean=72%). In contrast, the patients receiving typical antipsychotic medications had dramatically lower P50 suppression (mean=27%).. The results support the hypothesis that patients treated with atypical antipsychotic medications have normal P50 measures of sensory gating. Longitudinal within-subjects studies are warranted to clarify the mechanisms mediating this effect.

Topics: Acoustic Stimulation; Adult; Antipsychotic Agents; Auditory Perception; Benzodiazepines; Clozapine; Cognition Disorders; Electroencephalography; Evoked Potentials, Auditory; Female; Humans; Male; Olanzapine; Pirenzepine; Psychiatric Status Rating Scales; Risperidone; Schizophrenia; Schizophrenic Psychology

To identify which improvements in cognitive function are associated with symptom resolution in schizophrenic patients treated with atypical antipsychotics.. a prospective open trial with atypical neuroleptics (risperidone, clozapine, quetiapine).. Inpatient and outpatient units, Institute of Psychiatry.. Thirty-nine patients with schizophrenia according to DSM-IV criteria were included. Clinical and cognitive assessment were done at baseline (T0) and again after six months of treatment (T2). Twenty-five patients completed the trial.. New-generation antipsychotics during six months. Patients were considered as responders if their PANSS score decreased at least 20% (n = 15) and non-responders if it did not (n = 10).. a computerized cognitive assessment comprised tests of short-term-memory (digit span), explicit long-term memory (word pair learning), divided attention, selective attention and verbal fluency (orthographic and semantic). Clinical assessment included PANSS and ESRS.. A discriminant function analysis was performed to determine which changes in cognitive performance predicted symptomatic response status. Semantic fluency and orthographic fluency were significant predictors. Together they correctly predicted responder status in 88% of cases. Memory was not a significant predictor of symptomatic response.. Verbal fluency discriminated the responder from the non-responder group during a pharmacological treatment.

Topics: Adult; Antipsychotic Agents; Attention; Clozapine; Cognition Disorders; Dibenzothiazepines; Female; Humans; Male; Memory, Short-Term; Middle Aged; Neuropsychological Tests; Psychiatric Status Rating Scales; Quetiapine Fumarate; Retention, Psychology; Risperidone; Schizophrenia; Schizophrenic Language; Schizophrenic Psychology; Treatment Outcome; Verbal Behavior

A potential beneficial outcome of treatment with certain of the atypical neuroleptics is the reduced risk of cognitive impairment, stemming from purported low affinity for cholinergic receptors. In vitro experiments have shown that clozapine is highly anticholinergic and risperidone is minimally so. In vivo tests of the anticholinergic burden imposed by these medications and its potential cognitive consequences are needed. This study examines anticholinergic burden in schizophrenia patients taking clozapine and risperidone and tests whether this burden is associated with cognitive deficits.. Serum anticholinergic levels were determined in a sample of 22 chronic schizophrenia patients using the radioreceptor assay method of Tune and Coyle (1980). Fifteen patients received clozapine; 7 received risperidone. Mean +/- SD age of the sample, comprising 12 men and 10 women (68% white), was 44.7 +/- 8.4 years. Mean +/- SD age at onset of schizophrenia illness was 23.5 +/- 7.4 years. Two anticholinergic assays based on blood samples collected 1 week apart were available on each patient.. Data indicated that clozapine patients had significantly (p < .001) higher anticholinergic levels at both collection points, and levels for both drugs remained stable over time. The clozapine and risperidone patients had essentially equivalent scores on the cognitive measure.. These data suggest that anticholinergicity distinguishes clozapine and risperidone in vivo but that this effect is not associated with differences in global cognitive functioning. Results suggest that clozapine, despite producing moderately high in vivo serum anticholinergic levels, still holds clinical advantage over standard neuroleptics in terms of cognitive side effects. Reasons for this lowered risk of cognitive impairment are discussed.

Topics: Adult; Cholinergic Antagonists; Clozapine; Cognition Disorders; Female; Humans; Male; Middle Aged; Muscarinic Antagonists; Psychiatric Status Rating Scales; Quinuclidinyl Benzilate; Radioligand Assay; Receptors, Cholinergic; Risperidone; Schizophrenia; Schizophrenic Psychology; Tritium

Topics: Clozapine; Cognition Disorders; Drug Therapy, Combination; Humans; Selective Serotonin Reuptake Inhibitors; Serotonin Receptor Agonists; Sertraline

The surface EEGs of 32 medicated chronic schizophrenic patients, 12 unmedicated chronic schizophrenics and 35 matched healthy controls were analyzed by adaptive segmentation of continuous EEG during a rest condition, a mental arithmetic task, and a CNV paradigm. Results indicate increased duration of brain microstates in both unmedicated and medicated schizophrenics as well as reduced topographic variability. These findings did not vary across the different tasks. Comparing different cognitive tasks, schizophrenics and controls alike showed task-related changes of electric field topography, of EEG microstate duration and of the number of very short microstates (single-peak segments). However, the topography of the microstates during the tasks differed significantly in both medicated and unmedicated schizophenics from that of controls. Age, sex and educational levels did not influence these findings. Neuroleptic medication correlated negatively with microstate duration in a dose-dependent way. There was an inverse relationship between topographic variability and negative symptoms as well as BPRS scores. It is concluded that the temporo-spatial characteristics of brain electric activity indicate an impoverished array of functional modes and enhanced stability of brain electrical microstates in schizophrenia.

Topics: Adult; Antipsychotic Agents; Chronic Disease; Clozapine; Cognition Disorders; Electroencephalography; Female; Humans; Male; Reaction Time; Schizophrenia; Schizophrenic Psychology

This study examined the cognitive functioning of 10 treatment-resistant schizophrenic patients after a minimum of a 1-year trial on clozapine. Results indicated significant improvements on prorated Wechsler Adult Intelligence Scale-Revised (WAIS-R) Full Scale, Verbal, and Performance IQs and on the WAIS-R Similarities and Digit Symbol subtests. A trend was also found for improvement on the Wisconsin Card Sorting Test. It was concluded that clozapine treatment is associated with global cognitive improvements in patients with treatment-resistant schizophrenia. Clozapine treatment may also improve performance on the Wisconsin Card Sorting Test in a subset of patients. Improvement did not appear to be related to the reduction of any cognitive effects of the typical neuroleptics upon their discontinuation.

Topics: Adult; Antipsychotic Agents; Clozapine; Cognition; Cognition Disorders; Female; Humans; Male; Neuropsychological Tests; Schizophrenia

Topics: Antipsychotic Agents; Clinical Trials as Topic; Clozapine; Cognition Disorders; Humans; Research Design; Schizophrenia; Schizophrenic Psychology; Treatment Outcome

The long-term effects of a combination of clozapine and psychosocial treatment were evaluated in a sample of treatment-refractory state hospital patients with schizophrenia.. A repeated-measure design was used. Thirty-one patients with schizophrenia received both clozapine and an enhanced psychosocial treatment program. Data were collected at baseline and at one-year, two-year, and three-year follow-ups. Psychiatric symptoms, cognitive functioning, dyskinetic movements, and discharge rate were evaluated.. Significant reductions in psychiatric symptoms and improvement in cognitive functioning were found. Differences in the pattern of reductions in positive and negative symptoms over the course of the study were noted. The majority of subjects improved sufficiently to be discharged.. Clozapine, when combined with psychosocial treatment, is effective for treatment of patients with schizophrenia who are not responsive to other medications.

Topics: Adult; Antipsychotic Agents; Clozapine; Cognition Disorders; Female; Follow-Up Studies; Humans; Long-Term Care; Male; Middle Aged; Neuropsychological Tests; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenic Psychology; Socioenvironmental Therapy; Treatment Outcome

A reduced P300 amplitude has often been found to be related to schizophrenic psychopathology. It is still unclear, however, whether this relationship is trait- or state-dependent. We investigated 88 stabilized schizophrenic outpatients during a 2-year follow-up period. Multivariate analyses revealed that patients who had reduced P300 amplitudes showed pronounced residual symptoms, especially thought disorder (Brief Psychiatric Rating Scale). Intraindividual changes in that psychopathology were not correlated to corresponding changes of the P300 amplitude, so the relationship between schizophrenic psychopathology and P300 amplitude appears to be, at least in part, trait-dependent. A reduced P300 amplitude may characterize a subgroup of schizophrenic patients with a disposition to cognitive disturbances and incomplete remissions.

Topics: Adult; Antipsychotic Agents; Clozapine; Cognition Disorders; Evoked Potentials; Female; Follow-Up Studies; Humans; Male; Perazine; Schizophrenia; Schizophrenic Psychology; Sex Factors

Topics: Adult; Amnesia; Clozapine; Cognition Disorders; Dose-Response Relationship, Drug; Female; Humans; Mental Recall; Neuropsychological Tests; Schizophrenia; Schizophrenic Psychology

Cognitive functions and psychopathology were assessed in 36 treatment-refractory schizophrenic patients before initiation of clozapine, and at 6 weeks and 6 months, thereafter. Before treatment, cognitive impairment was found in each measure of memory, attention, and executive function as compared with 26 normal controls. After both 6 weeks and 6 months of treatment, significant improvement occurred in the Controlled Oral Word Association Test, a measure of retrieval from reference memory. Improvement was also noted at 6 months in the Category Instance Generation Test, another measure of retrieval from reference memory, and in some, but not all, tests of executive function, attention, and recall memory. Clozapine treatment also resulted in significant improvement in Brief Psychiatric Rating Scale (BPRS) Total and Positive symptom scores at both 6-week and 6-month assessment points. There was some evidence for a relationship between improvement in psychopathology and cognitive function. The improvement in cognitive function during clozapine treatment could have consequences for capacity to work and social function.

Topics: Adult; Clozapine; Cognition Disorders; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Male; Middle Aged; Neuropsychological Tests; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenic Psychology; Wechsler Scales

Topics: Clozapine; Cognition Disorders; Humans; Neuropsychological Tests; Psychiatric Status Rating Scales; Risk Factors; Schizophrenia; Schizophrenic Psychology

The literature was surveyed concerning the frequency and conditions for confusional states and deliria following Amitriptyline and Clozapine treatment, and certain discrepancies were noted. As a result a retrospective comparative investigation was carried out as to the frequency and the conditions for such events in a group of patients treated along the same lines. While our experience with Amitriptyline is not different from that reported by others, this does not seem to be the case with Clozapine. Confusional states and deliria are four times as frequent as the average reported in the literature; it is clear that they depend on conditions different from those of confusional states and deliria due to Amitriptyline; there is a slightly significant (p less than 0.05) correlation between the appearance of confusion and a temperature of over 37.5 degrees C. The anticholinergic properties of Amitriptyline and of Clozapine cannot explain the difference in frequency, nor the differing conditions for the appearance, of pharmacogenic confusional states and deliria with those two substances.

Topics: Adult; Amitriptyline; Austria; Clozapine; Cognition Disorders; Confusion; Delusions; Dibenzazepines; Female; Humans; Male