Scot E. Purdon

A meta-analysis of neuropsychological change to clozapine, olanzapine, quetiapine, and risperidone in schizophrenia

Cognitive impairment is a core feature of schizophrenia and a major impediment to social and vocational rehabilitation. A number of studies have claimed cognitive benefits from treatment with various atypical antipsychotic drugs (APDs). The currently available evidence supporting cognitive improvement with atypical APDs was evaluated in two meta-analyses. Studies that (1) prospectively examined cognitive change to the atypical APDs clozapine, olanzapine, quetiapine, and risperidone, (2) included a commonly used neuropsychological test, and (3) provided data from which relevant effect sizes could be calculated, were included. Forty-one studies met these criteria. Neuropsychological test data from each study were combined into a Global Cognitive Index and nine cognitive domain scores. Two meta-analyses were carried out. The first included 14 controlled, random assignment trials that assigned subjects to an atypical APD and a typical APD control arm. The second analysis included all prospective investigations of atypical treatment and the within-group change score divided by its standard deviation served as an estimate of effect size (ES). The first analysis revealed that atypicals are superior to typicals at improving overall cognitive function (ES=0.24). Specific improvements were observed in the learning and processing speed domains. The second analysis extended the improvements to a broader range of cognitive domains (ES range=0.17-0.46) and identified significant differences between treatments in attention and verbal fluency. Moderator variables such as study blind and random assignment influence results of cognitive change to atypical APDs. Atypical antipsychotics produce a mild remediation of cognitive deficits in schizophrenia, and specific atypicals have differential effects within certain cognitive domains.

One-year double-blind study of the neurocognitive efficacy of olanzapine, risperidone, and haloperidol in schizophrenia

Neurocognitive deficits in schizophrenia can reach 1 to 2 standard deviations below healthy controls. The comparative effect of typical and atypical antipsychotic medications on neurocognition is controversial, and based primarily on studies with small samples and large doses of typical comparator medications. The present study assessed neurocognitive efficacy. It was hypothesized that olanzapine treatment would improve neurocognitive deficits to a greater degree than either risperidone or haloperidol treatment. This was a double-blind, randomized, controlled, parallel study with neurocognition assessed at baseline, and 8, 24, and 52 weeks. Per protocol, the haloperidol arm was discontinued. Four hundred and fourteen inpatients or outpatients with schizophrenia and schizoaffective disorder were treated with oral olanzapine (n = 159), risperidone (n = 158), or haloperidol (n = 97). Individual domains (executive function, learning and memory, processing speed, attention/vigilance, verbal working memory, verbal fluency, motor function, and visuospatial ability) were transformed into composite scores and compared between treatment groups. At the 52-week endpoint, neurocognition significantly improved in each group (p < 0.01 for olanzapine and risperidone, p = 0.04 for haloperidol), with no significant differences between groups. Olanzapine- and risperidone-treated patients significantly (p < 0.05) improved on domains of executive function, learning/memory, processing speed, attention/vigilance, verbal working memory, and motor functions. Additionally, risperidone-treated patients improved on domains of visuospatial memory. Haloperidol-treated patients improved only on domains of learning/memory. However, patients able to remain in treatment for the entire 52 weeks benefited more from olanzapine or risperidone treatment than haloperidol treatment.

A meta-analysis of cognitive change with haloperidol in clinical trials of atypical antipsychotics : Dose effects and comparison to practice effects

Prospective, double-blind, randomized trials comparing atypical antipsychotic drugs (APDs) to typical APDs, such as haloperidol, indicate that atypical APDs provide a modest benefit to cognitive function in schizophrenia. However, the validity of this inference has been contested by suggestions that the cognitive improvements observed with atypical APDs reflect practice effects associated with repeated testing on the same neuropsychological instruments, or an avoidance of a deleterious effect of haloperidol on cognitive function that might be dose related. These alternate hypotheses were assessed by meta-analyses that 1) examined the relationship between cognitive change and dose of haloperidol within the control arms of prospective atypical vs. typical APD clinical trials; and 2) compared the magnitude of change observed within the haloperidol arms of these studies to estimated practice effects for several commonly used neuropsychological measures. The results indicate that overall cognitive performance improves while on haloperidol. Studies that used a low dose of haloperidol (<10 mg) did not yield larger effect sizes for overall cognitive function or specific neuropsychological measures than studies that used a high dose (>10 mg), although doses greater than 24 mg appear to have deleterious effects. For two of the six neuropsychological tests examined (digit symbol substitution and verbal fluency) the magnitude of change observed was significantly less than practice effects. The results indicate that although haloperidol may cause deleterious effects at very high doses, or in specific cognitive domains, these effects are not likely to explain the broader range of cognitive improvements observed with atypical APDs.

Cognitive improvement in schizophrenia with novel antipsychotic medications

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.

Abnormal prefrontal cortical activity and connectivity during response selection in first episode psychosis, chronic schizophrenia, and unaffected siblings of individuals with schizophrenia

The search for genes conferring liability for schizophrenia may be aided by the identification of endophenotypes. Response selection is a heritable cognitive function that is impaired in patients with schizophrenia and their unaffected siblings. The abnormalities in cerebral function that presumably underlie the deficit in patients and unaffected siblings remain to be elucidated. Cerebral neurophysiology during performance of a 4-choice reaction time (CRT) task in 25 patients with schizophrenia (15 medication free first episode (FEP) and 10 chronic patients), 32 controls, and 12 unaffected siblings of individuals with schizophrenia was investigated using fMRI. CRT was impaired in both medication free FEP and chronic patients with schizophrenia, and unaffected siblings. FEP patients, chronic patients, and unaffected siblings demonstrated greater BOLD response in the right dorsolateral prefrontal cortex (dlPFC) during CRT task blocks. The nature of the altered activation in the dlPFC was further examined using functional connectivity analysis. This revealed marked reductions in connectivity between the right dlPFC and multiple brain regions in both patient groups and, to a lesser degree, unaffected siblings. The magnitude of connectivity between right dlPFC and inferior parietal lobule correlated with task performance in the combined patient/unaffected siblings group, but not controls suggesting that the network of brain regions recruited to perform the task differed as a function of genetic liability for schizophrenia. The findings suggest that altered activity and connectivity of the right dlPFC appears to be related to genetic vulnerability for schizophrenia and may represent a potential endophenotype of the disorder.

Procedural learning in schizophrenia after 6 months of double-blind treatment with olanzapine, risperidone, and haloperidol

RationaleFirst generation antipsychotics induce extrapyramidal motor symptoms (EPS), presumably through dopamine D2 receptor blockade at the dorsal striatum. This may also produce impairment of cognitive processes, such as procedural learning, that are dependent on this region. Haloperidol and, to a lesser extent, risperidone, are active in the dorsal striatum and may induce EPS and impairment of procedural learning. In contrast, the prototypical second-generation antipsychotic, clozapine, is less active in the dorsal striatum and does not induce EPS or impair procedural learning. Olanzapine is pharmacologically similar to clozapine and has a low incidence of EPS induction.ObjectivesTo assess the hypothesis that olanzapine would not have a deleterious effect on procedural learning.MethodsThirty-nine subjects with early phase schizophrenia were randomly assigned to double blind treatment with haloperidol, risperidone, or olanzapine. They were administered the Tower of Toronto test at an unmedicated baseline and again following 6 weeks and 6 months of treatment.ResultsProcedural learning, defined as the improvement observed between two blocks of five trials of the Tower of Toronto, was preserved after 6 weeks of all three treatments but showed a substantial decline after 6 months of treatment with haloperidol or risperidone.ConclusionsThese data are consistent with the differential activity of the three medications in dorsal striatum structures and suggest that the advantages of olanzapine over haloperidol and risperidone in relation to extrapyramidal syndromes may also generalize to procedural learning. The results also suggest that the procedural learning disadvantages of haloperidol and risperidone accrue slowly but are apparent after 6 months of treatment.

Risperidone in the treatment of pervasive developmental disorder.

Elevated concentrations of blood serotonin have been documented in autistic children and mentally retarded adults. Antiserotonergic pharmacotherapy has been partially effective in treating a subgroup of children with autistic disorder. Therefore, the possibility is raised that an antiserotonergic treatment may be of value to adult psychiatric patients with a history of pervasive developmental disorder. Two such cases are described where the patients underwent psychiatric and neuropsychological examination before and after treatment with risperidone, a potent 5-HT2 antagonist with additional D2 antagonistic properties. Particular improvements were documented in both patients, despite long histories of cognitive compromise and high likelihood of damage to the central nervous system.

Elevated 3T proton MRS glutamate levels associated with poor Continuous Performance Test (CPT-0X) scores and genetic risk for schizophrenia.

Glutamate was quantified by proton magnetic resonance spectroscopy ((1)H-MRS) in the medial frontal lobes of 15 adult siblings of individuals with schizophrenia (HR) and 14 healthy volunteers (HV), all of whom also completed a Continuous Performance Test (CPT). Subjects were free of psychopathology but the HR group showed greater variability in glutamate levels. After median stratification, the high glutamate group contained a larger proportion of HR than HV subjects and scored lower on the CPT. Elevated glutamate may relate to poor sustained attention and elevated risk of schizophrenia, suggesting a potential role for glutamate in an endophenotype for schizophrenia.

Neuropsychological change in schizophrenia after 6 weeks of clozapine

Neuropsychological change after 6weeks of clozapine treatment was examined in 18 treatment-refractory patients to test anticipated domain-specific cognitive improvements. The first aim of this study was to test the assumption that increased homogeneity of sample and treatment would yield an experimental design with sufficient sensitivity to detect general intellectual changes with clozapine that were not apparent in one previous investigation. The second aim was to test predictions derived from a domain-specific review of all other investigations with clozapine suggesting salient gains on tests sensitive to motor and mental speed, visual spatial manipulation, and new learning of verbal material. The results showed that the comprehensive neuropsychological test battery was sensitive to general cognitive changes with clozapine, and supported the hypothesized domain-specific gains on tests of motor and mental speed, visual spatial manipulation and new verbal learning. Novel gains were also apparent on tests of new learning with nonverbal material. The results are discussed in relation to aspects of experimental design necessary for the evaluation of prospective medication-induced changes in cognitive skill, particularly in future investigations designed to differentiate between second-generation antipsychotic medications.

Procedural learning in schizophrenia investigated with functional magnetic resonance imaging.

A cerebral basis for the acquisition and retention of procedural knowledge in schizophrenia was examined with 1.5 T functional MRI during an embedded sequence Serial Reaction Time Task (SRTT) in 10 chronic medicated patients and 15 healthy controls. Comparable procedural learning was observed in both groups, suggesting that the impairment reported in previous schizophrenia samples may not be robust. Consistent with previous fMRI reports, procedural learning in the control group was associated with activity in the dorsal striatum, anterior cingulate, parietal cortex and frontal cortex. Greater procedural learning related activity was observed in the control relative to the schizophrenia group in the bilateral frontal, left parietal and bilateral caudate regions. Patients did not activate frontal or parietal areas while responding to the embedded sequence within the SRTT, but greater activation during procedural learning was observed relative to the control sample in the right anterior cingulate, left globus pallidus and the right superior temporal gyrus. Thus, despite comparable instantiation of procedural learning in schizophrenia, the cerebral activation associated with this cognitive skill was abnormal. The paucity of activity in bilateral frontal cortex, left parietal cortex and bilateral caudate nucleus may represent cerebral dysfunction associated with schizophrenia, whereas the hyperactivation of the right superior temporal gyrus, the right anterior cingulate cortex and the left globus pallidus may represent a compensatory cerebral action capable of facilitating near-normal task performance. The results are thus consistent with a neurodevelopmental pathology impinging on fronto-subcortical circuitry.