Association between polymorphism of the SNAP29 gene promoter region and schizophrenia.
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Adult↗
Biomedical subjects
Robert W Buchanan
Publications and source records attributed to Robert W Buchanan.
Dihydropyrimidinase-related protein 2 (DRP-2) gene and association to deficit and nondeficit schizophrenia.
A previous study has shown an association between the *2236T > C allele polymorphism of the dihydropyrimidinase-related protein 2 (DRP-2) gene and schizophrenia in a Japanese sample [Nakata et al. (2003); Biological Psychiatry 53:571-576]. DRP-2 is an important molecule in guiding neuronal development and its gene is located in 8p21, a chromosomal region that was previously shown to have significant linkage to schizophrenia and to several deficit symptoms of schizophrenia. We compared the frequency of the DRP-2 *2236T > C polymorphism between subjects with (n = 117) and without (n = 72) schizophrenia, and then further evaluated whether the association was specific for the deficit (n = 24) and nondeficit (n = 93) forms of schizophrenia. In both Caucasians and African-Americans, the C allele occurred more frequently in schizophrenia cases than controls, with this difference achieving statistical significance in Caucasians (C allele frequency: 42.0% in cases vs. 25.0% in controls, P = 0.014) but not African Americans (52.6% in cases vs. 50.0% in controls, P = 0.93). In Caucasians, the frequency of the C allele was significantly higher in both the deficit (allele frequency 53.3%, P = 0.009) and nondeficit (39.2%, P =0.050) forms of schizophrenia compared to controls (allele frequency 25.0%). We conclude that the DRP-2 *2236 C allele may mark another polymorphism in DRP-2, or in a nearby gene, that may influence susceptibility to schizophrenia.
Adult↗
Significance and meaning of neurological signs in schizophrenia: two decades later.
OBJECTIVE: Patients with schizophrenia are characterized by neurological abnormalities, which can be assessed by bedside clinical examination. These abnormalities have been argued to represent core features of the illness. We review studies published since our last review in 1988 that address the validity of neurological signs as a trait feature of schizophrenia. METHODS: We conducted a literature search in the following computer databases: MEDLINE, PSYCHLIT, EMBASE, and COCHRANE. The search was limited to articles published from January 1988 to May 2005. RESULTS: Neurological signs occur in the majority of patients with schizophrenia. Their occurrence is independent of demographic and most medication variables. Neurological signs are strongly associated with negative symptoms and cognitive impairments. There is also evidence to suggest that their occurrence is under genetic control. CONCLUSIONS: There is compelling evidence to suggest the hypothesis that neurological signs represent a trait feature of schizophrenia.
Antipsychotic Agents↗
Voxel-based morphometry versus region of interest: a comparison of two methods for analyzing gray matter differences in schizophrenia.
Many previous studies exploring cortical gray matter (GM) differences in schizophrenia have used "region of interest" (ROI) measurements to manually delineate GM volumes. Recently, some investigators have instead employed voxel-based morphometry (VBM), an automated whole-brain magnetic resonance image measurement technique. The purpose of the current study was to compare the above methods in calculating GM distributions in schizophrenia patients relative to matched controls. Using ROIs, Buchanan et al. (Buchanan, R.W., Francis, A., Arango, C., Miller, K., Lefkowitz, D.M., McMahon, R.P., Barta, P.E. and Pearlson, G.D., 2004. Morphometric assessment of the heteromodal association cortex in schizophrenia. Am J Psychiatry. 161 (2), 322-331.) found decreased dorsolateral prefrontal GM volume and altered symmetry of inferior parietal GM in schizophrenia patients. We hypothesized that VBM analyses of the same data would complement the ROI findings. As predicted, VBM analyses replicated results of less left inferior and right superior frontal cortical GM in schizophrenia. Additionally, VBM uncovered a significantly lower concentration of GM in the middle and superior temporal gyri, sought but not detected using ROIs, but did not replicate the parietal changes. The principal explanation for these differences may be the methodological differences between voxel-averaged, landmark-based ROI analyses and the single, voxel-by-voxel whole brain VBM measurements. Although VBM is rapid and fully automated, it is not a replacement for manual ROI-based analyses. Both methods provide different types of information and should thus be used in tandem.
Adult↗
A summary of the FDA-NIMH-MATRICS workshop on clinical trial design for neurocognitive drugs for schizophrenia.
OBJECTIVE: On April 23, 2004, a joint meeting of the FDA, NIMH, MATRICS investigators, and experts from academia and the pharmaceutical industry was convened to develop guidelines for the design of clinical trials of cognitive-enhancing drugs for neurocognitive impairments in patients with schizophrenia. METHOD: Experts were asked to address specific questions relating to clinical trial design of adjunctive/co-treatment and broad spectrum agents. At the workshop, experts reviewed relevant evidence before offering the discussion panel proposed guidelines for a given subset of questions. The discussion panel, which consisted of presenters and representatives from FDA, NIMH, academia, and industry, deliberated to reach consensus on suggested guidelines. When evidence was insufficient, suggested guidelines represent the opinion of a cross-section of the presenters and discussion panel. RESULTS: Guidelines were developed for inclusion criteria, the use of co-primary outcome measures, and statistical approaches for study design. Consensus was achieved regarding diagnostic and concomitant medication inclusion criteria and on the use of cognitive screening measures. A key guideline was to limit the trial to patients in the residual phase of their illness, who have a predefined level of positive, negative, and affective symptoms. The most difficult issues were the feasibility of including a co-primary measure of functional improvement and the choice of comparator agent for a trial of a broad spectrum agent (with antipsychotic and cognitive-enhancing effects). CONCLUSIONS: The suggested guidelines represent reasonable starting points for trial design of cognitive-enhancing drugs, with the understanding that new data, subsequent findings, or other methodological considerations may lead to future modifications.
Antipsychotic Agents↗
Olanzapine treatment of residual positive and negative symptoms.
OBJECTIVE: Olanzapine has been hypothesized to have superior efficacy in patients with treatment-resistant schizophrenia. The authors examined the comparative efficacy and safety of olanzapine and haloperidol in outpatients with partially responsive schizophrenia. METHOD: Sixty-three outpatients with schizophrenia who met retrospective and prospective criteria for either residual positive or residual negative symptoms entered a 16-week double-blind, parallel-groups comparison of olanzapine and haloperidol. RESULTS: There were no significant differences between the two drugs in their effect on positive or negative symptoms. There were no significant differences between the two treatment groups on measures of social and functional outcome. Olanzapine-treated patients had a significant reduction in extrapyramidal symptoms and subjective measures of stiffness and dry mouth, but the increases in systolic blood pressure and weight in olanzapine-treated patients were significantly greater than they were in haloperidol-treated patients. CONCLUSIONS: Olanzapine has limited differential benefit for either positive or negative symptoms in patients with treatment-resistant schizophrenia. Although olanzapine is associated with fewer extrapyramidal symptoms, other side effects may offset this benefit.
Adult↗
Brief cognitive assessment in schizophrenia: normative data for the Repeatable Battery for the Assessment of Neuropsychological Status.
BACKGROUND: The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) is a brief, standardized cognitive screening instrument that assesses several domains of interest and offers an efficient approach to screening for cognitive impairment in schizophrenia (SC). Prior studies have established the clinical validity and test-retest reliability of the RBANS in SC. AIMS: The purpose of the current study was to guide clinical interpretation by providing normative data for the use of the RBANS as a measure of cognitive impairment in SC. We also sought to evaluate the role of demographic factors and to present percentile data accordingly. METHODS: 575 patients (391 male, 184 female) meeting the diagnostic criteria for SC or schizoaffective disorder were recruited from 4 inpatient (n=117) and 6 outpatient (n=458) sites in 2 different mental health treatment systems. All participants were administered the RBANS according to standardized instructions and a subgroup of 242 patients were also administered the Wide Range Achievement Test (3rd Edition) (WRAT-3) Reading subtest. RESULTS: RBANS Total Scale score for patients with SC was approximately 2 standard deviations below the normal mean, was approximately 1 standard deviation below WRAT-3 Reading scores, and expected patterns of impairment were observed: measures of language and visuospatial ability were preserved relative to those of memory and attention. Aside from weak associations with Language (0.139) and Attention (0.112), age was not significantly associated with RBANS Index scores (which are age adjusted in healthy controls). Education was significantly associated with all RBANS scores and one-way ANOVA indicates that those with more than high school education scored consistently higher than the other two groups (less than and equal to a complete high school education). Normative tables with age and education based percentiles are presented. CONCLUSIONS: The RBANS is an efficient screening tool for assessing cognitive impairment in patients with SC thereby making it a useful instrument for clinical and research applications.
Adolescent↗
Evoked gamma band synchronization and the liability for schizophrenia.
OBJECTIVE: Electroencephalographic (EEG) synchronization in the gamma band is thought to represent a neuronal mechanism by which the brain integrates information processed in different cortical areas to build a coherent internal representation. Previous studies have reported abnormal gamma range ( approximately 40 Hz) synchronization in schizophrenic patients. We tested a group of first-degree relatives of schizophrenic probands who have schizophrenia spectrum personality symptoms, and a group of schizophrenic patients, to examine whether individuals with increased liability for schizophrenia have reduced gamma synchronization. METHOD: A steady-state auditory evoked potential paradigm was used to evaluate the brain's capacity to sustain 20, 30, and 40 Hz EEG synchronization in 11 relatives, 24 schizophrenic patients (11 on conventional, 13 on new generation antipsychotic medications), and 17 normal controls. RESULTS: Relatives with schizophrenic spectrum personality symptoms had reduced power at 40 Hz synchronization compared to normal controls (p=0.022). Previous findings of reduced steady-state gamma band synchronization in schizophrenic patients were not directly replicated in this study. Patients as a group did not significantly differ from controls, but patients taking new generation antipsychotics had significantly enhanced 40 Hz synchronization compared to patients taking conventional antipsychotics (p<0.001). There were no group differences in 20 or 30 Hz synchronization. CONCLUSIONS: Gamma band synchronization was found to be reduced in first-degree relatives with schizophrenia spectrum personality symptoms. Patients on new generation antipsychotic medications may exhibit enhanced gamma band synchronization.
Adult↗
Gamma/beta oscillation and sensory gating deficit in schizophrenia.
Sensory gating can be measured by the suppression of auditory evoked potentials in a paired-click paradigm. The normal gating of the P50 response to the second stimulus (S2) is impaired in many schizophrenic patients. Various in vitro and in vivo evoked potential paradigms have shown that a stimulus evokes early gamma frequency oscillation, which is followed by beta frequency oscillation. The gamma-to-beta shift in response to the first stimulus (SI) in the paired-click paradigm may contain critical electrophysiological signals that modulate the S2 suppression. The results of the present study showed that post-SI beta frequency response was inversely correlated to the S2 P50 response in patients with schizophrenia.
Acoustic Stimulation↗
Summer birth and deficit schizophrenia: a pooled analysis from 6 countries.
BACKGROUND: In some reports, summer birth has been associated with deficit schizophrenia. Deficit schizophrenia and nondeficit schizophrenia also differ in several other ways. OBJECTIVE: To conduct a combined analysis of the published and unpublished data sets from the northern hemisphere that relate deficit and nondeficit schizophrenia to month of birth. DATA SOURCES: Studies of season of birth in which it was possible to make a deficit/nondeficit categorization. STUDY SELECTION: Published studies with samples of convenience and all known population-based studies with the deficit/nondeficit categorization were included. The studies came from 6 countries. DATA EXTRACTION: Three published studies of samples of convenience, 2 population-based prevalence studies, and 5 population-based studies that approximated incident samples were included. Month of birth was compared for deficit and nondeficit schizophrenia, using meta-analytic fixed-effects models. DATA SYNTHESIS: A group x month goodness-of-fit chi2 showed a significant difference between deficit and nondeficit subjects in season of birth (P < .001) in the studies that approximated incidence. This difference was largely due to an increase in deficit schizophrenia births in June and July (odds ratio, 1.9; 95% confidence interval, 1.3-2.9). Similar results were found in the prevalence studies. A similar pattern was found in 2 of the 3 samples of convenience, but when combined, these 3 samples did not show a significant deficit/nondeficit difference. CONCLUSIONS: Deficit schizophrenia has a season of birth pattern that differs from that of nondeficit schizophrenia. This analysis supports the notion of a separate disease within schizophrenia.
Cohort Studies↗
The deficit syndrome in schizophrenia: implications for the treatment of negative symptoms.
Schizophrenia psychopathology clusters around several symptom domains. One of these domains is negative symptomatology. We have defined the deficit syndrome as a disease entity characterized by the presence of primary enduring negative symptoms. A focus on primary negative symptoms demonstrates that deficit and nondeficit schizophrenia subgroups differ on clinical features, associated neuroimaging findings, neuropsychological and neurological measures, pattern of risk factors, and pharmacological response profiles. In the present article we focus on the importance of the distinction between primary and secondary negative symptoms for pathophysiology research. The development and mechanistic understanding of anti-negative symptom drugs may be informative regarding pathophysiology of primary negative symptoms. Although new antipsychotics are effective for secondary negative symptoms they have shown no efficacy for the deficit syndrome and new mechanisms of drug action appear to be required to address this aspect of the disease syndrome. The loss of precious human experiences and the association with poor long-term functional outcome justifies a focused and dedicated effort to discover the causes and treatments of this distinctive aspect of schizophrenia.
Affect↗
The family pictures test as a measure of impaired feature binding in schizophrenia.
We investigated the use of the Family Pictures test from the Wechsler Memory Scale III as a measure of the ability to bind the multiple features of a complex visual scene in a study group of 77 patients with schizophrenia and 44 healthy controls. Patients demonstrated impaired recall of all scene features as well as a reduction in the number of features recalled for each remembered character. Secondary analyses using patients and controls matched for character recall also showed reduced feature binding in the patient group. Such feature binding deficits likely implicate hippocampal dysfunction, consistent with neuroimaging evidence of structural and functional compromise of the medial temporal lobe in schizophrenia.
Adult↗
The Schizophrenia Patient Outcomes Research Team (PORT): updated treatment recommendations 2003.
Since publication of the original Schizophrenia Patient Outcomes Research Team (PORT) treatment recommendations in 1998, considerable scientific advances have occurred in our knowledge about how to help persons with schizophrenia. Today an even stronger body of research supports the scientific basis of treatment. This evidence, taken in its entirety, points to the value of treatment approaches combining medications with psychosocial treatments, including psychological interventions, family interventions, supported employment, assertive community treatment, and skills training. The most significant advances lie in the increased options for pharmacotherapy, with the introduction of second generation antipsychotic medications, and greater confidence and specificity in the application of psychosocial interventions. Currently available treatment technologies, when appropriately applied and accessible, should provide most patients with significant relief from psychotic symptoms and improved opportunities to lead more fulfilling lives in the community. Nonetheless, major challenges remain, including the need for (1) better knowledge about the underlying etiologies of the neurocognitive impairments and deficit symptoms that account for much of the disability still associated with schizophrenia; (2) treatments that more directly address functional impairments and that promote recovery; and (3) approaches that facilitate access to scientifically based treatments for patients, the vast majority of whom currently do not have such access.
Antipsychotic Agents↗
Prefrontal cortex, structural analysis: segmenting the prefrontal cortex.
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Brain Mapping↗
Morphometric assessment of the heteromodal association cortex in schizophrenia.
OBJECTIVE: The heteromodal association cortex has been hypothesized to be selectively involved in the pathophysiology of schizophrenia. To test this hypothesis, the authors measured prefrontal, inferior parietal, and superior temporal gyrus volumes and examined the pattern of connections among these regions. METHOD: Forty-four patients with schizophrenia or schizoaffective disorder and 34 healthy comparison subjects were included in the study. A spoiled gradient recall acquisition in the steady-state three-dimensional magnetic resonance imaging sequence was used for morphometric assessment of the heteromodal association cortex. RESULTS: Patients with schizophrenia had significantly smaller inferior prefrontal region volumes and significant reversal of the normal asymmetry of the inferior parietal cortex. No significant group differences were found in superior temporal gyrus volume. The groups differed significantly in the correlation between inferior prefrontal region volumes and angular gyrus volumes. CONCLUSIONS: The results suggest that patients with schizophrenia may be characterized by selective abnormalities of the heteromodal regions involved in the neuroanatomy of language.
Adult↗
Physical health monitoring of patients with schizophrenia.
OBJECTIVE: Schizophrenia is associated with several chronic physical illnesses and a shorter life expectancy, compared with life expectancy in the general population. One approach to improving the health of patients with schizophrenia is to improve the monitoring of physical health that occurs in psychiatric settings. The authors discuss a consensus panel's recommendations for improving the physical health monitoring of patients with schizophrenia who are treated in outpatient settings. METHOD: A consensus meeting including psychiatric and other medical experts assembled on October 17-18, 2002, to evaluate the existing literature and to develop recommendations for physical health monitoring of patients with schizophrenia. Conference participants reviewed the literature in the following areas: 1) weight gain and obesity; 2) diabetes; 3) hyperlipidemia; 4) prolongation of the QT interval on the ECG; 5) prolactin elevation and related sexual side effects; 6) extrapyramidal side effects, akathisia, and tardive dyskinesia; 7) cataracts; and 8) myocarditis. Experts for each topic area formulated monitoring recommendations that were discussed by all of the participants until a consensus was reached. RESULTS: Consensus recommendations included regular monitoring of body mass index, plasma glucose level, lipid profiles, and signs of prolactin elevation or sexual dysfunction. Information from monitoring should guide the selection of antipsychotic agents. Specific recommendations were made for cardiac monitoring of patients who receive medications associated with QT interval prolongation, including thioridazine, mesoridazine, and ziprasidone, and for monitoring for signs of myocarditis in patients treated with clozapine. Patients who receive both first- and second-generation antipsychotic medications should be examined for extrapyramidal symptoms and tardive dyskinesia. Patients with schizophrenia should receive regular visual examinations. CONCLUSIONS: The conference participants recommended that mental health care providers perform physical health monitoring that typically occurs in primary care settings for their patients who do not receive physical health monitoring in those settings. This change in usual practice is recommended on the basis of the conference participants' belief that this additional monitoring will result in the earlier detection of common, serious risk factors that could, without detection and intervention, contribute to impaired health of patients with schizophrenia.
Adult↗
The Texas Medication Algorithm Project antipsychotic algorithm for schizophrenia: 2003 update.
BACKGROUND: The Texas Medication Algorithm Project (TMAP) has been a public-academic collaboration in which guidelines for medication treatment of schizophrenia, bipolar disorder, and major depressive disorder were used in selected public outpatient clinics in Texas. Subsequently, these algorithms were implemented throughout Texas and are being used in other states. Guidelines require updating when significant new evidence emerges; the antipsychotic algorithm for schizophrenia was last updated in 1999. This article reports the recommendations developed in 2002 and 2003 by a group of experts, clinicians, and administrators. METHOD: A conference in January 2002 began the update process. Before the conference, experts in the pharmacologic treatment of schizophrenia, clinicians, and administrators reviewed literature topics and prepared presentations. Topics included ziprasidone's inclusion in the algorithm, the number of antipsychotics tried before clozapine, and the role of first generation antipsychotics. Data were rated according to Agency for Healthcare Research and Quality criteria. After discussing the presentations, conference attendees arrived at consensus recommendations. Consideration of aripiprazole's inclusion was subsequently handled by electronic communications. RESULTS: The antipsychotic algorithm for schizophrenia was updated to include ziprasidone and aripiprazole among the first-line agents. Relative to the prior algorithm, the number of stages before clozapine was reduced. First generation antipsychotics were included but not as first-line choices. For patients refusing or not responding to clozapine and clozapine augmentation, preference was given to trying monotherapy with another antipsychotic before resorting to antipsychotic combinations. CONCLUSION: Consensus on algorithm revisions was achieved, but only further well-controlled research will answer many key questions about sequence and type of medication treatments of schizophrenia.
Algorithms↗
Association between Val108/158 Met polymorphism of the COMT gene and schizophrenia.
Schizophrenia is a complex disorder with a multifactorial polygenic inheritance with several genes conferring susceptibility at many genetic locations, each with a small effect. An attractive candidate gene for schizophrenia is the catechol-O-methyltransferase (COMT) gene, which is a modulator of dorsolateral prefrontal cortical function. A missense G to A mutation in this gene that results in a substitution of Methionine (Met) for Valine (Val) at codon 108/158 (Val(108/158) Met) has recently been identified in association to schizophrenia. We compared allele frequencies of the variant Val allele between 96 schizophrenia cases and 80 normal controls. We selected controls from a similar pool to cases in ethnicity and gender. The frequency of the Val allele was significantly higher in schizophrenia cases compared to controls (0.620 vs. 0.506; P = 0.043). Calculation of the population attributable risk suggests that the Val allele accounts for as much as 23% of schizophrenia in this population (range: 3-38%). These results provide support for a role of this variant in the etiopathophysiology of schizophrenia.
Adult↗