Search

OBJECTIVE: Many psychotropic medications used to treat schizophrenia have significant anticholinergic properties, which are linked to cognitive impairment and dementia risk in healthy subjects. Clarifying the impact of cognitive impairment attributable to anticholinergic medication burden may help optimize cognitive outcomes in schizophrenia. The aim of this study was to comprehensively characterize how this burden affects functioning across multiple cognitive domains in schizophrenia outpatients. METHODS: Cross-sectional data were analyzed using inferential statistics and exploratory structural equation modeling to determine the relationship between anticholinergic medication burden and cognition. Patients with a diagnosis of schizophrenia or schizoaffective disorder (N = 1,120) were recruited from the community at five U.S. universities as part of the Consortium on the Genetics of Schizophrenia–2. For each participant, prescribed medications were rated and summed according to a modified Anticholinergic Cognitive Burden (ACB) scale. Cognitive functioning was assessed by performance on domains of the Penn Computerized Neurocognitive Battery (PCNB). RESULTS: ACB score was significantly associated with cognitive performance, with higher ACB groups scoring worse than lower ACB groups on all domains tested on the PCNB. Similar effects were seen on other cognitive tests. Effects remained significant after controlling for demographic characteristics and potential proxies of illness severity, including clinical symptoms and chlorpromazine-equivalent antipsychotic dosage. CONCLUSIONS: Anticholinergic medication burden in schizophrenia is substantial, common, conferred by multiple medication classes, and associated with cognitive impairments across all cognitive domains. Anticholinergic medication burden from all medication classes—including psychotropics used in usual care—should be considered in treatment decisions and accounted for in studies of cognitive functioning in schizophrenia.

ObjectiveThe Consortium on the Genetics of Schizophrenia Family Study evaluated 12 primary and other supplementary neurocognitive and neurophysiological endophenotypes in schizophrenia probands and their families. Previous analyses of prepulse inhibition (PPI) and P50 gating measures in this sample revealed heritability estimates that were lower than expected based on earlier family studies. Here the authors investigated whether gating measures were more heritable in multiply affected families with a positive family history compared with families with only a single affected proband (singleton).MethodA total of 296 nuclear families consisting of a schizophrenia proband, at least one unaffected sibling, and both parents underwent a comprehensive endophenotype and clinical characterization. The Family Interview for Genetic Studies was administered to all participants and used to obtain convergent psychiatric symptom information for additional first-degree relatives. Among the families, 97 were multiply affected, and 96 were singletons.ResultsBoth PPI and P50 gating displayed substantially increased heritability in the 97 multiply affected families (47% and 36%, respectively) compared with estimates derived from the entire sample of 296 families (29% and 20%, respectively). However, no evidence for heritability was observed for either measure in the 96 singleton families. Schizophrenia probands derived from the multiply affected families also displayed a significantly increased severity of clinical symptoms compared with those from singleton families.ConclusionsPPI and P50 gating measures demonstrate substantially increased heritability in schizophrenia families with a higher genetic vulnerability for illness, providing further support for the commonality of genes underlying both schizophrenia and gating measures.

The Consortium on the Genetics of Schizophrenia has undertaken a large multisite study to characterize 12 neurophysiological and neurocognitive endophenotypic measures as a step toward understanding the complex genetic basis of schizophrenia. The authors previously demonstrated the heritability of these endophenotypes; in the present study, genetic linkage was evaluated.Each family consisted of a proband with schizophrenia, at least one unaffected sibling, and both parents. A total of 1,286 participants from 296 families were genotyped in two phases, and 1,004 individuals were also assessed for the endophenotypes. Linkage analyses of the 6,055 single-nucleotide polymorphisms that were successfully assayed, 5,760 of which were common to both phases, were conducted using both variance components and pedigree-wide regression methods.Linkage analyses of the 12 endophenotypes collectively identified one region meeting genome-wide significance criteria, with a LOD (log of odds) score of 4.0 on chromosome 3p14 for the antisaccade task, and another region on 1p36 nearly meeting genome-wide significance, with a LOD score of 3.5 for emotion recognition. Chromosomal regions meeting genome-wide suggestive criteria with LOD scores2.2 were identified for spatial processing (2p25 and 16q23), sensorimotor dexterity (2q24 and 2q32), prepulse inhibition (5p15), the California Verbal Learning Test (8q24), the degraded-stimulus Continuous Performance Test (10q26), face memory (10q26 and 12p12), and the Letter-Number Span (14q23).Twelve regions meeting genome-wide significant and suggestive criteria for previously identified heritable, schizophrenia-related endophenotypes were observed, and several genes of potential neurobiological interest were identified. Replication and further genomic studies are needed to assess the biological significance of these results.

Genes affecting glutamate neurotransmission featured prominently in associations between 94 genes and 12 inherited physiological or cognitive characteristics of schizophrenia. Of 16,620 possible SNP-trait associations, 47 showed strong significance.

The genetics of schizophrenia has been approached utilizing a variety of methods. One emerging strategy is the use of endophenotypes in order to understand and identify the functional importance of genetically transmitted, brain-based deficits across schizophrenia kindreds. The endophenotype strategy is a topic of this issue of Schizophrenia Bulletin. Endophenotypes are quantitative, heritable, trait-related deficits typically assessed by laboratory-based methods rather than clinical observation. Endophenotypes are seen as closer to genetic variation than are clinical symptoms of schizophrenia, and are therefore closely linked to heritable risk factors. There has been a broad expansion of opportunities available to psychiatric neuroscientists who use the endophenotype strategy to understand the genetic basis of schizophrenia. In this context, genetic variation such as single nucleotide polymorphisms (SNPs) induces abnormalities in endophenotypic domains such as neurocognition, neurodevelopment, metabolism, and neurophysiology. This article discusses the challenges that abound in genetic research of schizophrenia, including issues in ascertainment, epistasis, ethnic diversity, and the potentially normalizing effects of second-generation antipsychotic medications on neurocognitive and neurophysiological measures. Robust strategies for meeting these challenges are discussed in this review and the subsequent articles in this issue. This article summarizes conceptual advances and progress in the measurement and use of endophenotypes in schizophrenia that form the basis of the multisite National Institute of Mental Health Consortium on the Genetics of Schizophrenia. The endophenotype strategy offers powerful and exciting opportunities to understand the genetically conferred neurobiological vulnerabilities and possible new strong inference and molecularly based treatments for schizophrenia.

Objective: This study examined the short-term effects of first- and second-generation antipsychotic medications on social cognition and basic cognition. Method: One hundred patients with schizophrenia or schizoaffective disorder participated in an 8 week, double-blind study of risperidone, olanzapine, and haloperidol. Participants were administered multiple measures of social cognition, basic cognition, and clinical symptoms at baseline, the end of week 4, and the end of week 8. Seventy-three patients completed the baseline assessment and at least one other assessment. Data were analyzed with mixed-effects analyses of covariance. For data reduction, the social cognitive measures were clustered into a summary score, and the cognitive measures were clustered into two summary scores: general cognitive ability and processing speed. (The effects on thinking of risperidone and olanzapine can be found at NCT00108368, www.clinicaltrials.gov.) Results: There were no treatment-related differences on any of the three summary scores. Social cognition did not show within-group changes over time either by itself or after control for the cognitive clusters. One cognitive score (general cognitive ability) increased during the study period for all three medication groups. Conclusions: The present study included a rather thorough assessment of social cognition and did not find any evidence of between-group or within-group effects of antipsychotic medication on social cognition.

In patients with schizophrenia, information processing deficits, such as those reported in studies that measured prepulse inhibition of the human startle response and habituation of startle magnitude, may be improved with atypical antipsychotic treatment. However, it remains unclear whether antipsychotic medication is directly responsible for the improvement or whether differences in prepulse inhibition reflect other factors, such as acuity status. The present study investigated the effects of antipsychotics on prepulse inhibition and startle habituation in acutely hospitalized patients with schizophrenia.Forty-one acutely psychotic schizophrenia patients (21 who were unmedicated at the time of admission and 20 who had been receiving antipsychotic treatment) were tested within 72 hours of hospital admission. Thirteen healthy subjects were also studied for comparative purposes. Primary dependent measures were startle responsivity, reactivity, prepulse inhibition, and startle habituation.Schizophrenia patients, whether medicated or unmedicated at admission, showed prepulse inhibition deficits compared with healthy subjects and did not statistically differ from each other in startle magnitude, prepulse inhibition, or habituation. There was a higher number of startle "nonresponders" among those who had been receiving medication versus those unmedicated at the time of admission.The present findings suggest that antipsychotic effects on prepulse inhibition may not be evident at a time when schizophrenia patients are acutely symptomatic. These results suggest that the neurobiological substrate underlying prepulse inhibition deficits may be dysregulated during acute psychotic states while the patients are in early phases of medication treatment.

Patients with schizophrenia spectrum disorders have been shown to have deficits in sensorimotor gating as assessed by prepulse inhibition of the startle response. The authors hypothesized that nonschizophrenic relatives of patients with schizophrenia would also have prepulse inhibition deficits, thereby reflecting a genetically transmitted susceptibility to sensorimotor gating deficits.Twenty-five comparison subjects, 23 patients with schizophrenia, 34 relatives of the schizophrenic patients, and 11 subjects with schizotypal personality disorder were assessed in an acoustic startle paradigm. The eye-blink component of the startle response was assessed bilaterally by using electromyographic recordings of orbicularis oculi.The patients with schizophrenia, their relatives, and subjects with schizotypal personality disorder all had reduced prepulse inhibition relative to comparison subjects, and these deficits were more evident in measures of right eye-blink prepulse inhibition. Comparison subjects demonstrated greater right versus left eye-blink prepulse inhibition, whereas the probands, their relatives, and subjects with schizotypal personality disorder showed less asymmetry of prepulse inhibition.These data suggest a genetically transmitted deficit in prepulse inhibition (sensorimotor gating) in patients with schizophrenia spectrum disorders, including subjects with schizotypal personality disorder and relatives of patients with schizophrenia.

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.

The schizophrenia spectrum includes individuals with schizophrenia, their relatives, and individuals with schizotypal personality disorder. Subjects in the schizophrenia spectrum have disorders of attention, cognition, and information processing. Attention and information processing can be assessed by testing suppression of the P50 event-related potential; the amplitude of the P50 wave is measured in response to each of two auditory clicks. In normal subjects, the P50 wave following the second click is suppressed, or "gated." Schizophrenic patients and their relatives show less suppression of the second P50 wave. Deficits in P50 suppression have high heritability and show linkage to the alpha-7 subunit of the nicotinic cholinergic receptor gene in families with schizophrenia, suggesting that deficits in P50 suppression are trait markers for gating abnormalities in schizophrenia spectrum subjects. Although schizotypal subjects have been shown to have deficits in sensorimotor gating as measured by prepulse inhibition, to the authors' knowledge P50 sensory gating in schizotypal personality disorder has yet to be reported.P50 suppression in 26 subjects with schizotypal personality disorder and 23 normal subjects was assessed through auditory conditioning and testing.The subjects with schizotypal personality had significantly less P50 suppression than did the normal subjects.Subjects with schizotypal personality disorder may have trait-linked sensory gating deficits similar to those in patients with schizophrenia and their relatives. Because these subjects may manifest sensory gating deficits without overt psychotic symptoms, it is likely that these deficits represent a core cognitive dysfunction of the schizophrenia spectrum.

Information processing, inhibitory, and gating deficits in human and animal model studies of schizophrenia are demonstrated by using prepulse inhibition of the startle reflex. Prepulse inhibition deficits in schizophrenic patients correlate with core cognitive symptoms, such as thought disorder and distractibility, but their relationship to positive and negative symptoms of schizophrenia is less clear.Fifty-one male schizophrenic patients and 26 male normal comparison subjects were tested for prepulse inhibition of the eyeblink component of the startle reflex measured by electromyogram recording. Startling stimuli (118 dB) were presented alone (pulse only) or were preceded 60 msec by discrete prepulse stimuli of 2, 4, 8, or 16 dB above the background 70-dB noise level. In addition, patients were assessed for demographic variables, generalized symptoms (Brief Psychiatric Rating Scale), and positive and negative symptoms.Schizophrenic and comparison groups differed significantly in the amount of prepulse inhibition produced by the 16-dB prepulse, with schizophrenic patients showing the expected deficient prepulse inhibition. Latency of the eyeblink response was generally slower for the schizophrenic patients, but the prepulse-induced latency facilitation for schizophrenic patients and comparison subjects did not differ significantly. The pattern of prepulse inhibition deficits in schizophrenic patients remained, with age and education controlled, in an analysis of covariance and subgroup matching. Deficient prepulse inhibition correlated with both positive and negative symptoms of schizophrenia.Under these experimental conditions, schizophrenia-linked deficits in prepulse inhibition detected with a relatively strong prepulse are correlated with both positive and negative symptoms of schizophrenia. The level of correlation, while significant in this cohort, is not as robust as that in previous reports linking prepulse inhibition deficits with other measures, such as thought disorder. Future work should probably focus on the relationship of prepulse inhibition deficits to measures such as thought disorder rather than positive and negative symptoms.

This study's goal was to replicate the finding that family members of schizophrenia patients show poor P50 suppression during a paired-click auditory evoked response paradigm.The paired-click paradigm was used to test 44 schizophrenia patients, 60 of their clinically unaffected first-degree relatives, and 45 normal subjects. Two clicks (83 dB[A] over a 60-dB[A] white noise background) separated by 500 msec were presented 60 times to all subjects. P50 responses to the first and second clicks were selected from the digitally filtered data by using standard methods and the Cz recording site.The schizophrenia patients had smaller P50 responses to click 1 than either their relatives or the normal subjects; the patients and their relatives, who did not significantly differ, had larger P50 responses to click 2 than the normal subjects. Schizophrenia patients had worse P50 suppression than either their family members or the normal subjects; the patients' family members had worse P50 suppression than the normal subjects.Family members of schizophrenia patients have worse P50 suppression than normal subjects. To the authors' knowledge, this is the first demonstration independent of the group associated with the University of Colorado that schizophrenia patients' family members have poor P50 suppression. This result is intrinsically important, perhaps especially because a recent report suggests genetic linkage of poor P50 suppression to the cholinergic receptor's alpha7 nicotinic subunit.

OBJECTIVE: Careful assessment of research subjects is important because the inclusion of subjects who manifest psychopathology and significant substance abuse in normal comparison groups will decrease statistical and experimental power. The current study evaluated the usefulness of an MMPI-derived algorithm in identifying tendencies toward psychosis and substance abuse in putatively normal research volunteers. METHOD: Ninety-eight adults who were recruited as normal comparison research subjects completed the MMPI, psychiatric interviews, questionnaires, and selected neuropsychological tests. The MMPI classified 81 presumed normal subjects into four subgroups: 1) not psychosis prone/substance abuse not likely, 2) not psychosis prone/substance abuse likely, 3) psychosis prone/substance abuse not likely, and 4) psychosis prone/substance abuse likely. RESULTS: The MMPI psychosis-prone and substance abuse factors identified significantly distressed and dysfunctional individuals with a relatively high degree of accuracy. CONCLUSIONS: It is becoming increasingly apparent that the cursory self-report screening of normal subjects may result in unacceptable levels of psychopathology in comparison groups. The current results also indicate that an adequate substance abuse evaluation is extremely important and that brief self-report information may be misleading. Empirically derived assessment tools, such as the MMPI, may prove useful in allowing researchers to more accurately define control parameters and group membership.

Two distinct measures have been used to assess inhibitory gating deficits in schizophrenia patients: P50 suppression and prepulse inhibition of the startle response. It remains unclear whether both measures can be assessed in a single testing session.Twelve normal subjects underwent testing in a carefully designed combined P50/prepulse inhibition session using stimulus characteristics similar to those described in the existing literature.The levels of both P50 suppression and prepulse inhibition obtained in the combined session were highly similar to those obtained in independent testing of previous cohorts of normal subjects. As in previous experiments, P50 suppression and prepulse inhibition were not significantly correlated.Measuring P50 suppression and prepulse inhibition in a single session is feasible and offers a unique opportunity to assess these two distinct gating measures contemporaneously in cohorts of normal comparison subjects and schizophrenia patients, so that temporal shifts in one or both measures are minimized.

Objective: It has been widely hypothesized that sensory gating failures and sensory overload occur in schizophrenic patients compared to normal subjects. The authors ofthis study sought to confirm and extend results ofearlier studies that showed specific sensory gating deficits in schizophrenic patients. Method: Age- and sex-matched schizophrenic patients (N=20) and normal subjects (N=20) were tested using electrophysiologically recorded P50 event-related potentials to assess the overall competence ofthe subjects’ central sensory inhibitory capacity by measuring sensory filtering or gating. P50 area responses to two 75-dB (conditioning and test) click stimuli of O.04-msec duration, averaged over 60 trials, were recorded for each subject. Normally, the first (conditioning) click stimulus induces gating mechanisms that result in diminished or gated P50 event-related potentials in response to the second click stimulus. Results: The schizophrenic subjects manifested a significant sensory gating deficit at frontal, central, and parietal electrode placement sites, with a nonsignificant tendency for the deficit to be most prominent in the frontal areas of the brain. Conclusions: These data reflect a regionally diffuse loss of normal sensory gating in schizophrenic patients. (Am J Psychiatry 1992; 149:488-493)

Clinicians' attitudes about the posthospitalization outcome of patients who are irregularly discharged from the hospital (i.e., against medical advice or AWOL) have been pessimistic, but unsystematic follow-up data of such patients compared with regularly discharged patients suggest that outcomes for the two groups are similar. Because of this discrepancy, the authors used data from a controlled, systematic study of a large sample of voluntary inpatients that measured global outcome over 2 years. Their findings suggest that 1 year and 2 years after admission, most patients who were irregularly discharged had outcomes similar to those of patients with regular discharges. There was, however, a subgroup of irregularly discharged patients who had worse outcomes.

The authors evaluated the effects of antipsychotic medication and schizophrenia on speed of information processing. Medicated (N - 20) as well as unmedicated (N = 16) schizophrenic patients showed more evidence of slow information processing than did depressed control subjects (N = 20). The medicated schizophrenic patients had higher levels of general psychopathology but also showed superior information processing speed compared with the unmedicated schizophrenic patients. These data confirm that the schizophrenic patients are slow information processors and that antipsychotic medication probably does not cause, and may actually reverse, slowness of information processing in schizophrenic patients.

We have attempted to survey the current practice of inpatient treatment for the new cohort of chronic patients and to view it through the lenses of new glasses. Most controlled outcome studies have shown that outpatient treatment, which includes partial hospitals and clinics, is equal in efficacy to inpatient treatment, and that outcomes for shorter treatment are equal to those for longer treatment except for the two subgroups noted. Based on the data, we have descnibed enabling factors, indications, and contraindications for hospitalization. Our belief is that some chronic patients require periodic rehospitalization, but only some, and in these cases the focus should be on highly specific, problem-oriented treatment, most of which can be accomplished in about 30 days. In part, this guideline challenges the traditional assumption that most acutely disorganized patients require inpatient care to provide central structure and treatment until they can funciion without such support. Even with these guidelines...

The basic behavioral terms "aversive stimulation" and "negative reinforcement" are defined and the frequent misuse of these terms in the current literature is illustrated. The author notes the theo...