Slow-wave sleep and symptomatology in schizophrenia and related psychotic disorders

Deficits in slow-wave sleep (SWS), or delta sleep, are frequently seen in schizophrenia, but their relationship with schizophrenic symptomatology remains unclear. We examined the association between visually scored and automated measures of SWS and positive and negative symptoms in a series of unmedicated patients with schizophrenia and related psychotic disorders. Total and average automated delta wave counts were significantly inversely associated with negative symptoms overall, and the psychomotor poverty syndrome in particular. Total delta counts were also inversely related to the disorganization syndrome. No relation was seen between reality distortion or the Brief Psychiatric Rating Scale (BPRS) positive symptoms and SWS. These findings support the view that SWS deficits may be related to negative symptoms of schizophrenia and may perhaps be mediated by impaired functioning of frontothalamic neural circuits.     

Licking behavior in the rat: measurement and situational control of licking frequency

OBJECTIVE: In a preliminary report, the authors observed that clozapine was superior to haloperidol in the treatment of positive and negative symptoms in stable outpatients with schizophrenia. In this final report, they examine the effects of clozapine on positive and negative symptoms in patients with and without the deficit syndrome to determine which patients receive the positive symptom advantage of clozapine and the extent of clozapine's therapeutic effects on negative symptoms. In addition, they examine the long-term effects of clozapine on positive, negative, and affective symptoms, social and occupational functioning, and quality of life. METHOD: Seventy-five outpatients with schizophrenia, who met retrospective and prospective criteria for residual positive or negative symptoms, were entered into a 10-week double-blind, parallel-groups comparison of clozapine and haloperidol. Patients who completed the double-blind study were then entered into a 1-year open-label clozapine study. RESULTS: For patients who completed the 10-week double-blind study, clozapine was superior to haloperidol in treating positive symptoms. This effect was not observed in the intent-to-treat analyses. There was no evidence of any superior efficacy or long-term effect of clozapine on primary or secondary negative symptoms. Long-term clozapine treatment was associated with significant improvements in social and occupational functioning but not in overall quality of life. CONCLUSIONS: For schizophrenic patients who are able to tolerate clozapine therapy, clozapine has superior efficacy for positive symptoms but not negative symptoms and is associated with long-term improvements in social and occupational functioning for patients with and without the deficit syndrome.     

Spontaneous abnormal involuntary movements in first-episode schizophrenia and schizophreniform disorder: baseline rate in a group of patients from an Irish catchment area

OBJECTIVE: This study investigated the rate of spontaneous abnormal involuntary movements in a group of patients presenting with a first episode of schizophrenia or schizophreniform psychosis. METHOD: Seventy-nine patients with a first episode of schizophrenia or schizophreniform psychosis who presented to a catchment area psychiatric service over a 3-year period, and who were neuroleptic-naive or had been medicated for less than 1 month, were examined for the presence of involuntary movements with use of the Abnormal Involuntary Movement Scale. RESULTS: Six patients (7.6%) had spontaneous dyskinesia as defined by the criteria of Schooler and Kane, and nine other patients had mild orofacial involuntary movements. The patients with spontaneous dyskinesia had completed significantly fewer years of education than the patients without dyskinesia. Spontaneous involuntary movements were unrelated to age at presentation for treatment. CONCLUSIONS: Spontaneous abnormal involuntary movements were evident among a proportion of patients with first-episode schizophrenia or schizophreniform psychosis at baseline presentation and were associated with reduced educational attainment. This finding supports previous suggestions that abnormal involuntary movements in schizophrenia may be related to the pathophysiology of the illness and therefore cannot be attributed entirely to the adverse effects of neuroleptic medication.     

Correlation of positive symptoms exclusively to hyperperfusion or hypoperfusion of cerebral cortex in never-treated schizophrenics

BACKGROUND: Studies of schizophrenia by single photon emission computed tomography (SPECT) and positron emission tomography (PET) have shown both regional cerebral hyperperfusion and hypoperfusion. The aim of this study was to examine the inter-relations between regional cerebral blood flow (rCBF), psychopathology, and effects of neuroleptic therapy. METHODS: 24 never-treated patients with acute schizophrenia were examined with hexamethylpropyleneamine-oxime brain SPECT and assessed psychopathologically according to the positive and negative syndrome scale; they were studied again after neuroleptic treatment and psychopathological remission. rCBF values that deviated from those of 20 controls by more than 2 SD were regarded as abnormal. FINDINGS: Both hyperperfused and hypoperfused patterns were found among schizophrenia patients during acute illness. The seven positive symptoms on the symptom scale showed different correlations with rCBF: formal thought disorders and grandiosity correlated positively (and strongly) with bifrontal and bitemporal rCBF; delusions, hallucinations, and distrust correlated negatively (and strongly) with cingulate, left thalamic, left frontal, and left temporal rCBF. Stereotyped ideas as a negative symptom correlated negatively (and strongly) with left frontal, cingulate, left temporal, and left parietal rCBF. After neuroleptic treatment (and reduction of positive symptoms), only negative symptoms correlated exclusively with bifrontal, bitemporal, cingulate, basal ganglia, and thalamic hypoperfusion. INTERPRETATION: Different positive symptoms are accompanied by different rCBF values--some related to hyperperfusion, others to hypoperfusion. This finding may help to explain observed inconsistencies of perfusion patterns in drug-na?ve schizophrenics.     

Construction of vectors expressing bioactive heterodimeric and single-chain murine interleukin-12 for gene therapy

OBJECTIVE: We examined the prevalence, correlates, and predictive value of an abbreviated somatization index, based on specific symptom thresholds, in primary care patients using services at a university-affiliated clinic. METHOD: We interviewed 1456 patients with a survey instrument that included the Composite International Diagnostic Interview (CIDI) to elicit symptoms and diagnoses of several psychiatric disorders as well as demographic information and a measure of disability. Statistical analyses examined the relationship of abridged somatization with physical functioning and various demographic and diagnostic factors. RESULTS: About one fifth of this primary care sample met the abridged somatization criteria. "Somatizers," defined according to these criteria, had significantly higher levels of psychiatric comorbidity and disability than "nonsomatizers". Analyses taking into account the number and type of organ/body systems represented by the unexplained symptoms showed that this dimension adds specificity to the prediction of outcomes. Thus, regardless of the total number of medically unexplained symptoms, abridged somatization with unexplained symptoms attributable to four or more organ/body systems showed the strongest association with disability and psychopathology. CONCLUSIONS: Abridged Somatization is a frequent syndrome in primary care that is strongly associated with psychopathology and physical disability. Our research also yielded a new series of abridged somatization subtypes (eg, "discrete" vs. "comorbid" and "simple" vs. "polymorphous") that may effectively separate among various psychopathologies, and may become useful tools for future research with somatizing patients.     

Working Memory Impairments in Schizophrenia: A Meta-Analysis.

Working memory (WM) deficit is a cardinal cognitive symptom of schizophrenia, but the differences among the tasks and measures used to assess WM make it difficult to compare across studies. The authors conducted a meta-analytic review to address 3 major questions: (a) Do patients with schizophrenia show WM deficits across diverse methodology; (b) Is WM deficit supramodal; and (c) Does the WM deficit worsen with longer delays? The results indicate that significant WM deficit was present in schizophrenia patients in all modalities examined. Increasing delay beyond 1 s did not influence the performance difference between schizophrenia patients and healthy control participants in WM. These results suggest that WM deficit in schizophrenia is modality independent and that encoding and/or early part of maintenance may be problematic. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Selective effects on prefrontal cortex serotonin by dopamine D3 receptor agonism: interaction with low-dose haloperidol

1. Negative symptoms of schizophrenia are characterized by amotivation, anhedonia and anergia. These aspects of the symptom profile can be modeled by D3 agonism in animal behavioral models. 2. Serotonergic systems have been implicated in pathophysiologic substrates for this disorder; most notably, in deficit state schizophrenia, as newer 'atypical' neuroleptics which are especially efficacious for treating this syndrome antagonize central 5-HT2 receptors. 3. FC regions may also be important in chronic negative symptoms, as hypofrontality has been associated with these schizophrenic features. 4. The author examined effects of a behaviorally-active dose of the D3 agonist, 7OH, on 5-HT metabolism in FC, and the ability of a low-dose neuroleptic treatment to antagonize this biochemical effect. 5. Acute administration of 7OH induced a selective decrease of 5-HT turnover in the FC without affecting metabolism of this transmitter in more subcortical DA regions. 6. Hal, which has previously been demonstrated to antagonize electrophysiologic, biochemical and behavioral effects of 7OH, was without effect on agonist-induced decreases in 5-HT turnover. 7. The biochemical association between D3 agonism and reductions of FC 5-HT may be significant for pathophysiologic mechanisms of negative symptoms, and antagonism of this effect may differ for neuroleptics with varying efficacy in alleviating these symptoms.     

The effects of environmental conditions on the in vitro activity of selected antimicrobial agents against Escherichia coli

Serotonin (5-hydroxytryptamine, 5-HT) may play an important role in the pathogenesis of schizophrenia. Previous studies suggested that the efficacy of atypical neuroleptic drugs (e.g., risperidone and clozapine) on negative symptoms may be related to the 5-HT2a receptor. Although association studies between MspI polymorphism (T102C) and the 5-HT2a receptor gene and schizophrenia have been reported, their results are still controversial. The aim of this study was to examine the association between T102C polymorphism of the 5-HT2a receptor gene and schizophrenia as well as the association between the polymorphism and negative symptoms in a Japanese population (106 patients with schizophrenia and 109 healthy controls). No significant positive associations were observed. Our results suggest that the 5-HT2a receptor gene is not involved in the pathogenesis of schizophrenia or negative symptoms.     

Occurrence and clinical correlates of psychiatric comorbidity in patients with psychotic disorders

BACKGROUND: The aim of this study was to explore patterns and clinical correlates of psychiatric comorbidity in patients with schizophrenia spectrum disorders and mood spectrum disorders with psychotic features. METHOD: Ninety-six consecutively hospitalized patients with current psychotic symptoms were recruited and included in this study. Index episode psychotic diagnosis and psychiatric comorbidity were assessed using the Structured Clinical Interview for DSM-III-R-Patient Version (SCID-P). Psychopathology was assessed by the SCID-P, Brief Psychiatric Rating Scale, Scale for the Assessment of Negative Symptoms, and Hopkins Symptom Checklist. Awareness of illness was assessed with the Scale to Assess Unawareness of Mental Disorders. RESULTS: The total lifetime prevalence of psychiatric comorbidity in the entire cohort was 57.3% (58.1% in schizophrenia spectrum disorders and 56.9% in mood spectrum psychoses). Overall, panic disorder (24%), obsessive-compulsive disorder (24%), social phobia (17.7%), substance abuse (11.5%), alcohol abuse (10.4%), and simple phobia (7.3%) were the most frequent comorbidities. Within the group of mood spectrum disorders, negative symptoms were found to be more frequent among patients with psychiatric comorbidity than among those without comorbidity, while such a difference was not detected within the group of schizophrenia spectrum disorders. Social phobia, substance abuse disorder, and panic disorder comorbidity showed the greatest association with psychotic features. An association between earlier age at first hospitalization and comorbidity was found only in patients with unipolar psychotic depression. Patient self-reported psychopathology was more severe in schizophrenia spectrum patients with comorbidity than in those without, while such a difference was less pronounced in mood spectrum psychoses. CONCLUSION: These findings suggest that psychiatric comorbidity is a relevant phenomenon in psychoses and is likely to negatively affect the phenomenology of psychotic illness. Further studies in larger psychotic populations are needed to gain more insight into the clinical and therapeutic implications of psychiatric comorbidity in psychoses.     

Visual hallucinations in schizophrenia: Confusion between imagination and perception.

Objective: An association between hallucinations and reality-monitoring deficit has been repeatedly observed in patients with schizophrenia. Most data concern auditory/verbal hallucinations. The aim of this study was to investigate the association between visual hallucinations and a specific type of reality-monitoring deficit, namely confusion between imagined and perceived pictures. Method: Forty-one patients with schizophrenia and 43 healthy control participants completed a reality-monitoring task. Thirty-two items were presented either as written words or as pictures. After the presentation phase, participants had to recognize the target words and pictures among distractors, and then remember their mode of presentation. Results: All groups of participants recognized the pictures better than the words, except the patients with visual hallucinations, who presented the opposite pattern. The participants with visual hallucinations made more misattributions to pictures than did the others, and higher ratings of visual hallucinations were correlated with increased tendency to remember words as pictures. No association with auditory hallucinations was revealed. Conclusions: Our data suggest that visual hallucinations are associated with confusion between visual mental images and perception. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Clinical, neuropsychological, and brain structural correlates of smooth-pursuit eye tracking performance in chronic schizophrenia.

Examined the relation of smooth-pursuit eye tracking dysfunction to neuropsychological performance, brain structural anomalies, and clinical state in a sample of 61 patients with chronic schizophrenia. No association was found between impaired pursuit oculomotion and measures of chronicity or clinical state. Likewise, no association emerged between eye tracking integrity and brain structural anomalies. Patients with dysfunctional eye tracking were more likely to have impaired performance on tests that assess frontal lobe functioning. In addition, they had more negative symptoms and a relative absence of positive symptoms. Because negative symptoms are often found among patients wih frontal lobe impairment, their association with abnormal eye tracking provides converging support for the hypothesis that the cortical locus of deviant smooth-pursuit eye tracking is in the frontal lobes. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Glutamatergic neurotransmission involves structural and clinical deficits of schizophrenia

BACKGROUND: Phencyclidine and ketamine induce a syndrome closely resembling schizophrenia due to their blockade of N-methyl-D-aspartate (NMDA) receptor. These findings suggested that some aspects of schizophrenia are associated with decreased NMDA--glutamatergic function. We hypothesized that structural and symptomatic deficits in schizophrenia are related to glutamatergic neurotransmission. METHODS: We studied the relationships among cerebrospinal fluid (CSF) glutamatergic markers, clinical presentation of schizophrenia, and CT parameters of brain structure in drug-free schizophrenics. RESULTS: We found no significant differences between patients with schizophrenia and controls in CSF glutamatergic markers. When patients with schizophrenia were considered as a group, significant negative correlations between glutamatergic markers and brain structural measures as well as clinical measures were observed. Cluster analysis reveals a group of lower indices of glutamatergic neurotransmission, and more prominent thought disorder as well as ventricular enlargement, and a group with increased glutamate level. CONCLUSIONS: The findings support the hypothesis that altered glutamatergic neurotransmission plays a role in the brain structure and the clinical symptoms of schizophrenia.     

Obstetric complications and age at onset in schizophrenia: an international collaborative meta-analysis of individual patient data

OBJECTIVE: An excess of obstetric complications in the histories of schizophrenic patients is a well-replicated finding, but less consistent results have been found concerning the relationships between obstetric complications and family history of schizophrenia, age at onset of schizophrenia, and gender. Small sample size limited the power of previous studies that attempted to assess such relationships. The aim of this study was to use data on individual patients from all available studies to examine the links between a history of obstetric complications and family history of schizophrenia, age at onset, and gender. METHOD: Raw data from 854 schizophrenic patients concerning history of obstetric complications rated according to the Lewis and Murray scale were obtained from 11 different research groups. Weighted average estimates were calculated with the use of regression techniques. RESULTS: A significant association was found between age at onset of schizophrenia and obstetric complications: the earlier the age at onset, the more likely the history of obstetric complications. Subjects with onset of schizophrenia before age 22 were 2.7 times more likely than those with onset at a later age to have had a history of abnormal presentation at birth and 10 times more likely to have had a history of complicated Cesarean birth. No association was found between obstetric complications and family history of schizophrenia or gender. CONCLUSIONS: The association between obstetric complications and early age at onset of schizophrenia indicates that the pathophysiology of early-onset schizophrenia involves neurodevelopmental impairment.     

Red cell membrane fatty acids, cytosolic phospholipase-A2 and schizophrenia

Forty subjects with schizophrenia and 40 age- and sex-matched controls were recruited, and blood samples were obtained for analysis of red cell membrane fatty acid composition by capillary gas chromatography. A blood sample was also taken from the same population to test for allelic association between schizophrenia and a polymorphism close to the promoter site of the cytosolic phospholipase-A2 gene which is mapped to chromosome 1q25. The schizophrenic population was heterogeneous with regards age, symptoms severity and treatment. A significantly higher percentage concentration of dihomogamma-linolenic acid (DGLA) was found in the red cell membranes of schizophrenics compared to matched controls. All other fatty acids examined showed no difference from the normal population. No correlation was found between any demographic factor, treatment variable, diet, drug use, alcohol or tobacco consumption which could explain the biochemical findings. A negative correlation was found between the concentration of DGLA in red blood cell (RBC) membranes and severity of symptoms of schizophrenia. In particular, there was a significant correlation (r = -0.41, p = 0.009) between DGLA percentage concentrations and 'disorganised' symptoms. No association was found between schizophrenia and alleles of the polymorphism near the phospholipase-A2 gene or between fatty acid concentrations and the presence of any particular alleles. This study therefore finds support for membrane phospholipid abnormalities in patients with schizophrenia and particular symptom clusters, but does not replicate a previous report of an allelic association between a polymorphism close to the site of the cytosolic phospholipase-A2 gene and schizophrenia.     

Heterogeneity of auditory verbal working memory in schizophrenia.

The heterogeneity of schizophrenia remains an obstacle for understanding its pathophysiology. Studies using a tone discrimination screening test to classify patients have found evidence for 2 subgroups having either a specific deficit in verbal working memory (WM) or deficits in both verbal and nonverbal memory. This study aimed to (a) replicate in larger samples differences between these subgroups in auditory verbal WM; (b) evaluate their performance on tests of explicit memory and sustained attention; (c) determine the relation of verbal WM deficits to auditory hallucinations and other symptoms; and (d) examine medication effects. The verbal WM and tone discrimination performance did not differ between medicated (n = 45) and unmedicated (n = 38) patients. Patients with schizophrenia who passed the tone screening test (discriminators; n = 60) were compared with those who did not (nondiscriminators; n = 23) and healthy controls (n = 47). The discriminator subgroup showed poorer verbal WM than did controls and a deficit in verbal but not visual memory on the Wechsler Memory Scale–Revised (Wechsler, 1987), whereas the nondiscriminator subgroup showed overall poorer performance on both verbal and nonverbal tests and a marked deficit in sustained attention. Verbal WM deficits in discriminators were correlated with auditory hallucinations but not with negative symptoms. The results are consistent with a verbal memory deficit in a subgroup of schizophrenia having intact auditory perception, which may stem from dysfunction of language-related cortical regions, and a more generalized cognitive deficit in a subgroup having auditory perceptual and attentional dysfunction. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Identifying subtypes of schizophrenia by cluster analyses

The existence of two subtypes of schizophrenia (positive and negative) is well established. The evidence in favor of other subtypes, particularly a disorganized subtype, is still the subject of some debate. The aim of the study reported in this article is to investigate the possibility of further subtypes of schizophrenia by applying a particular method of cluster analysis to a particular set of data. Ward's method of cluster analysis was applied to the Positive and Negative syndrome Scale (PANSS) scores of 138 patients, defined as having schizophrenia by one of four diagnostic criteria. The validity of the cluster solution was assessed both by examining differences between clusters on a number of clinical characteristics recorded for each patient and by comparing the results obtained from the PANSS with those derived from a cluster analysis using two other instruments (the Scale for the Assessment of Negative Symptoms and the Scale for the Assessment of Positive Symptoms). Results from the cluster analysis suggest the existence of at least four subtypes of schizophrenia: positive, negative, mixed, and disorganized. A fifth subtype includes patients with few symptoms, suggesting the simple schizophrenia named by Bleuler. Evidence for the validity of these subtypes was provided by the differences observed between the clusters on a number of clinical characteristics and by the similarity of the cluster solution obtained from the different instruments. In conclusion, the negative-positive dichotomy in schizophrenia is an oversimplification, and the existence of a more complex structure needs to be taken into account in future research.     

VBR in schizophrenia: relationship to family history of psychosis and season of birth

Ventricular enlargement has been consistently demonstrated in schizophrenia using both CT and MRI. Despite this, the structural changes that underlie increased ventricle-brain ratio (VBR) and its relationship to environmental factors (intrauterine viral exposure, obstetric complications, etc.) and family history of schizophrenia remain poorly defined. Increased VBR has been shown in some studies to correlate with an absence of family history of schizophrenia and with Winter-Spring birth. In an attempt to obtain a clearer picture of the contribution of environmental and genetic factors to VBR, we studied 54 patients with DSM III-R schizophrenia. VBR was determined from head CT scans via computerized planimetry. Family history of psychosis and non-psychotic mood disorder was determined with the family informant method. Season of birth was encoded in several ways, including season, trimester and dichotomously. Patients without a family history of psychosis had significantly larger VBR than patients with such a history; family history of mood disorder was not related to VBR. Season of birth was not predictive of VBR. Family history of psychosis and season of birth were not related to each other. These results are in line with prior work demonstrating an association between increased VBR and sporadic (non-familial) schizophrenia. We did not find a relationship between VBR and season of birth, which suggests that risk of perinatal viral exposure and other seasonal environmental factors may not account for the ventricular enlargement in non-familial schizophrenia observed in our sample.     

Mechanical cardiac assistance

In neuropsychological vulnerability research the visual backward masking task, the Span of Apprehension, the degraded stimulus Continuous Performance Test (dsCPT), and the Wisconsin Card Sorting Test have been described as putative indicators for the predisposition to develop negative (schizophrenic) symptoms. The present study assesses the stability of the association between neuropsychological tests and negative symptoms by examining clinically improved patients. The interdependence between the four cognitive measures and clinical symptomatology was examined in 31 patients with DSM III-R and ICD-10 schizophrenia suffering predominantly from negative symptoms. Backward masking performance was related to affective flattening and anxiety-depression. False alarm rate on dsCPT was associated positively with affective flattening and hallucinations, and negatively with avolition. Card sorting preseverative errors correlated negatively with anhedonia, non-preservative errors correlated positively with avolition. Correlations notwithstanding, the data provide evidence in support of the relative independence of neuropsychological functions and negative symptoms in clinically improved schizophrenics.