Platelet 5-HT(2A) receptors in schizophrenic patients with and without neuroleptic treatment

It has been suggested that abnormal function of the serotonergic system may be implicated in the pathophysiology of schizophrenia. In order to examine the role of this system in schizophrenia, we have determined 5-HT(2A) receptors on human platelets of 20 control subjects and 37 schizophrenic patients by using [3H]spiperone and ketanserin. The data showed that the maximum number (B(max)) of 5-HT(2A) receptors for schizophrenic patients without neuroleptic therapy was significantly higher than that for control subjects. The B(max) values for [3H]spiperone binding to platelets of schizophrenic patients on butyrophenone, phenothiazine, benzisoxazole and thioxanthene therapies were significantly lower than those obtained from the drug-free group, but were comparable to control values. The effect of various medication periods on platelet 5-HT(2A) receptors was also examined. We found that after 2-4 weeks, 1-4 months, 4-12 months and more than 1 year of neuroleptic treatments, the B(max) values were significantly decreased when compared with values in the drug-free group. The present results indicate that treatment with various types of neuroleptics decreases the hypersensitivity of platelet 5-HT(2A) receptors. Significant clinical improvements occurred in all types of neuroleptic-treated groups and for all different treatment durations in this study. The precise mechanisms of how neuroleptics achieve their therapeutic effects still need to be further delineated.     

Hypofrontality -- a risk-marker related to schizophrenia?

In order to better understand whether cortical hypoactivation and hypofrontality is a possible risk marker for schizophrenia, we investigated resting EEG activity in 39 unmedicated schizophrenics and 21 persons with schizotypal personality. Compared to a normal control group, we found an increased, frontally pronounced delta activity in schizophrenic patients, a result that is in accordance with other studies. Subjects with schizotypal personality, who are believed to have an increased risk for schizophrenia, did not show an increase of delta activity. From this result, we concluded that cortical hypoactivation and hypofrontality -- defined as an increase of frontally pronounced delta activity during resting EEG -- cannot be interpreted as a risk factor for schizophrenia. However, since it is controversial whether subjects with schizotypal personality are at increased risk for schizophrenia, further studies in unaffected family members of schizophrenic patients are needed.     

H-spiperone binding sites in lymphocytes as possible vulnerability marker in schizophrenia

The binding parameters for the dopamine antagonist ³H-spiperone to lymphocytes were investigated in nonmedicated schizophrenics (N = 43), in medicated schizophrenics (N = 25), as well as in 38 first- and second-degree relatives of schizophrenics, in a psychiatric control group (N = 27) and in normal, healthy controls (N = 40). The density of lymphocyte ³H-spiperone binding sites (B_max) was significantly increased in all acute and chronic schizophrenic patients and in patients undergoing neuroleptic treatment for 2 weeks to several months and remained on a constant level during a drug-free remission period, suggesting that B_max is a state independent variable. Elevated binding seems to be associated with schizophrenia; it could not be found in other psychiatric patients. In pedigree and family studies it became obvious that all relatives with one or more previous episodes of schizophrenia had similar increased binding capacity. But even in some well-state relatives elevated spiperone binding could be found, although they never had symptoms of the disease. Among these relatives of schizophrenics, there was an association between increased spiperone binding and the transmission of the disease. Although conclusive data about the precise genetic control obtainable in twin studies are still missing, we would suggest that elevated lymphocyte spiperone binding may be a marker of susceptibility to schizophrenia.     

Schizotypal personality disorder in individuals with and without schizophrenic relatives: similarities and contrasts in neurocognitive and clinical functioning.

Schizophrenia-spectrum disorders may reflect the genotype for schizophrenia. One such disorder, Schizotypal Personality Disorder (SPD), was examined as a function of family history of schizophrenia. Clinical profiles and neurocognitive functioning were evaluated in 25 schizotypal subjects (10 SPD with schizophrenic relatives and 15 SPD without schizophrenic relatives), and in 24 normal controls. The primary finding is that vigilance performance was similarly impaired in both SPD groups. An additional neurocognitive impairment, comprehension of grammatical constructions, was observed only in the SPD group with schizophrenic relatives. Of interest, the clinical profiles of the two SPD groups did not differ significantly. These results suggest that schizotypal personality disorder is associated with a continuum of neurocognitive vulnerability that increases as a function of family history of schizophrenia.     

CSF levels of receptor-active endorphins in schizophrenic patients: correlations with symptomatology and monoamine metabolites

Cerebrospinal fluid (CSF) levels of an opioid receptor-active, chromatographically separated endorphin fraction (Fraction I) were measured in 45 schizophrenic patients and 18 healthy volunteers. Significantly increased levels of Fraction I differentiated the patient group from controls, with no difference being found between newly admitted untreated and chronic previously neuroleptic-treated subjects. Fraction I levels did not correlate with age, weight, height, duration of illness, total time hospitalized, or age when symptoms first appeared. No differences were found between patients with or without a family history of schizophrenia. Fraction I levels were negatively correlated with "hallucinations" and "indecision" on the Comprehensive Psychopathological Rating Scale. Increased levels of Fraction I were associated with low levels of the dopamine metabolite homovanillic acid in drug-free schizophrenics. This relationship was not present after neuroleptic treatment or in healthy controls. No relationship was found between Fraction I and the serotonin metabolite 5-hydroxyindoleacetic acid. Neuroleptic treatment did not significantly change Fraction I levels; when only patients above the control range were considered, however, a significant decrease was observed. The data support our previous hypothesis of an increased opioid activity in schizophrenia and further indicate a concomitant dysfunction of brain endorphin and dopamine activity in schizophrenic patients.     

Prospective memory deficits in subjects with schizophrenia spectrum disorders: a comparison study with schizophrenic subjects, psychometrically defined schizotypal subjects, and healthy controls

Memory impairment is one of the core deficits in schizophrenia. This study explored the memory profiles of schizophrenic and psychometrically defined schizotypal subjects. The study participants included 15 patients with schizophrenia, 41 schizotypal subjects, and 20 healthy controls. All of the participants completed verbal and visual memory, working memory, and prospective memory tasks. The results showed that patients with schizophrenia were impaired in all aspects of memory function, whereas the schizotypal subjects tended to show moderate to large impairment effect sizes in prospective memory. It is suggested that prospective memory be considered a potential endophenotype of schizophrenia.     

Three-dimensional analysis with MRI and PET of the size, shape, and function of the thalamus in the schizophrenia spectrum.

OBJECTIVE: In an exploration of the schizophrenia spectrum, the authors compared thalamic size, shape, and metabolic activity in unmedicated patients with schizophrenia and schizotypal personality disorder to findings in age- and sex-matched healthy control subjects. METHOD: Coregistered magnetic resonance imaging (MRI) and positron emission tomography scans were obtained in 27 schizophrenic patients, 13 patients with schizotypal personality disorder, and 32 control subjects who performed a serial verbal learning test during tracer uptake. After thalamus edges were outlined on 1.2-mm MRI scans, a radial warping program yielded significance probability mapping in three dimensions. RESULTS: Significance probability mapping (with resampling) identified an area in the region of the mediodorsal nucleus bilaterally with significantly lower relative metabolism in the schizophrenia group than in either the control or schizotypal personality disorder groups, which did not differ from each other. The three groups did not differ significantly in total thalamic volume in square millimeters or thalamic volume relative to brain volume. Shape analyses revealed that schizophrenic patients had significantly fewer pixels in the left anterior region, whereas patients with schizotypal personality disorder had significantly fewer pixels in the region of the right mediodorsal nucleus than did control subjects. CONCLUSIONS: Schizophrenic patients showed significant metabolism and shape differences from control subjects in selective subregions of the thalamus, whereas patients with schizotypal personality disorder showed only a difference in shape. Because the mediodorsal and anterior nuclei have different connections with limbic and prefrontal structures, the anterior thalamic shrinkage and mediodorsal metabolic and shape changes might relate to the different clinical pictures in schizotypal personality disorder and schizophrenia.     

ERPs changes during neuroleptic treatment in schizophrenia--a vulnerability marker in schizophrenia]

P300 amplitude reduction and P300 latency prolongation are consistent findings in schizophrenia, but it is unclear if these abnormalities were the effect of current or past neuroleptic treatment or were present at the onset of illness. We previously recorded ERPs in drug free schizophrenic patients (45 neuroleptic-naive and 56 previously treated with neuroleptics). In that study, P300 amplitude reduction was observed in both the neuroleptic-naive and the previously treated patients. However, both N200 and P300 latencies were prolonged only in the previously treated schizophrenic patients. In this study, we investigated ERPs in 60 drug free schizophrenic patients before and after neuroleptic treatment was begun. According to DSM-IV, schizophrenia subtype classification, 26 cases were paranoid type, 14 were disorganized, 2 catatonic and 18 undifferentiated. Twenty six of the patients were neuroleptic-naive and 34 had been previously treated. Sixty gender- and age-matched healthy controls were also investigated. ERPs were recorded during an auditory oddball task. The scalp EEGs were recorded from AgAgCl electrodes at 16 sites according to the international 10-20 system. Clinical symptoms were assessed using the Brief Psychiatric Rating Scale (BPRS). Before treatment, all schizophrenic patients displayed larger N200 amplitudes than the controls; however, increases in N200 amplitudes were not observed after neuroleptic treatment was begun. Both N200 and P300 latencies in the patients before treatment were prolonged only in those previously treated. Neuroleptic-naive patients demonstrated prolongation of both N200 and P300 latencies only after treatment. P300 amplitudes in patients were increased by neuroleptic treatment; but patients had smaller P300 amplitudes than the controls even after treatment. The change in P300 amplitudes (Pz) and the change in total BPRS scores by neuroleptic treatment were positively correlated in the patients whose duration of illness was six months or less (mean: 2.4 months). However, no correlation was observed for patients whose duration of illness was over six months (mean: 49.7 months). There were no significant differences in ERPs changes among subtypes. These results suggested that the P300 amplitude should be considered a vulnerability marker in schizophrenia and that both N200 and P300 latencies might be markers for neuroleptic exposure.     

Caudate size in first-episode neuroleptic-naive schizophrenic patients measured using an artificial neural network.

BACKGROUND: Structural brain imaging studies have demonstrated an increase in caudate volume in schizophrenic patients medicated with typical neuroleptics and a volume decrease following treatment with atypical neuroleptics. The measurement of striatal volume in patients who have never been treated with neuroleptics may indicate whether these changes are superimposed on intrinsic basal ganglia pathology in schizophrenia or are solely neuroleptic-induced. METHODS: We studied 36 first-episode, neuroleptic-naive schizophrenic patients and 43 control subjects using an artificial neural network (ANN) to identify and measure the caudate nucleus. The resulting volumes were analyzed using an ANCOVA controlling for intracranial volume, age, gender, and socioeconomic status. RESULTS: The mean volume difference between the caudate nuclei of patients and control subjects was .297 mL, the caudate nuclei of the patients being smaller than those of controls. When we covaried for intracranial volume, this was a statistically significant difference in caudate volume (n = 79; df = 1,75; F = 4.18; p > .04). CONCLUSIONS: Caudate nuclei of neuroleptic naive schizophrenic patients are significantly smaller than those of controls. This suggests that patients suffering from schizophrenia may have intrinsic pathology of the caudate nucleus, in addition to the pathology observed as a consequence of chronic neuroleptic treatment.     

Prolactin bioassay in schizophrenia before and after neuroleptics.

Fifteen drug-free schizophrenic male inpatients and 14 normal control subjects were studied. The schizophrenic subjects had a significantly lower ratio of bioassay prolactin to radioimmunoassay prolactin before neuroleptic treatment than they did after treatment. The ratio was lower in the drug-free patients as compared with normal controls. These findings suggest that neuroleptic medications may alter the molecular forms of serum prolactin. The results also suggest that drug-free schizophrenic patients may have a different pattern of prolactin variants than normal subjects and that this difference could be secondary to a disordered tuberoinfundibular dopamine system or long-term effects of neuroleptic drugs.     

Platelet monoamine oxidase activity in schizophrenia: Relationship to family history of the illness and neuroleptic treatment

Platelet monoamine oxidase (MAO) activity was determined in a large population of drug-free and haloperidol-treated schizophrenic patients and healthy controls and, in a second study, in a sample of schizophrenics after a wash-out period and at different times during treatment with haloperidol. Enzyme activity was significantly decreased in both acute and chronic haloperidol-treated schizophrenics, but not in drug-free schizophrenics, compared with normal controls. No significant difference was observed between drug-free schizophrenics with a family history of the illness and those without such history, and between healthy relatives of schizophrenic patients and normal controls without a family history of schizophrenia.MAO activity was significantly reduced after 14 and 21 days of haloperidol treatment, and such reduction did not correlate with response to treatment. These data strongly support the idea that neuroleptic intake may, at least in part, explain low MAO values repeatedly reported in schizophrenics.     

The role of NGF and IL-2 serum level in assisting the diagnosis in first episode schizophrenia

Development of reliable diagnostic bio-markers for schizophrenia remains a diagnostic challenge. Serum NGF and IL-2 were analyzed to examine the diagnostic efficiency and predictive capability of these two biomarkers in relation to schizophrenia diagnosis. Thirty neuroleptic naïve subjects with first-episode schizophrenia, thirty patients with major depressive disorder (MDD) and twenty-eight healthy control subjects participated in the study. One-way ANOVA demonstrated significantly lower serum IL-2 and NGF among schizophrenic patients and patients with MDD compared with healthy controls. Receiver operating characteristic (ROC) curve analysis was used to ascertain diagnostic efficiency of serum IL-2 and NGF levels. Area under the ROC curve (AUC) revealed a high level of differentiation between schizophrenic patients and healthy controls for both IL-2 and NGF serum concentrations. Diagnostic efficiency of combined NGF and IL-2 serum levels was also high in schizophrenic patients compared with healthy controls. Serum NGF and IL-2 are promising as potential screening or diagnostic biomarkers for schizophrenia and may be a useful adjunct for clinical assessment.     

DRD3 and DAT1 genes in schizophrenia: an association study

OBJECTIVE: To investigate the role of the dopamine receptor 3 (DRD3) and transporter 1 (DAT1) genes in schizophrenia or in modulating its phenotype. METHODS: a Ser9Gly polymorphism in codon 9 of the DRD3 and a VNTR polymorphism in the DAT1genes were examined in two groups of schizophrenic patients, one of excellent neuroleptic responders (N=42) and one of nonresponders (N=64). A group of healthy volunteers screened for major psychiatric disorders was also included (N=89). In addition, age at onset of psychotic symptoms, attention performance and family loading for schizophrenia spectrum disorders were compared between patients with different genotypes in the DRD3 and DAT1 genes. RESULTS: No significant differences in the allelic distribution of the DRD3 and DAT1 polymorphisms were detected between schizophrenic patients and controls. A trend toward an excess of DRD3 genotype Gly/Gly was observed in neuroleptic nonresponder schizophrenic patients compared to controls (chi(2)=3. 30, df=1, p=0.07). No significant differences in age at onset of psychotic symptoms, attention task performance or family loading for schizophrenia spectrum disorders were observed between groups with different DRD3 and DAT1 genotypes. CONCLUSION: These results do not support the role of either of these genes in increasing susceptibility to schizophrenia or in modulating its phenotype in the studied population.     

Changes in the serotonin transporter in the hippocampus of subjects with schizophrenia identified using [3H]paroxetine

Summary [³H]paroxetine binding to membrane from hippocampus, obtained at autopsy, from 24 schizophrenic and 24 non-schizophrenic subjects has been measured. The affinity of [³H]paroxetine binding to hippocampal membrane was decreased in subjects with schizophrenia (Kd=0.50 ± 0.04 vs. 0.24 ± 0.02nM; mean ± S.E.M. p < 0.001) but was not different in schizophrenic subjects who had or had not committed suicide (Kd=0.50 ± 0.07 vs. 0.50 ± 0.04nM). The density of [³H]paroxetine binding sites did not differ between the schizophrenic and non-schizophrenic subjects. For the schizophrenic subjects, there was no relationship between ante-mortem neuroleptic drug treatment and [³H]paroxetine binding to the hippocampal membrane. Finally, this study has shown that neuroleptic drug treatment of rats does not alter [³H]paroxetine binding to the hippocampal membranes. Thus, it would seem that the changes in the affinity of [³H]paroxetine binding to the hippocampus of schizophrenic subjects are not likely to be due to neuroleptic drug treatment but may be involved in the pathology of the illness.     

Volumetric magnetic resonance imaging study of the anterior cingulate gyrus in schizotypal disorder

Lack of normal structural asymmetry of the anterior cingulate gyrus (ACG) in patients with schizophrenia has been reported in our previous study. However, to our knowledge, no morphological studies of the brain have examined changes in ACG volume in patients with schizotypal features. We investigated the volume of the gray matter and the white matter of the ACG by three-dimensional magnetic resonance imaging (MRI) in 24 patients who met the ICD-10 criteria for schizotypal disorder (12 males, 12 females) in comparison with 48 age- and gender-matched healthy control subjects (24 males, 24 females) and 40 patients with schizophrenia (20 males, 20 females). As we reported previously, right ACG gray matter volume was significantly reduced in the female patients with schizophrenia compared with the female controls. On the other hand, the gray and white matter volume of the ACG in the patients with schizotypal disorder did not differ significantly from the values in the healthy controls or the patients with schizophrenia. However, the female patients with schizotypal disorder showed a lack of right-greater-than-left asymmetry of the ACG gray and white matter found in the female controls. These results suggest that both schizotypal and schizophrenic subjects share, at least in part, the same cerebral asymmetry abnormalities. Received: 28 May 2002 / Accepted: 30 October 2002 Correspondence to T. Takahashi     

Volumetric MRI study of the short and long insular cortices in schizophrenia spectrum disorders

We have previously reported volume reductions of the insular cortex in schizophrenia, but it is still not clear whether insular cortex volume loss preferentially involves the anterior (short insular cortex) or posterior (long insular cortex) portion. On the other hand, no volumetric studies of the brain have examined changes in insular cortex volume in subjects with schizotypal features. In this study, we separately investigated the volumes of the short and long insular cortex portions using magnetic resonance imaging in 37 schizotypal disorder patients (24 males, 13 females), 62 schizophrenia patients (32 males, 30 females), and 69 healthy controls (35 males, 34 females). While the volumes of the short and long insular cortex were significantly reduced in schizophrenia patients compared with schizotypal disorder patients and control subjects, there was no difference between schizotypal disorder patients and control subjects. These results suggest that the volume reduction of the insular cortex may be specific to overt schizophrenia without topographically specific localization.     

Cognitive and brain function in schizotypal personality disorder

Schizotypal personality disorder, a diagnosis defined partially in terms of a genetic relatedness to schizophrenia, has begun to receive extensive investigative study. While the exact etiologic relationship between schizotypal personality disorder and schizophrenia remains to be determined, three models have been considered: (1) the two may be distinct disorders, (2) they may be essentially identical disorders but expressed with different degrees of severity, or (3) they may be related disorders with a partially overlapping etiology that might account for the many similarities yet the lack of psychosis or severe deficits in schizotypal individuals. Some of the recent research in the structural and functional neuroanatomy, neurochemistry, cognitive function, and pharmacology of schizotypal personality disorder is reviewed with citation of the most recent findings from our laboratory and others. Both schizotypal and schizophrenic subjects appear to show abnormalities in temporal lobe volume, but schizotypal subjects do not appear to show the volumetric decreases in frontal cortex that schizophrenic patients evidence. Abnormalities in thalamic nuclei parallel these findings-the pulvinar, which projects to temporal association and sensory cortices, is reduced in both disorders, but the mediodorsal nucleus, which projects extensively to the frontal cortex, is reduced in schizophrenic patients but not in schizotypal patients. Functional imaging studies suggest that there may be abnormalities in frontal activation in both disorders, but that schizotypal individuals can recruit alternative regions to accomplish tasks requiring frontal lobe activation that may help compensate. Imaging studies of the subcortex including FDG/PET imaging of metabolic activity during a verbal learning task, SPECT imaging studies which measure binding of IBZM and its displacement following amphetamine administration, and plasma HVA determinations following 2-deoxyglucose administration all suggest the possibility of relatively reduced dopaminergic subcortical activity in schizotypal individuals compared to schizophrenic patients. Cognitive function is also impaired in the areas of working memory, verbal learning, and attention in schizotypal patients, as in schizophrenic patients, and they may be particularly susceptible to cognitive tasks with high context dependence, as in schizophrenia. Preliminary trials of catecholaminergic agents suggest that these agents may be able to improve these impaired cognitive functions.     

Evidence for decreased DARPP-32 in the prefrontal cortex of patients with schizophrenia

BACKGROUND: The neurotransmitters dopamine and glutamate have been implicated in the prefrontal dysfunction associated with schizophrenic illness. Studies suggest that the D1 subclass of dopamine receptor and the N-methyl-D-aspartate subclass of glutamate receptor are involved in this prefrontal dysfunction. These 2 receptors regulate, in opposing directions, the amount of phosphorylated activated DARPP-32, a potent inhibitor of protein phosphatase 1 that modulates the activity of several classes of receptors and ion channels. Thus, DARPP-32 occupies a key regulatory position, and may play an important role in the pathophysiological changes in dopamine and glutamate function reported in patients with schizophrenia. METHODS: The amounts of DARPP-32, synapsin I, and the alpha subunit of calcium/calmodulin-dependent protein kinase II were measured by immunoblotting in postmortem samples from 14 schizophrenic subjects and their age-, gender-, and autolysis time-matched control subjects. Possible confounding influences of neuroleptic treatment were analyzed by comparing subjects with Alzheimer disease who were and were not treated with neuroleptic agents. RESULTS: DARPP-32 was significantly reduced in the dorsolateral prefrontal cortex in more schizophrenic subjects relative to matched controls. The ratios of 2 other synaptic phosphoproteins, synapsin I and the alpha subunit of calcium/calmodulin-dependent protein kinase II, did not differ between schizophrenic and control subjects, nor between subjects with Alzheimer disease who were and were not treated with neuroleptic agents. CONCLUSIONS: Our findings are consistent with a selective reduction in DARPP-32 levels in schizophrenic subjects. This may be involved in the prefrontal dysfunction associated with schizophrenia.     

The sequestration of [3H]spiperone by lymphocytes in schizophrenics and their first-degree relatives: a limited vulnerability marker?

The sequestration of [3H]spiperone by lymphocytes was studied in preserved cells obtained from 22 schizophrenic subjects and 40 of their relatives, and the results were compared with those obtained from 25 healthy control subjects. Mean displaceable sequestration values, obtained from measurements made at a single radioligand concentration (1nM) which optimised the relative contribution of "high affinity" sequestration, were found to be similar for all groups of subjects. Furthermore, displaceable spiperone sequestration was abnormally high in only a small proportion of the schizophrenics (13.6%) and their relatives (5%). There was no evidence that either exposure to neuroleptic medication or duration of illness had an effect on sequestration values. The results suggest that, at least until the required experimental conditions are better established, [3H]spiperone sequestration by lymphocytes does not offer a useful vulnerability marker for schizophrenia.     

Cellular immunity in schizophrenic patients before and during neuroleptic treatment.

A possible connection between immunological alterations and schizophrenia has been discussed for many years. We studied 55 schizophrenic patients in an acute stage of illness before they began neuroleptic treatment. 35 patients who showed clinical improvement on neuroleptics, and 51 healthy controls. Our interest was focused on parameters of cellular immunity. We found an increased lymphocyte response to stimulation with pokeweed mitogen (PWM) and phytohemagglutinin (PHA) in patients before neuroleptic therapy and also an increased response to stimulation with PWM and PHA during treatment compared to controls. Stimulation with antigens generally showed a lower lymphocyte response in patients than in controls, but the difference was only significant after stimulation with tuberculin before neuroleptic treatment and after stimulation with varidase, diphteria-toxoid, tuberculin, vaccinia, and rubella during neuroleptic treatment. The number of CD3+ and CD4+ cells, but not the number of CD8+ cells, was increased before and during treatment in comparison to controls. Suppressor-cell activity was reduced in three different suppressor cell assays before and during neuroleptic medication compared to controls. We therefore conclude that alterations of the immunological system which are, as has been demonstrated, not due to treatment with neuroleptics might play a role in schizophrenia.