Effects of typical, atypical, and no antipsychotic drugs on visual contrast detection in schizophrenia

OBJECTIVE: Visual contrast detection has been reported in some studies to be normal in schizophrenia patients, but in other studies impairments have been reported. Because contrast detection in the visual processing system is mediated by dopamine, and because the pharmacotherapy of schizophrenia involves blocking dopamine postsynaptic receptor sites, the authors investigated the effects of dopamine-blocking antipsychotic drugs on visual contrast detection in schizophrenia. METHOD: Visual contrast detection thresholds were measured in healthy subjects and schizophrenia patients receiving typical and atypical antipsychotic drugs; a two-alternative, forced-choice psychophysical method was used. Also included were six patients receiving no antipsychotic treatment as well as clinically unaffected first-degree relatives of the schizophrenia patients. RESULTS: Patients receiving atypical antipsychotic drugs showed unimpaired visual contrast detection, those given typical antipsychotic drugs exhibited higher visual contrast detection thresholds, and the unmedicated schizophrenic patients showed visual contrast detection thresholds significantly below those of healthy subjects. CONCLUSIONS: Dopamine modulation via D(2) receptor blockade affects sensory processes in schizophrenia, shifting visual contrast detection from hypersensitivity in the unmedicated state to normal and even to hyposensitive levels. Thus, antipsychotic drug treatment may account for the inconsistent reports concerning visual contrast detection in schizophrenia.     

Neural response to experimental heat pain in stable patients with schizophrenia

Diminished pain sensitivity in schizophrenia has been reported in clinical studies. While the role of antipsychotic medications as a cause of the decrease in pain perception has been questioned, little is known about neural pain processing in treated schizophrenia patients. The aim of this pilot study was to examine the blood oxygen level-dependent (BOLD) changes induced by an experimental pain tolerance (endure) hot stimuli vs. non-painful stimuli in clinically stable patients with schizophrenia and in healthy controls. Twelve patients with schizophrenia, treated with risperidone and considered clinically stable, and 13 gender- and age-matched healthy controls were studied using painful and non-painful thermal stimuli in a periodic block design. BOLD changes were assessed using high field, 3?T functional Magnetic Resonance Imaging (fMRI). Pain tolerance in stable patients was not statistically different than healthy controls. Interestingly, patients showed higher activation in the primary somatosensory cortex (S1) and superior prefrontal cortex, and less activation in the posterior cingulate cortex and brainstem than controls. Our pilot study indicates that pain tolerance is similar in clinically stable patients and controls, although the neural processing of pain is not normalized with antipsychotic treatment.     

Effects of antipsychotic treatment on membrane phospholipid metabolism in schizophrenia

Summary. Several studies have shown an increased membrane phospholipid turnover in brain and blood cells of schizophrenic patients. However the specificity of these findings for schizophrenia and the effects of longterm antipsychotic treatment had yet to be demonstrated. In the present study we measured the concentrations of phospholipids in platelet membranes from 67 neuroleptic-free schizophrenic patients compared to both healthy and psychiatric controls, followed by repeated measurements during a 6 months antipsychotic treatment period. At baseline, levels of the main phospholipid components phosphatidylcholine (PC) and phosphatidylethanolamine (PE) were decreased and lysophosphatidylcholine (LPC), a major breakdown product of phospholipid metabolism, was increased in schizophrenic patients compared to healthy and to psychiatric controls, suggesting a specificity of the findings for schizophrenia. During the first 3-weeks on antipsychotic drug treatment LPC levels decreased to control values, but increased again during the following 6 months, reaching significantly higher levels than controls at the end of this period. Thus, at least in peripheral cells an increased breakdown of phospholipids in schizophrenia appears to be present during the acute episode, being influenced only by initial antipsychotic treatment, but without evidence of a long lasting treatment effect on membrane metabolism. Received October 10, 2000; accepted March 13, 2001     

Influence of gender and hemispheric lateralization on heat pain perception in major depression

Increased incidence of clinical pain complaints from patients with major depression, as well as increased experimental pain thresholds have been reported. The basis of this phenomenon remains unclear, as well as its relation to medication, clinical recovery, gender and lateralization of hemispheric function. We aimed to further elucidate heat pain perception in depression applying a testing battery including assessment (on both arms) of warmth perception, heat pain perception and heat pain tolerance, and the jaw opening reflex (duration of ES2 component) as a putative indicator of descending pain inhibition. The battery was applied to 20 patients and 20 age- and sex-matched controls. Patients were assessed: on admission (acutely depressed, off-medication), few days after admission (depressed, on medication), and after clinical recovery (mostly on medication), and controls at corresponding intervals. Significant elevated heat pain thresholds were found off and on medication in the acute stage (mainly in women) and after recovery on the right arm only. Elevated heat pain tolerance (on the right arm only) was seen in medicated patients in the acute and recovered stage. Significant prolongation of ES2 duration was only found in acutely depressed patients off medication. While confirming hypalgesia to heat pain in major depression, our findings demonstrate a close relation to gender and strong influence of lateralization after recovery. Altered pain processing at brain stem level might only partially be responsible for the observed finding.     

Veränderte Wahrnehmung zeitlicher Relationen bei schizophrenen Psychosen

Basic perceptual skills involving the central nervous system require the orderly temporal integration of internal as well as external information. Current research in schizophrenia increasingly centers on the accompanying neurocognitive deficits. In association with schizophrenic psychoses, there have been frequent reports of altered temporal processes, but explicit research on the perception of temporal relationship is still rare. Using concrete operationalized neuropsychological procedures, the present pilot study addressed the question whether schizophrenic patients (n = 27) differ from a healthy control group (n = 18) concerning their ability to judge correctly the temporal order of visual stimuli. We found a significant impairment in basal temporal perception among patients. Moderating variables such as antipsychotic medication, attention deficits, or motivation effects did not appear to be essential explanatory factors for this finding. Thus, our findings indicate a fundamental disturbance in the temporal coordination of neuronal network functions in association with schizophrenic psychoses and are in line with neurophysiological, neuroanatomical, and neuropsychological overlappings of schizophrenia and temporal perception.     

Bcl-2 associated with positive symptoms of schizophrenic patients in an acute phase

B cell lymphoma protein-2 (Bcl-2) may contribute to the pathophysiology of schizophrenia in the brain. The aim of this study was to investigate the serum levels of Bcl-2 in schizophrenic patients in an acute phase, and evaluate Bcl-2 level changes after antipsychotic treatment. We consecutively enrolled 41 schizophrenia patients in an acute phase; 28 were followed up with a 4-week antipsychotic treatment. Serum Bcl-2 levels were measured with assay kits. All patients were evaluated by examining the correlation between Bcl-2 levels and Positive and Negative Syndrome Scale (PANSS) scores, using Pearson correlation coefficients. In schizophrenic patients in an acute phase, positive PANSS subscores were significantly negatively correlated with Bcl-2 levels. In addition, we found Bcl-2 levels had a significantly negative correlation with PANSS total scores and positive subscores in male patients in an acute phase. Using the paired t-test, we found no significant changes in Bcl-2 levels in schizophrenia patients who had received the 4-week treatment with antipsychotic drugs (n=28). In conclusion, our results suggest that Bcl-2 might be an indicator of schizophrenia severity in the acute phase. In addition, Bcl-2 levels might be associated with positive symptoms in male patients with schizophrenia.     

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 (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.     

Monocytic, Th1 and th2 cytokine alterations in the pathophysiology of schizophrenia

A growing body of evidence suggests that changes in the serum levels and cellular production of various cytokines are associated with the immunological abnormalities of schizophrenia. Several studies have examined alterations in T helper type 1 (Th1) and T helper type 2 (Th2) cytokines in schizophrenia. We explored monocytic, Th1 and Th2 cytokines in 43 schizophrenia patients and 50 normal controls. The mitogen-induced production of tumor necrosis factor alpha (TNF-alpha), interleukin 6 (IL-6), IL-4, gamma-interferon (IFN-gamma) and IL-2 was measured with enzyme-linked immunosorbent assays before and after antipsychotic treatment. IL-6 and TNF-alpha production by schizophrenic patients was significantly higher than by normal controls, while IL-2, IL-4 and IFN-gamma production was significantly lower in schizophrenic patients. After 6 weeks of antipsychotic treatment, IL-6 and TNF-alpha production was significantly decreased, while IL-4, IFN-gamma and IL-2 productions were not significantly changed. Our results suggest that increased monocytic cytokines and decreased Th1 and Th2 cytokines may be associated with the immunopathogenesis of acute psychotic schizophrenia, and that antipsychotics may play an important role in immune response by decreasing elevated monocytic cytokines.     

Similarities in age differences in heat pain perception and thermal sensitivity

Age differences in the thresholds for heat pain, warmth and cold were studied in 64 healthy persons from 17 to 63 years of age (32 women, 32 men). The stimuli were applied to the thenar and the dorsum pedis with a contact thermode. The thresholds increased significantly with age in all modalities on the foot, but not on the hand. Furthermore, the quotients of the individual foot and hand thresholds revealed a significant relative increase in all thresholds on the foot. The length of the afferent pathways seems to influence the degree of age-related changes both in heat pain perception and in thermal sensitivity, resulting in a distal-proximal pattern of age-dependent decline.     

Pain sensitivity in major depression and its relationship to central serotoninergic function as reflected by the neuroendocrine response to clomipramine

Several studies reported a decreased pain sensitivity in patients with depression, but the underlying neurobiological mechanisms of this phenomenon are unclear. While there is extensive evidence that the serotoninergic system plays a key role in pain modulation, especially in pain inhibitory mechanisms via descending pathways, as well as in the pathophysiology of depression, no study so far has examined its potential relevance in mediating the alteration of pain processing. The present study addresses the question of whether indices of serotoninergic dysfunction, as investigated by a neuroendrocine challenge paradigm, are related to pain sensitivity. Nineteen drug-free inpatients with unipolar major depression underwent a neuroendocrine challenge test by measuring cortisol and prolactin in response to intravenously administered clomipramine (12.5 mg). Heat/cold pain thresholds, warmth/cold detection thresholds, measures of current pain complaints and mood were assessed the day before and three day after challenge procedure. When patients were classified in subgroups based on a median split of their cortisol response values, the low-responsive group showed significantly elevated heat pain thresholds and nearly significantly elevated cold pain thresholds compared to the high-responsive group. No such group differences were found with regard to somatosensory thresholds, measures of pain complaints and mood. Subgrouping on the basis of prolactin responsiveness did not reveal significant differences in any parameter. In summary, a decreased pain sensitivity was demonstrated in patients characterized by a reduced neuroendocrine responsiveness to clomipramine, suggesting an involvement of serotoninergic dysfunction underlying altered pain perception in depression.     

Tactile Perception in Adults with Autism: a Multidimensional Psychophysical Study

Although sensory problems, including unusual tactile sensitivity, are heavily associated with autism, there is a dearth of rigorous psychophysical research. We compared tactile sensation in adults with autism to controls on the palm and forearm, the latter innervated by low-threshold unmyelinated afferents subserving a social/affiliative submodality of somatosensation. At both sites, the groups displayed similar thresholds for detecting light touch and innocuous sensations of warmth and cool, and provided similar hedonic ratings of the pleasantness of textures. In contrast, increased sensitivity to vibration was seen in the autism group on the forearm, along with increased sensitivity to thermal pain at both sites. These findings suggest normal perception along with certain areas of enhanced perception in autism, consistent with previous studies.     

Depression in patients with schizophrenia during an acute psychotic episode.

There is disagreement about whether depressive symptoms in schizophrenia are part of the basic disease process, or whether they represent adverse effects of treatment with antipsychotic medications. In a sample of initially antipsychotic drug-free acutely hospitalized patients with schizophrenia (N = 104), we measured change in depressive symptoms after 4 weeks of treatment. We also examined the relationship of changes in depressive symptoms to changes in positive and negative schizophrenic symptoms. Depressive symptoms improved after 4 weeks of antipsychotic medication treatment, and their improvement corresponded with improvement in both positive and negative schizophrenic symptoms. These results suggest that depressive symptoms in schizophrenia are related to the disease process itself, at least during acute exacerbations of schizophrenia. Depressive symptoms may be responsive to antipsychotic medications directly or as a secondary response to improvement in positive and negative symptoms.     

Higher levels of serum copper in schizophrenic patients treated with depot neuroleptics

The findings of previous research on the status of trace elements in patients with schizophrenia have been controversial. We studied 62 outpatients with a DSM-IV diagnosis of schizophrenia, and compared them with sex- and age-matched healthy controls. Serum copper levels were significantly higher in schizophrenic patients (mean 117.4 microg/dl; S.D. 23.4) than in healthy controls (105.6+/-27.9). Those patients on treatment with depot neuroleptics had higher copper levels. Zinc levels did not differ between patients and healthy controls. Altered levels of trace elements in schizophrenic patients may be a consequence of antipsychotic treatment.     

Abnormal expression of epidermal growth factor and its receptor in the forebrain and serum of schizophrenic patients

Epidermal growth factor (EGF) comprises a structurally related family of proteins containing heparin-binding EGF-like growth factor (HB-EGF) and transforming growth factor alpha (TGFalpha) that regulates the development of dopaminergic neurons as well as monoamine metabolism. We assessed the contribution of EGF to schizophrenia by measuring EGF family protein levels in postmortem brains and in fresh serum of schizophrenic patients and control subjects. EGF protein levels were decreased in the prefrontal cortex and striatum of schizophrenic patients, whereas the levels of HB-EGF and TGFalpha were not significantly different in any of the regions examined. Conversely, EGF receptor expression was elevated in the prefrontal cortex. Serum EGF levels were markedly reduced in schizophrenic patients, even in young, drug-free patients. Chronic treatment of animals with the antipsychotic drug haloperidol had no influence on EGF levels in the brain or serum. These findings suggest that there is abnormal EGF production in various central and peripheral tissues of patients with both acute and chronic schizophrenia. EGF might thus provide a molecular substrate for the pathologic manifestation of the illness, although additional studies are required to determine a potential link between impaired EGF signaling and the pathology/etiology of schizophrenia.     

Effect of antipsychotic medication on speed of information processing in schizophrenic patients

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.     

Elevated plasma superoxide dismutase in first-episode and drug naive patients with schizophrenia: inverse association with positive symptoms

Excessive free radical production or oxidative stress may be involved in the pathophysiology of schizophrenia as evidenced by increased superoxide dismutase (SOD) activities, a critical enzyme in the detoxification of superoxide radicals. This study compared plasma SOD activities in 78 never-medicated first-episode and 100 medicated chronic schizophrenia patients to 100 healthy control subjects and correlated these SOD activities with the Positive and Negative Syndrome Scale (PANSS) among the schizophrenic patients. We found that both first-episode and chronic patients had significantly increased plasma SOD activities compared to controls, and that chronic schizophrenic patients on antipsychotic medication had significantly higher SOD activities than first episode schizophrenic patients. Plasma SOD activities were also negatively correlated with positive symptoms of schizophrenia, but only in first-episode patients. Thus, oxidative stress appears to be greater in first episode schizophrenic patients with fewer positive symptoms and may become greater as schizophrenia becomes more chronic, although we cannot exclude the possibility that chronic antipsychotic treatment may increase SOD activities and presumed oxidative stress in schizophrenia.     

Human and animal studies of schizophrenia-related gating deficits

Prepulse Inhibition (PPI) of the startle response and the P50 auditory-evoked potential suppression are used to assess impairments in the regulation of the neural substrates and to determine the clinical significance of inhibitory deficits in schizophrenia. The study of gating deficits in schizophrenia and in related animal model studies have already advanced our understanding of the neural substrates of information processing abnormalities in patients with schizophrenia. Individuals with schizotypal personality disorder as well as clinically unaffected family members of patients with schizophrenia show PPI and P50 suppression deficits. These "schizophrenic spectrum" populations are not grossly psychotic, nor are they receiving antipsychotic medications. Therefore, the gating deficits are presumed to reflect core (eg, intermediate phenotypic) schizophrenialinked information processing abnormalities. Several studies have reported that gating deficits are associated with clinical ratings of psychiatric symptoms, thought disorder, and neuropsychologic deficits in patients with schizophrenia. In addition, recent human pharmacologic studies have indicated that gating deficits can be reversed by rationallyselected compounds. Animal model studies have generally shown convergence with the human studies and may lead to improved identification of efficacious new antipsychotic medications for patients with schizophrenia.     

Decreased serotonin2A receptors in Brodmann’s area 9 from schizophrenic subjects

There have been repeated reports of a decrease in serotonin_2A receptors in the frontal cortex from subjects with schizophrenia. Similarly, in rats treated with antipsychotic drugs, it has been shown that many antipsychotic drugs decrease cortical serotonin_2A receptors, an affect not seen with the antipsychotic drug haloperidol. We therefore compared the density of serotonin_2A receptors in frontals cortex from schizophrenic subjects treated with haloperidol, schizophrenic subjects treated with other antipsychotic drugs, and nonschizophrenic subjects. Independent of antipsychotic drug treatment, serotonin_2A receptors were decreased in the frontal cortex from schizophrenic subjects. Importantly, the density of serotonin_2A receptors was not different in schizophrenic subjects whether or not they had been treated with haloperidol. This study suggests that data obtained from treating rats with antipsychotic drugs cannot be simplistically extrapolated to studies on tissue obtained postmortem from schizophrenic subjects treated with the same drugs.     

Bipolar and schizophrenic patients differ in patterns of visual motion discrimination

BACKGROUND: Since Kraepelin's early distinction between bipolar disorder and schizophrenia, it has been assumed that these disorders represent two different pathophysiological processes, although they share many clinical symptoms. Previous studies showed that velocity discrimination, a sensitive psychophysiological measure of the visual motion system, is deficient in schizophrenia. Here we examined whether the motion processing impairment found in schizophrenia also occurs in bipolar disorder. METHODS: We compared 16 bipolar patients, 25 schizophrenic patients, and 25 normal controls on a velocity discrimination task. We measured the psychophysical threshold for velocity discrimination and contrast detection (as a control task) in all subjects. RESULTS: Bipolar patients showed normal velocity discrimination thresholds at intermediate velocities, the range in which velocity cues dominate velocity discrimination, and at low velocities. Schizophrenic patients, however, showed elevated velocity discrimination thresholds at intermediate and low velocities. At higher velocities, both bipolar and schizophrenic patients showed elevated thresholds. All subjects showed normal contrast detection thresholds. CONCLUSIONS: Normal velocity discrimination in the intermediate range of velocity indicates unimpaired motion processing in bipolar disorder. The abnormal velocity discrimination of both schizophrenic and bipolar patients at higher velocities may reflect impaired temporal processing rather than impaired motion processing per se. These results suggest that the pathophysiological processes of bipolar disorder and schizophrenia diverge at the stage of visual motion processing, a sensory component mediated primarily in the extrastriate cortex.     

Bipolar and schizophrenic patients differ in patterns of visual motion discrimination

BackgroundSince Kraepelin's early distinction between bipolar disorder and schizophrenia, it has been assumed that these disorders represent two different pathophysiological processes, although they share many clinical symptoms. Previous studies showed that velocity discrimination, a sensitive psychophysiological measure of the visual motion system, is deficient in schizophrenia. Here we examined whether the motion processing impairment found in schizophrenia also occurs in bipolar disorder.MethodsWe compared 16 bipolar patients, 25 schizophrenic patients, and 25 normal controls on a velocity discrimination task. We measured the psychophysical threshold for velocity discrimination and contrast detection (as a control task) in all subjects.ResultsBipolar patients showed normal velocity discrimination thresholds at intermediate velocities, the range in which velocity cues dominate velocity discrimination, and at low velocities. Schizophrenic patients, however, showed elevated velocity discrimination thresholds at intermediate and low velocities. At higher velocities, both bipolar and schizophrenic patients showed elevated thresholds. All subjects showed normal contrast detection thresholds.ConclusionsNormal velocity discrimination in the intermediate range of velocity indicates unimpaired motion processing in bipolar disorder. The abnormal velocity discrimination of both schizophrenic and bipolar patients at higher velocities may reflect impaired temporal processing rather than impaired motion processing per se. These results suggest that the pathophysiological processes of bipolar disorder and schizophrenia diverge at the stage of visual motion processing, a sensory component mediated primarily in the extrastriate cortex.