Positive Schizophrenic Symptoms Research Articles

Phencyclidine (PCP): A Dangerous Drug, but Useful in Schizophrenia Research

Phencyclidine (PCP) is a dangerous drug, and the federal government has placed it on Schedule II of the Controlled Substance Act (see http://www.mninter.net/∼publish/csa2.htm#Schedule%20III). Typically, users smoke PCP, and it is often mixed with parsley, marijuana, or cocaine. Most researchers have conducted experiments on animals rather than on people, and a few have been done on persons diagnosed with schizophrenia, so answers to questions about its addictive potential or development of tolerance are not clear. In healthy volunteers, PCP can induce symptoms that mimic those of schizophrenia, lasting from a few days to more than a week. The neurotransmitter glutamate and N-methyl-D-aspartate (NMDA) appear to play a role in the mechanism by which PCP induces positive and negative schizophrenic symptoms and cognitive defects (D. C. Javitt & S. R. Zukin, 1991; A. Lahti, B. Koffel, D. LaPorte, & C. A. Tarnminga, 1995; T. W. Robbins, 1990). Because PCP can induce symptoms that are almost indistinguishable from those associated with schizophrenia, further research may lead to new medications that could be helpful to people who do not respond to neuroleptics that are currently available.

In vivo extrastriatal and striatal D2 dopamine receptor blockade by amisulpride in schizophrenia.

Amisulpride, a substituted benzamide with high affinity for dopamine D2 and D3 receptors only, has been reported to have therapeutic effects on both negative and positive schizophrenic symptoms, although at distinct dose ranges (50-300 mg/day vs. 400-1,200 mg/day). The purpose of this study was to investigate the binding of amisulpride to extrastriatal (i.e., thalamus and temporal cortex) and striatal D2 dopamine receptors with respect to plasma amisulpride determinations. Ten patients with schizophrenia treated with amisulpride over a wide range of doses (25-1,200 mg/day) were studied. Positron emission tomography images were acquired by using 76Br-FLB-457, a highly specific antagonist of the D2 and D3 dopamine receptors. Binding indexes (BI) in the regions studied were estimated with reference to values from six healthy subjects. A curvilinear relationship was demonstrated between plasma concentration of amisulpride and the BI in extrastriatal regions. The BI also varied as a function of plasma concentration in striatum. Furthermore, the data provide evidence for different binding profiles: low plasma concentrations (28-92 ng/mL) induced marked extrastriatal binding and low striatal binding, whereas higher plasma concentrations (>153 ng/mL) induced marked binding both in extrastriatal and striatal regions. Dose-dependent differential binding profiles of amisulpride to D2 receptors in extrastriatal and striatal regions were demonstrated, and two therapeutic ranges of plasma concentrations for negative and positive schizophrenic symptoms, respectively, are suggested.

Latent inhibition, but not prepulse inhibition, is reduced during withdrawal from an escalating dosage schedule of amphetamine.

The enhanced locomotor and stereotypic responses of the rat to repeated amphetamine (AMPH) administration are considered to be an animal model of positive schizophrenic symptoms. In contrast, behaviors observed during withdrawal from repeated AMPH are believed to model depression or anxiety. In the present study, the authors tested whether AMPH withdrawal might also elicit behaviors consistent with animal models of schizophrenia, specifically, disruptions in latent inhibition (LI) of 2-way active avoidance and prepulse inhibition (PPI) of startle. Rats treated with escalating doses of AMPH (6 days, 1-5 mg/kg ip) or saline were tested for LI and PPI during withdrawal. LI was eliminated by prior AMPH treatment in rats tested at 4, 13, and 28 days of withdrawal. In contrast, PPI did not differ between AMPH and control groups. These results support an interrelationship between repeated-AMPH and LI-disruption, but not PPI-disruption, models of schizophrenia.

Neurotoxicity of NMDA antagonists: a glutamatergic theory of schizophrenia based on selective impairment of local inhibitory feedback circuits

Modulation of recurrent inhibition is critical not only for the normal function of highly excitable regions of the brain, especially the limbic system, but may also be a primary determining factor for the viability of neurons in these regions. Standard extracellular and intracellular recordings from in vitro brain slices of rat hippocampi were employed to show that recurrent inhibition onto CA1 neurons can be modulated by N-methyl-D-aspartate (NMDA) antagonists. Besides reducing the amplitude of inhibitory postsynaptic potentials (IPSPs) at resting membrane potential conditions, different NMDA antagonists, including the endogenous substance N-acetyl-L-aspartyl-L-glutamic acid (NAAG), are able to block long-term potentiation (LIP) of recurrent inhibition completely at concentrations that are not sufficient to block LTP of the excitatory drive onto pyramidal neurons. This LTP of recurrent inhibition may play a significant role in stimulus discrimination and learning, as simulated in a biophysical computer model of a basic neuronal circuit. Both the amplitude of the IPSP and LTP of the recurrent inhibitory circuit also undergo developmental changes showing their highest expression and vulnerability to chronic NMDA antagonist injections in juvenile rats. Finally, blocking NMDA receptor-dependent transmission in the recurrent inhibition loop may lead to an overall increased excitability of the neuronal network. This may resemble the positive schizophrenic symptoms observed in man, presumably caused by elevated levels of the endogenous NMDA antagonist NAAG.

Risperidone is associated with blunting of D-fenfluramine evoked serotonergic responses in schizophrenia

The high 5-HT affinity of some atypical antipsychotic agents is thought to contribute to their clinical efficacy. We examined central 5-HT responses in two groups of ten schizophrenic patients by measuring serum prolactin and cortisol responses to the neuroendocrine challenge D-fenfluramine. One group of patients with schizophrenia was tested after a 2-week neuroleptic free period. A similar group were tested after a mean of 12 weeks treatment with the atypical antipsychotic risperidone. A significant elevation of baseline serum prolactin levels, consistent with dopaminergic antagonism was seen after risperidone treatment. Significantly reduced 5-HT mediated serum prolactin responses were seen in risperidone treated patients. D-fenfluramine evoked serum prolactin responses were positively correlated with positive but not negative schizophrenic symptoms for all 20 patients. Risperidone treatment was associated with a significant functional in-vivo 5-HT antagonism similar to clozapine. 5-HT antagonism may contribute to the efficacy of risperidone against positive schizophrenic symptoms.

Cortical and hippocampal EEG power spectra in animal models of schizophrenia produced with methamphetamine, cocaine, and phencyclidine.

Cortical and hippocampal EEGs in animal models of schizophrenia were compared to those obtained with psychotomimetics or antipsychotic agents by utilizing power spectral analysis. Models of positive schizophrenic symptoms were created with methamphetamine (MAP) and cocaine, and a model of both negative and positive symptoms was created with PCP. MAP caused a prolonged decrease in the cortical EEG power spectra, cocaine caused a marked decrease for a short time, and PCP produced no significant changes. In the hippocampal spectra, MAP induced a marked increase in the T2(6.0-7.9 Hz)/ T1(4.0-5.9 Hz) ratio, PCP caused a decrease of this ratio after an initial increase, and cocaine produced no significant change. (An increase in the T2/T1 ratio represents a shift of theta waves to higher frequencies.) Since apomorphine (a DA agonist) and MK-801 (an NMDA antagonist) caused the T2/T1 ratio to increase, positive schizophrenic symptoms caused by MAP may be related to the DA and NMDA systems. 3-PPP (a sigma agonist) caused biphasic changes similar to those induced by PCP. Haloperidol and chlorpromazine caused a decrease of the T2/T1 ratio. These results indicate that cortical and hippocampal EEG power spectra (especially the hippocampal T2/T1 ratio) can be used to characterize both qualitatively and quantitatively models of schizophrenia.

The Glutamate Hypothesis of Schizophrenia

The glutamate hypothesis of schizophrenia has been developed based on the observation that psychotic symptoms induced by phencyclidine and related agents, which are antagonists at the N-methyl-D-aspartate (NMDA) glutamate receptor, closely resemble both the positive and negative symptoms of schizophrenia. In contrast to the dopamine hypothesis, which explains primarily with positive schizophrenic symptoms, the glutamate hypothesis may provide a more comprehensive view of the illness.

Symptom stability in geriatric chronic schizophrenic inpatients: A one-year follow-up study

The results of previous studies of symptom stability in schizophrenia suggest that negative symptoms manifest traitlike characteristics while positive symptoms fluctuate over time. Various prospective studies of chronic schizophrenic patients have found consistent results, regardless of the follow-up period, yet there is little research addressing symptomatology in geriatric schizophrenic patients. Since these patients have a very poor outcome and more severe negative symptoms, their symptoms might differ from younger patients. This study examined the course of symptomatology in 178 geriatric schizophrenic inpatients who were assessed twice at a 1-year interval with the Positive and Negative Syndrome Scale (PANSS). Intraclass correlations revealed that the distribution of negative symptoms was considerably more stable than that of positive symptoms over the interval, and subtypes based on negative symptoms were the only ones that manifested consistent stability over time. There was also a significant increase in negative symptom severity for the sample, with a slight decrease in positive symptom severity. Thus, even in chronic inpatients, with a very extended illness, positive symptom severity is not particularly stable within patients. These data indicate that the characteristics of negative and positive schizophrenic symptoms are similar in younger and geriatric schizophrenic patients, suggesting a continuity of the illness process. Tentative evidence for increasing severity of negative symptoms over a brief follow-up period suggests the possibility of a steady worsening of clinical state in very elderly patients who remained hospitalized.

The Nithsdale Schizophrenia Surveys

A population of adult schizophrenic patients was assessed to discover how the patients viewed their childhood, whether their view differed from non-schizophrenic adults, and to determine any association between parental rearing practices as perceived by the patient, childhood personality as perceived by the mother, and current symptoms. Type and level of expressed emotion shown by parents towards patients was also examined. Parental attitudes, as perceived by 50 schizophrenic patients, were assessed by the EMBU scale. Patients' premorbid personality and social adjustment were assessed through interviews with patients' mothers by the Scale for the Assessment of Premorbid Schizoid and Schizotypal Traits and the Premorbid Social Adjustment Scale. Current symptoms were assessed by the Positive and Negative Syndrome Scale and Subjective Deficit Syndrome Scale. Patients saw little difference between fathers' and mothers' attitudes. There was a positive correlation between parental rejection and overprotection, and a negative correlation between rejection and warmth. There were no significant correlations between parental rearing attitudes and patients' childhood personality; there was a significant correlation between parental attitudes and current symptoms. Rejection and overprotection were associated with more severe, warmth with less severe symptoms, especially so for positive schizophrenic symptoms and general psychopathology. Although there was no association between the general level of expressed emotion shown by the parent towards the adult patient, and patients' perceived parental rearing attitudes, parents with high expressed emotion on the basis of hostility had higher rejection scores on the parental rearing attitudes scale. Schizophrenic patients saw their parents as showing much less warmth, and the severity of currents symptoms was associated with perceived parental rearing attitudes. The hostility component of high expressed emotion may be a parental trait which exists before the illness begins.

Negative symptoms in schizophrenia: considerations for clinical trials. Working group on negative symptoms in schizophrenia.

There is little agreement about the methodology of clinical trials of antipsychotic drugs in patients with negative symptoms. A literature review revealed wide variation in experimental design, rating scales and study duration. This reflects differing views as to the definition and response to treatment of negative symptoms. Some degree of standardization would improve comparability of studies and aid the development of new compounds. Patients included in such studies should have displayed negative symptoms for at least 6 months. Depressive symptoms, positive schizophrenic symptoms and extrapyramidal signs may all influence or be confused with negative symptoms and may respond to treatment; they should be at a low level at baseline and should be measured during the study period. Studies should last at least 8 weeks. Several scales are available for measuring negative symptoms and are reviewed; a global impression score should be used additionally.

Schizophrenic symptoms: A theory based on a neurophysiological model

Under normal conditions, just a few mental subunits are simultaneously at a conscious level according to a previously presented model. The present paper explains how a somewhat increased number of simultaneously appearing subunits can cause the positive schizophrenic symptoms (thought disturbances, hallucinations, etc). Negative schizophrenic symptoms can develop when too few mental subunits are appearing at a time. Neuroleptic drugs are proposed to act by reducing the number of simultaneously appearing subunits.

Manodepressive disorders: A theory based on a neurophysiological model

In a previously presented model, a column in the cerebral cortex has activity at two separate levels. A few columns are under normal conditions at the high level of activity at a time while the rest are kept at the low level. The effects of changes in the number of columns that are at the high level of activity simultaneously have been dealt with in previous papers. It has been concluded that a somewhat increased number results in positive schizophrenic symptoms, and that too few can give negative schizophrenic symptoms. In the present paper, the effects of changes in a second parameter are discussed. This parameter is the length of time during which a cerebral column is at the high level of activity. It is explained how too short duration causes the manic phase in manodepressive disorders, and too long duration the depressive phase.

Placebo-Controlled, Double-Blind Study of the Effects of Proglumide in the Treatment of Schizophrenia

A double-blind, placebo-controlled, randomized study was performed to determine whether proglumide added to ongoing neuroleptic medication was efficacious in the treatment of 32 patients with persistent positive and negative schizophrenic symptoms. Patients treated with both proglumide and placebo showed a significant improvement over the 8 weeks of the study, but no significant difference between the patients taking proglumide and those taking placebo could be demonstrated. In addition, proglumide had no effect on plasma homovanillic acid concentrations or neuroleptic drug activity. The results suggest that, at least for the dose of proglumide used in this study (15 mg/day), the addition of this particular cholecystokinin antagonist does not potentiate the antipsychotic efficacy of neuroleptic medication in patients with persistent schizophrenic symptoms.

Bromocriptine in Augmentation of Antipsychotic Response in Chronic Schizophrenia: A Negative Pilot Report

To further assess the usefulness of bromocriptine in treatment of schizophrenia seven inpatient chronic schizophrenics with acute exacerbation who had failed to respond to four weeks of antipsychotic therapy were treated with bromocriptine 2.5 mg daily for a treatment duration varying from one dose to four weeks while their antipsychotic dose was continued unchanged. Mean age of patients was 38.9 +/- 11.6 years and mean number of prior psychiatric hospitalizations was 12.0 +/- 7.2. Patients were rated with the Brief Psychiatric Rating Scale prior to the first bromocriptine dose, at 24 hours after dosage initiation, and at weekly intervals. One patient showed clinically significant improvement in both positive and negative schizophrenic symptoms. One patient showed slight improvement in unusual thought content, and four patients were clinically unchanged. One patient significantly worsened after the first dose. Factors possibly contributing to response and non-response are discussed. This is a report of an open study in 7 patients. It is the only report of bromocriptine treatment in patients previously shown unresponsive to antipsychotics and whose antipsychotics dose was held constant throughout the study. Addition of bromocriptine to the antipsychotic regimen remains an unproven treatment approach which may be considered only in patients refractory to or inadequately controlled with antipsychotics.

Savoxepine: invalidation of an “atypical” neuroleptic response pattern predicted by animal models in an open clinical trial with schizophrenic patients

The new tetracyclic compound savoxepine exhibits potent antidopaminergic effects with preferential activity in the hippocampus as compared to striatum in rat brain. As a result of behavioural animal models and regional differences in dopamine receptor binding characteristics, it has been suggested to possess an "atypical" neuroleptic response pattern. In an open clinical trial, savoxepine was administered to 12 in-patients suffering from paranoid schizophrenia and schizophreniform disorder (DSM-III). Eight patients were treated with a stable dose of 0.5 mg per day throughout the study, while in the remaining patients higher doses up to 20 mg/day were administered. Mean total BPRS scores and subscores demonstrated a moderate improvement of mainly positive schizophrenic symptoms. In contrast to animal test results, savoxepine in a broad dose range produced typical untoward extrapyramidal symptoms in the majority of patients. Our results indicate that savoxepine may not possess the expected "atypical" neuroleptic response pattern, and that the predictive validity of the animal models in question used to separate antipsychotic effects from extrapyramidal reactions may be ill-founded.

Hypofrontality and cognitive impairment in schizophrenia: Dynamic single-photon tomography and neuropsychological assessment of schizophrenic brain function

Regional cerebral blood flow (rCBF) was assessed in 40 chronic male schizophrenic patients (20 medicated, 20 unmedicated) and 31 matched normal controls with Dynamic Single-photon Emission Computed Tomography (D-SPECT). Blind analyses of normalized color-coded tomograms revealed significant bifrontal and bitemporal rCBF deficits in the patient group. Frontal flow deficits were most prominent in paranoid patients ( n=21) and right temporal deficits were most prominent in nonparanoid patients ( n=19). These relative regional declines were observed within the context of significantly elevated hemispheric blood flow in schizophrenics compared with controls. Reduced left frontal rCBF was associated with neuropsychological impairment on the Wisconsin Card Sorting Test and Luria-Nebraska Battery. Increased hemispheric CBF was correlated with the presence of positive schizophrenic symptoms. Medication status was unrelated to rCBF. These findings demonstrate that hypofrontality has important implications for cognitive function in some schizophrenic individuals.

Multivariate analysis of monoamine indices in patients with chronic schizophrenia

Levels of dopamine (DA), dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), noradrenaline (NA), 5-hydroxyindoleacetic acid (5-HIAA) in cerebrospinal fluid and serum levels of prolactin (PRL) and dopamine-beta-hydroxylase (DBH) were measured in 42 chronic schizophrenic inpatients grouped according to their scores on the Brief Psychiatric Rating Scale (BPRS) and the Abnormal Involuntary Movement Scale (AIMS). Factor analysis was carried out on various combinations of variables. In patients with tardive dyskinesia (TD), cerebrospinal fluid DA, DOPAC, HVA, NA, and serum DBH were distributed into three factors; in patients without TD, these substances were assembled in only one factor. Cerebrospinal fluid DA, DOPAC, and HVA were dispersed in two factors in patients with severe positive symptoms versus one factor in subjects with mild productive signs. Factor structures diverged only when the variables listed above were included in the analysis. These findings support the hypothesis that both the dopaminergic and the noradrenergic system contribute to TD and that positive schizophrenic symptoms are associated with dopaminergic dysregulation.

3H-spiperone binding sites in post-mortem brains from schizophrenic patients: Relationship to neuroleptic drug treatment, abnormal movements, and positive symptoms

In post-mortem putamen samples from 27 schizophrenics and 27 controls D2 receptors were measured by Scatchard analysis using 3H-spiperone as a ligand. Maximum number of binding sites (Bmax) and apparent dissociation constant (KD) were significantly increased only in patients in whom neuroleptic medication had been given within a three-month period before death. When the neuroleptic medication had been withdrawn at least 3 month before death, there was a slight, but not significant, reduction in Bmax values and unchanged KD values. Withdrawal of neuroleptic drugs was followed by a normalization of the KD values within 2 weeks and a slower reduction of Bmax values. There were 6 schizophrenic patients with mainly positive schizophrenic symptoms and 17 patients with mainly negative symptoms; positive schizophrenic symptoms were not related to higher Bmax values. There was no difference in 3H-spiperone binding between patients with and without movement disorders (tardive dyskinesia or extrapyramidal symptoms).

Pathology, Phenomenology and the Dopamine Hypothesis of Schizophrenia

The dopamine hypothesis of schizophrenia implies that positive schizophrenic symptoms should be understandable by reference to brain structures receiving a dopamine innervation, or in terms of the functional role of dopamine itself. The basal ganglia, ventral striatum, septo-hippocampal system, and prefrontal cortex, sites of mesotelencephalic dopamine innervation, are examined and it is argued that their dysfunction could form the basis of particular schizophrenic symptom classes. The postulated involvement of dopamine in reinforcement processes might further assist such interpretations. This type of analysis can be extended to other categories of schizophrenic psychopathology.

CSF dopamine turnover and positive schizophrenic symptoms after withdrawal of long-term neuroleptic treatment

Dopamine (DA), dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA) were measured in cerebrospinal fluid (CSF) of 14 schizophrenic inpatients before and 2 weeks after withdrawal of long-term neuroleptic medication. Total neuroleptic-like activity (NLA) in serum was determined at the same times. DA and its metabolites (DOPAC and HVA) were significantly reduced after neuroleptic discontinuation. NLA was substantially diminished. The decrease in DA and DOPAC was positively correlated with positive symptoms of postwithdrawal deterioration, and low prewithdrawal DOPAC level predicted severe relapse. These results are compatible with the hypothesis linking an overregulated central DA system to the positive symptoms of schizophrenia.