ro-16-0154 and Schizophrenia

Several lines of evidence from post-mortem, brain imaging, and genetic studies in schizophrenia patients suggest that Gamma-amino butyric acid (GABA) deficits may contribute to the pathophysiology of schizophrenia. Pharmacological induction of a transient GABA-deficit state has been shown to enhance vulnerability of healthy subjects to the psychotomimetic effects of various drugs. Exacerbating or creating a GABA deficit was hypothesized to induce or unmask psychosis in schizophrenia patients, but not in healthy controls. To test this hypothesis, a transient GABA deficit was pharmacologically induced in schizophrenia patients and healthy controls using iomazenil, an antagonist and partial inverse agonist of the benzodiazepine receptor. In a double-blind, randomized, placebo-controlled study, clinically stable chronic schizophrenia patients (n=13) received iomazenil (3.7 μg administered intravenously over 10 min). Psychosis was measured using the Brief Psychiatric Rating Scale and perceptual alterations were measured using the Clinician Administered Dissociative Symptoms Scale before and after iomazenil administration. These data were compared with the effects of iomazenil in healthy subjects (n=20). Iomazenil produced increases in psychotic symptoms and perceptual alterations in schizophrenia patients, but not in healthy controls. The greater vulnerability of schizophrenia patients to the effects of iomazenil relative to controls provides further support for the GABA-deficit hypothesis of schizophrenia.

Topics: Adult; Analysis of Variance; Anxiety; Brief Psychiatric Rating Scale; Double-Blind Method; Flumazenil; Humans; Iodine Radioisotopes; Male; Middle Aged; Receptors, GABA; Schizophrenia

The role of the inhibitory neurotransmitter gamma aminobutyric acid (GABA) in schizophrenia has previously been investigated using postmortem material. Recently, using single photon emission tomography (SPET) with the selective benzodiazepine antagonist 123I-Iomazenil as the radioligand, we have demonstrated an in vivo relationship between reduced GABAA/benzodiazepine receptor binding and the severity of positive symptomatology in schizophrenia. The present study aimed to build on this using the same in vivo scanning techniques, and relating findings to cognitive functioning.. Ten nonpsychiatric control subjects and 15 schizophrenic patients, matched for age and handedness, were scanned. A battery of neuropsychologic tests was also administered.. Correlational analysis revealed a pattern of increased correlations between GABAA/benzodiazepine receptor binding and task performance, in the schizophrenic group compared to the control group.. Findings are preliminary but suggest a relationship between reduced GABAA/benzodiazepine receptor binding and poorer cognitive functioning, involving memory and visual attention processes, in the schizophrenic group but not in the control group. A role for GABA in the pathophysiology of schizophrenia is suggested. Limitations of the present study and suggestions for future research are discussed.

Topics: Adult; Cognition; Female; Flumazenil; Humans; Image Processing, Computer-Assisted; Iodine Radioisotopes; Male; Neuropsychological Tests; Psychiatric Status Rating Scales; Psychomotor Performance; Receptors, GABA-A; Schizophrenia; Schizophrenic Psychology; Tomography, Emission-Computed, Single-Photon

Deficits in gamma-amino-butyric acid (GABA) neurotransmitter systems have been implicated in the pathophysiology of schizophrenia for more than two decades. Previous postmortem and in vivo studies of benzodiazepine (BDZ) receptor density have reported alterations in several brain regions of schizophrenic patients. The goal of this study was to better characterize possible alterations of the in vivo regional distribution volume (VT) of BDZ receptors in schizoprenia, using the selective BDZ antagonist [123I]iomazenil and single photon emission computerized tomography (SPECT). Regional BDZ VT was measured under sustained radiotracer equilibrium conditions. The reproducibility and reliability of this measurement was established in four healthy volunteers. No differences in regional BDZ VT were observed between 16 male schizophrenic patients and 16 matched controls. No relationships were observed between BDZ VT and severity of psychotic symptoms in any of the regions examined. In conclusion, this study failed to identify alterations of BDZ receptors density in schizoprenia. If this illness is associated with deficits in GABA transmission, these deficits do not substantially involve BDZ receptor expression or regulation.

Topics: Adult; Flumazenil; Humans; Iodine Radioisotopes; Magnetic Resonance Imaging; Male; Middle Aged; Outcome Assessment, Health Care; Receptors, GABA-A; Schizophrenia; Tomography, Emission-Computed, Single-Photon

Deficient inhibitory neurotransmission of gamma-aminobutyric acid (GABA) has been implicated in the pathophysiology of schizophrenia based on postmortem studies. However, in vivo studies have shown predominantly negative or conflicting results. The goal of this study was to better characterize possible changes of the regional GABA(A)-benzodiazepine receptor distribution volume (BZR V3-p) in schizophrenia in vivo, using a larger sample size than previous studies. Single photon emission computed tomography (SPECT) with [123I]iomazenil was used with a constant infusion paradigm to measure the BZR V3-p under sustained radiotracer equilibrium conditions. Twenty-five patients with schizophrenia and 24 matched healthy control subjects were studied. Positive and Negative Syndrome Scale (PANSS) ratings were done in all subjects. Statistical parametric mapping (SPM) 96 was used to compare patients and control subjects as well as to study the relationship between SPECT results and composite PANSS scores based on two factorial models: the pentagonal model (positive, negative, dysphoric mood, activation, and autistic preoccupation factors) and the taxometric model (disorganized dimension). On the basis of 'absolute' values of V3-p with no normalization for total brain uptake, the schizophrenic patients showed no significant differences in BZR levels compared to the healthy control subjects. With a global normalization procedure, which is more sensitive to relative regional differences in activity, BZR V3-p was significantly decreased in the patients in the left precentral gyrus (BA 6). The relative BZR V3-p showed a significant positive correlation with duration of illness in the superior occipital gyri (BA 19). No significant correlations were observed between either absolute or relative BZR V3-p and either age or any of the composite PANSS scores based on any of the two factorial models in either patients or control subjects. No significant differences were observed between cigarette smoking vs. non-smoking patients, nor between the patients on atypical antipsychotics vs. on typical antipsychotics vs. not on any antipsychotics. In general, no significant differences in BZR V3-p were observed between patients and control subjects, except for a decrease in relative BZR V3-p in the left precentral gyrus. Grey matter atrophy is unlikely to be the cause for this decrease. However, we could not exclude that possibility. The positive correlation with duration of illness mi

Topics: Adult; Brain; Brain Mapping; Cerebral Cortex; Dominance, Cerebral; Female; Flumazenil; Frontal Lobe; Humans; Iodine Radioisotopes; Male; Middle Aged; Psychiatric Status Rating Scales; Receptors, GABA-A; Schizophrenia; Tomography, Emission-Computed, Single-Photon

Although there is evidence from postmortem studies suggestive of deficient inhibitory neurotransmission of gamma-aminobutyric acid (GABA) in schizophrenia, no direct in vivo evidence has been obtained to date. The authors used single photon emission computed tomography (SPECT) with iodine-123-labeled iomazenil ([123I]iomazenil), a radioligand that selectively binds with high affinity to the benzodiazepine subunit of the GABAA receptor complex in the human brain, to investigate the presence of benzodiazepine receptor abnormalities in the cerebral cortex of living subjects with schizophrenia.. Dynamic [123I]iomazenil SPECT was performed in 15 patients (14 patients with DSM-III-R schizophrenia and one with schizophreniform disorder) and 12 healthy subjects over a period of 2 hours. The time-integral method was used to generate ratios of "specific" to "nonspecific" [123I]iomazenil binding at equilibrium for several cortical regions.. No overall between-group differences in benzodiazepine receptor binding were found, but significant correlations emerged between the severity of schizophrenic symptoms and [123I]iomazenil binding in limbic cortical regions: positive symptom scores were negatively correlated with benzodiazepine receptor binding in the left medial temporal region, and negative symptoms were inversely related to receptor binding in the medial frontal region. These correlations were not significant when a Bonferroni correction for multiple comparisons was applied.. These preliminary results are consistent with previous research implicating limbic cortical regions in the pathophysiology of schizophrenia, suggesting that reduced inhibitory GABAergic tone in these areas may contribute to the appearance of schizophrenic symptoms.

Topics: Adolescent; Adult; Cerebral Cortex; Female; Flumazenil; Frontal Lobe; gamma-Aminobutyric Acid; Humans; Male; Psychiatric Status Rating Scales; Receptors, GABA-A; Schizophrenia; Schizophrenic Psychology; Severity of Illness Index; Temporal Lobe; Tomography, Emission-Computed, Single-Photon

Clinical studies indicate that patients with acute schizophrenia may benefit from benzodiazepine treatment. Therefore we investigated the benzodiazepine receptor distribution and diazepam binding in 20 patients with DSM-III schizophrenia using single photon emission computed tomography (SPECT) with iomazenil as the ligand. In each patient, two SPECT images were obtained: SPECT 1 was obtained 2 h after intravenous injection of 200 MBq I-123-iomazenil. Following SPECT 1, patients received 10 mg diazepam intravenously. Twenty min later, SPECT 2 was started. The highest iomazenil uptake was found in the occipital cortex followed by the frontal and temporal cortices. Baseline iomazenil uptake in the medial frontal cortex was significantly (P < 0.05) correlated with the BPRS total score (r = 0.46). Diazepam injection led to a significant activity decrease in iomazenil binding which was greatest in the frontal regions of interest. With respect to the medial frontal cortex, this effect was significantly (P < 0.05) more pronounced in patients with a remitting than a chronic course of the disorder. These findings suggest that changes of the benzodiazepine receptor system in the frontal cortex may be associated with severity and chronicity of schizophrenia.

Topics: Adult; Benzodiazepines; Binding Sites; Chronic Disease; Diazepam; Flumazenil; Frontal Lobe; Growth Hormone; Humans; Hydrocortisone; Occipital Lobe; Receptors, GABA-A; Schizophrenia; Temporal Lobe; Tomography, Emission-Computed, Single-Photon

Topics: Flumazenil; Frontal Lobe; gamma-Aminobutyric Acid; Humans; Magnetic Resonance Imaging; Prefrontal Cortex; Receptors, GABA-A; Schizophrenia; Schizophrenic Psychology; Severity of Illness Index; Tomography, Emission-Computed, Single-Photon