Ellen Cawthra

Codistribution of a sensory gating deficit and schizophrenia in multi-affected families

Because the clinical diagnosis of schizophrenia has not generally been an adequate phenotypic marker to detect the genes that convey risk for schizophrenia, efforts have been directed toward the identification of more elementary neuronal dysfunctions in schizophrenic patients and their families. Psychophysiological studies of sensory gating and selective attention suggest that defects in these brain functions are present in schizophrenic patients and some of their relatives. This study examines one of these defects in sensory gating, failure to suppress the P50 evoked response to repeated auditory stimuli. Six pedigrees, chosen because of the presence of large sibships containing several cases of schizophrenia, were studied. A mathematical model was developed to assess the familial association of the P50 defect with schizophrenia. The model preserves the quantitative nature of the data and is suitable for use in a sample with small numbers of pedigrees comprising many individuals. It is thus suitable for the evaluation of putative phenotypes in families to be studied by linkage analysis with polymorphic genetic markers. The results suggest that the P50 defect is familially associated with schizophrenia.

Auditory sensory gating, hippocampal volume, and catecholamine metabolism in schizophrenics and their siblings

Schizophrenia may result from the concerted action of several pathophysiological factors. This pilot study compared the distribution of measurements of three such putative factors in 11 schizophrenics and their siblings: a neurophysiological deficit in auditory sensory gating, diminished hippocampal volume, and increased catecholamine metabolism. Abnormal auditory sensory gating was found in all schizophrenics in the 11 families studied and in 8 of their 20 siblings. Compared with the schizophrenics, the clinically unaffected siblings with abnormal auditory gating had larger hippocampal volume. There was no similar difference for the siblings with normal gating. The siblings with abnormal auditory gating also had lower homovanillic acid levels than the other siblings. The data suggest that a familial neuronal deficit, identified by diminished sensory gating, may be a necessary, but not sufficient factor in the pathogenesis of schizophrenia. Individuals with this deficit are generally clinically unaffected, except for schizophrenics, who also have other abnormalities, such as diminished hippocampal volume and increased catecholamine metabolism.

Auditory P50 in Schizophrenics on Clozapine: Improved Gating Parallels Clinical Improvement and Changes in Plasma 3-Methoxy-4-Hydroxyphenylglycol

Schizophrenic patients have decreased inhibition of the P50 auditory evoked potential response to the second of two paired click stimuli delivered 500 ms apart. This deficit in inhibitory gating does not change during treatment with typical neuroleptics. We recently reported that neuroleptic-resistant schizophrenics had enhanced P50 gating after 1 month of clozapine treatment, if they responded with decreased clinical symptoms. This study reports the outcome of more prolonged treatment. Ten treatment-refractory schizophrenic patients were studied at baseline, after 1 month on clozapine, and again after 15 ± 6.1 (SD) months of clozapine treatment. Eight subjects reached a clinically stable improved state, at which time they had significantly improved P50 auditory gating. One patient had a return of impaired gating after stopping clozapine, as did another during a clinical relapse. Decreasing plasma 3-methoxy-4-hydroxyphenylglycol levels with clozapine treatment were correlated with improved P50 gating and improved Brief Bsychiatric Rating Scale-positive scores. This study provides further evidence that improved P50 gating in schizophrenic patients treated with clozapine coincides with clinical improvement and that this improvement can be sustained for at least 1 year.

Reversal of Diminished Inhibitory Sensory Gating in Cocaine Addicts by a Nicotinic Cholinergic Mechanism

Cocaine addiction, as with other stimulant abuse, produces psychotic symptoms. Although often moderate to mild in severity, these symptoms are, nevertheless, associated with poorer over-all outcome. Recent studies suggest diminished nicotinic cholinergic neurotransmission as a mechanism of a physiological deficit found in schizophrenia, failure of auditory sensory inhibition. Diminished inhibitory sensory gating also occurs in cocaine addicts, probably because of their increased catecholaminergic neurotransmission, which blocks the inhibition. In the present study, 11 cocaine addicts in the first week of detoxification were recorded electrophysiologically, after which the effects of 6 mg of nicotine gum, were assessed in a double-blind placebo-controlled crossover design. The test was repeated 10 days later. Treatment with nicotine, but not placebo, briefly reversed the inhibitory abnormality on both test days. Although nicotine itself may not be a desirable therapeutic agent, because desensitization of nicotinic receptors limits the time course of its effect, the study identifies a previously unexploited therapeutic target for new drug development for the neuropsychiatric sequelae of cocaine addiction.

Psychiatric hospitalization and veterans with traumatic brain injury: a retrospective study.

ObjectiveTo determine risk factors for psychiatric hospitalization after traumatic brain injury (TBI) in veterans. Subjects and proceduresMedical records of 96 veterans with histories of TBI (17 mild, 33 moderate, and 46 severe) were reviewed for information concerning psychiatric history, including hospitalization and substance misuse. ResultsSubjects with a history of problematic drug and alcohol use had a significantly higher probability of psychiatric hospitalization than those without such a history. Gender, age, problematic alcohol use without problematic drug use, injury severity, time since injury, years of follow-up, and a history of psychiatric symptoms (including those attributed to general medical conditions) were not identified as significant risk factors. Ninety-one veterans (95%) had a history of psychiatric difficulty. In addition, the probability of post-TBI problematic drug and alcohol use, given a pre-TBI history of such use, was significantly higher than the probability given no history. ConclusionsVeterans with problematic drug and alcohol use are at increased risk for psychiatric hospitalization after TBI. In addition, the likelihood of problematic post-TBI drug and alcohol use was significantly greater for those with a preinjury history. Ninety-five percent of veterans in the current sample endorsed lifetime histories of psychiatric difficulty. These findings highlight the need for evidence-based means of psychiatric and/or substance abuse treatment of those with a history of TBI.

114. Ondansetron improves P50 auditory sensory gating in medicated schizophrenic patients

P50 auditory sensory gating is impaired in schizophrenic patients. A schizophrenic patient does not show a decrease in the amplitude of the P50 waveform of the auditory evoked potential to the second of two closely paired click stimuli. In contrast, a normal control has a greatly decreased amplitude of the P50 waveform to the second stimulus. Expressed as a percentage (amplitude to the 2 stimulus/amplitude to the first stimulus 3 100), the P50 ratio is significantly higher in schizophrenic patients. This genetic deficit in inhibitory neuronal processing is mediated by the alpha-7 nicotinic receptor, which is rapidly desensitizing to nicotine. Nicotine briefly ameliorates this deficit in schizophrenic patients, but the effect is usually lost after one hour. Clozapine treatment, but not conventional antipsychotic medication, improves P50 auditory gating. We hypothesized that blockade of the 5HT3 receptor by clozapine may result in release of acetylcholine which then acts directly at the alpha-7 nicotinic receptor to enhance gating. To test this hypothesis, we gave 16 mg of oral ondansetron, a selective 5HT3 receptor antagonist, to 7 stable medicated schizophrenic outpatients in a double-blind placebo design. On two different days, the same subject had baseline auditory evoked responses recorded followed by either oral ondansetron or placebo. ERPs were recorded hourly for the next three hours. Ondansetron, but not placebo, resulted in a significant decrease in P50 ratio in these patients (Repeated measures ANOVA: F 5 21.44, d.f. 5 1, 12, p 5 0.001) that lasted significantly longer than nicotine treatment. These results support a possible role of 5HT3 antagonism in enhancing P50 gating by atypical antipsychotics.