Varenicline and P50 auditory gating in medicated schizophrenic patients: a pilot study.

Most schizophrenic patients have a deficit in auditory sensory gating that appears to be mediated by the alpha-7 nicotinic receptor. This pilot study examines the effects of varenicline, an alpha-7 agonist, on the P50 auditory evoked potential in six schizophrenic patients. The study was canceled because of concerning side effects consistent with those reported by the FDA. However, in this small group of subjects, varenicline did not consistently enhance P50 auditory gating.

Sensitivity and specificity of the Beck Depression Inventory-II in persons with traumatic brain injury.

OBJECTIVES: Our objective was to examine the Beck Depression Inventory-II (BDI-II) in a traumatic brain injury (TBI) sample using a receiver operating characteristic (ROC) curve to determine how well the BDI-II identifies depression. An ROC curve allows for analysis of the sensitivity and specificity of a diagnostic test using various cutoff points to determine the number of true positives, true negatives, false positives, and false negatives. DESIGN: This was a secondary analysis of data gathered from an observational study. We examined BDI-II scores in a sample of 52 veterans with remote histories of TBI. SETTING: This study was completed at a Veterans Affairs (VA) Medical Center. PARTICIPANTS: Participants were veterans eligible to receive VA health care services. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Outcome measures included the BDI-II and the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-IV). RESULTS: We generated an ROC curve to determine how well the BDI-II identifies depression using the SCID-IV as the criterion standard for diagnosing depression, defined here as a diagnosis of major depressive disorder. Results indicated a cutoff score of at least 19 if one has a mild TBI or at least 35 if one has a moderate or severe TBI. These scores maximize sensitivity (87%) and specificity (79%). CONCLUSIONS: Clinicians working with persons with TBI can use the BDI-II to determine whether depressive symptoms warrant further assessment.

An exploratory study of neuroimaging, neurologic, and neuropsychological findings in veterans with traumatic brain injury and/or posttraumatic stress disorder.

Seventy-two veterans with traumatic brain injury (TBI), posttraumatic stress disorder (PTSD), or both participated in assessment procedures to evaluate between group differences. Half the sample was randomly selected for magnetic resonance imaging (MRI). Neurologic examinations were conducted using the Neurologic Rating Scale (NRS). Neuropsychological measures included the Paced Auditory Serial Addition Test (PASAT), Rey Auditory Verbal Learning Test (RAVLT), Conners' Continuous Performance Test II (CPT II), and Halstead Impairment Index (HII) including the Booklet Category Test (BCT). Data were analyzed using linear regression. Participants with moderate/ severe TBI were significantly more likely to have trauma-related imaging findings, and more severe TBI predicted lower scores on the NRS. No significant between-group differences were identified on the HII, PASAT, RAVLT, or CPT II. TBI group performance was significantly better on the BCT. More severe TBI predicted abnormal imaging findings and lower NRS scores. Hypothesized between-group differences on neuropsychological measures were not supported.

Utility of the trauma symptom inventory for the assessment of post-traumatic stress symptoms in veterans with a history of psychological trauma and/or brain injury.

Correspondence of three core Trauma Symptom Inventory (TSI) posttraumatic stress disorder (PTSD) scales (Intrusive Experiences, Defensive Avoidance, and Anxious Arousal) and the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-IV) PTSD module were examined among 72 veterans with traumatic brain injury (TBI), PTSD, or both conditions. Subjects were classified into PTSD only, TBI only, or co-occurring PTSD and TBI groups based on TBI assessment and SCID-IV PTSD diagnosis. Linear regression was used to model TSI T-Scores as a function of group. Scores on all three scales significantly differed between the TBI and PTSD groups (PTSD only and co-occurring PTSD and TBI) in the expected direction. Study findings indicate that despite the potential overlap of symptoms between PTSD and TBI, the TSI appears to be a useful measure of trauma-related symptoms in veterans who may also have a TBI, particularly mild TBI. Limitations and areas for future research are discussed.

Suicide among incarcerated veterans.

Both veterans and jail/prison inmates face an increased risk of suicide. The incarcerated veteran sits at the intersection of these two groups, yet little is known about this subpopulation, particularly its risk of suicide. A Pubmed/Medline/PsycINFO search anchored to incarcerated veteran suicide, veteran suicide, suicide in jails/prisons, and veterans incarcerated from 2000 to the present was performed. The currently available literature does not reveal the suicide risk of incarcerated veterans, nor does it enable meaningful estimates. However, striking similarities and overlapping characteristics link the data on veteran suicide, inmate suicide, and incarcerated veterans, suggesting that the veteran in jail or prison faces a level of suicide risk beyond that conferred by either veteran status or incarceration alone. There is a clear need for a better characterization of the incarcerated veteran population and the suicide rate faced by this group. Implications for clinical practice and future research are offered.

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

OBJECTIVE: To determine risk factors for psychiatric hospitalization after traumatic brain injury (TBI) in veterans. SUBJECTS AND PROCEDURES: Medical 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. RESULTS: Subjects 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. CONCLUSIONS: Veterans 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.

A review of "suicidal intent" within the existing suicide literature.

The results of a systematic literature review that investigated suicide intent are presented. Of the 44 relevant articles identified, 17 investigated the relationships between various suicide risk factors and suicide intent and 25 publications investigated the relationships between suicide intent and various suicide outcomes. Despite recent advancements in the definition and nomological validity of suicide intent, a high degree of variability in the empirical measurement and analysis of suicide intent was found. Such variability limits future research related to measuring suicidal risk and outcomes, reporting suicide intent, or the meaningful comparison of diagnostic approaches or treatments across multiple studies.

Proof-of-concept trial of an alpha7 nicotinic agonist in schizophrenia.

CONTEXT: The alpha7 nicotinic acetylcholine receptor gene, CHRNA7, is associated with genetic transmission of schizophrenia and related cognitive and neurophysiological sensory gating deficits. Cognitive dysfunction is responsible for significant psychosocial disability in schizophrenia. Nicotine, a low-potency agonist at the alpha7 receptor, has some positive effects on neurophysiological and neurocognitive deficits associated with schizophrenia, which suggests that more effective receptor activation might meaningfully enhance cognition in schizophrenia. OBJECTIVES: To determine if 3-[(2,4-dimethoxy)benzylidene]anabaseine (DMXB-A), a natural alkaloid derivative and a partial alpha7 nicotinic cholinergic agonist, significantly improves neurocognition, and to assess, by effects on P50 auditory evoked potential inhibition, whether its neurobiological actions are consistent with activation of alpha7 nicotinic receptors. DESIGN: Randomized, double-blind crossover trial of 2 drug doses and 1 placebo. SETTING: General clinical research center. PATIENTS: Twelve persons with schizophrenia who did not smoke and were concurrently treated with antipsychotic drugs. One person was withdrawn because of a transient decrease in white blood cell count. INTERVENTION: Administration of DMXB-A. MAIN OUTCOME MEASURES: Total scale score of the Repeatable Battery for the Assessment of Neuropsychological Status and P50 inhibitory gating. RESULTS: Significant neurocognitive improvement was found on the Repeatable Battery for the Assessment of Neuropsychological Status total scale score, particularly for the lower DMXB-A dose compared with placebo. Effects were greater than those of nicotine in a similar study. Significant improvement in P50 inhibition also occurred. Patients generally tolerated the drug well. CONCLUSIONS: An alpha7 nicotinic agonist appears to have positive effects on neurocognition in persons with schizophrenia. Longer trials are needed to determine the clinical utility of this novel treatment strategy.

Improved p50 auditory gating with ondansetron in medicated schizophrenia patients.

OBJECTIVE: Most schizophrenia patients have a deficit in auditory sensory gating, which appears to be mediated by the alpha-7 nicotinic receptor, that is not improved with conventional antipsychotic treatment. This study examined the effects of ondansetron, a highly selective 5-HT3 antagonist, on the P50 auditory evoked potential. METHOD: Eight medicated outpatients with schizophrenia were given either ondansetron (16 mg) or placebo in a double-blind, placebo-controlled design. Evoked potentials were recorded at baseline and 1 hour, 2 hours, and 3 hours after receipt of drug. RESULTS: There was a highly significant improvement in P50 gating after ondansetron treatment. The maximal treatment difference was at 2 hours posttreatment (ondansetron: mean=41.4%, SD=39.7%; placebo: mean=80.2%, SD=21.3%). CONCLUSIONS: Ondansetron significantly enhanced P50 auditory gating in schizophrenia patients treated with typical antipsychotics.

M50 sensory gating predicts negative symptoms in schizophrenia.

Impaired auditory sensory gating is considered characteristic of schizophrenia and a marker of the information processing deficit inherent to that disorder. Predominance of negative symptoms also reflects the degree of deficit in schizophrenia and is associated with poorer pre-morbid functioning, lower IQ, and poorer outcomes. However, a consistent relationship between auditory sensory gating and negative symptoms in schizophrenia has yet to be demonstrated. The absence of such a finding is surprising, since both impaired auditory gating and negative symptoms have been linked with impaired fronto-temporal cortical function. The present study measured auditory gating using the P50 event related potential (ERP) in a paired-click paradigm and capitalized on the relative localization advantage of magnetoencephalography (MEG) to assess auditory sensory gating in terms of the event related field (ERF) M50 source dipoles on bilateral superior temporal gyrus (STG). The primary hypothesis was that there would be a positive correlation between lateralized M50 auditory sensory gating measures and negative symptoms in patients with schizophrenia. A standard paired-click paradigm was used during simultaneous EEG and MEG data collection to determine S2/S1 sensory gating ratios in a group of 20 patients for both neuroimaging techniques. Participants were administered the Schedule for the Assessment of Negative Symptoms (SANS), the Positive and Negative Symptom Scale (PANSS), and the Calgary Depression Scale for Schizophrenia. Consistent with previous reports, there was no relationship between ERP P50 sensory gating and negative symptoms. However, right (not left) hemisphere ERF M50 sensory gating ratio was significantly and positively correlated with negative symptoms. This finding is compatible with information processing theories of negative symptoms and with more recent findings of fronto-temporal abnormality in patients with predominantly negative symptoms.

Association of promoter variants in the alpha7 nicotinic acetylcholine receptor subunit gene with an inhibitory deficit found in schizophrenia.

BACKGROUND: The alpha7 neuronal nicotinic acetylcholine receptor subunit gene (CHRNA7) has been implicated as a candidate gene for schizophrenia, and for an auditory sensory processing deficit found in the disease, by both genetic linkage at 15q14 and biochemical data. The expression of CHRNA7 is reduced in several brain regions in schizophrenic subjects compared with control subjects. This study presents DNA sequence analysis of the core promoter region for CHRNA7 in schizophrenic and control subjects. METHODS: Single-strand conformation polymorphism analysis and DNA sequencing were used for mutation screening of the core promoter in the CHRNA7 gene. The sample included subjects from 166 schizophrenic families and 165 controls. Controls had no evidence of current or past psychosis and had auditory evoked potentials recorded. RESULTS: Multiple polymorphic patterns were identified in the CHRNA7 core promoter in both schizophrenic and control subjects. Functional analysis of polymorphisms indicated that transcription was reduced. The prevalence of functional promoter variants was statistically greater in schizophrenic subjects than in the controls. Presence of an alpha7 promoter polymorphism in controls was associated with failure to inhibit the P50 auditory evoked potential response. CONCLUSIONS: Although linkage disequilibrium with other genetic alterations cannot be excluded, the CHRNA7 core promoter variants, found in this study, may contribute to a common pathophysiologic feature of schizophrenia.

Varied effects of atypical neuroleptics on P50 auditory gating in schizophrenia patients.

OBJECTIVE: Sensory gating deficits found in schizophrenia can be assessed by using a paired auditory stimulus paradigm to measure auditory evoked response. The ratio of the P50 response amplitude of the second or test stimulus to that of the first or conditioning stimulus is expressed as a percentage. Normal subjects generally suppress the second response and typically have ratios of less than 40%. Subjects with schizophrenia and half their first-degree relatives have deficits in sensory gating, with P50 ratios that are generally greater than 50%. Treatment with typical neuroleptics does not reverse this deficit. However, previous studies have shown that treatment with clozapine, an atypical neuroleptic, ameliorates this deficit in clinically responsive patients. This study sought to determine whether other atypical neuroleptics improve P50 ratios. METHOD: P50 evoked potential recordings were obtained from 132 patients with schizophrenia and 177 healthy comparison subjects. Eighty-eight patients were being treated with atypical neuroleptics (clozapine [N=26], olanzapine [N=31], risperidone [N=22], and quetiapine [N=9]). Thirty-four patients were taking typical neuroleptics, and 10 were unmedicated. RESULTS: Healthy subjects exhibited P50 suppression that was significantly better than the schizophrenia patients receiving typical neuroleptics (mean=19.8% [SD=21.0%] versus 110.1% [SD=87.9%]). Patients receiving atypical neuroleptics had a mean P50 ratio that fell between these two means (mean=70.4%, SD=53.7%). When patients treated with different atypical neuroleptics were compared, only the clozapine group had mean P50 ratios that were in the normal range. All other groups exhibited auditory P50 response inhibition that was significantly poorer than that of the healthy subjects. CONCLUSIONS: Improvement in P50 gating appears to be greatest in patients treated with clozapine.

Lateralization of auditory sensory gating and neuropsychological dysfunction in schizophrenia.

OBJECTIVE: Sensory gating assessed via EEG in a paired-click paradigm has often served as a neurophysiological metric of attentional function in schizophrenia. However, the standard EEG measure of sensory gating using the P50 component at electrode Cz does not foster differential assessment of left and right hemisphere contributions. Magnetoencephalography (MEG) is complementary to EEG, and its analogous M50 component may be better suited for localization and analysis of such lateralized cortical generators. The authors hypothesized that 1) auditory gating would be evident in M50 sources in superior temporal gyrus, demonstrating ratios similar to P50; 2) M50 would resemble P50 in distinguishing gating in comparison subjects and patients with schizophrenia, but M50 would show lateralization of the gating deficit; and 3) P50 and M50 sensory gating ratios would predict neuropsychological measures in patients and comparison subjects, with the MEG identification of left and right hemisphere sources allowing for the evaluation of lateralization in brain-behavior relationships. METHOD: Event-related EEG and MEG recordings were simultaneously obtained from 20 patients with schizophrenia and 15 comparison subjects. P50 amplitudes, M50 dipole source strengths, and P50 and M50 gating ratios were compared and assessed with respect to scores on neuropsychological performance measures. RESULTS: M50 dipoles localizing to superior temporal gyrus demonstrated gating similar to that of P50. As expected, patients demonstrated less P50 gating than did comparison subjects. Left (but not right) hemisphere M50 gating 1) correlated with EEG gating, 2) differentiated patients and comparison subjects, and 3) correlated with neuropsychological measures of sustained attention and working memory. CONCLUSIONS: Converging evidence from EEG, MEG, and neuropsychological measures points to left hemisphere dysfunction as strongly related to the well-established sensory gating deficit in schizophrenia.

Clozapine improves deficient inhibitory auditory processing in DBA/2 mice, via a nicotinic cholinergic mechanism.

RATIONALE: Insufficient inhibitory processing of the P50 auditory evoked potential (AEP) is observed in most schizophrenia patients and is not improved by typical antipsychotic drugs, such as haloperidol. This inhibitory processing deficit is associated with a subnormal level of hippocampal alpha7 nicotinic receptors (nAChRs), and drugs that activate these receptors normalize the deficit. The atypical antipsychotic clozapine also normalizes this deficit in schizophrenia patients, but by an unknown mechanism. OBJECTIVE: Similar to schizophrenia patients, DBA/2 mice spontaneously exhibit a deficit in inhibitory processing of the P20-N40 AEP, which is a rodent analogue of the human P50 AEP. The present study determined whether clozapine improved this deficit in DBA/2 mice, and by what mechanism. METHOD: Using a conditioning-testing paradigm with paired auditory stimuli to assess inhibitory P20-N40 AEP processing in DBA/2 mice, the effects of clozapine (0.1, 1, 3.33, or 10 mg/kg, i.p.) and haloperidol (1 mg/kg, i.p.) were assessed. The effect of clozapine (1 mg/kg) was assessed alone and after pre-administration of either alpha-bungarotoxin, an alpha7 nAChR antagonist, or dihydro-beta-erythroidine, an alpha4beta2 nAChR antagonist. RESULTS: In a dose-dependent manner, clozapine improved the deficient inhibitory processing of the P20-N40 AEP normally exhibited by DBA/2 mice. Like alpha7 agonists, 1 mg/kg clozapine selectively increased the inhibition of the P20-N40 response to the second of paired auditory stimuli. The normalizing effect of 1 mg/kg clozapine was blocked by alpha-bungarotoxin, but not by dihydro-beta-erythroidine. Haloperidol did not improve DBA/2's deficient P20-N40 AEP processing. CONCLUSIONS: Clozapine improved the deficient inhibitory processing of the P20-N40 AEP in DBA/2 mice, apparently through stimulation of alpha7 nicotinic receptors. This effect was not shared by the typical antipsychotic haloperidol.

Input dysfunction, schizotypy, and genetic models of schizophrenia.

Peter Venables proposed that an input dysfunction, which causes the brain to lose its ability to control the flood of sensory information into its higher level processing areas, might be an important pathophysiological mechanism in schizophrenia. The hypothesis was part of his general belief that even the most severe psychopathology arises from aberrations in normal brain psychophysiology. Neurobiological and genetic investigations based on his initial observations include the demonstration that diminished inhibition of the auditory-evoked response to repeated stimuli is a genetically determined deficit, linked to one of the chromosomal loci that is also responsible for the part of the genetically transmitted risk for schizophrenia. Increasing evidence that schizophrenia is a multigenetic illness prompts reconsideration of the nature of schizotypy. Individual genes that convey part of the risk for schizophrenia may be quite common in the general population and cause relatively subtle changes in psychophysiology. Thus, as predicted by Venables, the substrates of schizotypy and schizophrenia may arise from variants in normal brain function.

Increased hippocampal volume in schizophrenics' parents with ancestral history of schizophrenia.

OBJECTIVE: Decreased hippocampal volume is one of the hypothesized pathological features of schizophrenia, but it is not known if this abnormality is familially transmitted. The aim of this study was to measure the hippocampal volume of the parents of schizophrenic probands, in relationship to the apparent transmission of genetic risk. METHOD: Eighteen subjects from families consisting of a schizophrenic proband and two clinically unaffected parents were studied. Probands were compared to six control subjects, matched for age, sex, and educational level. The six families were selected so that only one parent had an ancestral family history of schizophrenia. The volumes of both hippocampi were measured by magnetic resonance imaging and adjusted for age and whole brain volume. RESULTS: The total hippocampal volumes of the parents with ancestral family history of schizophrenia were significantly larger than those of their schizophrenic offspring. CONCLUSIONS: This study suggests that decreased hippocampal volume in schizophrenia is not a familially transmitted abnormality. Rather, it appears that clinically unaffected parents who transmit apparent genetic risk for schizophrenia may have increased hippocampal volume, which may be a protective factor against the illness.

A 1-year open-label trial of olanzapine in school-age children with schizophrenia.

OBJECTIVE: To determine the response of children with childhood-onset schizophrenia to a 1-year prospective, open-label trial of olanzapine. METHODS: Twenty children (age range 6-15 years) with childhood-onset Diagnostic and Statistical Manual of Mental Disorders (fourth edition) schizophrenia participated. The treating clinician was free to vary or discontinue dosing and use additional medications. Symptoms were assessed by the Brief Psychiatric Rating Scale-Child version (BPRS-C), Scale for the Assessment of Positive Symptoms, and Scale for the Assessment of Negative Symptoms. Extrapyramidal symptoms, akathisia, temperature, and weight were monitored. RESULTS: BPRS-C subscales of thought disturbance and psychomotor excitation, and the Scale for the Assessment of Positive Symptoms demonstrated significant decreases by 6 weeks of treatment; BPRS-C anxiety and the Scale for the Assessment of Negative Symptoms (SANS) showed significant improvement after 1 year of treatment. Seventy-four percent of subjects were considered treatment responders, with a greater than 20% reduction in total BPRS-C score and overall impairment of mild or better. Weight gain (body mass index) was above that expected for normal development in every child. No child developed neuroleptic-related dyskinesias. Seventy-four percent (n = 14) of patients completed this 1-year, open-label trial. Of the 5 subjects who discontinued, weight gain was noted as the reason for 4 subjects. CONCLUSIONS: Olanzapine appears useful in the treatment of childhood-onset schizophrenia, although there may be a delayed onset of benefit for anxiety and negative symptoms. Weight gain is problematic, but the emergence of dyskinesias may be rare. Additional controlled trials are indicated.

Risk of death for veterans on release from prison.

We sought to determine, among veterans released from Washington state prisons from 1999 through 2003, the risk of death from all causes, whether those veterans have faced a higher risk of death than have nonveterans, and whether having VA benefits decreased the risk of death. We linked data from a retrospective cohort study to data from the Veterans Benefit Administration. Mortality rates were compared between veteran and nonveteran former inmates. The crude rate of veteran mortality was 1,195 per 100,000 person-years, significantly higher than that of nonveterans (p < .001), but adjustment for demographic factors demonstrated no significant increased risk. VA benefits were associated with a reduced risk for all-cause deaths (hazard ratio, .376; 95% confidence interval, 0.18-0.79). Veterans share the heightened risk of death after release from prison faced by all released inmates and should be included in efforts to reduce the risks associated with transitioning from prison to the community. VA benefits appear to offer a protective effect, particularly against medical deaths.

Neuropsychological test performance in soldiers with blast-related mild TBI.

This exploratory study was conducted to increase understanding of neuropsychological test performance in those with blast-related mild traumatic brain injury (mTBI). The two variables of interest for their impact on test performance were presence of mTBI symptoms and history of posttraumatic stress disorder (PTSD). Forty-five soldiers postblast mTBI, 27 with enduring mTBI symptoms and 18 without, completed a series of neuropsychological tests. Seventeen of the 45 met criteria for PTSD. The Paced Auditory Serial Addition Test (Frencham, Fox, & Mayberry, 2005; Spreen & Strauss, 1998) was the primary outcome measure. Two-sided, 2-sample t tests were used to compare scores between groups of interest. Presence of mTBI symptoms did not impact test performance. In addition, no significant differences between soldiers with and without PTSD were identified. Standard neuropsychological assessment may not increase understanding about impairment associated with mTBI symptoms. Further research in this area is indicated.

Inhibition of the P50 cerebral evoked response to repeated auditory stimuli: results from the Consortium on Genetics of Schizophrenia.

Inhibition of the P50 evoked electroencephalographic response to the second of paired auditory stimuli has been frequently examined as a neurophysiological deficit in schizophrenia. The Consortium on the Genetics of Schizophrenia (COGS), a 7-site study funded by the National Institute of Mental Health, examined this endophenotype in recordings from 181 probands with schizophrenia, 429 of their first degree relatives, and 333 community comparison control subjects. Most probands were treated with second generation antipsychotic medications. Highly significant differences in P50 inhibition, measured as either the ratio of amplitudes or their difference in response to the two stimuli, were found between the probands and the community comparison sample. There were no differences between the COGS sites for these findings. For the ratio parameter, an admixture analysis found that nearly 40% of the relatives demonstrated deficiencies in P50 inhibition that are comparable to the deficit found in the probands. These results indicate that P50 auditory evoked potentials can be recorded across multiple sites and reliably demonstrate a physiological abnormality in schizophrenia. The appearance of the physiological abnormality in a substantial proportion of clinically unaffected first degree relatives is consistent with the hypothesis that deficits in cerebral inhibition are a familial neurobiological risk factor for the illness.