Alan Breier

Anxiogenic properties of yohimbine. I. Behavioral, physiological and biochemical measures

SummaryThe anxiogenic effects of yohimbine, a specific alpha-2-receptor antagonist were examined by administering 20 mg yohimbine orally to 8 panic patients on placebo treatment, 7 panic patients on alprazolam treatment and 12 controls using a double-blind randomized design, instructions that minimized the expectancy of experiencing a panic attack and two additional structured situations. Yohimbine induced more pronounced increases in anxiety and panicky ratings, norepinephrine secretion, maximum heart rate and high heart rate variability and decreases in skin temperature in panic patients compared with controls. However, possibly owing to an instructional set and experimental, design that distracted patients from unpleasant bodily sensations no panic attacks were observed.

Temporal Discounting of Rewards in Patients With Bipolar Disorder and Schizophrenia

Patients with bipolar disorder (BD) and schizophrenia (SZ) often show decision-making deficits in everyday circumstances. A failure to appropriately weigh immediate versus future consequences of choices may contribute to these deficits. We used the delay discounting task in individuals with BD or SZ to investigate their temporal decision making. Twenty-two individuals with BD, 21 individuals with SZ, and 30 healthy individuals completed the delay discounting task along with neuropsychological measures of working memory and cognitive function. Both BD and SZ groups discounted delayed rewards more steeply than did the healthy group even after controlling for current substance use, age, gender, and employment. Hierarchical multiple regression analyses showed that discounting rate was associated with both diagnostic group and working memory or intelligence scores. In each group, working memory or intelligence scores negatively correlated with discounting rate. The results suggest that (a) both BD and SZ groups value smaller, immediate rewards more than larger, delayed rewards compared with the healthy group and (b) working memory or intelligence is related to temporal decision making in individuals with BD or SZ as well as in healthy individuals.

Metacognition, social cognition, and symptoms in patients with first episode and prolonged psychoses.

While it has been documented that persons with prolonged schizophrenia have deficits in metacognition and social cognition, it is less clear whether these difficulties are already present during a first episode. To explore this issue we assessed and compared metacognition using the Metacognition Assessment Scale-Abbreviated (MAS-A) and social cognition using the Eyes, Hinting and Bell-Lysaker Emotional Recognition Tests (BLERT) in participants with first episode psychosis (FEP; n=26), participants with a prolonged psychosis (n=72), and a psychiatric control group consisting of persons with a substance use disorder and no history of psychosis (n=14). Analyses revealed that both psychosis cohorts scored lower than controls on the MAS-A total and all subscales except metacognitive mastery. Compared to the FEP group, the persons with prolonged psychosis demonstrated greater metacognitive capacities only in those MAS-A domains reflective of the ability to understand the mental state of others and to see that others may have motivations and desires separate from their own. Other domains of metacognition did not differ between psychosis groups. The Eyes, Hinting and BLERT scores of the two psychosis groups did not differ but were poorer than those produced by the control group. Exploratory correlations in the FEP group showed a pattern similar to that previously observed in prolonged psychosis. Taken together, these findings suggest that while certain domains of metacognition could improve with prolonged psychosis, difficulties with global metacognition and social cognition may be stable features of the disorder and perhaps unique to psychosis.

Effects of Acute Metabolic Stress on Striatal Dopamine Release in Healthy Volunteers

Several lines of evidence indicate that a variety of metabolic stressors, including acute glucose deprivation are associated with dopamine release. Pharmacologic doses of the glucose analogue, 2-deoxyglucose (2DG) cause acute glucoprivation and are associated with enhanced dopamine turnover in preclinical studies. In this study, we utilized [11C]raclopride PET to examine 2DG-induced striatal dopamine release in healthy volunteers. Six healthy volunteers underwent PET scans involving assessment of 2DG-induced (40 mg/kg) decrements in striatal binding of the D2/D3 receptor radioligand [11C]raclopride. Decreases in [11C]raclopride specific binding reflect 2DG-induced changes in synaptic dopamine. Specific binding significantly decreased following 2DG administration, reflecting enhanced synaptic dopamine concentrations (p = .02). The administration of 2DG is associated with significant striatal dopamine release in healthy volunteers. Implications of these data for investigations of the role of stress in psychiatric disorders are discussed.

Disturbed resting state EEG synchronization in bipolar disorder: A graph-theoretic analysis.

Disruption of functional connectivity may be a key feature of bipolar disorder (BD) which reflects disturbances of synchronization and oscillations within brain networks. We investigated whether the resting electroencephalogram (EEG) in patients with BD showed altered synchronization or network properties. Resting-state EEG was recorded in 57 BD type-I patients and 87 healthy control subjects. Functional connectivity between pairs of EEG channels was measured using synchronization likelihood (SL) for 5 frequency bands (δ, θ, α, β, and γ). Graph-theoretic analysis was applied to SL over the electrode array to assess network properties. BD patients showed a decrease of mean synchronization in the alpha band, and the decreases were greatest in fronto-central and centro-parietal connections. In addition, the clustering coefficient and global efficiency were decreased in BD patients, whereas the characteristic path length increased. We also found that the normalized characteristic path length and small-worldness were significantly correlated with depression scores in BD patients. These results suggest that BD patients show impaired neural synchronization at rest and a disruption of resting-state functional connectivity.

Auditory Steady State Response in the Schizophrenia, First-Degree Relatives, and Schizotypal Personality Disorder

The power and phase synchronization of the auditory steady state response (ASSR) at 40 Hz stimulation is usually reduced in schizophrenia (SZ). The sensitivity of the 40 Hz ASSR to schizophrenia spectrum phenotypes, such as schizotypal personality disorder (SPD), or to familial risk has been less well characterized. We compared the ASSR of patients with SZ, persons with schizotypal personality disorder, first degree relatives of patients with SZ, and healthy control participants. ASSRs were obtained to 20, 30, 40 and 50 Hz click trains, and assessed using measures of power (mean trial power or MTP) and phase consistency (phase locking factor or PLF). The MTP to 40 Hz stimulation was reduced in relatives, and there was a trend for MTP reduction in SZ. The 40 Hz ASSR was not reduced in SPD participants. PLF did not differ among groups. These data suggest the 40 Hz ASSR is sensitive to familial risk factors associated with schizophrenia.

Computer-assisted cognitive remediation for schizophrenia: A randomized single-blind pilot study

Cognitive impairment is a core symptom in schizophrenia that has a significant impact on psychosocial function, but shows a weak response to pharmacological treatment. Consequently, a variety of cognitive remediation strategies have been evaluated to improve cognitive function in schizophrenia. The efficacy of computer-based cognitive remediation as a stand-alone intervention on general measures of neuropsychological function remains unclear. We tested the effectiveness of biweekly training using computerized cognitive remediation programs on neuropsychological and event-related potential outcome measures. Schizophrenia patients were randomly assigned to cognitive remediation training (N=17), active control (TV-watching; N=17), or treatment-as-usual (N=10) groups for ten weeks and run in parallel. Cognitive and ERP measures revealed no differential improvement over time in the cognitive remediation group. Practice effects might explain change over time on several cognitive measures for all groups, consistent with studies indicating task-specific improvement. Computer-assisted cognitive remediation alone may not be sufficient for robust or generalized effects on cognitive and electrophysiological measures in schizophrenia patients.

Effects of acute metabolic stress on the peripheral vasopressinergic system in schizophrenia

Although both vasopressin and stress have been implicated in the course of schizophrenia, it is unknown whether schizophrenic patients have altered stress-induced function of the vasopressinergic system. We examined the effects of acute metabolic stress induced by pharmacological doses (40 mg/kg) of 2-deoxyglucose (2DG) on plasma concentrations of vasopressin in 13 patients with schizophrenia (with no history of polydipsia and hyponatremia) and 12 healthy control subjects. Baseline vasopressin levels were lower in the schizophrenic patients and progressively increased in both groups throughout the 60 min following 2DG administration to a similar absolute amount, thus remaining lower in the schizophrenic group. Concomitantly, patients with schizophrenia had significantly higher 2DG-induced plasma homovanillic acid (HVA) and 5-hydroxyindoleacetic acid levels. Vasopressin responses correlated positively and significantly with the HVA responses in schizophrenics and with the pituitary-adrenal axis responses in controls. These results suggest two different patterns of neuroendocrine alterations in schizophrenia, namely a relatively normal vasopressin response to 2DG despite significantly decreased baseline levels and exaggerated responses of the peripheral dopaminegic and serotonergic systems in the face of normal baseline concentrations.

Inverse relationship between plasma epinephrine and testosterone levels during acute glucoprivation in healthy men

In healthy men, a decrease in plasma testosterone levels was observed in the context of metabolic stress. While physiological mechanisms underlying this response are unclear, there are several lines of evidence suggesting circulating epinephrines influence on plasma testosterone levels. The purpose of this study was to directly relate stress-induced changes in plasma testosterone and epinephrine. The stressor used was blockade of glucose metabolism with pharmacological doses (40 mg/kg) of 2 deoxyglucose (2DG). Arterial plasma samples from 10 healthy males were assayed at 20 minutes intervals for 60 minutes for the concentrations of testosterone, epinephrine and related biochemicals. Bolus administration of 2DG resulted in progressive decline in testosterone and increases in epinephrine and norepinephrine plasma levels (mean change from baseline: 29, 2530 and 186%, respectively). Inverse correlation was detected between both absolute (r(s)=-0.72; df=8; p=0.017) and baseline-corrected testosterone concentrations at the 60 minute time point and epinephrine area under the curve values. Our results suggest that adrenomedullary activation may be involved in stress-induced testosterone effects. The implications of these data for the understanding of the role of catecholamines in glucoprivic stress response are discussed.

A Phase II study of a histamine H3 receptor antagonist GSK239512 for cognitive impairment in stable schizophrenia subjects on antipsychotic therapy

This Phase II exploratory study assessed GSK239512, a brain penetrant histamine H₃ receptor antagonist, versus placebo on cognitive impairment in 50 stable outpatients with schizophrenia. Subjects were randomized to placebo or GSK239512 for 7 weeks (4 weeks titration). GSK239512 was associated with a small positive effect size (ES) on the CogState Schizophrenia Battery (CSSB) Composite Score (ES=0.29, CI=-0.40, 0.99) relative to placebo (primary endpoint). GSK239512s ES on CSSB domains were generally positive or neutral except Processing Speed, which favored placebo (ES=-0.46). Effects on the MATRICS Consensus Cognitive Battery were mostly neutral or favored placebo. GSK239512 was generally well tolerated with an adverse event profile consistent with the known class pharmacology. There was no evidence of overall beneficial effects of GSK239512 for CIAS in this population.