Increased brain serotonin turnover in panic disorder patients in the absence of a panic attack: reduction by a selective serotonin reuptake inhibitor

Since the brain neurotransmitter changes characterising panic disorder remain uncertain, we quantified brain noradrenaline and serotonin turnover in patients with panic disorder, in the absence of a panic attack. Thirty-four untreated patients with panic disorder and 24 matched healthy volunteers were studied. A novel method utilising internal jugular venous sampling, with thermodilution measurement of jugular blood flow, was used to directly quantify brain monoamine turnover, by measuring the overflow of noradrenaline and serotonin metabolites from the brain. Radiographic depiction of brain venous sinuses allowed differential venous sampling from cortical and subcortical regions. The relation of brain serotonin turnover to serotonin transporter genotype and panic disorder severity were evaluated, and the influence of an SSRI drug, citalopram, on serotonin turnover investigated. Brain noradrenaline turnover in panic disorder patients was similar to that in healthy subjects. In contrast, brain serotonin turnover, estimated from jugular venous overflow of the metabolite, 5-hydroxyindole acetic acid, was increased approximately 4-fold in subcortical brain regions and in the cerebral cortex (P < 0.01). Serotonin turnover was highest in patients with the most severe disease, was unrelated to serotonin transporter genotype, and was reduced by citalopram (P < 0.01). Normal brain noradrenaline turnover in panic disorder patients argues against primary importance of the locus coeruleus in this condition. The marked increase in serotonin turnover, in the absence of a panic attack, possibly represents an important underlying neurotransmitter substrate for the disorder, although this point remains uncertain. Support for this interpretation comes from the direct relationship which existed between serotonin turnover and illness severity, and the finding that SSRI administration reduced serotonin turnover. Serotonin transporter genotyping suggested that increased whole brain serotonin turnover most likely derived not from impaired serotonin reuptake, but from increased firing in serotonergic midbrain raphe neurons projecting to both subcortical brain regions and the cerebral cortex.     

Loyalty and Creativity in a Disciplinary Organization

The relationship between loyalty to rules and the creativity that attempts to improve those same rules was examined among Norwegian army officers deployed in international operations. Today's army officers are faced with rapidly changing work conditions and unpredictable enemies, both of which challenge and outdate rules and routines. They thus may experience that they are either guided by too few or inadequate rules, or by many rules that need to be constantly updated. Assuming that following rules is advantageous to officers, then, contrary to classical theory, it was hypothesized that officers scoring both low and high on loyalty to rules would score high on creativity. Hierarchical regression analyses revealed a significant U‐shaped relationship between loyalty to rules and creativity.     

EFFECTS OF POINT‐LOSS PUNISHERS ON HUMAN SIGNAL‐DETECTION PERFORMANCE

Three experiments using human participants varied the distribution of point‐gain reinforcers or point‐loss punishers in two‐alternative signal‐detection procedures. Experiment 1 varied the distribution of point‐gain reinforcers for correct responses (Group A) and point‐loss punishers for errors (Group B) across conditions. Response bias varied systematically as a function of the relative reinforcer or punisher frequencies. Experiment 2 arranged two conditions — one where an unequal ratio of reinforcement (5:1 or 1:5) was presented without punishment (R‐only), and another where the same reinforcer ratio was presented with an equal distribution of point‐loss punishers (R+P). Response bias was significantly greater in the R‐only condition than the R+P condition, supporting a subtractive model of punishment. Experiment 3 varied the distribution of point‐gain reinforcers for correct responses across four unequal reinforcer ratios (5:1, 2:1, 1:2, 1:5) both without (R‐only) and with (R+P) an equal distribution of point‐loss punishers for errors. Response bias varied systematically with changes in relative reinforcer frequency for both R‐only and R+P conditions, with 5 out of 8 participants showing increases in sensitivity estimates from R‐only to R+P conditions. Overall, the results indicated that punishers have similar but opposite effects to reinforcers in detection procedures and that combined reinforcer and punisher effects might be better modeled by a subtractive punishment model than an additive punishment model, consistent with research using concurrent‐schedule choice procedures.     

Determining risk in pediatric research with no prospect of direct benefit: time for a national consensus on the interpretation of federal regulations

United States federal regulations for pediatric research with no prospect of direct benefit restrict institutional review board (IRB) approval to procedures presenting: 1) no more than "minimal risk" ( section sign 45CFR46.404); or 2) no more than a "minor increase over minimal risk" if the research is commensurate with the subjects' previous or expected experiences and intended to gain vitally important information about the child's disorder or condition ( section sign 45CFR46.406) (DHHS 2001). During the 25 years since their adoption, these regulations have helped IRBs balance subject protections with the pursuit of scientific knowledge to advance children's welfare. At the same time, inconsistency in IRB application of these regulations to pediatric protocols has been widespread, in part because of the ambiguity of the regulatory language. During the past decade, three federally-charged committees have addressed these ambiguities: 1) the National Human Research Protections Advisory Committee (NHRPAC) (Washington, DC), 2) the Institute of Medicine (IOM) Committee on the Ethical Conduct of Clinical Research Involving Children (Washington, DC); and 3) the United States Department of Health and Human Services Secretary's Advisory Committee for Human Research Protections (SACHRP) (Washington, DC). The committees have reached similar conclusions on interpretation of language within regulations section sign section sign 45CFR46.404 and 406; these conclusions are remarkably consistent with recent international recommendations and those of the original National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research (1977) report from which current regulations are based. Drawing on the committees' public reports, this article identifies the ethical issues posed by ambiguities in regulatory language, summarizes the committees' deliberations, and calls for a national consensus on recommended criteria.     

Positive and Negative Expectations of Hopelessness as Longitudinal Predictors of Depression,Suicidal Ideation,and Suicidal Behavior in High‐Risk Adolescents

The relationship between hopelessness and depression in predicting suicide‐related outcomes varies based on the anticipation of positive versus negative events. In this prospective study of adolescents at elevated risk for suicide, we used two Beck Hopelessness Scale subscales to assess the impact of positive and negative expectations in predicting depression, suicidal ideation, and suicidal behavior over a 2‐ to 4‐year period. In multivariate regressions controlling for depression, suicidal ideation, and negative‐expectation hopelessness, positive‐expectation hopelessness was the only significant predictor of depressive symptoms and suicidal behavior. Clinical interventions may benefit from bolstering positive expectations and building optimism.