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.     

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.     

Perspective-Taking Judgments of Medication Acceptance: Inferences from Relative Importance about the Impact and Combination of Information

Perspective-taking judgments of medication acceptance were studied for hypothetical mental health treatment scenarios. Three types of information were manipulated in all possible subsets: level of trust in the medication prescriber, severity of the hypothetical mental health condition being experienced, and the potential side effects of the medication. Subjects made judgments from four perspectives: self perspective and that of three other hypothetical people who were each said to place the most importance on one of the three cues. The results showed individual differences in self-reports of the relative importance of the cues which, in turn, predicted differences in judgment patterns. Subjects modified their cue use when making judgments from the perspectives of hypothetical others. The interaction patterns and rank orders of the perspective-taking judgments resembled the individual differences in judgments made from subjects’ own perspectives, but the perspective-taking judgments showed extreme effects of the most important cue. There was also some influence of subjects’ own perspectives on their perspective-taking judgments. When only a subset of the three cues was given, the judgment pattern depended on the importance of the cue that was omitted. The relative weight averaging model accounted for the judgments of only a minority of the subjects. Models which propose that subjects infer the value of missing information were also unsuccessful in explaining the data of the majority. Modifications of those models are proposed.     

Treatment of families in conflict: Recurrent themes in literature and clinical practice

This article undertakes to demonstrate, through works of great literature throughout the ages, that our best writers have always understood the primacy and linkages between individual growth, character and destiny, and the context of the various living systems that impinge upon each individual, the primary context being the family of origin. Beginning with the immortal classic, theSophoclean Trilogy, which inspired Freud's use of the major character's name in these three dramas, Oedipus has been used to explain the psychological complex which Freud regarded as universal. The author in this article finds a rather different point of view borne out by these same dramas, as well as in the other literary works cited. It is the discovery that the identified patient is not Oedipus, but his natural and adoptive families.This often-quoted classic in family therapy literature is slightly revised and reprinted, with permission, fromNew Directions in Mental Health, NY: Grune & Stratton, 1968.