John A. Sweeney

Statistical issues in the identification of risk factors for suicidal behavior: The application of survival analysis

Studies of suicide risk factors generally examine suicidal behavior as a dichotomous outcome. Survival analytic techniques are discussed in which the time until a suicide attempt from a specific point, such as prior attempt or onset of illness, is also examined. These procedures can incorporate information on those lost to followup or censored. One survival analytic technique, Coxs proportional hazards model, is a particularly informative statistical technique for the study of suicidal risk factors because several covariates can be incorporated. Illustrative analyses estimate the significance of different risk factors, and demonstrate that there is a 32% increase in the relative risk of a suicide attempt associated with each prior attempt.

Beta adrenergic receptors and cyclic AMP levels in intact human lymphocytes: Effects of age and gender

A saturable, stereospecific high affinity beta 2 adrenergic receptor was demonstrated on intact human peripheral blood lymphocytes using the ligand [125I]-iodocyanopindolol ([125I]ICYP). A method is described for parallel measurements of saturation binding isotherms and isoproterenol-cAMP responsiveness in split samples of intact lymphocytes isolated from 40 ml. of whole blood. A significant positive correlation between beta receptor density (Bmax) and the ratio of maximal isoproterenol-generated cAMP to basal levels was found in healthy subjects (r = 0.65, p less than 0.001). A significant positive correlation was found between age and the fold increase over basal cAMP levels induced by isoproterenol. Older females had a significantly higher fold increase in cAMP levels after isoproterenol than older males. These effects were largely accounted for by the lower basal levels of cAMP in older subjects. Beta receptor binding indices (Bmax and KD) did not differ between males and females, or change with aging. The effects of age and sex upon cAMP levels appear to be at least partly mediated by mechanisms independent of the beta receptor. The method, which describes a convenient assay for parallel measurement of beta receptor binding and cAMP levels in small blood samples, represents a useful model for studying human beta receptor function.

Assessment of binding indices and physiological responsiveness of the 5-HT2 receptor on human platelets

This is the first report of parallel studies of binding indices and physiological responsiveness of the Serotonin-two (5-HT2) receptor on the human platelet membrane. Binding indices were measured by a microassay employing [125I]ILSD as radioligand and ketanserin to define specific binding. A single receptor population was found, characterized by a KD of 1.69 +/- 0.45 nM and Bmax of 14.5 +/- 6.0 pmol/g protein in healthy subjects. Functional responsiveness of the platelet 5-HT2 receptor complex was assessed by measurement of the extent to which serotonin (10uM) augmented platelet aggregation induced by threshold concentrations of adenosine diphosphate (ADP). A statistically significant positive correlation was found between the number of platelet 5-HT2 receptor sites (Bmax) and the magnitude of the serotonin-amplified aggregation response (r = .70, n = 38, p less than 0.001). Assessment of binding indices and physiological responsiveness of the platelet 5-HT2 receptor complex should facilitate study of age, hormonal, disease, and drug effects on 5-HT2 receptor function in human subjects.

Assessment of cognitive functioning in poly-substance abusers

Neuropsychological deficits of memory and spatial perception have been associated with substance abuse. The present study assessed the degree to which verbal abstraction is impaired in substance abusers because this function typically is reduced in diffuse cerebral disorders. Test scores of 100 consecutively admitted substance-abusing patients indicated that performance on the Similarities test of the WAIS was actually higher than Vocabulary scores. This finding was replicated with the WAIS-R on a second sample of 100 patients who demonstrated impaired memory and psychomotor speed. These findings indicated that verbal abstraction was unimpaired in two large samples of poly-substance abusers. Further, the superiority of Similarities over Vocabulary scores suggests that in poly-substance abusers, Similarities scores may be a better index of premorbid intellectual competence than the more typically used Vocabulary scores.

Neuroendocrine and behavioral responses to challenge with the indirect serotonin agonist dl-fenfluramine in adults with obsessive-compulsive disorder ☆

Neuroendocrine and behavioral responses to a single 60-mg oral dose of the indirect serotonin agonist dl-fenfluramine were assessed in unmedicated adults with obsessive-compulsive disorder (OCD) and neuroendocrine results contrasted with those in normal control subjects. Net fenfluramine-induced prolactin release did not differ significantly between OCD patients and normal controls. Prolactin responses in the OCD group were not significantly correlated with baseline Yale-Brown Obsessive Compulsive Scale scores for either obsessions or compulsions, but were positively correlated with the baseline Hamilton Depression Scale score and Hamilton Anxiety Scale score. No clear difference in the severity of patients obsessions or compulsions was found following challenge with fenfluramine versus placebo. Although the present study does not demonstrate a serotonergic abnormality in OCD, this may be more a reflection of limitations of the test procedures than evidence that central nervous system (CNS) serotonergic function is normal in the disorder.

Peripheral Blood Cell Biological Markers in Depression

The classical monoamine hypotheses of depressive illness have postulated a deficiency of norepinephrine and/or serotonin at functionally important receptors in the central nervous system (CNS).1,2 An alternative “receptor hypothesis” would explain reduced transmission by a deficiency in signal amplification by the receptor complex. This focus on the receptor gained impetus from studies showing that virtually all effective somatic antidepressant treatment modalities shared the common effect of down-regulation and/or desensitization of β-adrenergic receptor complexes.3,4 Moreover, a significant number of antidepressants down-regulate 5- HT2 (serotonin; 5-hydroxytryptamine) receptors, although, in contrast, electroconvulsive shock up-regulates 5-HT2 receptors.4,5