The pharmacokinetics and safety of desvenlafaxine in subjects with chronic renal impairment.

BACKGROUND: Desvenlafaxine (administered as desvenlafaxine succinate), the major active metabolite of venlafaxine, is a new serotonin-norepinephrine reuptake inhibitor (SNRI) approved for the treatment of major depressive disorder (MDD). OBJECTIVE: To assess the pharmacokinetics, safety, and tolerability of desvenlafaxine in healthy volunteers vs. those with renal impairment. MATERIALS AND METHODS: A single, oral, 100 mg dose of desvenlafaxine was administered to healthy subjects (n = 8) and subjects with mild (n = 9), moderate (n = 9), or severe (n = 7) renal impairment (24-h creatinine clearance, ml/min: 50 - 80, 30 - 50, or < 30 ml/min, respectively) or end-stage renal disease (ESRD; on dialysis.

24-Hour monitoring of cortisol and corticotropin secretion in psychotic and nonpsychotic major depression.

BACKGROUND: Considerable research has been devoted to the hypothalamic-pituitary-adrenal (HPA) axis in depression, but relatively little attention has been given to intensive monitoring of hormone secretion over time. Such research is potentially important because the HPA axis has prominent circadian and ultradian periodicity. Comparison of depressed patients with and without psychotic features is also important because HPA axis abnormalities may be especially pronounced in psychotic depressed patients. METHODS: Eleven patients with psychotic major depression (PMD patients), 38 patients with nonpsychotic major depression (NPMD patients), and 33 healthy control subjects, all drug free, were studied. Patients with PMD and NPMD were outpatients recruited primarily by advertisement. Subjects were admitted to a General Clinical Research Center and had blood drawn through an intravenous line for determination of cortisol and corticotropin (ACTH) levels every hour for 24 hours. RESULTS: Among NPMD patients, the 24-hour cortisol amplitude was significantly (P =.02) reduced in comparison with control subjects, while ACTH indices did not differ between NPMD patients and the control group. Among PMD patients, the ACTH 24-hour mean was significantly (P =.03) increased compared with controls, while PMD patients and the control group did not differ significantly in cortisol indices. CONCLUSION: In the population studied, PMD and NPMD patients have distinct profiles of HPA axis dysregulation.

Acute and delayed effects of corticotropin-releasing hormone on dopamine activity in man.

Interactions between the hypothalamic-pituitary-adrenal (HPA) axis and central dopamine systems have been hypothesized to play a role in the pathophysiology of psychosis, but the normal physiology of HPA axis-dopamine interactions has not been fully defined. We report results from two uncontrolled pilot studies which explored the effects of ovine corticotropin-releasing hormone (CRH) on dopamine activity in healthy human subjects. Administration of CRH did not produce changes in plasma levels of homovanillic acid (HVA), the major dopamine metabolite, over the subsequent 3.5 hours. However, when the effects of CRH were followed over a longer period in a small subgroup, we found that CRH administration produced a two-fold rise in plasma HVA levels 20 hours later, without affecting plasma levels of 3-methoxy-4-hydroxyphenylglycol (MHPG), a major metabolite of norepinephrine. Thus, the findings of these pilot studies suggest that CRH may exert delayed but not acute effects on dopamine activity in man.

Hypothalamic-pituitary-adrenal axis effects on plasma homovanillic acid in man.

BACKGROUND: Effects of the hypothalamic-pituitary-adrenal (HPA) axis on central dopaminergic systems have been proposed to underlie the development of psychotic symptoms in depression. This study examined HPA axis hormone effects on plasma levels of homovanillic acid (HVA), the dopamine metabolite, in healthy volunteers, using a placebo-controlled, double-blind, random-assignment, crossover design. On the basis of preliminary studies, we hypothesized that HPA axis hormones would produce delayed effects on plasma HVA levels measured in the afternoon. METHODS: Ten healthy subjects underwent a standard protocol on four occasions and each time received ovine corticotropin-releasing hormone, synthetic adrenocorticotropic hormone (ACTH), cortisol, or placebo. Plasma HVA was measured at 9 AM and 4 PM on Day 1, immediately prior to administration of the test substance at 7 PM, then at 30-60-min intervals until 11 PM. Plasma HVA levels were subsequently obtained at 9 AM and 4 PM on Days 2 and 3. RESULTS: As predicted, there were significant differences between test substances in delayed effects on afternoon HVA levels measured on Days 2 and 3, with cortisol and ACTH producing greater increases in HVA than placebo. Acute effects of HPA axis hormones on HVA were not found, while differences between test substances in delayed effects on morning HVA levels approached significance. CONCLUSIONS: HPA axis hormones exert delayed effects on plasma HVA levels in healthy humans.

Acute antidepressant effects of intravenous hydrocortisone and CRH in depressed patients: a double-blind, placebo-controlled study.

OBJECTIVE: The primary objective of this investigation was to examine the acute antidepressant effects of intravenous hydrocortisone and ovine corticotropin releasing hormone (CRH) infusions in patients with major depression. METHOD: Twenty-two patients who met DSM-III-R criteria for nonpsychotic major depression were randomly assigned to receive intravenously 1 mg/kg of ovine CRH, 15 mg of hydrocortisone, or saline under double-blind conditions on day 1. Standard depression rating scales were completed on day 1 before the study medications were administered and again the following day (day 2). RESULTS: Patients treated with hydrocortisone demonstrated a significantly greater reduction in total 21-item Hamilton Depression Rating Scale scores (mean reduction=8.4 points or 37%) than patients given ovine CRH (mean=1.2 points) or placebo (mean=1.3 points). CONCLUSIONS: Acute hydrocortisone infusion is associated with a rapid and robust reduction in depressive symptoms. The authors discuss the therapeutic implications of these findings.

Cortisol feedback during the HPA quiescent period in patients with major depression.

OBJECTIVE: The authors tested the hypothesis that patients with major depression have a defect in the mechanism by which cortisol exerts negative feedback on the hypothalamic-pituitary-adrenal (HPA) axis during the HPA axis quiescent period. METHOD: Twenty-nine patients with major depression and 25 healthy comparison subjects were randomly assigned to administration of 15 mg cortisol or placebo infused over 2 hours beginning at 7:00 p.m. Cortisol and ACTH levels were measured at baseline and every 30 minutes from 7:30 p.m. to 11:00 p.m. RESULTS: Differences between the patients and the comparison subjects in the ACTH response to the cortisol infusion, relative to the ACTH response to placebo, were not found. CONCLUSIONS: The results provide some evidence that patients with major depression do not have an abnormality of cortisol feedback during the HPA axis quiescent period.

Neuropsychological deficits in psychotic versus nonpsychotic major depression and no mental illness.

OBJECTIVE: At least three studies have indicated that patients with psychotic major depression studied under non-drug-free conditions differ from patients with nonpsychotic major depression and healthy comparison subjects on several measures of neuropsychological performance. The current study explored specific impairments in cognitive function in subjects with psychotic major depression, subjects with nonpsychotic major depression, and healthy comparison subjects studied under drug-free conditions. METHOD: A battery of neuropsychological tests was administered to 11 patients with psychotic major depression, 32 patients with nonpsychotic major depression, and 23 normal comparison subjects under drug-free conditions. The three groups did not differ statistically in age, sex, or level of education. To ensure that participants had minimal levels of severity and endogenicity, all patients were required to have a score of at least 20 on the 21-item Hamilton Depression Rating Scale and a score of at least 7 on the Core Endogenomorphic Scale, which uses eight items from the Hamilton depression scale. RESULTS: Patients with psychotic major depression demonstrated significantly greater impairment than patients with nonpsychotic major depression and/or comparison subjects in attention and response inhibition (as measured by the Stroop color-word subscale score) as well as in verbal declarative memory (as measured by the Paragraph Recall Test). CONCLUSIONS: These data indicate that patients with psychotic major depression demonstrate impairment in functions thought to be mediated by the frontal cortex and mediotemporal lobes.

Cortisol feedback effects on plasma corticotropin levels in healthy subjects.

An abnormality of rapid cortisol feedback on activity of the hypothalamic-pituitary-adrenal axis has been reported in depression. However, there is controversy regarding the existence of rapid cortisol feedback on corticotropin (ACTH) secretion in humans. We investigated the effects of cortisol on ACTH levels in healthy subjects using a placebo-controlled, double blind, random assignment, cross-over design. Ten medication-free volunteers with no psychiatric history and no active medical problems underwent a standard protocol on two occasions separated by at least 2 weeks. Each time, subjects were admitted to a General Clinical Research Center and had infusion of 15 mg cortisol (hydrocortisone sodium succinate) over 120 min or placebo. Serum levels of cortisol and plasma ACTH levels were determined at baseline and over the 4 h after the start of the infusion. Over the two GCRC admissions subjects received both cortisol and placebo infusions, and the order of the two infusions was randomized. Compared to placebo, cortisol infusion produced a significant decrease in plasma ACTH levels beginning within 60 min from the start of the infusion. We conclude that cortisol infusion produces early inhibition of ACTH secretion in normal humans.

Diurnal variation of plasma cortisol and homovanillic acid in healthy subjects.

We investigated the relationship between plasma levels of cortisol, the dopamine metabolite homovanillic acid (HVA) and norepinephrine in healthy human subjects. Plasma cortisol and HVA levels were measured at 0800h, and in an integrated sampling procedure involving samples every 15 min between 1300 and 1600h. Plasma norepinephrine was measured at 0800 and 1300h. Cortisol, HVA and norepinephrine indices did not show significant correlations with each other. Both cortisol and HVA showed significant decreases over time. Longitudinal Random Effects (LRE) models were used to test whether individual cortisol and HVA curves over time were correlated; significant correlations were not found with this procedure. While significant correlations between cortisol and catecholamine indices have been reported in depressed patients, our results do not suggest such correlations in healthy subjects.

Late feedback effects of hypothalamic-pituitary-adrenal axis hormones in healthy subjects.

We tested the hypothesis that hypothalamic-pituitary-adrenal (HPA) axis hormones exert prolonged negative feedback on corticotropin (ACTH) secretion. Ten healthy subjects underwent a standard protocol 4 x and each time received i.v., under double blind conditions and in random order, corticotropin-releasing hormone (CRH) 1 microgram/kg, co-syntropin (ACTH1-24) 0.25 mg, cortisol (hydrocortisone) 15 mg, or placebo. Subjects had a venipuncture for cortisol and ACTH levels at 0900h on Day 1, then had i.v. insertion and cortisol and ACTH levels measured at 1600 and 1855h. The test substance was given at 1900h and cortisol and ACTH levels were monitored until 2300h, when the i.v.'s were discontinued. Subjects then had venipunctures for cortisol and ACTH levels at 0900 and 1600h on Day 2 and 3. Hormones had the expected acute effects. Hormones did not differ from placebo in effects on cortisol levels measured over Days 2 and 3. There were significant differences between test substances in effects on afternoon ACTH levels on Days 2 and 3, with ACTH levels increasing significantly less from baseline to Day 2 and 3 after CRH administration than after placebo, and tending to increase less from baseline to Day 3 after ACTH administration than after placebo. Examination of Day 2 and 3 morning ACTH levels showed a significant interaction between the test substances and time (Day 2 vs. 3), and interpretation of this interaction is not straightforward. We conclude that CRH and possibly ACTH exert late inhibitory effects on ACTH secretion measured in the afternoon of the 2 days following hormone administration.

A cognitive perspective on object relations, drive development and ego structure in the second and third years of life.

This paper extends a recent line of research by correlating Piaget's theory of cognitive development with several psychoanalytic perspectives on development during the second and third years of life. The concrete, imagistic, unintegrated nature of mental representations associated by Mahler and Kernberg with this period, along with the mental operation of splitting, are related to preconceptual representation, a cognitive mode described by Piaget. Psychoanalytic perspectives on the body ego and object world associated with the anal period are also seen to involve concrete, unintegrated representations which show correspondence with preconceptual cognition. Parallels are explored between cognitive stages and the psychoanalytic understanding of ego and superego development. While psychoanalysis is not a cognitive psychology, aspects of its theory are concerned with cognitive structure and are enriched by a consideration of cognitive development.

Suicide notes in adolescence.

Suicide rates for adolescents have shown a substantial increase over the past 30 years, but there is little information regarding the clinical status of adolescents who end their lives. In the adult literature, one avenue to understanding the psychologic condition immediately prior to the self-destructive act has been the study of suicide notes, and the present study constitutes the first systematic investigation of notes left by children or adolescents. Records of death were examined in the Office of the Coroner, City of Montreal, and all suicides between ages 10 and 20 were identified for the years 1978 to 1982. Seventeen individuals who left notes were identified, comprising 10% of the population of suicides. Suicides who left notes did not differ from the total group in age and sex distribution but were more likely to choose shooting as a method. The content of the notes was studied in terms of 11 variables which had proven characteristic of suicide notes in the adult literature, and the results were compared to those reported for adults. In general, our results support a psychoanalytic perspective which understands suicide as resulting from an ambivalent attachment to an object, loss of the object, internalization, and the direction of aggression against the self. Cases appeared to fall into two clusters. Older adolescents were more concrete, left specific instructions, did not address the note, did not give a reason for the act, and tended to choose intoxication as a method.(ABSTRACT TRUNCATED AT 250 WORDS)

An epidemiologic study of adolescent suicide.

This study investigated suicides by persons aged ten to nineteen during the years 1978 to 1982 in the City of Montreal. Records of death in the Office of the Coroner, City of Montreal, were examined and suicides designated according to standard criteria. Age, sex, method of suicide, and month of death were noted. Mean incidence of suicide for the entire sample was 5.92 per 100,000 population. The mean figure for males was 9.52 and for females 2.32, with the incidence greater among males in each of the five years. Incidence of suicide in the fifteen to nineteen year old group was approximately ten times that in the ten to fourteen year old group, a difference which was constant across sex and across the five year period. Among boys, hanging was the most frequent method of suicide, with firearms second, and jumping from a height or in front of a vehicle third. Among girls, drug intoxication was most common, with firearms and jumping ranking second and third respectively. No monthly periodicity was found. The epidemiology of adolescent suicide in Montreal appears to be similar to that reported in other locations.