Utility of an oral diffusion sink (ODS) device for quantification of saliva corticosteroids in human subjects.

Measurement of cortisol by assay of single blood or saliva samples is inherently imprecise due to the episodic secretion of cortisol. In addition, assay of blood usually quantifies total cortisol, rather than separating free hormone, which is proportionately the much smaller fraction. Furthermore, the free fraction may be disproportionately higher in hypercortisolism. Urinary free cortisol is one measure that provides both a time integral and a focus on the free fraction, but it is inconvenient and prone to collection error in unsupervised ambulatory subjects. The Oral Diffusion Sink (ODS) apparatus takes up corticosteroids from saliva according to first-order kinetics and may provide a practical alternative. We assessed the utility of the ODS in a study of seven healthy volunteers admitted to the CRC for three days. Data on day two from 0700-1100 h and 1100-1500 h were compared between the ODS and three other means of assessing cortisol: urinary free cortisol (UFC), blood, and saliva. The subjects all tolerated wearing the ODS device without any complaint. High correlations were observed between ODS values vs. data for UFC, plasma, and saliva determinations. In summary, the ODS device was well tolerated and collected reliable corticosteroid data, and thus provides a new, non-invasive methodology for studies of HPA function in health and disease.

Chronic treatment with amitriptyline produces supersensitivity to nicotine.

The authors used a thermoregulation paradigm to evaluate effects of amitriptyline (AMI) on the sensitivity of a nicotinic mechanism involved in the regulation of core temperature in rats. Treatment with this tricyclic was associated with a significant increase in the hypothermic response to nicotine. Supersensitivity persisted for a minimum of 7.5 days following the last dose of AMI, and a significant proportion of animals displayed increased sensitivity after 14.5 days of abstinence. Implications for the mechanism of action of AMI are highlighted.

Plasma dexamethasone levels in children given the dexamethasone suppression test.

To determine whether children who demonstrate dexamethasone suppression test (DST) nonsuppression have lower plasma dexamethasone levels than DST suppressors, we administered the DST to 73 patients ranging in age from 5-14 years. Plasma dexamethasone levels and postdexamethasone cortisol levels were measured at 4:00 PM on day 2. We found: (1) DST nonsuppressors had significantly lower plasma dexamethasone levels (p less than 0.03) than suppressors; similar trends were observed when the population was divided into depressed and nondepressed patients; (2) mg/m2 dose of dexamethasone was directly correlated with plasma dexamethasone (p less than 0.003) and inversely correlated with postdexamethasone plasma cortisol levels (p less than 0.04); and (3) a statistically significant inverse correlation between plasma dexamethasone levels and postdexamethasone cortisol levels (p less than 0.04). Our findings show that plasma dexamethasone levels are important in evaluating DST results in psychiatrically disturbed children and suggest that dexamethasone dosage for use in the DST in children might be better calculated in terms of body surface area.

Amitriptyline supersensitizes a central cholinergic mechanism.

The withdrawal of tricyclic antidepressants produces symptoms characteristic of cholinergic overdrive states. The authors previously proposed that these states are the consequence of the pharmacological induction of cholinergic system supersensitivity by chronic treatment with antidepressants, combined with a reduction in the plasma level of a competitive muscarinic receptor antagonist when the dose of a tricyclic is decreased. This is consistent with the facts that all tricyclic antidepressants are antimuscarinic agents and that classical antimuscarinic compounds, such as scopolamine, up-regulate and supersensitize muscarinic cholinergic systems. The authors present evidence that chronic treatment with amitriptyline supersensitizes a central cholinergic mechanism. Core body temperature is subject to influence by a central (hypothalamic) muscarinic mechanism, which is rendered supersensitive to cholinomimetic challenge by treatment with scopolamine. The authors telemetrically measured the hypothermic responses of adult male rats to various doses of the muscarinic agonist oxotremorine before and in the course of chronic treatment with amitriptyline. Treatment with amitriptyline resulted in marked enhancement of the cholinomimetic-induced hypothermia. Methylscopolamine nitrate, a peripherally active antimuscarinic agent, did not block the hypothermic response to oxotremorine, whereas scopolamine, a centrally active antimuscarinic compound, did. This study indicates that the chronic administration of amitriptyline can produce supersensitivity of a central muscarinic cholinergic mechanism. Clinical and theoretical implications of this finding are discussed.

Panic disorder in psychiatrically hospitalized children.

In a sample of 136 psychiatrically hospitalized children, panic disorder was identified in four boys and three girls. Six had separation anxiety disorder, and four had depressive disorders. This report documents the occurrence of panic disorder in children.

Comorbidity of other psychiatric disturbances in depressed, psychiatrically hospitalized children.

Twenty-five (16%) of 160 psychiatrically hospitalized children were given diagnoses of depressive disorders. None of 12 diagnostic categories from DSM-III axes I and II occurred significantly more frequently among these depressed children than among the non-depressed children in this sample.

Depressive symptoms and suicidal behavior in adolescents.

Depressive symptoms and suicidal behavior in 64 adolescent psychiatric patients were assessed by a structured interview and the Schedule for Affective Disorders and Schizophrenia. The medical seriousness of suicidal behavior was associated with conscious intent to die and with the number of previous nonlethal suicide attempts. Suicidal behavior was associated with depressed mood, negative self-evaluation, anhedonia, insomnia, poor concentration, indecisiveness, lack of reactivity of mood, psychomotor disturbance, and alcohol and drug abuse. The results suggest that adolescents can be reliable reporters of their suicide potential and that clinicians need to be sensitive to symptoms of major depressive disorder in assessing potentially suicidal adolescents.

The Internet and the future of psychiatry.

OBJECTIVE: The Internet is a rapidly growing communications resource that is beginning to have an impact on medicine, and it is anticipated that the Internet will soon have a major effect on psychiatry. It is essential for psychiatrists to have a conceptual framework for understanding the many aspects of the Internet. METHOD: Using a four-layer model, the authors describe the components of the Internet and how these work together to establish communication. They discuss some of the practical implications of the model, potential future applications of the Internet, and some of the challenges its use will create. RESULTS: In the Internet model described, the bottom three layers involve hardware and modes of information transmission; the fourth layer is human interaction. The Internet has great potential in psychiatric education, clinical care, research, and administration, but major adjustments in individual and organizational expectations and responses will be needed. These changes relate to the speed, dispersion, volume, privacy, and permanence of communication. CONCLUSIONS: The growth of the Internet and related information technologies is inevitable and has diverse technical and social implications. As psychiatrists, we must remain effective communicators of information and adjust to a changing world with new roles and skills that will permit us to best serve our professional mission.

Suicidal behavior among serious juvenile offenders.

Seventy-one incarcerated juvenile offenders were diagnosed according to DSM-III and assessed for suicidal behavior. Subjects diagnosed as having major affective disorders or borderline personality disorders showed the highest degree of suicidal tendency and had made the most serious attempts.

Time of origin of opioid peptide-containing neurons in the rat hypothalamus.

By using a combined technique of immunocytochemistry and [3H]thymidine autoradiography, we have determined the "birth date" of opioid peptide-containing neurons in several hypothalamic nuclei and regions. These include proopiomelanocortin (POMC) neurons (represented by ACTH immunoreactivity) in the arcuate nucleus; dynorphin A neurons in the supraoptic and paraventricular nuclei and the lateral hypothalamic area; and leu-enkephalin neurons in the periventricular, ventromedial, and medial mammillary nuclei, as well as in preoptic and perifornical areas. Arcuate POMC neurons were born very early in embryonic development, with peak heavy [3H]thymidine nuclear labelling occurring on embryonic day E12. Supraoptic and paraventricular dynorphin A neurons were also labelled relatively early (peak at E13). The lateral hypothalamic dynorphin A neurons showed peak heavy labelling also on day E12. By contrast, leu-enkephalin neurons in the periventricular nucleus and medial preoptic area exhibited peak heavy nuclear labelling on day E14. Furthermore, perifornical and ventromedial leu-enkephalin neurons were also born relatively early (peak on days E12 and E13, respectively). However, the leu-enkephalin neurons in the medial mammillary nucleus were born the latest of all cell groups studied (i.e., peak at E15). The results indicate a differential genesis of these opioid peptide-containing neuronal groups in different hypothalamic nuclei and regions.

A double-blind, placebo-controlled study of the effect of imipramine on TRH-induced urinary urgency in healthy men.

We studied the effect of imipramine (IMI) on thyroid releasing hormone (TRH)-induced urinary urgency as a way of investigating the mechanism of the beneficial effect of IMI on enuresis. In a double-blind study, 12 normal, healthy men between 21 and 39 yr of age ranked their urge to urinate at 30-sec intervals following IV injection of TRH (500 micrograms) or saline. The subjects then were randomly assigned to either IMI (1 mg/kg) or placebo groups for 10 days, and the procedure was repeated. Compared to saline, TRH produced a significant elevation in urinary urgency in all subjects. IMI did not significantly blunt TRH-induced urinary urgency. Thus, the mechanism by which IMI affects enuresis is likely not mediated at the level of the urinary urgency induced by TRH.

Nifedipine-haloperidol combination in the treatment of Gilles de la Tourette's syndrome: a case study.

Anecdotal case reports have been published describing the use of the calcium channel blockers verapamil and nifedipine to provide rapid and dramatic relief in refractory Gilles de la Tourette's syndrome (TS). The authors' case presentation illustrates that, although these two drugs may not always work alone, they can be successfully used in combination with other medications for treating refractory TS.

Postnatal development of ACTH and alpha-MSH in the medulla oblongata of rat: alpha-MSH is the predominant peptide.

ACTH and alpha-MSH levels were measured by radioimmunoassays in extracts of the caudal medulla oblongata of developing rats on postnatal (P) days 1-42 at 7 day intervals, and in adult rats. From P1 to adulthood, ACTH increased greater than 11-fold from 7.2 +/- 1.9 fmol to 82.4 +/- 12.6 fmol per medulla section (mean +/- S.E.M.). In comparison, alpha-MSH increased greater than 7-fold from 68.75 +/- 11.0 fmol to 491 +/- 97.8 fmol during this time period. ACTH/microgram of soluble protein decreased during postnatal development from 0.006 +/- 0.01 to 0.005 +/- 0.001 fmol/microgram of protein and alpha-MSH increased from 0.06 +/- 0.01 fmol/microgram of protein to 0.11 +/- 0.009 fmol/microgram of protein between P1 and P7, decreased to 0.015 +/- 0.003 fmol/microgram of protein by P42 and increased to 0.03 +/- 0.006 fmol/protein per unit protein by adulthood. These data indicate a significant shift in the levels of alpha-MSH detected during development with a decrease in the concentration of material occurring from early postnatal development (P1-P7) to adulthood, which does not appear to be solely related to a regional increase in protein. These studies, as well as radioimmunoassays for ACTH and alpha-MSH in combination with sizing chromatography of pooled extracts at P1, P7 and the adult, demonstrated the predominance of alpha-MSH at all ages.

MSG effects on beta-endorphin and alpha-MSH in the hypothalamus and caudal medulla.

Monosodium glutamate (MSG) was given to neonatal male rats to determine its effects on neurons containing beta-endorphin (beta-END) and alpha-melanocyte stimulating hormone (alpha-MSH) within the basal hypothalamus (arcuate nucleus) and caudal medulla [nucleus tractus solitarius (NTS)] and on the levels of beta-END and alpha-MSH within these areas. Immunocytochemical studies demonstrated a reduction in the number of cells within the medial hypothalamic area (arcuate nucleus) among MSG-treated animals versus saline controls. MSG did not reduce the number of cell bodies within the caudal medulla (NTS). MSG significantly reduced beta-END and alpha-MSH immunoreactive levels in the basal hypothalamus as determined by radioimmunoassay. Whereas a significant reduction in the level of beta-END occurred in the ventral caudal medulla (VCM), none occurred in the dorsal caudal medulla (DCM). In contrast, levels of alpha-MSH increased significantly in the DCM among animals receiving MSG compared to control animals. This study documents the contribution of beta-endorphin containing neurons of the basal hypothalamus to areas of the caudal medulla. The effect of MSG on beta-endorphin and alpha-MSH neurons in these areas and their differential effects on levels in the caudal medulla areas raises questions about the sites of origin of these peptides.

Postnatal development of beta-endorphin immunoreactivity in the medulla oblongata of rat.

Beta-endorphin (B-END) like immunoreactivity (i.r.) levels were measured by radioimmunoassay in the medulla oblongata of developing rats on postnatal ages P1-P42 at 7 day intervals, and in adult rats. From P1 to P42, B-END i.r. increased from 77.0 +/- 1.3 fm to 900.0 +/- 21.6 fm per medulla region (Mean +/- S.E.M.). Adult levels of B-END i.r. were 852.0 +/- 17.0 fm per medulla region. When B-END i.r. was determined per unit protein during this developmental period, a statistically significant change in levels was noted. B-END i.r. dropped from P1 to P7, and then increased from P7 to P14 (P less than 0.01). From P14 through adult, levels did not change significantly. Despite a "drop-out" in the observed immunostaining of B-END neurons in caudal medulla (perikarya in the nucleus tractus solitarius) at P21, radioimmunoassayable levels of this peptide remained constant from P21 through adult per unit protein.

Development of hypothalamic opioid neurons: a combined immunocytochemical and [3H]thymidine autoradiographic study.

Using a combined technique of immunocytochemistry and [3H]thymidine autoradiography, we have determined the "birth-date" of opioid peptide containing neurons in three hypothalamic nuclei. These include proopiomelanocortin neurons (indicated by ACTH immunoreactivity) in the arcuate nucleus, dynorphin A neurons in the supraoptic nucleus, and [Leu]enkephalin neurons in the periventricular nucleus. Arcuate proopiomelanocortin neurons were born very early in embryonic development, with peak heavy [3H]thymidine nuclear labelling occurring on embryonic day E12. Supraoptic dynorphin A neurons were also labelled relatively early (peak at E13). By contrast, [Leu]enkephalin neurons in the periventricular nucleus exhibited peak heavy nuclear labelling on day E14. The results indicate a differential genesis of these three opioid peptide containing neuronal groups in three different hypothalamic nuclei.

Pseudoarylsulfatase A deficiency in a psychiatrically disturbed adolescent.

A case of pseudoarylsulfatase A deficiency in an adolescent boy presenting with affective lability, impulsivity, aggression, inattention, and academic difficulties is described. Genetically related to metachromatic leukodystrophy, pseudoarylsulfatase A deficiency has generally been felt to be a benign disorder. Pseudodeficiency of arylsulfatase A has, however, been associated with serious psychiatric morbidity in recent studies. Possible explanations for this association are suggested. To the best of the authors' knowledge, this is the first case report of pseudoarylsulfatase A deficiency in a psychiatrically disturbed adolescent.

Prepubertal anorexia nervosa and major depressive disorder.

A case of a 9-year-old girl with anorexia nervosa and a major depressive disorder is reported. The age of onset brings into focus the relationship between depressive disorders, weight loss, and anorexia nervosa in children. The increasing incidence of childhood dieting and the implications of the prepubertal onset for hypotheses of the etiology of anorexia nervosa are discussed.

Effects of depression on memory performance and metamemory in children.

OBJECTIVE: To investigate the effects of depression on memory performance and metamemory in children. METHOD: Performance on automatic memory tasks (frequency of occurrence), effortful memory tasks (Children's Auditory Verbal Learning Test), and a Metamemory Battery were examined in 21 unmedicated, depressed children and 21 nondepressed controls (matched for age, gender, and full-scale IQ). Subjects were divided into three groups based on depression severity (high depressed, low depressed, nondepressed). RESULTS: High depressed patients demonstrated performance deficits relative to nondepressed and low depressed children on the Children's Auditory Verbal Learning Test, Immediate Recall trial. Both groups of depressed children performed more poorly on the Metamemory Battery when compared to nondepressed children. Severity of depression differentiated overall performance. Metamemory performance of depressed subjects indicates possible difficulty with overestimation of memory abilities. No differences were found on automatic memory task performance. CONCLUSIONS: Memory impairment in depression varies as a function of severity and may be evident only when a certain level of depression is reached. Overestimation of memory ability by depressed children may be an attempt to compensate for feelings of inadequacy or inferiority. It may also lead depressives to use poor judgment in selecting appropriate solutions for problems. Targeting these cognitive distortions could be a focal point of clinical and educational interventions.

Characterization of beta-endorphin-related peptides in the caudal medulla oblongata and hypothalamus of the prenatal, postnatal and adult rat.

A comparison was made of beta-endorphin (B-END) concentrations versus post-translation products during the perinatal period in the hypothalamus and the caudal medulla oblongata. The concentration of B-END-like immunoreactivity did not differ statistically between embryonic day 21 (E21) and postnatal day 1 (P1) in either area. There were significant differences in forms, with a shift from larger precursors at E21 to smaller peptides at P1, with the predominant form of B-END being the 31 residue form at E21 in both regions. B-END varied between the two regions at P1, the 27-26 residue predominant in the hypothalamus, and the 31 residue in the caudal medulla.