Correlations between motor persistence and plasma levels in methylphenidate-treated boys with ADHD.

Following a 0.9 mg/kg methylphenidate loading dose, serial plasma level determinations, self-scored mood ratings, and measures of motor persistence were gathered on eight previously unmedicated boys with attention deficit disorder with hyperactivity (ADHD) during a 9-h period. The measures were repeated using the same loading dose after 6 months of maintenance treatment with methylphenidate (1.3 mg/kg x d). Kinetic-dynamic modelling suggests inverse correlative relationships between motor performance errors and plasma levels. Pharmacokinetic parameters did not change between acute and maintenance drug treatment phases, and there was no evidence of long-term tolerance.

Corticotropin-releasing hormone challenge in prepubertal major depression.

This study investigates cortisol and ACTH (corticotropin) responses to an infusion of human CRH (corticotropin-releasing hormone) in prepubertal children with major depressive disorder (MDD). Following a period of 24 hours of adaptation to the laboratory environment with an intravenous catheter in place, 34 children with MDD and 22 healthy controls received 1 microgram/kg of human CRH at 5:00 PM. Blood samples for cortisol and ACTH were measured at baseline and post-CRH. Overall, there were no significant differences between the MDD and the normal controls in baseline or post CRH stimulation values of either cortisol or ACTH. Melancholic (n = 4) patients had significantly higher baseline cortisol levels than nonmelancholic (n = 24) patients. Compared with the outpatients and the nonmelancholics, the inpatients (n = 10) and the melancholics showed significantly lower total ACTH secretion (effect size: 0.9 and 1.4, respectively) after CRH infusion. These results are consistent with a broad literature suggesting that the HPA axis abnormalities occur less frequently in early-onset depression than reported in adult studies. The pattern of results in the subgroups of inpatients and in melancholic children, however, raise questions about possible continuities with adult studies.

A case-control family history study of depression in adolescents.

OBJECTIVE: To examine whether depression aggregates in the families of depressed adolescents and to determine whether clinical features and/or comorbid syndromes in the depressed adolescents change the risk of psychopathology in relatives. METHOD: Lifetime prevalence rates of psychopathology in the first-degree (n = 228) and second-degree (n = 736) relatives of 76 adolescents with major depressive disorder (MDD) and the first-degree (n = 107) and second-degree (n = 323) relatives of 34 normal control adolescents were assessed by the Family History-Research Diagnostic Criteria (FH-RDC) method using the parent/guardian as the family informant. RESULTS: Compared with the first-degree relatives of normal controls, the relatives of depressed adolescents had significantly higher lifetime rates of MDD (25% versus 13%) and "any" of the FH-RDC psychiatric disorders (53% versus 36%). The second-degree relatives of adolescents with MDD had significantly higher lifetime rates of FH-RDC "other" psychiatric disorder (12% versus 7%) and "any" of the FH-RDC psychiatric disorders (22% versus 15%) but not MDD (5% versus 6%) compared with the relatives of normal controls. The first-degree relatives of depressed adolescents who were also suicidal had increased lifetime rates of suicidal behavior which significantly cosegregated with MDD. Comorbid conduct disorder in the depressed adolescent was associated with increased rates of antisocial personality disorder in the first-degree relatives and also tended to cosegregate with MDD. CONCLUSIONS: The current study provides further evidence for the familial aggregation of depression in adolescent-onset MDD. This study also suggests that the familial aggregation of nonaffective psychiatric disorders depends on the clinical features and comorbid syndromes present in the depressed adolescent proband.

Stimulatory tests of growth hormone secretion in prepubertal major depression: depressed versus normal children.

OBJECTIVE: Blunted stimulation of growth hormone (GH) secretion after pharmacological stimuli has been linked to depressive and anxiety disorders throughout the life span. This study sought to better characterize this dysregulation in prepubertal depression. METHOD: GH regulation was compared in 38 medically healthy prepubertal children with current major depressive disorder and 19 control children who were medically and psychiatrically healthy. The study evaluated GH stimulatory responses to three pharmacological challenge agents: (1) insulin-induced hypoglycemia, using 0.1 IU/kg intravenous regular insulin; (2) 1.3 micrograms/kg intravenous clonidine; and (3) 1.0 microgram/kg intravenous human growth hormone-releasing hormone (GHRH). RESULTS: The results provide replication and extension of earlier findings. GH responses to insulin-induced hypoglycemia and to GHRH stimulation were blunted in depressed children compared to the normal controls. Clonidine stimulation results yielded a similar picture but did not reach statistical significance. CONCLUSIONS: Overall these results further strengthen the evidence showing GH dysregulation in childhood depression. However, the blunted GH response seen with GHRH (which reflects pituitary hyporesponsivity) was in contrast to our original hypothesis and has implications regarding the site (or sites) of dysregulation.

The 24-hour pattern of prolactin secretion in depressed and normal adolescents.

Plasma prolactin concentrations were measured at 20-min intervals over a 24-hr period in 49 adolescents with major depressive disorder (MDD) and 39 normal control adolescents. Neither the pattern nor the amount of prolactin secretion was significantly different between these two groups. There were significant gender differences, with girls secreting more prolactin than boys, but no significant gender-by-diagnosis interactions were found. With the possible exception of psychosis, dividing the MDD sample based on clinical characteristics failed to reveal differences. These findings are discussed in the context of changes in prolactin in childhood depression using a serotonergic challenge study, as well as in relation to baseline prolactin studies in adult depression.

Cholinergic REM induction test with arecoline in depressed children.

Children with major depressive disorder often fail to exhibit electroencephalographic (EEG) sleep abnormalities similar to those reported in depressed adults. It was hypothesized that a cholinergic rapid eye movement (REM) induction test would contribute to the identification of EEG sleep abnormalities in depressed children. To test this hypothesis, prepubertal children meeting research diagnostic criteria for major depressive disorder (n = 33) and carefully screened healthy control children (n = 15) were enrolled in a 4-day psychobiologic protocol that included 1 night with infusion of arecoline (0.5 mg) during the first non-REM sleep period. Although there had been no significant group differences in baseline sleep measures, results on the arecoline night revealed significantly shorter REM latency in the group of depressed children compared with the control children (mean +/- SD = 105 +/- 51 minutes vs. 140 +/- 46 minutes). The design of the protocol (with an interval break immediately preceding the arecoline night) prevented a direct estimation of arecoline effects within subjects; however, these data provide promising preliminary results regarding cholinergic REM induction tests in childhood depression.

The psychosocial functioning and family environment of depressed adolescents.

OBJECTIVE: This study examined measures of functional impairment and family relations in a sample of 62 adolescents with major depressive disorder (MDD) and 38 normal controls with no history of psychiatric illness. METHOD: Ratings of the following domains were obtained: mother-child relations, father-child relations, spousal relations, sibling relations, peer relations, and school performance. Ratings of each domain for the 3-month period preceding the assessment were derived from information obtained using a semistructured interview administered independently to the adolescents and one of their parents. RESULTS: Adolescents with MDD were found to have severe difficulties in all areas. Ninety percent of the depressed adolescents had scores greater than 2 SD above the mean of the normal controls on one or more of the domain ratings. In addition, adolescents with difficulties in parent-child relations were more likely than those adolescents without problems in family relations to have difficulties in peer relations and school performance. CONCLUSIONS: The authors discuss the importance of systematically examining psychosocial variables in future studies of the etiology, course, and treatment of MDD in adolescents.

Neuroendocrine response to L-5-hydroxytryptophan challenge in prepubertal major depression. Depressed vs normal children.

The neuroendocrine response to L-5-hydroxytryptophan was compared in 37 prepubertal children who met the Research Diagnostic Criteria for major depressive disorder with that in 23 normal children with no lifetime history of any psychiatric disorder and very low rates of depression in both first- and second-degree relatives. Intravenous L-5-hydroxytryptophan (0.8 mg/kg) was given over a 1-hour interval after preloading with oral carbidopa, an inhibitor of peripheral but not central L-5-hydroxytryptophan metabolism. L-5-Hydroxytryptophan, a precursor of serotonin, increases serotonin turnover in the central nervous system when given after carbidopa. Seven (19%) of the 37 children with major depressive disorder and two (9%) of the 23 normal children had nausea or vomiting and therefore did not complete the full infusion. They were subsequently excluded from data analysis. After this stimulation, prolactin, cortisol, and growth hormone secretion were compared between diagnostic groups. The depressed children secreted significantly less cortisol (effect size, 0.70) and significantly more prolactin (effect size, 0.83). There was a sex-by-diagnosis interaction in prolactin response to L-5-hydroxytryptophan and, on examination, the prolactin hypersecretion was seen in depressed girls but not in depressed boys compared with same-sex controls. There was no significant stimulation of growth hormone in either group. These findings are consistent with dysregulation of central serotonergic systems in childhood major depression.

The dexamethasone suppression test in adolescent outpatients with major depressive disorder.

OBJECTIVE: The purpose of the study was to determine whether the dexamethasone suppression test (DST) would discriminate between outpatient adolescents with major depressive disorder and normal adolescent comparison subjects. METHOD: Depressed patients were accepted into the study only if they fulfilled the Research Diagnostic Criteria for major depressive disorder. The depressed subjects (N = 44) and the normal subjects (N = 38) were studied in the same environment and under the same conditions. The subjects received 1 mg of dexamethasone at 11:00 p.m. The next day, blood for determining plasma cortisol concentrations was drawn through an indwelling catheter every 60 minutes from 8:00 a.m. until 11 p.m. RESULTS: After dexamethasone, the cortisol levels of the adolescents with major depressive disorder and the normal subjects were not significantly different. Only six (14%) of the depressed subjects and one (3%) of the normal subjects showed evidence of nonsuppression (cortisol value greater than 5 micrograms/dl). Analyses of subgroups of the depressed patients based on suicidal tendencies and endogenous subtype also failed to reveal significant differences in cortisol values. Estimates of the severity of depression showed significant negative correlations with cortisol values among the depressed patients. CONCLUSIONS: In contrast with previous studies of adolescent inpatients, the DST did not discriminate between the adolescent outpatients with major depressive disorder and the normal comparison subjects in this study. Possible reasons for the discrepancies, such as severity of the depression and inpatient status, are discussed.

The dexamethasone suppression test in children and adolescents: a review and a controlled study.

Dexamethasone Suppression Test (DST) studies conducted in children and adolescents are reviewed, together with factors hypothesized to explain discrepancies in rates of DST nonsuppression across studies. These factors are then examined in a controlled study of 27 adolescents with major depressive disorder (MDD) and 34 normal controls (NC). Subjects were given 1 mg of dexamethasone at 11:00 PM, and the following day serum samples for cortisol were collected each hr from 8 AM to 11 PM through an indwelling catheter. There were no significant differences found between the MDD and NC subjects on any postdexamethasone cortisol measure. Further, cortisol suppressors and nonsuppressors were not distinguished by any of the hypothesized factors identified from the review, including inpatient status, presence of suicidality, endogenous features, psychotic symptoms, or prior history of MDD. Questions about the appropriateness of the 1 mg dose of dexamethasone (currently the standard dose used with adolescents) are raised, together with a discussion of the effects of stress on DST findings.

A secular increase in child and adolescent onset affective disorder.

Both longitudinal and cross-sectional studies utilizing population and family study samples have found evidence for a secular increase in major affective disorders in adults. Applying techniques used in cross-sectional studies in adults to family study data of children and adolescents, the authors demonstrate evidence of a parallel secular increase for child and adolescent onset affective disorders. Normal and depressed prepubertal probands were identified. All full siblings were directly interviewed for lifetime episodes of affective disorder. Analysis of the siblings (probands not further analyzed in this article) by the Cox proportional hazards model demonstrates that the risk for affective disorder is higher in siblings born more recently.

Regulation of sleep and growth hormone in adolescent depression.

This article reviews findings of sleep, growth hormone (GH), and cortisol measures from a number of separate controlled studies of prepubertal and adolescent depression carried out by Puig-Antich and colleagues since 1978. New data are presented comparing 24-hour GH measures in adolescents with major depressive disorder (MDD) (N = 44; mean age = 14.8 +/- 2.0) to normal control adolescents (N = 37; mean age = 15.3 +/- 1.5). There were no significant overall group differences in summary GH measures between MDD and normal controls. Splitting the MDD group on the basis of suicidality (definite plan or attempt) (N = 20), revealed a significant blunting of sleep GH compared to the nonsuicidal group (N = 24). These results are discussed in the context of the other sleep and neuroendocrine findings in this population, with evidence for dysregulation around sleep onset. The influences of development on sleep and GH regulation are also considered.

Nocturnal urinary excretion of 6-hydroxymelatonin sulfate in prepubertal major depressive disorder.

Levels of the melatonin metabolite, 6-hydroxymelatonin sulfate, were measured in overnight urine from 31 prepubertal children with major depressive disorder and 15 normal control children with very low family loading for affective disorder. The two groups did not differ with regard to their nocturnal excretion of this compound, nor was any depressive subgroup identified whose 6-hydroxymelatonin sulfate excretion differed from that of the control group. Previous studies of pineal function in depression are reviewed and discussed in the context of the present investigation.

Dexamethasone suppression test in children with major depressive disorder.

The authors report a study of 24-hour serial cortisol determinations, measured during baseline and after the administration of 0.25 and 0.5 mg of dexamethasone in a sample of predominantly outpatient children with major depressive disorder, nonaffective psychiatric controls, and normal controls. In this sample, 24-hour baseline cortisol and the dexamethasone suppression test (DST) do not discriminate between the three groups. In addition, the authors measured 24-hour serum dexamethasone levels. There were no significant between group differences in serum dexamethasone. These results raise questions as to the utility of this test in the diagnosis of affective disorders in children. Possible reasons for the discrepancies in the dexamethasone suppression test results between in- and outpatient studies are discussed.

Electroencephalographic sleep measures in prepubertal depression.

Two nights of electroencephalographic (EEG) sleep recording were performed in a group of prepubertal subjects with major depressive disorder (MDD) (n = 36, mean age = 10.4, SD = 1.5) and age-matched normal control children (n = 18, mean age = 10.1, SD = 1.6). All subjects were medically healthy and free of medications at the time of the study. There were no significant group differences for any major sleep variable after the initial adaptation night in this study. One subgroup of MDD subjects (n = 8) showed reduced REM latency on both recording nights, decreased stage 4 sleep, and increased REM time; this subgroup had significantly higher severity scores for depression but did not otherwise appear to be clinically distinct from the rest of the MDD subjects. Overall, the results indicate that the EEG sleep changes associated with depression in adults occurred less frequently in prepubertal MDD subjects.

24-hour cortisol measures in adolescents with major depression: a controlled study.

Plasma cortisol levels were determined every 20 min for 24 hr in depressed adolescents (n = 27) meeting research diagnostic criteria (RDC) for major depressive disorder (MDD) and normal controls (n = 32). All subjects were between 12 and 18 years of age, at least Tanner Stage III of sexual development, medically healthy, and medication free at the time of the studies. The results showed that cortisol secretory patterns were very similar between the two groups with the exception that the depressed adolescents showed significantly elevated cortisol levels around sleep onset (a period when cortisol is usually suppressed). Subgroup analyses showed that most of these differences were contributed by the suicidal/inpatient depressed adolescents. The cause of the elevated cortisol during the normally quiescent period warrants further investigation and may be related to other biological disturbances around sleep onset (difficulty initiating sleep, reduced rapid eye movement (REM) latency, and alterations in sleep-stimulated growth hormone secretion).

Thyroid stimulating hormone response to thyrotropin in prepubertal depression.

In an effort to evaluate whether differences exist in the hypothalamic-pituitary-thyroid axis of depressed children, a thyrotropin releasing hormone (TRH) stimulation test was administered to 55 prepubertal subjects who were divided into three groups matched for age and sex: a depressed group (endogenous N = 15, nonendogenous N = 15), a psychiatric nondepressed control group (N = 16), and a normal control group (N = 9). Each subject was tested at two dosages of TRH, 2 micrograms/kg and 7 micrograms/kg. Increasing age and female sex were positively correlated with a greater thyroid stimulating hormone (TSH) response. TSH response to TRH was examined with subjects reclassified by severe suicidal ideation, severe aggression, and parental history of alcoholism. Results of this study are contrasted with the adult psychiatric literature.

EEG sleep of young adults with major depression: a controlled study.

The EEG sleep of 75 subjects aged 16-25 years was studied. Thirty-eight were in an episode of RDC major depression, and 37 were normal controls. Only one sleep continuity measure differed between the two groups: sleep latency was significantly longer in the depressive group. REM period latencies and other sleep variables did not differ between the groups. Subgroup analyses, within the depressed group with respect to inpatient status, revealed significantly higher REM density (P less than 0.03) and a marginally shortened REM period latency (P less than 0.07) among the inpatient depressives. Subgroup analysis across suicidal ratings revealed a significantly higher REM density (P less than 0.04) among suicidal depressives. Severity estimates of depression did not correlate with sleep findings. These results parallel another recent report on adolescent depressed subjects, suggesting that inpatient and/or suicidal status is an important variable in the expression of EEG sleep abnormalities in the adolescent/young adult age group.

Hormonal responses to dextroamphetamine in depressed and normal adolescents.

Because of its neuroendocrine effects, amphetamine infusion has been used as a probe to investigate neurobiological correlates of depressive illness. In two separate studies, a total of 72 adolescents with major depressive disorder and 66 normal adolescents were given dextroamphetamine, 0.15 mg/kg, intravenously. Their cortisol, growth hormone, and prolactin responses were measured. These endocrine responses did not reliably distinguish adolescents with major depressive disorder from those without it, nor did they reliably delineate any specific depressive subgroup. These findings are compared with those from similar studies of adult depression.

Is locked seclusion necessary for children under the age of 14?

A retrospective study of the effect of the implementation of an unlocked seclusion policy was conducted on three child psychiatric inpatient units in a state hospital in Pennsylvania. Unlocked seclusion was associated with 1) increased use of tranquilizing medications administered as needed on all three units, 2) increased clustering of medications, administered as needed, in the units that used seclusion most, 3) diverse changes in the three units regarding frequency and clustering of unlocked seclusion, and 4) increased correlations between medications administered as needed and seclusion, particularly in the more behaviorally disturbed children. These findings suggest that locked seclusion may be a necessary therapeutic intervention, particularly with severely disturbed children with serious conduct and impulsive disorders.