Cortisol secretion in prepubertal children with major depressive disorder. Episode and recovery.

Plasma cortisol concentrations were measured every 20 minutes for 24 hours in a group of 45 rigorously assessed, drug-free, prepubertal children who met the unmodified Research Diagnostic Criteria for major depressive disorder (MDD), 20 children with nonaffective psychiatric disorders, and eight normal controls. All children were studied in a low-stress environment. There were no significant differences in plasma cortisol concentration among the three groups as measured by 24-hour mean, peak, nocturnal rise, or nadir values. Division of the MDD group into subgroups based on endogenicity, psychotic symptoms, and suicidality also failed to reveal significant differences for cortisol secretion. Hypersecretion of cortisol (defined as 2 SDs above the grand mean) was identified in only four children with depressive illness and one normal control. Following clinical recovery, 24 depressed children were restudied in a drug-free state and compared with themselves during the episode of illness and with both groups of controls. No significant differences in plasma cortisol concentrations were found. All four depressed hypersecretors were restudied after clinical recovery, and one showed persistence of hypersecretion. These results suggest that abnormalities of cortisol secretion occur infrequently in prepubertal children with major depression when they are studied in a nonstressful environment.

Growth hormone secretion in prepubertal children with major depression. IV. Sleep-related plasma concentrations in a drug-free, fully recovered clinical state.

Prepubertal children with major depressive disorder have shown increased growth hormone (GH) secretion during sleep while in a depressive episode. When restudied in a fully recovered state (for at least three months) and drug free (for at least one month), their increased GH secretory pattern during sleep had not changed. Illness-recovery correlations using area under the curve for GH secretion during sleep were highly significant, whereas paired comparisons showed no significant differences. In addition, children who had recovered from major depressive episodes secreted significantly more GH during sleep than did nondepressed neurotic and normal children. No significant differences in delta-sleep were found in the depressed group between ill and recovered states nor among those who had recovered from major depressive episodes or controls. It is concluded that increased GH secretion during sleep is independent of depressive episodes, remains unaltered after full recovery, and may be a true marker of trait for major depressive disorder in prepuberty.

Growth hormone secretion in prepubertal children with major depression. I. Final report on response to insulin-induced hypoglycemia during a depressive episode.

Insulin tolerance tests (ITTs) were carried out on 46 drug-free prepubertal children with severe emotional disorders. Thirteen met unmodified Research Diagnostic Criteria for major depressive disorder, definite endogenous subtype, 17 met the criteria for nonendogenous major depressive disorder, and 16 fit DSM-III criteria for nondepressed neurotic disorders. The group with endogenous depression had significant hyposecretion of growth hormone (GH) in this test when compared with the other groups. Since GH hyposecretion in response to ITT has been found in most studies to be associated with endogenous major depression in adults, the data support the validity of the diagnosis of prepubertal endogenous major depressive disorder and the hypothesis of similarity or identity of prepubertal and adult major depressive disorders.

Growth hormone secretion in prepubertal children with major depression. III. Response to insulin-induced hypoglycemia after recovery from a depressive episode and in a drug-free state.

Insulin tolerance tests (ITTs) were performed after at least four months of sustained recovery from an episode of a major depressive disorder in 18 drug-free prepubertal children. Eleven had a definite endogenous subtype; seven did not. Sixteen children with nondepressed neurotic disorders made up a control group. The children with past endogenous depression continued to have significant hyposecretion of growth hormone (GH) in this test when compared with the other groups. Illness-recovery correlations were highly significant for the major depressive group as a whole. Paired comparisons of both depressive groups were not significantly different from illness to recovery. We conclude that prepubertal children with endogenous major depression continue to have hyposecretion of GH in response to ITTs in a recovered state and that this neuroendocrine marker is state independent. A GH hyporesponse to ITT may be a true marker of a past episode or of trait for endogenous major depressive disorder in prepuberty.

Serial dexamethasone suppression tests in initial suppressors and nonsuppressors treated with electroconvulsive therapy.

Four different methods of quantifying the 1-mg Dexamethasone Suppression Test (DST) were contrasted with serial testing in endogenous depressives receiving electroconvulsive therapy (ECT). Of three continuous measures in 38 patients with pretreatment DSTs, only the log-transformed value for plasma cortisol was normally distributed, indicating that it possessed superior psychometric properties. Pretreatment Hamilton Depression Rating Scores (HAM-D) correlated positively with pretreatment DST status, with a similar association noted between posttreatment DST status and HAM-D scores. There was no uniform effect of ECT on the DST. Although pretreatment nonsuppressors showed a trend toward decreased postdexamethasone cortisol values, initial suppressors (cutoff: 5 micrograms/dl) evidenced a significant increase in these values, and 35.3% of initial suppressors were nonsuppressors at final DST assessment. These trends were noted in the DST assessment done following the third ECT treatment, suggesting an effect of regression to the mean. The findings highlight the importance of following initial DST suppressors in studies of this type.

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.

Serum prolactin levels in homosexual and bisexual men with HIV infection.

OBJECTIVE: Prolactin is a neurohormone that may be secreted in response to stress and also has regulatory effects on the immune system. Some, but not all, studies suggest that prolactin levels are higher than normal in persons with HIV infection. The authors measured prolactin levels in HIV-positive and HIV-negative homosexual and bisexual men to assess possible differences in levels and then examined relationships between prolactin level and measures of medical status, anxiety, depression, stress, and neuropsychological test performance. METHOD: Blood for prolactin level determination was obtained from 121 HIV-seropositive and 79 HIV-seronegative homosexual and bisexual men enrolled in a longitudinal study. The men also underwent a daylong assessment that included medical, immunological, psychiatric, psychosocial, psychosexual, and neuropsychological evaluations. RESULTS: There was no statistically significant difference in serum prolactin level among the seronegative men, the seropositive men with no or minimal physical symptoms, and the seropositive men with significant physical symptoms of HIV infection. Furthermore, within the HIV-seropositive group, the correlations between serum prolactin level and measures of depression, anxiety, stress, and neuropsychological test performance were all nonsignificant. CONCLUSIONS: Serum prolactin level does not seem to respond to HIV infection or to be related to stress or psychiatric symptoms in HIV-infected men. As none of the subjects had AIDS, the possibility cannot be ruled out that prolactin level increases in very late stages of HIV infection.

Glucocorticoid level and neuropsychiatric symptoms in homosexual men with HIV infection.

OBJECTIVE: There is a controversial literature suggesting that stress, anxiety, and depression are harmful to the immune system and therefore to health. Preclinical studies indicate that activation of the hypothalamic-pituitary-adrenal (HPA) axis by stress may be responsible for immunocompromise. The goal of this study was to assess this phenomenon in human immunodeficiency virus (HIV) infection. METHOD: Homosexual men in the community who did not meet modified Centers for Disease Control criteria for acquired immune deficiency syndrome (AIDS) were recruited for the study; 113 of the men were HIV positive and 77 were HIV negative. Very few of the men studied suffered from depression or anxiety disorder at the time of the first assessment. Twenty-four-hour urinary free cortisol levels were obtained from the 112 HIV-positive and 75 HIV-negative men whose 24-hour urine volumes were 500 ml or more. Cortisol levels were correlated with measures of medical, immunological, neurological, and psychiatric status. RESULTS: Small but significant correlations between 24-hour urinary free cortisol and medical status, level of depression, and level of anxiety were found in the HIV-positive group. There was no relationship between cortisol level and the number of CD4+ or CD8+ T lymphocytes or the CD4-CD8 ratio. CONCLUSIONS: Although HPA activation may be associated with stress in cases of HIV infection, it does not seem to be associated with further loss of CD4+ T lymphocytes. Subjects with HIV infection with the most evidence of medical complications may also be the most anxious and depressed.

Plasma cortisol secretion and REM period latency in adult endogenous depression.

The authors studied the relationship of plasma cortisol secretion and REM period latency in 25 patients with endogenous depression. The 8 patients (32%) with cortisol hypersecretion had a significantly shortened REM period latency in comparison with the 17 with normal cortisol secretion. Furthermore, an extremely short REM latency (20 minutes or less) occurred almost exclusively in those with cortisol hypersecretion. The authors discuss possible neurotransmitter disturbances responsible for these abnormalities and the clinical implications of these findings.

Dexamethasone suppression tests in patients with obsessive-compulsive disorder.

Obsessive-compulsive disorder and major depressive disorder are associated by several lines of evidence. To explore the possible relationship between the two disorders, the authors administered 1-mg dexamethasone suppression tests to 18 patients with obsessive-compulsive disorder and 51 patients with major depressive disorder. None of the obsessive-compulsive patients were classified as nonsuppressors on the basis of a 4:00 p.m. serum cortisol level, whereas 37% of the depressed patients were nonsuppressors. The mean cortisol levels of the two groups differed significantly. Factors that may influence hypothalamic-pituitary-adrenal function, such as age, depressive symptoms, and severity of illness, are discussed in light of these results.

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.

Cortisol levels, immune status, and mood in homosexual men with and without HIV infection.

OBJECTIVE: Alteration in cortisol levels has been reported in HIV infection and may be related to levels of psychiatric distress and immune function. The goals of this study were to assess cortisol levels in subjects with HIV infection and to determine whether stress-related activation of the hypothalamic-pituitary-adrenal (HPA) axis results in compromised immune function. METHOD: As part of a longitudinal study, the authors assessed urinary free cortisol levels of HIV-positive and HIV-negative homosexual men at four time points during a period of 2 years. Subjects' scores on the Hamilton depression and anxiety rating scales, medical stage of HIV infection, and CD4+ and CD8+ cell counts were also assessed. Repeated measures analysis of variance was used to determine whether subjects' cortisol levels at the four time points differed according to their serological status. Pearson correlation coefficients were computed to examine the relationships among mood ratings, cortisol levels, medical stages, and cell counts. RESULTS: Cortisol levels did not differ significantly between the HIV-positive and the HIV-negative subjects and were not associated with stage of medical illness in HIV infection. An association between cortisol level and depressed and anxious mood was found only at the first assessment. Cortisol level was not associated with CD4+ cell count in either group of subjects. CONCLUSIONS: There were no significant elevations of cortisol levels in the HIV-infected subjects, nor was there consistent evidence for stress-related activation of the HPA axis in either the HIV-positive or the HIV-negative subjects.

Methylphenidate response, psychopathology and tardive dyskinesia as predictors of relapse in schizophrenia.

Despite the proven efficacy of acute and maintenance pharmacotherapy in schizophrenia, practical methods for identifying patients who require continuous treatment to prevent relapse have not been established. We hypothesized that a pathologic overactivity of mesolimbic and mesocortical dopamine neural systems, that mediates positive psychotic symptoms in the acute phase of the illness, persists in some outpatients who are vulnerable to relapse despite appearing clinically stable. To test and determine if putative measures of central nervous system dopamine activity predict outcome, 41 stable outpatients receiving neuroleptic maintenance treatment underwent provocative tests with methylphenidate in a randomized double-blind placebo controlled design in which behavioral, neuromotor, biochemical, and cardiovascular responses were measured. Patients were then withdrawn from medication and monitored for 52 weeks, or until relapse. The results indicate that psychotic symptoms and their activation by methylphenidate, and the presence of tardive dyskinesia are associated with each other and with a higher risk of relapse. These findings partially support our hypothesis and offer potentially useful measures for the identification of candidates for reduced dose neuroleptic maintenance treatment strategies in schizophrenia.

The relationship of the dexamethasone suppression test (1 mg and 2 mg) to basal plasma cortisol levels in endogenous depression.

The 1 mg and 2 mg dexamethasone suppression tests (DST) were evaluated in two groups of endogenously depressed patients (n = 39 and n = 30, respectively) who also had a 1300-1600 hr basal cortisol assessment. Non-suppressors (on both DSTs) had significantly higher basal plasma cortisol levels and thus were significantly associated with relative cortisol hypersecretion. However, there was only a partial overlap between DST response and basal plasma cortisol, with a large variation of cortisol levels among non-suppressors. The 2 mg DST appears to be more specific for cortisol hypersecretion than the 1 mg DST. If cortisol hypersecretion is to be identified, neither the 1 mg or 2 mg DST is an adequate assessment nor a substitute for a basal cortisol assessment.

Predictors of response to clozapine.

Clinical and biological measures were examined for their relationship to clinical response to clozapine. Associations were found between therapeutic response and the following variables: male gender, paranoid schizophrenia subtype diagnosis, older age at onset of illness, shorter duration of illness, higher levels of pretreatment acute EPS, low pretreatment CSF HVA/5-HIAA, greater decrease in prolactin (PRL) and increase in growth hormone (GH) response to apomorphine stimulation pretreatment and greater inhibition by clozapine treatment of PRL and GH response to apomorphine, and plasma clozapine levels above 350 ng/mL. These results are consistent with other investigators' findings and have practical and heuristic implications for the use of clozapine and understanding its mechanism of action.

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.

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.

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.

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.

Growth hormone response to desmethylimipramine in depressed and suicidal adolescents.

Desipramine 75 mg i.m. was given in the morning to 20 adolescents with major depressive disorder and 23 normal controls. Depressed adolescents secreted significantly less growth hormone (GH) over the next 2 h than did normal adolescents, although a substantial proportion of the differences were accounted for by the depressed adolescents who had a specific suicidal plan or attempt during the episode. Severity of depression or the presence of other depressive symptoms did not predict GH secretion within the depressed group. Age, sex and maturational factors in the control of GH are discussed. It is concluded that these differences in GH secretion probably reflect differences in CNS beta-adrenergic and/or serotonergic function. Suicidality and depression may have different psychobiological correlates in adolescents.