Psychotic symptoms in prepubertal major depressive disorder.

Symptoms of psychosis and psychoticlike phenomena were systematically inquired for, using a semistructured diagnostic interview protocol, in 58 prepubertal children who fulfilled Research Diagnostic Criteria for major depressive disorder. Subjects were classical into endogenous and nonendogenous subtypes. Forty-eight percent of the sample reported hallucinations. Thirty-six percent (including 48% of those in the endogenous subtype and 24% of those in the nonendogenous subtype) reported auditory hallucinations that consisted of one or more words other than their names, experienced in clear consciousness. Sixteen percent reported visual or tactile hallucinations. Four children were rated as having delusional ideas. Symptoms were analyzed in terms of contents, formal characteristics, thematic and temporal consistency with depressed mood, extent of the child's belief in the reality of the experience, frequency, and experienced location of auditory hallucinations. The psychopathologic meaning of the reported phenomena is uncertain.

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.

Electroencephalographic sleep of adolescents with major depression and normal controls.

Forty-nine, mostly outpatient (86%), nonbipolar adolescents, aged Tanner stage III to 18 years, with a current diagnosis of major depressive disorder and 40 adolescents without current presence or history of psychiatric disorder were studied polysomnographically for three consecutive nights. Sleep latency was significantly longer in the depressive groups. The nonendogenous depressive patients exhibited significantly more awake time and lower sleep efficiency during the sleep period. No significant group differences were found for first rapid eye movement (REM) period latency, REM density, or any other REM sleep measures. Age correlated significantly with REM latency and delta sleep time, especially among depressive patients. No significant correlations between sleep measures and severity of illness were found. It appears that the classic REM sleep findings associated with the adult depressive syndrome are not present among depressive adolescents, indicating a later ontogeny for these abnormalities.

Sleep architecture and REM sleep measures in prepubertal major depressives. Studies during recovery from the depressive episode in a drug-free state.

The sleep of 28 fully recovered, drug-free, prepubertal patients with major depressive disorder was recorded for three consecutive nights in the laboratory. Recovered depressives had significantly shorter first rapid eye movement period (REMP) latencies and a higher number of REMPs compared with themselves when depressed and with nondepressed neurotic and normal children. In addition, most sleep continuity measures improved considerably on recovery. We suggest that a short first REMP latency may be a marker of past episode or of trait in prepubertal major depressives.

Psychosocial functioning in prepubertal major depressive disorders. I. Interpersonal relationships during the depressive episode.

Psychosocial environment and relationships with parents, peers, and siblings of 115 prepubertal children were measured by interview with their parent(s) for the three-month period preceding the assessment. The children had a current diagnosis of major depression (52 children) or nondepressed neurotic disorder (23) or were assessed to be normal (40). Most aspects of psychosocial relationships were found to be significantly impaired in the psychiatric groups. This impairment was generally worse in the depressives and significantly worse for aspects of verbal and affective communication with parents and siblings. Prepubertal children with major depressive disorder regularly present social relation deficits in which two components can be distinguished: one general to childhood psychiatric disorder and another specific to major depression.

Psychosocial functioning in prepubertal major depressive disorders. II. Interpersonal relationships after sustained recovery from affective episode.

Psychosocial relationships with parents, peers, and siblings, as well as school functioning, were measured at two points in time by parental interview in 21 prepubertal children: during an episode of major depression and after they had sustained an affective recovery from the index episode for at least four months. School functioning was completely normalized, but deficits in the child's intrafamilial and extra-familial relationships had improved only partially. The pattern of improvement was merely quantitative. Moderate deficits during the depressive episode reached, after affective recovery, the level of the normal control group. In contrast, severe deficits only improved to a moderate level of severity. It is suggested that treating the affective disorder is not sufficient in many children with major depression and that efficacy studies of psychotherapeutic interventions in affectively recovered children are needed.

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.

A controlled family history study of prepubertal major depressive disorder.

First-degree (N = 195) and second-degree (N = 785) adult relatives of prepubertal children with major depression (N = 48), children with nonaffective psychiatric disorders (N = 20), and normal children (N = 27) were assessed by the Family History-Research Diagnostic Criteria method (FH-RDC), except for the adult informant (usually the mother), who was directly interviewed. Compared with normal controls, prepubertal children with major depressive disorder (MDD) had significantly higher familial rates of psychiatric disorders in both first- and second-degree relatives, especially MDD, alcoholism, and "other" (mostly anxiety) diagnoses. Relatives of children in the nonaffective psychiatric control (PC) group had low rates of alcoholism, high rates of other (anxiety) disorder diagnoses, and intermediate rates of MDD (accounted for by those children with separation anxiety). This suggests that prepubertal onset of major depression may be especially likely in families with a high aggregation of affective disorders when these families also have a high prevalence of alcoholism, and that a proportion of children without affective disorder but with separation anxiety disorder in this study were at high risk for the development of affective illness later in life. These results support the validity of prepubertal-onset depressive illness as a diagnostic category, and are consistent with high familial rates of MDD and other psychiatric disorders found in family studies of adolescent and early-onset adult probands with major affective disorders, and with studies of the offspring of parents with major affective disorders. Within the child MDD group substantial heterogeneity was found. Low familial rates of MDD were associated with suicidality and comorbid conduct disorder in the child probands. The highest familial rates of MDD, approximately threefold those in the normal controls, and all the bipolar relatives, were found in the families of prepubertal probands with MDD who never had a concrete suicidal plan or act and who were without comorbid conduct disorder. A useful nosological continuum in which to classify prepubertal MDD may be to place at one end those patients with comorbid conduct disorder and at the other end those patients with manifestations related to bipolarity, including hypomania, mania, and psychotic subtype.

Imipramine in prepubertal major depressive disorders.

The potential effectiveness of imipramine hydrochloride (up to 5 mg/kg/d) was investigated in 53 prepubertal children suffering from major depressive disorder. Two complementary strategies were used simultaneously: a five-week, double-blind, placebo-controlled design (N = 38), and a plasma level/clinical response study (N = 30). Fifteen of the 16 children randomly assigned to active drug in the first study also participated in the second. Subjects were assessed using the Schedule for Affective Disorders and Schizophrenia for School Age Children and diagnosed according to unmodified Research Diagnostic Criteria. Response rates in the double-blind study were similar in both groups (imipramine, 56%; placebo, 68%). In the plasma level study, total maintenance plasma level (imipramine plus desipramine) was found to positively and linearly predict clinical response of the depressive syndrome (P less than .003). No evidence of a curvilinear relationship was found. Depressive hallucinations during the episode negatively predicted clinical response (P less than .05). Weight-corrected imipramine dosage did not predict either clinical response or plasma level in the individual subject. No predictors of response were found in the placebo group. These results suggest that the mean imipramine dosage was too low, and that future double-blind, placebo-controlled studies of imipramine in prepubertal major depression should include plasma level titration to above 150 ng/mL and an initial placebo washout period.

The clinical picture of major depression in children and adolescents.

Symptom frequency and severity were compared in two sequential clinically referred samples of 95 children and 92 adolescents, aged 6 to 18 years, all medically healthy, assessed with the Schedule for Affective Disorders and Schizophrenia for School Age Children, Present Episode, who met unmodified Research Diagnostic Criteria for major depressive disorder (MDD). There were no significant differences between the two groups in the majority of depressive symptoms. However, prepubertal children had greater depressed appearance, somatic complaints, psychomotor agitation, separation anxiety, phobias, and hallucinations, whereas adolescents had greater anhedonia, hopelessness, hypersomnia, weight change, use of alcohol and illicit drugs, and lethality of suicide attempt, but not severity of suicidal ideation or intent. Adolescents with a duration of the depressive episode of two years or greater had significantly higher rates of suicidal ideation and intent, lethality, and number of suicide attempts than youngsters with depressive episodes of shorter duration. A principal components factor analysis of psychiatric symptoms was carried out in all 296 youngsters evaluated during the same period who met DSM-III criteria for any Axis I diagnosis. The majority had an affective disorder. Factors were quite similar for both adolescents and children and included an "endogenous" and an "anxious" factor, as in many studies of adult depression. In addition, three other factors were found: negative cognitions, appetite and weight changes, and a conduct factor. Suicidal ideation was a component of both the negative cognitions factor and the conduct factor.(ABSTRACT TRUNCATED AT 250 WORDS)

Sleep architecture and REM sleep measures in prepubertal children with major depression: a controlled study.

We performed a three-night polysomnographic study of 54 rigorously assessed, drug free, prepubertal children who fit unmodified Research Diagnostic Criteria for major depressive disorder, and two groups of nondepressed controls (25 with emotional disorders and 11 who were normal). The groups did not differ polysomnographically, even though a high proportion of depressives and neurotics reported sleep disturbance in structured interviews. Sleep stage data do not appear to differentiate children with prepubertal major depressive disorders from nondepressed neurotic or normal children. Other psychobiologic findings in prepubertal depressives together with marked age effects on polysomnographic correlates of adult major depressive disorders suggest the hypothesis that polysomnographic abnormalities in adult major depressives are secondary to an interaction between depression and age.

Growth hormone secretion in prepubertal children with major depression. II. Sleep-related plasma concentrations during a depressive episode.

Plasma growth hormone (GH) concentrations were determined every 20 minutes during sleep in 71 prepubertal children: 22 had endogenous major depressive disorder, 20 had nonendogenous major depressive disorder, 21 had nondepressed neurotic disorders, and eight were normal. Both depressive groups secreted significantly more GH during sleep than did controls. Measures included maximal GH plasma peak and area under the curve (AUC) during the total sleep period, during the first three hours after sleep onset, and during the first five hours after sleep onset. An AUC cutoff of 2,000 ng X min/mL identified positively half the prepubertal children with major depression; with a specificity of 78% (v neurotics) and 100% (v normal children). Increased GH secretion during sleep may be a marker of illness, a past episode, or trait for prepubertal major depression regardless of endogenicity.

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.

The assessment of affective disorders in children and adolescents by semistructured interview. Test-retest reliability of the schedule for affective disorders and schizophrenia for school-age children, present episode version.

The reliability of assessment of Research Diagnostic Criteria and DSM-III axis I affective disorders in children and adolescents was studied using a semistructured diagnostic interview. The Schedule for Affective Disorders and Schizophrenia (SADS) for School-Age Children (Kiddie SADS) Present Episode Version, an adaptation of the adult SADS for children was used. Fifty-two subjects, aged 6 through 17 years, were interviewed in a test-retest format by one of three pairs of interviewers. Assessment of symptoms and composite scales of the depressive syndrome were determined to have acceptable reliability, as were three depressive diagnoses. Conduct disorder was assessed with high reliability. Four anxiety disorders and their composite symptoms were assessed with unacceptable reliability; only separation anxiety was assessed with acceptable reliability. The results of this study showed generally lower reliability of symptoms, scales, and diagnoses than did two studies of adults using the SADS.

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.

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.

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).

Prepubertal endogenous major depressives hyposecrete growth hormone in response to insulin-induced hypoglycemia.

Insulin tolerance tests (ITT) were carried out during illness in 27 drug-free prepubertal children with emotional disorders: 10 fit unmodified Research Diagnostic Criteria (RDC) for major depressive disorder endogenous subtype, 10 fit RDC for nonendogenous major depressive disorder, and 7 fit DSM-III criteria for nondepressed neurotic disorders. The endogenous depressed group hyposecreted growth hormone (GH) in this test as compared to the other groups. Since GH hyposecretion in response to ITT is a characteristic of adult endogenous depressives, the data support the validity of the diagnosis of prepubertal endogenous major depressive disorder and the hypothesis of similarity of prepubertal and adult major depressions.