Randomized, controlled trial of amitriptyline versus placebo for adolescents with "treatment-resistant" major depression.

OBJECTIVE: To assess the response to a serotonergic/noradrenergic tricyclic antidepressant, amitriptyline (AMI), in a group of adolescents with treatment-resistant major depressive disorder (MDD). METHOD: Twenty-seven depressed adolescents admitted to a state hospital underwent a 10-week randomized, controlled trial with a flexible dose of AMI or placebo. RESULTS: There were no differences between patients taking AMI (n = 13) and placebo (n = 14). Both treatment groups showed approximately 70% to 80% improvement on the clinical outcome measurements, and 65% to 70% showed functional improvement. At the end of the protocol, 30% of patients still fulfilled criteria for MDD and had impaired functioning. Patients taking AMI experienced significantly more dry mouth and tachycardia. The final AMI dose was 173.1 mg/day +/- 56.3 mg/day; blood levels were 226.2 ng/mL +/- 80.8 ng/mL. CONCLUSIONS: No significant differences were found between AMI and placebo, in part because of the high placebo response rate. Although both treatment groups showed substantial response, at the end of treatment a substantial proportion of patients still had MDD of subsyndromal symptoms of depression. This and other studies of tricyclic antidepressants question the use of this medication as first-line treatment for youths with MDD.

Neuroendocrine response to 5-hydroxy-L-tryptophan in prepubertal children at high risk of major depressive disorder.

BACKGROUND: Altered serotonergic function has been observed in prepubertal children and adults with an acute episode of major depressive disorder (MDD). However, it is not known whether these alterations are present prior to the onset of MDD. METHODS: A serotonergic precursor, 5-hydroxy-L-tryptophan (L-5HTP) (oxitriptan) (0.8 mg/kg), was administered through an indwelling catheter to 36 children at high risk of MDD (with high family loading for MDD), 31 children with MDD, and 23 low-risk normal controls (with low family loading for mood disorders and no history of psychopathology). Blood samples for cortisol, prolactin (PRL), and growth hormone were obtained every 15 minutes for 180 minutes, beginning 30 minutes before L-5HTP infusion. RESULTS: Children at high risk of MDD and children with MDD had similar hormonal responses following L-5HTP infusion. After controlling for baseline values, both groups secreted significantly less cortisol and more PRL than did the low-risk normal controls, with the PRL finding being limited to girls. There were no between-group differences in baseline cortisol, PRL, or growth hormone secretion measures. CONCLUSIONS: Before the onset of affective illness, high-risk children had the same pattern of neuroendocrine response to the L-5HTP challenge as did children with MDD. These results extend earlier findings of altered serotonergic regulation in association with early-onset depression and indicate that these alterations may represent a trait marker for depression in children.

A randomized, controlled trial of amitriptyline in the acute treatment of adolescent major depression.

OBJECTIVE: To determine amitriptyline's (AMI) efficacy in the acute treatment of adolescent major depressive disorder (MDD). METHOD: Subjects aged 12 through 17 years meeting Research Diagnostic Criteria for MDD, diagnosed with the Schedule for Affective Disorders and Schizophrenia for School-Age Children (K-SADS), participated in a 2-week placebo-washout followed by an 8-week, randomized, double-blind, parallel-design, placebo-controlled trial of AMI, 5 mg/kg per day. The K-SADS nine-item scale, the Hamilton Depression Rating Scale, and the Clinical Global Impressions rating scale were used as outcome measures. RESULTS: Thirty-one subjects were randomized (18 AMI, 13 placebo). Twenty-two subjects were study completers (12 AMI, 10 placebo). AMI's efficacy was suggested by the Clinical Global Impressions but not the K-SADS-derived data. Perhaps the primary limitation of the current study is its small sample size. CONCLUSION: No definitive recommendation can be made regarding the efficacy of tricyclic antidepressants in the treatment of adolescent MDD.

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.

Fluoxetine for childhood anxiety disorders.

OBJECTIVE: The objective of this open study was to determine the efficacy and safety of fluoxetine for the treatment of children and adolescents with anxiety disorders. METHOD: Twenty-one patients with overanxious disorders, social phobia, or separation anxiety disorder, who were unresponsive to previous psychopharmacological and psychotherapeutic interventions, were treated openly with fluoxetine for up to 10 months. Patients with lifetime histories of obsessive-compulsive disorder (OCD) or panic disorder, or with current major depression, were excluded. Beneficial and adverse effects of fluoxetine were ascertained using the improvement and severity subscales of the Clinical Global Impression Scale (CGIS) in two ways: (1) independent chart reviews by two child psychiatrists and (2) prospective assessments by the treating nurses and the patients' mothers. RESULTS: Eighty-one percent (n = 17) of patients showed moderate to marked improvement in anxiety symptoms. The severity of anxiety as measured by the CGIS was also significantly reduced from marked to mild (effect size: 2.3). There were no significant side effects. CONCLUSIONS: These results suggest that fluoxetine may be an effective and safe treatment for nondepressed children and adolescents with anxiety disorders other than OCD and panic disorder. Future investigations using double-blind, placebo-controlled methodologies are warranted.

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.

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.

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.