Neal D. Ryan

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.

Imipramine in adolescent major depression: plasma level and clinical response

ABSTRACT Thirty‐four adolescents with mean age 14.25 years who met RDC criteria for major depressive disorder as assessed with the K‐SADS, were treated for 6 weeks on a fixed schedule of imipramine hydrochloride titrated to a dosage of 5.0 mg/kg/day except as limited by side effects. Mean dose was 246 mg/day (4.5 mg/kg/day). In spite of good indications of compliance with treatment only 44% of the adolescents improved to the level of no or only slight depressed mood or anhedonia, though most had less depressive symptomatology at the end of treatment. There was neither a linear nor curvilinear relationship between total plasma level of IMI plus DMI and clinical response, despite a wide range of both plasma level (77 ng/ml to 986 ng/ml) and outcome. Adolescents with associated separation anxiety had significantly poorer response to treatment of their depressive disorder than those with major depression alone. Poor response was also weakly associated with being female, having endogenous subtype of depression, and having higher plasma IMI (but not DMI) level. In the context of similar studies of IMI on depression in other age groups, it is hypothesized that high levels of sex hormones during adolescence and young adulthood may interfere with IMIs antidepressant effects. It is concluded that other types of antidepressants should be tested in adolescents with major depression.

Cortisol secretion in adolescents with major depressive disorder

Plasma cortisol concentrations were determined every 20 min for 24 h, in a nonstressful environment, among 48 rigorously assessed, mostly outpatient, drug‐free adolescent subjects during an episode of major depression (MDD) and among 40 normal adolescent subjects. There were no significant differences in the 24‐h mean, peak, or nadir, or the time of the nocturnal rise, in plasma cortisol in the 2 groups. Analyses of different subgroups of MDD adolescents according to suicidality, severity of depression, separation anxiety, psychotic subtype, endogenicity, duration of episode, and sex also revealed no significant group differences. Only one adolescent (with MDD) was identified clearly as a hypersecretor of cortisol. These results indicate that abnormalities of spontaneous cortisol secretion are an unusual finding among adolescents with major depression when studied in a nonstressful environment.

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.

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.

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.

Localizing functional activity in the brain through time-frequency analysis and synthesis of the EEG

Multichannel electroencephalograms (EEGs) are processed using time-frequency (TF) analysis and synthesis techniques to geometrically localize neuroelectric generators of specific activity contained within the observed EEG. The TF domain techniques are utilized to separate the signals of interest from the remainder of the EEG, by allowing the definition of regions of interest which contain the signals for which we desire to localize the underlying neuronal generators. This approach essentially introduces a filtering technique which allows the distortionless separation of the signals of interest from all other components recorded. The source of the functional activity in the brain is estimated and mapped numerically by a least-squares approach. We have applied these techniques to identify the anatomical location of the sleep spindle, a component of the EEG observed during sleep, which is of importance in understanding the generation of sleep and sleep patterns.

Three tests of cortisol secretion in adult endogenous depressives.

ABSTRACT Seventy‐nine drug‐free adult patients fitting RDC criteria for major depressive disorder endogenous subtype (EMDD), and 64 normal adult volunteers, were studied al pretreatment with at least one of three tests of cortisol secretion. The tests were: 1) Mean half‐hourly cortisol concentrations from 1 p.m. to 4 p.m. (1‐4 PM CORT); 2) plasma cortisol response to 0.15 mg/kg of dextroamphetamine hydrochloride (DACT) in the afternoon; 3) dexamethasone suppression test (DST) using 1 or 2 mg. Thirty‐six depressives and 27 volunteers underwent all three tests. Analysis of the data was performed for each test singly, for all pairs of tests and for all three tests in same subjects. Results show that the single most sensitive cortisol test for depressions is the DACT (72 %), with a specificity of 88 %. These tests may measure different underlying path (c)physiologies associated with depression.

Relative Safety of Single Versus Divided Dose Imipramine in Adolescent Major Depression

Abstract Twenty-nine adolescents with Major Depressive Disorder were treated with imipramine on a t.i.d. dosage schedule for 3 weeks titrating to a maximal 5.0 mg/kg/day as limited by side effects (X = 4.5 ± 0.7). They were then randomly divided into two groups: 16 received their total dose at 10 P.M., after standard divided doses at 7 A.M. and 3 P.M. that same day, and then no more imipramine during the subsequent 24 hours, whereas 13 continued t.i.d. dosage. EKG and plasma TCA levels in both groups were serially examined over the next 24 hours. There were no significant differences between groups in the per subject means or maxima of any EKG parameter. These data suggest that a once daily dosage schedule for imipramine is safe in adolescents once they are at steady rate. Although there was a strong relationship between the tricyclic plasma levels and EKG parameters throughout the day, EKG parameters cannot be used to predict plasma levels—there was wide variation in this relationship between individuals, and even within individual adolescents the plasma level could change over a wide range without any change in EKG parameters.

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.