Treatment of consecutive episodes of major depression in the elderly.

OBJECTIVE: The purpose of this study was to determine treatment outcome in elderly patients with consecutively treated episodes of recurrent unipolar major depression. METHOD: Subjects were 32 "young" elderly patients with recurrent unipolar depression (mean age = 66.8 years, SD = 5.1) and with two consecutively treated episodes of major depression. Both index and subsequent episodes of major depression were treated in open trial with combined nortriptyline and interpersonal psychotherapy. Rates of remission in index and subsequent episodes were compared by using nonparametric statistics and survival analysis with proportional hazards modeling. RESULTS: Of 30 patients who completed treatment of the subsequent episode, 27 (90%) achieved stable remission of symptoms in both consecutively treated episodes, whereas three patients (10%) did not. Twenty-two (81%) of 27 patients who responded to treatment had a shorter time to remission in treatment of the subsequent episode than in the index episode. Survival analysis with proportional hazards modeling detected a significant difference in time to remission of the index and subsequent episodes (32 paired observations). CONCLUSIONS: In this research study group, recurrent episodes of unipolar major depression in the young elderly were successfully treated to remission in over 80% of patients by using combined pharmacotherapy and psychotherapy similar to that employed in treatment of the index episode. Remission rate and time to remission in consecutively treated episodes were comparable to those in a group of midlife patients with recurrent depression reported by Kupfer et al. in 1989. Thus, recurrent depressive disorder appears to be as treatable in the young elderly as it is in midlife patients.

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.

Efficacy of phenelzine and haloperidol in borderline personality disorder.

OBJECTIVE: To compare the efficacy of a neuroleptic (haloperidol) to a monoamine oxidase inhibitor antidepressant (phenelzine sulfate) against the affective, cognitive, and impulsive-aggressive symptoms of criteria-defined borderline inpatients in an effort to dissect apart affective and schizotypal symptom patterns or subtypes using medication response. DESIGN: Randomized, double-blind, placebo-controlled trial. SETTING: Inpatient unit of a tertiary care university psychiatric hospital serving a large public catchment area. PATIENTS: One hundred eight consecutively admitted borderline inpatients defined by Gunderson's Diagnostic Interview for Borderline Patients and DSM-III-R criteria, randomly assigned to 38 phenelzine, 36 haloperidol, and 34 placebo trials. INTERVENTIONS: Following 1 week free of medication, haloperidol (average dose, 4 mg/d), phenelzine sulfate (average dose, 60 mg/d), or placebo were given for 5 weeks with weekly symptom ratings and plasma drug level determinations. MAIN OUTCOME MEASURES: Efficacy was measured on depression (Hamilton Rating Scale, Beck Depression Inventory), global severity (Global Assessment Scale, Symptom Checklist-90 items [SCL-90]), anxiety, anger-hostility (SCL-90, Inpatient Multidimensional Psychiatric Scale [IMPS], Buss-Durkee Hostility Inventory), psychoticism (Schizotypal Symptom Inventory, SCL-90, IMPS), impulsivity (Ward Scale, Barratt Impulsiveness Scale, Self-Report Test of Impulse Control), and borderline psychotherapy (Borderline Syndrome Index). RESULTS: Three-way comparisons between groups indicated superior efficacy for phenelzine, followed by placebo and haloperidol on measures of depression, borderline psychopathologic symptoms, and anxiety. Pairwise comparisons between medication and placebo revealed significant efficacy for phenelzine against anger and hostility but no efficacy against atypical depression or hysteroid dysphoria. We were unable to replicate prior reports of efficacy for the neuroleptic. CONCLUSIONS: Pharmacologic dissection of borderline personality disorder patients into affective and schizotypal subtypes could not be demonstrated.

Combined pharmacotherapy and psychotherapy in the acute and continuation treatment of elderly patients with recurrent major depression: a preliminary report.

OBJECTIVE: The authors examined the rate of response to the combination of nortriptyline and interpersonal psychotherapy for acute and continuation treatment of elderly patients with recurrent major depression. METHOD: The subjects were 73 elderly patients, 61 of whom completed treatment. Nortriptyline steady-state blood levels were maintained at 80-120 ng/ml, and interpersonal psychotherapy was administered weekly for 9.1 weeks (medium) of acute therapy and was decreased from biweekly to triweekly during 16 weeks of continuation therapy. During acute treatment nonresponding patients also received brief adjunctive pharmacotherapy with lithium or perphenazine. RESULTS: Of the 61 subjects given adequate trials of nortriptyline and interpersonal psychotherapy, 48 (78.7%) achieved full remission (Hamilton depression rating of 10 or lower over 16 weeks of continuation therapy), 10 patients (16.4%) did not respond (Hamilton rating never below 15), and three achieved only partial remission (Hamilton rating of 11-14). Early versus late onset was not associated with a difference in response rate. During the placebo-controlled, double-blind transition to maintenance therapy, 19 (76.0%) of the 25 patients randomly assigned to placebo maintenance conditions showed continued recovery and six relapsed. None of the 24 patients assigned to nortriptyline conditions relapsed. CONCLUSIONS: Use of nortriptyline plus interpersonal psychotherapy for 9.1 weeks (median) of acute and 16 weeks of continuation therapy appears to be associated with good response and relatively low attrition but about a 25% chance of relapse during double-blind discontinuation of nortriptyline. These data require confirmation in a controlled clinical trial of acute and continuation therapy.

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.

Debrisoquine hydroxylation phenotyping in geriatric psychopharmacology.

The metabolic ratios (MRs) between debrisoquine (DBQ) and 4-hydroxydebrisoquine in urine after a single dose of 10 mg DBQ was determined in 175 unmedicated, healthy subjects older than age 59 (mean of 75 years). Creatinine clearance was determined on the same 8-hour urine collection. Test procedures were well tolerated in all cases. Although age was significantly correlated with creatinine clearance (r = -.38), there was no relationship between age and MR. Analysis by kernel density estimation revealed a bimodal distribution of MRs with an antimode of 11.6. Six subjects (3.4%) were categorically slow DBQ metabolizers (MR greater than 11.6). The proportion of elderly slow metabolizers approaches the lower range determined in a younger population. Our findings, that DBQ oxidative metabolism does not necessarily change with aging, alone, and that (genetic) slow DBQ metabolizers endure into old age, remaining at risk for treatment with many commonly used psychotropics, suggests the need to study the relevance of metabolic phenotyping in elderly psychiatric patients.

Serum nortriptyline levels in nursing mothers and their infants.

The nortriptyline levels of seven depressed mothers and their breast-fed infants were obtained. Nortriptyline was not detected in the infants' sera. However, two of four infants evaluated developed low concentrations of 10-hydroxynortriptyline. No adverse effects were observed.

Acute open-trial nortriptyline therapy of bereavement-related depression in late life.

BACKGROUND: The aim of this study was to generate preliminary data on the clinical efficacy of nortriptyline in bereavement-related depression in late life. METHODS: Data are presented on 13 patients (5 men, 8 women), ranging in age from 61 to 78 years (mean = 71.1). Mean time from spousal loss to the beginning of treatment was 11.9 months (range 2-25). Subjects were required to meet Research Diagnostic Criteria for syndromal current major depression and to have a stable Hamilton Rating Scale for Depression (HAM-D) score of greater than or equal to 15. Ten of the 13 volunteers were experiencing their first lifetime episode of major depression. Patients were treated with nortriptyline (mean dose = 49.2 mg/day; mean steady-state level = 68.1 ng/mL). Ratings performed at base-line and weekly during therapy were used to assess symptomatology, intensity of grief, level of functioning, social support, physical impairment, and medication side effects. RESULTS: Pretreatment HAM-D ratings average 22.1 +/- 3.6; posttreatment, 7.2 +/- 2.8, representing a 67.9% decrease. All other rating scales showed significant clinical improvement, except the Texas Revised Inventory of Grief (a measure of grief intensity) (pretreatment, 51.4 +/- 7.3; posttreatment, 46.6 +/- 6.9, only a 9.3% decrease). CONCLUSIONS: These results suggest that nortriptyline is associated with significant symptomatic improvement in all areas of bereavement-related depression except continued intensity of grief after a median treatment interval of 6.4 weeks. This study indicates the need for a controlled clinical trial to determine the placebo response rate, the relapse rate after discontinuation of medication, and the value of combination therapy (using both pharmacotherapy and psychotherapy).

Clomipramine and EEG sleep in depression.

Recent studies with clomipramine (CMI) have demonstrated that a pulse-loading approach is associated with a rapid improvement in symptomatology in the absence of continuous treatment. In the present study, sleep changes were evaluated to ascertain the rapidity of clomipramine's effect on electroencephalographic sleep, especially rapid eye movement (REM) and delta wave sleep measures. Clomipramine produced rapid changes in sleep with reduced sleep continuity and almost complete suppression of REM sleep as well as a redistribution of slow wave sleep. Delta waves during sleep were also found to be shifted to the earlier part of the night and increased in intensity. Spectral analysis revealed an increase in power in the delta frequency range that was correlated with clinical responsiveness. These studies point toward a role for clomipramine in the rapid treatment of depression and confirm that sleep physiology may be a good predictor of antidepressant action.

Early recurrence in unipolar depression.

While some advances have occurred in the maintenance treatment of unipolar depression, empirical data on recurrences of illness following the discontinuation of medication are sparse. We examined survival time during the first 18 months after discontinuation of medication in 74 patients with recurrent unipolar depression. Although demographic characteristics, clinical characteristics, and pharmacologic treatment variables failed to predict time to recurrence, continued interpersonal psychotherapy was significantly related to longer survival time.

Open-trial maintenance pharmacotherapy in late-life depression: survival analysis.

We report preliminary findings from an ongoing, open trial of maintenance nortriptyline pharmacotherapy in 27 elderly depressed patients (median trial length: 18 months). While patients were on maintenance nortriptyline (mean dose: 50 mg/day) with steady-state plasma levels in the range of 50-150 ng/ml, 58% of Q-6 monthly ratings on the Hamilton Rating Scale for Depression have been 10 or lower, Folstein Mini-Mental State ratings have remained above 27, and a minimal level of side effects with no increase over time has been observed. Four of 27 patients (14.8%) have suffered recurrences and have required rehospitalization at 6, 9, 10, and 13 months. Survival analysis showed an 85% survival rate (without recurrence) at 12 months and 81.5% at 18 months. Mean survival time without recurrence is 21.3 months to date. Although our pilot experience with maintenance nortriptyline in late-life depression appears more favorable than outcomes reported in earlier naturalistic studies (where no attempt was made to keep patients in systematic maintenance therapy), the need for controlled studies of maintenance therapies in late-life depression is nonetheless underscored by the current data and other naturalistic data from the United Kingdom.