Antidepressants and breast-feeding.
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Antidepressive Agents, Tricyclic↗
Biomedical subjects
J M Perel
Publications and source records attributed to J M Perel.
Nocturnal ACTH, cortisol, growth hormone, and prolactin secretion in prepubertal depression.
OBJECTIVE: To examine nocturnal secretion of adrenocorticotropin, cortisol, growth hormone, and prolactin in 38 medically healthy children with prepubertal major depression compared with 28 medically and psychiatrically healthy control children. METHOD: Prior to sampling, subjects underwent an "adaptation night" with the intravenous catheter in place and electroencephalographic (EEG) electrodes for standard all-night polysomnogram. On the following night, plasma samples were obtained every 20 minutes through an indwelling catheter. Hormonal concentrations were measured by specific radioimmunoassay and aligned by EEG-confirmed sleep onset. Areas under the curve were calculated for total secretion and compared using analysis of variance. RESULTS: Prepubertal depressed children had lower cortisol secretion during the first 4 hours after sleep onset compared with controls. Adrenocorticotropin, prolactin, and growth hormone secretion did not differ between groups. Examination of clinical characteristics in depressed children revealed lower nocturnal adrenocorticotropin concentrations in depressed inpatients versus depressed outpatients and in depressed sexually abused versus depressed nonabused children. A significant sex by diagnosis effect revealed lower growth hormone secretion in depressed females compared with depressed males. CONCLUSIONS: In contrast to neuroendocrine challenge studies in these same subjects, nocturnal neuroendocrine measures did not reveal any of the expected group differences. These results emphasize the contrasts between unstimulated and challenge studies of neuroendocrine secretion and of the importance of considering clinical characteristics and maturation influences in biological studies of prepubertal depression.
Adolescent↗
Treatment outcome in recurrent major depression: a post hoc comparison of elderly ("young old") and midlife patients.
OBJECTIVE: The authors compared response rates, the temporal course of response to acute treatment, and relapse rates during continuation treatment of elderly and midlife patients with recurrent major depression. METHOD: They analyzed results from two separate controlled studies of maintenance therapies for recurrent major depression, in which 148 elderly patients (mean age = 67.9 years) and 214 midlife patients (mean age = 38.5 years) were treated in open acute and continuation therapy with a combination of interpersonal psychotherapy and a tricyclic antidepressant (nortriptyline for the elderly, imipramine for the midlife patients). In an intent-to-treat analysis, remission rates during acute treatment and relapse rates during continuation treatment were examined. Random regression analysis of weekly Hamilton depression scale ratings was used to compare the temporal course of response. RESULTS: During acute-phase therapy, 78.4% (N = 116) of the elderly patients and 69.6% (N = 149) of the midlife patients had remissions. The midlife patients had a faster reduction of Hamilton depression ratings. Following stabilization, 15.5% of the elderly patients and 6.7% of the midlife patients relapsed. Ultimately, 66.2% of the late-life patients and 57.0% of the midlife patients recovered fully. CONCLUSIONS: Older patients appear to benefit as much as, but perhaps more slowly then, midlife patients from treatment of major depression. Continuation treatment should be vigorous and closely monitored, given the apparently higher relapse rates among the elderly. These conclusions should be viewed as preliminary because of the post hoc nature of the analysis reported here.
Adult↗
High relapse rate after discontinuation of adjunctive medication for elderly patients with recurrent major depression.
OBJECTIVE: The authors documented outcomes of elderly depressed patients requiring adjunctive medication during acute-phase pharmacotherapy because of slow or partial response to nortriptyline. Twenty-eight patients (17.7%) received inpatient care at some point during acute-phase treatment. METHOD: Rates of response, relapse, and sustained remission were examined in 158 elderly patients with recurrent major depression, grouped by whether they received brief treatment with adjunctive medication (lithium, perphenazine, or paroxetine) (N = 39) or did not (N = 119). RESULTS: The group receiving adjunctive medication had a lower rate of response to acute therapy (64.1% versus 83.2%), a higher relapse rate during continuation therapy (52.0% versus 6.1%), and a lower rate of sustained remission (recovery) (48.7% versus 76.5%) than did the group without augmentation. CONCLUSIONS: Elderly depressed patients requiring augmented pharmacotherapy to achieve remission may need continuation of adjunctive medication to remain well and to avoid early relapse. Alternatively, factors that lead to augmentation in the first place (e.g., heightened anxiety) may also increase the risk of relapse.
Age Factors↗
Nortriptyline treatment of breast-feeding women.
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Breast Feeding↗
Antidepressant treatment during breast-feeding.
OBJECTIVE: The primary purpose of this article is to review critically the literature about use of antidepressants during lactation. Strategies for the clinical management of depressed breast-feeding mothers are also suggested. METHOD: The authors conducted a computerized search of MEDLINE for articles. The review includes studies in which serum levels of drugs were obtained from nursing infants. RESULTS: Fifteen published reports were located that provided information for the following nine antidepressants: amitriptyline, nortriptyline, desipramine, clomipramine, doxepin, dothiepin, fluoxetine, sertraline, and bupropion. CONCLUSIONS: Amitriptyline, nortriptyline, desipramine, clomipramine, dothiepin, and sertraline were not found in quantifiable amounts in nurslings, and no adverse effects were reported. Therefore, these are the drugs of choice for breast-feeding women. Adverse effects were described in some young infants whose mothers had been treated with doxepin or fluoxetine during breast-feeding. The collective serum level data suggest that infants older than 10 weeks are at low risk for adverse effects of tricyclics, and there is no evidence of accumulation. Research needs include an expanded database of mother-baby serum levels, behavioral assessments of infants during nursing, and longitudinal developmental evaluation of nurslings. Prescription of an antidepressant for a breast-feeding woman is a case-specific risk-benefit decision.
Age Factors↗
The relationship of plasma imipramine and N-desmethylimipramine to response in panic disorder.
This report is a descriptive summary of the relationship between response and plasma tricyclic concentrations found in our previously reported dose-ranging study of imipramine (IMI) in panic disorder (Mavissakalian & Perel 1995). In addition, we explore the relative strength with which plasma levels of the parent compound (IMI) and N-desmethylimipramine predict the probability of response in the total plasma range for which there was continued improving response. The results, which indicated that IMI was the better predictor, are briefly discussed from a neurobiochemical perspective. Specifically, it is suggested that imipramine's effects are mediated predominantly through its serotonergic action and that the increased noradrenergicity of the drug with increasing total plasma concentrations reduces its potency, in particular its antiphobic effects, in panic disorder with agoraphobia.
Adult↗
Quantitative determination of perphenazine and its metabolites in plasma by high-performance liquid chromatography and coulometric detection.
An accurate, reliable method has been developed for the therapeutic monitoring of perphenazine (PPZ) and its major metabolites in human plasma samples. Steady-state plasma levels of PPZ and its metabolites were quantitated for 30 elderly patients (mean age: 75) undergoing concurrent treatment with nortriptyline (NT) and PPZ, doses ranging from 4 to 32 mg/day for PPZ. The assay was suitable with patients on concurrent medications, and smaller patient plasma volumes (1 ml) were used indicating sufficient sensitivity and specificity. After plasma extraction and separation on a Nucleosil 5-microns C18 column, the recoveries (mean +/- S.D.) of PPZ and its metabolites were determined; perphenazine 92 +/- 7.5%, deshydroxyethylperphenazine 81 +/- 7.2%, perphenazine sulfoxide 68 +/- 6.4%, and 7-hydroxyperphenazine 45 +/- 5.5%. The assay also had limits of quantitative detectability for PPZ and its metabolites as follows: perphenazine 0.5 ng/ml, deshydroxyethylperphenazine 1.0 ng/ml, perphenazine sulfoxide 0.5 ng/ml, and 7-hydroxyperphenazine 5 ng/ml. Inter-assay reproducibility (C.V.) for the quality controls and patient samples ranged from 18.8 to 2.4%. The sensitivity and reproducibility of this method should improve PPZ therapeutic drug monitoring and research on interactions in depressed geriatric patients.
Aged↗
Does recruitment method make a difference? Effects on protocol retention and treatment outcome in elderly depressed patients.
The specific aim of this study was to contrast effects of recruitment method (solicited, referred) on demographic, psychosocial, medical, and treatment outcome measures in an ongoing clinical trial of maintenance therapies in late-life depression. Data from 125 elderly patients (56 solicited via media campaign, 69 clinically referred) with recurrent, unipolar major depression were available for analysis. Several statistical contrast procedures, including group t tests, chi 2 tests, survival analysis, and logistic regression, were used to assess differences in patient profiles related to method of recruitment. Referred patients included a higher proportion of African Americans and had a lower level of education, fewer economic resources, and higher chronic medical burden. Solicited patients had been in the index episode longer than the referred patients at the time of protocol entry and were 3.4 times more likely to have experienced a "provoking agent" (severe life event or chronic difficulty) during the 6 months that preceded the onset of depressive symptoms. In contrast to these demographic and illness history differences, there were no differences in treatment response rates or time to response related to recruitment method. Solicited patients had an overall treatment response rate of 71% versus 62% in the referred group. Median time to response was 14.3 weeks in the solicited group and 13.6 weeks in the referred group. These results suggest that the inclusion of solicited patients in geriatric depression clinical trials does not bias short-term treatment outcome.
Adjustment Disorders↗
Effect of alosetron (a new 5-HT3 receptor antagonist) on the pharmacokinetics of haloperidol in schizophrenic patients.
Alosetron is under clinical development for the treatment of schizophrenia. This study evaluated the effect of oral alosetron dosing on the pharmacokinetics of haloperidol, the latter being administered daily to 13 schizophrenic patients for 56 days. Alosetron 1 mg daily or placebo was given by random assignment for 2 weeks. After a two-week alosetron washout period (during which patients received placebo), patients received the alternate treatment for another two weeks. Serial blood samples were collected for high-performance liquid chromatography determination of plasma haloperidol, reduced haloperidol, and alosetron at selected times for 24 hours after administration of haloperidol and alosetron on study days 21 and 49. Mean pharmacokinetic parameters of haloperidol in the presence of alosetron and placebo treatments were not significantly (P > .05) different: dose-normalized Cmax (6.40 versus 5.75 ng/mL), dose-normalized Cmin (2.00 versus 1.90 ng/mL), dose-normalized AUC (85.97 versus 68.48 ng.hr/mL), and CL/f (78.23 versus 104.7 L/hr). A two-compartment model was used to assess the concentration- and time-independent pharmacokinetics of haloperidol after multiple dosing. The model confirmed that there was no change in the pharmacokinetics of haloperidol when alosetron was administered concomitantly. Mean AUC ratios of reduced haloperidol to haloperidol (0.18) in the presence of alosetron were similar to values obtained in the absence of alosetron, indicating that alosetron had no influence on the metabolism of haloperidol. Mean pharmacokinetic parameters of alosetron were similar to those in previous studies in healthy subjects.
Adult↗
Maintenance therapies for late-life recurrent major depression: research and review circa 1995.
Major depression in the elderly is often a relapsing, chronic illness with high risk for chronic invalidism, poor treatment compliance, and suicide. In most cases, maintenance treatment to prevent recurrence and to enhance the quality of life is thought to be indicated. We review recent data from our ongoing studies that support both the efficacy and the safety of pharmacotherapeutic and psychotherapeutic maintenance treatments. However, the challenges of conducting maintenance therapy research (particularly with a placebo control) with the elderly are many, involving such areas as recruitment, retention, compliance, choice of outcome measures, and informed consent. We discuss each of these challenges and our responses to them. Finally, we suggest that maintenance therapy trials should be extended in several directions: (a) long-term treatment of bipolar and delusional subtypes in the elderly, as well as depression associated with progressive neurodegenerative disorders such as Alzheimer's dementia; (b) assessment of the benefits and risks of long-term therapy with other than tricyclic and monoamine oxidase inhibitor antidepressant agents, such as selective serotonin reuptake inhibitors; and (c) development of models of long-term course, including the interaction of treatments with medical and psychosocial variables that can have a profound impact on illness onset and offset. These issues are illustrated with a discussion of a new protocol designed to test the acute and maintenance efficacy of antidepressant therapy for depressed patients with Alzheimer's disease.
Alzheimer Disease↗
Imipramine treatment of panic disorder with agoraphobia: dose ranging and plasma level-response relationships.
OBJECTIVE: The aim of this study was to characterize the specific effects of imipramine in the treatment of panic disorder with agoraphobia and to delineate dose-response and possibly plasma level-response relationships. METHOD: Eighty patients with panic disorder with agoraphobia were randomly assigned, for an 8-week, double-blind dose-ranging trial, to placebo or to a weight-adjusted dose of imipramine: (low) 0.5 mg/kg per day, (medium) 1.5 mg/kg per day, or (high) 3.0 mg/kg per day. Plasma levels of imipramine and N-methylimipramine, patients' and clinicians' ratings of panic and phobic symptoms, and response to treatment according to operationalized criteria were ascertained after 4 and 8 weeks. RESULTS: Rates of dropouts due to drug side effects were 6%, 15%, and 36% in the low-, medium-, and high-dose groups, respectively; 63 patients completed the study. Compliance with the drug regimen was high. There was a positive dose-response relationship, with significant group differences involving primarily the high- and medium-dose groups versus the placebo group. There were no significant differences between the placebo and low-dose groups or the medium- and high-dose groups. For phobias, the best total drug plasma level was in the range of 110-140 ng/ml; higher levels had a detrimental effect. For panic, the probability of response increased quickly with greater plasma levels and then tapered off, with no improvement at levels beyond 140 ng/ml. CONCLUSIONS: The results provide strong evidence that imipramine has specific, clinically significant effects in this disorder, with practical implications for target doses and optimal plasma concentrations, and suggest that different mechanisms underlie the drug's antipanic and antiphobic effects.
Adult↗
Comparative neurotransmitter reuptake and anticholinergic potencies of the 8-hydroxy metabolites of clomipramine.
We hypothesize that 8-hydroxy-clomipramine (8-OH-CMI), the major hydroxy metabolite of clomipramine (CMI), may have antidepressant properties with less anticholinergic potency than CMI. We compared the potencies of 8-OH-CMI and CMI for inhibition of serotonin and norepinephrine reuptake and the potencies of these compounds for blockade of muscarinic receptors. We also compared the antimuscarinic potencies of desmethylclomipramine (DCMI) and 8-hydroxy-desmethylclomipramine (8-OH-DCMI). We found that 8-OH-CMI inhibits the uptake of serotonin and norepinephrine to the same extent as CMI and that 8-OH-CMI has far less antimuscarinic potency than CMI. We also found that 8-OH-DCMI has about one-tenth the antimuscarinic potency of DCMI. Since the therapeutic efficacy of CMI may be related to its effect on the reuptake of neurotransmitters, and since the extent of clinical anticholinergic effects of tricyclic antidepressants has been shown to be related to their in vitro antimuscarinic potencies, these results raise the possibility that 8-OH-CMI may be an analogue of CMI with fewer anticholinergic side effects than the parent compound.
Animals↗
Preliminary report: double-blind, placebo-controlled study of fluoxetine in depressed alcoholics.
The selective serotonergic agonist fluoxetine has demonstrated efficacy in the treatment of depression and has possible efficacy in the treatment of nondepressed and depressed alcoholics. However, no double-blind, placebo-controlled trials with any selective serotonergic medication have been reported in patients who have both major depression and alcoholism. In this study, 21 patients with DSM-III-R diagnoses of both major depressive disorder and alcohol dependence were randomized to fluoxetine or placebo in a 12-week, double-blind, parallel group trial. The patients reported a high level of current episode (52.4%), prior episode (61.9%), and lifetime (76.2%) suicidal behavior. Total alcohol consumption during the 12-week treatment course was significantly lower in the fluoxetine group than the placebo group, after controlling for baseline differences in consumption. The fluoxetine group demonstrated a four-fold greater improvement in depressive symptoms, but this difference did not reach statistical significance in this small sample. These preliminary findings suggest that fluoxetine has potential for treating the excessive alcohol ingestion of depressed alcoholics and may have potential for treating the depressive symptoms of these patients as well.
Adolescent↗
Prospective cytochrome P450 phenotyping for neuroleptic treatment in dementia.
Older patients have more adverse experiences when treated with psychotropics than younger patients. Age-associated physiological changes, such as reductions in hepatic mass and blood flow, magnify genetic and acquired variations in drug metabolism. Cytochrome P450 2D6 (debrisoquine hydroxylase), which is responsible for the metabolism of several antidepressants and neuroleptics, is constitutionally deficient in up to 10 percent of the population. In this study of 45 elderly patients suffering from dementia and treated with perphenazine, 5 patients who were prospectively identified as poor P450 2D6 metabolizers had significantly greater side effects than the 40 extensive metabolizers.
Aged↗
Serum clomipramine and metabolite levels in four nursing mother-infant pairs.
BACKGROUND: Women with postpartum-onset obsessive compulsive disorder may elect treatment with clomipramine. There is minimal information to guide the clinician who must advise breastfeeding women about clomipramine therapy. METHOD: Four clomipramine-treated breastfeeding mother-infant pairs were assessed for serum concentrations of clomipramine, N-desmethylclomipramine, and corresponding 8-hydroxymetabolites. RESULTS: Although the mothers exhibited a wide range of serum concentrations, the parent drug and metabolites were either nondetectable or below the quantifiable limit in the sera of all infants. No adverse clinical effects were observed. CONCLUSION: This report adds to the growing literature that suggests that tricyclic use during breastfeeding rarely results in measurable drug levels in infant sera.
Adult↗
Effect of pulse loading with clomipramine on EEG sleep.
Two different initial dosing regimens with clomipramine (CMI) were used to compare early response indicators and dose strategies. Thirty-two inpatients with major depressive disorder were randomized in a double-blind protocol. The pulse-loading group received 150 and 200 mg of CMI on 2 consecutive evenings and then received a placebo for 8 days. The traditional dosing group began at 50 mg of CMI followed by gradual increases every second day until 200 mg was reached. After 10 days, both groups were placed on an adjustable dosing schedule of CMI, initially set at 200 mg, for an additional 2 weeks. Significant drug effects were noted on several sleep parameters demonstrating suppression of rapid eye movement (REM) sleep. In the pulse-loading group, drug responders were found to have a significantly faster and more robust rebound in REM sleep than nonresponders. Both measures of REM activity and REM sleep time showed a significant difference between the groups. In addition, a significant correlation was found between falling levels of the desmethylclomipramine metabolite of CMI and REM sleep activity during the rebound phase. The clinical and theoretical implications of these findings are discussed.
Adult↗
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.
Age Factors↗