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Biomedical subjects

J M Perel

Publications and source records attributed to J M Perel.

At least 91 records · Page 5Linked to original sources
PubMed1992

Protective effects of imipramine maintenance treatment in panic disorder with agoraphobia.

OBJECTIVE: This study was designed to assess and compare the differential relapse rates of patients with panic disorder and agoraphobia after discontinuation of acute treatment (6 months) or acute plus maintenance treatment (18 months) with imipramine. METHOD: Sixteen patients with panic disorder and agoraphobia who had shown marked and stable response to 6 months of acute imipramine treatment and a comparable group of 14 patients who had been in remission during an additional year of half-dose imipramine maintenance treatment entered a 3-month, double-blind discontinuation study followed by a 3-month drug-free period. Assessments of the patients were made according to operationalized response/relapse criteria, and plasma drug concentrations were monitored. RESULTS: Survival analysis revealed significantly different cumulative probabilities of continued response 6 months after discontinuation of imipramine treatment between the patients who had received only acute treatment and those who had received acute and maintenance treatment. CONCLUSIONS: The results support the hypothesis that successful imipramine maintenance treatment of patients with panic and agoraphobia can have protective effects against relapse, at least in the first 6 months after the maintenance treatment period.

Adult↗
PubMed1992

Relationship of pharmacologic compliance to long-term prophylaxis in recurrent depression.

This report examines the relationship of long-term medication compliance (as measured by stability of level/dose ratios and total blood level averages) to prophylaxis in recurrent unipolar patients. Of the 53 patients assigned to active imipramine conditions in a long-term maintenance treatment protocol, 42 were evaluated as clearly compliant, 8 were clearly noncompliant, and 3 were not classifiable. We examined a number of demographic and clinical variables in an attempt to find possible predictors of compliance. No differences were observed between compliant and noncompliant patients with respect to sex, age at screening, age at the onset of their recurrent unipolar illness, duration of the index episode, number of previous episodes, bipolar II vs. recurrent unipolar subtype, endogenous vs. nonendogenous subtype, or baseline severity of depression as assessed by the Hamilton Rating Scale for Depression. However, medication compliance was found to be significantly associated with effective prophylaxis. There was a significantly larger proportion (6 of 12) of noncompliant patients among those experiencing a recurrence in one of the two active medication conditions than among those who remained well for 3 years (2 of 28). The value associated with this difference was p = .04. We conclude that effective prophylaxis is strongly related to stability of medication blood levels which fall within the therapeutic range.

Adult↗
PubMed1992

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.

Aged↗
PubMed1992

Nortriptyline and weight change in depressed patients over 60.

Weight change in pounds and body mass index was documented in 29 geriatric patients with recurrent depression successfully treated with nortriptyline over a 30-week period of acute and continuation therapy (925 patient-weeks of nortriptyline treatment). Weight before index episode as documented by physician records, and weight at three points (beginning of treatment, end of acute therapy, and end of continuation therapy) were recorded. Weight changes over the interval between these times and net weight change over the entire interval were then calculated. Only five patients (17.2%) gained a clinically significant (greater than 10 lb) amount of weight during treatment, ranging from 10 to 43 lb above premorbid weights. Seven of 29 patients (24.1%) showed a net weight loss below premorbid levels (maximum loss 12.5 lb), and 6 patients (20.7%) showed no weight change. The pattern of weight gain was variable; no correlations were found between initially high body mass index and weight gain over the entire interval. These data suggest that nortriptyline is apparently not a potent weight promoter in this group.

Aged↗
PubMed1992

Comparative cardiotoxicity of nortriptyline and its isomeric 10-hydroxymetabolites.

The potential cardiotoxicity of the hydroxymetabolites of nortriptyline (NT) has been raised by inferential data from clinical studies and by the experimentally demonstrated cardiac effects of 2-OH-imipramine. Cardiac output, arterial pressure, and a continuous electrocardiogram were assessed after intravenous de novo administration of NT or its hydroxymetabolites to 41 swine. NT at doses ranging from 3.5 to 7 mg base per kilogram caused significantly more arrhythmias than did E-10-hydroxynortriptyline (E-10-OH-NT) but was not significantly different from Z-10-hydroxynortriptyline (Z-10-OH-NT) in this effect. Z-10-OH-NT, in contrast, to its geometrical isomer caused marked bradycardia, and decrements in blood pressure and cardiac output. NT and Z-10-OH-NT, but not E-10-OH-NT, produced dose-correlated declines in cardiac output. The hydroxymetabolites had smaller volumes of distribution, shorter half-lives and larger free fractions compared with NT. The differing cardiotoxicity of the hydroxymetabolites could not be accounted for by differing pharmacokinetic properties.

Animals↗
PubMed1992

Haloperidol induced CSF protein variations in schizophrenic patients: as studied by two-dimensional electrophoresis.

High resolution two-dimensional electrophoresis of cerebrospinal fluid (CSF) from 10 schizophrenic patients demonstrated a 21% average difference in the number of proteins which could be detected in patients undergoing haloperidol therapy when compared with CSF from the same patients after withdrawal from neuroleptic treatment. Proteins affected were trace proteins, as we found no significant variation in either the total CSF protein content or the integrated protein density on each electrophoretic gel. Three mechanisms which might account for these observations are: (1) a small change in liver protein synthesis or degradation would have little if any visible effect on the concentration of major blood or CSF proteins, such as albumin, but it could significantly alter trace proteins, such as alpha 2-haptoglobin, since their concentrations are orders of magnitude less than that of the major proteins, (2) haloperidol might alter the blood-CSF protein filtration system which could affect the visibility of the trace proteins, and (3) proteins synthesized in the Central Nervous System (CNS) or enhanced in the CSF could be differentially affected by haloperidol. While additional research will be required to determine the basis for the effects of haloperidol on CSF proteins, the current studies provide information which may be helpful in delineating disease specific protein alterations from those induced by drug therapy.

Adult↗
PubMed1991

Determination of imipramine, desipramine and their hydroxy metabolites by reversed-phase chromatography with ultraviolet and coulometric detection.

A reversed-phase high-performance liquid chromatographic method is described which analyzes imipramine, desipramine and their corresponding 2-hydroxy metabolites with sequential ultraviolet and coulometric detection from a single common extraction step, so that a wider dynamic range of plasma concentrations can be measured requiring smaller sample volumes. Applicability is broader including single-dose pharmacokinetic studies as well as steady-state concentrations. The extraction procedure gives excellent recoveries for imipramine, desipramine and their metabolites (mean +/- S.D.): ultraviolet detection, imipramine 99.5 +/- 0.68%, desipramine 100 +/- 0.0%, 2-hydroxyimipramine 97.8 +/- 3.5% and 2-hydroxydesipramine 93.1 +/- 4.22%; coulometric detection, imipramine 97.5 +/- 1.9%, desipramine 98.3 +/- 1.2%, 2-hydroxyimipramine 90.3 +/- 4.0% and 2-hydroxydesipramine 86.6 +/- 7.5%.

Chromatography, High Pressure Liquid↗
PubMed1991

Fluvoxamine versus desipramine: comparative polysomnographic effects.

Electroencephalogram sleep measures over a 4-week period were obtained on 35 inpatients with major depression (unipolar) who received either fluvoxamine or desipramine in a randomized double-blind trial. Fluvoxamine showed immediate rapid eye movement (REM) sleep suppression and an alerting effect on sleep continuity measures. In contrast, desipramine administration was associated with REM suppression and sleep continuity improvement. The "alerting" quality of fluvoxamine, similar to other serotonergic antidepressants, appears to be unrelated to a lack of clinical efficacy, but may be related to persistent REM sleep suppression. However, it is premature to comment on the serotonin specificity for REM sleep.

Adult↗
PubMed1991

S-mephenytoin 4-hydroxylation in older Americans.

To examine whether a drug-metabolizing enzyme changes with normal aging, the S:R index of S-mephenytoin 4-hydroxylation was determined in 150, unmedicated elderly Americans (mean age 75.4). Ten (6.7%) were identified as categorically slow metabolizers (S:R ratios greater than or equal to .95). This increased incidence of slow metabolizers was accounted for by a significant and previously unreported, increased proportion of slow metabolizers among the black (18.5%) as compared to the white subjects (4.1%) (P = .017). There was no relationship found between S:R ratios and age or creatinine clearance.

Aged↗
PubMed1991

Biphasic effect of tricyclic antidepressants on the release of norepinephrine from the adrenergic nerves of the rabbit heart.

The release of norepinephrine (NE) from the right atrium of the rabbit heart was used as a model to investigate biphasic effects due to tricyclic antidepressants, similar to those clinically observed in the treatment of depression and known as "therapeutic window". Strips of the atrium were loaded with 3H-NE, and then superfused by Krebs solution. The basal release and the electrical stimulation evoked release of 3H-NE were measured in the presence and absence of four clinically used tricyclic antidepressants: imipramine, amitriptyline, desipramine and nortriptyline. In addition, guanethidine, an adrenergic neuron blocker, was also studied. At lower concentrations (0.5-10 microM) tricyclic antidepressants increased, whereas higher concentrations (50-100 microM), inhibited the evoked release of NE. This inhibition was not prevented by the alpha2 adrenoceptor antagonist yohimbine, excluding the possibility of alpha 2 adrenoceptor-mediated inhibition of NE release. In higher concentrations the tricyclic antidepressants increased the basal release of NE in a Ca-independent way. Secondary amine derivatives were more potent inhibitors of the evoked release, and enhance the resting basal release of NE to a greater extent than the tertiary ones. Similarly, guanethidine (1-50 microM) also decreased the evoked release and increased the basal release of NE in a concentration dependent manner. Yohimbine failed to counteract the inhibition caused by guanethidine and the increment of the basal release was Ca-independent. It is concluded that the effect of tricyclic antidepressants in potentiating the release of NE is masked by their adrenergic neuron blocking properties, i.e. they inhibit the release of NE.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Strategies for evaluating treatments for major depression in primary care patients.

Primary care physicians are being urged to provide patients experiencing a major depression treatments validated with psychiatric patients. The propriety of transferring clinical technologies from one care-giving sector to another is questionable, however, as it has little scientific support. We suggest that clinical trials be initiated so as to expand the available knowledge base. This paper analyzes the methodologic issues involved in pursuing such experimental research and urges that it be conducted despite the possible need for initial design compromises.

Adult↗
PubMed1991

Immediate effects of intravenous clomipramine on sleep and sleep-related secretion in depressed patients.

An i.v. challenge dose of clomipramine (12.5 mg) was given to eight outpatients with major depression. The procedure facilitated the examination of all-night sleep and sleep-related neuroendocrine changes (cortisol, growth hormone, and prolactin). In comparison to baseline saline nights, the patients experienced a profound suppression of rapid eye movement (REM) sleep throughout the night with no rebound recovery in the second half of the night. Furthermore, REM-suppressing effects were noted on the following no-drug night. In contrast, little effect on delta wave sleep was found, except for increased consolidation of delta waves within stage 3 and 4 sleep. Delta sleep measures were significantly correlated with levels of cortisol and growth hormone.

Adult↗
PubMed1991

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.

Breast Feeding↗
PubMed1991

Adjunctive lithium carbonate in nortriptyline-resistant elderly depressed patients.

Recent reports supporting the use of lithium carbonate as an adjunct to tricyclic antidepressants for the treatment of refractory depression have not utilized standardized tricyclic antidepressant therapy, nor have they addressed the efficacy of lithium augmentation in a geriatric population. A 3-week open trial was added to the medication regimen of 15 elderly depressed inpatients who had already failed 4 weeks of therapeutic levels of nortriptyline. Treatment response was determined by the 17-item Hamilton Rating Scale for Depression (HAM-D). Two of 15 partial responders before lithium augmentation became complete responders. Of the remaining 13 "nonresponders" before lithium augmentation, one had a complete response, 7 had a partial response and 5 remained nonresponders. Although there was a mean HAM-D change of 8.3 points after lithium augmentation (24.7 +/- 5.9 to 16.4 +/- 6.8, p less than .001), when considering the previously reported similar efficiency of extended nonaugmented nortriptyline, these data do not strongly support lithium augmentation in elderly subjects who fail to respond after 4 weeks of nortriptyline. Further study is needed to determine what role, if any, lithium augmentation should play in the treatment of geriatric depression.

Aged↗
PubMed1991

A preliminary trial of fluoxetine in refractory borderline patients.

Borderline personality disorder is characterized by many of the symptoms associated with serotonin dysregulation, including affective lability, suicidal behaviors, and impulsive aggression. These provide an ideal clinical model for studying the treatment of these serious symptom presentations. The recent development of selective serotonin reuptake inhibitors such as fluoxetine makes it possible to study the role of serotonin in the etiology of affective and behavioral dyscontrol in borderline personality disorder. In this preliminary medication trial, 5 borderline personality disorder patients with severe symptoms resistant to phenelzine and neuroleptics were treated openly with fluoxetine 20 to 40 mg for 8 weeks, with weekly ratings of symptoms. The findings from this work suggested efficacy for fluoxetine in treating the depressive and impulsive symptoms of refractory patients with borderline personality disorder.

Adult↗
PubMed1991

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).

Age Factors↗
PubMed1990

Three-year outcomes for maintenance therapies in recurrent depression.

We conducted a randomized 3-year maintenance trial in 128 patients with recurrent depression who had responded to combined short-term and continuation treatment with imipramine hydrochloride and interpersonal psychotherapy. A five-cell design was used to determine whether a maintenance form of interpersonal psychotherapy alone or in combination with medication could play a significant role in the prevention of recurrence. A second question was whether maintaining antidepressant medication at the dosage used to treat the acute episode rather than decreasing to a "maintenance" dosage would provide prophylaxis superior to that observed in earlier trials in which a maintenance dosage strategy was employed. Survival analysis demonstrated a highly significant prophylactic effect for active imipramine hydrochloride maintained at an average dose of 200 mg and a modest prophylactic effect for monthly interpersonal psychotherapy. We conclude that active imipramine hydrochloride maintained at an average dose of 200 mg is an effective means of preventing recurrence and that monthly interpersonal psychotherapy serves to lengthen the time between episodes in patients not receiving active medication.

Adult↗