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Biomedical subjects

J M Perel

Publications and source records attributed to J M Perel.

At least 19 recordsLinked to original sources
PubMed1992

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.

Adolescent↗
PubMed1992

Five-year outcome for maintenance therapies in recurrent depression.

After conducting 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, we asked those individuals who survived the 3-year trial receiving active medication (with or without psychotherapy) to continue in a 2-year additional randomized trial of active medication vs placebo. The question was whether maintaining antidepressant medication at the dosage used to treat the acute episode beyond 3 years would continue to provide a significant prophylactic effect compared with medication discontinuation after the 3 years of effective maintenance treatment. Survival analysis demonstrated a highly significant continued prophylactic effect for active imipramine hydrochloride treatment maintained at an average dose of 200 mg. We conclude that active imipramine treatment is an effective means of preventing recurrence beyond 3 years and that patients with previous episodes less than 2 1/2 years apart, therefore, merit continued prophylaxis for at least 5 years.

Adult↗
PubMed1992

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.

Adult↗
PubMed1992

Clinical experiments in maintenance and discontinuation of imipramine therapy in panic disorder with agoraphobia.

Several issues remain to be ascertained beyond the acute response to imipramine hydrochloride in patients with panic disorder. Study 1 consisted of a prospective, systematic characterization of half-dose 12-month maintenance in patients with panic disorder with agoraphobia who had shown marked and stable response to 6 months of acute-phase treatment with imipramine. Study 2 assessed the 6-month cumulative relapse rate following discontinuation of acute-phase imipramine treatment in a comparable sample of patients. The same assessment battery was used in both studies, and the integrity of experimental drug conditions was verified by plasma drug level determinations. In contrast to the high relapse rate following discontinuation of acute-phase treatment, none of the patients showed relapse or had sustained worsening in panic or phobia measures during the half-dose maintenance period. The results underscore the importance of pharmacological prophylaxis and provide empirical guidelines for a successful low-dose maintenance regimen for patients with panic disorder and agoraphobia who respond markedly to imipramine.

Adult↗
PubMed1992

Imipramine and 2-hydroxyimipramine: comparative cardiotoxicity and pharmacokinetics in swine.

The hemodynamic, cardiographic, and initial pharmacokinetic characteristics of the de novo administration of the 2-hydroxymetabolite (2-OH-IMI) of imipramine (IMI), compared with its parent was studied in a swine preparation. Cardiac output, arterial pressure, and the continuous electrocardiogram were assessed after the intravenous administration of the drug or its metabolite. Plasma, sampled over 120 min and CSF sampled at 60 min were analyzed by reverse phase HPLC with spectroflurometric detection. Equilibrium dialyses were performed on plasma sampled at 60 min. 2-OH-IMI, in doses of 5-6 mg/kg, compared to dosages of IMI up to 8.5 mg/kg, produced a significantly greater incidence of life-threatening arrhythmias, and caused profound and significant decreases in blood pressure and cardiac output. 2-OH-IMI had a smaller volume of distribution (Vd) and shorter half-life. CNS penetration, as estimated by CSF/plasma ratios, was significantly greater for 2-OH-IMI. These phenomena were partly accounted for by significantly less protein binding for the hydroxymetabolite. It is concluded that 2-OH-IMI has increased penetrance into the CNS despite a smaller Vd and that it is significantly more cardiotoxic than its parent.

Animals↗
PubMed1992

Pharmacodynamics of pemoline in attention deficit disorder with hyperactivity.

The onset, duration, and offset of pemoline action to improve cognitive performance is examined intensively in 25 prepubescent males suffering from attention-deficit disorder with hyperactivity (ADDH). The purpose was to characterize the pharmacodynamics of pemoline in ADDH patients through correlation of plasma pemoline concentration with psychometric measures of memory search efficiency and paired-associates learning, with the physiological effect of pemoline on dopaminergic transmission concurrently measured by analysis of plasma prolactin response. The effect of pemoline on neuroprocessing is apparent within the first 2 hours after administration with an inverse relationship between plasma pemoline and prolactin concentration present at hour one only (r = 0.84; p = 0.005). Pemoline therapy for 3 weeks does not significantly affect area under the curve for pemoline or prolactin nor did the effect on memory search efficiency decrease, suggesting no apparent tolerance.

Attention↗
PubMed1992

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.

Age Factors↗
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↗