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It has been reported that imipramine reduces the titre of rheumatoid factor in schizophrenic patients. Twenty out-patients suffering from classical rheumatoid arthritis and having rheumatoid factor titre equal to, or greater than 1:64, were treated in a double-blind trial with imipramine 75 mg or matching placebo. In this study the dose of imipramine used failed to affect the levels of rheumatoid factor.
BACKGROUND: Our investigation involved a quantitative literature review technique known as meta-analysis to compare the efficacy of three newer antidepressants and imipramine. METHOD: We examined seven major journals in psychiatry from 1980 through 1990, inclusive, and selected those investigations of imipramine, trazodone, bupropion, and fluoxetine that met our minimal criteria for interpretability. These criteria included: (1) the presence of a placebo control, (2) double-blind status, (3) the use of the Hamilton Rating Scale for Depression as a dependent variable measure, (4) the use of nongeriatric adults with a diagnosis of major depression by DSM or RDC standards, and (5) the presence of reported means and standard deviations in the investigation, or sufficient data that allowed such to be computed. Each study of four antidepressants was analyzed for an effect size of the drug investigated. The effect size allows for a determination of the efficacy of a particular drug as compared with placebo, measured in standard deviation units. RESULTS: The data indicated that all four agents are effective as compared with placebo. Furthermore, there is no evidence that the newer heterocyclic agents are less effective than imipramine, as an ANOVA showed no statistically significant difference between the effect sizes of the four antidepressants. CONCLUSION: These data are discussed in terms of characteristics of the various investigations and the need for further research comparing the efficacy of psychopharmacologic agents.
Approximately 20 million patients suffer from major depressive disorder each year, indicating a need for antidepressant agents that are synonymous with effectiveness, tolerability and patient compliance. The authors examined the effects of fluvoxamine, a selective serotonin reuptake inhibitor, in the treatment of outpatients meeting DSM-III-R criteria for major depressive disorder. A randomized, double-blind, parallel group, placebo- and imipramine-controlled single center study was conducted in 150 outpatients. Patients were randomized to receive up to 150 mg/day of fluvoxamine as a single bedtime dose, 240 mg/day of imipramine on a twice-daily (BID) schedule, or placebo for six weeks. Efficacy measurements included HAM-D, MADRS, CGI, Raskin-Covi and SCL-56 scales. The HAM-D total score indicated that both active treatment groups showed significantly (p < or = 0.05) greater therapeutic benefit than did placebo. Severely depressed patients (HAM-D > or = 30) responded better to fluvoxamine in five of six measures. Side-effects from fluvoxamine were similar to those reported for other selective serotonin reuptake inhibitors (nausea, somnolence) and were well tolerated. Imipramine was associated with anticholinergic effects such as dry mouth and dizziness. The pharmacokinetic properties of fluvoxamine which allow the drug to be administered as a single daily dose should aid in the maintenance of patient compliance, while offering significant clinical benefit in the improvement of depressive symptoms.
In some previous studies, acute administration of some antidepressants has been reported to cause significant changes in the levels of blood glucose and insulin in the rabbit. In the present study the effects of several antidepressants representing classical groups of antidepressants, namely imipramine (CAS 50-49-7, I), maprotiline (CAS 10347-81-6, M) and bupropion (CAS 34911-55-2, (B) on insulin secretion from the isolated islets of Langerhans in mice was studied. Maprotiline and bupropion stimulated insulin release, while imipramine was without any effect in presence of 8.3 mmol/l glucose. On the other hand, in presence of 16.7 mmol/l imipramine and maprotiline suppressed the stimulated insulin secretion. Bupropion inversely significantly stimulated the insulin secretion in presence of 16.7 mmol/l glucose. It is concluded that the changes of blood glucose and plasma insulin observed in vivo may at least in part be due to respective changes of insulin secretion. The treatment of diabetic patients receiving antidepressant drugs with hypoglycaemic agents should be taken in consideration.
In two unrelated cases, a 7-year-old boy and a 21-year-old woman died suddenly while receiving chronic imipramine therapy. In the boy, concentrations of imipramine were: Left femoral blood 0.5 mg/L, right femoral blood 1.2 mg/L, aorta blood 1.0 mg/L, liver 68 mg/Kg, and for the active metabolite, desipramine, left femoral blood 6.7 mg/L, right femoral blood 9.9 mg/L, aorta blood 8.7 mg/L, liver 400 mg/Kg. In the woman, the imipramine concentrations were: Femoral blood 0.6 mg/L, liver 37 mg/Kg, and of the active metabolite, desipramine, femoral blood 3.74 mg/L, liver 261 mg/Kg. In both cases, the scene investigation strongly indicated that neither individual had ingested an acute overdose. The very high ratios of desmethyl metabolite to parent drug are consistent with this observation. Impaired metabolism due to a genetically determined "slow metabolizer" phenotype of cytochrome CYP2D6, and/or concurrent therapy with phenothiazines, is suggested as a possible mechanism for the apparent fatal accumulation of these tricyclic antidepressants.
A depression-like state was induced by chronic (3-week) exposure of Wistar rats to a very mild, unpredictable stress which is a model of depression, developed by Willner's group. Five-week daily administration of imipramine reversed the stress-induced deficit in sucrose consumption. Eight-week stress induced an increase in the ability of splenocytes to produce interleukin 1 (IL-1) and interleukin 2 (IL-2) and to proliferate after stimulation with concanavalin A. Antidepressant effects of imipramine were accompanied by a decrease in the ability of splenocytes to produce IL-1 and IL-2 and to proliferate. Administration of imipramine alone did not modify the activity of those cells.
The effects of repeated treatment with imipramine on the reactivity of CA1 neurons in the rat hippocampus to the 5-HT4 receptor agonist zacopride and the direct adenylate cyclase activator forskolin were compared ex vivo to assess whether a modulation of signal transduction pathway may contribute to the antidepressant-induced adaptive changes in the responsiveness of pyramidal neurons to 5-HT4 receptor activation. The population spike recorded in the CA1 cell layer was a measure of pyramidal cell excitability, while the dendritic field excitatory postsynaptic potential (fEPSP) recorded in the stratum radiatum of the CA1 region was employed to assess the effects of the tested drugs on the excitatory amino-acid-mediated synaptic transmission. Zacopride (5 microM) and forskolin (1 microM) increased the amplitude of the half-maximal population spike (by 37 +/- 5% and 42 +/- 4%, respectively). Forskolin, but not zacopride, increased the slope of the fEPSP (by 13 +/- 2%). Repeated treatment with imipramine (14 days, twice daily, 10 mg/kg po) attenuated the excitatory effect of zacopride and forskolin on the population spike and the effect of forskolin on the fEPSP. It is concluded that the reduction in the responsiveness of CA1 cells to zacopride, induced by repeated administration of imipramine, may be due to modifications of the signal transduction pathway, i.e. adenylate cyclase and protein kinase A, which is responsible for the 5-HT4 receptor-mediated decrease in the activity of potassium channels.
Effects of repeated imipramine treatment on inositol phosphates accumulation and on the reactivity of neurons to metabotropic glutamate receptor (mGlu) agonist (1S,3R)-1-carboxycyclopentane-3acetic acid (1S,3R-ACPD) were investigated in the rat hippocampal slices. The concentration-dependent increase in inositol phosphate accumulation in the slices from CA1 region of hippocampus induced by 1S,3R-ACPD was not modified by imipramine treatment. 1S,3R-ACPD produced a concentration-dependent increase in population spike amplitude recorded in the CA1 cell layer. This effect of 1S,3R-ACPD was markedly attenuated by repeated imipramine administration. Our results indicate that antidepressant treatment may induce a subsensitivity of mGlu receptors in the CA1 region of hippocampus when estimated by electrophysiological, but not biochemical measures.
The plasma concentration of alpha 1-acid glycoprotein, a putative endogenous inhibitor of the site labeled by tritiated imipramine, was measured by a radial immunodiffusion assay in 36 normal human volunteers and 51 drug-free patients who fulfilled DSM-III criteria for major depression. The depressed patients exhibited a significant elevation in the plasma concentration (+/- SEM) of alpha 1-acid glycoprotein (79.6 +/- 4 mg/dL) when compared with the age- and sex-matched controls (61.7 +/- 3 mg/dL). Fourteen of the 51 patients with major depression had plasma alpha 1-acid glycoprotein concentrations that were higher than the highest values of the normal controls. There was no relationship between plasma alpha 1-acid glycoprotein concentrations and sex or affinity of platelet tritiated imipramine binding of either the normal volunteers or the depressed patients. In the depressed patients, there was a significant positive correlation between plasma concentrations of alpha 1-acid glycoprotein and postdexamethasone plasma cortisol concentrations, and two measures of depression severity, the Montgomery-Asberg Rating Scale for Depression and the Center for Epidemiologic Studies-Depression Scale, and a significant negative correlation with age. These data provide the first evidence of alterations of an endogenous inhibitor of the tritiated imipramine binding site/serotonin transporter in depressed patients.
Although depressive symptoms occur in a considerable number of women following a decrease in circulating estrogen levels, a biological correlate of these mood changes has not been identified. In a prospective, double-blind, cross-over investigation of surgically menopausal women, an increase in the number of tritiated imipramine binding sites on platelets and an improvement of mood occurred with estrogen treatment and were reversed when placebo was administered. In vitro studies indicated that this effect was not due to a direct interaction of the steroid with the imipramine binding site at the same concentrations of estradiol induced in the in vivo study. Together with other evidence, these findings suggest that pharmacological but not physiological doses of estrogen can enhance the density of tritiated imipramine binding sites on platelets in women.
Ten patients with DSM-III diagnoses of nonbipolar recurrent major depression were studied in an attempt to assess the relationship between 3H-imipramine binding site density and clinical depressive state. They were compared with eight healthy controls who had no past or family history of affective disorders. Evaluations with the Hamilton Rating Scale for Depression and the Self-Rated Scale for Depression were done on the same day as platelet collection at baseline, and also at 2 and 5 weeks after the beginning of treatment with tricyclic antidepressants. The number (Bmax) and the affinity (Kd) of platelet 3H-imipramine binding sites were highly correlated with the improvement of the clinical depression. These results raise the interesting possibility that a decrease in 3H-imipramine binding sites may be a state-dependent marker in patients suffering from nonbipolar recurrent major depression.
This study is a part of our ongoing work toward developing pharmacological methods for enhancing and inducing ejaculation in stallions with ejaculatory dysfunction. We evaluated a combination treatment of imipramine hydrochloride followed 10 minutes later by xylazine hydrochloride for the induction of ex copula ejaculation. Eight pony stallions each underwent 6 treatment trials conducted at 4-day intervals. The trials were conducted in the animals' stalls, where they were observed for 90 minutes following treatment. To evaluate the effect of pretreatment sexual stimulation on the rate of ejaculation for each of the 8 stallions, 3 of the 6 trials were preceded by exposure to a restrained ovariectomized pony mare. For 7 of the 8 stallions, 1 to 4 of the 6 trials resulted in induced ejaculation, for a total of 16 ejaculations in the 48 trials. Six of the ejaculations occurred with imipramine treatment alone, before the administration of xylazine. All ejaculations were associated with erection and masturbation. Six of 24 trials (25%) preceded by sexual stimulation resulted in ejaculation, while 10 of 24 trials (42%) without sexual prestimulation resulted in ejaculation. These proportions were not different (P = 0.11). Induced ejaculates were collected into a plastic bag positioned over the prepuce by a girth strap for the comparison of semen characteristics with 2 base line ejaculates obtained in copula from these stallions during the week preceding the series of induced ejaculation trials (with similar 4-day intervals from previous ejaculation). The induced ejaculates were of lower total volume, higher concentration, lower gel volume, higher total numbers of spermatozoa, and lower pH (P < 0.05) than the base line in copula ejaculates. Together, these semen characteristics suggest increased emission of the sperm-rich fraction and reduced emission of accessory gland fluids, probably resulting from imipramine treatment.
Seven structurally-related compounds consisting of three antidepressant drugs (imipramine, desmethylimipramine and amitriptyline), three tranquillizing agents (promazine, chlorpromazine and chlorprothixene) and a hybrid, desmethylpromazine, have been examined in a series of tests involving autonomic functions and antagonism of reserpine. Activities of the compounds in antagonizing reserpine-induced ptosis in rabbits and prolongation of alcohol hypnosis in mice give good correlation with their clinical actions, whilst their activities in augmenting excitation of rats by amphetamine and yohimbine toxicity in mice, and in reversing reserpine-induced bradycardia in rats offer further evidence for drug-induced sensitization to adrenergic or tryptaminic mechanisms, which is not however specific for antidepressant agents. No evidence has been obtained to indicate that a central parasympatholytic action is an important component of the antidepressant activity of imipramine and related drugs.
Tritiated imipramine binding in platelets has been used to evaluate serotonin activity in depression in previous studies. This article examined this marker as a possible measure of central nervous system serotonergic activity for depression in patients with Parkinson's disease (PD). The number of binding sites was significantly lower in depressed patients with PD than in a healthy control group. Patients with PD who were not depressed had lower values than the comparison group, but this difference was not significant. We also found a significant correlation between the receptor site values in platelets and cerebrospinal fluid levels of the serotonin metabolite, 5-hydroxyindoleacetic acid (r = .59), but this was independent of a diagnosis of depression. Receptor site values were examined to identify appropriate cutoff scores to predict depression in the group of patients with PD. A maximum sensitivity of 50% was achieved with a specificity of 64%. Our results strongly support a generalized alteration in serotonin metabolism in depressed patients with PD, but tritiated imipramine binding in platelets is not a useful diagnostic tool for depression.
OBJECTIVE: To document acute angle closure glaucoma temporally related to ingestion of oral imipramine hydrochloride. PATIENTS: Four patients with narrow angles received routinely prescribed doses of imipramine that triggered acute angle closure glaucoma. OUTCOME: Laser iridotomy was successful in all patients. CONCLUSIONS: Psychoactive drugs should be prescribed cautiously in patients with known narrow angles and should be monitored by an ophthalmologist.
Differential effects of chlorpromazine, imipramine hydrochloride, and a placebo were examined in 159 black and 555 white depressed patients in a multihospital collaborative study. In making these comparisons, the effects of age and social class were controlled. The major study findings were the differential effects of the active drugs for the black men and women. Chlorpromazine was the most efficacious treatment for black women, whereas imipramine was most efficacious for black men. These differences occurred on global ratings of improvement as well as on specific symptoms such as depression, anxiety, guilt-worthlessness, sleep disturbances, and social participation. Black patients also evidenced a higher improvement rate at one week, irrespective of treatment, than did the white patients.
Sixty depressed nonschizophrenic patients were admitted to a research unit. Following one drug-free week and one week of placebo, patients received 3.5 mg/kg of imipramine hydrochloride for 28 days. Plasma levels of imipramine and its metabolite desipramine hydrochloride (desmethylimipramine) were measured three times weekly and the relationship between plasma steady-state levels and clinical outcome was examined. Steady-state levels ranged from 50 to 1,050 ng/ml. There was a statistically and clinically significant relationship between plasma levels and response. The relationship existed across the entire sample, and was accentuated when the bipolar and unipolar nondelusional populations were examined. Because a strong relationship between sex and outcome was observed, the unipolar nondelusional patients were stratified by sex and a significant relationship still persisted. Only the unipolar delusional patients failed to demonstrate an association between blood level and clinical response.
Two groups of young rhesus monkeys were subjected to repetitive peer separations, a procedure that has been shown to produce depressivelike reactions in infant monkeys. Midway through the procedure one group was treated with the antidepressant imipramine hydrochloride, the other with a saline placebo. In comparison with placebo treatment, the imipramine treatment yielded significant behavioral improvement in a form and with a time course similar to that seen when the drug is given clinically to human depressives. We discuss the implications of the findings.