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PubMed1991

Treatment of depression with E-10-hydroxynortriptyline--a pilot study on biochemical effects and pharmacokinetics.

The major metabolite of nortriptyline, i.e. E-10-hydroxynortriptyline (E-10-OH-NT), was given as a racemate in increasing doses from 75 to 225 mg/day to five patients with major depressive episode. Plasma concentrations of both the (-)- and (+)-enantiomers were linearly related to the doses. The mean ratio between them was 3.6 +/- 0.53, indicating stereospecific kinetics during maintenance treatment. Lumbar punctures were performed in four of the patients before and after 3 weeks of E-10-OH-NT treatment. There was a 18% mean decrease (P less than 0.01) in the noradrenaline metabolite HMPG in cerebrospinal fluid (CSF), supporting previous in vitro data showing that E-10-OH-NT inhibits noradrenaline uptake in vivo. During treatment, the median depression score measured by the Montgomery-Asberg Depression Rating Scale declined from 32 to 14 (P less than 0.05). As the study was open, the clinical outcome is not conclusive but does not contradict the hypothesis that E-10-OH-NT has antidepressant properties. If present at all, side effects were mild and did not interfere with the treatment.

Adult↗
PubMed1993

CSF/plasma ratio of 10-hydroxynortriptyline is influenced by sex and body height.

The CSF/plasma ratios of nortriptyline (NT) and its major metabolite 10-hydroxy-NT (10-OH-NT) were investigated retrospectively in 25 depressed patients. For 10-OH-NT (but not NT), a significant influence of sex and body height was found, most conspicuously in males, in whom the ratio related to body height curvilinearly (N = 8; R = 0.93; P < 0.01). In males, the NT/10-OH-NT ratio in plasma correlated with body height (N = 8; r = 0.80; P < 0.05). Hypothetically, CSF circulation is partly influenced by body height, which accounts for a steeper gradient of 10-OH-NT across the blood-brain barrier in taller persons. From the lumbar site, the more polar 10-OH-NT is assumed to be eliminated by bulk flow via the villi, while the less polar NT exits by diffusion in the choroid plexus. Prospective studies are urgently needed to further evaluate the distribution of antidepressants in the CSF.

Adult↗
PubMedDate not supplied

Population pharmacokinetics and pharmacodynamics: potential use for gathering dose-concentration-response.

The population approach is a general term covering different aspects of kinetic and dynamic data collected mainly from drug-treated patients and new techniques allowing evaluation of sparse observations from each subject. Such data originate from clinically relevant conditions and can give information on several qualities of a drug. An example is given with the tricyclic antidepressant nortriptyline for which the kinetics and the concentration-effect relationship have been thoroughly documented previously with conventional techniques. We have evaluated retrospective data from a therapeutic drug monitoring service using a nonparametric population kinetic method (NPML) that allows description of kinetic outliers and nonlinear relationships between kinetic parameters and covariates. In addition, drug interactions, nonlinear kinetics and dosing habits were studied with other techniques corroborating previous results and adding new information. The concentration-effect relationship could not be evaluated from our data as information on efficacy and adverse effects was of too low quality. However, several controlled studies have defined a therapeutic concentration interval and a discussion on dosing strategies is based on this interval. Collection of sparse data in patients during phases II-IV of drug development as a complement to conventional studies is highly recommendable.

Adult↗
PubMed2006

Optimization of solid-phase microextraction procedures for the determination of tricyclic antidepressants and anticonvulsants in plasma samples by liquid chromatography.

Simple, sensitive, and reproducible off-line solid-phase microextraction and liquid chromatography (SPME/LC) methods are described for the determination of seven anticonvulsants and tricyclic antidepressants in human plasma. Factorial design and simplex methodology were applied in the optimization of the SPME procedure for tricyclic antidepressants analyses. Important factors in the SPME efficiency are discussed, such as the fiber coatings (both lab-made and commercial), extraction time, pH, ionic strength, influence of plasma proteins, and desorption conditions. The development of the lab-made fiber coatings, namely, octadecylsilane, aminosilane, and polyurethane, are further described and applied to anticonvulsants analyses. The investigated plasmatic range for the evaluated anticonvulsants, using CW-TPR fiber, were the following: phenylethylmalonamide (3.00-40.0 microg mL(-1)), phenobarbital (5.00-40.0 microg mL(-1)), primidone (3.00-40.0 microg mL(-1)), carbamazepine and carbamazepine-epoxide (2.00-24.0 microg mL(-1)), phenytoin (2.00-40.0 microg mL(-1)), and lamotrigine (0.50-12.0 microg mL(-1)). The antidepressants' linear plasmatic concentration ranged from 75.0 to 500 ng mL(-1) for imipramine, amitriptyline, and desipramine, and from 50.0 to 500 ng mL(-1) for nortriptyline, being in all cases, the limit of quantification represented by the lowest value. The precision (interassays) for all investigated drugs in plasma sample spiked with different concentrations of each analyte and submitted to the described procedures were lower than 15%. The off-line SPME/LC methodologies developed allow anticonvulsants and antidepressants analyses from therapeutic to toxic levels for therapeutic drug monitoring.

Amitriptyline↗
PubMed2002

The role of CYP2C19 in amitriptyline N-demethylation in Chinese subjects.

OBJECTIVE: To determine the role of cytochrome P(450) (CYP)2C19 in N-demethylation of amitriptyline (AT) in healthy Chinese subjects. METHODS: One hundred and one subjects were genotyped for CYP2C19 using polymerase chain reaction-restriction fragment length polymorphism analysis. Twelve unrelated adult men (19.7+/-0.6 years, 61.8+/-3.8 kg) were chosen and orally given a single dose of 50 mg AT, and the blood samples were drawn from a forearm vein at 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 24, 48, 72, and 96 h after AT administration. Plasma concentrations of AT and nortriptyline (NT) were determined using high-performance liquid chromatography with an ultraviolet detector. RESULTS: The mean area under the plasma concentration-time curve (AUC(AT)) of CYP2C19 poor metabolizers (PMs, n=6) was significantly higher than that of CYP2C19 extensive metabolizers (EMs, n=6) (2207+/-501 ng/ml x h(-1) vs 1596+/-406 ng/ml x h(-1), P<0.05). In contrast, the mean AUC(NT(0-)(infinity)()) of PMs was significantly lower than that of EMs (294+/-70 ng/ml x h(-1) vs 684+/-130 ng/ml x h(-1), P<0.0001). Other pharmacokinetic parameters such as clearance, half-life, maximum plasma concentration, and time to peak plasma concentration showed no significant difference between PMs and EMs (0.41+/-0.12 l /h x kg(-1) vs 0.50+/-0.15 l /h x kg(-1), 25.0+/-6.2 h vs 24.1+/-4.4 h, 96+/-25 ng/ml vs 75+/-27 ng/ml, 4.0+/-1.4 h vs 3.7+/-1.5 h, respectively). CONCLUSION: The genetic defects of CYP2C19 have a significant effect on AT pharmacokinetics, and CYP2C19 plays an important role in N-demethylation of AT in vivo at a clinically therapeutic dose.

Administration, Oral↗
PubMed1992

Inhibition and metabolite complexation of rat hepatic microsomal cytochrome P450 by tricyclic antidepressants.

Administration of imipramine (IMIP) and other tricyclic antidepressants to humans and experimental animals has been associated with inhibition of hepatic cytochrome P450 (P450)-mediated drug oxidation. This study investigated the capacity of several structurally related tricyclic antidepressants to inhibit microsomal P450 activity in vitro. It was found that IMIP, desipramine (DES), amitriptyline (AMIT) and nortriptyline (NOR) were poor inhibitors of P450 activity unless they were preincubated with microsomes and NADPH prior to transfer to flasks containing substrate. Thus, subsequent experiments characterized the time-dependent intensification of inhibition produced by the drugs. Preincubation of the N-methylaminoalkyl agents DES and NOR (200 microM) with NADPH-supplemented microsomes for 30 min led to an approximate 30% decrease in spectrally apparent P450 content; the N,N-dimethylaminoalkyl drugs IMIP and AMIT did not significantly decrease apparent P450 content. Analysis of optical difference spectra of microsomes during NADPH-mediated metabolism of these drugs revealed a prominent increase in absorbance at 454 nm with DES and NOR but not IMIP or AMIT. Monospecific antibodies to the male-specific P450 2C11 and, to a lesser extent, P450 3A2 were effective in preventing the formation of the DES metabolite 454 nm-Soret peak. In addition, the 454 nm absorbance was not produced by the incubation of DES with NADPH-fortified hepatic microsomes from adult female or immature male rats. Studies with the steroid substrate testosterone, which undergoes P450-specific positional hydroxylation, indicated that P450 2C11-mediated 2 alpha- and 16 alpha-hydroxylation were most susceptible to the time-dependent intensification of inhibition produced by DES (8.5 and 7.0 min preincubation required for loss of 50% activity, respectively) and NOR (4.0 and 4.0 min for loss of 50% of both activities). The 6 beta- (P450 3A2) and 7 alpha-hydroxylase (P450 2A1) pathways were somewhat less susceptible to inhibition than 2 alpha- and 16 alpha-hydroxylation. These findings suggest that DES and NOR form a metabolite intermediate (MI)-complex, characterized by a Soret region absorbance maximum near 454 nm in the optical difference spectrum, with microsomal P450 in male rat liver in vitro. Studies with the steroid substrate testosterone as well as immunoinhibition experiments are consistent with the proposition that this MI complex forms principally with the male-specific enzymes P450 2C11 and 3A2. Although a human orthologue of P450 2C11 has not yet been identified, P450s of the 3A subfamily are quantitatively important enzymes in human liver. MI complexation of such enzymes could be a feasible underlying mechanism for certain clinically important drug interactions involving tricyclic antidepressants.

Amitriptyline↗
PubMed1992

Pharmacological comparison of the rat and guinea-pig cortical high affinity 5-hydroxytryptamine uptake system.

The pharmacological characteristics of the high affinity [3H]5-hydroxytryptamine ([3H]5-HT) uptake system were investigated in the cerebral cortex of the rat and guinea-pig. In crude cortical synaptosomal preparations from the rat and guinea-pig, [3H]5-HT accumulated with high affinity (Km, 72 +/- 12 and 57 +/- 14 nM for rat and guinea-pig cortical synaptosomal preparation, respectively, mean +/- SEM, N = 5) and with a comparable maximum activity (Vmax, 1.22 +/- 0.21 and 0.90 +/- 0.19 pmol/min/mg protein for rat and guinea-pig cortical synaptosomal preparation, respectively, mean +/- SEM, N = 5). Competition studies employing a range of structurally diverse competing compounds showed that the [3H]5-HT uptake was pharmacologically similar in both preparations. However, citalopram possessed approximately 10-fold weaker affinity to prevent [3H]5-HT uptake in the guinea-pig preparation when compared to the rat and all of the tricyclic antidepressants assessed in the present studies (amitriptyline, nortriptyline, desipramine and imipramine) displayed higher affinity in the guinea-pig preparation when compared to the rat. It is concluded that the high affinity 5-HT uptake systems in the rat and guinea-pig cortex are similar but may not be identical.

Amitriptyline↗
PubMed1987

Clinical predictors of response to antidepressants in elderly patients.

A group of 42 patients, ages 55 and above, suffering from major depression were examined in an attempt to isolate clinical variables that would predict response to antidepressants. These patients were part of a placebo-controlled, double-blind study and were given either nortriptyline or phenelzine for 5-7 weeks. There was no significant difference in response rates between patients subclassified as endogenous or nonendogenous by either RDC or Newcastle criteria. No difference in response rates was found between the DSM-III melancholic and nonmelancholic subtypes. Neither drug preferentially treated a subtype. None of the 21 variables representing symptoms, demographic traits, or characteristics of the depressive illness were found to be significant predictors of antidepressant response.

Aged↗
PubMed1976

Tricyclic antidepressants and cardiac conduction: changes in ventricular automaticity.

Ventricular dysrhythmias result from changes in the automaticity or the conduction properties of the specialized conduction system. Tricyclic antidepressants have been reported to cause ventricular dysrhythmias in humans and experimental animals. Consequently, it seemed to interest to determine whether these substances influence ventricular automaticity. Ventricular rhythm was produced in anesthetized dogs by blocking atrioventricular conduction. Low doses of imipramine, amitriptyline and nortriptyline resulted in small but significant increases in automaticity. Relatively high doses of these agents suppressed automaticity markedly. These changes could play a role in the development of dysrhythmias.

Amitriptyline↗
PubMed1979

Mianserin potentiates responses to acetylcholine in the rat anococcygeus muscle.

In the rat anococcygeus muscle, mianserin (1 and 10 muM) increased the magnitude of the maximal contractile responses to acetylcholine and carbamylcholine without affecting the maximal responses to (--)-noradrenaline. The potentiating effect of mianserin on responses to acetylcholine was maintained in the presence of 5muM phentolamine, following 6-hydroxy dopamine incubation of the tissues (1 mM for 3h) and in the presence of 1 muM nortriptyline. It is suggested that mianserin increases the sensitivity to acetylcholine by an action at the level of, or distal to, the cholinergic receptor.

Acetylcholine↗
PubMed1987

Regulation of high- and low-affinity [3H]imipramine recognition sites in rat brain by chronic treatment with antidepressants.

Specific binding of [3H]imipramine to its recognition sites in frontal cortex and levels of serotonin (5-HT), 5-hydroxyindoleacetic acid (5-HIAA) and norepinephrine (NE) as well as uptake of serotonin by crude synaptosomal (P2) fraction were determined in a group of rats chronically (for 21 days) treated with different types of antidepressant drugs: nortriptyline, fluoxetine, iprindole, phenelzine (10 mg/kg per day), maprotiline (20 mg/kg per day) and vehicle only (controls). Quantitative analysis of imipramine competition curves confirmed the existence of two classes of [3H]imipramine sites: high-affinity with IC50 and 11.2 nM and low-affinity with IC50 of 630 nM for the competing ligand. The proportion of high- and low-affinity sites was 73 +/- 4 and 26 +/- 4%, respectively. Chronic treatment with all antidepressant drugs except iprindole significantly decreased the affinity but not the proportion of high-affinity sites for imipramine. IC50 of imipramine at low-affinity sites was even more markedly increased at low-affinity sites by all treatments except for phenelzine. Fluoxetine was by far the most effective in altering the affinity of both high- and low-affinity [3H]imipramine recognition sites. Both NE and 5-HT levels were significantly enhanced only by phenelzine treatment, whereas 5-HT and 5-HIAA levels were found to be lower after fluoxetine. Kinetics of 5-HT uptake were altered significantly only in rats treated with fluoxetine: rate of 5-HT uptake (Vmax) was decreased by 43% and Km value increased from 104 to 184 nM. Changes in affinity of imipramine for its binding sites were not found to be associated with the effect of tested drugs on 5-HT levels or uptake. They may be due to adaptive alterations in physico-chemical properties of binding proteins although the presence of residual drug interfering with the binding assay cannot be excluded. The observed changes are likely to represent the condition during chronic administration of these drugs in clinical therapy of depression.

Animals↗
PubMed1984

Tricyclic antidepressant drugs affect histamine receptors in human leukocytes.

Tricyclic antidepressant drugs bind to histamine receptors in rodent and other mammalian tissues. However, a readily accessible, normal human tissue for studies of these drugs has not been available. We showed that freshly isolated human leukocytes can be used for this purpose. Following isolation by dextran sedimentation, leukocytes were incubated for 30 sec. in histamine concentrations from 1.0 nM to 1.0 mM. A dose-related increase in intracellular cyclic AMP was observed. When the cells were preincubated for 10 min. in the tricyclic, nortriptyline, and then challenged with histamine, the concentration of histamine needed for a comparable cyclic AMP increase was elevated 100-fold over non-preincubated cells. These results indicate that the tricyclic drug interacts with histamine receptors on leukocytes, and that these cells may be used for biochemical and clinical studies of these drugs.

Adult↗
PubMed1994

Alpha-adrenergic receptors mediate imipramine/alarm substance-induced reaction in rats.

The mechanism of adverse imipramine-induced reactions (jitteriness, convulsions) was investigated by precipitating such reactions in rats with three injections (IP) of imipramine (5-40 mg/kg) at 24, 5, and 1 h before testing, and comparing their occurrence with comparable treatments using specific noradrenergic and serotonergic reuptake inhibitors [nortriptyline (10 or 30 mg/kg, IP), citalopram (0.5-5.0 mg/kg, IP)]. This initial study indicated that these reactions were mediated by imipramine's noradrenergic effects. Subsequent combinations of imipramine and an alpha 2 agonist (clonidine, 5 mg/kg) and antagonist (yohimbine, 2 mg/kg), and a beta-adrenergic antagonist (propranolol, 2 or 5 mg/kg) (all administered IP 0.5 h after the last injection of imipramine) suggested imipramine's adverse effects were mediated by alpha 2 receptors. The possible involvement of the locus ceruleus in these effects was considered.

Animals↗
PubMed1984

Weight gain. A side-effect of tricyclic antidepressants.

Body weight and appetite were evaluated in 40 depressed outpatients from a private psychiatric practice who were receiving low-modest doses of tricyclic antidepressants. Amitriptyline (maximum of 150 mg/day), nortriptyline (maximum of 50 mg/day), and imipramine (maximum of 80 mg/day) were given for an average of 6 months of treatment. There was a mean weight increase of 1.3-2.9 lbs/month, which led to an average total weight gain of 3-16 lbs, depending on drug, dose and duration. These weight increases were linear over time and were accompanied by marked increases in the preference for sweets. Ultimately, excessive weight gain was the most common cause of discontinuation of treatment, occurring in one-half of the patients. Significant weight loss occurred upon discontinuation of drug. These findings show that chronic administration of low-modest doses of tricyclic antidepressants frequently cause considerable weight gain and can significantly interfere with the ability to provide long-term maintenance therapy.

Adult↗
PubMedDate not supplied

The usefulness of DST in predicting response to antidepressants: a placebo-controlled study.

Seventy-two out-patients, 55 years or older, suffering from major depression were treated with either nortriptyline or phenelzine for seven weeks under placebo-controlled double-blind conditions. The dexamethasone suppression test (DST) was administered at baseline and at weeks 3 and 7 of treatment, and its usefulness in predicting and/or paralleling clinical response was examined. No correlation was found between baseline DST results and treatment response with antidepressants. Of 13 patients whose abnormal baseline DSTs normalized during treatment, six were responders and seven were nonresponders (P = 0.24). However, all (seven) patients whose DSTs persisted to be abnormal throughout the seven weeks did not respond. The authors conclude that the DST has not been shown to have practical value as an indicator of impending recovery from major depression in the elderly, but its failure to normalize may have ominous prognostic significance.

Aged↗
PubMedDate not supplied

Relapse of depressed patients after effective continuation therapy.

Forty-one elderly depressed patients who had responded to either nortriptyline or phenelzine were given continuation treatment for approximately 4 months (mean = 16.5 weeks) after which 19 were switched under double-blind conditions to placebo. At the end of 8 weeks, three (15.8%) of the placebo patients had relapsed and three (13.6%) of the patients kept on antidepressants had relapsed. Patients who had more prior episodes of depression had a greater risk of relapsing. The implications of these findings for continuation pharmacologic treatment in the elderly depressed are discussed.

Aged↗
PubMed1993

Depressive symptoms and measures of disability: a prospective study.

OBJECTIVE: The purpose of this study was to test the hypothesis that decreases in severity of depressive symptoms in patients with chronic tinnitus would correlate with reductions in measures of functional disability. METHOD: This study describes the correlations between several measures of functional disability and Hamilton depression scores in two groups of patients with major depression and depressive symptoms (D-NOS) who were patients enrolled in a 12-week placebo-controlled, double-blind trial of nortriptyline. These patients had chronic severe tinnitus which was associated in most patients with high frequency hearing loss. The effect of whether affective symptoms improved and the patient's initial depression status (major depression versus depressive symptoms) are examined in order to increase understanding about the correlations between depressive symptoms and functional disability. RESULTS: Most measures of functional disability decreased synchronously with Hamilton Depression Scale scores in both patients with major depression and those with subclinical depressive symptoms. Patients whose depression improved had a significantly greater change in each disability measure than patients whose depression did not improve. This significant decrease in functional disability was seen in 11 of 13 scales in the improved D-NOS group, versus only 3 of the 13 scales in the unimproved D-NOS group; 9 of 13 scales of functional disability significantly decreased in the improved major depression group, versus 3 of 13 scales in the unimproved major depression group. CONCLUSIONS: The results suggest that there was a significant correlation between improvement in both major depression and depression-NOS symptoms, and decreases in measures of functional disability in an aging population with a chronic medical illness.

Adaptation, Psychological↗
PubMed1991

Genotoxicity evaluation of five tricyclic antidepressants in the wing somatic mutation and recombination test in Drosophila melanogaster.

Five tricyclic antidepressants were tested for genotoxicity using the somatic mutation and recombination test (SMART) in wing cells of Drosophila melanogaster. Three-day-old larvae trans-heterozygous for 2 linked recessive wing hair mutants (multiple wing hairs and flare) were fed the test compounds in water mixed with a standard dry food for 48 h. Wings of the emerging adult flies were scored for the presence of spots of mutant cells which can be the consequence of either somatic mutation or mitotic recombination. Desipramine and imipramine were clearly genotoxic at concentrations above 1 mM whereas amitriptyline, nortriptyline and protriptyline were not genotoxic at concentrations up to 100 mM. This seems to implicate the nitrogen atom at position 5 in the 7-membered ring of the tricyclic molecule as being responsible for the genotoxic property of the compounds in Drosophila.

Amitriptyline↗