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PubMed1994

Blood levels of mianserin and amitriptyline and clinical response in aged depressed patients.

Steady-state plasma levels of mianserin, amitriptyline, and nortriptyline were determined by HPLC in two groups of elderly depressed patients who underwent a 5-week treatment with mianserin (60 mg/day in three oral doses) or amitriptyline (75 mg/day in three oral doses). Both treatments proved to be effective in reducing depressive symptoms. In the mianserin group, responder patients had steady-state plasma concentrations of mianserin higher than nonresponders. No relationship was found between amitriptyline, nortriptyline, or amitriptyline+nortriptyline plasma levels and clinical response in amitriptyline treated patients.

Aged↗
PubMed1984

Salivation after single-doses of the new antidepressants femoxetine, mianserin and citalopram. A cross-over study.

Twelve healthy volunteers were given oral single doses of a reference drug (nortriptyline), test drugs, and placebo on a randomised single-blind basis at weekly intervals. The doses corresponded to average daily patient medication. Spontaneous whole mouth salivation was measured before (at 10 p.m.) and 10 hours after drug administration (at 8 a.m.). Drug plasma levels were determined after 4 and 10 hours. When analysing the salivations 10 hours after drug administration adjusted for the effects of the pre-treatment salivations, statistically significant inhibition of salivation was found after nortriptyline (56%), femoxetine (34%), and mianserin (29%) when compared with placebo, while for citalopram and cis- and trans-flupenthixol no significant inhibition of salivation was demonstrated (Fig. 1, Table 5). From the estimated log linear regression coefficients, relating adjusted salivation rates and drug plasma levels 10 hours after drug administration (Table 6), and reported average steady-state plasma drug levels (Table 7), semiquantitative predictions of the average level of anticholinergic activity during long-term treatment may be made: For femoxetine and mianserin, moderate anticholinergic activity, less pronounced than with nortriptyline, are predicted, while for citalopram no such activity can be predicted (Table 7).

Adolescent↗
PubMed1997

Amitriptyline accumulation and elimination in Calliphora vicina larvae.

Calliphora vicina larvae reared on artificial foodstuffs spiked with human equivalent therapeutic (100 ng/g), toxic (300 ng/g), lethal (500 ng/g), and 10 x lethal (5,000 ng/g) concentrations of amitriptyline and nortriptyline, alone and in various combinations, were harvested at various stages of development and analysed for drug content by high-pressure liquid chromatography (HPLC) and gas chromatography-mass spectrometry (GC-MS). Mean (range) larval amitriptyline concentrations (ng/g) in larvae reared on foodstuffs containing 100 ng/g, 500 ng/g, and 5,000 ng/g amitriptyline were 3.21 (<1-5.72), 21.3 (14.2-27.4), and 50.1 (38.8-64.3), respectively, on day 5; 6.62 (5.98-7.72), 22.5 (16.4-32.4), and 38 (22.8-50.9) on day 8; and 4.45 (3.45-5.93), 25.2 (18.6-38.4), and 26.2 (22.7-29.7) on day 11. Nortriptyline concentrations (ng/g) in larvae reared on foodstuffs containing 100 ng/g, 500 ng/g, and 5,000 ng/g nortriptyline were 6.86 (4.48-8.96), 14.1 (11.9-17.8), and 18.5 (16.7-20.6), respectively, on day 5; 8.32 (4.9-11.7), 12.9 (11.5-14.2), and 18.8 (11.5-23) on day 8; and 5.06 (3.27-7.25), 19.4 (17.8-22.4), and 26.6 (11.7-44.7) on day 11. Among 45 separate larval rearings fed on the same foodstuff, mean larval weight ranged from 24-96 mg and larval amitriptyline concentration from <1-148 ng/g. Biological variability in larval drug concentrations were greatest in larvae reared on high drug concentrations. Such variability makes quantitative extrapolation back to the drug concentration in foodstuff unreliable. Larval drug accumulation became unpredictable when larvae encounter more than one drug or different concentrations of a single drug. Drug concentrations measured were partly due to surface contamination with drug-rich putrefactive residue and they also depend partly on the analytical method used. Fly larvae are unreliable samples for quantitative toxicological analysis.

Administration, Oral↗
PubMed1985

Separate and combined anxiolytic and anti-depressant treatment of mixed anxiety/depression. A double-blind, placebo controlled comparison. Sussex Clinical Trials Group.

233 patients attending their general practitioners for mixed anxiety/depressive states were treated on a double-blind random allocation basis with one tablet to be taken three times daily, containing either 0.5 mg fluphenazine, 10 mg nortriptyline, a combination of 0.5 mg fluphenazine and 10 mg nortriptyline (Motival), or placebo. After 7 and 28 days' treatment, the combination product was found to be statistically superior to each of its active ingredients alone, as well as to placebo, with respect to anxiety, depression and non-specific symptoms. Side effects were not a clinical problem and occurred with similar frequency in each treatment group. The superiority of Motival over each of its constituents is in keeping with previous studies showing advantages of the combination of fluphenazine and nortriptyline over anxiolytic and anti-depressant drugs on their own.

Adolescent↗
PubMed1979

Physico-chemical modification of lidocaine uptake in rat lung tissue.

The uptake of lidocaine, methyllidocaine, bupivacaine, etidocaine was studied in rat lung slices at different pH-values. The accumulation of the quaternary analogue, methyllidocaine, was not changed in the pH interval 7.0--8.0. The uptake of the three other substances was about 3--4 times lower at pH 7.0 than at pH 8.0. The rank order of distribution at a fixed cation/base ratio was bupivacaine greater than etidocaine greater than lidocaine. Interactions between lidocaine and other substances were studied in lung slices and in isolated perfused lungs. Bupivacaine and nortriptyline counteracted the accumulation of 14C-lidocaine in lung slices in a dose-dependent manner. Nortriptyline was more effective than bupivacaine. In isolated perfused lung, bolus injections of nortriptyline and lidocaine rapidly displaced 14C-lidocaine from the tissue. In this study we suggest that the base form of local anaesthetics accumulate in the lung tissue, while the cationic form binds to accessible binding sites in the cell membranes.

Animals↗
PubMed1985

Plasma 10-hydroxynortriptyline and ECG changes in elderly depressed patients.

Among 18 elderly depressed patients given ECGs before and during nortriptyline treatment, plasma E-10-hydroxynortriptyline and the sum of E-10-hydroxynortriptyline and nortriptyline distinguished the group with conduction/repolarization effects. Plasma nortriptyline, age, drug dose, and baseline cardiovascular status did not.

Age Factors↗
PubMed1998

Cardiovascular effects of fluoxetine in depressed patients with heart disease.

OBJECTIVE: The purpose of this study was to determine the cardiovascular effects of fluoxetine in depressed patients with cardiac disease. METHOD: Twenty-seven depressed patients (26% of whom were female and whose average age was 73 years) who had congestive heart failure, conduction disease, and/or ventricular arrhythmia were studied in an open medication trial of fluoxetine, up to 60 mg/day, for 7 weeks. The main outcome measures were heart rate and rhythm measured by 24-hour ECG recordings, ejection fraction determined by radionuclide angiography, cardiac conduction intervals, and blood pressure. Baseline values were compared with those at weeks 2 and 7 of fluoxetine treatment. In 60 comparable patients, values of these same cardiovascular measures at baseline and after 3 weeks of treatment with a tricyclic antidepressant, nortriptyline, were also examined. RESULTS: Fluoxetine induced a statistically significant 6% decrease in heart rate, a 2% increase in supine systolic pressure, and a 7% increase in ejection fraction. There was no effect on cardiac conduction, ventricular arrhythmia, or orthostatic blood pressure. Overall, 4% of the fluoxetine patients had an adverse cardiovascular effect. In contrast, nortriptyline treatment caused a significant increase in heart rate and orthostatic hypotension, and 20% of the nortriptyline-treated patients had an adverse cardiovascular effect. CONCLUSIONS: In depressed patients with heart disease, fluoxetine treatment was not associated with the cardiovascular effects documented for the tricyclic antidepressants or with significant adverse cardiac events. However, limited conclusions about fluoxetine's cardiovascular effects and safety can be drawn from this study of only 27 patients monitored for 7 weeks.

Adult↗
PubMed2001

Comparison between noradrenergic and serotonergic medications using the social adjustment scale: is drive enhancement necessary for recovery of social functioning?

The Social Adjustment Scale (SAS) was used to assess social functioning sequentially over 13 weeks in a group of 188 depressed outpatients randomized to either the noradrenergic antidepressant, nortriptyline, or the selective serotonin reuptake inhibitor, fluoxetine. Over the period of 13 weeks, there were no differences in total SAS scores between the nortriptyline and the fluoxetine group. In comparing the SAS subscale scores, which may measure different areas of motivation and behaviour (drive), there were differences between the two groups in only two subscales. At 13 weeks, the group randomized to fluoxetine were more impaired in marital role (p = 0.026) whereas, at 6 weeks, the group randomized to nortriptyline were more impaired in friction scores (p = 0.012). These results do not support the concept of specific augmentation of drive-related behaviour by noradrenergic medication. This challenges the earlier findings relating to drive enhancement and social adjustment using such medication.

Adrenergic Agents↗
PubMed1980

Radioimmunoassay for tricyclic antidepressants.

A sensitive radioimmunoassay for the determination of tricyclic antidepressants is described. The antibodies were produced in rabbits immunized with a conjugate of N-succinyl-nortriptyline and human serum albumin and they were shown to be specific for the tricyclic antidepressant group of drugs. The assay was tested for the determination of amitriptyline and nortriptyline concentrations in plasma or serum. Specificity was achieved by coupling a simple extraction procedure (based on selective extraction of amitriptyline and nortriptyline at different pH-values) to the assay. Using [3H]imipramine as the tracer the sensitivity of the assay is 3.8-18.0 nmol/l depending on whether the extraction procedure is used or not and it can be carried out with 50-200 microliter sample volumes. Because of its advantages (sensitivity, specificity, simplicity, small sample volumes, low cost) this procedure is suitable for drug monitoring both during controlled tricyclic therapy and pharmacokinetic studies.

Amitriptyline↗
PubMed1992

Amitriptyline and amitriptyline metabolites in blood and cerebrospinal fluid following human overdose.

The toxicokinetics of amitriptyline were studied in nine patients admitted to hospital in Matthew-Lawson Coma Scale grade III-IV after an estimated ingestion of 1-5 g amitriptyline. Gastric lavage was performed and 50 g activated charcoal were given orally. Venous blood samples were taken on admission and at 1, 2, 4, 8, and 24 h, and in some patients at 36 and 48 h after admission. Arterial blood samples were taken at 1, 4, 8, and 24 h after admission. Lumbar punctures were performed 1 h after admission in 8 patients and again 4 h later in 5 patients. A urine sample was screened for other drugs. The bound and unbound fraction of amitriptyline and its metabolites nortriptyline, E and Z forms of 10-OH-amitriptyline and nortriptyline were analyzed in plasma, whole blood, red blood cells, and cerebrospinal fluid using an HPLC technique. The T1/2 alpha and T1/2 beta for amitriptyline were 1.5 - 3.1 and 15 - 43 h respectively. The rate of elimination of amitriptyline was not dose-dependent. The arteriovenous differences in the total amitriptyline+nortriptyline concentration were maximal in patients admitted soon after intake of drugs. Amitriptyline concentrations in cerebrospinal fluid were quantitatively similar to the unbound amitriptyline concentration in blood. The highest cerebrospinal fluid amitriptyline concentration was 506 nmol/L. There were large individual differences in plasma, blood and cerebrospinal fluid concentrations between different individuals. Repeated quantitative analysis of amitriptyline and its metabolites is unlikely to contribute to the clinical management of most patients with amitriptyline overdose.

Adult↗
PubMed2003

The relationship of personality disorders to treatment outcome in depressed outpatients.

BACKGROUND: Many clinicians believe that depressed patients with comorbid personality disorder(s) may respond differently to standard treatments than patients with depression alone. Personality disorders appear to be common among patients with depression, suggesting potentially significant treatment implications for a large group of patients. METHOD: Subjects with DSM-III-R major depression were recruited for a study looking at prediction of antidepressant response. All patients were assessed using the Structured Clinical Interviews for DSM-III-R Axis I and Axis II, as well as rated on the Hamilton Rating Scale for Depression and the Montgomery-Asberg Depression Rating Scale (MADRS). Patients were then randomly assigned to treatment with fluoxetine or nortriptyline and reassessed at 6 weeks. The major outcome measure was percentage reduction in MADRS scores. RESULTS: Of the 183 patients who completed the personality disorder assessment, 45% had at least 1 comorbid personality disorder. Subjects with comorbid personality disorders were slightly younger, more depressed at baseline, had poorer social adjustment, more general psychopathology, and more chronic depression. Despite these differences, the presence of a comorbid personality disorder did not adversely affect overall outcome at 6 weeks, but there was an interaction between having a comorbid personality disorder and drug type. The major effect was that patients with a cluster B personality disorder did relatively poorly on nortriptyline compared with fluoxetine treatment. CONCLUSION: The finding that the presence of a comorbid personality disorder does not affect overall treatment response is similar to that reported by some recent studies. The finding that patients with cluster B personality disorders respond poorly to nortriptyline is also consistent with a small literature on borderline personality disorder.

Adult↗
PubMed2005

Weight changes in postpartum women with remitted depression.

OBJECTIVE: To compare weight loss after birth in women who took the antidepressants nortriptyline or sertraline or placebo in 2 clinical studies designed to prevent recurrent postpartum major depression. METHOD: Data were collected from 1995 to 2001. All subjects had at least 1 prior episode of Research Diagnostic Criteria- or DSM-IV-defined major depressive disorder. Data on weight were available for 467 weeks from 60 women who were weighed 8 times from 2 to 17 weeks postpartum. The dependent measures were weight at weeks 11 and 17 and weight change from weeks 2 to 17 postpartum. RESULTS: At week 17, the women's weights ranged from 109 to 268 lb. Their weight change ranged from +14 to -19 lb over the 15-week postpartum period (mean = -1.8, SD = 5.1 lb). After controlling for week 2 weights, the mean weights at week 17 for the women treated with nortriptyline, sertraline, or placebo were not significantly different. Of 60 women with 3 or more weight assessments, those who were randomly assigned to nortriptyline lost weight more rapidly than the other 2 groups; however, the mean weight change across all groups was only -1.8 lb (SD = 5.1 lb). CONCLUSIONS: Weight loss was not compromised by antidepressant pharmacotherapy. Postpartum weight retention occurred in this group of nondepressed women with previous histories of major depression independent of drug treatment.

Adolescent↗
PubMed1976

Treatment of depression with tricyclic drugs--pharmacokinetic and pharmacodynamic aspects.

A series of studies on the pharmacokinetic and pharmacodynamic properties of some tricyclic antidepressants is reviewed. During treatment with the same oral dose of these drugs, patients develop widely differing plasma levels. The importance of this variability for the clinical effects has been studied in detail for the monomethylated compound, nortriptyline. There is an association between side-effects and high plasma levels of this drug. In endogenously depressed patients, the relationship between plasma level and effect appears to be curvilinear. The tricyclic antidepressants differ in their capacity to inhibit transmitter uptake into noradrenaline- and serotonin neurons respectively. Nortriptyline is a preferential noradrenaline uptake inhibitor, while the dimethylated compound, chlorimipramine also has a profound influence on serotonin neurons. These differential effects are also reflected in changes in the levels of the transmitter metabolites in cerebrospinal fluid (CSF). The CSF studies have also supported the hypothesis of a biochemical heterogeneity of the depressive syndrome. The levels of the serotonin metabolite, 5-HIAA were bimodally distributed in CSF. In patients with a low level of 5-HIAA there was a significant correlation between the CSF metabolite level and the severity of the depression, and these patients also appeared to be more suicide-prone than those with higher 5-HIAA levels. These patients seemed to be less amenable to treatment with nortriptyline. The effect of chlorimipramine treatment in this subgroup of depressives is presently being explored.

Antidepressive Agents, Tricyclic↗
PubMed2000

Drug treatment of depression in frail elderly nursing home residents.

The authors conducted a randomized, double-blind, 10-week clinical trial of two doses of nortriptyline in eight nursing homes. Sixty-nine patients, average age 79.5 years, were randomized to receive regular doses (60 mg-80 mg/day) vs. low doses (10 mg-13 mg/day) of nortriptyline. Among the more cognitively intact patients, there was a significant quadratic relationship defining a "therapeutic window" for nortriptyline plasma levels and clinical improvement. There were also significant differences in plasma level-response relationships between depressed patients who were cognitively impaired and those who were more cognitively intact. Depression remains a syndrome that responds to specific treatment, even in frail nursing home patients, and those depressions that occur in patients with significant dementia may represent a treatment-relevant condition with a different plasma level-response relationship than in depression alone.

Aged↗
PubMed1975

The effect of toxic and therapeutic doses of tricyclic antidepressant drugs on intracardiac conduction.

Intracardiac conduction studies using His bundle electrography (HBE) were performed in 14 patients admitted to hospital following an overdosage of one of the tricyclic antidepressant drugs and in another 12 patients before and during administration of therapeutic doses of nortriptylline. Amongst the former group, 7 of 8 patients showed impaired distal intracardiac conduction (H-V interval) following overdosages of nortriptyline, imipramine or amitriptyline but none of the 6 patients with doxepin overdosage. The prolonged H-V interval had returned to normal at a repeat study 7 days later. In the therapeutic dose study, 5 of 12 patients showed an increase in the H-V interval by more than 10 msec during treatment with nortriptyline. Four of these 5 patients had plasma nortriptyline levels of over 200 ng/ml. Tricyclic antidepressant drugs show a quinidine-like effect in toxic, and in some patients, in therapeutic doses. This finding may having a bearing on the treatment of cardiac arrhythmias in patients following overdosage with these drugs and may provide a clue to the reported increase in the incidence of sudden deaths in 'cardiac patients' following therapeutic doses of such agents.

Antidepressive Agents, Tricyclic↗
PubMed1984

Implications of dosing tricyclic antidepressants and benzodiazepines in geriatrics.

It is important to understand both the kinetic and the dynamic implications of dosing TCAs and BZs in the elderly, for whom these drugs are frequently prescribed. The TCAs are used to treat responsive signs and symptoms including such somatic complaints as chest pain, dizziness, and arthralgias, as well as the endogenous signs such as loss of appetite with associated weight loss, psychomotor retardation, loss of libido, and insomnia. The pharmacokinetic studies of TCAs such as desipramine and nortriptyline have shown few, if any, age-related changes. The dose required for responsivity is significantly reduced for both TCAs (desipramine and nortriptyline) in the elderly, which may suggest increased end-organ responsiveness. The major recommendations for treatment of depression with nortriptyline in the elderly are (1) to administer small doses in order to avoid side effects, and (2) to expect a longer response time for the antidepressant effect than in young and middle-aged depressed patients. Although the BZs are extensively prescribed in the elderly, primarily for insomnia and anxiety, the physiologic and biochemical changes of aging alter the kinetics and dynamics of these extensively metabolized and slowly eliminated drugs. Based on the kinetic data and information in Tables 1 and 2, the relatively sensitive elderly population should receive a reduced dosage. Careful evaluation of the patient and the kinetic profile of the agent employed will ensure safe use of these drugs. A clear understanding of anxiety and respect for the alterations in the pharmacokinetics and pharmacodynamics of these agents in the elderly will allow the physician to prescribe the BZs wisely. As with the TCAs, remember to administer doses of BZs that are reduced by 50 to 75 per cent of the usual recommended doses for young and middle-aged individuals and to increase dosage in small increments. Ultimately, sound, scientifically based, clinical judgment that considers the needs of the patient is the best guide for the selection of an appropriate BZ.

Adipose Tissue↗
PubMed1981

Tricyclic antidepressants: a simplified approach for the routine clinical monitoring of parent drug and metabolites in plasma using HPLC.

A simplified procedure for the routine clinical monitoring of amitriptyline, nortriptyline, imipramine and their metabolites in plasma using high performance liquid-chromatography (HPLC) has been developed. Commonly encountered problems in the analyses of tricyclic antidepressants such as low recovery, adsorption to glass and extensive "clean-up" procedures have been avoided by judicious choice of solvents, extraction procedures and chromatographic technique. The method involves a single extraction of 1 ml of plasma at pH 10.5 with iso-octane:methyl t-butyl ether (9:1) in a disposable polypropylene tube, solvent transfer to and evaporation in a similar tube followed by direct HPLC of the extract on a 10 micrometer silica gel column using methanol containing 0.1% concentrated ammonium hydroxide as the mobile phase and detection at 254 nm. Good chromatographic separation of amitriptyline (AT), 10-hydroxy-amitriptyline (10-OH-AT), nortriptyline of amitriptyline (NT), 10-hydroxy-nortriptyline (10-OH-NT), imipramine (IM) and desmethyl-imipramine (DMI) is achieved. IM is used as an internal standard for the analysis of plasma samples from patients receiving AT and NT, while NT is used as the internal standard for analysis of IM and its metabolite DMI. Overall recoveries exceed 80% and the limits of sensitivity are about 25 ng/ml for each compound quantitated. Although the utility of the method is illustrated in the analysis of a selection of plasma samples from patients receiving various therapeutic doses of AT, NT and IM, it would appear that the procedure offers a simplified approach for the analysis of other tricyclic antidepressants in a clinical setting.

Amitriptyline↗
PubMed1983

Displacement of lidocaine from serum alpha 1-acid glycoprotein binding sites by basic drugs.

Since little is known of the number and types of binding sites on alpha 1-acid glycoprotein (AAG) and because drug-drug protein binding interactions often fail to fit a simple model, a study of the effect of 9 known AAG binding drugs on lidocaine free fraction (LFF) was performed. Serum was obtained from 10 healthy males, pooled and various concentrations (from 0.15 to 1000 micrograms/ml) of amitriptyline, bupivacaine, chlorpromazine, disopyramide, imipramine, meperidine, nortriptyline, propranolol and quinidine were added. LFF was determined by equilibrium dialysis at an initial lidocaine concentration of 2.0 micrograms/ml. LFF increased from 0.30 +/- 0.019 (mean +/- SD) in the absence of displacing agents to maximum values ranging from 0.59 (nortriptyline) to 0.73 (bupivacaine). Plots of LFF vs. the logarithm of displacing drug concentration yielded simple sigmoidal curves in all cases. LFF was increased 50% by an initial bupivacaine concentration of 6.0 micrograms/ml with all other drugs requiring more than 10 micrograms/ml to increase LFF to that extent. Lidocaine binding in a 4.5 g/dl albumin solution was unaffected by concentrations of quinidine, meperidine, nortriptyline and bupivacaine up to 200 micrograms/ml. Addition of AAG to serum reduced LFF as expected. A plot of the reciprocal of bound drug concentration vs. the reciprocal of free drug concentration in the presence and absence of quinidine suggested a competitive binding interaction. These data indicate that the binding interactions between lidocaine and the various displacing compounds are not significantly complicated by cooperative effects and that, with the possible exception of bupivacaine, displacement of lidocaine by any of these drugs is likely to be of clinical significance.

Binding Sites↗