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PubMed1989

External quality assurance of tricyclic antidepressant measurements in serum: eight years of progress?

Comparison of the precision and accuracy of measurements made between December 1979 and January 1988 of tricyclic antidepressant drug concentrations in freeze-dried external quality-assurance samples of human serum showed only occasional significant differences between the different chromatographic techniques used for drug assay. Larger differences between data collected in different years correlated with changes in the source of the sample matrix and the personnel responsible for sample preparation. Measurements of amitriptyline and imipramine were more precise than those of nortriptyline and desipramine; the mean coefficients of variation of measurements were 20.2, 19.6, 26.6 and 25.3%, respectively. The data indicate the need for further interlaboratory studies directed at reducing the high level of variability in tricyclic measurements.

Amitriptyline↗

PubMed1991

Extremely long plasma half-life of amitriptyline in a woman with the cytochrome P450IID6 29/29-kilobase wild-type allele--a slowly reversible interaction with fluoxetine.

A 61-year-old woman, a nonsmoker, was admitted to the hospital because of endogenous depression. No concomitant disease, especially kidney or liver dysfunction, was diagnosed. After 9 days of treatment with 125 mg of amitriptyline (AMI) daily, she developed signs of a severe anticholinergic syndrome. Plasma concentrations of AMI (510 ng/ml) and nortriptyline (NOR; 320 ng/ml) were very high and the half-life of AMI was about 120 h. The debrisoquine metabolic ratio was 0.55 and 0.79 on two occasions, which shows that she had no deficiency of cytochrome P450IID6. This result was confirmed with a dextromethorphan test, analysis of restriction fragment length polymorphisms (29/29-kb fragments), and genotyping with allele-specific polymerase chain reaction (homozygous 29 kb wild-type alleles). Patients with high plasma levels of tricyclic antidepressants are usually poor metabolizers of debrisoquine. Before the administration of AMI, our patient was pretreated with fluoxetine. A slowly reversible interaction with fluoxetine or an extremely long-lasting metabolite may be responsible for the long plasma half-life of AMI.

Alleles↗

PubMed2005

Trajectories of treatment response in late-life depression: psychosocial and clinical correlates.

The authors examined the effect of psychosocial and clinical variables on treatment response trajectory in elderly patients with major depressive disorder. Three studies provided data on treatment response in 360 elderly depressed subjects who participated in protocols using either nortriptyline or paroxetine as monotherapy or, in 2 studies, combined with interpersonal psychotherapy. Treatment response was assessed with the Hamilton Rating Scale for Depression-17 Item (HRSD-17) score over 12 weeks of acute treatment in each study. The mixture-modeling method of trajectory analysis was used to identify different subpopulations of response, and to determine whether baseline HRSD-17 score, depressive illness course (single or recurrent), current episode duration, Interpersonal Self Evaluation List-Self-esteem factor, age at study entry, and medical burden were risk factor covariates associated with response trajectory. As a contrast, logistic regression was used to assess the association between the same covariates and the probability of response (defined as HRSD-17 < or =10 and 50% reduction from baseline). In each study, there were 2 response trajectories with similar course, but with different speed. We classified the trajectories as "rapid response" and "slower response." Baseline HRSD-17 score was a significant predictor of response trajectory, with higher initial score related to slower response trajectory. Higher self-esteem was associated with more rapid response trajectory. In the logistic regression analysis, in two of the studies, higher baseline HRSD-17 score was a significant risk factor for nonresponse. In the study without psychotherapy, higher self-esteem was associated with responding to treatment. Thus, trajectory analysis can identify different trajectories of responders and determine psychosocial and clinical variables associated with response trajectory in the acute treatment of geriatric depression. Further study focusing on risk factors associated with slower response may help optimize treatment in elderly patients who do not respond quickly to first-line therapies.

Age Factors↗

PubMed2003

Hopelessness and suicidal ideation in outpatients with treatment-resistant depression: prevalence and impact on treatment outcome.

Depression and hopelessness are risk factors for suicide. The purpose of this study was to examine the extent of suicidal ideation and hopelessness in outpatients with treatment-resistant depression (TRD) and to study the impact of suicidal ideation and hopelessness on treatment with nortriptyline (NT). The degree of suicidal ideation and hopelessness was assessed during the screen visit with the use of items #3 and #30 of the Hamilton Depression Rating Scale (HAM-D) in 89 patients with TRD who entered a 6-week open trial of NT. Forty of these patients also completed the Beck Hopelessness Index (BHI) during the screen visit. In separate logistic regressions, the scores from the BHI and the two HAM-D items were then tested as predictors of clinical response to the 6-week trial with NT, controlling for the severity of depression. More than half of patients reported thoughts or wishes of death to self and significant hopelessness. A greater degree of hopelessness before treatment in completers, reflected by the score on the HAM-D item #30, predicted response to NT. More than half of patients with prominent hopelessness who completed the trial responded. Patients with TRD are more likely than not to report prominent suicidal ideation and hopelessness. Furthermore, a full 6-week trial of NT, a relatively noradrenergic tricyclic antidepressant, may be particularly useful in patients who have failed to respond to several antidepressants and also report significant hopelessness.

Adolescent↗

PubMed1984

Simultaneous measurement of various antidepressants in the plasma of depressed patients by high performance liquid chromatography.

A simultaneous analytical method was reported for measuring the plasma levels of amitriptyline, imipramine, clomipramine, maprotiline, nortriptyline, desipramine, desmethylclomipramine, desmethylmaprotiline and amoxapine by high performance liquid chromatography (HPLC). The total plasma levels of each parent drug plus its desmethyl metabolite were monitored in 29 depressed patients administered with amitriptyline, maprotiline or amoxapine using the present analytical method. There were significant linear correlations between the dose per kg body weight and the total plasma levels with amitriptyline and maprotiline, but no such correlation was found with amoxapine. The ratios of total plasma levels to dose per kg body weight of these three drugs were lower in outpatients than in inpatients. These results indicate that the monitoring of plasma levels of antidepressants is useful in treating depression.

Adult↗

PubMed1975

Assessment of cardiovascular side effects of therapeutic doses of tricyclic anti-depressant drugs.

An assessment of the side effects of therapeutic doses of tricyclic anti-depressant drugs was attempted in 32 patients with depressive illness. The patients studied had no evidence of clinical heart disease or hypertension and were not receiving any other drugs. Moderate increase in heart rate and mild prolongation of atrioventricular conduction occurred. No significant effect on the corrected QT interval or blood pressure was found. There was no correlation between the increased heart rate, prolongation of the atrioventricular conduction time (PR interval) and plasma nortriptyline levels measured in 20 out of 32 patients.

Adult↗

PubMed1984

Fluphenazine/nortriptyline in the irritable bladder syndrome. A double-blind placebo controlled study.

A double-blind, placebo controlled, randomised order crossover study was carried out on the effect of Motival (0.5 mg fluphenazine with 10 mg nortriptyline) 3 times daily on the bladder function and psychiatric morbidity of 13 women without evidence of infection, complaining of recurrent dysuria and frequency. Bladder function was assessed symptomatically and by ambulatory urodynamics, and patients completed the General Health Questionnaire, a validated instrument for the detection of psychiatric disturbance. Correction of the urodynamic abnormalities was associated with Motival treatment in 5 of the 8 patients with unstable bladders, compared with none of 7 patients receiving placebo (P less than 0.02). Motival was also associated with a greater frequency of symptomatic improvement. Only 2 patients were classified as psychiatrically disturbed, suggesting that the therapeutic effect of Motival is not related to its psychotropic properties.

Adolescent↗

PubMed1992

Amitriptyline prevents N-methyl-D-aspartate (NMDA)-induced toxicity, does not prevent NMDA-induced elevations of extracellular glutamate, but augments kainate-induced elevations of glutamate.

The effect of amitriptyline on kainate- and N-methyl-D-aspartate (NMDA)-induced toxicity and release of amino acids from cerebellar granule neurons was studied. The ED50 for amitriptyline, imipramine, and nortriptyline protection against NMDA-induced toxicity was 6.9, 6.5, and 1.3 microM, respectively. None of these compounds protected against kainate-induced toxicity. Even though amitriptyline was protective against NMDA-induced toxicity, it had no effect on the NMDA-induced increase in extracellular levels of glutamate or aspartate from these cells, indicating a dissociation between NMDA receptor activation (as indicated by glutamate content elevations) and NMDA-induced toxicity. However, kainate and quisqualate treatment resulted in elevations of glutamate and taurine levels that were further augmented in the presence of 25 microM amitriptyline. These findings confirm the reports of others that tricyclic antidepressants have neuroprotective effects related to the NMDA receptor and expand on these reports by showing that even though there is protection against toxicity, the NMDA receptor is nevertheless activated, suggesting an involvement of these compounds at sites removed from the receptor. Furthermore, this is the first report showing an interaction of tricyclic antidepressants with the function of non-NMDA receptors.

Amitriptyline↗

PubMed1994

Mice plasma and brain pharmacokinetics of amitriptyline and its demethylated and hydroxylated metabolites after half-life repeated administration. Comparison with acute administration.

Kinetics of amitriptyline (AMI), its demethylated metabolites nortriptyline (NOR) and demethylnortriptyline (DM-NOR), and its hydroxylated metabolites, the E and Z isomers or 10-hydroxy-amitriptyline (E- and Z-10-OH-AMI) and of 10-hydroxynortriptyline (E- and Z-10-OH-NOR) were studied in plasma and brain from Swiss CD1 mice after six successive intraperitoneal injections of amitriptyline (10 mg/kg) administered every elimination half-life time (t1/2 = 3.1 h) to obtain the steady state. In these conditions, AMI was metabolised rapidly. Compared with acute administration, hydroxylation reactions were saturated by the repeated AMI injections and demethylation became preponderant both in plasma and brain. Thus, plasma levels of demethylated metabolites, NOR and DM-NOR, increased (49% and 13% of total AUC against 22% and 7% in acute conditions, respectively), while levels of AMI and its hydroxylated metabolites, 10-OH-AMI and 10-OH-NOR, decreased (8%, 2.5% and 27.5% against 17%, 8% and 46% in acute conditions, respectively). Likewise in brain tissue, when AMI was repeatedly administered, NOR and DM-NOR increased (62% and 22% against 29% and 11%, respectively) while AMI and 10-OH-AMI decreased (11.5% and 1% against 47% and 9%, respectively). These differences may account for modified pharmacological effects seen after half-life repeated administration of AMI since demethylated metabolites exert a more marked inhibiting effect than AMI on noradrenaline reuptake.

Amitriptyline↗

PubMed1968

The effect of antidepressants and "tranquilizers" on the response of mice to ethanol.

1. The techniques and apparatus used for investigation of the interaction of various psychotropic drugs with ethanol in mice are described. The parameters measured were (a) length of loss of righting reflexes; (b) continuous coma; (c) subjects remaining in coma 12 hr after dosing; (d) changes in toxicity.2. The following drugs were tested: amitriptyline, trimipramine, imipramine, nortriptyline, desipramine, thioridazine, phenelzine, methylphenidate, chlorpromazine, trifluoperazine, phenobarbitone, and diazepam. The total number of mice used was 3,140.3. Imipramine caused no significant changes in the effects of ethanol. Methylphenidate and desipramine protected the mice against ethanol induced coma. All other drugs induced statistically significant potentiation of the depressant and toxic effects of ethanol in mice.4. Late (delayed) deaths after a tricyclic antidepressant have been noted in animals and man.5. It is suggested that the potentiation of alcohol by some psychotropic drugs may add to the hazards of drug overdosage and contribute to traffic accidents. Hence it is necessary to test all psychotropic drugs for interaction with alcohol.

Accidents, Traffic↗

PubMed1979

Cardiovascular side effects of long-term therapy with tricyclic antidepressants in the aged.

In a study to determine the nature and frequency of cardiac side effects during long-term administration of tricyclic antidepressant drugs in usual dosages in the aged, 32 geriatric patients were followed for an average of 36.6 weeks. Ten of them received amitriptyline in a daily dosage of 20-75 mg for 53 weeks (average); in 2, electrocardiographic side effects developed, viz, inversion of the T waves or evidence of acute coronary insufficiency. Imipramine was administered to 21 patients in a daily dosage of 20-100 mg (average, 66 mg) over a period of 40 weeks; in 3 instances major side effects developed--intermittent left bundle-branch block, acute coronary insufficiency with node dysfunction, or T-wave inversion with sinus tachycardia; in 1 instance there was a minor side effect, viz, tachycardia only. In 1 patient, acute myocardial infarction developed after two 10-mg doses of nortriptyline. Five of the 7 patients with cardiac side effects had prior organic heart disease. It was concluded that the incidence of cardiac side effects in aged persons given tricyclic antidepressant drugs in the usual therapeutic dosages for a prolonged period is great enough to warrant frequent careful monitoring of cardiac status during therapy.

Aged↗

PubMedDate not supplied

Recovery from severe cyclic antidepressant overdose with hypertonic saline/dextran in a swine model.

OBJECTIVE: To determine the effect of a hypertonic saline and dextran (HSD) solution on blood pressure and QS duration during severe cyclic antidepressant (CA) toxicity in swine. METHODS: Ten domestic swine weighing 20-24 kg were anesthetized and placed on mechanical ventilation. Nortriptyline solution was infused intravenously to achieve hypotension (systolic blood pressure equal to 50% of baseline) and a QRS duration of 120 msec. After reaching toxicity, the animals received in a randomized fashion either 10 mL/kg of a 7.5% saline/6% dextran solution or an equal volume of 0.9% saline as a rapid intravenous bolus. The animals were observed for one hour or until they died. Blood pressure and ECG were recorded continuously. Arterial pH was maintained in the physiologic range by controlled ventilation. RESULTS: Mean systolic blood pressure 10 minutes after treatment was 45 +/- 8 torr in the normal- saline group compared with 115 +/- 12 torr in the HSD group (p < 0.05). Mean QRS duration 10 minutes after treatment was 180 +/- 8 msec in the normal-saline group; it was 88 +/- 13 msec in the HSD group (p < 0.05). All normal-saline--group animals died within 20 minutes, and four of the five animals in the HSD group survived to 60 minutes (p < 0.05). The mean peak sodium concentration was 157 mmol/dL (mEq/dL) in the HSD group, and this was transient. CONCLUSION: In this swine model of severe CA toxicity, a solution of 7.5% saline/6% dextran significantly reversed hypotension and QRS prolongation. HSD also improved survival to 60 minutes.

Animals↗

PubMed1978

Effects of tricyclic antidepressants on human plasma levels of TSH, GH and prolactin.

Six healthy male volunteers were given chlorimipramine 25 mg t.i.d. or nortriptyline 25 mg t.i.d. in a randomized order of 7 days. Plasma samples were assayed for TSH, GH and prolactin before and after stimulation with TRH 200 microgram i.v. It was found that the tricyclic antidepressants did not exert any influence on plasma hormonal levels compared with no treatment conditions. Diminished TSH-responses following daily TRH injections were demonstrated in endogenously depressed and chronic schizophrenic patients. A decreased TSH-response was observed in healthy volunteers after a second TRH injection with an interval of 2 days between the TRH injections. A complete restoration of the TSH-response was obtained after an interval of 4 days.

Adult↗

PubMed1981

MAO inhibition and control of anxiety following amitriptyline therapy. A pilot study.

In a pilot study, 32 patients with mixed states of anxiety, depression, somatization and panic received amitriptyline for 4 weeks, the dose ranging from 50 to 300 mg/day. Steady-state plasma levels of the drug and activity of platelet monoamine oxidase were measured after 4 weeks. Clinical change was rated, using the SCL-90. Amitriptyline produced a small but significant inhibition of platelet monoamine oxidase activity (range 1.4--82%). A significant positive correlation was noted between MAO inhibition and improvement on somatization, and psychological and panic-phobic components of anxiety, but not for depression. No significant correlations were observed between improvement and combined or separate ami- + nortriptyline plasma levels.

Adult↗

PubMed1983

Mixed anxiety/depressive illness in general practice. A therapeutic comparison of nomifensine with fluphenazine/nortriptyline.

The effect of the dopamine agonist antidepressant drug, nomifensine, on mixed anxiety/depressive states in general practice was assessed by means of a double-blind comparison with a standard fluphenazine/nortriptyline preparation. 57 patients were randomly allocated to 4 weeks' treatment with either nomifensine 25-50 mg taken three times daily, or a tablet containing 1.5 mg fluphenazine with 30 mg nortriptyline (Motipress) taken once daily. The overall response to both treatments was satisfactory, but Motipress was significantly superior (P less than 0.01) to nomifensine in the relief of fatigue and loss of energy, irritability, poor concentration and difficulty in coping, and there was also evidence of greater relief of depressive symptoms. In mixed anxiety/depressive states in general practice, nomifensine offers no advantage over a simple one tablet daily Motipress regimen.

Adolescent↗

PubMed1980

Electrocardiographic and cardiovascular changes in cats and dogs caused by high doses of amitriptyline given as conventional tablets or a sustained release preparation.

Electrocardiographic and haemodynamic changes have been compared in anesthetized cats and in conscious dogs after high doses of amitriptyline given as conventional tablets or as a sustained release form. Plasma or serum levels of amitriptyline and nortriptyline were determined. In anaesthetized cats tablets caused marked ECG changes in all 6 animals combined with pronounced acidosis in 3 of the animals. The sustained release form caused no electrocardiographic changes in 4 animals and moderate disturbances in 2 animals, without acidosis in any of the 6 cats. Almost identical haemodynamic changes were seen in both groups. The plasma levels did not indicate poorer absorption from one preparation than from the other. In conscious dogs tablets caused marked clinical signs including restlessness, sedation and convulsions (2 dogs). Pronounced electrocardiographic changes were seen in all 4 dogs. Bundle branch block developed in 3 dogs. The sustained release preparation caused slight to moderate sedation and no convulsions. Pronounced electrocardiographic changes without bundle branch block were seen in one dog. Moderate changes were seen in the remaining dogs. Acidosis was most pronounced after the tablets. The serum drug levels clearly show that the absorption is much slower after administration of the sustained release preparation than after tablet administration and that somewhat lower amounts of drug are absorbed from the sustained release preparation than from tablets. It is evident from the present studies, that administration of high doses of amitryptyline as a sustained release preparation causes less toxic manifestations than given as conventional tablets. Part of the explanation may be that less amitryptyline is absorbed from the sustained release preparation than from tablets because of the high dose (dogs), but the main reason is most likely that the absorption from the sustained release preparation is much slower than the absorption from tablets.

Amitriptyline↗

PubMed1991

Stereoselective efflux of (E)-10-hydroxynortriptyline enantiomers from the cerebrospinal fluid of depressed patients.

In 5 patients treated with nortriptyline or amitriptyline for at least 9 months, the cerebrospinal fluid (CSF)/plasma ratio for 10-hydroxynortriptyline (10-OH-NT) ranged from 0.085 to 0.172, which is similar to the ratio previously measured in patients treated for 3 weeks. In 4 other patients treated with racemic (E)-10-OH-NT, the mean concentration ratio between (-)- and (+)-(E)-10-OH-NT was 3.56 in plasma, 2.39 in plasma ultrafiltrate and 1.42 in CSF (one-way ANOVA; P less than 0.001). The mean free fraction in plasma determined by ultrafiltration for (-)-(E)-10-OH-NT was 28.9 +/- S.D.1.1% and for the (+)-enantiomer 43.7 +/- 0.8% (P less than 0.001) confirming the difference in protein binding shown previously in healthy subjects. There was a correlation between the concentration of 10-OH-NT (sum of enantiomers) in CSF and plasma ultrafiltrate (r = 0.96; n = 7; P less than 0.001). The concentration in CSF was, however, only about 50% of that in the plasma ultrafiltrate and this seems to be due to a stereoselective transport of (E)-10-OH-NT out from the CSF. The secretion from the CSF is more pronounced for the (-)-compared to the (+)-enantiomer, which is consistent with the stereoselectivity of the renal secretion of these compounds.

Adult↗

PubMed1972

Drug interaction: inhibitory effect of neuroleptics on metabolism of tricyclic antidepressants in man.

Total urinary excretion of radioactivity after oral or intravenous administration of a test dose of (14)C-imipramine was measured in eight patients. They were tested before, during, and after treatment with neuroleptics. Excretion diminished while the patients were being treated with perphenazine, haloperidol, or chlorpromazine, though not during flupenthixol treatment.Total urinary excretion of radioactivity and plasma levels of metabolites and unchanged drug were measured in five patients after a test dose of (14)C-nortriptyline. Each patient was tested before and again during perphenazine treatment. In all patients perphenazine treatment caused: (1) decrease of total urinary excretion, (2) decreased plasma level of metabolites, and (3) increased plasma level of unchanged nortriptyline.These results indicate that neuroleptics inhibit the metabolism of tricyclic antidepressants in man.

Adult↗