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PubMed1975

Anomalous results of studies on drug interaction in man. I. Nortriptyline and antipyrine.

Conflicting results were obtained in three drug interaction experiments designed to determine in man effects of chronic nortriptyline administration on plasma antipyrine half-lives. In an apparently similar design, each experiment utilized normal volunteers whose plasma antipyrine half-lives were measured before and after chronic nortriptyline administration. The same dose of liquid nortriptyline (0.2 mg/kg p.o. t.i.d. for 8 days) was used in each experiment. All subjects in the first study prolonged their plasma antipyrine half-lives, whereas seven of nine subjects in the second study significantly shortened their plasma antipyrine half-lives. In the third experiment seven of nine subjects showed no significant change in plasma antipyrine half-life. An explanation for these conflicting results obtained in the same laboratory under apparently similar experimental conditions was sought in the nature of the volunteers and in subtle changes in such variables as differences in the batches and length of storage of liquid nortriptyline.

Adult↗

PubMed1993

Nortriptyline-induced depression of ventilatory control in a patient with chronic obstructive pulmonary disease.

Psychiatric disorders occur frequently in patients with COPD, but therapy with psychotropic drugs is often limited by concomitant depression of ventilatory drive. We present a patient with COPD and major depression who developed hypercapnic respiratory failure while receiving nortriptyline and oxazepam. Because of known respiratory depressant effects of the latter drug, nortriptyline alone was resumed upon recovery. Depression of CO2 sensitivity and ventilatory load compensation with a concomitant increase in exercise tolerance with decreased dyspnea was observed while she was receiving nortriptyline. These results demonstrate a previously unreported depressant effect of nortriptyline on ventilatory control, and they suggest the need for further investigation of the ventilatory effects of this drug in patients with pulmonary disease.

Aged↗

PubMed1983

The methylphenidate test for differentiating desipramine-responsive from nortriptyline-responsive depression.

Monitoring tricyclic antidepressant concentrations in the plasma of 43 patients with major depressive disorders indicated that some responded to imipramine or desipramine but not to amitriptyline or nortriptyline, or vice versa, even though plasma levels were within therapeutic ranges. Mood elevation by methylphenidate predicted marked improvement from treatment with imipramine or desipramine but not with amitriptyline or nortriptyline. When methylphenidate failed to improve mood, patients responded to amitriptyline or nortriptyline but not to desipramine. These results suggest differential drug responses with different tricyclic antidepressants, the clinical utility of the methylphenidate test, and the heterogeneity of depressions. The authors question the mechanism of action of nortriptyline via blockade of norepinephrine reuptake.

Adolescent↗

PubMed2006

A comparison of mirtazapine and nortriptyline following two consecutive failed medication treatments for depressed outpatients: a STAR*D report.

OBJECTIVE: Few controlled studies have addressed the issue of which antidepressant medications should be recommended for outpatients who have not responded to multiple treatment trials. This study compared the efficacy of switching to mirtazapine to that of switching to a tricyclic antidepressant (nortriptyline) following two prospective, consecutive, unsuccessful medication treatments for nonpsychotic major depressive disorder. METHOD: Following lack of remission or an inability to tolerate an initial trial of citalopram for up to 12 weeks (first step) and a second trial with either monotherapy involving another antidepressant or augmentation of citalopram with bupropion or buspirone (second step), adult outpatients (N=235) with nonpsychotic major depressive disorder were randomly assigned to 14 weeks of treatment with mirtazapine (up to 60 mg/day) (N=114) or nortriptyline (up to 200 mg/day) (N=121). The primary outcome, symptom remission, was defined a priori as a total exit score of </=7 on the 17-item Hamilton Rating Scale for Depression. The 16-item Quick Inventory of Depressive Symptomatology-Self-Report (QIDS-SR(16)), obtained at treatment visits, provided secondary outcomes of remission (score </=5 at exit) and response (>/=50% reduction in score from baseline). RESULTS: For mirtazapine, remission rates were 12.3% and 8.0% per the Hamilton and QIDS-SR(16) scores, respectively. For nortriptyline, remission rates were 19.8% and 12.4%, respectively. QIDS-SR(16) response rates were 13.4% for mirtazapine and 16.5% for nortriptyline. Neither response nor remission rates statistically differed by treatment, nor did these two treatments differ in tolerability or adverse events. CONCLUSIONS: Switching to a third antidepressant monotherapy regimen after two consecutive unsuccessful antidepressant trials resulted in low remission rates (<20%) among patients with major depressive disorder.

Adult↗

PubMed1983

Cimetidine's effect on steady-state serum nortriptyline concentrations.

A cimetidine-nortriptyline interaction in a 52-year-old black male is reported. After concomitant administration of cimetidine and nortriptyline for two weeks, steady-state nortriptyline concentrations fell 42 percent when cimetidine was discontinued. Later, during rechallenge with cimetidine, serum nortriptyline concentrations increased significantly, but subsequently fell again when cimetidine was discontinued. The possible clinical consequences of this interaction are discussed.

Cimetidine↗

PubMedDate not supplied

Pharmacokinetics of single oral doses of nortriptyline in depressed elderly hospital patients and young healthy volunteers.

A single oral dose of 75mg nortriptyline was given to a group of 20 depressed elderly patients in hospital. Subsequent plasma nortriptyline concentrations were used to calculate the half-life and clearance of the drug. These measurements were compared with those made previously in 17 healthy young volunteer subjects. Plasma nortriptyline half-life was longer and clearance slower (p < 0.002) in the elderly group than in the volunteers. There was no correlation of age with either of these parameters within the 2 groups, and no differences in nortriptyline pharmacokinetics could be detected between the male and female volunteer subjects. The possible reasons for these findings and their clinical consequences are discussed.

Administration, Oral↗

PubMed1991

Drug interaction between rifampin and nortriptyline: a case report.

This case illustrates a pharmacokinetic interaction between the tricyclic antidepressant, nortriptyline, and the antituberculosis drug, rifampin. Higher than expected doses of nortriptyline were required to obtain a therapeutic drug level while the patient was receiving rifampin. Following the discontinuation of rifampin, the patient became drowsy and the serum nortriptyline levels rose precipitously into the toxic range. The authors suggest that patients receiving rifampin and nortriptyline, (or other psychotropic drugs) be monitored closely and that similar drug interactions be anticipated.

Depressive Disorder↗

PubMed2003

Psychiatric comorbidity as a predictor of clinical response to nortriptyline in treatment-resistant major depressive disorder.

BACKGROUND: A number of studies of major depressive disorder suggest that psychiatric co-morbidity may contribute to treatment resistance. The purpose of this study was to test whether the presence of comorbid Axis I and Axis II disorders predicts clinical response to an open trial of nor-triptyline among patients with treatment-resistant depression. METHOD: Ninety-two outpatients with treatment-resistant DSM-III-R major depressive disorder were enrolled in a 6-week open trial of nor-triptyline (Nov. 1992-Jan. 1999). The presence of comorbid Axis I and Axis II disorders was established at baseline with the use of the Structured Clinical Interview for DSM-III-R. Chi-square analyses were used to test Axis I or Axis II co-morbid conditions as a predictor of clinical response to nortriptyline. RESULTS: Thirty-nine patients (42.4%) responded to nortriptyline. The presence of avoidant personality disorder (p <.01) predicted poorer response to nortriptyline. The response rate was 16.7% for patients with and 48.6% for patients without comorbid avoidant personality disorder. No other comorbid diagnoses were found to predict clinical response in a statistically significant manner. CONCLUSION: The presence of avoidant personality disorder conferred a poorer prognosis in treatment-resistant depression patients treated with nortriptyline.

Adolescent↗

PubMed2005

Olanzapine/fluoxetine combination for treatment-resistant depression: a controlled study of SSRI and nortriptyline resistance.

BACKGROUND: This 8-week, double-blind, multicenter study was undertaken to replicate, in a larger sample of patients with treatment-resistant major depressive disorder (MDD; DSM-IV criteria), the results of a pilot study of the olanzapine/fluoxetine combination. METHOD: The study was begun in August 1999. The primary entry criterion was a history of failure to respond to a selective serotonin reuptake inhibitor (SSRI). Patients (N = 500) who subsequently failed to respond to nortriptyline during an open-label lead-in phase were randomly assigned to 1 of 4 treatment groups: olanzapine (6-12 mg/day) plus fluoxetine (25-50 mg/day) combination, olanzapine (6-12 mg/day), fluoxetine (25-50 mg/day), or nortriptyline (25-175 mg/day). The primary outcome measure was baseline-to-endpoint mean change in score on the Montgomery-Asberg Depression Rating Scale (MADRS). RESULTS: At the 8-week study endpoint, MADRS total scores decreased by a mean 8.7 points from baseline (28.5) with the olanzapine/fluoxetine combination, 7.0 points from baseline (28.4) with olanzapine (p = .08), 8.5 points from baseline (28.4) with fluoxetine (p = .84), and 7.5 points from baseline (28.8) with nortriptyline (p = .30), with no significant differences among the therapies. The olanzapine/fluoxetine combination was associated with significantly (p < or = .05) greater improvement (decrease) in MADRS scores than olanzapine at weeks 2, 4, 6, and 7; than fluoxetine at weeks 2 through 5; and than nortriptyline at weeks 1 through 4. A post hoc analysis of a subgroup of patients who had an SSRI treatment failure during their current MDD episode (N = 314) revealed that the olanzapine/fluoxetine combination group had a significantly (p = .005) greater decrease in MADRS scores than the olanzapine group at endpoint. Safety data for the olanzapine/fluoxetine combination were similar to those for its component monotherapies. CONCLUSIONS: The olanzapine/fluoxetine combination did not differ significantly from the other therapies at endpoint, although it demonstrated a more rapid response that was sustained until the end of treatment. The results raised several methodological questions, and recommendations are made regarding the criteria for study entry and randomization.

Adult↗

PubMed1976

Rapid radioisotopic procedure for determination of nortriptyline in plasma.

With the widespread use of tricyclic antidepressant drugs, the relationship between the concentration of the drug in the plasma and the therapeutic response is of considerable interest. We describe a double-isotope derivative dilution procedure for measuring plasma nortriptyline. In the method, [14C]nortriptyline is used for estimating procedural losses and [3H]acetic anhydride for derivative formation. The assay is rapid and adequately specific, sensitive, precies, and reproducible for routine clinical use. We used it to investigate the variation in steady-state drug concentrations in plasma of persons who were on a 150 mg/day dose of nortriptyline. Intra-individual variation from day to day was 10-14%. This variation was not significantly affected by the dosage schedule, the time of sampling after an oral dose, or the storage of the plasma samples. For 19 patients on 150 mg of nortriptyline per day, the mean concentration in plasma was 181 +/- 22 (SE) mug/liter, a value that compares well with our previous findings and those of other groups.

Carbon Radioisotopes↗

PubMed1991

[Severe nortriptyline poisoning in poor metabolizers of the sparteine type].

Approximately 7% of the Danish population are so called poor metabolizers (PM) as regards the model compound sparteine. These individuals lack the P450 isozyme which is mainly responsible for elimination of at least 20 different medicaments including nortriptyline. A woman aged 42 years suffering from depression was treated with 100 mg nortriptyline daily and, during the course of treatment, she developed a toxic serum nortriptyline level (approximately 2,100 nM). Treatment was withdrawn temporarily on account of severe side-effects. The depression recurred. During the medicine-free period, a sparteine test was performed and this demonstrated that the patient was a poor metabolizer. Scarcely two months after hospitalization, treatment was recommenced with 25 mg nortriptyline daily after which the patient's depression disappeared completely without any side-effects of note.

Adult↗

PubMed1989

Effects of nortriptyline on the activities of human and rat liver microsome bufuralol 1'-hydroxylase in vitro.

The effects of nortriptyline in vitro on the activities of optical isomer and racemate bufuralol 1'-hydroxylase in man and Wistar rat liver microsomal fractions were studied. There was a dose-dependent inhibitory effect of nortriptyline on bufuralol 1'-hydroxylase in both species. While the concentration of nortriptyline greater than or equal to 0.32 mumol/L and greater than or equal to 1.6 mumol/L, the activities of (+), (-) and (+/-) bufuralol 1'-hydroxylase were significantly reduced in man and rat, respectively. The values of inhibitor concentration causing 50% reduction (IC50) to (+), (-) and (+/-) bufuralol 1'-hydroxylase were 10, 19 and 14 mumol/L for human and 4, 10, 6 mumol/L for rat, respectively. It was shown by improved Dixon's plot that the inhibitory type was competitive, and the inhibitory constant (Ki) values to (+), (-) and (+/-) bufuralol 1'-hydroxylase were 5, 3, 4 mumol/L for human and 55, 29, 43 mumol/L for rat, respectively. These results indicate that nortriptyline is a very potent competitive inhibitor to bufuralol 1'-hydroxylase in man and Wistar rat.

Animals↗

PubMed1987

A placebo-controlled comparison of the effect of nortriptyline and phenelzine on orthostatic hypotension in elderly depressed patients.

Seventy-five patients, 55 years or older, were treated for major depression with either nortriptyline, phenelzine, or placebo during a 7-week period. There was a significantly greater mean orthostatic fall in systolic pressure in patients treated with nortriptyline and phenelzine as compared to the placebo group, but no significant difference was evident between the nortriptyline and phenelzine groups. The orthostatic changes appeared during the first week of treatment and were not correlated with plasma level of nortriptyline, percent platelet monoamine oxidase inhibition, or pretreatment orthostatic changes.

Aged↗

PubMed1986

Pretreatment orthostatic hypotension as a predictor of response to nortriptyline in geriatric depression.

The consequences of orthostatic hypotension, a serious and common problem among the elderly, are falls, transient ischemic attacks, strokes, and myocardial infarctions. Depressed elderly taking tricyclic antidepressants (TCAs) are at increased risk, and the pretreatment presence of orthostatic hypotension is considered a relative contraindication to TCA treatment. Recently, it was reported that the presence of pretreatment orthostatic hypotension in geriatric outpatients with unipolar depression predicted good clinical response to imipramine or doxepin. We investigated the predictive value of pretreatment systolic orthostatic pressure changes (PSOP) in unipolar depressed elderly outpatients (mean age, 64) who were to receive a 16-week course of nortriptyline or interpersonal psychotherapy. Overall, PSOP was significantly correlated with improvement on both the Beck Depression Inventory and the Hamilton Depression Rating Scale. Although both groups responded equally to treatment, PSOP was more strongly correlated with improvement on the Beck Depression Inventory (r = 0.74, p less than 0.01) in the nortriptyline-treated group than in the group treated with interpersonal therapy (r = 0.31, not significant). The nortriptyline-treated subjects with a PSOP of greater than or equal to 10 mm Hg had a greater improvement than those with a PSOP of less than 10 mm HG (t = -2.36, p less than 0.05). No episodes of symptomatic orthostatic hypotension occurred in the nortriptyline-treated subjects. The results suggest that orthostatic hypotension, a relative contraindication to TCA use, may potentially identify patients more likely to respond to TCAs.

Aged↗

PubMed1986

Nortriptyline kinetics in Hispanic and Anglo subjects.

Nortriptyline kinetics are compared between 10 Hispanic and 10 Anglo healthy, nondepressed volunteers matched for age, sex, and weight. All subjects were given a single oral dose of 75 mg of nortriptyline, and blood samples were drawn at various times over the next 96 hours. Nortriptyline concentration in plasma was determined by gas chromatography with nitrogen detector. From the nortriptyline concentration in plasma and time curve, various kinetic parameters were computed for each individual. There were large interindividual differences in various kinetic parameters. However, no statistically significant differences were found in any of the kinetic parameters between the Hispanic and Anglo groups. These results suggest that there are no major differences in pharmacokinetics and that purported hypersensitivity in Hispanic depressed patients to antidepressant treatment may be due to receptor hypersensitivity.

Absorption↗

PubMed1986

Nortriptyline in depressed patients with left ventricular impairment.

Previous studies of the effect of tricyclic antidepressants on left ventricular function in depressed patients with moderate to severe ventricular impairment have focused primarily on imipramine hydrochloride. In a prior study, we found that although imipramine had no effect on ejection fraction as measured by first-pass radionuclide angiography, the treatment could not be tolerated by 50% of the patients because of intolerable drug-induced orthostatic hypotension. Nortriptyline hydrochloride is an effective antidepressant that, in depressed patients without heart disease, causes significantly less orthostatic hypotension than imipramine. To see if this advantage could be safely extended to patients with congestive failure, we measured the effect of nortriptyline on ejection fraction and blood pressure in 21 depressed patients with left ventricular impairment. Ejection fraction was unchanged by nortriptyline treatment, and orthostatic hypotension developed in only one (5%) of 21 patients. Nortriptyline emerges as a relatively safe treatment for depression in patients with left ventricular impairment.

Aged↗

PubMed1985

Serial monitoring and achievement of steady state nortriptyline plasma levels in depressed children and adolescents: preliminary data.

Children and adolescents 6 to 16 years old (N = 25), who were diagnosed as having major depressive disorder, received a fixed daily dose of nortriptyline during an 8-week period. Nortriptyline plasma levels were drawn and assayed weekly. Data were analyzed for the total sample (N = 25) and separately for the subgroup of 6 to 9 year olds (N = 9) and for the subsample of 10 to 16 year olds (N = 16). There were no significant differences between the day 7 (week 1) plasma levels and the means of weeks 2 to 8 or between the means of weeks 1 to 4 and 5 to 8 within the total sample or within either subgroup. These findings suggest that nortriptyline steady state plasma levels within the pediatric age range are achieved by day 7 (week 1) and that nortriptyline (during the pediatric years) does not induce its own metabolism during an 8-week period. The achievement of steady state by day 7 is similar to that found in adults. The mean coefficients of variation were calculated for the total sample and for each subsample and were 13.7 +/- 4.0% (range, 8 to 20%) for the 6 to 9 year olds; 13.8 +/- 3.2% (range, 10 to 21%) for the 10 to 16 year olds; and 13.8 +/- 3.4% (range, 8 to 21%) for the total sample. These coefficients of variation are similar to the 10 to 20% range reported in adult subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗

PubMedDate not supplied

Demethylation and hydroxylation of amitriptyline, nortriptyline, and 10-hydroxyamitriptyline in human liver microsomes.

The rates of demethylation and hydroxylation of amitriptyline, nortriptyline, and 10-hydroxyamitriptyline by microsomes from adult human livers were determined by use of mass-fragmentographic or liquid-chromatographic quantitation of the formed metabolites. The demethylation rates of amitriptyline and 10-hydroxyamitriptyline were higher than the hydroxylation rates of amitriptyline and nortriptyline, especially at high substrate concentration. The amitriptyline demethylation rates were 96-570 and 1750-9230 pmol per mg of protein per 10 min at substrate concentrations of 5 and 100 micro M, respectively. The corresponding rates for the hydroxylations were 43-146 and 305-871, respectively. At high substrate concentration (250 micro M) the curve of concentration vs. rate for 10-hydroxylation of amitriptyline seemed to approach a plateau, whereas those for demethylation did not. Interaction between amitriptyline and nortriptyline at the microsomal level was studied by use of deuterium-labeled amitriptyline, and these two compounds were found to inhibit the hydroxylation of each other. In contrast to hydroxylation, the demethylation of labeled amitriptyline increased upon addition of nortriptyline. These results suggest that the well-established variation in steady-state plasma levels of tricyclic antidepressants is due to interindividual differences in liver enzyme activity.

Amitriptyline↗