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PubMedDate not supplied

Treatment of poststroke generalized anxiety disorder comorbid with poststroke depression: merged analysis of nortriptyline trials.

OBJECTIVE: The existence of anxiety disorders plays an important role in the prognosis and associated impairment among patients with poststroke depression. The authors examined the efficacy of nortriptyline treatment for patients with comorbid generalized anxiety disorder (GAD) and depression after stroke. METHODS: Data from three studies were merged to provide 27 patients with comorbid GAD and depression, who participated in double-blind treatment studies comparing nortriptyline (N=13) and placebo (N=14). Severity of anxiety was measured with the Hamilton Rating Scale for Anxiety (Ham-A), and severity of depression was measured with the Hamilton Rating Scale for Depression (Ham-D). Activities of daily living were assessed by use of the Johns Hopkins Functioning Inventory (JHFI). RESULTS: There were no significant differences between the nortriptyline and placebo groups in demographic characteristics, stroke type, and neurological findings. Patients receiving nortriptyline treatment showed significantly greater improvement on the Ham-A, Ham-D, and JHFI than patients receiving placebo. The anxiety symptoms showed earlier improvement than depressive symptoms in patients treated with nortriptyline. CONCLUSIONS: These findings suggest that poststroke GAD comorbid with poststroke depression may be effectively treated with nortriptyline, and data indicate the need for a trial specifically designed to examine treatment of anxiety disorder.

Aged↗

PubMed1997

Hydroxylation and demethylation of the tricyclic antidepressant nortriptyline by cDNA-expressed human cytochrome P-450 isozymes.

The metabolism of nortriptyline was studied in vitro using cDNA-expressed human cytochrome P450 isozymes 1A2, 3A4, 2C19, and 2D6, CYP2D6 was the sole isozyme mediating hydroxylation of nortriptyline, the quantitatively most important metabolic pathway, and only (E)-10-OH-nortriptyline was formed. CYP2D6, 2C19, and 1A2, mentioned in decreasing order of significance, mediated the demethylation reaction of nortriptyline, whereas 3A4 did not participate in the metabolism of nortriptyline. Concerning the quantitative relations, CYP2D6 exhibited a high affinity with respect to hydroxylation and demethylation (K(m) 0.48-0.74 mumol/l), a high hydroxylation capacity (Vmax 130 mol/hr/mol CYP) and a somewhat lower demethylation capacity (Vmax 19 mol/ hr/mol CYP). The affinities of 1A2 and 2C19 were 100-fold lower (K(m) 54-118 mumol/l). The capacity of 1A2 was low (Vmax 6.8 mol/hr/ mol CYP), whereas 2C19 had the highest demethylation capacity (Vmax 93 mol/hr/mol CYP). Taking into account the relative amounts of CYP isozymes present in the liver, about 90% of the metabolism was estimated to depend on CYP2D6, with CYP2C19 and 1A2 mediating the remaining 10%. In subjects lacking the 2D6 isozyme, CYP2C19 and 1A2 are expected to be of major importance for elimination of nortriptyline.

Antidepressive Agents, Tricyclic↗

PubMed2004

A randomized trial of nortriptyline combined with transdermal nicotine for smoking cessation.

BACKGROUND: Smoking cessation rates with current therapy are suboptimal. Tricyclic antidepressants improve cessation rates. We hypothesized that addition of nortriptyline hydrochloride to transdermal nicotine would enhance cessation rates. METHODS: We conducted a randomized, double-blind, placebo-controlled trial at a Department of Veterans Affairs medical center. Subjects were aged 18 to 65 years, smoked 10 or more cigarettes per day, and did not have current major depression. Nortriptyline hydrochloride or matched placebo was started at 25 mg 14 days before quit day, titrated to 75 mg/d as tolerated, and continued for 12 weeks after quit day. Transdermal nicotine (21 mg/d) was started on quit day and continued for 8 weeks. The behavioral intervention consisted of 12 brief, individual visits. Withdrawal symptoms were measured by means of a daily diary, and smoking cessation was defined as self-reported abstinence, expired carbon monoxide level of 9 ppm or less, and a 6-month urine cotinine level less than 50 ng/mL (284 nmol/L). RESULTS: A total of 158 patients were randomized (79 to nortriptyline and 79 to placebo). There was no significant reduction in withdrawal symptoms. The cessation rates at 6 months were 23% (18/79) and 10% (8/79), respectively (absolute difference, 13%; 95% confidence interval, 1.3%-24.5%; P = .052). Nortriptyline caused frequent side effects, including dry mouth (38%) and sedation (20%). CONCLUSIONS: Nortriptyline combined with transdermal nicotine resulted in an increased cessation rate with little effect on withdrawal symptoms. This combination may represent an option for smokers in whom standard therapy has failed.

Administration, Cutaneous↗

PubMed1978

High plasma nortriptyline levels in the treatment of depression. I.

Following a 3-day single-dose kinetic study, 21 moderate to severely depressed inpatients were treated with 100 mg of nortriptyline nightly. Eighteen patients completed the 4-wk trial. The severity of depression was measured by weekly Hamilton Rating Scale and global rating. Blood for plasma nortriptyline estimation was taken at weekly intervals 12 h following the nighttime dose. There was a 6-fold variation in mean plasma nortriptyline levels, ranging from 120 microgram/L to 681 microgram/L. Patients with high plasma levels (greater than 200 microgram/L) showed significantly poorer clinical responses than those with levels in routine treatment, high plasma nortriptyline levels are significantly less effective than intermediate levels. Single-dose pharmacokinetic data obtained on the same patients showed a highly significant correlation with mean steady-state plasma levels obtained, which themselves correlated with clinical response. The value of predicting high plasma nortriptyline levels which are associated with poor response is discussed.

Adult↗

PubMed1979

A method for the determination of amitriptyline and its metabolites nortriptyline, 10-hydroxyamitriptyline, and 10-hydroxynortriptyline in human plasma using stable isotope dilution and gas chromatography-chemical ionization mass spectrometry (GC-CIMS).

A gas chromatography--mass spectrometry (GC-MS) method has been developed to measure amitriptyline and its metabolites nortriptyline, 10-hydroxyamitriptyline, and 10-hydroxynortriptyline in human plasma. Deuterated analogs of each compound were synthesized as internal standards. Isobutane was used as both gas chromatography (GC) carrier gas and chemical ionization (CI) reagent gas. In order to obtain compounds with satisfactory GC and mass spectrometry (MS) properties, the two alcohol metabolites were dehydrated without loss of label during sample preparation. Selective ion monitoring of the MH+ ions of the protio- and deuterio- compounds gave ion ratios which were converted to plasma concentrations using standard curves. For amitriptyline and nortriptyline, which are assayed using multiple deuterated analogs as internal standards, the curves are straight lines. For 10-hydroxyamitriptyline and 10-hydroxynortriptyline, which are assayed using monodeuterated analogs as internal standards, the curves are nonlinear and are analyzed using an iterative computer procedure. Assay sensitivity is 0.5 ng/ml for amitriptyline, nortriptyline, and 10-hydroxyamitriptyline and 1 ng/ml for 10-hydroxynortriptyline. Assay precision and accuracy in terms of percent error are both less than 5%. Following oral administration of a single 75-mg dose of amitriptyline to two subjects, the mean plasma levels of amitriptyline, nortriptyline, 10-hydroxyamitriptyline, conjugated 10-hydroxyamitriptyline, 10-hydroxynortriptyline, and conjugated 10-hydroxynortriptyline were 36, 8, 10, 66, 16, and 46 ng/ml, respectively, at 2 hr after dosing and 3, 4, 0.5, 1, 6, and 17 ng/ml, respectively, at 72 hr after dosing. Analyses of plasma samples from 12 subjects who had been receiving 50 mg amitriptyline therapy three times a day for an average +/- SD of 32 +/- 5 days gave a mean concentration of 81 +/- 40 ng/ml for amitriptyline, 71 +/- 57 ng/ml for nortriptyline, 12 +/- 5 ng/ml for 10-hydroxyamitriptyline, 91 +/- 30 ng/ml for conjugated 10-hydroxyamitriptyline, 82 +/- 27 ng/ml for 10-hydroxynortriptyline, and 176 +/- 64 ng/ml for conjugated 10-hydroxynortriptyline.

Amitriptyline↗

PubMed1982

Amitriptyline and nortriptyline response profiles in unipolar depressed patients.

The relationship between steady-state plasma concentration and clinical response was studied in 22 hospitalized unipolar depressed patients. In a double-blind format the patients were randomly assigned to receive amitriptyline or nortriptyline. Dosage was adjusted based on plasma level with the aim of achieving a concentration of 60-180 ng/ml. By week 4 of treatment, 83% of amitriptyline patients and all nortriptyline patients were within the targeted plasma range. Based on final ratings of clinical state, the drug level adjustment improved the outcome for nortriptyline-treated patients, but not amitriptyline-treated patients. Nortriptyline patients with plasma levels of 60-230 ng/ml had lower Hamilton Rating Scale depression scores than patients outside that range. By contrast, amitriptyline plasma levels were not associated with depression ratings. After 1 week, patients treated with nortriptyline had a significantly greater mean reduction in Hamilton depression score, i.e., 55% compared to 25% for amitriptyline patients.

Adolescent↗

PubMed1977

Effect of simultaneous treatment with low doses of perphenazine on plasma and urine concentrations of nortriptyline and 10-hydroxynortriptyline.

Plasma levels of nortriptyline and perphenazine were measured in six patients on continuous nortriptyline treatment before, during and after oral administration of perphenazine 4 mg t.i.d. In four patients the plasma levels of the conjugated and unconjugated principal metabolite 10-hydroxynortriptyline were also measured. Urinary excretion of conjugated and unconjugated 10-hydroxynortriptyline and plasma levels of perphenazine were determined in all six patients. During treatment with perphenazine two patients showed a slight increase in the plasma level of nortriptyline. The changes in metabolite excretion rate were inconclusive. Thus, there did not appear to be any important pharmacokinetic interaction between the two drugs at the doses used, which were normal therapeutic doses. The previously reported inhibitory effect of perphenazine on the metabolism of nortriptyline probably depended therefore, either on administration of a higher dose of perphenazine, or on treatment in the reverse sequence--a single dose of nortriptyline was given to patients already receiving perphenazine.

Adult↗

PubMedDate not supplied

Cost-effectiveness of bupropion, nortriptyline, and psychological intervention in smoking cessation.

Sustained-release bupropion and nortriptyline have been shown to be efficacious in treating cigarette smoking. Psychological intervention is also recognized as efficacious. The cost and cost-effectiveness of the 2 drug therapies have not been estimated. It was hypothesized that nortriptyline would be more cost-effective than bupropion. Hypotheses were not originally proposed concerning the cost-effectiveness of psychological versus drug treatment, but the 2 were compared using exploratory analyses. This was a 3 (bupropion versus nortriptyline versus placebo) by 2 (medical management alone versus medical management plus psychological intervention) randomized trial. Participants were 220 cigarette smokers. Outcome measures were cost and cost-effectiveness computed at week 52. Nortriptyline cost less than bupropion. Nortriptyline was more cost-effective than bupropion; the difference was not statistically significant. Psychological intervention cost less than the 2 drug treatments, and was more cost-effective, but not significantly so. Prospective investigations of the cost and cost-effectiveness of psychological and pharmacological intervention, using adequate sample sizes, are warranted.

Adult↗

PubMed1995

Moclobemide and nortriptyline in elderly depressed patients. A randomized, multicentre trial against placebo.

Moclobemide and nortriptyline were compared with placebo in a double-blind randomized multinational (Canada, Denmark and UK) trial comprising 109 patients of > 60 years of age with major depression (DSM-III-R). Patients were randomized to 7 weeks of treatment with doses of 400 mg/day moclobemide, 75 mg/day nortriptyline or placebo. It was necessary to adjust nortriptyline dosage in < 20% of patients to maintain serum levels within the postulated therapeutic window of 50-170 ng/ml. At end of treatment, the remission rates were 23% for moclobemide, 33% for nortriptyline and 11% for placebo. Anticholinergic and orthostatic events occurred more often with patients on nortriptyline than either moclobemide or placebo.

Aged↗

PubMed1989

Steady state pharmacokinetics of nortriptyline in the frail elderly.

The frail elderly, for whom chronic disease and disability are essentially universal, are at high risk for depression and are specifically vulnerable to the adverse effects of antidepressant medication. There have, however, been few investigations of either the pharmacokinetics or the clinical investigations of either the pharmacokinetics or the clinical response to antidepressants in such patients. We report on the pharmacokinetics of nortriptyline at steady state in a group of 22 patients, average age 84, living within an institutional setting. Comparison of our findings with those previously reported for younger and healthier subjects suggests that there are no clinically significant group differences in nortriptyline kinetics. Plasma levels of nortriptyline and those of both the trans- and cishydroxylated metabolites are linear with daily dose. Mean (and SD) for the parameter (plasma level/dose) was 1.21 (0.63) ng/ml/mg/day for the parent compound, 1.41 (0.86) for the trans metabolite, and 0.30 (0.16) for the cis metabolite. There was no significant correlation across individuals between the accumulation of the parent compound and the metabolites. Based upon these data, the average dose of nortriptyline required to achieve a plasma level of 100 ng/ml is 80 mg/day. Dose requirements, however, vary between individuals by a factor of 20. Plasma levels measured 24 hours after a 25-mg test dose of nortriptyline can allow early identification of slow metabolizers. Twenty-four-hour plasma levels (mean 8.8 ng/ml, SD 3.2) were significantly correlated with steady state levels at 25 mg/day (r = 0.71), steady state levels at 50 mg/day (r = 0.73), and each individual's average (plasma level/dose) (r = 0.57).

Aged↗

PubMed1997

Maintenance nortriptyline effects on electroencephalographic sleep in elderly patients with recurrent major depression: double-blind, placebo- and plasma-level-controlled evaluation.

Our aim was to contrast the effects of maintenance nortriptyline and placebo on electroencephalographic sleep measures in elderly recurrent depressives who survived 1-year without recurrence of depression. Patients on nortriptyline took longer to fall asleep and did not maintain sleep better than patients on placebo; however, maintenance nortriptyline was associated with more delta-wave production and higher delta-wave density in the first non-REM (NREM) period relative to the second. Nortriptyline levels were positively but weakly related to all-night delta-wave production during maintenance (accounting for 6.6% of the variance in delta-wave counts). Total phasic REM activity increased 100% under chronic nortriptyline relative to placebo, with a robust increase in the rate of REM activity generation across the night. Effective long-term pharmacotherapy of recurrent major depression is associated with enhancement in the rate of delta-wave production in the first NREM period (i.e., delta sleep ratio) and of REM activity throughout the night.

Aged↗

PubMed1996

Effects of divalproex sodium on amitriptyline and nortriptyline pharmacokinetics.

BACKGROUND: Divalproex sodium has been found to be efficacious in the prophylaxis of migraine headaches and the management of the manic phase of bipolar syndrome. Because amitriptyline is also prescribed in these patient populations, data are needed on their potential for interaction. METHODS: The effect of concomitant administration of divalproex sodium on the pharmacokinetics of amitriptyline and its active metabolite, nortriptyline, was investigated in an open-label, sequential, two-period phase I study. Ten healthy male and five healthy female subjects received 50 mg amitriptyline hydrochloride on two occasions: (1) alone (period 1) and (2) 2 hours after receiving the ninth dose of 500 mg divalproex sodium (Depakote) administered once every 12 hours (period 2). RESULTS: Amitriptyline area under the curve was increased 31% from the combined effect of decreased first-pass metabolism and inhibition of systemic metabolism. The elevated nortriptyline plasma levels reflected primarily the increase in amitriptyline concentrations but also appeared to involve modest inhibition of nortriptyline elimination. For the sum of amitriptyline and nortriptyline concentrations, the peak plasma concentration mean was 19% higher with concomitant divalproex dosing. The mean area under the curve for the sum of amitriptyline and nortriptyline concentrations was 42% higher with concomitant divalproex dosing than it was for dosing with amitriptyline alone. CONCLUSION: These results suggested that a lower dose of amitriptyline might be considered when divalproex is administered concomitantly.

Adult↗

PubMed1977

Effect of activated charcoal on absorption of nortriptyline.

The ability of 'Medicoal', a new effervescent, activated charcoal preparation, to adsorb nortriptyline, has been investigated both in vitro and in vivo. A single dose of the effervescent charcoal 30 min after a dose of 75 mg nortriptyline produced a 60% mean reduction in both peak plasma levels and nortriptyline availability in healthy volunteers. Multiple doses of the effervescent charcoal produced 70% mean reduction in peak nortriptyline levels and availabiltiy. Activated charcoal is recommended for the treatment of tricyclic antidepressant poisoning. In in-vitro tests, a 10 g packet of the effervescent preparation containing 5 g activated charcoal) had an adsorptive capacity of approximately 3000 mg nortriptyline, a dose not usually exceeded in most cases of trycyclic antidepressant overdose.

Absorption↗

PubMed1986

The antiarrhythmic effect of nortriptyline in cardiac patients with ventricular premature depolarizations.

The effect of nortriptyline against ventricular arrhythmias was determined in 16 cardiac patients with 30 or more ventricular premature depolarizations per hour. Nortriptyline was administered orally, 0.5 mg/kg body weight per day, and increased by 0.5 mg/kg per day every third day until ventricular premature depolarizations were suppressed (greater than or equal to 80%), adverse effects occurred or a total daily dose of 3.5 mg/kg per day was given. Each patient had daily 24 hour continuous electrocardiograms, 12 lead standard electrocardiograms and physical examination; blood pressure was measured in the supine and standing position four times a day. Each patient also had radionuclide angiography at rest to measure ejection fraction before and at the effective or maximal dose. Thirteen patients (81%) had an antiarrhythmic response and 11 met the study criterion of at least 80% improvement. Doses ranged from 50 to 200 mg/day (mean 111 +/- 45), steady state plasma concentration ranged from 46 to 410 ng/ml (mean 153 +/- 96) and half-life of elimination of nortriptyline was 4 to 22 hours (mean 13 +/- 4). Administration of nortriptyline did not depress mean ejection fraction (before 42 +/- 12%, after 41 +/- 12%); it was associated with an orthostatic decrease in systolic blood pressure (mean -13 +/- 13 mm Hg). Nortriptyline is an effective antiarrhythmic agent which may be given twice a day even in patients with impaired ventricular function.

Adult↗

PubMed2001

Citalopram versus nortriptyline in late-life depression: a 12-week randomized single-blind study.

OBJECTIVE: The aim of this single-blind study was to examine the efficacy and tolerability of citalopram compared to nortriptyline in moderate to severe major depressive patients aged 60 years or over. METHOD: In- and out-patients (N=58) with unipolar major depression were randomized to 12-week flexible dose treatment with nortriptyline or citalopram. RESULTS: No significant differences between the number of drop-outs in either group were observed, but the autonomic side-effects were significantly higher for nortriptyline than for citalopram. A significantly higher remission rate to nortriptyline than to citalopram was demonstrated, particularly if severe patients (endogenous or psychotic patients) were assessed. CONCLUSION: The remission rate to a therapeutic plasma level of nortriptyline appears to be higher than the remission rate to a standard dose of citalopram in a group of elderly major depressed patients, especially those with endogenous or psychotic features. On the other hand, citalopram appears to be better tolerated.

Age of Onset↗

PubMed2003

Double-blind comparison of fluoxetine and nortriptyline in the treatment of moderate to severe major depression.

BACKGROUND: Depression is an international public health problem. Impairment in social and occupational functioning, increased comorbidity with other psychiatric and medical conditions, and an increased risk of mortality are a few of its consequences. Some psychiatrists have the impression that selective serotonin re-uptake inhibitors may not work as well as tricyclic anti-depressants in severe depression and/or melancholia. On the contrary, there is a general belief that selective serotonin re-uptake inhibitors are superior to the tricyclic anti-depressants in having fewer side-effects, particularly cardiovascular effects. The objective of this double-blind study was to compare the efficacy and safety of fluoxetine and nortriptyline in patients with moderate to severe major depression. METHODS: A total of 48 adult outpatients who met the Diagnostic and Statistical Manual of Mental Disorders (DSM IV), forth edition for major depression, based on the structured clinical interview for DSM IV participated in the trial. Patients had a baseline Hamilton Rating Scale for Depression score of at least 20. In this double-blind, single-center trial, patients were randomly assigned to receive nortriptyline 150 mg/day (group 1) or fluoxetine 60 mg/day (group 2) for 6-weeks. The outcome of the two groups was assessed using Hamilton Depression Rating Scale, a side-effect checklist and a regular ECG assessment. RESULTS: The results suggest that the efficacy of nortriptyline is superior to fluoxetine in this group of major depressed patients. No significant differences were observed between dropout rates in the two groups but anti-cholinergic side-effects were significantly more frequent with nortriptyline than with fluoxetine but there was no significant difference in cardiovascular effects in particular QTc prolongation. CONCLUSION: The results of the current study suggest that nortriptyline was more effective than fluoxetine in the treatment of moderate to severe depression. A larger study is warranted.

Adult↗

PubMed2003

Single-blind comparison of venlafaxine and nortriptyline in elderly major depression.

The objective of this single-blind study was to compare the efficacy and safety of venlafaxine extended-release and nortriptyline in elderly patients with moderate to severe major depression. In- and out-patients (N=68) with unipolar major depression were randomized to receive 6-month treatment with either nortriptyline or venlafaxine. Outcomes of the two groups were compared using measures including the Hamilton Depression Rating Scale (HDRS) and the Newcastle Scale. Side effects were assessed with the UKU side-effect rating scale. Of the 34 venlafaxine-treated patients, 22 were remitters, 7 were nonremitters, and 5 dropped out. The intent-to-treat remission rate was 71% (22 of 31). Of the 34 who received nortriptyline, 21 were remitters, 7 were nonremitters, and 6 dropped out. The intent-to-treat remission rate was 70% (21 of 30). These results suggest that the remission rate with a therapeutic plasma level of nortriptyline is similar to the remission rate with a standard dose of venlafaxine in this group of elderly major depressed patients. No significant differences were observed between dropout rates in the two groups, but autonomic side-effects were significantly more frequent for nortriptyline than for venlafaxine. These results confirm the efficacy and safety of venlafaxine extended-release for treating elderly major depression.

Aged↗

PubMed1979

Specific radioimmunoassay of amitriptyline and nortriptyline.

1 Antisera to nortriptyline were prepared by immunizing rabbits with N-succinylnortriptyline--bovine serum albumin conjugate. 2 A sensitive radioimmunoassay has been developed for the tricyclic antidepressants amitriptyline and nortriptyline. 3 amitriptyline and nortriptyline are separated from each other and from interfering metabolites before assay. 4 Using [3H]-imipramine and [3H]-succinylnortriptyline as tracers the radioimmunoassay can measure amitriptyline and nortriptyline levels down to 2--3 ng/ml using 0.05 ml plasma sample. 5 Agreement between the radioimmunoassay and a gas-chromatographic assay was excellent for both amitriptyline and nortriptyline.

Amitriptyline↗