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PubMed1984

Nortriptyline capacity-limited metabolism: a case report.

A case report of a 62-year-old patient is presented with apparent dose-dependent kinetics for nortriptyline following the administration of therapeutic doses of the drug. Twelve-hour measurements of total plasma nortriptyline following steady state administration of the drug at 10 mg every other day, 10 mg daily, and 25 mg daily were 38, 86, and 647 ng/ml and while free plasma nortriptyline concentrations were 0.37, 0.9, and 6.6 ng/ml, respectively. Half-lives calculated from samples collected at 12, 24, and 36 hours status after administration of steady state 10 mg every other day, 10 mg daily, and 25 mg daily maintenance doses were 30.4, 36.7, and 64 hours, respectively. Toxicity did not occur despite excessive total plasma tricyclic antidepressant concentrations as a result of abnormally increased plasma protein binding of nortriptyline. The case is contrasted to the usual pharmacokinetic characteristics for the tricyclic antidepressants.

Blood Proteins↗

PubMed1982

Nortriptyline and EEG sleep in depressed patients.

The effect of nortriptyline was assessed on the EEG sleep of 20 inpatients with major depressive syndrome. While 25 mg of nortriptyline had an immediate effect on REM sleep variables, relatively little influence on sleep continuity measures was noted. Subsequent administration of 75 and 100 mg of nortriptyline produced continued REM sleep suppression over several weeks. In summary, nortriptyline altered EEG sleep in a pattern similar to that of amitriptyline. REM latency and REM sleep time were consistently reduced by drug administration, while REM activity was only transiently altered as with amitriptyline. The comparison with amitriptyline showed, for the most part, similar influences on REM sleep without the sedative effects of amitriptyline.

Adult↗

PubMed1980

Drug interactions of amitriptyline and nortriptyline with warfarin in the rat.

Treatment of rats with amitriptyline or nortriptyline for 6 days at 6, 15 and 30 mg/kg produced no increases in the activities of aniline hydroxylase and aminopyrine N-demethylase or the content of microsomal protein and cytochrome P-450. Significant decreases in aminopyrine N-demethylase activity and cytochrome P-450 content were observed at 30 mg/kg. This inhibition of activity appeared to be at the level of cytochrome P-450 and not a cytotoxic effect in liver cells. Concomitant administration of amitriptyline or nortriptyline (6, 15 and 30 mg/kg)with warfarin to rats produced a dose dependent increase in the prothrombin time. At high doses of the tricyclic antidepressants, these increases in prothrombin time correlated with increases observed in the plasma half-life of warfarin. In vitro studies suggested that amitriptyline and nortriptyline inhibited the metabolism of warfarin. A double-reciprocal plot (Lineweaver-Burk method) showed this inhibition to be competitive. Nortriptyline produced greater inhibition of warfarin metabolism than amitriptyline and correspondingly greater enhancement of the anticoagulant effect.

Amitriptyline↗

PubMed1993

Downregulation of serotonin receptor subtypes by nortriptyline and adinazolam in major depressive disorder: neuroendocrine and platelet markers.

Neuroendocrine and platelet markers of serotonin (5-hydroxytryptamine, 5-HT) receptor functioning are useful tools for studying the downregulation of 5-HT receptors, a leading hypothesis for the mechanism of action of antidepressant drugs. The 5-HT releaser fenfluramine raises body temperature as well as plasma concentrations of ACTH, cortisol, and prolactin. Pretreatment with the 5-HT1 antagonist pindolol did not block the hyperthermic response to fenfluramine, mediating its actions via non-5-HT1 receptor subtypes (presumably 5-HT2/1C). We observed blunted hyperthermic responses to fenfluramine in unmedicated patients with major depressive disorder. We also observed that the neuroendocrine responses to fenfluramine were decreased by chronic treatment with the tricyclic antidepressant nortriptyline but not by chronic treatment with tricyclic antidepressant nortriptyline but not by chronic treatment with adinazolam, a triazolobenzodiazepine with purported antidepressant activity. IC50 values for ketanserin inhibition of 5-HT-induced platelet shape change response, a marker of 5-HT2/1c receptors, were elevated after nortriptyline treatment in depressed patients, and this increase could be accounted for by those subjects who responded well to antidepressant treatment. Adinazolam treatment did not alter the platelet shape change response. Our data suggest that downregulation of 5-HT2/1c receptors may be linked to the clinical response of depressed patients treated with nortriptyline.

Anti-Anxiety Agents↗

PubMed1997

Nortriptyline and its hydroxymetabolites in breastfeeding mothers and newborns.

We previously reported the serum nortriptyline levels of a series of breastfeeding mother-infant pairs. Nortriptyline was below the level of detectability in the infants' sera; however, two young infants aged 10 weeks or less had low concentrations of 10-hydroxy-nortriptyline. Because very young breastfeeding infants are likely to be at increased risk for toxicity, we have focused our study on breastfeeding newborns. We present additional data from six mothers and their infants (4 weeks of age), as well as data from one prematurely born baby. We were able to quantify nortriptyline in one infant and another had higher levels of hydroxymetabolites than previously reported, although still very low. No adverse clinical effects were observed in the infants.

Breast Feeding↗

PubMed1977

Sampling time, dosage schedule, and nortriptyline plasma levels.

Steady-state nortriptyline plasma levels were determined in eight patients at 9 AM, 12 PM, 3 PM, and 6 PM during treatment with nortriptyline hydrochloride administered as a single daily bedtime (hs) dose at 10 PM and repeated after changing the dosage schedule to three times a day (tid) with divided doses at 10 AM, 4 PM, and 10 PM. Overall, the mean levels were stable during the sampling period and comparable on the two schedules. As expected, the plasma level decreased at the later sampling times on the hs schedule and increased on the tid schedule. In seven of the eight patients, the differences on the two dosage schedules were less than 30 ng/ml, which is not considered clinically significant. One patient had a higher plasma nortriptyline level on the tid schedule, which was clinically significant. Standardization of sampling time is of importance when comparing plasma levels and therapeutic response in treatment studies.

Depression↗

PubMed1980

Subtypes of depression based on excretion of MHPG and response to nortriptyline.

We investigated the relationship between urinary excretion of MHPG and the clinical response of 17 depressed patients to nortriptyline hydrochloride. Plasma concentrations of nortriptyline were monitored to assure optimal doses. Patients were classified as having "low" or "normal-high" excretion of MHPG based on one to five 24-hour urine specimens. Hamilton Depression Rating Scale scores were not reduced significantly more among the nine low excreters as compared with the eight normal-high excreters. However, when a true bimodal distribution of MHPG excretion was created by comparing only the six lowest excreters with the six highest excreters, the low group improved significantly more than the high group. This differential response to nortriptyline somewhat supports the notion that MHPG excretion may predict response to specific tricyclics. Collecting urine for MHPG determination in depressed patients is not easy; the variability of excretion within patients is considerable, and the range of MHPG excretion closely parallels that in normal persons. The clinical utility of this procedure is still to be determined.

Adult↗

PubMed2004

No evidence of increased adverse drug reactions in cytochrome P450 CYP2D6 poor metabolizers treated with fluoxetine or nortriptyline.

The polymorphic enzyme cytochrome P450 CYP2D6 is involved in the metabolism of many antidepressants, including nortriptyline and fluoxetine. Some 7%-10% Caucasians have inactivating mutations in both alleles of the CYP2D6 gene, and are referred to as poor metabolizers (PMs). Several case reports and clinical studies suggest that CYP2D6 PMs are at a greater risk of developing adverse drug reactions (ADRs) on antidepressant medication than extensive metabolizers (EMs). However, few clinical trials have investigated whether CYP2D6 PM genotype is predictive of ADRs during antidepressant treatment. This paper explores the link between CYP2D6 genotype and antidepressant-associated ADRs in outpatients being treated for major depression with either nortriptyline or fluoxetine. Patients were randomized to fluoxetine (n=65) or nortriptyline (n=60) for the 6 week trial. CYP2D6 genotypes predicted that of these patients 115 were EM and the remaining 10 were PMs. ADRs attributed to antidepressant usage were recorded over the 6-week trial. Although the type of ADR was, as expected, different between drugs, the frequency of ADRs experienced did not differ significantly between the two antidepressants or between CYP2D6 PMs and EMs. In addition, the frequency at which PMs discontinued antidepressant medication was not noticeably different from EMs, although with only 10 PMs the study is under powered to detect moderate or small differences. These findings suggest that inability to efficiently metabolize antidepressants that are CYP2D6 substrates does not necessarily lead to increased occurrence of antidepressant-associated ADRs. Thus, for clinicians prescribing antidepressant monotherapy, CYP2D6 polymorphisms are probably not of relevance to antidepressant side effects and therapy.

Adolescent↗

PubMed1987

The effect of the tricyclic antidepressant drug, nortriptyline on left ventricular ejection fraction and left ventricular volumes.

Eight patients with major depression but otherwise healthy underwent radionuclide cardiography before and during nortriptyline treatment. The second examination was performed when the nortriptyline plasma concentration was within the therapeutic range (60-150 micrograms X l-1). Heart rate, arterial blood pressure, left ventricular ejection fraction, left ventricular volumes, systolic pressure-volume ratio, and cardiac output were determined. Heart rate increased in mean by 13% (P less than 0.05). All other variables were unchanged. We conclude that nortriptyline in therapeutic doses produces no major adverse effect on left ventricular function. Routine radionuclide cardiography might be a suitable method to detect among those treated with tricyclic antidepressants the occasional susceptible patient. This may particularly apply to patients with known heart disease and to elderly patients.

Adult↗

PubMed1975

Kinetics of nortriptyline in man according to a two compartment model.

Plasma concentrations of nortriptyline have been assayed in four subjects after intravenous infusion of 57 mg nortriptyline hydrochloride. The data were evaluated according to a two compartment open model. The calculated best-fitting curves were in good agreement with the experimental data, better than could be expected from a simpler model. This justifies the assumption that the kinetics of nortriptyline in man may be described by this model with an appropriate input function. The data permitted estimation of all the parameters of the model. The meaning of the parameters is discussed, particularly in relation to individual variation.

Adult↗

PubMed1978

Effect of delayed administration of activated charcoal on nortriptyline absorption.

Activated charcoal is known to reduce the absorption of therapeutic doses of nortriptyline in vivo when administered 30 min after drug ingestion. In a group of volunteers, one sachet (10 g) of a new activated charcoal preparation, 'Medicoal' was found to produce a highly significant reduction in nortriptyline absorption when given as long as four hours after nortriptyline dosing. Activated charcoal may therefore be useful in the treatment of tricyclic antidepressant poisoning even if a delay of several hours ensues before medical help is sought.

Adult↗

PubMed1994

Methylphenidate and nortriptyline in the treatment of poststroke depression: a retrospective comparison.

The hospital charts of elderly stroke patients with major depression, as determined by DSM-III-R criteria, who were treated with either methylphenidate (n = 28) or nortriptyline (n = 30) were retrospectively reviewed. Fifty-three percent of the methylphenidate patients experienced complete remission of depressive symptoms. Similarly, 43% of the patients in the nortriptyline group showed remission of depressive symptomatology. Whereas the response rates between the two treatment groups were not significantly different in the patients who did respond to treatment (chi 2 = .608, df = 1, p = NS), the speed of response was significantly better in the methylphenidate group (t[13] = 15.9, p < .001). The average peak response time for the methylphenidate patients was 2.4 days compared to 27 days for the nortriptyline group. This finding is consistent with previous reports suggesting a rapid response to methylphenidate and other psychostimulants, typically between 24 and 72 hours. Adverse side effects, such as cardiac changes, did not differ between groups, generally falling in the mild range of severity. These data suggest that the rapid effects of methylphenidate may be especially useful to speed recovery from depression so that patients can participate more fully in rehabilitation programs.

Aged↗

PubMed1989

Plasma levels of nortriptyline and 10-hydroxynortriptyline and treatment-related electrocardiographic changes in the elderly depressed.

Thirty-one elderly depressed patients were treated for seven weeks with nortriptyline with plasma levels kept between 50-180 ng/ml. Electrocardiograms were taken at the third and seventh weeks of treatment. There were significant increases in the PR interval, QTc interval, and heart rate from before and after treatment. However, there were no consistent correlations between electrocardiographic changes during treatment and plasma levels of nortriptyline, 10-hydroxynortriptyline and either of its two isomers (E-10-hydroxynortriptyline, Z-10-hydroxynortriptyline). Increased QRS duration after seven weeks of treatment was correlated with daily dose of nortriptyline.

Aged↗

PubMed1985

Plasma tyrosine/neutral amino acid ratio correlated with clinical response to nortriptyline in endogenously depressed patients.

Ratios in plasma of tryptophan (Trp) and tyrosine (Tyr) to other large neutral amino acids were determined in 26 endogenous depressives before and after treatment with nortriptyline in doses adequate to achieve a steady-state serum level between 70 and 130 ng/ml, i.e., within the recommended therapeutic range. Pretreatment plasma Trp ratio and Tyr ratio were normal and did not change significantly during treatment. The plasma Trp and Tyr concentrations and the plasma Trp ratio showed no significant association with the therapeutic response. However, the pretreatment plasma Tyr ratio correlated significantly and directly with the final Hamilton rating score, and inversely with the per cent reduction of Hamilton rating score. Moreover, depressives with plasma Tyr ratio below the normal mean showed significantly greater clinical improvement than patients with higher plasma Tyr ratio with comparable serum nortriptyline levels. Evidence has been presented that biochemical variables in depressed patients are important determinants of clinical improvement following pharmacotherapeutic treatment. Moreover, the results suggest that the plasma Tyr ratio may be a guideline for antidepressant response to nortriptyline.

Adult↗

PubMed1989

Factors affecting the delay of antidepressant effect in responders to nortriptyline and phenelzine.

Seventy-six elderly depressed patients who had responded to either nortriptyline or phenelzine after a trial of up to 3 months were examined. The mean week of response was nearly 6 weeks. Patients who were more severely depressed took longer to respond. Patients with endogenous depression responded sooner on nortriptyline than did patients with nonendogenous depression. For patients on nortriptyline, lower plasma levels in the early weeks of treatment may delay response while differences in platelet monoamine oxidase inhibition in the early weeks of treatment do not appear to affect week of response for patients on phenelzine.

Aged↗

PubMed1991

Simulated home treatment of depression with nortriptyline.

1. Twenty-two patients hospitalized for treatment of depression were treated under conditions simulating those of home treatment. 2. Full doses of nortriptyline, from 100 to 150 mg/day, were started after baseline observations were made. 3. Two patients were dropped from the study, one for orthostatic hypotension, one for an aberrant response to nortriptyline. Two additional patients developed orthostasis which was easily managed. Otherwise no unusual side effects were noted. 4. After six days of treatment, 9 of 20 patients showed significant improvement with an overall reduction in scores on the Hamilton Depression Scale of 49% for the entire group. 5. Using the weight-adjusted dosage schedule, 18 of the 21 patients attained plasma concentrations of nortriptyline within the presumed therapeutic range; however, no clear relationship could be established between plasma concentrations and clinical response. 6. With proper selection of patients, it should be possible to treat at home some patients who currently are considered to require hospitalization.

Adult↗

PubMed1993

Sleep deprivation accelerates the response to nortriptyline.

1. The authors examined the effect of total sleep deprivation (SD) in combination with nortriptyline in 20 patients with major depressive disorder (MDD). Patients underwent a 36-hour SD procedure followed by nortriptyline started on the evening after SD, with ratings for two weeks. 2. Eleven (55%) patients were responders; they showed a rapid and sustained remission after SD, whereas non-responders demonstrated the delayed results expected with nortriptyline. 3. High initial depression scores and absence of depersonalization were associated with response to SD, while being female and middle insomnia were associated with response to the combined regimen. 4. The combination of SD with antidepressants proves to be an effective and safe treatment modality.

Adult↗

PubMed1986

Uptake of serotonin into rat platelets and synaptosomes: comparative structure-activity relationships, energetics and evaluation of the effects of acute and chronic nortriptyline administration.

In order to establish whether the uptake systems in platelets and synaptosomes are equivalent, the structure-activity relationships for drug-induced inhibition of serotonin uptake were examined in vitro. The rank order for potency of inhibitors was the same in platelets as in synaptosomes, namely imipramine greater than nortriptyline greater than desmethylimipramine much much greater than norepinephrine greater than histamine; in addition, serotonin uptake was clearly distinguishable from the norepinephrine synaptic uptake mechanism, which displayed a different rank order. The synaptosomal uptake of serotonin was, however, much more dependent upon maintenance of Na+-K+-ATPase activity for its energy source than was the platelet uptake mechanism. Acute administration of nortriptyline produced substantial inhibition of platelet serotonin uptake and a smaller degree of inhibition of synaptosomal uptake; inhibition was detectable even after extensive washing of the platelet and synaptosome preparations, and was associated with persistent binding of the drug to the organelles. Chronic infusion of nortriptyline (20 mg/kg for 21 days, followed by a 24 hr washout period to dissipate persistent binding) did not alter the uptake capacity of synaptosomal or platelet preparations, but did cause a shift in the drug specificity of inhibitors. The latter effect was in opposite directions in platelets vs. synaptosomes. These data indicate that the platelet uptake mechanism does bear some resemblance to that seen in serotonergic neurons, but that the energy source for transport differs and the two mechanisms respond differently to prolonged drug administration in vivo. The use of uptake as a marker during the course of antidepressant administration is likely to be confounded by persistent direct drug effects on these organelles.

Animals↗