High plasma nortriptyline levels in the treatment of depression. I

Montgomery, Stuart; Braithwaite, R. A.; Dawling, Sheila; McAuley, R

doi:10.1002/cpt1978233309

Cited by 65 publications

(15 citation statements)

References 4 publications

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“…Subsequent studies have confirmed this finding of an upper therapeutic limit lying between 600-800 nM (30)(31)(32)(33). It has been speculated that NT acts as a postsynaptic blocker of monoamine receptors at high concentrations (29).…”

Section: Introductionsupporting

confidence: 63%

“…Another similar study found very few circulatory signs, apart from one subject who developed a first degree heart block at NT concentratiohs between 760-1000 nM (11). Serious AE seen at high concentrations in other studies are first degree heart block at 1000 nM (30) and confusion at 1200 nM (33). Two more benign AE which still can be very disturbing to the patient are saliva hyposecretion and accommodation disturbances.…”

Section: Introductionmentioning

confidence: 99%

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Population pharmacokinetics and pharmacodynamics: potential use for gathering dose-concentration-response

Jerling

1996

European Journal of Drug Metabolism and Pharmacokinetics

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The population approach is a general term covering different aspects of kinetic and dynamic data collected mainly from drug-treated patients and new techniques allowing evaluation of sparse observations from each subject. Such data originate from clinically relevant conditions and can give information on several qualities of a drug. An example is given with the tricyclic antidepressant nortriptyline for which the kinetics and the concentration-effect relationship have been thoroughly documented previously with conventional techniques. We have evaluated retrospective data from a therapeutic drug monitoring service using a nonparametric population kinetic method (NPML) that allows description of kinetic outliers and nonlinear relationships between kinetic parameters and covariates. In addition, drug interactions, nonlinear kinetics and dosing habits were studied with other techniques corroborating previous results and adding new information. The concentration-effect relationship could not be evaluated from our data as information on efficacy and adverse effects was of too low quality. However, several controlled studies have defined a therapeutic concentration interval and a discussion on dosing strategies is based on this interval. Collection of sparse data in patients during phases II-IV of drug development as a complement to conventional studies is highly recommendable.

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Section: Introductionsupporting

confidence: 63%

Section: Introductionmentioning

confidence: 99%

Population pharmacokinetics and pharmacodynamics: potential use for gathering dose-concentration-response

Jerling

1996

European Journal of Drug Metabolism and Pharmacokinetics

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“…This curvilinear dose-response curve with nortriptyline is a well-established phenomenon replicated in several, fixeddose, follow-up studies 10 including those by Ziegler et al 7 and Montgomery et al 11,12 At the time, the explanation for this finding involved a therapeutic ''plateau'' being reached, above which nortriptyline began antagonizing adrenergic receptors and thereby blocking the antidepressant response observed at lower concentrations. 13 Based on pharmacokinetic data, CYP 2D6 PMs will develop a 3-to 10-fold higher nortriptyline concentration than CYP 2D6 EMs.…”

Section: The Case For Nortriptylinementioning

confidence: 88%

CYP 2D6 PM Status and Antidepressant Response to Nortriptyline and Venlafaxine

Macaluso

Preskorn

2011

Journal of Clinical Psychopharmacology

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W e propose that cytochrome P450 (CYP) 2D6 poor metabolizers (PMs) are inherently resistant to the beneficial effects of antidepressants that act by altering serotonin-norepinephrine neurotransmission and that this phenomenon is responsible for the curvilinear concentration-antidepressant response relationship observed with nortriptyline over 30 years ago.The impetus for this hypothesis was the recent finding by Lobello and colleagues 1 that CYP 2D6 PMs treated with venlafaxine (VEN) have low antidepressant response and remission rates: 2-to 3-fold lower than those achieved in CYP 2D6 extensive metabolizers (EMs) and comparable to rates seen in placebo-treated patients. The details concerning the work that lead to the finding of poor antidepressant response to VEN in CYP 2D6 PMs is summarized next. VENLAFAXINE AND CYP 2D6Venlafaxine is a model substrate of CYP 2D6, and the ratio of VEN to its major metabolite O-desmethylvenlafaxine (ODV) can be used to phenotype individuals as CYP 2D6 EMs or PMs as follows: ODV/VEN ratios greater than 1 predict EM status, whereas ratios less than 1 predict PM status. 2 Using this approach to phenotype patients, Lobello and colleagues 1 conducted a secondary analysis of the registration trial data of VEN to treat major depressive disorder, reassessing the data after dividing the VEN-treated population into 2 groups: phenotypic CYP 2D6 EMs and PMs. The analysis was based on 4 large placebo-controlled, double-blind, efficacy trials of VEN in which a plasma level of VEN and ODV was measured at the time of the trial. EMs had a 2-to 3-fold higher antidepressant response and remission rate on 4 of 5 efficacy measures when compared with PMs (P e 0.015). Both groups received the same average dose of VEN, achieved the same total concentration of VEN plus ODV, and had the same tolerability profile, ruling out differences in those parameters as an explanation for the differences in antidepressant efficacy observed. 1 Although the total concentration of VEN plus ODV was the same in both groups, the EMs achieved higher levels of ODV and lower levels of VEN, whereas the converse was true for the PMs. Of note, the finding by Lobello and colleagues was a replication of an earlier, smaller study by Borgherini and colleagues. 3 There are 2 possible explanations for the finding of poor antidepressant response to VEN in CYP 2D6 PMs. The first is VEN could be a prodrug that requires biotransformation to ODV to be an effective antidepressant. However, this explanation is inconsistent with the known pharmacology of VEN and ODV. The second is that CYP 2D6 PMs, for as yet unknown reasons, are less responsive to antidepressants, such as VEN, which are thought to work by affecting central serotonin and norepinephrine neurotransmission.Consistent with this second explanation, CYP 2D6 is expressed in the brain and is involved in the metabolism of serotonin. In addition, EMs and PMs are reported to differ in terms of personality type and to have differences in regional brain metabolism as determined using fu...

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“…1971; Kragh-S6rensen etal. 1973; Ziegler et al 1976;Montgomery et al 1978). NT is considered to Offprint requests to R. Malmgren be a fairly selective NE uptake inhibitor (Carlsson et al 1969a).…”

mentioning

confidence: 99%

Serotonin uptake inhibition during treatment of depression with nortriptyline caused by parent drug and not by 10-hydroxymetabolites

Malmgren

Åberg‐Wistedt

1987

Psychopharmacology

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Treatment of endogenous depression with nortriptyline (NT), at a daily dose of 150 mg, resulted in a pronounced improvement of seven of ten patients investigated. The concentration of the norepinephrine metabolite HMPG in cerebrospinal fluid (CSF) decreased by 29% (P less than 0.01) after 3 weeks of treatment. There was no significant effect of treatment on the serotonin and dopamine metabolites 5-HIAA and HVA. In previous larger materials, however, a decrease of 5-HIAA in CSF has been demonstrated. Platelets from the patients showed an increase in Km for serotonin uptake in response to NT treatment. The IC50 value of NT for serotonin uptake inhibition was 940 nM, while the corresponding value of the major metabolite of NT, i.e. E-10-OH-NT, was much higher (6700 nM). Thus, during treatment, the parent drug and not the metabolite was responsible for the serotonin uptake inhibition in platelets. There was a close correlation between Km and the plasma concentration of NT after 1 week of treatment (r = 0.88, P less than 0.01) but not after 3 weeks of treatment (r = 0.48; ns). There was no uniform effect of NT treatment on Vmax. It is concluded that clinical NT treatment results in uptake inhibition not only in norepinephrine but also in serotonin neurons.

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High plasma nortriptyline levels in the treatment of depression. I

Cited by 65 publications

References 4 publications

Population pharmacokinetics and pharmacodynamics: potential use for gathering dose-concentration-response

Population pharmacokinetics and pharmacodynamics: potential use for gathering dose-concentration-response

CYP 2D6 PM Status and Antidepressant Response to Nortriptyline and Venlafaxine

Serotonin uptake inhibition during treatment of depression with nortriptyline caused by parent drug and not by 10-hydroxymetabolites

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