Robin Braithwaite

PLASMA CONCENTRATION OF AMITRIPTYLINE AND CLINICAL RESPONSE

Abstract Plasma amitriptyline and nortriptyline concentrations were measured in fifteen depressive patients who were treated with 150 mg. amitriptyline daily for 6 weeks. There was a considerable variation in plasma levels of both amitriptyline and its metabolite nortriptyline in individual patients. There was no correlation after 4 weeks between plasma levels and the side-effects reported by the patient, but there was a highly significant positive correlation between plasma levels of both compounds and clinical improvement. Patients who had plasma concentrations of amitriptyline and nortriptyline below 120 ng. per ml. showed a poor clinical response.

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 hr following the nighttime dose. There was a 610ld variation in mean plasma nortriptyline levels, ranging from 120 µg/L to 681 µg/L. Patients with high plasma levels (<200 µg/L) showed significantly poorer clinical responses than those with levels below this limit. This study provides very strong support for the view that, 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.

Nortriptyline in depressed patients with high plasma levels. II

Eighteen depressed patients were routinely treated with 100 mg nonriptyline nightly for 4 wk. Steady‐state plasma nortriptyline concentrations were measured at weekly intervals for each patient at the same time as clinical assessments were carried out. Steady‐state nonriptyline levels ranged between 120 µg/L and 681 µg/L (mean, 293 µg/L), which represents a 6‐fold interindividual variation. A single oral dose of 100 mg nonriptyline was given to 17 of the 18 patients prior to treatment. Plasma nortriptyline concentrations were obtained at regular intervals over a 3‐day period. Several kinetic parameters were calculated for each patient. The plasma nonriptyline half‐life (t½) ranged from 22 to 88 hr and the plasma clearance ranged between 8 and 55 L/hr. Highly significant correlations were obtained between steady‐state nortriptyline levels and both t½ (p < 0.01) and clearance (p < 0.0001). A high correlation (p < 0.0001) was also obtained between single‐dose 48‐hr nonriptyline levels and steady‐state nonriptyline levels. We have been able to demonstrate a strong relationship between individual patient differences in nonriptyline kinetics and steady‐state plasma concentrations and associated therapeutic effects. The pharmacokinetic data obtained in the patients appear to be different to those reponed in studies carried out in normal healthy volunteers. Reasons for this are discussed. The use of simple kinetic parameters in predicting the high nonriptyline levels is also discussed.

Dosage adjustment from simple nortriptyline spot level predictor tests in depressed patients.

Summary20 routine patients with endogenous depression were investigated in a kinetic and 4 week treatment study. Steady-state plasma nortriptyline concentrations above 200μg/L were associated with a highly significant poorer therapeutic outcome.The correlations between the 24, 48 and 72 hour concentrations and steady-state concentration were very good (r = 0.81, 0.97, 0.94; p < 0.0001) and better than the correlation between half-life and steady-state (r = 0.65; p < 0.01). The Spearman rank correlations (Rs) between amelioration of depression measured by the Hamilton Rating Scale (HRS) and the 24, 48 and 72 hour concentrations were highly significant (Rs = 0.74, 0.79, 0.79; p < 0.001) but for half-life (Rs = 0.33) the correlation was not significant.The single 48 hour plasma nortriptyline concentration following a single oral dose is recommended as a reliable simplified monitoring test suitable for a busy clinic. The test is useful for dosage adjustment to maximise antidepressant action and minimise toxicity. A tentative dosage adjustment schedule for individualising antidepressant treatment with nortriptyline based on the 48 hour or the 24 hour plasma concentration is proposed.

Effect of delayed administration of activated charcoal on nortriptyline absorption

SummaryActivated 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 charchoal may therefore be useful in the treatment of tricyclic antide-pressant poisoning even if a delay of several hours ensues before medical help is sought.

Nortriptyline therapy in elderly patients: Dosage prediction after single dose pharmacokinetic study

SummarySixteen depressed elderly patients in hospital (mean age 81 years) received a single oral dose of nortriptyline prior to commencing treatment with this drug. Plasma nortriptyline measurements after the single dose were used to calculate the plasma drug clearance and to predict the daily dose required for each patient to achieve a steady-state concentration within the suggested therapeutic range of 50–150 µg·l−1. Using these dosage regimes, the mean observed steady-state concentration showed a significant correlation with the predicted values (r=0.71, p<0.002). All patients had steady-state concentrations within or very close to this suggested range (mean 106, range 38–157 µg·l−1). Use of the prediction test can prevent the development of toxic plasma concentrations and enhance the possibility of therapeutic success. Our findings suggest that a safe starting dose of nortriptyline for the elderly is 30 mg per day.

Age, depression and tricyclic antidepressant levels

Depressive illness is a common disease in the elderly and may occur as a result of, or alongside, other organic diseases. The incidence of depressive illness increases with age, and in recurrent depressive illness, the frequency of episodes also increases. The diagnosis of a depressive illness in the elderly patient generally presents few problems, although the appearance of pseudodementia may complicate the clinical picture in a small number of cases. Treatment with a tricyclic antidepressant drug (e.g. amitriptyline, imipramine, nortriptyline) is the usual therapeutic approach. However, many patients fail to show a satisfactory response and there is a high frequency of adverse effects—postural hypotension, confusional states and cardiotoxicity being of particular concern.