Lars F. Gram

QUANTITATIVE RATING OF DEPRESSIVE STATES

A step‐by‐step analysis of Becks and Hamiltons rating scales showed that both, scales failed to differentiate adequately between moderate and severe depression measured by a global clinical assessment. Each item of the scales was tested for calibration, ascending monotonicity, and dispersion parallel to the clinical assessment. Twelve items of Becks scale and six items of Hamiltons scale were found valid with respect to these criteria. Those items should be taken into account in future research for baseline ratings and for change ratings of depressive states quantitatively.

The Hamilton Depression Scale.: EVALUATION OF OBJECTIVITY USING LOGISTIC MODELS

The consistency of the Hamilton Depression Scale (HDS) as a measure of the severity of depressive states has been examined when the scale was used weekly during a trial with imipramine. By use of logistic models (Rasch) the consistency of the HDS has been considered across patient‐variables as age, sex, plasma levels of imipramine, and diagnosis. The results showed that the original 17‐item HDS was without adequate consistency, i.e. the total score of the sample of items was no one‐dimensional measure of depressive states. However, a melancholia subscale of the HDS contained items the total of which can be used to compare patients quantitatively, although in some part of the analysis one of these items showed ceiling effect. It was concluded that the melancholia sub‐scale (containing the items depressed mood, guilt, work and interests, retardation, psychic anxiety, and general somatic symptoms) can form the basis for further improvements in the field of quantitative rating scales for depressive states.

Imipramine: clinical effects and pharmacokinetic variability.

Sixty-six hospitalized depressed patients were treated for 4 weeks with imipramine (Tofranil®) 225 mg/day. Blood samples were drawn twice weekly 15 h after the last drug intake, and IP and DMI concentrations in plasma were assayed by quantitative in situ thin-layer chromatography. Clinical rating was carried out once weekly by Hamiltons Rating Scale (HRS), Becks Depression Inventory, WHO Depression Scale (Quantitative Part), and a side-effect scale. The patients were classified on the basis of the WHO Depression Scale (Qualitative Part) as ‘endogenous’ (N=37) or ‘non-endogenous’ depressions (N=29). Antidepressive effect was evaluated on the basis of the posttreatment rating scores.In patients classified as ‘endogenous’ depressions all 12 responding patients (HRS≦7) had plasma levels of IP>45 μg/l and DMI>75 μg/l, whereas 11 out of 14 nonresponding patients (HRS≧16) had plasma levels of one or both compounds below these limits. Ten out of 12 responders had levels of IP+DMI above 240 μg/l, and all nonresponders had levels of IP+DMI below this limit. Patients with partial response (HRS: 8–15) formed an overlapping group. There was no sign of an upper plasma level limit for the antidepressive effect of imipramine.The plasma level/effect relationship was less clear in patients with ‘non-endogenous’ depressions, since several of them responded at low plasma levels.Some relationship between effect on blood pressure (orthostatic effect) and high plasma levels of IP and DMI was found.Using a plasma level limit of IP≷45 μg/l and DMI≷75 μg/l, it was possible to predict the response of the ‘endogenous’ depression group for 10 out of 12 responders and 10 out of 14 nonresponders on the basis of plasma level measurements obtained after 1 week of treatment.

First-pass metabolism of imipramine in man

The systemic availability of orally administered imipramine (IP) varied from 29 to 77% in 4 subjects. The decrease in availability was due to an excess in metabolism after oral administration. This first%pass metabolism did not correlate with plasma half%life, apparent clearance, or the rate of metabolite excretion in urine. There was close correlation with the excess in formation of demethylated metabolites after oral administration, which suggests that the first%pass metabolism is mediated by demethylation, but does not correlate to the total rate of demethylation.

Plasma levels and antidepressive effect of imipramine

The relationship between the antidepressive effect of imipramine and the plasma concentrations of imipramine and the active metabolite desipramine was studied in 24 patients suffering from endogenous depression. After a placebo period of 7 days, the patients received imipramine, 75 mg 3 times a day. The dose was reduced in patients with pronounced side effects. Blood samples for drug assay were drawn in the morning, 15 hr after the last drug intake. Imipramine and desipramine in plasma were assayed by quantitative in situ thin‐layer chromatography. Individual variations in plasma concentration were 20‐ to 30‐fold in both imipramine and desipramine. Severity of depression was assessed on the Hamilton Rating Scale (HRS). Eleven of 12 patients who responded satisfactorily to the treatment (H RS post‐treatment score <8) had plasma concentration of imipramine ≧45 µg/L, and desipramine >75 µg/L, whereas the 12 patients not responding satisfactorily (post‐treatment score on HRS ≧8) all had concentrations of imipramine or desipramine or both below these limits.

Plasma Level Monitoring of Tricyclic Antidepressant Therapy

SummaryThe therapeutic effect of the tricyclic antidepressants is subject to marked interindividual differences in response Only. 50 to 70% of depressed patients usually benefit from treatment. The antidepressive effect is most clearly drug-related in endogenous depressions and less convincing in other types of depression. However, even within diagnostically homogenous groups of depressed patients, the antidepressive effect is variable. Some of this variability may be explained by the pronounced interindividual variation in pharmacokinetics of tricyclic anti-depressants, in particular variation in steady state plasma levels.Studies with nortriptyline in endogenous depressions have indicated that a therapeutic effect is only achieved when the plasma level is above 50 and below 150 to 180μg/L, above which patients respond poorly. For imipramine, most patients respond well when plasma levels of imipramme + desipramine are above 200 to 240μg/L. Very high plasma levels do not appear to impair the antidepressive effect of imipramme. The present data on other antidepressants are less clear.For nortriptyline and imipramine, as well as other antidepressants, there is a need for more studies on larger patient populations comprising different diagnostic categories, and designed and conducted with careful consideration of the number of methodological problems involved in interpreting plasma level/effect relationships. The use of plasma level monitoring in cases of intoxication with tricyclic antidepressants is potentially useful, but studies in this area are limited.

Assessment of symptom change from improvement curves on the Hamilton depression scale in trials with antidepressants

A total of 97 patients, who participated in two studies on the relationship between the clinical effect and plasma levels of imipramine and clomipramine, were examined for improvement curves by use of weekly ratings on the Hamilton Depression Scale (HDS). Although we confirmed that our six-item HDS subscale, in contrast to the total 17-item HDS, was a one-dimensional measure of depression, the Rasch analysis showed that the weekly improvement in subscale scores only applied to the individual patient, i.e. an average improvement curve for a group of depressed patients is an abstraction to which the individual curves cannot be transferred. Our results indicate, however, that when the subscale scores are transformed into three clinical categories of depression: no, mild (minor), moderate/-severe (major) they could be described by a common improvement curve for all patients. This is illustrated by the percentage of patients who, week to week, changed from major to minor or no depression, or from minor to no depression. We found no specific improvement pattern for imipramine or clomipramine which could be used diagnostically. There is reason to assume that patients completing a controlled trial necessarily will follow a monotonic improvement curve, and the improvement pattern of all patients fulfilling the entry criteria should, therefore, always be reported. The present study thus indicates that calculation of average improvement curves is neither clinically nor statistically meaningful, and should be replaced by measures of changes in number of patients in different main severity categories, or by the final rating score. No difference in outcome between imipramine and clomipramine was shown neither on the subscale nor on the 17-item HDS.

First‐pass metabolism of nortriptyline in man

The kinetics of nortriptyline were studied after oral and intravenous (iv) administration of test doses of 50 mg 14C‐nortriptyline. The systemic availability of orally administered nortriptyline varied from 0.46 to 0.59 in 6 subjects. The decrease in availability was due to metabolism after administration. Systemic clearance varied from 0.31 to 0.66 Llmin. From these measurements indirect estimates of the hepatic blood flow could be made, and a variation from 0.6 to 1.5 L/min was found. Quantitative measurements of first‐pass metabolism could also be obtained from urinary metabolite excretion data when the kinetics of metabolite formation and elimination were taken into account. From the second or third day after the test dose, the urinary excretion rate of total radioactivity declined monoexponentially with half‐lives closely corresponding to the plasma half‐lives of unchanged nortriptyline. Analysis of the data from the iv test according to a 2‐compartment open model showed that there was a close correlation between the rate constant of distribution from central to peripheral compartment (k12 and the elimination rate constant in the central compartment (ke1). Still, there was some variation in the kp1lk 12‐ratio, and this variation corresponded to the variation of the estimated hepatic blood flow.

The WHO Depression Scale RELATIONSHIP TO THE NEWCASTLE SCALES

The WHO (World Health Organization) Depression Scale is a new rating scale developed to evaluate the complete clinical history and description of depression. Items of the WHO scale were transformed to cover the items of the two Newcastle scales that are designed to differentiate between endogenous and non‐endogenous depressions. In 98 depressed inpatients examined prior to antidepressive therapy only moderate agreement between scores transformed to the two Newcastle scales was found. Also the distribution patterns of the scores on the two scales were different. In patients classified as endogenous on one or both scales a significant relationship between plasma levels of imipramine or clomipramine and antidepressive effect was found. In patients classified on both scales as doubtful – or non‐endogenous depressions – no such correlation could be identified. The initial severity of depression, as defined by the Hamilton Depression Scale, was the same in endogenous, doubtful and non‐endogenous depression according to the scores transformed to the two Newcastle scales.

Steady-state kinetics of imipramine in patients.

Steady-state plasma level kinetics were studied in 76 patients given imipramine (IP) 150 to 225 mg/day for 2–5 weeks. IP was given in three divided doses at 8.00 a.m., 1.00 p.m. and 5.00 p.m. Plasma concentrations of IP and its active metabolite desipramine (DMI) were determined by quantitative in situ thin-layer chromatography. The plasma levels of IP and DMI showed pronounced flucutations throughout the day with a ratio of about 2 between highest and lowest level. Patients with steady-state levels of IP and/or DMI below 50 μg/l reached this within 1 week of treatment. Patients with higher steady-state levels reached steady-state concentrations within 2–3 weeks. There were some intraindividual fluctuations in plasma levels from week to week after steady state had been reached (coefficient of variation: 10–20%). Interindividually, the steady-state levels corrected to a dose of 3.5 mg/kg per day varied considerably: IP: 6–356 μg/l, DMI: 24–659 μg/l and IP+DMI: 58–809 μg/l. The steady-state plasma levels showed a skew distribution that became normal by logarithmic transformation. The IP/DMI ratio ranged from 0.07 to 5.5 with a median value of 0.47. Compared to data from amitriptyline treated patients the IP/DMI ratios had significantly lower median value and larger variation than the corresponding plasma level ratios of amitriptyline/nortriptyline. Several statistically significant differences in steady-state levels between age groups were found. For IP: Women aged 30–39 had lower levels than women aged 20–29, 40–49, and 50–59, and men aged 50–59 and 60–65; men aged 30–39 had lower levels than men aged 60–65. For DMI: Women aged 30–39 had lower levels than women aged 50–59.