Adam Nagy

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.

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.

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.

The demethylation of imipramine and clomipramine as apparent from their plasma kinetics.

AbstractThe demetylation of imipramine and clomipramine was studied after administration by different routes of single doses of clomipramine hydrochloride and multiple doses of clomipramine as well as imipramine hydrochloride.Five healthy volunteers received 1 mg of clomipramine hydrochloride/kg body weight as single oral and intramuscular doses on different occasions for the purpose of studying the plasma levels of clomipramine and the desmethylclomipramine formed. Desmethyl-clomipramine was found in the plasma in four of the subjects after oral intake but only in one subject after intramuscular injection. The peak levles of clomipramine were considerably higher after intramuscular than after oral administration. The half-lives of clomipramine after oral administration ranged from 11.6–35.8 h

A pilot study of a new selective MAO inhibitor: Toloxatone

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Behandlingsalternativ vid ångesttillstånd, indikationer och behandlingsresultat

and after intramuscular administration from 20.1–39.6 h