Vincent E. Ziegler’s research while affiliated with Washington University in St. Louis and other places

Data collected to define therapeutic plasma levels for amitriptyline and nortriptyline were re-analyzed to test endogenous and non-endogenous symptoms as response predictors while controlling for plasma level variable. The selection criteria limited the range of historical predictors. Initial symptom quality was not predictive of outcome for the entire group of 44 patients or for the 27 with therapeutic plasma levels. Delusions were not associated with poor outcome. The authors conclude that historical components of the endogenous--non-endogenous distinction (e.g., premorbid personality, stability of symptoms over time, quality of remissions) may be more important as response predictors.

An eleven item clinician-administered Mania Rating Scale (MRS) is introduced, and its reliability, validity and sensitivity are examined. There was a high correlation between the scores of two independent clinicians on both the total score (0.93) and the individual item scores (0.66 to 0.92). The MRS score correlated highly with an independent global rating, and with scores of two other mania rating scales administered concurrently. The score also correlated with the number of days of subsequent stay in hospital. It was able to differentiate statistically patients before and after two weeks of treatment and to distinguish levels of severity based on the global rating.

Plasma levels of doxepin and its metabolite desmethyldoxepin were determined in 7 depressed patients treated with doxepin hydrochloride in 3 divided doses at 1000, 1600, and 2200 hours (t.i.d.), and repeated after changing the dosage schedule to a single daily bedtime (h.s.) dose at 2200 hours. Doxepin and its metabolite were measured at 9000, 1200, 1500, and 1800 hours. None of the individual patients showed clinically significant changes in their plasma concentration of tricyclic antidepressant on the 2 dosage schedules. No difference in the clinical condition of the patients was detected on the 2 dosage schedules using the Zung Self Rating Depression Scale, however patients experienced more morning sedation while on the single h.s. dosage. This study provides pharmacological support for the prescription of doxepin on a once daily basis.

The clinical pharmacokinetics of amitriptyline were studied in four volunteers after the oral administration of 75 mg. Peak amitriptyline plasma concentrations ranged from 10.8 to 43.7 ng/ml. The disappearance was biphasic and followed first-order kinetics. The mean elimination half-life was 36.1 hours. The mean estimated first-pass metabolism of amitriptyline was 60 per cent. Significant quantities of the metabolite, nortriptyline, were produced although peak concentrations ranged from only 5.9 to 12.3 ng/ml. The relationship between these findings to clinical practice and earlier reports is discussed.

Tricyclic antidepressant plasma levels were determined after administration if imipramine (11 patients) and desipramine (ten patients) as a single daily bedtime dose or in divided doses. Plasma levels of the tricyclics were relatively stable on both dosage schedules due to the long plasma half-lives of these drugs. No difference was found between the two dosage schedules and the therapeutic effectiveness or the severity of side effects. The majority of patients preferred the single dose schedule. These findings support the use of a single daily dose of imipramine and desipramine.

The kinetics of doxepin (DOX) hydrochloride were studied in 7 volunteers after the oral administration of 75 mg. Peak plasma concentrations of DOX ranged from 8.8 to 45.8 ng/ml and were reached within 4 hr. The disappearance of DOX was biphasic and followed first-order kinetics. The mean DOX half life (t1/2) was 16.8 hr and in individuals ranged from 8.2 to 24.5 hr. The mean apparent volume of distribution was 20.2 L/kg and ranged from 9.1 to 33.3 L/kg. The estimated first-pass metabolism of DOX ranged from 55% to 87% of the oral dose assuming complete absorption. Significant quantities of the metabolite desmethyldoxepin (DMD) were produced. Peak levels of DMD ranged from 4.8 to 14.5 ng/ml and were reached between 2 and 10 hr after administration. The mean t1/2 of DMD was 51.3 hr and in individuals ranged from 33.2 to 80.7 hr. There was no correlation between the DOX and DMD t1/2s. The amount of DMD produced correlated with the plasma concentration of DOX and appears to explain the correlation between the steady-state concentrations of DOX and DMD in patients given DOX.

The kinetics of protriptyline were examined in 8 subjects after a single oral dose of 30 mg protriptyline hydrochloride. Peak protriptyline levels ranged from 10.4 to 22.3 ng/ml and were reached 6 to 12 hr after the oral dose. The mean protriptyline half-life (t1/2) was 74.3 hr and ranged from 53.6 to 91.7 hr in individual subjects, confirming the long t1/2 of protriptyline reported by Moody and associates. The estimated first-pass metabolism of protriptyline was relatively small, ranging from 10% to 25% of the oral dose, assuming complete absorption. The mean volume of distribution was 22.5 L/kg and ranged from 15.0 to 31.2 L/kg. No relationship was found between the kinetics of protriptyline and those of doxepin studied previously in 7 of the 8 subjects.

The Zung Self-rating Depression Scale (ZSDS) correlated well (0.69) with the treating physician's global rating in 26 depressed out-patients during the six weeks of treatment with a tricyclic anti-depressant. In a larger sample of 41 patients, a high correlation was found between the ZSDS and the Hamilton Rating Scale. The sensitivity of the ZSDS was found to be adequate. The scale was able to differentiate, at the 0.05 level, four severity groups classified on the basis of the global rating. The importance of the direct relationship between the range of severity studied and the value of the correlation coefficient was discussed. Previous investigations and the results of this study indicate that the ZSDS is a valid and sensitive measure of clinical severity in depressed patients and support its continued use as a research instrument.

Nine or 10 serial steady-state plasma measurements of amitryptyline, desipramine, desmethyldoxepin, doxepin, imipramine, nortriptyline, or protriptyline were made in 23 depressed patients. Each patient was monitored for compliance by pill counts, and sampling time was controlled carefully to determine intrapatient variability of steady-state tricyclic levels on a day-to-day basis. The coefficients of variation during serial sampling of the various ingested drugs were: amitriptyline, 21%; desipramine, 26%; doxepin, 21%; imipramine, 14%; nortriptyline, 13%; and protriptyline, 17%. The therapeutic ranges for the tricyclic antidepressants are relatively wide, so coefficients of variation of these magnitudes indicate that the position of an individual patient in relation to the optimal therapeutic range can be reliably determined on a clinical basis.