• Combined monoamine oxidase (MAO) inhibitor-tricyclic antidepressant therapy and electroconvulsive therapy (ECT) were compared in a population of refractory depressive patients. Seventeen patients were randomly assigned to either of the treatment groups, and an independent observer was used to rate overall progress. Between four and ten ECTs or a combination of phenelzine and amitriptyline were administered. Assays for MAO activity and plasma levels of amitriptyline and nortriptyline were performed. In both psychotic and neurotic depression, ECT was superior. When depression was accompanied by character disorder, the response was generally poor. Adequate levels of MAO inhibition were obtained, but tricyclic antidepressant levels were low. Electroconvulsive therapy is still considered to be the treatment of choice for severe depression, whereas the combination of low doses of phenelzine and amitriptyline are ineffective. This treatment modality needs further investigation.

A Comparison of Electroconvulsive Therapy and Combined Phenelzine-Amitriptyline in Refractory Depression

tribution, and excretion of AT, NT, IMI, or DM1. The assay was usually by spectrophotometry or simple chemical analyses, some of which involved separation of parent drug from its metabolites by chromatography (1-9). None of these assays were sensitive enough for analysis of amounts of drugs likely to be in plasma or blood. Fluorimetric techniques were developed that had adequate sensitivity but were usually nonspecific because of metabolite interference (10-12). More suitable assays were developed in 1967, first by Moody and colleagues (13), who described a more advanced fluorimetric procedure for IMI and DM1, and then by Hammer and Brodie (14), who developed an isotope-derivative assay for NT or DM1. A further advance came h 1970-71 with the first suitable GC techniques for DM1, NT, and AT (15-18). Since then, the majority of published methods have involved GC, at first with the more conventional detectors, flame-ionization or electron-capture, but more recently with either nitrogen-specific detection or mass-fragmentography. Other contemporary methods investigated include thin-layer chromatography-densitometry (TLC-D), HPLC, and radioimmunoassay. In this review, we will discuss the approaches used since 1967, emphasizing specificity, sensitivity, accuracy, precision (reproducibility), expense, convenience, and ease of sample processing. A procedure will be considered specific if drug metabolites do not interfere and if only drugs that have been shown not to interfere with the assay procedure are administered concomitantly. The sensitivity required for the routine analysis of plasma amounts of most tricyclic drugs is ap

Measurement of tricyclic antidepressants. Part I. A review of methodology.

We describe a procedure for determining amitriptyline and imipramine and their active metabolites nortriptyline and desipramine, respectively, at therapeutic concentrations in human plasma by use of liquid chromatography. The drugs are extracted at pH 10.5 into hexane/isoamyl alcohol, which is evaporated and the residue chromatographed. Protriptyline is used as the internal standard. As little as 10 microgram of each drug per liter could be detected in plasma, the limit being established by variability in drug-free plasmas. The day-to-day coefficient of variation for each drug at a concentration of about 100 microgram/liter was about 7%. Doxepin and diphenhydramine interfere with the analysis of amitriptyline. Total analysis time for a single sample is 20 min.

Liquid-chromatographic procedure for tricyclic drugs and their metabolites in plasma.

Simplified method for monitoring tricyclic antidepressant therapy using gas--liquid chromatography with nitrogen detection.

This review, together with Part 1 (Clin. Chem. 26: 5-17, 1980), summarizes progress in measurement of tricyclic antidepressants in biological fluids and the application of the methodology to clinical practice. For many of the older drugs and for all of the new-generation antidepressants, further studies are required to delineate the precise relationship between plasma concentration and clinical response in well-defined diagnostic groups. For new drugs, rigorous evaluation of a method of measurement is required before it is applied to clinical studies. Assessment of drug interactions, inter-patient variability in plasma concentrations, and determination of the plasma concentrations required for therapeutic response all depend almost entirely on the quality of the assay methodology.

Measurement of tricyclic antidepressants. Part II. Applications of methodology.

We describe a comprehensive gas chromatographic analysis for therapeutic concentrations of amitriptyline, nortriptyline, imipramine, desipramine, doxepin, and desmethyldoxepin in plasma, with use of a nitrogen detector. All these drugs are extracted and chromatographed under identical conditions. Each tertiary amine tricyclic is well resolved from its secondary amine metabolite on a mixed-phase column and the concentrations of both are determined simultaneously, without derivatization. The lower limit of sensitivity is 10 microgram/liter of plasma (2-ml sample). Analytical recoveries of the tertiary and secondary amines are 100 and 80%, respectively. Between-run CV's for all of the drugs ranged between 5 and 7%.

Therapeutic monitoring of tricyclic antidepressants in plasma by gas chromatography.

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Therapeutic monitoring of tricyclic antidepressants in plasma by gas chromatography.