A significant proportion of depressed patients will experience multiple episodes of depression throughout their lifetimes, and, in recent years, attention has been paid to the identification of risk factors associated with a recurrent course of major depression. Residual depressive symptoms following acute phase therapy appears to be the most important clinical risk factor leading to recurrence. However, advances in empirically-supported treatment algorithms and guidelines, and in pharmacotherapy and psychotherapy, provide physicians with the tools necessary to improve short- and long-term outcomes in the treatment of depression. Additionally, recent developments in genetic and psychological vulnerability research have sought to further improve outcomes by identifying markers in patients who may likely experience multiple depressive episodes.

Despite increasing knowledge of the neurochemical bases of the action of the tricyclic drugs, little is known about the sequence of psychological effects which precede recovery in drug-responsive patients. This research was aimed at identifying the specific behavioural effects associated with the therapeutic action of amitriptyline in depression. The design involved measurement (post-hoc) of weekly changes in a severely depressed placebo-resistant group who recovered with drug treatment, compared with a group of similar patients treated for the equivalent four weeks, who showed minimal to no clinical response. The research strategy, in accordance with a dose–response paradigm, was to determine which of the early changes in emotion and behaviour found in treatment responders were systematically associated with plasma concentrations of amitriptyline or its major metabolite. Amitriptyline was found to act within seven days on the components of anxiety and on hostility in the responders, and on sleep disorder in all patients. After 12 to 14 days of treatment these effects increased, with improvements in other significant components distinguishing the responders from the non-responders. At the 12th to 14th treatment days when a steady state concentration of drug in plasma was approached, reductions in anxiety and hostility and in certain somatic components correlated significantly with plasma concentrations of amitriptyline. Implications of the findings for clarifying the specificity of clinical actions of the tricyclic drugs, and for understanding the psychobiological dynamics underlying rapid drug-induced recovery in depression, were explored.

Plasma drug concentrations and clinical response were measured in two groups of hospitalised depressed patients, who received amitriptyline or Imipramine double-blind, in a dosage of 250 mg for four weeks. Virtually no significant linear or curvilinear relationships were found between any plasma measure and any measure of clinical response. Modest but significant direct relationships were found between age and concentration of parent drugs but not demethylated metabolites. Blood drug level measurement therefore appears to be of little value in monitoring drug treatment of depressed in-patients.

Preliminary data are presented from the NIMH Collaborative Study on the psychobiology of depression, biological studies, dealing with relationships between the pre-treatment levels of the neurotransmitter metabolites 3-methoxy-4-hydrophenethyleneglycol (MHPG), 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA) and the subsequent therapeutic response of depressed patients to imipramine or amitriptyline. Eighty-seven depressed patients were studied during pre-treatment and treatment periods. It has been found that (1) both low pre-treatment urinary MHPG and low CSF 5-HIAA values are associated with a response to imipramine; these relationships were not artefacts due to sex or age; (2) there were no significant relationships between pre-treatment urinary MHPG, CSF MHPG, 5-HIAA, or HVA values and the subsequent response, or failure of response, to amitriptyline; (3) there was not a bimodal distribution for CSF 5-HIAA. For both males and females, there were positive and statistically significant correlations between CSF MHPG and urinary MHPG; for the females, there were positive and significant correlations between both urinary and CSF MHPG and CSF 5-HIAA. The theoretical and practical implications of these findings are discussed.

A preceding paper has reviewed the history, background, and rationale for this collaborative effort exploring the biologic basis of the affective disorders. This paper details the ‘flow’ of a subject through the experimental protocol, the instrumentation used to obtain the clinical and behavioural data, and the biologic methodologies employed in the analysis of the body fluids. Data management and analysis techniques developed for this study are also examined.