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.

As part of the Collaborative Study of the Psychobiology of Depression, we have examined the pretreatment growth hormone response (ΔGH) to insulin (0·1 U/kg) and the magnitude of the hypoglycaemic response in a large number of well-defined depressed patients (N = 132) and healthy controls (N = 80). After applying rigorous exclusion criteria, data were analysed from 93 patients and 66 controls for blood glucose response and from 56 patients and 52 controls for ΔGH. Depressed patients, either unipolar or bipolar, showed less of a fall in glucose than controls. A weak association was found between the magnitude of the fall in glucose and the severity of depression. No significant differences were found in values for ΔGH between the unipolar or bipolar depressed patients and controls either for males, pre-menopausal or postmenopausal females, or the total female group. These data do not support previous claims of a lowered ΔGH response to insulin in depressed patients. However, the resistance to hypoglycaemia seen in the depressed patients is consistent with previous reports.

Preliminary data from the National Institute of Mental Health – Clinical Research Branch Collaborative Program on the Psychobiology of Depression dealing with the human growth hormone (hGH) response to the Insulin Tolerance Test (ITT) during the pre-treatment (drug-free) period of the study are presented in this paper. Data are reported for 54 unipolar depressed, 21 bipolar depressed, and 40 normal control subjects, who represent approximately 50% of the final subject sample to be studied. In this population the unipolar depressed subjects showed a significantly greater resistance to insulin-induced hypoglycaemia than bipolar and control subjects. After applying the inclusion/exclusion criteria necessary to interpret hGH responses accurately, the data from only 54 subjects were acceptable. Mean peak hGH concentrations were not significantly different among the three groups. There was, however, a significant difference in the distributions of the hGH peak response, with the bipolar depressed population demonstrating greater variability in response than unipolar and control populations. These findings are discussed as they relate to previous reports and theoretical considerations.

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.

There are many reports which suggest that patients with affective illness (mania and/or depression) have abnormalities in the functioning of one or more neurobiological systems. At a conference convened by the Clinical Research Branch, Division of Extramural Research Programs, National Institute of Mental Health, these findings were reviewed and some of the factors impeding movement towards a more complete and integrated view of the functioning of neurobiological systems in patients with mania or depression were identified. As a result, a multi-research centre, collaborative approach to the study of the psychobiology of affective disorders was developed. In this collaborative programme, which has now been underway for several years, the focus has been upon: (a) the assessment of the functioning of several different types of biological systems in the same patient, both before and during treatment; (b) obtaining a reasonably large number of patients and comparison subjects; and (c) the use within and across centres of standardized diagnostic categories and behavioural rating methodologies. In this paper the history, background, and rationale for this collaborative effort are reviewed. Those biological systems chosen for study are noted, and issues such as reliability and validity of diagnoses, measurement of state variables, assessment of change with treatment, and logistical and coordinating problems are discussed.