It is now generally accepted that stressful life events and chronic difficulties can trigger the onset of depression in predisposed individuals. However, although much is known of the neurobiology of stress, few attempts have been made to provide a biological explanation for the mechanisms whereby life events might trigger depression. Enough is now known of the central control of hypothalamic pituitary adrenal (HPA) function and its response to stress to permit an examination of its role in the neurobiology of the triggering of depression by stress. This evidence is reviewed, and the proposal explored that stress triggers depression by a genomic action of corticosteroids.

The pituitary—adrenal axis participates in the diurnal response of the organism to the environment and in its response to stress. Circulating glucocorticoid and mineralocorticoid hormones act on cells in the brain via Type I and Type II receptors, which operate at the level of gene regulation, and mediate various feedback effects of adrenal steroids on brain chemistry and structure, including the operation of second-messenger generating systems, levels of structural proteins of glial cells, and the death and survival of neurons. The hippocampus is prominent in these effects, and it also displays the highest level of Type I receptors of any brain region. New concepts point to a special role of the hippocampus, a nexus of cognition and emotion, in the feedback actions of adrenal steroids during the diurnal rhythm, and in response to stress. The hippocampus is, therefore, a prime target area for investigation of the events which accompany stress, and which may be related to the maladaptive state that results in depressive illness. Initial studies are described which investigate the effects of tianeptine on pituitary—adrenal function, hippocampal morphology and Type I and Type II receptor levels.

Many kinds of stress stimulate the neuroendocrine systems controlling catecholamine and glucocorticoid secretion. Stress-induced stimulation of CRF-containing neurons appears to be mediated by serotonergic, noradrenergic, and possibly other neuronal pathways. Stress can alter various neurobiological and endocrine functions, two essential components of the neuroendocrine responses being release of adrenalin from chromaffin cells of the adrenal medulla and secretion of glucocorticoids from adrenocortical cells. Activation of adrenal steroid secretion is mainly by a reflex activation of hypothalamic neurons, which stimulate ACTH secretion from the anterior pituitary. While the neuropeptide CRF plays a major role in the neuroendocrine response to stress, the neuronal signals which are responsible for the regulation of CRF neurons have not been completely elucidated. A number of other regulatory substances may also participate, alone or with CRF, in the control of ACTH secretion by pituitary corticotrophs, and there is increasing evidence that classical neurotransmitters or neuropeptides may act directly on adrenocortical cells to modulate corticosteroid secretion. We review the neuronal, neuroendocrine, and humoral pathways which participate in the regulation of stress-induced corticosteroid secretion, and present preliminary data on the effect of the tricyclic antidepressant, tianeptine in the response of the HPA axis to stress.

Stressors induce behavioural disturbances and neurochemical changes in animals, some of which are reminiscent of the symptoms and presumed neurochemical concomitants of depression in humans. Just as in humans, where considerable inter-individual variability is evident in the symptom profile of depression, there is marked inter-individual and inter-strain variability in the behavioural effects of stressors in animals. It is proposed that stressors induce adaptive neurochemical changes, failure of which may engender behavioural disturbances. Variability in the symptoms of depression and in the efficacy of its pharmacological treatment may reflect the biochemical heterogeneity of the illness. Inter-individual differences in vulnerability to stressor-provoked neurochemical changes may contribute to the behavioural profiles observed.

Animal behavioural models of psychiatric disorders cannot exactly simulate human psychopathology, but they can be used to evaluate the behavioural changes induced by drugs and to suggest hypotheses about the functions of the CNS and its involvement in psychiatric disorders. This should lead to a more heuristic classification of psychotropic drugs and to clarification of their therapeutic possibilities. The following animal models simulate aspects of depressive disorders and are sensitive to the antidepressant effects of drugs. (i) The forced swimming test: described as ‘behavioural despair‘ on the assumption that the animal has given up hope of escaping. (ii) The ‘restraint stress‘ test: this may indicate a failure to adapt to stress. (iii) The learned-helplessness model: exposed to uncontrollable events, animals exhibit learning performance deficit and behavioural changes, including decreased locomotor activity and loss of appetite. (iv) Waiting behaviour: improvement in the ability to wait for and/or postpone an active response; this could be related to the reported beneficial effects of antidepressants on impulsive behaviour.

A model of depression based on measurements made after restraining rats for two hours has been developed. The model is associated with elevation in corticosterone, reflects the higher incidence of depression in women, and shows increased post-synaptic 5-HT function with adaptation. The effects of tianeptine and other antidepressants on the model were studied. Chronic pre-treatment with desipramine, sertraline (amine uptake inhibitors), and chlordiazepoxide normalised open field activity after restraint. Single high doses, post-restraint, of 8-OH-DPAT, gepirone (5-HT agonists), and tianeptine normalised open field activity, whereas desipramine, chlordiazepoxide, and diazepam did not. It is of considerable interest that tianeptine decreased the availability of 5-HT to receptors.

Tianeptine is a tricyclic antidepressant with an unusual chemical structure (a long lateral chain grafted on to a substituted dibenzothiazepin nucleus), and with biochemical and animal-behavioural properties which are strikingly different from those of classical tricyclics. Unlike the latter, which decrease serotonin (5-HT) uptake, acute and chronic tianeptine treatment enhances 5-HT uptake in rat brain and in rat and human platelets ex vivo. In vivo, tianeptine potentiates the depletion of rat brain 5-HT by 4-methyl-alpha-ethyl metatyramine and increases rat hippocampal 5-HIAA; 5-HT uptake inhibitors (e.g. fluoxetine) have opposite effects. On iontophoretic injection into CA1 pyramidal cells, tianeptine shortens the period of neuronal hypoactivity caused by GABA or 5-HT, whereas other tricyclics prolong it, and it enhances attention, learning, and memory in laboratory animals, while classical tricyclics have opposite effects. However, the relationships between these effects of tianeptine in animal experiments and their relevance to clinical findings remain to be determined.

Tianeptine is a new tricyclic compound whose principal action is to increase the reuptake of serotonin. In a multicentre trial in which 380 depressed patients were treated for one year, tianeptine produced a significant reduction in the MADRS scores from day 14, with a sustained reduction maintained for up to 12 months; other measures of efficacy (HRSA, HSCL, and CGI) also reflected the improvement. Only 11% of patients withdrew because of recurrence of depression and 2% because of side-effects, which were mainly drowsiness, irritability, and gastrointestinal disturbance. Apart from a minor reduction in heart rate, unaccompanied by any conduction changes, no clinically relevant changes in vital signs or laboratory tests were seen. Seven subjects who attempted suicide by tianeptine overdose had favourable outcomes, in spite of also taking other psychotropic drugs or alcohol. No evidence of tolerance or withdrawal symptoms was seen after treatment was stopped. These results suggest that tianeptine has the potential to provide safe antidepressant activity in both the acute and chronic phases of treatment.

Alcohol interferes with the central metabolism of the catecholamines and especially with indolamines (5-HT). Thus, the use of an antidepressant such as tianeptine, whose main neurochemical effect is to increase the reuptake of 5-HT, seems to be particularly indicated for the continued treatment of depressed patients after alcohol withdrawal. This study evaluated the therapeutic efficacy and acceptability during long-term administration of tianeptine in depressed patients (major depressive episode or dysthymic disorder) in a multicentre trial, after withdrawal from alcohol abuse or dependence. The results relate to 130 depressed patients, who abstained from alcohol and received treatment for a year. Only one patient dropped-out because of side-effects, and medication was interrupted in 5% of subjects because of alcoholic relapses. Prescribed in the long term, tianeptine did not produce orthostatic hypotension, changes in bodyweight, or alterations in the ECG. All changes found in haematological and biochemical investigations suggested an improvement in patients' physical state. This, and other studies, indicate that tianeptine appears to have the potential to be a safe antidepressant, which might be particularly useful in those patients who are susceptible to the side-effects of psychotropic drugs.

The clinical properties of tianeptine have been assessed in double-blind controlled studies, which involved depressed patients fulfilling DSM-III criteria for either major depression — single episode or recurrent (without melancholia and psychotic features) — or dysthymic disorder —with or without an additional diagnosis of alcohol abuse or dependence. Five studies have compared tianeptine with reference antidepressants: its efficacy has been found to be similar to that of amitriptyline in depressed out-patients. However, these data need to be confirmed by other controlled trials v. reference drugs and by at least two placebo-controlled studies. Tianeptine does not induce sleep disorders, anticholinergic effects, or modifications of cardiovascular variables or biological parameters (renal, haematological, or hepatic). After the end of treatment, the only signs of withdrawal have been some disturbances of sleep.