In the middle of the XX century J. Shildkraut (1961) was formulated so-called. catecholamine theory of the origin of depression. This theory suggested that dysregulation of the noradrenaline-sensitive brain system was one of the important links in the pathogenesis of depression.
Currently, it is known that the content of norepinephrine in brain cells is controlled by special nerve cell endings – presynaptic adrenoreceptors. Stimulation of these receptors inhibits the release of norepinephrine, which, in turn, leads to its lack of a synapse and a decrease in neurotransmission. The blockade of these receptors by antidepressants, in contrast, enhances the process of norepinephrine excretion.
Fundamental studies of the reticular formation of the brain have shown: antidepressants, whose action is aimed at changing the content of norepinephrine, have a general activating or psychostimulating effect. These drugs support the level of wakefulness, help to improve the processes of perception, thinking, memory, and increase concentration. However, despite the fact that taking antidepressants almost immediately increases the level of norepinephrine, the clinical effect of the drug appears much later.
According to the catecholamine hypothesis by J. Schildkraut (1978), the development of depressions, especially endogenous ones, is due to a decrease in the content of catecholamines, mainly norepinephrine, in certain brain structures. It was also assumed that the functional activity of noradrenergic systems during depression can be indirectly assessed by the content in the urine of such a metabolite of noradrenaline as MOFEG (3-methoxy-4 hydroxyphenylstillen glycol).
Based on a number of observations (Schildkraut J., 1978; Beckmann H., Goodwin F., 1980), it was suggested that the level of MOPEG may serve as a predictor of the effectiveness of therapy for various antidepressants. In depressed patients with a lower MOPEG content, a positive therapeutic effect of imipramine and desipramine is possible, but they are resistant to amitriptyline therapy.
It has been suggested that in this group of patients a violation of the metabolism of norepinephrine is primarily dominant. In contrast, depressed patients with a high daily level of excretion of MFEG respond better to amitriptyline therapy. At the same time, it was shown that in mentally healthy people the daily excretion of MOFEG fluctuates four times, and these fluctuations overlap the parameters of changes observed in patients suffering from depression (Hollister L. et al., 1978). In addition, it was found that during clinical remission, catecholamine shifts found in patients with depression do not normalize, and even during severe depression, catecholamine content may be within the normal range (Cazzulo C, Sacchetti E. et al., 1982).
Based on the data obtained by J. Costa, E. Silva (1980,), a theory emerged suggesting the presence of two options for the onset of depression: one related to the exhaustion of norepinephrine and more sensitive to treatment with certain antidepressants (desimipramine or imipramine) and the other related to serotonin deficiency and responding to therapy with other drugs (amitriptyline). Antidepressants have been assumed to have a therapeutic effect by facilitating the transmission of both norepinephrine and serotonin (Haefely W., 1985).
Recent studies in the field of brain physiology have shown that the brain system sensitive to norepinephrine has a pronounced effect on the system that is sensitive to serotonin. It turned out that nerve cells sensitive to norepinephrine control the rate of serotonin release by influencing the end of neurons located on the bodies of serotonergic neurons. The increase in the excitability of serotonergic neurons, in turn, enhances the release of serotonin in the nerve endings (De Boer T. et al., 1994).
Dopamine
The pathogenesis of depression can also be based on the lack of another biological substance, to some extent a precursor of norepinephrine – dopamine. It is assumed that he takes part in the regulation of the function of the motor sphere, has a psychostimulating effect and is responsible for the formation of a certain behavior. The proof of this hypothesis is the ability of the drug L-DOPA, which is a precursor of dopamine and noradrenaline, to promote the transition of depression into a state of increased activity (Bunney W. et al., 1970; Van Praag H., 1977). When using L DOPA in patients suffering from depression, quite often there was a positive effect in the form of changes in activity. So, in particular, R.Ya. Bovin, I.O. Aksyonova (1982), when using L-DOPA in therapeutically resistant depressive patients, noted a positive effect in the form of an increase in psychomotor activity in 25% of cases.
In addition, depression can be caused by taking medications that lower the dopamine content, for example, rauwolfia preparations. A decrease in dopamine is observed in a number of neurological and somatic diseases, which are also accompanied by depression, for example, in Parkinson’s disease.
Endorphins and other iromediators
In addition to mediators, with depression there may be changes in the endorphin-neuropeptides – biologically active substances that have the properties of a hormone and a mediator at the same time. Endorphins are responsible for the susceptibility of a person to pain. Low levels of endorphins in dysthymia explain poor tolerance to pain in people suffering from depression.
In disorders of the depressive spectrum, synaptic transmission disorders are detected, mainly related to the inhibitory GABA of the brain’s ergistic systems (a decrease in gamma-aminobutyric acid during depression). Standing out in the blood, gamma-aminobutyric acid lowers the level of anxiety. It also participates in the regulation of nerve impulse flow, blocking the release of other mediators, for example, dopamine and norepinephrine. As a result, there is a disorganization of the interaction of nerve cells that process sensory (extra-and interoceptive) information and the integration of motor and regulatory activity. At the same time, there are various disorders of mental activity with the corresponding neurological and vegetative manifestations (Eccles J., 1971; Guselnikov VI, Iznak AF, 1983; Glezer V.D., 1985).
In depression, there is a change in the concentration of biologically active substances not only between nerve cells, but also inside neurons. These substances in the wall of the nerve cell are split into smaller components, which increase the activity of neurons by changing the direction of movement of the mediators towards the center of the neuron, to its nucleus.