During depression, the rhythmic excretion of sex hormones is disturbed, the menstrual cycle changes, and blood pressure and body temperature fluctuate (Linkowski P., van Cauter E., Kerkhofs M., 1994). A sharp decrease in the level of estrogen in the blood can lead to impaired neuroendocrine regulation and mental disorders in women, since estrogens have an anti-dopaminergic effect. A drop in the level of estrogen leads to an increase in the sensitivity of the postsynaptic receptors in the brain, which may be the cause of the emergence of a mental disorder.
Many neurobiological theories of the onset of depression over the past 40 years have paid great attention to the deficiency of various mediators – chemical substances with the help of which excitation is transmitted through neuron networks from one nerve cell to another. Currently, more than 30 mediators are known, three —nadrenaline, serotonin, and dopamine have a major relationship with depression.
Norepinephrine is active in the first place in the hypothalamus and other structures of the limbic system. Reaction to stress, physiological cravings, emotions, and some processes of memory are usually associated with its action. Serotonin moves along the same nerve fibers, but is formed in neurons related to anxiety and sleep disorders. Dopamine is mainly associated with the emotional sphere of a person.
Connections between the neurons of the brain are due to the special plasticity of the nervous system and depend on hereditary factors, personal characteristics of a person and those stress situations that have occurred in his past experience. Between the processes of neurons there is a narrow gap – the gap or synapse, through which the nerve impulse is transmitted. The movement of a nerve impulse through a synapse from one nerve cell to another is carried out with the help of mediators. Before the mediator is active, the message must change its shape: from an electrical impulse to a chemical signal. The mediators accumulate in the axon, are released from it and go through the gap of the synapse to another neuron. Each mediator has its own chemical structure, which has a specific tropism for specific receptors – the receptor signal of the area of another neuron (one mediator can approach different types of receptors). After the message is transmitted from one neuron to another, the mediator is detached from the receptor and returns to the synapse slit, where it is either destroyed by the enzyme (monoamine oxidase), or is again included in the transmitting neuron (reverse capture).
Recently, in the pathogenesis of depression, special importance is attached to reducing the density and sensitivity of postsynaptic receptors of noradrenergic and serotonergic systems. Among the biological theories of the origin of depression, monoamine theory is the leading one. It links the development of depression with a deficiency of one of the three main biogenic amines – norepinephrine, serotonin, dopamine, and associates with this deficiency the mechanism of action of modern drugs proposed for the treatment of depression – antidepressants.
Serotonin
In the 70s of the 20th century, the serotonergic theory of the onset of depression was developed. According to this theory, serotonin was considered as a biologically active substance (biogenic amine). It is a mediator responsible for improving mood (thymoanaleptic effect), providing control over the level of aggressiveness, sudden inclinations (including sexual), appetite regulation, sleep-wakefulness cycle. And sensitivity to pain.
A number of clinical observations indicated a decrease in the level of 5-HIAA (5-hydroxyindole-acetic acid) – the end product of serotonin oxidation in the cerebral fluid of depressed patients (Murphy D. et al., 1978, Goodwin F. et al., 1978). However, the degree of reduction of 5-HIAA did not correlate with the severity of symptoms of depression.
Moreover, in most patients, the therapeutic effect of amitriptyline was significantly higher than that of melipramine, and after the relief of depression symptoms, the content of 5-HIAA increased (Asheroft G. et al., 1966; Mendels J. et al., 1975; Murphy D. etal., 1978 ).
It was noted that many antidepressants, especially SSRIs and MAO, reduce the content of 5-OIAA, possibly through a feedback mechanism, due to an increase in serotonin in the synaptic cleft. A study of depression revealed a marked decrease in serotonin levels in suicidal individuals and people with severe anxiety symptoms.
Based on a hypothesis suggesting a serotonin metabolic disorder, attempts were made to treat depression with tryptophan and 5 hydroxytryptophan. This approach was based on the fact that the symptoms of depression are usually exacerbated when there is a deficiency in the diet of tryptophan (Murphy D. et al., 1972).
The results of tryptophan therapy were mixed. In some cases, confirmed its high efficiency, not inferior to the effectiveness of such a powerful antidepressant, as imipramine. Other studies have indicated only minor improvements in the condition of patients after taking tryptophan (Murphy D. et al., 1974, Bowers M., 1974). In addition, some authors have emphasized the instability of the positive effect as a result of its reception.
A number of researchers cited facts that cast doubt on the fidelity of the serotonin hypothesis of the origin of depression. Thus, in particular, a decrease in serotonin excretion rates was found both during depression and during a period of elevated mood. So Sorrep A. et al. (1976) found a decrease in serotonin excretion rates during both depression and mania. In addition, there was a decrease in serotonin metabolism and in the period of clinical improvement in the treatment with antidepressants (Bowers M., Lumbar G., 1974; Lapin I.P., 1989).
The contradictions existing in the literature can be explained by the fact that the content of 5-HIAA rather reflects the peripheral link of serotonin metabolism (Zis A., Goodwin E, 1982). It is possible that a violation of serotonin metabolism occurs only in a certain part of patients with depression, in particular, due to internal neuroendocrine factors (Clure D., 1971, Asberg M., 1978; Gastpar M., 1978). Participation in the pathogenesis of depression of indoles and other mediators was not ruled out (Shaw D. et al., 1977, Bunney W. et al., 1970).
In favor of the serotonergic hypothesis of the development of depression is also evidenced by data relating to a decrease in the density of transporter proteins that carry out the reuptake of serotonin through the presynaptic nerve cell membrane.
Researchers believe that some clinical similarity between anxiety and depression implies the same changes in the neurobiological substrate. It is assumed that anxiety is associated with increased activity of the brain systems sensitive to serotonin. With prolonged anxiety, excessive activity of these systems can lead to a decrease in not only serotonin levels, but also norepinephrine, which ultimately leads to the development of depression. The development of this model can be considered the theory of the development of anxiously aggressive depression provoked by stress caused by cortisol and associated with serotonin. According to this theory, aggression also joins the anxious-depressive complex in this case.
In patients with an increased level of anxiety and aggressiveness of the end of the nerve cells of the brain, sensitive to serotonin, function at the minimum acceptable level. Under normal conditions, the weakness of this system is compensated. However, under stress, it begins to manifest itself, above all, by limiting the ability to control anxiety and aggressiveness. When people with signs of anxiously aggressive depression get into a traumatic situation, they have a feeling of tension and discomfort, the activity of the endocrine organs (hypothalamus — hypophysis — adrenal glands) is activated and the release of the stress hormone, cortisol, is enhanced. In this case, the inhibition of the tissues of the nervous system sensitive to serotonin under the action of cortisol is faster and stronger than in a healthy person. As a result, the patient loses the ability to manage anxiety and aggressiveness. Increased anxiety and aggressiveness, in turn, affect mood, causing further development of depression.
From the point of view of some scientists, depression is directly related to self-directed aggression. It was found that with depression, aggressiveness indicators significantly exceed the norm and dominate over indicators of the state of aggression directed outward. Based on the above, it was concluded that the relationship between anxiety, aggression and depression as progressively caused by the phenomena. The biological basis of this relationship may be changes in the concentration of serotonin degradation products due to a change in the level of aggression directed towards oneself.