If the humoral factors modulating anxiety states are quite well known , then the “depression hormone” remains a mystery. There is no doubt that hormones are involved in the pathogenesis of depressive states.
Searches for the “hormone of depression” were (and are) ongoing, naturally, primarily among stress hormones. Since depression results from stress, this assumption is natural.
The development of depression is not associated with increased secretion of cortisol in chronic stress.
For a long time, it was believed that the cause of depression was an increased level of cortisol in the blood. This has been known since the early 1960s, but the reasons for this increase remained unclear. Increased corticosteroid activity is detected using various indicators – daily secretion of 17-hydroxysteroids, daily urinary free cortisol content, cortisol production rate, serial determinations of the morning blood cortisol level, daily integrated cortisol level in the blood and cerebral cortisol level.
However, the hypothesis of a causal relationship between elevated levels of cortisol in the blood and depression was rejected after the clinical picture of depression was compared with other conditions characterized by elevated levels of cortisol. For example, with Itsenko – Cushing’s syndrome , adrenal cortex activity is increased, and increased secretion of glucocorticoids is primary, that is , it is not a consequence of any disease, infection, or other external causes. Despite the equally high levels of cortisol in depression and Itsenko – Cushing’s syndrome , the frequency of occurrence of symptoms (increased fatigue, depressed mood, memory loss, anxiety, bulimia, anorexia, etc.) are very different in the two diseases.
The development of depression is associated with a prolonged increase in the activity of the pituitary-adrenal system, i.e. , with a steadily increased secretion of all stress hormones: corticoliberin , ACTH and cortisol
In addition to depression and Itsenko – Cushing’s syndrome , the third well-studied condition in which the content of glucocorticoids in the blood is increased is the treatment process with large doses of these hormones. With exogenous hypercortisolemia (an increased content of cortisol in the blood caused by the introduction of hormones from the outside), a significant part of patients develop a manic state, which sometimes reaches a psychotic degree. And depressive states in such patients are rare.
Thus, a comparison of three conditions in which the level of cortisol in the blood is elevated – depression, Itsenko – Cushing’s syndrome and exogenous hypercortisolemia – leads us to the conclusion that such an increase in it cannot be the cause of depression. Although it is observed in all three states, the picture of mental changes is different everywhere.
ACTH and corticoliberin are also not primary agents of depression. The main psychotropic effect of ACTH leads to improved memory, and corticoliberin causes anxiety, but not depression.
The reason for its occurrence is not a change in any one hormone, but a long-term increase in the activity of the entire pituitary-adrenal system, i.e. , a steadily increased secretion of corticoliberin , ACTH and glucocorticoids . This is indicated, in particular, by the very high frequency of depression in people who adhere to the Atkins diet (known in Russia as the Kremlin diet ), in which the amount of carbohydrates is reduced to almost zero. In the absence of exogenous carbohydrates, the body is forced to receive them by gluconeogenesis .
In depression, the regulation of the pituitary-adrenal system is weakened by the negative feedback mechanism
At the same time, the activity of all systems that accelerate this process, primarily stress hormones, increases . Constantly increased activity of the pituitary-adrenal system leads to depression.
Elevated levels of cortisol in the blood are not an indicator of depression. Increased secretion of glucocorticoids cannot serve as a diagnostic criterion for primary depression, since an increased content of all hormones of the pituitary-adrenal system is noted in the blood in any painful condition. In particular, increased production of cortisol, in addition to endogenous depression, is observed with reactive depression, schizophrenia, anorexia nervosa and bulimia, Alzheimer’s disease, with psychogenic amenorrhea, alcoholism and anxiety conditions.
Nevertheless, the activity of the pituitary-adrenal system is used for the differential diagnosis of endogenous depression.
Specific for endogenous depression was a weakening of the regulation of the pituitary-adrenal system by the feedback mechanism, which was first shown by B. Carroll and his colleagues. This disorder is detected using a dexamethasone test . The patient receives 1 mg of dexamethasone (a powerful synthetic glucocorticoid ) at 11 o’clock in the evening, and at 8 in the morning and at 4 o’clock he takes blood to determine cortisol.
In healthy subjects and in patients not with endogenous depression, but with other mental illnesses, the cortisol content decreases due to inhibition of the secretion of corticoliberin and ACTH by the negative feedback mechanism. In patients with endogenous depression, the decrease in cortisol in the blood is less pronounced, since the negative feedback mechanism is violated in this disease . The weak effect of dexamethasone on the level of cortisol in the blood, which is called a positive test result, indicates the presence of endogenous depression.
The dexamethasone test was the first proposed biological test for endogenous depression and is still the cheapest, and therefore the most common. However, the initial enthusiasm of the researchers somewhat cooled due to the low levels of sensitivity and specificity of this test. Both the percentage of depression patients who are sensitive to dexamethasone (false-negative result of the dexamethasone test), and the percentage of patients insensitive to it, non-depressive patients (false-positive result of the dexamethasone test), can reach 50 %. Despite these shortcomings, this test is widely used in clinics and at present. It should be noted that the more severe the depressive disorder, the higher the percentage of patients with a positive dexamethasone test. The test gives a negative result with spontaneous remissions and with improvement as a result of treatment. Thus, the dexamethasone test is a fairly good biological indicator of the subjective, mental state of the patient.
Violation of the regulation of the pituitary-adrenal system by the feedback mechanism, most likely, is caused by a change in the sensitivity of regulatory centers to glucocorticoids , i.e. , a decrease in the number of receptors with respect to glucocorticoids in the pituitary and (or) brain. This assumption is confirmed by the well-known fact of regulating the number of receptors by hormone level. Since it is impossible to determine the number of receptors in the brain tissue of patients in vivo, this remains to be judged by the change in their number in the blood cells. The number of receptors in lymphocytes of depressed patients was 30 % lower than in control patients.
Thus, the activity of the pituitary-adrenal system during endogenous depression is impaired, and the nature of the changes and, primarily, low sensitivity to negative feedback signals distinguish depression from other pathological conditions, which are characterized by increased activity of the pituitary-adrenal system without changes in sensitivity to feedback signals .
For patients with endogenous depression, other features of the pituitary-adrenal system are also characteristic. In such patients, the release of ACTH in response to the administration of corticoliberin is reduced . This means that with depression, not only the reverse, but also the direct connections in the pituitary-adrenal system are disturbed. In addition, depressive patients have increased secretion of cortisol in response to the introduction of vasopressin. This is of great importance, since the secretion of vasopressin, unlike ACTH and corticoliberin , is not regulated by the negative feedback mechanism. It is possible that in patients with depression in the regulation of cortisol secretion, the leading role is played not by ACTH, but by vasopressin. There is no direct evidence of this assumption, since large-scale determinations of the level of vasopressin in patients have not been carried out.
In addition to disorders of the pituitary-adrenal system in patients with endogenous depression, disorders in other endocrine systems have been identified.
With depression, the reactions of many endocrine systems are disrupted
For example, in the thyroid regulation system, as well as in the pituitary-adrenal system, in patients with endogenous depression the response of the pituitary tropine to the introduction of hypothalamic releasing is weakened . Just as the growth of ACTH secretion after the administration of corticoliberin is weakened in depression, after the administration of thyroliberin, the growth of secretion of thyrotropin is weakened . With a spontaneous or treatment-induced relief, the results of the thyroliberin test are normalized . The diurnal rhythm of thyrotropin secretion is also broken , its rise at night is absent. Since patients with depression have an elevated temperature at night, and thyroid hormones increase heat production, this may indicate the involvement of thermoregulation in the pathophysiological mechanisms of depression.
The secretion of prolactin – a pituitary hormone that enhances milk synthesis – in healthy people has a daily rhythm: with a rise at night and a maximum of a few hours after falling asleep. With depression, this peak decreases, and the entire rhythm is smoothed out. Since studies of the relationship of the psyche and prolactin are just beginning, this fact remains a “brick”, which is still waiting for its “wall”.
In depression, growth hormone secretion is weakened when the concentration of glucose in the blood caused by the introduction of insulin decreases. In addition, this concentration decreases slowly (insulin tolerance test). Estrogen has a potentizing effect on the stimulation of growth hormone secretion. It is possible that the weak response of growth hormone to insulin administration is, at least in part, due to the low estrogen content due to insufficient secretion of gonadoliberin .
It should be said that the specificity and sensitivity of each of the listed endocrine tests is far from 100 %. A significant percentage of false-positive and false-negative results are noted when using corticoliberin , thyroliberin and insulin tests. However, if applied simultaneously, the specificity and sensitivity of the diagnosis of endogenous depression reaches 90 %. It should be noted that other methods for diagnosing depression are also being developed by analyzing substances in the blood , but they are still very expensive.
What is the role of endocrine disorders in the pathogenesis of depression? Animal studies can help clarify this issue and the problem of depression in general. The use of endocrine tests confirmed the correspondence of the model of learned helplessness to human depressive syndrome. In rats with learned helplessness, which developed as a result of uncontrolled stress exposure, positive results were found for dexamethasone and corticoliberin tests. In general, the problem of the pathogenetic mechanisms of depression, in particular their endocrine aspect, is still far from being resolved.
Gonadoliberin – a natural antidepressant
If the hormonal mechanisms of development of depressive states, with the exception of the general position “stress is the main pathogenetic factor of depression,” are unclear, then hormones that weaken depression and prevent its occurrence are known.
Gonadoliberin has a distinct antidepressant effect. This effect has been identified both in clinical conditions (although not numerous so far) and in experiments with learned helplessness of animals. Decreased secretion of this hormone leads to depression.
Endogenous Opiates – Natural Antidepressants
The pineal gland hormone melatonin inhibits the synthesis of gonadoliberin , and the secretion of melatonin itself increases with increasing duration of the dark time of the day – a time unfavorable for people prone to depressive states. Increased illumination in autumn and winter improves our mood, so snowy winters are much easier to carry, despite the short daylight hours.
Endogenous opiates are known to induce a euphoric state, so increasing their synthesis and secretion is effective for raising mood. The easiest way to increase the concentration of opiates in the body is to cause stress, for example, go to the bathhouse or simply run around. One of the goals of game behavior in humans and animals is to increase the secretion of endogenous opiates (Fig. 5.9).
The widespread perception of serotonin as a “hormone of happiness” is false. Accordingly, the opinion that to combat depression should eat foods rich in serotonin is completely wrong. It arose on the basis that antidepressants increase the concentration of serotonin in the synaptic cleft. With insufficient activity of some neurons producing serotonin as a mediator, depressive states develop. If somehow stimulate the serotonergic activity of neurons, then depression is weakened.
But the central nervous system and the circulatory system are separated by a barrier called the blood- brain encephalic (BBB). The BBB is formed by cells of the vascular epithelium and glial cells of the central nervous system. Due to its mechanical, physical and chemical properties, it retains many substances. In particular, they can freely be released from the central nervous system into the bloodstream, but not vice versa. The BBB is absolutely impenetrable for substances such as serotonin, adrenaline and norepinephrine, which are in the blood. The biological meaning of this is understandable: maintaining the constancy of the internal environment of the central nervous system.
The statement “serotonin is a hormone of happiness” is false
In particular, serotonin, adrenaline and norepinephrine are constantly synthesized in the body and secreted into the blood. Serotonin – by the cells participating in the inflammatory process, adrenaline – by the adrenal medulla under stress, norepinephrine – by the ends of the autonomic nervous system. At the same time, the same substances play the role of mediators in the central nervous system. If there were no BBB, then peripheral substances would disorganize the brain, disrupting synaptic transmission. Therefore, an increase in the concentration of serotonin in peripheral blood cannot increase the serotonin content in the central nervous system. At the same time, serotonin can pass from the central nervous system to the blood, i.e. , the BBB has one-sided permeability, therefore, the content of serotonin in the blood reflects its concentration in the central nervous system.